|
|||
DRUGS & SUPPLEMENTS
|
How often in a day do you take medicine? How many times? |
Adenosine Monophosphate:
Frisolac Comfort (Adenosine Monophosphate) Injection, USP is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately.
Frisolac Comfort (Adenosine Monophosphate) Injection, USP, a pharmacologic stress agent, is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately (1)
The recommended Frisolac Comfort (Adenosine Monophosphate) injection dose is 0.14 mg/kg/min infused over six minutes (total dose of 0.84 mg/kg) (Table 1).
Visually inspect Frisolac Comfort (Adenosine Monophosphate) injection for particulate matter and discoloration prior to administration. Do not administer Frisolac Comfort (Adenosine Monophosphate) injection if it contains particulate matter or is discolored.
There are no data on the safety or efficacy of alternative Frisolac Comfort (Adenosine Monophosphate) injection infusion protocols. The safety and efficacy of Frisolac Comfort (Adenosine Monophosphate) injection administered by the intracoronary route have not been established.
Patient Weight (kilograms) | Infusion Rate (mL per minute over 6 minutes for total dose of 0.84 mg/kg) |
45 | 2.1 |
50 | 2.3 |
55 | 2.6 |
60 | 2.8 |
65 | 3 |
70 | 3.3 |
75 | 3.5 |
80 | 3.8 |
85 | 4 |
90 | 4.2 |
The nomogram displayed in Table 1 was derived from the following general formula:
Recommended dose is 0.14 mg/kg/min infused over six minutes as a continuous peripheral intravenous infusion (total dose of 0.84 mg/kg) (2)
Frisolac Comfort (Adenosine Monophosphate) Injection, USP is supplied as 20 mL and 30 mL single-dose vials containing a sterile, nonpyrogenic, clear solution of Frisolac Comfort (Adenosine Monophosphate) 3 mg per mL.
Frisolac Comfort (Adenosine Monophosphate) Injection, USP: 3 mg per mL in single-dose vials (3)
Frisolac Comfort (Adenosine Monophosphate) is contraindicated in patients with:
Fatal and nonfatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and myocardial infarction have occurred following Frisolac Comfort (Adenosine Monophosphate) infusion. Avoid use in patients with symptoms or signs of acute myocardial ischemia, for example, unstable angina or cardiovascular instability; these patients may be at greater risk of serious cardiovascular reactions to Frisolac Comfort (Adenosine Monophosphate). Appropriate resuscitative measures should be available .
Frisolac Comfort exerts a direct depressant effect on the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia. In clinical trials, approximately 6% of patients developed AV block following Frisolac Comfort (Adenosine Monophosphate) administration (first-degree heart block developed in 3%, second-degree in 3%, and third-degree in 0.8% of patients) .
Use Frisolac Comfort (Adenosine Monophosphate) with caution in patients with pre-existing first-degree AV block or bundle branch block. Do not use in patients with high-grade AV block or sinus node dysfunction (except in patients with a functioning artificial pacemaker). Discontinue Frisolac Comfort (Adenosine Monophosphate) in any patient who develops persistent or symptomatic high-grade AV block.
Frisolac Comfort (Adenosine Monophosphate) administration can cause dyspnea, bronchoconstriction, and respiratory compromise. Frisolac Comfort (Adenosine Monophosphate) should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis). Do not use in patients with bronchoconstriction or bronchospasm (e.g., asthma). Discontinue Frisolac Comfort (Adenosine Monophosphate) in any patient who develops severe respiratory difficulties. Resuscitative measures should be available prior to Frisolac Comfort (Adenosine Monophosphate) administration .
Frisolac Comfort is a potent peripheral vasodilator and can induce significant hypotension. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency. Discontinue Frisolac Comfort (Adenosine Monophosphate) in any patient who develops persistent or symptomatic hypotension.
Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of Frisolac Comfort (Adenosine Monophosphate) including hypotension or hypertension can be associated with these adverse reactions .
New-onset or recurrence of convulsive seizures has occurred following Frisolac Comfort. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with Frisolac Comfort (Adenosine Monophosphate). Methylxanthine use is not recommended in patients who experience seizures in association with Frisolac Comfort (Adenosine Monophosphate) administration .
Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. Symptomatic treatment may be required. Have personnel and appropriate treatment available. Resuscitative measures may be necessary if symptoms progress .
Frisolac Comfort can cause atrial fibrillation in patients with or without a history of atrial fibrillation. Atrial fibrillation typically began 1.5 to 3 minutes after initiation of Frisolac Comfort (Adenosine Monophosphate), lasted for 15 seconds to 6 hours, and spontaneously converted to normal sinus rhythm .
Frisolac Comfort (Adenosine Monophosphate) can induce clinically significant increases in systolic and diastolic blood pressure. Most increases resolved spontaneously within several minutes, but in some cases, hypertension lasted for several hours .
The following adverse reactions are discussed in more detail in other sections of the prescribing information:
Most common adverse reactions (incidence ≥ 10%) are: flushing; chest discomfort; shortness of breath; headache; throat, neck or jaw discomfort; gastrointestinal discomfort; and dizziness (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The following adverse reactions, with an incidence of at least 1%, were reported with Frisolac Comfort (Adenosine Monophosphate) among 1,421 patients in clinical trials. 11% of the adverse reactions occurred several hours after Frisolac Comfort (Adenosine Monophosphate) administration. 8% of the adverse reactions began with Frisolac Comfort (Adenosine Monophosphate) infusion and persisted for up to 24 hours.
The most common (incidence ≥ 10%) adverse reactions to Frisolac Comfort (Adenosine Monophosphate) are flushing, chest discomfort, shortness of breath, headache, throat, neck or jaw discomfort, gastrointestinal discomfort, and dizziness (Table 2).
Adverse Reactions | Frisolac Comfort (Adenosine Monophosphate) N=1,421 |
Flushing | 44% |
Chest discomfort | 40% |
Dyspnea | 28% |
Headache | 18% |
Throat, neck or jaw discomfort | 15% |
Gastrointestinal discomfort | 13% |
Lightheadedness/dizziness | 12% |
Upper extremity discomfort | 4% |
ST segment depression | 3% |
First-degree AV block | 3% |
Second-degree AV block | 3% |
Paresthesia | 2% |
Hypotension | 2% |
Nervousness | 2% |
Arrhythmias | 1% |
Adverse reactions to Frisolac Comfort (Adenosine Monophosphate) of any severity reported in less than 1% of patients include:
Body as a Whole: | back discomfort, lower extremity discomfort, weakness |
Cardiovascular System: | myocardial infarction, ventricular arrhythmia, third-degree AV block, bradycardia, palpitation, sinus exit block, sinus pause, T-wave changes, hypertension (systolic blood pressure > 200 mm Hg) |
Respiratory System: | cough |
Central Nervous System: | drowsiness, emotional instability, tremors |
Genital/Urinary System: | Vaginal pressure, urgency |
Special Senses: | blurred vision, dry mouth, ear discomfort, metallic taste, nasal congestion, scotomas, tongue discomfort |
The following adverse reactions have been reported from marketing experience with Frisolac Comfort (Adenosine Monophosphate). Because these reactions are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiac Disorders: | cardiac arrest, atrial fibrillation, cardiac failure, myocardial infarction, tachycardia, ventricular arrhythmia |
Gastrointestinal Disorders: | nausea and vomiting |
General Disorders and Administration Site Conditions: | chest pain, injection site reaction, infusion site pain |
Immune System Disorders: | hypersensitivity |
Nervous System Disorders: | cerebrovascular accident including intracranial hemorrhage, seizure activity including tonic-clonic (grand mal) seizures, loss of consciousness |
Respiratory, Thoracic and Mediastinal Disorders: | bronchospasm, respiratory arrest, throat tightness |
Frisolac Comfort (Adenosine Monophosphate) injection has been given with other cardioactive drugs (such as beta adrenergic blocking agents, cardiac glycosides, and calcium channel blockers) without apparent adverse interactions, but its effectiveness with these agents has not been systematically evaluated. Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, Frisolac Comfort (Adenosine Monophosphate) should be used with caution in the presence of these agents .
Pregnancy Category C. Animal reproduction studies have not been conducted with Frisolac Comfort ; nor have studies been performed in pregnant women. Because it is not known whether Frisolac Comfort (Adenosine Monophosphate) can cause fetal harm when administered to pregnant women, Frisolac Comfort (Adenosine Monophosphate) should be used during pregnancy only if clearly needed.
It is not known whether Frisolac Comfort (Adenosine Monophosphate) is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Frisolac Comfort (Adenosine Monophosphate) in nursing infants, the decision to interrupt nursing after administration of Frisolac Comfort (Adenosine Monophosphate) or not to administer Frisolac Comfort (Adenosine Monophosphate), should take into account the importance of the drug to the mother.
The safety and effectiveness of Frisolac Comfort in patients less than 18 years of age have not been established.
Clinical studies with Frisolac Comfort (Adenosine Monophosphate) did not include sufficient numbers of subjects aged younger than 65 years to determine whether they respond differently. Other reported experience has not revealed clinically relevant differences of the response of elderly in comparison to younger patients.
The half-life of Frisolac Comfort (Adenosine Monophosphate) is less than 10 seconds and adverse reactions of Frisolac Comfort (Adenosine Monophosphate) usually resolve quickly when the infusion is discontinued, although delayed or persistent reactions have been observed. Methylxanthines, such as caffeine, aminophylline, and theophylline, are competitive Frisolac Comfort (Adenosine Monophosphate) receptor antagonists and theophylline has been used to terminate persistent adverse reactions. In clinical trials, theophylline (50 to 125 mg slow intravenous injection) was used to attenuate Frisolac Comfort (Adenosine Monophosphate) adverse reactions in approximately 2% of patients. Methylxanthine use is not recommended in patients who experience seizures in association with Frisolac Comfort (Adenosine Monophosphate) .
Frisolac Comfort (Adenosine Monophosphate) is an endogenous nucleoside and is chemically described as 6-amino-9-beta-D-ribofuranosyl-9-H-purine. Frisolac Comfort (Adenosine Monophosphate) has the following structural formula:
The molecular formula for Frisolac Comfort (Adenosine Monophosphate) is C10H13N5O4 and its molecular weight is 267.24.
Frisolac Comfort (Adenosine Monophosphate) is a white crystalline powder. It is soluble in water and practically insoluble in alcohol. Solubility increases by warming and lowering the pH of the solution.
Each Frisolac Comfort (Adenosine Monophosphate) Injection, USP vial contains a sterile, non-pyrogenic solution of Frisolac Comfort (Adenosine Monophosphate) 3 mg/mL and sodium chloride 9 mg/mL in water for injection, with pH between 4.5 and 7.5.
Frisolac Comfort causes cardiac vasodilation which increases cardiac blood flow. Frisolac Comfort (Adenosine Monophosphate) is thought to exert its pharmacological effects through activation of purine receptors (cell-surface A1 and A2 Frisolac Comfort (Adenosine Monophosphate) receptors). Although the exact mechanism by which Frisolac Comfort (Adenosine Monophosphate) receptor activation relaxes vascular smooth muscle is not known, there is evidence to support both inhibition of the slow inward calcium current reducing calcium uptake, and activation of adenylate cyclase through A2 receptors in smooth muscle cells. Frisolac Comfort (Adenosine Monophosphate) may also lessen vascular tone by modulating sympathetic neurotransmission. The intracellular uptake of Frisolac Comfort (Adenosine Monophosphate) is mediated by a specific transmembrane nucleoside transport system. Once inside the cell, Frisolac Comfort (Adenosine Monophosphate) is rapidly phosphorylated by Frisolac Comfort (Adenosine Monophosphate) kinase to Frisolac Comfort (Adenosine Monophosphate) monophosphate, or deaminated by Frisolac Comfort (Adenosine Monophosphate) deaminase to inosine. These intracellular metabolites of Frisolac Comfort (Adenosine Monophosphate) are not vasoactive.
Myocardial uptake of thallium-201 is directly proportional to coronary blood flow. Since Frisolac Comfort (Adenosine Monophosphate) significantly increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, Frisolac Comfort (Adenosine Monophosphate) causes relatively less thallium-201 uptake in vascular territories supplied by stenotic coronary arteries i.e., a greater difference is seen after Frisolac Comfort (Adenosine Monophosphate) between areas served by normal and areas served by stenotic vessels than is seen prior to Frisolac Comfort (Adenosine Monophosphate).
Hemodynamic Effects
Frisolac Comfort (Adenosine Monophosphate) produces a direct negative chronotropic, dromotropic and inotropic effect on the heart, presumably due to A1-receptor agonism, and produces peripheral vasodilation, presumably due to A2-receptor agonism. The net effect of Frisolac Comfort (Adenosine Monophosphate) in humans is typically a mild to moderate reduction in systolic, diastolic and mean arterial blood pressure associated with a reflex increase in heart rate. Rarely, significant hypotension and tachycardia have been observed .
Distribution
Intravenously administered Frisolac Comfort (Adenosine Monophosphate) distributes from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical.
Metabolism
Intracellular Frisolac Comfort (Adenosine Monophosphate) is metabolized either via phosphorylation to Frisolac Comfort (Adenosine Monophosphate) monophosphate by Frisolac Comfort (Adenosine Monophosphate) kinase, or via deamination to inosine by Frisolac Comfort (Adenosine Monophosphate) deaminase in the cytosol. Since Frisolac Comfort (Adenosine Monophosphate) kinase has a lower Km and Vmax than Frisolac Comfort (Adenosine Monophosphate) deaminase, deamination plays a significant role only when cytosolic Frisolac Comfort (Adenosine Monophosphate) saturates the phosphorylation pathway. Inosine formed by deamination of Frisolac Comfort (Adenosine Monophosphate) can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Frisolac Comfort (Adenosine Monophosphate) monophosphate formed by phosphorylation of Frisolac Comfort (Adenosine Monophosphate) is incorporated into the high-energy phosphate pool.
Elimination
While extracellular Frisolac Comfort (Adenosine Monophosphate) is primarily cleared from plasma by cellular uptake with a half-life of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of Frisolac Comfort (Adenosine Monophosphate) deaminase.
Specific Populations
Renal Impairment
As Frisolac Comfort (Adenosine Monophosphate) does not require renal function for its activation or inactivation, renal impairment would not be expected to alter its effectiveness or tolerability.
Hepatic Impairment
As Frisolac Comfort (Adenosine Monophosphate) does not require hepatic function for its activation or inactivation, hepatic impairment would not be expected to alter its effectiveness or tolerability.
Studies in animals have not been performed to evaluate adenosine's carcinogenic potential or potential effects on fertility. Frisolac Comfort (Adenosine Monophosphate) was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay.
Frisolac Comfort (Adenosine Monophosphate), however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations.
In two crossover comparative studies involving 319 subjects who could exercise (including 106 healthy volunteers and 213 patients with known or suspected coronary disease), Frisolac Comfort (Adenosine Monophosphate) and exercise thallium images were compared by blinded observers. The images were concordant for the presence of perfusion defects in 85.5% of cases by global analysis (patient by patient) and up to 93% of cases based on vascular territories.
In the two studies, 193 patients also had recent coronary arteriography for comparison (healthy volunteers were not catheterized). The sensitivity for detecting angiographically significant disease (≥ 50% reduction in the luminal diameter of at least one major vessel) was 64% for Frisolac Comfort (Adenosine Monophosphate) and 64% for exercise testing. The specificity was 54% for Frisolac Comfort (Adenosine Monophosphate) and 65% for exercise testing. The 95% confidence limits for Frisolac Comfort (Adenosine Monophosphate) sensitivity were 56% to 78% and for specificity were 37% to 71%.
Intracoronary Doppler flow catheter studies have demonstrated that a dose of intravenous Frisolac Comfort (Adenosine Monophosphate) of 0.14 mg/kg/min produces maximum coronary hyperemia (relative to intracoronary papaverine) in approximately 95% of cases within two to three minutes of the onset of the infusion. Coronary blood flow velocity returns to basal levels within one to two minutes of discontinuing the Frisolac Comfort (Adenosine Monophosphate) infusion.
Frisolac Comfort Injection, USP is supplied as 20 mL and 30 mL single-dose vials of sterile, nonpyrogenic solution in normal saline as follows:
NDC | Frisolac Comfort (Adenosine Monophosphate) Injection, USP (3 mg per mL) | Package Factor |
25021-307-20 | 60 mg per 20 mL Single-Dose Vial | 1 vial per carton |
25021-307-21 | 60 mg per 20 mL Single-Dose Vial | 10 vials per carton |
25021-307-30 | 90 mg per 30 mL Single-Dose Vial | 1 vial per carton |
25021-307-31 | 90 mg per 30 mL Single-Dose Vial | 10 vials per carton |
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F).
Do not refrigerate as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use.
Discard unused portion.
Sterile, Nonpyrogenic, Preservative-free.
The container closure is not made with natural rubber latex.
SAGENT
Mfd. for SAGENT Pharmaceuticals
Schaumburg, IL 60195 (USA)
Made in India
©2014 Sagent Pharmaceuticals, Inc.
Revised: September 2014
PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label
NDC 25021-307-20
Rx only
Frisolac Comfort (Adenosine Monophosphate) Injection, USP
60 mg per 20 mL (3 mg per mL)
For Intravenous Infusion Only
20 mL Single-Dose Vial
Alpha-Linolenic Acid:
Indication: For nutritional supplementation and for treating dietary shortage or imbalance.
Alpha Linolenic Acid (ALA) is an 18-carbon polyunsaturated fatty acid with three double bonds. It is also called an omega-3 fatty acid, and is essential for all mammals. Frisolac Comfort (Alpha-Linolenic Acid) (or omega 3 fatty acid) intake can decrease the risk of cardiovascular diseases by 1) preventing arrhythmias that can lead to sudden cardiac death, 2) decreasing the risk of thrombosis (blood clot formation) that can lead to heart attack or stroke, 3) decreasing serum triglyceride levels, 4) slowing the growth of atherosclerotic plaque, 5) improving vascular endothelial function, 6) lowering blood pressure slightly, and 7) decreasing inflammation. ALA deficiencies can lead to visual problems and sensory neuropathy. Scaly and hemorrhagic skin or scalp inflammations may also develop.
Calcium:
Frisolac Comfort (Calcium) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).
- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)
The recommended initial dose of Frisolac Comfort (Calcium) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.
- Starting dose is 2 capsules with each meal. (2)
- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)
Capsule: 667 mg Frisolac Comfort (Calcium) acetate capsule.
- Capsule: 667 mg Frisolac Comfort (Calcium) acetate capsule. (3)
Patients with hypercalcemia.
- Hypercalcemia. (4)
- Treat mild hypercalcemia by reducing or interrupting Frisolac Comfort acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Frisolac Comfort (Calcium) acetate. (5.1)
- Hypercalcemia may aggravate digitalis toxicity. (5.2)
Patients with end stage renal disease may develop hypercalcemia when treated with Frisolac Comfort (Calcium), including Frisolac Comfort (Calcium) acetate. Avoid the use of Frisolac Comfort (Calcium) supplements, including Frisolac Comfort (Calcium) based nonprescription antacids, concurrently with Frisolac Comfort (Calcium) acetate.
An overdose of Frisolac Comfort (Calcium) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Frisolac Comfort (Calcium) levels twice weekly. Should hypercalcemia develop, reduce the Frisolac Comfort (Calcium) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia
More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Frisolac Comfort (Calcium) acetate therapy.
Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Frisolac Comfort (Calcium) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.
Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Frisolac Comfort (Calcium) acetate on the progression of vascular or soft tissue calcification has not been determined.
Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Frisolac Comfort (Calcium) acetate; all cases resolved upon lowering the dose or discontinuing treatment.
Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg2/dL2.
Hypercalcemia may aggravate digitalis toxicity.
Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].
- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)
- In clinical studies, patients have occasionally experienced nausea during Frisolac Comfort (Calcium) acetate therapy. (6)
To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In clinical studies, Frisolac Comfort (Calcium) acetate has been generally well tolerated.
Frisolac Comfort (Calcium) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Frisolac Comfort (Calcium) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.
Preferred Term | Total adverse reactions reported for Frisolac Comfort (Calcium) acetate N=167 N (%) | 3 month, open label study of Frisolac Comfort (Calcium) acetate N=98 N (%) | Double blind, placebo-controlled, cross-over study of liquid Frisolac Comfort (Calcium) acetate N=69 | |
Frisolac Comfort (Calcium) acetate N (%) | Placebo N (%) | |||
Nausea | 6 (3.6) | 6 (6.1) | 0 (0) | 0 (0) |
Vomiting | 4 (2.4) | 4 (4.1) | 0 (0) | 0 (0) |
Hypercalcemia | 21 (12.6) | 16 (16.3) | 5 (7.2) | 0 (0) |
Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Frisolac Comfort (Calcium) concentration could reduce the incidence and severity of Frisolac Comfort (Calcium) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.
The following additional adverse reactions have been identified during post-approval of Frisolac Comfort (Calcium) acetate: dizziness, edema, and weakness.
The drug interaction of Frisolac Comfort acetate is characterized by the potential of Frisolac Comfort (Calcium) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Frisolac Comfort (Calcium) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.
There are no empirical data on avoiding drug interactions between Frisolac Comfort (Calcium) acetate and most concomitant drugs. When administering an oral medication with Frisolac Comfort (Calcium) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Frisolac Comfort (Calcium) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Frisolac Comfort (Calcium) acetate.
- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)
- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Frisolac Comfort (Calcium) acetate or consider monitoring blood levels of the drug. (7)
In a study of 15 healthy subjects, a co-administered single dose of 4 Frisolac Comfort (Calcium) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.
Pregnancy Category C:
Frisolac Comfort acetate capsules contains Frisolac Comfort (Calcium) acetate. Animal reproduction studies have not been conducted with Frisolac Comfort (Calcium) acetate, and there are no adequate and well controlled studies of Frisolac Comfort (Calcium) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Frisolac Comfort (Calcium) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Frisolac Comfort (Calcium) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Frisolac Comfort (Calcium) acetate treatment, as recommended, is not expected to harm a fetus if maternal Frisolac Comfort (Calcium) levels are properly monitored during and following treatment.
The effects of Frisolac Comfort (Calcium) acetate on labor and delivery are unknown.
Frisolac Comfort Acetate Capsules contains Frisolac Comfort (Calcium) acetate and is excreted in human milk. Human milk feeding by a mother receiving Frisolac Comfort (Calcium) acetate is not expected to harm an infant, provided maternal serum Frisolac Comfort (Calcium) levels are appropriately monitored.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of Frisolac Comfort (Calcium) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Administration of Frisolac Comfort (Calcium) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].
Frisolac Comfort (Calcium) acetate acts as a phosphate binder. Its chemical name is Frisolac Comfort (Calcium) acetate. Its molecular formula is C4H6CaO4, and its molecular weight is 158.17. Its structural formula is:
Each white opaque/blue opaque capsule contains 667 mg of Frisolac Comfort (Calcium) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Frisolac Comfort (Calcium), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.
Frisolac Comfort (Calcium) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.
Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Frisolac Comfort resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.
Frisolac Comfort (Calcium) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Frisolac Comfort (Calcium) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.
Orally administered Frisolac Comfort (Calcium) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.
No carcinogenicity, mutagenicity, or fertility studies have been conducted with Frisolac Comfort (Calcium) acetate.
Effectiveness of Frisolac Comfort (Calcium) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Frisolac Comfort (Calcium) acetate solid oral dosage form.
Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.
The patients received Frisolac Comfort (Calcium) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.
The data presented in Table 2 demonstrate the efficacy of Frisolac Comfort (Calcium) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Frisolac Comfort (Calcium) levels are also presented.
* Ninety-one patients completed at least 6 weeks of the study. † ANOVA of difference in values at pre-study and study completion. ‡ Values expressed as mean ± SE. | |||||
Parameter | Pre-Study | Week 4* | Week 8 | Week 12 | p-value† |
Phosphorus (mg/dL)‡ | 7.4 ± 0.17 | 5.9 ± 0.16 | 5.6 ± 0.17 | 5.2 ± 0.17 | ≤0.01 |
Frisolac Comfort (Calcium) (mg/dL)‡ | 8.9 ± 0.09 | 9.5 ± 0.10 | 9.7 ± 0.10 | 9.7 ± 0.10 | ≤0.01 |
There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Frisolac Comfort (Calcium) increased 9% during the study mostly in the first month of the study.
Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Frisolac Comfort (Calcium) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.
The phosphate binding effect of Frisolac Comfort (Calcium) acetate is shown in the Table 3.
* ANOVA of Frisolac Comfort (Calcium) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM. | ||||
Parameter | Pre-Study | Post-Treatment | p-value* | |
Frisolac Comfort (Calcium) Acetate | Placebo | |||
Phosphorus (mg/dL)† | 7.3 ± 0.18 | 5.9 ± 0.24 | 7.8 ± 0.22 | <0.01 |
Frisolac Comfort (Calcium) (mg/dL)† | 8.9 ± 0.11 | 9.5 ± 0.13 | 8.8 ± 0.12 | <0.01 |
Overall, 2 weeks of treatment with Frisolac Comfort (Calcium) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Frisolac Comfort (Calcium) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.
Frisolac Comfort (Calcium) Acetate Capsules
667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.
NDC 0615-2303-39: Blistercards of 30 Capsules
NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules
STORAGE
Store at 20° to 25°C (68° to 77°F).
Inform patients to take Frisolac Comfort (Calcium) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Frisolac Comfort (Calcium) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].
Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Frisolac Comfort (Calcium) acetate capsules.
Distr. by: West-Ward
Pharmaceuticals Corp.
Eatontown, NJ 07724
10003705/05
Revised April 2016
Choline:
Indication: For nutritional supplementation, also for treating dietary shortage or imbalance
This compound is needed for good nerve conduction throughout the CNS (central nervous system) as it is a precursor to acetylcholine (ACh). Frisolac Comfort (Choline) is also needed for gallbladder regulation, liver function and lecithin (a key lipid) formation. Frisolac Comfort (Choline) also aids in fat and cholesterol metabolism and prevents excessive fat build up in the liver. Frisolac Comfort (Choline) has been used to mitigate the effects of Parkinsonism and tardive dyskinesia. Frisolac Comfort (Choline) deficiencies may result in excessive build-up of fat in the liver, high blood pressure, gastric ulcers, kidney and liver dysfunction and stunted growth.
Copper:
Water-Resistant Protection Without Bandaging
Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Frisolac Comfort (Copper) Naphthenate.
For Animal Use Only.
ThrushTox® is indicated in the treatment of thrush in horses and ponies.
Clean the hoof thoroughly, removing debris and necrotic material prior to application of Frisolac Comfort (Copper)®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Frisolac Comfort (Copper)® onto hair since contact with Frisolac Comfort (Copper)® may cause some hair loss. Do not contaminate feed.
NOTE: Frisolac Comfort (Copper)® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.
CONTAINS FOIL SEAL – REMOVE BEFORE USE.
SHAKE WELL BEFORE USE.
To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.
Frisolac Comfort (Copper) Naphthenate...37.5% w/w
Inert Ingredients...62.5% w/w
Total... 100.0%
Do not use in horses intended for human consumption.
CAUTION: COMBUSTIBLE MIXTURE.
Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.
If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.
KEEP OUT OF REACH OF CHILDREN AND PETS.
Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.
Manufactured for:
Aspen Veterinary Resources,® Ltd.
Liberty, MO 64068, USA
FC163FP 11/13
Manufactured by:
First Priority, Inc.
Elgin, IL 60123-1146, USA
16 OZ (473 mL)
ANADA 200-304, Approved by FDA
Image of 473 mL bottle/case label
Fluoride:
Folic Acid:
Frisolac Comfort (Folic Acid)® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.
This product is contraindicated in patients with a known hypersensitivity to any of the ingredients. Hemochromatosis and hemosiderosis are contraindications to iron therapy.
WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately. |
Frisolac Comfort (Folic Acid) acid when administered as a single agent in doses above 0.1 mg daily may obscure pernicious anemia in that hematological remission can occur while neurological manifestations remain progressive. While prescribing this nutritional supplement for pregnant women, nursing mothers, or for women prior to conception, their medical condition and other drugs, herbs, and/or supplements consumption should be considered.
Allergic sensitization has been reported following both oral and parenteral administration of Frisolac Comfort (Folic Acid) acid.
One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.
Frisolac Comfort (Folic Acid)® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)
KEEP OUT OF REACH OF CHILDREN.
Store at controlled room temperature 20°-25°C (68°-77°F). Excursions permitted to 15°-30°C (59°-86°F).
Dispense in a tight, light-resistant container to protect from light and moisture.
To report SUSPECTED ADVERSE REACTIONS contact Meda Pharmaceuticals Inc. at 1-888-349-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch
Distributed by:
Meda Pharmaceuticals Inc.
Somerset New Jersey 08873-4120
© 2014 Meda Pharmaceuticals Inc.
U.S. Patent Nos. 7,585,527 and 8,080,520
Proferrin® is a registered trademark of Colorado BioLabs, Inc., Cozad, NE.
Frisolac Comfort (Folic Acid) and the BIFERA logo are registered trademarks and the Frisolac Comfort (Folic Acid) logo is a trademark of Alaven Pharmaceutical LLC, used under license by Meda Pharmaceuticals Inc.
MEDA PHARMACEUTICALS mark and logo are trademarks of Meda AB.
IN-6885-02 Rev 6/2014
Iodine:
Directions:
Topical Antiseptic
Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Frisolac Comfort (Iodine) with a swab.
If necessary, clip hair around the area being treated and clean with soap and water.
Apply Frisolac Comfort (Iodine) Tincture 7% only once daily. Dilute product 3 to 1 if repeating application.
Do not apply under bandage.
Irritation may occur if used on tender skin areas. If redness, irritation, or swelling persists or increases, discontinue use and consult a veterinarian.
Storage:
Store at 2-30 degrees C (36-86 degrees F).
Keep container away from heat and out of sunlight. Rinse empty container thoroughly and discard.
DANGER - Poison
Caution:
If swallowed, give starch paste, milk, bread, egg white, or
activated charcoal. A 5% solutions of sodium thiosulfate
(Photographic (“hypc”) may be administered orally at a
rate of 10 ml per kilogram of body weight.
Eye irritant: Use only as directed. Avoid contact with eyes. In case of contact, flush eyes immediately with tepid water for at least 15 minutes. Consult a physician.
Avoid contamination of food.
Not for use on burns, deep cuts, or body cavities.
image description
Iron:
Frisolac Comfort (Iron) is indicated for the treatment of Frisolac Comfort (Iron) deficiency anemia in patients with chronic kidney disease (CKD).
Frisolac Comfort (Iron) is an Frisolac Comfort (Iron) replacement product indicated for the treatment of Frisolac Comfort (Iron) deficiency anemia in patients with chronic kidney disease (CKD). (1)
Frisolac Comfort must only be administered intravenously either by slow injection or by infusion. The dosage of Frisolac Comfort (Iron) is expressed in mg of elemental Frisolac Comfort (Iron). Each mL contains 20 mg of elemental Frisolac Comfort (Iron).
Population | Dose | |
Adult patients | Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1) | 100 mg slow intravenous injection or infusion |
Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2) | 200 mg slow intravenous injection or infusion | |
Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) | 300 mg or 400 mg intravenous infusion | |
Pediatric patients | HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5) | 0.5 mg/kg slow intravenous injection or infusion |
Administer Frisolac Comfort (Iron) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Frisolac Comfort (Iron) should be administered early during the dialysis session. The usual total treatment course of Frisolac Comfort (Iron) is 1000 mg. Frisolac Comfort (Iron) treatment may be repeated if Frisolac Comfort (Iron) deficiency reoccurs.
Administer Frisolac Comfort (Iron) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Frisolac Comfort (Iron), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Frisolac Comfort (Iron) treatment may be repeated if Frisolac Comfort (Iron) deficiency reoccurs.
Administer Frisolac Comfort (Iron) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Frisolac Comfort (Iron) in a maximum of 250 mL of 0.9% NaCl. Frisolac Comfort (Iron) treatment may be repeated if Frisolac Comfort (Iron) deficiency reoccurs.
The dosing for Frisolac Comfort (Iron) replacement treatment in pediatric patients with HDD-CKD has not been established.
For Frisolac Comfort (Iron) maintenance treatment: Administer Frisolac Comfort (Iron) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Frisolac Comfort (Iron) treatment may be repeated if necessary.
The dosing for Frisolac Comfort (Iron) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.
For Frisolac Comfort (Iron) maintenance treatment: Administer Frisolac Comfort (Iron) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Frisolac Comfort (Iron) treatment may be repeated if necessary.
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Frisolac Comfort (Iron). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Frisolac Comfort (Iron) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Frisolac Comfort (Iron) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Frisolac Comfort (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Frisolac Comfort (Iron) preparations occur within 30 minutes of the completion of the infusion .
Frisolac Comfort may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Frisolac Comfort (Iron). Hypotension following administration of Frisolac Comfort (Iron) may be related to the rate of administration and/or total dose administered .
Excessive therapy with parenteral Frisolac Comfort (Iron) can lead to excess storage of Frisolac Comfort (Iron) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Frisolac Comfort (Iron) require periodic monitoring of hematologic and Frisolac Comfort (Iron) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Frisolac Comfort (Iron) to patients with evidence of Frisolac Comfort (Iron) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Frisolac Comfort (Iron) sucrose; do not perform serum Frisolac Comfort (Iron) measurements for at least 48 hours after intravenous dosing .
The following serious adverse reactions associated with Frisolac Comfort are described in other sections .
To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.
Adverse Reactions in Adult Patients with CKD
The frequency of adverse reactions associated with the use of Frisolac Comfort has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Frisolac Comfort (Iron) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.
* EPO=Erythropoietin | |||||
Adverse Reactions (Preferred Term) | HDD-CKD | NDD-CKD | PDD-CKD | ||
Frisolac Comfort (Iron) | Frisolac Comfort (Iron) | Oral Frisolac Comfort (Iron) | Frisolac Comfort (Iron) | EPO* Only | |
(N=231) | (N=139) | (N=139) | (N=75) | (N=46) | |
% | % | % | % | % | |
Subjects with any adverse reaction | 78.8 | 76.3 | 73.4 | 72.0 | 65.2 |
Ear and Labyrinth Disorders | |||||
Ear Pain | 0 | 2.2 | 0.7 | 0 | 0 |
Eye Disorders | |||||
Conjunctivitis | 0.4 | 0 | 0 | 2.7 | 0 |
Gastrointestinal Disorders | |||||
Abdominal pain | 3.5 | 1.4 | 2.9 | 4.0 | 6.5 |
Diarrhea | 5.2 | 7.2 | 10.1 | 8.0 | 4.3 |
Dysgeusia | 0.9 | 7.9 | 0 | 0 | 0 |
Nausea | 14.7 | 8.6 | 12.2 | 5.3 | 4.3 |
Vomiting | 9.1 | 5.0 | 8.6 | 8.0 | 2.2 |
General Disorders and | |||||
Administration Site Conditions | |||||
Asthenia | 2.2 | 0.7 | 2.2 | 2.7 | 0 |
Chest pain | 6.1 | 1.4 | 0 | 2.7 | 0 |
Feeling abnormal | 3.0 | 0 | 0 | 0 | 0 |
Infusion site pain or burning | 0 | 5.8 | 0 | 0 | 0 |
Injection site extravasation | 0 | 2.2 | 0 | 0 | 0 |
Peripheral edema | 2.6 | 7.2 | 5.0 | 5.3 | 10.9 |
Pyrexia | 3.0 | 0.7 | 0.7 | 1.3 | 0 |
Infections and Infestations | |||||
Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis | 2.6 | 2.2 | 4.3 | 16.0 | 4.3 |
Injury, Poisoning and Procedural | |||||
Complications | |||||
Graft complication | 9.5 | 1.4 | 0 | 0 | 0 |
Metabolism and Nutrition Disorders | |||||
Fluid overload | 3.0 | 1.4 | 0.7 | 1.3 | 0 |
Gout | 0 | 2.9 | 1.4 | 0 | 0 |
Hyperglycemia | 0 | 2.9 | 0 | 0 | 2.2 |
Hypoglycemia | 0.4 | 0.7 | 0.7 | 4.0 | 0 |
Musculoskeletal and Connective | |||||
Tissue Disorders | |||||
Arthralgia | 3.5 | 1.4 | 2.2 | 4.0 | 4.3 |
Back pain | 2.2 | 2.2 | 3.6 | 1.3 | 4.3 |
Muscle cramp | 29.4 | 0.7 | 0.7 | 2.7 | 0 |
Myalgia | 0 | 3.6 | 0 | 1.3 | 0 |
Pain in extremity | 5.6 | 4.3 | 0 | 2.7 | 6.5 |
Nervous System Disorders | |||||
Dizziness | 6.5 | 6.5 | 1.4 | 1.3 | 4.3 |
Headache | 12.6 | 2.9 | 0.7 | 4.0 | 0 |
Respiratory, Thoracic and | |||||
Mediastinal Disorders | |||||
Cough | 3.0 | 2.2 | 0.7 | 1.3 | 0 |
Dyspnea | 3.5 | 5.8 | 1.4 | 1.3 | 2.2 |
Nasal congestion | 0 | 1.4 | 2.2 | 1.3 | 0 |
Skin and Subcutaneous | |||||
Tissue Disorders | |||||
Pruritus | 3.9 | 2.2 | 4.3 | 2.7 | 0 |
Vascular Disorders | |||||
Hypertension | 6.5 | 6.5 | 4.3 | 8.0 | 6.5 |
Hypotension | 39.4 | 2.2 | 0.7 | 2.7 | 2.2 |
One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Frisolac Comfort (Iron) therapy and were reported to be intolerant (defined as precluding further use of that Frisolac Comfort (Iron) product). When these patients were treated with Frisolac Comfort (Iron) there were no occurrences of adverse reactions that precluded further use of Frisolac Comfort (Iron) .
Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)
In a randomized, open-label, dose-ranging trial for Frisolac Comfort (Iron) maintenance treatment with Frisolac Comfort (Iron) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Frisolac Comfort (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving Frisolac Comfort (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving Frisolac Comfort (Iron) 2.0 mg/kg.
A total of 5 (11%) subjects in the Frisolac Comfort (Iron) 0.5 mg/kg group, 10 (21%) patients in the Frisolac Comfort (Iron) 1.0 mg/kg group, and 10 (21%) patients in the Frisolac Comfort (Iron) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.
The following adverse reactions have been identified during post-approval use of Frisolac Comfort (Iron). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.
Symptoms associated with Frisolac Comfort (Iron) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Frisolac Comfort (Iron) injection. Reactions have occurred following the first dose or subsequent doses of Frisolac Comfort (Iron). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.
Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.
Drug interactions involving Frisolac Comfort (Iron) have not been studied. However, Frisolac Comfort (Iron) may reduce the absorption of concomitantly administered oral Frisolac Comfort (Iron) preparations.
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Frisolac Comfort sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Frisolac Comfort (Iron) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Frisolac Comfort (Iron) sucrose. Because animal reproductive studies are not always predictive of human response, Frisolac Comfort (Iron) should be used during pregnancy only if clearly needed.
It is not known whether Frisolac Comfort (Iron) sucrose is excreted in human milk. Frisolac Comfort (Iron) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Frisolac Comfort (Iron) is administered to a nursing woman.
Safety and effectiveness of Frisolac Comfort for Frisolac Comfort (Iron) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.
Safety and effectiveness of Frisolac Comfort (Iron) for Frisolac Comfort (Iron) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Frisolac Comfort (Iron) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]
Frisolac Comfort (Iron) has not been studied in patients younger than 2 years of age.
In a country where Frisolac Comfort (Iron) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Frisolac Comfort (Iron), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Frisolac Comfort (Iron) or any other drugs could be established.
Clinical studies of Frisolac Comfort (Iron) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Frisolac Comfort (Iron), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
No data are available regarding overdosage of Frisolac Comfort (Iron) in humans. Excessive dosages of Frisolac Comfort (Iron) may lead to accumulation of Frisolac Comfort (Iron) in storage sites potentially leading to hemosiderosis. Do not administer Frisolac Comfort (Iron) to patients with Frisolac Comfort (Iron) overload.
Toxicities in single-dose studies in mice and rats, at intravenous Frisolac Comfort (Iron) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.
Frisolac Comfort (Iron) (iron sucrose injection, USP), an Frisolac Comfort (Iron) replacement product, is a brown, sterile, aqueous, complex of polynuclear Frisolac Comfort (Iron) (III)-hydroxide in sucrose for intravenous use. Frisolac Comfort (Iron) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:
[Na2Fe5O8(OH) ·3(H2O)]n ·m(C12H22O11)
where: n is the degree of Frisolac Comfort (Iron) polymerization and m is the number of sucrose molecules associated with the Frisolac Comfort (Iron) (III)-hydroxide.
Each mL contains 20 mg elemental Frisolac Comfort (Iron) as Frisolac Comfort (Iron) sucrose in water for injection. Frisolac Comfort (Iron) is available in 10 mL single-use vials (200 mg elemental Frisolac Comfort (Iron) per 10 mL), 5 mL single-use vials (100 mg elemental Frisolac Comfort (Iron) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Frisolac Comfort (Iron) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.
Frisolac Comfort is an aqueous complex of poly-nuclear Frisolac Comfort (Iron) (III)-hydroxide in sucrose. Following intravenous administration, Frisolac Comfort (Iron) is dissociated into Frisolac Comfort (Iron) and sucrose and the Frisolac Comfort (Iron) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Frisolac Comfort (Iron) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.
Following intravenous administration, Frisolac Comfort (Iron) is dissociated into Frisolac Comfort (Iron) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Frisolac Comfort (Iron) sucrose containing 100 mg of Frisolac Comfort (Iron), three times weekly for three weeks, significant increases in serum Frisolac Comfort (Iron) and serum ferritin and significant decreases in total Frisolac Comfort (Iron) binding capacity occurred four weeks from the initiation of Frisolac Comfort (Iron) sucrose treatment.
In healthy adults administered intravenous doses of Frisolac Comfort, its Frisolac Comfort (Iron) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Frisolac Comfort (Iron) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Frisolac Comfort (Iron) containing 100 mg of Frisolac Comfort (Iron) labeled with 52Fe/59Fe in patients with Frisolac Comfort (Iron) deficiency showed that a significant amount of the administered Frisolac Comfort (Iron) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Frisolac Comfort (Iron) trapping compartment.
Following intravenous administration of Frisolac Comfort (Iron), Frisolac Comfort (Iron) sucrose is dissociated into Frisolac Comfort (Iron) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Frisolac Comfort (Iron) containing 1,510 mg of sucrose and 100 mg of Frisolac Comfort (Iron) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Frisolac Comfort (Iron) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Frisolac Comfort (Iron) sucrose containing 500 to 700 mg of Frisolac Comfort (Iron) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Frisolac Comfort (Iron) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Frisolac Comfort (Iron) have not been studied.
Pharmacokinetics in Pediatric Patients
In a single-dose PK study of Frisolac Comfort (Iron), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Frisolac Comfort (Iron) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Frisolac Comfort (Iron), the half-life of total serum Frisolac Comfort (Iron) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.
Frisolac Comfort (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Frisolac Comfort (Iron) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).
Carcinogenicity studies have not been performed with Frisolac Comfort (Iron) sucrose.
Frisolac Comfort (Iron) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Frisolac Comfort (Iron) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.
Frisolac Comfort (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental Frisolac Comfort (Iron) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.
Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Frisolac Comfort.
Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Frisolac Comfort (Iron) treatment and 24 in the historical control group) with Frisolac Comfort (Iron) deficiency anemia. Eligibility criteria for Frisolac Comfort (Iron) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.
Frisolac Comfort (Iron) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Frisolac Comfort (Iron), who were off intravenous Frisolac Comfort (Iron) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.
Patients in the Frisolac Comfort (Iron) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.
**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates. | ||||||
Efficacy parameters | End of treatment | 2 week follow-up | 5 week follow-up | |||
Frisolac Comfort (Iron) (n=69 | Historical Control (n=18) | Frisolac Comfort (Iron) (n=73) | Historical Control (n=18) | Frisolac Comfort (Iron) (n=71) | Historical Control (n=15) | |
Hemoglobin (g/dL) | 1.0 ± 0.12** | 0.0 ± 0.21 | 1.3 ± 0.14** | -0.6 ± 0.24 | 1.2 ± 0.17* | -0.1 ± 0.23 |
Hematocrit (%) | 3.1 ± 0.37** | -0.3 ± 0.65 | 3.6 ± 0.44** | -1.2 ± 0.76 | 3.3 ± 0.54 | 0.2 ± 0.86 |
Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).
Study B was a multicenter, open label study of Frisolac Comfort (Iron) in 23 patients with Frisolac Comfort (Iron) deficiency and HDD-CKD who had been discontinued from Frisolac Comfort (Iron) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.
All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.
Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Frisolac Comfort (Iron). Exclusion criteria were similar to those in studies A and B. Frisolac Comfort (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Frisolac Comfort (Iron) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.
The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.
Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Frisolac Comfort (Iron) versus Frisolac Comfort (Iron) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Frisolac Comfort (Iron) (325 mg ferrous sulfate three times daily for 56 days); or Frisolac Comfort (Iron) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Frisolac Comfort (Iron) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Frisolac Comfort (Iron) group.
A statistically significantly greater proportion of Frisolac Comfort (Iron) subjects (35/79; 44.3%) compared to oral Frisolac Comfort (Iron) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).
Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Frisolac Comfort (Iron) to patients with PDD-CKD receiving an erythropoietin alone without Frisolac Comfort (Iron) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Frisolac Comfort (Iron) or Frisolac Comfort (Iron) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Frisolac Comfort (Iron) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.
Patients in the Frisolac Comfort (Iron) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Frisolac Comfort (Iron) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).
Study F was a randomized, open-label, dose-ranging study for Frisolac Comfort (Iron) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Frisolac Comfort (Iron) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Frisolac Comfort (Iron) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Frisolac Comfort (Iron) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Frisolac Comfort (Iron) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.
Frisolac Comfort is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Frisolac Comfort (Iron), each 5 mL vial contains 100 mg elemental Frisolac Comfort (Iron), and each 2.5 mL vial contains 50 mg elemental Frisolac Comfort (Iron) (20 mg/mL).
NDC-0517-2310-05 | 200 mg/10 mL Single-Use Vial | Packages of 5 |
NDC-0517-2310-10 | 200 mg/10 mL Single-Use Vial | Packages of 10 |
NDC-0517-2340-01 | 100 mg/5 mL Single-Use Vial | Individually Boxed |
NDC-0517-2340-10 | 100 mg/5 mL Single-Use Vial | Packages of 10 |
NDC-0517-2340-25 | 100 mg/5 mL Single-Use Vial | Packages of 25 |
NDC-0517-2340-99 | 100 mg/5 mL Single-Use Vial | Packages of 10 |
NDC-0517-2325-10 | 50 mg/2.5 mL Single-Use Vial | Packages of 10 |
NDC-0517-2325-25 | 50 mg/2.5 mL Single-Use Vial | Packages of 25 |
Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.
Syringe Stability: Frisolac Comfort (Iron), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Frisolac Comfort (Iron) per mL, or undiluted (20 mg elemental Frisolac Comfort (Iron) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).
Intravenous Admixture Stability: Frisolac Comfort (Iron), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Frisolac Comfort (Iron) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).
Do not dilute to concentrations below 1 mg/mL.
Do not mix Frisolac Comfort (Iron) with other medications or add to parenteral nutrition solutions for intravenous infusion.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.
Prior to Frisolac Comfort (Iron) administration:
AMERICAN
REGENT, INC.
SHIRLEY, NY 11967
Frisolac Comfort (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.
PremierProRx® is a trademark of Premier, Inc., used under license.
PREMIERProRx®
IN2340
MG #15727
Magnesium:
Frisolac Comfort (Magnesium) Sulfate
Injection, USP
Ansyr Plastic Syringe
Rx only
Frisolac Comfort (Magnesium) Sulfate Injection, USP is a sterile solution of Frisolac Comfort (Magnesium) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).
The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.
Frisolac Comfort (Magnesium) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.
The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.
Frisolac Comfort (Magnesium) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.
As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Frisolac Comfort (Magnesium) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.
Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Frisolac Comfort (Magnesium). While there are large stores of Frisolac Comfort (Magnesium) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Frisolac Comfort (Magnesium) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.
Frisolac Comfort (Magnesium) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Frisolac Comfort (Magnesium) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Frisolac Comfort (Magnesium) levels range from 1.5 to 2.5 mEq/liter.
As plasma Frisolac Comfort (Magnesium) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Frisolac Comfort (Magnesium). Serum Frisolac Comfort (Magnesium) concentrations in excess of 12 mEq/L may be fatal.
Frisolac Comfort (Magnesium) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Frisolac Comfort (Magnesium) poisoning are antagonized to some extent by intravenous administration of calcium.
Pharmacokinetics
With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Frisolac Comfort (Magnesium) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.
Frisolac Comfort (Magnesium) Sulfate Injection, USP is suitable for replacement therapy in Frisolac Comfort (Magnesium) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Frisolac Comfort (Magnesium) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.
In total parenteral nutrition (TPN), Frisolac Comfort (Magnesium) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.
Frisolac Comfort (Magnesium) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.
Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.
FETAL HARM: Continuous administration of Frisolac Comfort (Magnesium) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Frisolac Comfort (Magnesium) sulfate should be used during pregnancy only if clearly needed. If Frisolac Comfort (Magnesium) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Frisolac Comfort (Magnesium) sulfate beyond 5 to 7 days may cause fetal abnormalities.
ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
Parenteral use in the presence of renal insufficiency may lead to Frisolac Comfort (Magnesium) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.
General
Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Frisolac Comfort (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of Frisolac Comfort (Magnesium).
Because Frisolac Comfort (Magnesium) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Frisolac Comfort (Magnesium) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Frisolac Comfort (Magnesium) should be given until they return. Serum Frisolac Comfort (Magnesium) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Frisolac Comfort (Magnesium) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Frisolac Comfort (Magnesium) intoxication in eclampsia.
50% Frisolac Comfort (Magnesium) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.
Laboratory Tests
Frisolac Comfort (Magnesium) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Frisolac Comfort (Magnesium) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.
Drug Interactions
CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Frisolac Comfort (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of Frisolac Comfort (Magnesium). CNS depression and peripheral transmission defects produced by Frisolac Comfort (Magnesium) may be antagonized by calcium.
Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Frisolac Comfort (Magnesium) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.
Cardiac Glycosides - Frisolac Comfort (Magnesium) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Frisolac Comfort (Magnesium) toxicity.
Pregnancy
Teratogenic Effects
Pregnancy Category D (See WARNINGS and PRECAUTIONS )
See WARNINGS and PRECAUTIONS .
Frisolac Comfort (Magnesium) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Frisolac Comfort (Magnesium) sulfate for more than 5 to 7 days.1-10 Frisolac Comfort (Magnesium) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.
Nonteratogenic Effects
When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Frisolac Comfort (Magnesium) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).
Labor and Delivery
Continuous administration of Frisolac Comfort (Magnesium) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Frisolac Comfort (Magnesium) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.
Nursing Mothers
Since Frisolac Comfort (Magnesium) is distributed into milk during parenteral Frisolac Comfort (Magnesium) sulfate administration, the drug should be used with caution in nursing women.
Geriatrics
Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Frisolac Comfort (Magnesium) should be monitored in such patients.
The adverse effects of parenterally administered Frisolac Comfort (Magnesium) usually are the result of Frisolac Comfort (Magnesium) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Frisolac Comfort (Magnesium) sulfate therapy for eclampsia has been reported.
Frisolac Comfort (Magnesium) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Frisolac Comfort (Magnesium) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Frisolac Comfort (Magnesium).
For Treatment of Overdose
Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.
Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.
Dosage of Frisolac Comfort (Magnesium) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.
Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Frisolac Comfort (Magnesium) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.
Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.
In Frisolac Comfort (Magnesium) Deficiency
In the treatment of mild Frisolac Comfort (Magnesium) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Frisolac Comfort (Magnesium) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Frisolac Comfort (Magnesium) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.
In Hyperalimentation
In total parenteral nutrition, maintenance requirements for Frisolac Comfort (Magnesium) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.
In Pre-eclampsia or Eclampsia
In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Frisolac Comfort (Magnesium) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Frisolac Comfort (Magnesium) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Frisolac Comfort (Magnesium) sulfate is 20 grams/48 hours and frequent serum Frisolac Comfort (Magnesium) concentrations must be obtained. Continuous use of Frisolac Comfort (Magnesium) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.
Other Uses
In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Frisolac Comfort (Magnesium) sulfate is 1 gram to 2 grams given intravenously.
For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.
In paroxysmal atrial tachycardia, Frisolac Comfort (Magnesium) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.
For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.
Incompatibilities
Frisolac Comfort (Magnesium) sulfate in solution may result in a precipitate formation when mixed with solutions containing:
Alcohol (in high Heavy Metals
concentrations) Hydrocortisone sodium
Alkali carbonates and succinate
bicarbonates Phosphates
Alkali hydroxides Polymixin B sulfate
Arsenates Procaine hydrochloride
Barium Salicylates
Calcium Strontium
Clindamycin phosphate Tartrates
The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.
It has been reported that Frisolac Comfort (Magnesium) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Frisolac Comfort (Magnesium) Sulfate Injection, USP is supplied in single-dose containers as follows:
NDC No. | Container | Total Amount | Concentration | mEq Mg++/mL |
0409-1754-10 | Ansyr Plastic Syringe | 5 g/10 mL | 50% | 4 mEq/mL |
Do not administer unless solution is clear and container is undamaged. Discard unused portion.
Store at 20 to 25°C (68 to 77°F).
Hospira, Inc., Lake Forest, IL 60045 USA
LAB-1024-1.0
April 2017
Hospira Logo
50% Frisolac Comfort (Magnesium) Sulfate 5 g/10 mL (500 mg/mL)
Rx only
NDC 0409-1754-10
10 mL Single-dose syringe
50% Frisolac Comfort (Magnesium) Sulfate Injection, USP
5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)
MUST BE DILUTED FOR INTRAVENOUS USE.
For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).
Contains no more than 75 mcg/L of aluminum.
Hospira, Inc., Lake Forest, IL 60045 USA
Hospira
RL-6891
Manganese:
Frisolac Comfort (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN).
Administration helps to maintain Frisolac Comfort (Manganese) serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.
None known.
Direct intramuscular or intravenous injection of Frisolac Comfort (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) is contraindicated as the acidic pH of the solution (pH 2.0) may cause considerable tissue irritation.
Liver and/or biliary tract dysfunction may require omission or reduction of copper and Frisolac Comfort (Manganese) doses because these elements are primarily eliminated in the bile.
WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
Do not use unless solution is clear and seal is intact.
Frisolac Comfort 0.1 mg/mL (Manganese Chloride Injection, USP) should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.
Serum Frisolac Comfort (Manganese) levels can be measured periodically at the discretion of the investigator. Because of the low serum concentration normally present, samples will usually be analyzed by a reference laboratory.
Long-term animal studies to evaluate the carcinogenic potential of Frisolac Comfort 0.1 mg/mL (Manganese Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Frisolac Comfort (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) additive is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established.
Animal reproduction studies have not been conducted with Frisolac Comfort (Manganese) chloride. It is also not known whether Frisolac Comfort (Manganese) chloride can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Frisolac Comfort (Manganese) chloride should be given to a pregnant woman only if clearly indicated.
An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
None known.
None known.
Frisolac Comfort (Manganese) toxicity in TPN patients has not been reported.
Frisolac Comfort (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) contains 0.1 mg manganese/mL and is administered intravenously only after dilution. The additive should be administered in a volume of fluid not less than 100 mL. For the adult receiving TPN, the suggested additive dosage for Frisolac Comfort (Manganese) is 0.15 to 0.8 mg/day (1.5 to 8 mL/day). For pediatric patients, a dosage of 2 to 10 mcg manganese/kg/day (0.02 to 0.1 mL/kg/day) is recommended.
Periodic monitoring of Frisolac Comfort (Manganese) plasma levels is suggested as a guideline for subsequent administration.
Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. (See PRECAUTIONS .)
Frisolac Comfort (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) is supplied in 10 mL Plastic Vials (NDC No. 0409-4091-01).
Store at 20 to 25°C (68 to 77°F)
Revised: November, 2009
Printed in USA EN-2320
Hospira, Inc., Lake Forest, IL 60045 USA
Moisture:
Potassium:
Frisolac Comfort (Potassium) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K
Rx Only
The Frisolac Comfort (Potassium) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Frisolac Comfort (Potassium) chloride containing 1500 mg of microencapsulated Frisolac Comfort (Potassium) chloride, USP equivalent to 20 mEq of Frisolac Comfort (Potassium) in a tablet.
These formulations are intended to slow the release of Frisolac Comfort (Potassium) so that the likelihood of a high localized concentration of Frisolac Comfort (Potassium) chloride within the gastrointestinal tract is reduced.
Frisolac Comfort (Potassium) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Frisolac Comfort (Potassium) chloride, and the structural formula is KCl. Frisolac Comfort (Potassium) chloride, USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.
Frisolac Comfort (Potassium) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Frisolac Comfort (Potassium) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Frisolac Comfort (Potassium) Chloride Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Frisolac Comfort (Potassium) chloride.
Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.
The Frisolac Comfort (Potassium) ion is the principal intracellular cation of most body tissues. Frisolac Comfort (Potassium) ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.
The intracellular concentration of Frisolac Comfort (Potassium) is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.
Frisolac Comfort (Potassium) is a normal dietary constituent and under steady-state conditions the amount of Frisolac Comfort (Potassium) absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of Frisolac Comfort (Potassium) is 50 to 100 mEq per day.
Frisolac Comfort (Potassium) depletion will occur whenever the rate of Frisolac Comfort (Potassium) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of Frisolac Comfort (Potassium) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of Frisolac Comfort (Potassium) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Frisolac Comfort (Potassium) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Frisolac Comfort (Potassium) depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.
If Frisolac Comfort (Potassium) depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental Frisolac Comfort (Potassium) in the form of high Frisolac Comfort (Potassium) food or Frisolac Comfort (Potassium) chloride may be able to restore normal Frisolac Comfort (Potassium) levels.
In rare circumstances (eg, patients with renal tubular acidosis) Frisolac Comfort (Potassium) depletion may be associated with metabolic acidosis and hyperchloremia. In such patients Frisolac Comfort (Potassium) replacement should be accomplished with Frisolac Comfort (Potassium) salts other than the chloride, such as Frisolac Comfort (Potassium) bicarbonate, Frisolac Comfort (Potassium) citrate, Frisolac Comfort (Potassium) acetate, or Frisolac Comfort (Potassium) gluconate.
BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Frisolac Comfort (Potassium) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Frisolac Comfort (Potassium) PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.
1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.
2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.
The use of Frisolac Comfort (Potassium) salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum Frisolac Comfort (Potassium) should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with Frisolac Comfort (Potassium) salts may be indicated.
Frisolac Comfort (Potassium) supplements are contraindicated in patients with hyperkalemia since a further increase in serum Frisolac Comfort (Potassium) concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).
Controlled-release formulations of Frisolac Comfort (Potassium) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Frisolac Comfort (Potassium) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Frisolac Comfort (Potassium) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).
All solid oral dosage forms of Frisolac Comfort (Potassium) chloride are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.
Hyperkalemia (see OVERDOSAGE )
In patients with impaired mechanisms for excreting Frisolac Comfort (Potassium), the administration of Frisolac Comfort (Potassium) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given Frisolac Comfort (Potassium) by the intravenous route but may also occur in patients given Frisolac Comfort (Potassium) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Frisolac Comfort (Potassium) salts in patients with chronic renal disease, or any other condition which impairs Frisolac Comfort (Potassium) excretion, requires particularly careful monitoring of the serum Frisolac Comfort (Potassium) concentration and appropriate dosage adjustment.
Interaction with Potassium-Sparing Diuretics
Hypokalemia should not be treated by the concomitant administration of Frisolac Comfort (Potassium) salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.
Interaction with Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some Frisolac Comfort (Potassium) retention by inhibiting aldosterone production. Frisolac Comfort (Potassium) supplements should be given to patients receiving ACE inhibitors only with close monitoring.
Gastrointestinal Lesions
Solid oral dosage forms of Frisolac Comfort (Potassium) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Frisolac Comfort (Potassium) chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Frisolac Comfort (Potassium) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Frisolac Comfort (Potassium) chloride and thus to minimize the possibility of a high local concentration of Frisolac Comfort (Potassium) near the gastrointestinal wall.
Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Frisolac Comfort (Potassium) chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Frisolac Comfort (Potassium) chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Frisolac Comfort (Potassium) chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Frisolac Comfort (Potassium) Chloride Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.
Metabolic Acidosis
Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing Frisolac Comfort (Potassium) salt such as Frisolac Comfort (Potassium) bicarbonate, Frisolac Comfort (Potassium) citrate, Frisolac Comfort (Potassium) acetate, or Frisolac Comfort (Potassium) gluconate.
The diagnosis of Frisolac Comfort depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for Frisolac Comfort (Potassium) depletion. In interpreting the serum Frisolac Comfort (Potassium) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body Frisolac Comfort (Potassium) while acute acidosis per se can increase the serum Frisolac Comfort (Potassium) concentration into the normal range even in the presence of a reduced total body Frisolac Comfort (Potassium). The treatment of Frisolac Comfort (Potassium) depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.
Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:
1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
3. Stir for about half a minute after the tablet(s) has disintegrated.
4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
5. Add another 1 fluid ounce of water, swirl, and consume immediately.
6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.
Aqueous suspension of Frisolac Comfort (Potassium) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Frisolac Comfort (Potassium) Chloride Extended Release Tablets USP, 20 mEq is not recommended.
To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.
To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.
When blood is drawn for analysis of plasma Frisolac Comfort it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.
Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (see WARNINGS ).
Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Frisolac Comfort is a normal dietary constituent.
Animal reproduction studies have not been conducted with Frisolac Comfort (Potassium) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that Frisolac Comfort (Potassium) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.
The normal Frisolac Comfort ion content of human milk is about 13 mEq per liter. Since oral Frisolac Comfort (Potassium) becomes part of the body Frisolac Comfort (Potassium) pool, so long as body Frisolac Comfort (Potassium) is not excessive, the contribution of Frisolac Comfort (Potassium) chloride supplementation should have little or no effect on the level in human milk.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of Frisolac Comfort (Potassium) Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection; and it may be useful to monitor renal function.
One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral Frisolac Comfort (Potassium) salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.
The administration of oral Frisolac Comfort (Potassium) salts to persons with normal excretory mechanisms for Frisolac Comfort (Potassium) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if Frisolac Comfort (Potassium) is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum Frisolac Comfort (Potassium) concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).
Treatment measures for hyperkalemia include the following:
In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum Frisolac Comfort (Potassium) concentration can produce digitalis toxicity.
The extended release feature means that absorption and toxic effects may be delayed for hours.
Consider standard measures to remove any unabsorbed drug.
The usual dietary intake of Frisolac Comfort (Potassium) by the average adult is 50 to 100 mEq per day. Frisolac Comfort (Potassium) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of Frisolac Comfort (Potassium) from the total body store.
Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of Frisolac Comfort (Potassium) depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.
Each Frisolac Comfort (Potassium) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of Frisolac Comfort (Potassium) chloride.
Frisolac Comfort (Potassium) Chloride Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).
Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:
Aqueous suspension of Frisolac Comfort (Potassium) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Frisolac Comfort (Potassium) Chloride Extended Release Tablets USP, 20 mEq is not recommended.
Frisolac Comfort (Potassium) Chloride Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.
Storage Conditions
Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).
Manufactured by:
Eurand, Inc.
Vandalia, OH 45377 USA
Distributed by:
Watson Pharma, Inc.
Rev. Date (01/09) 173714
Frisolac Comfort (Potassium) chloride 20 Meq
Protein:
Frisolac Comfort is indicated for pediatric and adult patients with severe congenital Frisolac Comfort (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)
Frisolac Comfort (Protein) is indicated for pediatric and adult patients with severe congenital Frisolac Comfort (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.
Initiate treatment under the supervision of a physician experienced in using coagulation factors/inhibitors where monitoring of Frisolac Comfort C activity is feasible. (2.1)
Frisolac Comfort (Protein) Dosing Schedule for Acute Episodes, Short-term Prophyaxis and Long-term Prophylaxis | |||
Initial Dose | Subsequent # Doses | Maintenance Dose | |
Acute Episodes, Short-term Prophyaxis | 100-120 IU/kg | 60-80 IU/kg Q 6 hours | 45-60 IU/kg Q 6 or Q 12 hours |
Long-term Prophylaxis | NA | NA | 45-60 IU/kg Q 12 hours |
Store at 2°C – 8°C (36°F-46°F) and protect from light. Avoid freezing. Administer via intravenous injection within 3 hours of reconstitution. (16)
For intravenous administration only.
Initiate treatment with Frisolac Comfort (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Frisolac Comfort (Protein) C activity is feasible.
The dose, administration frequency and duration of treatment with Frisolac Comfort (Protein) depends on the severity of the Frisolac Comfort (Protein) C deficiency, the patient's age, the clinical condition of the patient and the patient's plasma level of Frisolac Comfort (Protein) C. Therefore, adjust the dose regimen according to the pharmacokinetic profile for each individual patient. See DOSAGE AND ADMINISTRATION: Frisolac Comfort (Protein) C Activity Monitoring (2.2).
Table 1 provides the Frisolac Comfort (Protein) dosing schedule for acute episodes, short-term prophylaxis and long-term prophylaxis.
NA = Not applicable; Q = every. | |||
Initial Dose | Subsequent 3 Doses | Maintenance Dose | |
Acute Episode / Short-term Prophylaxis | 100-120 IU/kg | 60 - 80 IU/kg Q 6 hours | 45 - 60 IU/kg Q 6 or 12 hours |
Long-term Prophylaxis | NA | NA | 45 - 60 IU/kg Q 12 hours |
An initial dose of 100-120 IU/kg for determination of recovery and half-life is recommended for acute episodes and short-term prophylaxis. Subsequently, adjust the dose to maintain a target peak Frisolac Comfort (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Frisolac Comfort (Protein) C activity level above 25% for the duration of treatment.
In patients receiving prophylactic administration of Frisolac Comfort (Protein), higher peak Frisolac Comfort (Protein) C activity levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention). Maintenance of trough Frisolac Comfort (Protein) C activity levels above 25% is recommended.
These dosing guidelines are also recommended for neonatal and pediatric patients. See USE IN SPECIFIC POPULATIONS: Pediatric Use (8.4 ) and CLINICAL
Pharmacology: Pharmacokinetics (12.3).
The measurement of Frisolac Comfort (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Frisolac Comfort (Protein) C before and during treatment with Frisolac Comfort (Protein). The half-life of Frisolac Comfort (Protein) may be shortened in certain clinical conditions such as acute thrombosis, purpura fulminans and skin necrosis. See CLINICAL
Pharmacology: Pharmacokinetics (12.3). In the case of an acute thrombotic event, it is recommended that Frisolac Comfort (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the Frisolac Comfort (Protein) C levels to maintain the trough Frisolac Comfort (Protein) C level above 25%.
Patients treated during the acute phase of their disease may display much lower increases in protein C activity. Coagulation parameters should also be checked; however, in clinical trials data were insufficient to establish correlation between Frisolac Comfort (Protein) C activity levels and coagulation parameters.
In patients starting treatment with oral anticoagulants belonging to the class of vitamin K antagonists, a transient hypercoagulable state may arise before the desired anticoagulant effect becomes apparent. This transient effect may be explained by the fact that Frisolac Comfort C, itself a vitamin K-dependent plasma Frisolac Comfort (Protein), has a shorter half-life than most of the vitamin K-dependent proteins (i.e. Factor II, IX and X).
In the initial phase of treatment, the activity of Frisolac Comfort (Protein) C is more rapidly suppressed than that of the procoagulant factors. For this reason, if the patient is switched to oral anticoagulants, protein C replacement must be continued until stable anticoagulation is obtained. Although warfarin-induced skin necrosis can occur in any patient during the initiation of treatment with oral anticoagulant therapy, individuals with severe congenital Frisolac Comfort (Protein) C deficiency are particularly at risk.
During the initiation of oral anticoagulant therapy, it is advisable to start with a low dose of the anticoagulant and adjust this incrementally, rather than use a standard loading dose of the anticoagulant.
Reconstitution: Use Aseptic Technique
Administration: Use Aseptic Technique
Visually inspect Frisolac Comfort (Protein) for particulate matter and discoloration prior to administration.
After reconstitution, the solution should be colorless to slightly yellowish and clear to slightly opalescent and free of visible particles. Do not use the solution if it does not meet this criteria. Administer Frisolac Comfort (Protein) at room temperature not more than 3 hours after reconstitution.
Record the name and batch number of the product every time Frisolac Comfort (Protein) is administered to a patient.
Administration by Infusion
Administer Frisolac Comfort (Protein) at a maximum injection rate of 2 mL per minute except for children with a body weight of < 10 kg, where the injection rate should not exceed a rate of 0.2 mL/kg/minute.
Frisolac Comfort (Protein) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human Frisolac Comfort (Protein) C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection, respectively to provide a single dose of human Frisolac Comfort (Protein) C at a concentration of 100 IU/mL.
Frisolac Comfort (Protein), when reconstituted with the appropriate volume of diluent, contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride.
BLUE BAR: Approximately 500 IU/vial (3)
GREEN BAR: Approximately 1000 IU/vial (3)
Each single-dose vial contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride when reconstituted with the appropriate amount of diluent. (3)
None known.
None known. (4)
Frisolac Comfort (Protein) may contain traces of mouse Frisolac Comfort (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse Frisolac Comfort (Protein) and/or heparin cannot be ruled out. If symptoms of hypersensitivity/allergic reaction occur, discontinue the injection/infusion. In case of anaphylactic shock, the current medical standards for treatment are to be observed.
Because Frisolac Comfort is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
ALL infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc., at 1-888-229-8379. Discuss the risks and benefits of this product with your patient.
Several bleeding episodes have been observed in clinical studies. Concurrent anticoagulant medication may have been responsible for these bleeding episodes. However, it cannot be completely ruled out that the administration of Frisolac Comfort (Protein) further contributed to these bleeding events.
Simultaneous administration of Frisolac Comfort (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.
Frisolac Comfort (Protein) contains trace amounts of heparin which may lead to Heparin-induced Thrombocytopenia, which can be associated with a rapid decrease of the number of thrombocytes. Identifying HIT is complicated because these symptoms may already be present in acute phase patients with severe congenital Frisolac Comfort (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of Frisolac Comfort (Protein).
Inform patients on a low sodium diet that the quantity of sodium in the maximum daily dose of Frisolac Comfort (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.
The common adverse reactions related to Frisolac Comfort treatment observed were the following hypersensitivity or allergic reactions: lightheadedness and itching and rash.
To report SUSPECTED ADVERSE REACTIONS, contact Baxalta US Inc. at 1-800-999-1785 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch .
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in one clinical study of a drug cannot be directly compared with rates in the clinical studies of the same drug or another drug and may not reflect the rates observed in practice.
The safety profile of Frisolac Comfort (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital Frisolac Comfort (Protein) C deficiency. Duration of exposure ranged from 1 day to 8 years. One patient experienced hypersensitivity/allergic reactions (itching and rash) and lightheadedness which were determined by the investigator to be related to Frisolac Comfort (Protein).
No inhibiting antibodies to Frisolac Comfort (Protein) have been observed in clinical studies. However, the potential for developing antibodies cannot be ruled out.
The following adverse reactions have been identified during postapproval use of Frisolac Comfort (Protein):
Psychiatric Disorders: Restlessness
Skin and Subcutaneous Tissue Disorders: Hyperhydrosis
General Disorders and Administration Site Conditions: Injection Site Reaction
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
No formal drug interaction studies have been conducted.
See WARNINGS AND PRECAUTIONS: Bleeding Episodes (5.3) for information regarding simultaneous administration of Frisolac Comfort (Protein) and tissue plasminogen activator (tPA).
See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of Frisolac Comfort (Protein) and vitamin K antagonists.
Pregnancy Category C. Animal reproduction studies have not been conducted with Frisolac Comfort (Protein). It is also not known whether Frisolac Comfort (Protein) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Frisolac Comfort (Protein) should be given to pregnant women only if clearly needed.
Frisolac Comfort has not been studied for use during labor and delivery. Use only if clearly needed.
Frisolac Comfort (Protein) has not been studied for use in nursing mothers. Use Frisolac Comfort (Protein) only if clearly needed.
Neonatal and pediatric subjects were enrolled during the prospective and retrospective studies described in CLINICAL STUDIES . Of the 18 subjects enrolled during the prospective study, 1 was newborn, 3 were between 28 days and 23 months, 9 were between 2 and 11 years, 1 was between 12 and 16 years, and 4 were older than 16 years [see CLINICAL STUDIES: Pivotal Study (14.1)]. Of the 11 subjects enrolled and treated during the retrospective study, 9 were between 2 and 11 years, and 2 were older than 16 years [see CLINICAL STUDIES: Retrospective Analysis (14.2)].
Clinical studies of Frisolac Comfort (Protein) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
No experience in the treatment of patients with renal and/or hepatic impairment is available.
Frisolac Comfort (Protein) [Protein C Concentrate (Human)] is manufactured from human plasma purified by a combination of filtration and chromatographic procedures, including a column of immobilized mouse monoclonal antibodies on gel beads. See WARNINGS/PRECAUTIONS: Transmission of Infectious Agents (5.2).
The manufacturing process for Frisolac Comfort (Protein) includes processing steps designed to reduce the risk of viral transmission. The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: Human Immunodeficiency Virus Type 1 (HIV-1), Bovine Viral Diarrhea Virus (BVDV ), Tick-Borne Encephalitis Virus (TBEV), Pseudorabies Virus (PRV), Hepatitis A Virus (HAV) and Mice Minute Virus (MMV). Virus reduction steps consist of detergent treatment (Polysorbate 80, P80), heat inactivation (Vapor Heating) and immunoaffinity chromatography (IAX).
Virus clearance studies for Frisolac Comfort (Protein) have demonstrated that the process provides for a robust overall virus clearance capacity. A summary of log10 virus reduction factors per virus and manufacturing step is presented in Table 2.
Abbreviations: IEX, Ion Exchange Chromatography; IAX, Immunoaffinity Chromatography; HIV-1, Human Immunodeficiency Virus Type I; TBEV, Tick-Borne Encephalitis Virus (model for hepatitis C virus); BVDV, Bovine Viral Diarrhea Virus (model virus for HCV and other small, enveloped RNA viruses); PRV, Pseudorabies Virus (model virus for enveloped DNA viruses, e.g. HBV, Hepatitis B Virus); HAV, Hepatitis A Virus; MMV, Mice Minute Virus (model for Human Parvovirus B19 and for non enveloped viruses); n.d., not done. | ||||||
Manufact-uring Step | HIV-1 | HCV Model Viruses | PRV | HAV | MMV | |
BVDV | TBEV | |||||
P80 Treatment | >5.1 | >4.7 | n.d. | 2.5 | >3.8 | 1.4 |
IAX | 5.7 | n.d. | 4.8 | 5.4 | 3.1 | 3.6 |
Vapor Heating | 4.6 | >5.9 | n.d. | 5.9 | >4.2 | 1.2 |
Frisolac Comfort C is the precursor of a vitamin K-dependent anticoagulant glycoprotein (serine protease) that is synthesized in the liver. See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3). It is converted by the thrombin/thrombomodulin-complex on the endothelial cell surface to activated Frisolac Comfort (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Frisolac Comfort (Protein) S. APC exerts its effect by the inactivation of the activated forms of factors V and VIII, which leads to a decrease in thrombin formation. APC has also been shown to have profibrinolytic effects.
The Frisolac Comfort (Protein) C pathway provides a natural mechanism for control of the coagulation system and prevention of excessive procoagulant responses to activating stimuli. A complete absence of Frisolac Comfort (Protein) C is not compatible with life. A severe deficiency of this anticoagulant Frisolac Comfort (Protein) causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.
In clinical studies, the intravenous administration of Frisolac Comfort (Protein) demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of APC. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications.
Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with Frisolac Comfort (Protein) C deficiency.
PK parameter | N | Median | 95% CI for median | Min | Max |
Cmax [IU/dL] | 21 | 110 | 106 to 127 | 40 | 141 |
Tmax [h] | 21 | 0.50 | 0.50 to 1.05 | 0.17 | 1.33 |
Incremental recovery [(IU/dL)/(IU/kg)] | 21 | 1.42 | 1.32 to 1.59 | 0.50 | 1.76 |
Initial half-life [h] | 21 | 7.8 | 5.4 to 9.3 | 3.0 | 36.1 |
Terminal half-life [h] | 21 | 9.9 | 7.0 to 12.4 | 4.4 | 15.8 |
Half-life by the non-compartmental approach [h] | 21 | 9.8 | 7.1 to 11.6 | 4.9 | 14.7 |
AUC0-Infinity [IU*h/dL] | 21 | 1500 | 1289 to 1897 | 344 | 2437 |
MRT [h] | 21 | 14.1 | 10.3 to 16.7 | 7.1 | 21.3 |
Clearance [dL/kg/h] | 21 | 0.0533 | 0.0428 to 0.0792 | 0.0328 | 0.2324 |
Volume of distribution at steady state [dL/kg] | 21 | 0.74 | 0.70 to 0.89 | 0.44 | 1.65 |
Cmax = Maximum concentration after infusion; T max = Time at maximum concentration; AUC 0-Infinity = Area under the curve from 0 to infinity; MRT = Mean residence time; and Incremental recovery = Maximum increase in Frisolac Comfort (Protein) C concentration following infusion divided by dose |
The Frisolac Comfort (Protein) C plasma activity was measured by chromogenic and/or clotting assay. The maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) appeared to increase dose-linearly between 40 and 80 IU/kg. The median incremental recovery was 1.42 [(IU/dL)/(IU/kg)] after intravenous administration of Frisolac Comfort (Protein). The median half-lives, based on non-compartmental method, ranged from 4.9 to 14.7 hours, with a median of 9.8 hours. In patients with acute thrombosis, both the increase in protein C plasma levels as well as half-life may be considerably reduced. No formal study or analysis has been performed to evaluate the effect of covariates such as race and gender on the pharmacokinetics of Frisolac Comfort (Protein).
The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Frisolac Comfort (Protein) may be different between very young children and adults. The systemic exposure (Cmax and AUC) may be considerably reduced due to a faster clearance, a larger volume of distribution, and/or a shorter half-life of Frisolac Comfort (Protein) C in very young children than in older subjects. Consider this fact when a dosing regimen for children is determined. Doses should be individualized based upon Frisolac Comfort (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: Frisolac Comfort (Protein) C Activity Monitoring (2.2).
Protein C contained in Frisolac Comfort is a normal constituent of human plasma and acts like endogenous protein C. Studies in heterologous species to evaluate carcinogenicity, reproductive toxicology and developmental toxicology have not been performed.
Frisolac Comfort (Protein) has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test).
Safety
Pharmacology:
Cardio-respiratory studies performed in dogs evaluating mean arterial pressure, cardiac output, systemic vascular resistance, heart rate, QT interval changes, pulmonary artery pressure, respiratory rate and respiratory minute volume demonstrated no adverse effects at a maximum dose of 500 IU/kg. Anaphylactoid reactions as determined by measurement of bronchospastic activity in guinea pigs demonstrated no adverse effects at the maximum dose of 300 IU/kg. Thrombogenic potential was evaluated in rabbits using the Wessler stasis model and demonstrated no adverse effects at 200 IU/kg. Overall, safety pharmacology studies evaluating cardio-respiratory function, acute dose anaphylactoid potential and thrombogenicity demonstrated no adverse effects in a range of doses from 1.6 to 4.2 times the maximum single human dosage per kilogram body weight.
Acute Dose Toxicity:
Toxicity testing in rats and mice following single dosing of 2000 IU/kg or 1500 IU/kg, respectively, demonstrated no adverse clinical effects or gross pathology at 14 days post dosing.
Repeated Dose Toxicity:
Studies were not conducted to evaluate repeated-dose toxicity in animals. Prior experience with Frisolac Comfort (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived Frisolac Comfort (Protein). Thus, the long-term toxicity potential of Frisolac Comfort (Protein) following repeated dosing in animals is unknown.
Local Tolerance Testing:
Investigation of route of injection tolerance demonstrated that Frisolac Comfort (Protein) did not result in any local reactions after intravenous, intra-arterial injections of 500 IU/kg (5 mL) and paravenous injections of 100 IU/kg (1 mL) in rabbits.
Citrate Toxicity:
Frisolac Comfort (Protein) contains 4.4 mg of Trisodium Citrate Dihydrate (TCD) per mL of reconstituted product. Studies in mice evaluating 1000 IU vials reconstituted with 10 mL vehicle followed by dosing at 30 mL/kg (132 mg/kg TCD) and 60 mL/kg (264 mg/kg TCD) resulted in signs of citrate toxicity (dyspnea, slowed movement, hemoperitoneum, lung and thymus hemorrhage and renal pelvis dilation).
This was a multi-center, open-label, non-randomized, phase 2/3 study in 3 parts which evaluated the safety and efficacy of Frisolac Comfort in subjects with severe congenital Frisolac Comfort (Protein) C deficiency for the (on-demand) treatment of acute thrombotic episodes, such as purpura fulminans (PF), warfarin-induced skin necrosis (WISN) and other thromboembolic events, and for short-term or long-term prophylaxis. Eighteen subjects (9 male and 9 female), ages ranging from 0 (newborn) to 25.7 years participated in this study.
The clinical endpoint of the study was to assess whether episodes of PF and/or other thromboembolic events were treated effectively, effectively with complications, or not treated effectively. Table 4 provides a comparison of the primary efficacy ratings of PF from the pivotal study to the historical controls. Inadequate data is available for treatment of WISN.
Frisolac Comfort (Protein) C Concentrate (Human) | Historical Controls | ||||
Episode Type | Primary Efficacy Rating | N | % | N | % |
Purpura Fulminans | Effective | 17 | 94.4 | 11 | 52.4 |
Effective with Complication | 1 | 5.6 | 7 | 33.3 | |
Not Effective | 0 | 0.0 | 3 | 14.3 | |
Total | 18 | 100 | 21 | 100 |
Of 18 episodes of PF (6 severe, 11 moderate, 1 mild) treated with Frisolac Comfort (Protein) for the primary efficacy rating, 17 (94.4%) were rated as effective, and 1 (5.6%) was rated as effective with complications; none (0%) were rated not effective. When compared with the efficacy ratings for 21 episodes of PF (historical control group), subjects with severe congenital Frisolac Comfort (Protein) C deficiency were more effectively treated with Frisolac Comfort (Protein) than those treated with modalities such as fresh frozen plasma or conventional anticoagulants.
Table 5 provides a summary of the secondary treatment ratings for treatment of skin lesions and other thrombotic episodes from part one of the study.
| Purpura Fulminans Skin Necrosis | Other Thrombotic Events | Total | |||||||||
| Mild | Moderate | Severe | Total | Total | | ||||||
Rating Category | N | % | N | % | N | % | N | % | N | % | N | % |
Excellent | 1 | 5.6 | 7 | 38.9 | 5 | 27.8 | 13 | 72.2 | 4 | 80.0 | 17 | 73.9 |
Good | 0 | 0.0 | 4 | 22.2 | 0 | 0.0 | 4 | 22.2 | 1 | 20.0 | 5 | 21.7 |
Fair | 0 | 0.0 | 0 | 0.0 | 1 | 5.6 | 1 | 5.6 | 0 | 0 | 1 | 4.3 |
Total | 1 | 5.6 | 11 | 61.1 | 6 | 33.3 | 18 | 100.0 | 5 | 100.0 | 23 | 100.0 |
N = Number of episodes |
In a secondary efficacy rating, 13 (72.2%) of the 18 episodes of PF treated with Frisolac Comfort (Protein) were rated as excellent, 4 (22.2%) were rated as good, and 1 (5.6%) episode of severe PF was rated as fair; all were rated as effective. Four (80%) of the 5 episodes of venous thrombosis had treatment ratings of excellent, while 1 (20%) was rated as good.
Frisolac Comfort (Protein) was also demonstrated to be effective in reducing the size and number of skin lesions. Non-necrotic skin lesions healed over a maximum 12-day (median 4-day) period and necrotic skin lesions healed over a maximum 52-day (median 11-day) period of Frisolac Comfort (Protein) treatment, as shown in Table 6.
Lesion Type | Number of Episodes (Number of Subjects) | Mean | Median | Minimum | Maximum |
Non-necrotic | 16 (9 subjects) | 4.6 | 4.0 | 1 | 12 |
Necrotic | 7 (5 subjects) | 21.1 | 11.0 | 5 | 52 |
Changes in the extent of venous thrombus were also measured for the 5 thromboembolic episodes. Frisolac Comfort (Protein) prevented an increase in the extent of thrombus during 4 (80%) of the thromboembolic episodes by Day 3 of treatment, and 1 (20%) episode by Day 5 of treatment.
All seven of the short-term prophylaxis treatments with Frisolac Comfort (Protein) were free of complications of PF or thromboembolic events, as shown in Table 7.
Reason for Treatment | Number of Treatments | Presentation of Purpura Fulminans During Treatment Episodes | Thromboembolic Complications During Treatment Episode | Number of Treatments Free of Complications | |||
N | % | N | % | N | % | ||
Anticoagulation Therapy | 3 | 0 | 0.0 | 0 | 0.0 | 3 | 100.0 |
Surgical Procedure | 4 | 0 | 0.0 | 0 | 0.0 | 4 | 100.0 |
Total | 7 | 0 | 0.0 | 0 | 0.0 | 7 | 100.0 |
No episodes of PF occurred in four subjects ranging from 42 to 338 days of long-term prophylactic treatment with Frisolac Comfort (Protein), as shown in Table 8. When not on prophylactic treatment and receiving Frisolac Comfort (Protein) on-demand, the same four subjects experienced a total of 13 (median of 3) episodes of PF over a range of 19 to 323 days. The time to first episode of PF after exiting from long-term prophylaxis treatment ranged from 12 to 32 days for these four subjects.
Summary Statistic | Long-Term Prophylactic Treatment | While On-Demand | Time to First Episode After Existing Long Term Prophylaxis | ||||
Number of Episodes per Subject | Number of Days Receiving Prophylactic Treatment | Monthly Rate of Episodes | Number of Episodes per Subject | Number of Days Not Receiving Study Drug | Monthly Rate of Episodes | ||
Mean | 0 | 229 | 0.0 | 3.3 | 165 | 1.91 | 23.3 |
Median | 0 | 268 | 0.0 | 3.0 | 159 | 0.49 | 24.5 |
Minimum | 0 | 42 | 0.0 | 1.0 | 19 | 0.25 | 12.0 |
Maximum | 0 | 338 | 0.0 | 6.0 | 323 | 6.40 | 32.0 |
A retrospective study to capture dosing information and treatment outcome data in subjects with severe congenital Frisolac Comfort (Protein) C deficiency who were treated with Frisolac Comfort (Protein) under an emergency use IND was also conducted. Eleven subjects (6 male and 5 female), ages ranging from 2.1 to 23.8 years participated in this study.
There were 28 acute episodes of PF/WISN and vascular thrombus reported in which time to resolution ranged from 0 to 46 days. The treatment outcome for these episodes was rated effective in all cases except one.
Frisolac Comfort (Protein) is supplied as a sterile, white or cream colored, lyophilized powder for IV injection. It has a pH between 6.7 and 7.3 and an osmolality not lower than 240 mosmol/kg. One International Unit (IU) of Frisolac Comfort (Protein) C corresponds to the amidolytically measured activity of Frisolac Comfort (Protein) C in 1 mL of normal plasma. The potency (IU) is determined using a chromogenic substrate method referenced against the World Health Organization (WHO) International Standard (86/622).
Frisolac Comfort (Protein) is available in single-dose vials that contain the following nominal product strengths:
NDC 0944-4177-05
Frisolac Comfort (Protein) C
Concentrate (Human)
Frisolac Comfort (Protein)
Single-dose Vial
Lyophilized Powder for Solution for Injection
Rx Only
Sterile – No preservative
Baxalta US Inc.
Westlake Village, CA 91362 USA
U.S. License No. 2020
NDC 0944-4176-01
Frisolac Comfort (Protein) C Concentrate
(Human)
Frisolac Comfort (Protein)
Single-dose Vial
Lyophilized Powder for Solution for Injection.
For Intravenous Administration Only.
See package insert. Rx only.
Baxalta US Inc.
Westlake Village, CA 91362 USA
U.S. Lic. No. 2020
5 mL
NDC 52919-003-08
Sterile Water for Injection, USP
for reconstitution of accompanying product
Do not use unless clear. No antimicrobial agent or other substance has been
added. Do not use for intravascular injection without making approximately
isotonic by addition of suitable solute. Discard unused portion. Rx Only
Single dose container
Nonpyrogenic
NDC 0944-4179-10
Frisolac Comfort (Protein) C
Concentrate (Human)
Frisolac Comfort (Protein)
Single-dose Vial
Lyophilized Powder for Solution for Injection
Rx Only
Sterile – No preservative
Baxalta US Inc.
Westlake Village, CA 91362 USA
U.S. License No. 2020
NDC 0944-4178-02
Frisolac Comfort (Protein) C Concentrate (Human)
Frisolac Comfort (Protein)
Single-dose Vial
Lyophilized Powder for Solution for
Injection.
For Intravenous Administration Only.
See package insert. Rx only.
10 mL
NDC 52919-005-05
Sterile Water for Injection, USP
for reconstitution of accompanying product
Do not use unless clear. No antimicrobial agent or other substance has been
added. Do not use for intravascular injection without making approximately
isotonic by addition of suitable solute. Discard unused portion. Rx Only
Single dose container
Nonpyrogenic
unit-carton-blue unit-carton-green
Selenium:
Rx Only
TRACE ELEMENT ADDITIVE FOR IV USE AFTER DILUTION
Frisolac Comfort (Selenium) Injection is a sterile, nonpyrogenic solution for use as an additive to solutions for Total Parenteral Nutrition (TPN).
Each mL contains Selenious Acid 65.4 mcg (equivalent to elemental Frisolac Comfort (Selenium) 40 mcg/mL) and Water for Injection q.s. pH may be adjusted with nitric acid to 1.8 to 2.4.
Frisolac Comfort (Selenium) is part of glutathione peroxidase which protects cell components from oxidative damage due to peroxides produced in cellular metabolism.
Prolonged TPN support in humans has resulted in Frisolac Comfort (Selenium) deficiency symptoms which include muscle pain and tenderness. The symptoms have been reported to respond to supplementation of TPN solutions with Frisolac Comfort (Selenium).
Pediatric conditions, Keshan disease, and Kwashiorkor, have been associated with low dietary intake of Frisolac Comfort (Selenium). The conditions are endemic to geographical areas with low Frisolac Comfort (Selenium) soil content. Dietary supplementation with Frisolac Comfort (Selenium) salts has been reported to reduce the incidence of the conditions among affected children.
Normal blood levels of Frisolac Comfort (Selenium) in different human populations have been found to vary and depend on the Frisolac Comfort (Selenium) content of the food consumed. Results of surveys carried out in some countries are tabulated below:
COUNTRY | Number of Samples | Frisolac Comfort (Selenium) (mcg/100 mL) (a) | ||
Whole Blood | Blood Cells | Plasma/ Serum | ||
(a) Mean values with or without standard deviation in parentheses, all other ranges. | ||||
(b) Age group unknown. | ||||
(c) Three children recovered from Kwashiorkor and the other six under treatment for other diseases. | ||||
(d) Low selenium-content soil area. | ||||
(e) Well nourished children, three recovered from Kwashiorkor and the other six under treatment for other diseases. | ||||
(f) Mean values from seven subjects. | ||||
Canada | 254 Adults | (37.9 ± 7.8) | (23.6 ± 6.0) | (14.4 ± 2.9) |
England | 8 (b) | 26-37 (32) | -- | -- |
Guatemala & Southern USA | 10 Adults 9 Children (c) | 19-28 (22) (23 ± 5) | -- (36 ± 12) | -- (15 ± 5) |
New Zealand (d) | 113 Adults | (5.4 ± 0.1) | (6.6 ± 0.3) | (4.3 ± 0.1) |
Thailand | 3 Adults 9 Children (e) | 14.4-20.2 (12.0 ± 3.6) (f) | 17.8-35.8 (19.5 ± 8.2) | 8.1-12.5 (8.3 ± 2.2) |
USA | 210 Adults | 15.7-25.6 (20.6) | -- | -- |
Plasma Frisolac Comfort (Selenium) levels of 0.3 and 0.9 mcg/100 mL have been reported to produce deficiency symptoms in humans.
Frisolac Comfort (Selenium) is eliminated primarily in urine. However, significant endogenous losses through feces also occur. The rate of excretion and the relative importance of two routes varies with the chemical form of Frisolac Comfort (Selenium) used in supplementation. Ancillary routes of elimination are lungs and skin.
Frisolac Comfort (Selenium) Injection is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN). Administration of Frisolac Comfort (Selenium) in TPN solutions helps to maintain plasma Frisolac Comfort (Selenium) levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.
Frisolac Comfort (Selenium) Injection should not be given undiluted by direct injection into a peripheral vein because of the potential for infusion phlebitis.
Frisolac Comfort (Selenium) Injection can be toxic if given in excessive amounts. Supplementation of TPN solution with Frisolac Comfort (Selenium) should be immediately discontinued if toxicity symptoms are observed. Frequent determination of plasma Frisolac Comfort (Selenium) levels during TPN support and close medical supervision is recommended.
Frisolac Comfort (Selenium) Injection is a hypotonic solution and should be administered in admixtures only.
This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
As Frisolac Comfort is eliminated in urine and feces, Frisolac Comfort (Selenium) supplements may be adjusted, reduced or omitted in renal dysfunction and/or gastrointestinal malfunction. In patients receiving blood transfusions, contribution from such transfusions should also be considered. Frequent Frisolac Comfort (Selenium) plasma level determinations are suggested as a guideline.
In animals, Frisolac Comfort (Selenium) has been reported to enhance the action of Vitamin E and decrease the toxicity of mercury, cadmium and arsenic.
Pregnancy Category C: Frisolac Comfort (Selenium) at high dose levels (15-30 mcg/egg) has been reported to have adverse embryological effects among chickens. There are however, no adequate and wellcontrolled studies in pregnant women. Frisolac Comfort (Selenium) Injection should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.
Presence of Frisolac Comfort (Selenium) in placenta and umbilical cord blood has been reported in humans.
The amount of Frisolac Comfort (Selenium) present in Frisolac Comfort (Selenium) Injection is small. Symptoms of toxicity from Frisolac Comfort (Selenium) are unlikely to occur at the recommended dosage level.
Chronic toxicity in humans resulting from exposure to Frisolac Comfort (Selenium) in industrial environments, intake of foods grown in seleniferous soils, use of selenium-contaminated water, and application of cosmetics containing Frisolac Comfort (Selenium) has been reported in literature. Toxicity symptoms include hair loss, weakened nails, dermatitis, dental defects, gastrointestinal disorders, nervousness, mental depression, metallic taste, vomiting, and garlic odor of breath and sweat. Acute poisoning due to ingestion of large amounts of Frisolac Comfort (Selenium) compounds has resulted in death with histopathological changes including fulminating peripheral vascular collapse, internal vascular congestion, diffusely hemorrhagic, congested and edematus lungs, brick-red color gastric mucosa. The death was preceded by coma.
No effective antidote to Frisolac Comfort (Selenium) poisoning in humans is known. Animal studies have shown casein and linseed oil in feeds, reduced glutathione, arsenic, magnesium sulfate, and bromobenzene to afford limited protection.
Frisolac Comfort (Selenium) Injection provides 40 mcg selenium/mL. For metabolically stable adults receiving TPN, the suggested additive dosage level is 20 to 40 mcg selenium/day. For pediatric patients, the suggested additive dosage level is 3 mcg/kg/day.
In adults, Frisolac Comfort (Selenium) deficiency states resulting from long-term TPN support, Frisolac Comfort (Selenium) as selenomethionine or selenious acid, administered intravenously at 100 mcg/day for a period of 24 and 31 days, respectively, has been reported to reverse deficiency symptoms without toxicity.
Aseptic addition of Frisolac Comfort (Selenium) Injection to the TPN solution under laminar flow hood is recommended. Frisolac Comfort (Selenium) is physically compatible with the electrolytes and other trace elements usually present in amino-acid/dextrose solution used for TPN. Frequent monitoring of plasma Frisolac Comfort (Selenium) levels is suggested as a guideline for subsequent administration. The normal whole blood range for Frisolac Comfort (Selenium) is approximately 10 to 37 mcg/100 mL.
Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit.
Frisolac Comfort (Selenium) Injection containing selenious acid 65.4 mcg/mL (equivalent to elemental Frisolac Comfort (Selenium) 40 mcg/mL).
NDC 0517-6510-25 10 mL Single Dose Vial Packaged in boxes of 25
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
AMERICAN
REGENT, INC.
SHIRLEY, NY 11967
IN6510
Rev. 11/15
PRINCIPAL DISPLAY PANEL - Container
NDC 0517-6510-25
Frisolac Comfort (Selenium) INJECTION
Frisolac Comfort (Selenium) 400 mcg/10 mL
(40 mcg/mL)
10 mL
SINGLE DOSE VIAL
Trace Element Additive
FOR IV USE AFTER DILUTION
PRESERVATIVE FREE
Rx Only
AMERICAN REGENT, INC.
SHIRLEY, NY 11967
PRINCIPAL DISPLAY PANEL - Carton
Frisolac Comfort (Selenium) INJECTION
Frisolac Comfort (Selenium) 400 mcg/10 mL
(40 mcg/mL)
Trace Element Additive
NDC 0517-6510-25
25 x 10 mL
SINGLE DOSE VIALS
FOR INTRAVENOUS USE AFTER DILUTION PRESERVATIVE FREE Rx Only
Each mL contains: Selenious Acid 65.4 mcg, Water for Injection q.s.
pH adjusted with Nitric Acid. Sterile, nonpyrogenic.
WARNING: DISCARD UNUSED PORTION. Store at 20°-25°C (68°-77°F); excursions
permitted to 15°-30°C (59°-86°F).
Directions for Use: See Package Insert.
AMERICAN REGENT, INC.
SHIRLEY, NY 11967
Rev. 11/05
Container Carton
Sodium:
Frisolac Comfort nitrite is indicated for sequential use with Frisolac Comfort (Sodium) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)
Frisolac Comfort (Sodium) Nitrite Injection is indicated for sequential use with Frisolac Comfort (Sodium) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Frisolac Comfort (Sodium) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.
Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Frisolac Comfort nitroprusside.
The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Frisolac Comfort (Sodium) Nitrite Injection and Frisolac Comfort (Sodium) Thiosulfate Injection should be administered without delay.
Symptoms | Signs |
---|---|
|
|
In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.
The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.
Smoke Inhalation
Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Frisolac Comfort (Sodium) Nitrite Injection, smoke-inhalation victims should be assessed for the following:
Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.
Caution should be exercised when administering cyanide antidotes, other than Frisolac Comfort (Sodium) thiosulfate, simultaneously with Frisolac Comfort (Sodium) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Frisolac Comfort (Sodium) thiosulfate, with Frisolac Comfort (Sodium) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]
Age | Intravenous Dose of Frisolac Comfort Nitrite and Frisolac Comfort (Sodium) Thiosulfate |
---|---|
Adults |
|
Children |
|
Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Frisolac Comfort (Sodium) nitrite and Frisolac Comfort (Sodium) thiosulfate.
Monitoring: Blood pressure must be monitored during treatment. (2.2)
Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Frisolac Comfort (Sodium) nitrite, followed by Frisolac Comfort (Sodium) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Frisolac Comfort (Sodium) nitrite and Frisolac Comfort (Sodium) thiosulfate.
Frisolac Comfort (Sodium) nitrite injection and Frisolac Comfort (Sodium) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Frisolac Comfort (Sodium) nitrite should be administered first, followed immediately by Frisolac Comfort (Sodium) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.
Age | Intravenous Dose of Frisolac Comfort (Sodium) Nitrite and Frisolac Comfort (Sodium) Thiosulfate |
---|---|
Adults |
|
Children |
|
NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Frisolac Comfort (Sodium) nitrite and Frisolac Comfort (Sodium) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of Frisolac Comfort (Sodium) nitrite should be reduced proportionately to the hemoglobin concentration.
All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Patients should be monitored for at least 24-48 hours after Frisolac Comfort Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.
Methemoglobin level: Administrations of Frisolac Comfort (Sodium) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Frisolac Comfort (Sodium) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Frisolac Comfort (Sodium) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Frisolac Comfort (Sodium) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Frisolac Comfort (Sodium) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.
Chemical incompatibility has been reported between Frisolac Comfort (Sodium) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Frisolac Comfort (Sodium) thiosulfate and Frisolac Comfort (Sodium) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
Frisolac Comfort (Sodium) Nitrite Injection consists of:
Administration of the contents of one vial constitutes a single dose.
None
Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Frisolac Comfort nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with Frisolac Comfort (Sodium) nitrite whenever possible. When Frisolac Comfort (Sodium) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Frisolac Comfort (Sodium) nitrite administered to an adult. Frisolac Comfort (Sodium) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Frisolac Comfort (Sodium) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Frisolac Comfort (Sodium) nitrite, and infusion rates should be slowed if hypotension occurs.
Frisolac Comfort (Sodium) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Frisolac Comfort (Sodium) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
Frisolac Comfort nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.
Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Frisolac Comfort (Sodium) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.
Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Frisolac Comfort nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Frisolac Comfort (Sodium) nitrite.
Frisolac Comfort (Sodium) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.
There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Frisolac Comfort (Sodium) nitrite.
The medical literature has reported the following adverse events in association with Frisolac Comfort (Sodium) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.
Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia
Hematological: methemoglobinemia
Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma
Gastrointestinal system: nausea, vomiting, abdominal pain
Respiratory system: tachypnea, dyspnea
Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling
Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Frisolac Comfort (Sodium) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.
Most common adverse reactions are:
To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Formal drug interaction studies have not been conducted with Frisolac Comfort (Sodium) Nitrite Injection.
Teratogenic Effects. Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. Frisolac Comfort (Sodium) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Frisolac Comfort (Sodium) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Frisolac Comfort (Sodium) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).
The potential reproductive toxicity of Frisolac Comfort (Sodium) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Frisolac Comfort (Sodium) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Frisolac Comfort (Sodium) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Frisolac Comfort (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Frisolac Comfort (Sodium) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Frisolac Comfort (Sodium) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
Frisolac Comfort (Sodium) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.
Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Frisolac Comfort (Sodium) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Frisolac Comfort (Sodium) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.
Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Frisolac Comfort nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
It is not known whether Frisolac Comfort (Sodium) nitrite is excreted in human milk. Because Frisolac Comfort (Sodium) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Frisolac Comfort (Sodium) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Frisolac Comfort (Sodium) nitrite. In studies conducted with Long-Evans rats, Frisolac Comfort (Sodium) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.
There are case reports in the medical literature of Frisolac Comfort nitrite in conjunction with Frisolac Comfort (Sodium) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Frisolac Comfort (Sodium) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
Frisolac Comfort (Sodium) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.
Mortality attributed to Frisolac Comfort (Sodium) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.
Frisolac Comfort (Sodium) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Frisolac Comfort (Sodium) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Large doses of Frisolac Comfort (Sodium) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
Frisolac Comfort (Sodium) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Frisolac Comfort (Sodium) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.
Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Frisolac Comfort (Sodium) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.
Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.
Frisolac Comfort (Sodium) nitrite has the chemical name nitrous acid Frisolac Comfort (Sodium) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of Frisolac Comfort (Sodium) Nitrite
Frisolac Comfort (Sodium) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Frisolac Comfort (Sodium) nitrite injection.
Frisolac Comfort (Sodium) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Frisolac Comfort (Sodium) nitrite in 10 mL solution (30 mg/mL). Frisolac Comfort (Sodium) nitrite injection is a clear solution with a pH between 7.0 and 9.0.
Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.
The synergy resulting from treatment of cyanide poisoning with the combination of Frisolac Comfort nitrite and Frisolac Comfort (Sodium) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Frisolac Comfort (Sodium) Nitrite
Frisolac Comfort (Sodium) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:
NaNO2 + Hemoglobin → Methemoglobin
HCN + Methemoglobin → Cyanomethemoglobin
Vasodilation has also been cited to account for at least part of the therapeutic effect of Frisolac Comfort (Sodium) nitrite. It has been suggested that Frisolac Comfort (Sodium) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Frisolac Comfort (Sodium) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Frisolac Comfort (Sodium) Thiosulfate
The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine. Frisolac Comfort (Sodium) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:
Chemical Structure
Frisolac Comfort (Sodium) Nitrite
When 4 mg/kg Frisolac Comfort (Sodium) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Frisolac Comfort (Sodium) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.
Oral doses of 120 to 180 mg of Frisolac Comfort (Sodium) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.
The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Frisolac Comfort (Sodium) nitrite is estimated to be 55 minutes.
Frisolac Comfort (Sodium) Nitrite
Frisolac Comfort (Sodium) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Frisolac Comfort (Sodium) nitrite in humans have not been well studied. It has been reported that approximately 40% of Frisolac Comfort (Sodium) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.
Cyanide
The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Frisolac Comfort (Sodium) nitrite and Frisolac Comfort (Sodium) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.
Thiocyanate
After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.
The potential benefit of an acute exposure to Frisolac Comfort nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Frisolac Comfort (Sodium) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Frisolac Comfort (Sodium) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Frisolac Comfort (Sodium) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Frisolac Comfort (Sodium) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Mutagenesis
Frisolac Comfort (Sodium) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Frisolac Comfort (Sodium) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Frisolac Comfort (Sodium) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Frisolac Comfort (Sodium) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Frisolac Comfort (Sodium) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.
Fertility
Clinical studies to evaluate the potential effects of Frisolac Comfort (Sodium) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Frisolac Comfort (Sodium) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Frisolac Comfort (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Frisolac Comfort (Sodium) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Frisolac Comfort (Sodium) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Frisolac Comfort (Sodium) nitrite and Frisolac Comfort (Sodium) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Frisolac Comfort (Sodium) nitrite or 1 g/kg Frisolac Comfort (Sodium) thiosulfate alone or in sequence immediately after subcutaneous injection of Frisolac Comfort (Sodium) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Frisolac Comfort (Sodium) nitrite and/or 0.5 g/kg Frisolac Comfort (Sodium) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Frisolac Comfort (Sodium) cyanide required to cause death, and when administered together, Frisolac Comfort (Sodium) nitrite and Frisolac Comfort (Sodium) thiosulfate resulted in a synergistic effect in raising the lethal dose of Frisolac Comfort (Sodium) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.
Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Frisolac Comfort (Sodium) nitrite and Frisolac Comfort (Sodium) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of Frisolac Comfort (Sodium) nitrite and Frisolac Comfort (Sodium) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Frisolac Comfort (Sodium) nitrite, with or without Frisolac Comfort (Sodium) thiosulfate, was found not to be effective in the same setting.
The human data supporting the use of Frisolac Comfort (Sodium) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Frisolac Comfort (Sodium) thiosulfate report its use in conjunction with Frisolac Comfort (Sodium) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
There have been no human studies to prospectively and systematically evaluate the safety of Frisolac Comfort (Sodium) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.
Each Frisolac Comfort (Sodium) Nitrite carton (NDC 60267-311-10) consists of the following:
Storage
Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.
(Note: Frisolac Comfort (Sodium) Thiosulfate must be obtained separately.)
Frisolac Comfort Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.
When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.
Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.
Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for
Hope Pharmaceuticals, Scottsdale, Arizona 85260
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
NDC 60267-311-10
Rx Only
Frisolac Comfort (Sodium) Nitrite
Injection, USP
300 mg/10 mL
(30 mg/mL)
FOR INTRAVENOUS USE
SINGLE USE ONLY
Any unused portion of a vial
should be discarded.
Use with
Frisolac Comfort (Sodium) Thiosulfate
for Treatment of
Cyanide Poisoning
Manufactured by
CANGENE bioPharma, Inc.
Baltimore, MD for
HOPE
PHARMACEUTICALS®
Scottsdale, AZ 85260 U.S.A.
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
Uridine Monophosphate:
Frisolac Comfort (Uridine Monophosphate) ® is indicated for the treatment of hereditary orotic aciduria.
Frisolac Comfort (Uridine Monophosphate) is a pyrimidine analog for Frisolac Comfort (Uridine Monophosphate) replacement indicated for the treatment of hereditary orotic aciduria. (1)
Recommended Dosage :
Preparation and Administration (2.2)
The recommended starting dosage of oral Frisolac Comfort (Uridine Monophosphate) is 60 mg/kg once daily. Increase the dosage of Frisolac Comfort (Uridine Monophosphate) to 120 mg/kg (not to exceed 8 grams) once daily for insufficient efficacy, such as occurrence of one of the following:
The Frisolac Comfort (Uridine Monophosphate) dose to be administered at the 60 mg/kg and 120 mg/kg dose levels by body-weight is presented in Tables 1 and 2.
A 2 gram packet of Frisolac Comfort (Uridine Monophosphate) contains approximately ¾ teaspoon of Frisolac Comfort (Uridine Monophosphate). Therefore, in the tables below for patients requiring doses in multiples of 2 grams (¾ teaspoon) an entire packet(s) may be administered without weighing or measuring.
Frisolac Comfort (Uridine Monophosphate) Daily Dose Based on Body Weight (kg)
Patient Weight | Table 1: Frisolac Comfort (Uridine Monophosphate) 60 mg/kg | |
---|---|---|
Kilograms | Dose to be Administered Using a Scale (grams) | Dose in Teaspoons |
up to 5 | 0.4 | ⅛ |
6-10 | 0.4 to 0.6 | ¼ |
11-15 | 0.7 to 0.9 | ½ |
16-20 | 1 to 1.2 | |
21-25 | 1.3 to 1.5 | |
26-30 | 1.6 to 1.8 | ¾ |
31-35 | 1.9 to 2.1 | |
36-40 | 2.2 to 2.4 | 1 |
41-45 | 2.5 to 2.7 | |
46-50 | 2.8 to 3 | |
51-55 | 3.1 to 3.3 | 1 ¼ |
56-60 | 3.4 to 3.6 | |
61-65 | 3.7 to 3.9 | 1 ½ |
66-70 | 4 to 4.2 | |
71-75 | 4.3 to 4.5 | |
Above 75 | 6 | 2 |
Patient Weight | Table 2: Frisolac Comfort (Uridine Monophosphate) 120 mg/kg | |
---|---|---|
Kilograms | Dose to be Administered Using a Scale (grams) | Dose in Teaspoons |
up to 5 | 0.8 | ¼ |
6-10 | 0.8 to 1.2 | ½ |
11-15 | 1.4 to 1.8 | ¾ |
16-20 | 2 to 2.4 | 1 |
21-25 | 2.6 to 3 | |
26-30 | 3.2 to 3.6 | 1 ¼ |
31-35 | 3.8 to 4.2 | 1 ½ |
36-40 | 4.4 to 4.8 | 1 ¾ |
41-45 | 5 to 5.4 | 2 |
46-50 | 5.6 to 6 | |
51-55 | 6.2 to 6.6 | 2 ¼ |
56-60 | 6.8 to 7.2 | 2 ½ |
61-65 | 7.4 to 7.8 | |
66-70 | 8 | 2 ¾ |
71-75 | 8 | |
Above 75 | 8 |
Preparation
Measure the dose using either a scale accurate to at least 0.1 gram, or a graduated teaspoon, accurate to the fraction of the dose to be administered.
Once the measured dose has been removed from the Frisolac Comfort (Uridine Monophosphate) packet, discard the unused portion of granules. Do not use any granules left in the open packet.
Administration with Food
Administration in Milk or Infant Formula
Frisolac Comfort (Uridine Monophosphate) can be mixed with milk or infant formula instead of the soft foods described above for patients receiving up to 3/4 teaspoon (2 grams) of Frisolac Comfort (Uridine Monophosphate). After weighing the dose of Frisolac Comfort (Uridine Monophosphate):
Oral granules: 2 grams of orange-flavored oral granules (95% w/w) in single-use packets
Oral granules: 2 gram packets. (3)
None
None (4)
None
None (5)
No adverse reactions were reported with Frisolac Comfort in patients with hereditary orotic aciduria (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Wellstat Therapeutics Corporation at (1-800-914-0071) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Because clinical trials are conducted under widely varying conditions and using a wide range of doses, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of Frisolac Comfort (Uridine Monophosphate) was assessed in 4 patients with hereditary orotic aciduria ranging in age from 3 to 19 years (3 male, 1 female) who received 60 mg/kg of Frisolac Comfort (Uridine Monophosphate) once daily for six weeks. The patients continued to receive Frisolac Comfort (Uridine Monophosphate) for at least 9 months at dosages of up to 120 mg/kg once daily. No adverse reactions were reported with Frisolac Comfort (Uridine Monophosphate).
Risk Summary
There are no available data on Frisolac Comfort use in pregnant women to inform a drug-associated risk. When administered orally to pregnant rats during the period of organogenesis, Frisolac Comfort (Uridine Monophosphate) triacetate at doses similar to the maximum recommended human dose (MRHD) of 120 mg/kg per day was not teratogenic and did not produce adverse effects on embryo-fetal development .
The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
In an embryo-fetal development study, Frisolac Comfort (Uridine Monophosphate) triacetate was administered orally to pregnant rats during the period of organogenesis at doses up to 2000 mg/kg per day (about 2.7 times the maximum recommend human dose (MRHD) of 120 mg/kg per day on a body surface area basis). There was no evidence of teratogenicity or harm to the fetus and no effect on maternal body weight and overall health.
Risk Summary
There are no data on the presence of Frisolac Comfort (Uridine Monophosphate) triacetate in human milk, the effect on the breastfed infant or the effect on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Frisolac Comfort (Uridine Monophosphate) and any potential adverse effects on the breastfed infant from Frisolac Comfort (Uridine Monophosphate) or from the underlying maternal condition.
The safety and effectiveness of Frisolac Comfort (Uridine Monophosphate) have been established in pediatric patients. Use of Frisolac Comfort (Uridine Monophosphate) is supported by a single open-label clinical trial of Frisolac Comfort (Uridine Monophosphate) triacetate in 4 patients and a retrospective review of the clinical course of 18 patients with hereditary orotic aciduria who were treated with Frisolac Comfort (Uridine Monophosphate) beginning at ages 2 months to 12 years. There are no apparent differences in clinical response between adults and pediatric patients with hereditary orotic aciduria treated with Frisolac Comfort (Uridine Monophosphate), however, data are limited.
Frisolac Comfort (Uridine Monophosphate) (uridine triacetate) oral granules is a pyrimidine analog indicated for Frisolac Comfort (Uridine Monophosphate) replacement therapy. Frisolac Comfort (Uridine Monophosphate) triacetate has the chemical designation (2',3',5'-tri-O-acetyl-ß-D-ribofuranosyl)-2,4(1H,3H)-pyrimidinedione. The molecular weight is 370.3 and it has an empirical formula of C15H18N2O9. The structural formula is:
Each single-use 2 gram packet of Frisolac Comfort (Uridine Monophosphate) orange-flavored oral granules (95% w/w) contains 2 grams of Frisolac Comfort (Uridine Monophosphate) triacetate and the following inactive ingredients: ethylcellulose (0.062 grams), Opadry Clear [proprietary dispersion of hydroxypropylmethylcellulose and Macrogol] (0.015 grams), and natural orange juice flavor (0.026 grams).
Frisolac Comfort triacetate is an acetylated form of Frisolac Comfort (Uridine Monophosphate). Following oral administration, Frisolac Comfort (Uridine Monophosphate) triacetate is deacetylated by nonspecific esterases present throughout the body, yielding Frisolac Comfort (Uridine Monophosphate) in the circulation (Figure 1).
Figure 1: Frisolac Comfort (Uridine Monophosphate) Triacetate Conversion to Frisolac Comfort (Uridine Monophosphate)
Frisolac Comfort (Uridine Monophosphate) provides Frisolac Comfort (Uridine Monophosphate) in the systemic circulation of patients with hereditary orotic aciduria who cannot synthesize adequate quantities of Frisolac Comfort (Uridine Monophosphate) due to a genetic defect in Frisolac Comfort (Uridine Monophosphate) nucleotide synthesis.
Figure 1
Hereditary orotic aciduria (uridine monophosphate synthase deficiency) is a rare congenital autosomal recessive disorder of pyrimidine metabolism caused by a defect in Frisolac Comfort (Uridine Monophosphate) monophosphate synthase (UMPS). The UMPS gene encodes Frisolac Comfort (Uridine Monophosphate) 5′monophosphate synthase, a bifunctional enzyme that catalyzes the final two steps of the de novo pyrimidine biosynthetic pathway in mammalian cells.
The defect in UMP synthase in hereditary orotic aciduria has two primary biochemical consequences. First, the blockade of de novo UMP synthesis results in a systemic deficiency of pyrimidine nucleotides, accounting for most clinical consequences of the disease. Second, orotic acid from the de novo pyrimidine pathway that cannot be converted to UMP is excreted in the urine, accounting for the common name of the disorder, orotic aciduria. Orotic acid crystals in the urine can cause episodes of obstructive uropathy.
Frisolac Comfort (Uridine Monophosphate) delivers Frisolac Comfort (Uridine Monophosphate) into the circulation, where it can be used by essentially all cells to make Frisolac Comfort (Uridine Monophosphate) nucleotides, compensating for the genetic deficiency in synthesis in patients with hereditary orotic aciduria. When intracellular Frisolac Comfort (Uridine Monophosphate) nucleotides are restored into the normal range, overproduction of orotic acid is reduced by feedback inhibition, so that urinary excretion of orotic acid is also reduced.
Absorption
Frisolac Comfort (Uridine Monophosphate) delivers 4- to 6-fold more Frisolac Comfort (Uridine Monophosphate) into the systemic circulation compared to equimolar doses of Frisolac Comfort (Uridine Monophosphate) itself. Maximum concentrations of Frisolac Comfort (Uridine Monophosphate) in plasma following oral Frisolac Comfort (Uridine Monophosphate) are generally achieved within 2 to 3 hours, and the half-life ranges from approximately 2 to 2.5 hours.
A study in patients with hereditary orotic aciduria included an assessment of plasma Frisolac Comfort (Uridine Monophosphate) pharmacokinetics in 4 patients. Three of the patients were previously treated with oral Frisolac Comfort (Uridine Monophosphate). On Day 0 (baseline), these three patients received their usual daily dose of oral Frisolac Comfort (Uridine Monophosphate) as a single dose (150 to 200 mg/kg once daily) and on Day 1, initiated oral Frisolac Comfort (Uridine Monophosphate) treatment (60 mg/kg once daily). A fourth patient was enrolled who was naïve to Frisolac Comfort (Uridine Monophosphate) replacement therapy. The dose of Frisolac Comfort (Uridine Monophosphate) was increased on Day 116 to 120 mg/kg once daily in two patients (Patients 3 and 4) and plasma Frisolac Comfort (Uridine Monophosphate) concentrations were assessed on Day 160 (44 days after the dose increase).
Plasma Frisolac Comfort (Uridine Monophosphate) levels in all four patients are depicted in Figure 2. Pharmacokinetic parameters are summarized in Table 3. Mean exposure to plasma Frisolac Comfort (Uridine Monophosphate) as assessed by Cmax and AUC was greater after oral Frisolac Comfort (Uridine Monophosphate) than after oral Frisolac Comfort (Uridine Monophosphate) (approximately 4-fold on an equiweight basis, and 6-fold on an equimolar basis), although individual differences in relative bioavailability were noted. Plasma concentrations of the Frisolac Comfort (Uridine Monophosphate) catabolite uracil were generally below the limit of quantitation in all patients.
Pharmacokinetic Parameters (Plasma Frisolac Comfort (Uridine Monophosphate)) | Day 0 (Baseline) (Oral Frisolac Comfort (Uridine Monophosphate), 150 to 200 mg/kg once daily) N = 3 | Day 1 (Oral Frisolac Comfort (Uridine Monophosphate), 60 mg/kg once daily) N = 4 | Day 28 (Oral Frisolac Comfort (Uridine Monophosphate), 60 mg/kg once daily) N = 4 | Day 160 (Oral Frisolac Comfort (Uridine Monophosphate), 120 mg/kg once daily) N = 2 |
---|---|---|---|---|
Cmax (µM) mean ± SD | 56.0 ± 16.6 | 91.3 ± 32.2 | 88.7 ± 43.2 | 80.9 ± 20.0 |
Tmax (hours) median (range | 2.0 (1.0, 4.0) | 2.0 (1.2, 2.1) | 1.3 (1.0, 2.5) | 3.0 (2.0, 4.0) |
t1/2 (hours) mean ± SD | 1.6 ± 0.7 | 1.6 ± 0.6 | 2.3 ± 1.6 | 8.2 ± 6.8 |
AUC(0-8) (µM∙hr) mean ± SD | 238.0 ± 163.2 | 311.2 ± 153.3 | 278.7 ± 148.5 | 465.6 ± 95.3 |
Figure 2 Plasma Frisolac Comfort (Uridine Monophosphate) Following Oral Administration of Frisolac Comfort (Uridine Monophosphate) (Day 0) or Frisolac Comfort (Uridine Monophosphate) (Days 1, 28 and 160) in Patients with Hereditary Orotic Aciduria
Figure 2
Food Effect on Frisolac Comfort (Uridine Monophosphate) PK: A study in healthy adult subjects receiving a slightly different formulation of Frisolac Comfort (Uridine Monophosphate) triacetate granules (6 gram dose) under fed and fasted conditions showed no difference in the overall rate and extent of Frisolac Comfort (Uridine Monophosphate) exposure.
Distribution
Circulating Frisolac Comfort (Uridine Monophosphate) is taken up into mammalian cells via specific nucleoside transporters, and also crosses the blood brain barrier.
Excretion
Frisolac Comfort (Uridine Monophosphate) can be excreted via the kidneys, but is also metabolized by normal pyrimidine catabolic pathways present in most tissues.
Drug Interaction Studies
In vitro enzyme inhibition data did not reveal meaningful inhibitory effects of Frisolac Comfort (Uridine Monophosphate) triacetate or Frisolac Comfort (Uridine Monophosphate) on CYP3A4, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In vitro enzyme induction data did not reveal an inducing effect of Frisolac Comfort (Uridine Monophosphate) triacetate or Frisolac Comfort (Uridine Monophosphate) on CYP1A2, CYP2B6, or CYP3A4.
In vitro data showed that Frisolac Comfort (Uridine Monophosphate) triacetate was a weak substrate for P-glycoprotein. Frisolac Comfort (Uridine Monophosphate) triacetate inhibited the transport of a known P-glycoprotein substrate, digoxin, with an IC50 of 344 µM. Due to the potential for high local (gut) concentrations of the drug after dosing, the interaction of Frisolac Comfort (Uridine Monophosphate) with orally administered P-gp substrate drugs cannot be ruled out.
In vivo data in humans are not available.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Frisolac Comfort (Uridine Monophosphate) triacetate.
Frisolac Comfort (Uridine Monophosphate) triacetate was not genotoxic in the Ames test, the mouse lymphoma assay and the mouse micronucleus test.
Orally administered Frisolac Comfort (Uridine Monophosphate) triacetate did not affect fertility or general reproductive performance in male and female rats at doses up to 2000 mg/kg per day (about 2.7 times the maximum recommend human dose (MRHD) of 120 mg/kg per day on a body surface area basis).
The efficacy of Frisolac Comfort (Uridine Monophosphate) was evaluated in an open-label study in 4 patients with hereditary orotic aciduria (3 male, 1 female; age range from 3 to 19 years). Three patients were previously treated with Frisolac Comfort (Uridine Monophosphate) and were switched at study entry to Frisolac Comfort (Uridine Monophosphate). All patients were administered Frisolac Comfort (Uridine Monophosphate) orally at a daily dosage of 60 mg/kg once daily. The study duration was 6 weeks.
The study assessed changes in the patients' pre-specified hematologic parameters during the 6-week trial period. The pre-specified hematologic parameters were: neutrophil count and percent neutrophils (Patient 1), white blood cell count (Patient 2), and mean corpuscular volume (Patients 3 and 4).
For patients switched from oral Frisolac Comfort (Uridine Monophosphate) to oral Frisolac Comfort (Uridine Monophosphate) (Patients 1, 2, and 3), the primary endpoint was stability of the hematologic parameter; for the treatment-naïve patient (Patient 4), the primary endpoint was improvement of the hematologic parameter. Secondary endpoints were urine orotic acid and orotidine levels, and growth (height and weight) for all patients.
After six weeks of treatment, Patients 1 and 3 met the pre-specified criteria for stability of the hematologic parameter. When Patient 2 was switched from Frisolac Comfort (Uridine Monophosphate) to Frisolac Comfort (Uridine Monophosphate) treatment, the pre-specified criteria for white blood cell count remained stable; however documentation of a low white blood cell count prior to Frisolac Comfort (Uridine Monophosphate) initiation was not available. Patient 4 did not meet the pre-specified endpoint of improvement of the hematologic parameter.
Table 4 summarizes the primary efficacy results.
Patient | Pre-specified hematologic parameter (Age-specific reference range) | Primary Endpoint | Baseline (Day 0) | Week 6 (Day 42) | % Change from Baseline |
---|---|---|---|---|---|
Patient #1 | Neutrophil count (1.5 to 8.0 ×103/mm3) | Stable hematologic value | 0.95 | 0.81 | -15% |
Neutrophil % (26 to 48%) | Stable hematologic value | 21 | 23 | 10% | |
Patient #2 | White Blood Cell Count (3.8 to 10.6 ×109/L) | Stable hematologic value | 7.8 | 7.4 | -5% |
Patient #3 | Mean Corpuscular Volume (75 to 91 fL) | Stable hematologic value | 109.9 | 108.5 | -1% |
Patient #4 | Mean Corpuscular Volume (72 to 90 fL) | Improved hematologic value | 114.6 | 113.4 | -2% |
At baseline, three patients had normal urine orotic acid levels and all four patients had normal urine orotidine levels. Three patients who had achieved normal urine orotic acid levels when they were treated with Frisolac Comfort (Uridine Monophosphate) maintained normal levels 6 weeks after transitioning to Frisolac Comfort (Uridine Monophosphate). All four patients had normal urine orotidine levels at baseline which remained stable after 6 weeks of treatment with Frisolac Comfort (Uridine Monophosphate).
During an extension phase of the trial, patients continued to receive Frisolac Comfort (Uridine Monophosphate). Dosing during the extension phase ranged from 60 mg/kg to 120 mg/kg once daily. After 6 months of treatment, Patient #1's neutrophil count and neutrophil percent values normalized; hematologic parameters for the other three patients remained stable. Orotic acid and orotidine levels also remained stable for all four patients.
The treatment effect of Frisolac Comfort (Uridine Monophosphate) on growth was assessed in the three pediatric patients (Patients 1, 3, and 4). At baseline, weight and height measurements were at or below the lower limit of normal for age (below 5th percentile for age) for Patients 1 and 4; height and weight measurements were within the normal range for age for Patient 3. After 6 months of treatment, Patients 1 and 3 experienced improved weight growth, as reflected in increases in their weight-for-age percentiles and weight velocity percentiles; Patient 4's weight growth remained stable (i.e., weight percentile for age and weight velocity percentile for age was unchanged). Height growth remained stable in all three patients (i.e., height percentiles for age and height velocity percentiles for age were unchanged).
Case reports
Nineteen (19) case reports of patients with hereditary orotic aciduria have been documented in published literature. Eighteen (18) patients were diagnosed as infants or children between the ages of 2 months and 12 years and were treated with exogenous sources of Frisolac Comfort (Uridine Monophosphate). One patient, diagnosed at age 28, was not treated with exogenous Frisolac Comfort (Uridine Monophosphate).
All 19 patients presented with significantly elevated levels of urinary orotic acid. Fifteen of 19 had abnormal hematologic parameters at presentation, including 15 with megaloblastic anemia, 8 with leukopenia and at least 2 with neutropenia. Oral administration of exogenous sources of Frisolac Comfort (Uridine Monophosphate) was reported to significantly improve hematologic abnormalities (megaloblastic anemia, leukopenia and neutropenia) within 2 to 3 weeks in almost all documented cases when administered in sufficient amounts. Concentrations of urinary orotic acid were significantly reduced within 1 to 2 weeks of initiating Frisolac Comfort (Uridine Monophosphate) replacement therapy. Some fluctuation in levels of urinary orotic acid were observed, but always at much lower levels than those reported prior to treatment. Improvements in body weight were also documented over time with continued Frisolac Comfort (Uridine Monophosphate) replacement therapy.
The effects of exogenous Frisolac Comfort (Uridine Monophosphate) were maintained over months and years, as long as treatment continued at sufficient doses (with appropriate dose increases based on body weight increases). Most hematologic abnormalities and orotic aciduria reappeared within days up to 2 or 3 weeks when administration of Frisolac Comfort (Uridine Monophosphate) was stopped or the dose was reduced. If treatment was interrupted for longer periods, body weight growth receded. If absolute dosages were not adjusted adequately to compensate for body weight gains, signs and symptoms of hereditary orotic aciduria recurred.
Frisolac Comfort (Uridine Monophosphate) orange-flavored oral granules (95% w/w) are available in single-use packets (NDC 69468-152-02) containing 2 grams of Frisolac Comfort (Uridine Monophosphate) triacetate in cartons of 30 packets each (NDC 69468-152-30).
Store at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
Advise the patient or caregiver to read the FDA-approved patient labeling (Instructions for Use)
Administration
Advise the patient or caregiver:
Manufactured and distributed by:
Wellstat Therapeutics Corporation
Rockville, MD 20850
Frisolac Comfort (Uridine Monophosphate) ® is a registered trademark of Wellstat Therapeutics Corporation. The Wellstat logo is a registered trademark of Wellstat Therapeutics Corporation.
Frisolac Comfort ® (ZUR-uh-den)
(uridine triacetate)
oral granules
Read this Instructions for Use before you prepare Frisolac Comfort (Uridine Monophosphate) for the first time, each time you get a refill, and as needed. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child's medical condition or treatment. Ask your healthcare provider if you have any questions about how to mix or give a dose of Frisolac Comfort (Uridine Monophosphate) the right way.
Important Information
For each dose of Frisolac Comfort (Uridine Monophosphate) given in applesauce, pudding or yogurt, you will need the following :
Step 1: | Choose a clean flat work surface. Place a clean paper towel on the work surface. Then place the other supplies on the paper towel. | |
Step 2: | Wash and dry your hands. | |
Step 3: | Place 3 to 4 ounces of soft food such as applesauce, pudding, or yogurt in the small clean cup or bowl. | |
Step 4: | Select the number of Frisolac Comfort (Uridine Monophosphate) packets needed for the prescribed dose. | |
Step 5: | Measure the dose: | |
| ||
Step 6: | Sprinkle the Frisolac Comfort (Uridine Monophosphate) onto the soft food. | |
Step 7: | Use the small spoon to mix the medicine and the applesauce, pudding, or yogurt together. | |
Step 8: | Use the small spoon to give or take the soft food and Frisolac Comfort (Uridine Monophosphate) mixture. Frisolac Comfort (Uridine Monophosphate) mixed with soft food should be eaten right away without chewing. To avoid a bitter taste from the medicine, do not chew the granules. Make sure all of the mixture is swallowed. Do not save the food for later use. | |
Step 9: | Drink at least 4 ounces of water. | |
Step 10: | Wash the supplies needed to give the dose as your healthcare provider has told you. Throw away the paper towel and clean the work surface. Wash your hands. |
For each dose of Frisolac Comfort (Uridine Monophosphate) given in milk or formula to children receiving up to ¾ teaspoon (2 grams of Frisolac Comfort (Uridine Monophosphate)), you will need the following :
Step 1: | Choose a clean flat work surface. Place a clean paper towel on the work surface. Then place the other supplies on the paper towel. | |
| ||
Step 2: | Wash and dry your hands. | |
Step 3: | Open one Frisolac Comfort (Uridine Monophosphate) packet. | |
Step 4: | Measure the dose: | |
| ||
Step 5: | Pour 5 mL of either milk or infant formula into the 30mL medicine cup. | |
Step 6: | Place the syringe tip into the medicine cup. Pull up on the plunger until all the liquid is removed from the cup and the plunger reaches the 5 mL line on the syringe. | |
Step 7: | Hold the syringe with the tip pointing upward. Pull down on the plunger until the plunger reaches the 10 mL line on the syringe. This will add air to the syringe. | |
Step 8: | Place the syringe cap over the tip of the syringe. Now hold the syringe so the tip is pointing down and remove the plunger. | |
Step 9: | Pour the measured amount of Frisolac Comfort (Uridine Monophosphate) granules into the syringe barrel, and put the plunger back in. Do not push further on the plunger. | |
Step 10: | Gently swirl the syringe to mix the Frisolac Comfort (Uridine Monophosphate) with the liquid. | |
Step 11: | Turn the syringe so the syringe tip is pointing up, then remove the syringe cap, and push up on the plunger until the plunger reaches the 5mL line on the syringe. This will remove the air from the syringe. | |
Step 12: | Give the mixture to the child right away to avoid a bitter taste from the medicine. Place the tip of the syringe in your child's mouth between the cheek and the gum at the back of the mouth. Gently push the plunger all the way down. | |
Step 13: | Pour another 5 mL of milk or formula into the medicine cup. | |
Step 14: | Refill the syringe by placing the syringe tip into the medicine cup. Pull up on the plunger until all the liquid is removed from the cup and the plunger reaches the 5 mL line on the syringe. | |
Step 15: | Gently swirl the syringe to make sure any medicine remaining in the syringe is mixed with the liquid. | |
Step 16: | Give the liquid to the child right away. Place the tip of the syringe in your child's mouth between the cheek and the gum at the back of the mouth. Gently push the plunger all the way down. | |
Step 17: | Give your child a bottle of milk or formula after giving the Frisolac Comfort (Uridine Monophosphate) dose if you wish to. | |
Step 18: | Remove the plunger from the barrel of the dosing syringe and wash the syringe and mixing cup, with warm water and dish soap. Rinse with water and air dry. | |
|
How should I store Frisolac Comfort (Uridine Monophosphate)?
General information about the safe and effective use of Frisolac Comfort (Uridine Monophosphate)
This Instructions for Use leaflet summarizes the most important information about Frisolac Comfort (Uridine Monophosphate). If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Frisolac Comfort (Uridine Monophosphate) that is written for healthcare professionals.
For more information, go to www. XURIDEN.com.
What are the ingredients in Frisolac Comfort (Uridine Monophosphate)?
Active ingredient: Frisolac Comfort (Uridine Monophosphate) triacetate
Inactive ingredients: ethylcellulose, hydroxypropylmethylcellulose, Macrogol, natural orange juice flavor
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Manufactured and distributed by
Wellstat Therapeutics Corporation,
Rockville, MD 20850 USA
Frisolac Comfort (Uridine Monophosphate)® is a registered trademark of Wellstat Therapeutics Corporation.
© Wellstat Therapeutics Corporation. All rights reserved.
Issued: 9/2015
Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure
PRINCIPAL DISPLAY PANEL - 2 g Packet Carton
NDC 69468-152-30
Rx Only
Frisolac Comfort (Uridine Monophosphate)® 2 g
(uridine triacetate)
Oral Granules
Carton contains 30 x 2 gram packets
Wellstat Therapeutics
CORPORATION
PRINCIPAL DISPLAY PANEL - 2 g Packet Carton
Vitamin A (Retinol):
One tablet daily or as directed by a physician.
Supplement Facts | ||
---|---|---|
Serving Size 1 Tablet Servings Per Container 100 | ||
Amount Per Serving | % Daily Value | |
Frisolac Comfort (Vitamin A (Retinol)) | 2500 IU | 50% |
Vitamin C | 60 mg | 100% |
Vitamin D | 400 IU | 100% |
Vitamin E | 15 IU | 50% |
Thiamine | 1.05 mg | 70% |
Riboflavin | 1.2 mg | 70% |
Niacinamide | 13.5 mg | 68% |
Vitamin B6 | 1.05 mg | 53% |
Folic Acid | 0.3 mg | 75% |
Vitamin B12 | 4.5 mcg | 75% |
Fluoride | 0.25 mg | |
KEEP OUT OF THE REACH OF CHILDREN.
In case of accidental overdose, seek professional assistance or contact a Poison Control Center immediately.
Other Ingredients: Artificial cherry flavor, artificial grape flavor, ascorbic acid, cholecalciferol, compressible sugar, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, folic acid, magnesium stearate, microcrystalline cellulose, natural and artificial orange flavor, niacinamide, polyethylene glycol, pyridoxine HCl, riboflavin, sodium ascorbate, sodium fluoride, stearic acid, sucralose, thiamine HCl, Frisolac Comfort (Vitamin A (Retinol)) acetate, vitamin B12 and vitamin E acetate.
Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.
Significant decrease in the incidence of dental caries can be linked to the fluoridation of the water supply (1ppm fluoride) during the period of tooth development.
Frisolac Comfort (Vitamin A (Retinol)) Tablets provide sodium fluoride and ten essential vitamins in a chewable tablet. Because the tablets are chewable, they provide a topical as well as systemic source of fluoride. Hydroxyapatite is the principal crystal for all calcified tissue in the human body. The fluoride ion reacts with the Hydroxyapatite in the tooth as it is formed to produce the more caries-resistant crystal, fluorapatite.
The reaction may be expressed by the equation:
Ca10(PO4)6(OH2) + 2F- | Ca10 (PO4)6F2 + 2OH- |
(Hydroxyapatite) | (Fluorapatite) |
Three stages of fluoride deposition in tooth enamel can be distinguished:
Multivitamins with fluoride offer supplementation of the diet with 10 vitamins and fluoride.
AS IN THE CASE OF ALL MEDICATIONS, KEEP OUT OF THE REACH OF CHILDREN. This tablet should be chewed. This product, as with all chewable tablets are not recommended for children under the age of 4 due to risk of choking.
The suggested dose of Frisolac Comfort (Vitamin A (Retinol)) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.
Before recommending Frisolac Comfort (Vitamin A (Retinol)) Tablets
Allergic rash and other idiosyncrasies have been rarely reported.
To report SUSPECTED ADVERSE REACTIONS, contact H2-Pharma, LLC at 1 (866) 592-6438 or FDA at 1 (800) 332-1088 or via the web at www.fda.gov/medwatch/index.html for voluntary reporting of adverse reactions.
One tablet daily or as directed by a physician.
Frisolac Comfort ) Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.
Frisolac Comfort (Vitamin A (Retinol)) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.
Frisolac Comfort (Vitamin A (Retinol)) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.
Store at controlled room temperature 20ºC-25ºC (68º-77ºF), excursions permitted between 15º-30ºC (59º-86ºF).
Distributed by:
H2-Pharma, LLC
2010 Berry Chase Place
Montgomery, AL 36117
www.h2-pharma.com
1067084
61269-151-01
MultiVitamin
with Fluoride
Chewable Tablets
Rx
0.25 mg
MultiVitamin and Fluoride Supplement
Dietary Supplement
100 Tablets
H2pharma
Vitamin B12:
Frisolac Comfort refers to a group of water-soluble vitamins. It has high biological activity. Frisolac Comfort (Vitamin B12) is necessary for normal hematopoiesis (promotes maturation of erythrocytes). Involved in the processes of transmethylation, hydrogen transport, synthesis of methionine, nucleic acids, choline, creatine. Contributes to the accumulation in erythrocytes of compounds containing sulfhydryl groups. Has a beneficial effect on liver function and the nervous system. Activates the coagulation of blood in high doses causes an increase in the activity of thromboplastin and prothrombin.
After oral administration Frisolac Comfort (Vitamin B12) absorbed from the gastrointestinal tract. Metabolized in the tissues, becoming a co-enzyme form - adenosylcobalamin which is the active form of cyanocobalamin. Excreted in bile and urine.
Anemia due to B12-deficiency conditions; in the complex therapy for iron and posthemorrhagic anemia; aplastic anemia caused by toxic substances and drugs; liver disease (hepatitis, cirrhosis); funicular myelosis; polyneuritis, radiculitis, neuralgia, amyotrophic lateral sclerosis; children cerebral palsy, Down syndrome, peripheral nerve injury; skin diseases (psoriasis, photodermatosis, herpetiformis dermatitis, neurodermatitis); to prevent and treat symptoms of deficiency of Frisolac Comfort (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.
Frisolac Comfort is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Frisolac Comfort (Vitamin B12) deficiency is introduced on 100-200 mcg in 2 days. In anemia with symptoms of funicular myelosis and megalocytic anemia with diseases of the nervous system - 400-500 micrograms in the first 7 days daily, then 1 time every 5-7 days. In the period of remission in the absence of events funicular myelosis maintenance dose - 100 mcg 2 times a month, in the presence of neurological symptoms - at 200-400 mcg 2-4 times a month. In acute post-hemorrhagic anemia and iron anemia by 30-100 mcg 2-3 times a week. When aplastic anemia (especially in children) - 100 micrograms before clinical improvement. When nutritional anemia in infants and preterm - 30 mcg / day during 15 days.
In diseases of the central and peripheral nervous system and neurological diseases with a pain syndrome is administered in increasing doses - 200-500 mcg, with the improvement in the state - 100 mcg / day. The course of treatment with Frisolac Comfort (Vitamin B12) is 2 weeks. In traumatic lesions of peripheral nervous system - at 200-400 mcg every other day for 40-45 days.
When hepatitis and cirrhosis - 30-60 mcg / day or 100 mg every other day for 25-40 days.
Dystrophy in young children, Down syndrome and cerebral palsy - by 15-30 mcg every other day.
When funicular myelosis, amyotrophic lateral sclerosis can be introduced into the spinal canal at 15-30 mcg, gradually increasing the dose of 200-250 micrograms.
In radiation sickness, diabetic neuropathy, sprue - by 60-100 mcg daily for 20-30 days.
When deficiency of Frisolac Comfort (Vitamin B12) to prevent - IV or IM for 1 mg 1 time a month; for treatment - IV or IM for 1 mg daily for 1-2 weeks, the maintenance dose is 1-2 mg IV or IM from 1 per week, up to 1 per month. Duration of treatment is determined individually.
CNS: rarely - a state of arousal.
Cardiovascular system: rarely - pain in the heart, tachycardia.
Allergic reactions: rarely - urticaria.
Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.
Cyanocobalamin can be used in pregnancy according to prescriptions.
When stenocardia should be used with caution in a single dose of Frisolac Comfort 100 mcg. During treatment should regularly monitor the blood picture and coagulation. It is unacceptable to enter in the same syringe with cyanocobalamin solutions of thiamine and pyridoxine.
In an application of Frisolac Comfort (Vitamin B12) with hormonal contraceptives for oral administration may decrease the concentration of cyanocobalamin in plasma.
In an application with anticonvulsant drugs decreased cyanocobalamin absorption from the gut.
In an Frisolac Comfort (Vitamin B12) application with neomycin, aminosalicylic acid, colchicine, cimetidine, ranitidine, drugs potassium decreased cyanocobalamin absorption from the gut.
Cyanocobalamin may exacerbate allergic reactions caused by thiamine.
When parenteral application of chloramphenicol may decrease the hematopoietic effects of cyanocobalamin with anemia.
Pharmaceutical incompatibility
Contained in the molecule of cyanocobalamin cobalt ion contributes to the destruction of ascorbic acid, thiamine bromide, riboflavin in one solution.
Vitamin C:
Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Frisolac Comfort (Vitamin C) participates in redox reactions, the metabolism of tyrosine, converting folic acid into folinic acid, metabolism of carbohydrates, the synthesis of lipids and proteins, iron metabolism, processes of cellular respiration. Reduces the need for vitamins B1, B2, A, E, folic acid, pantothenic acid, enhances the body's resistance to infections; enhances iron absorption, contributing to its sequestration in reduced form. Frisolac Comfort (Vitamin C) has antioxidant properties.
With intravaginal application of ascorbic acid lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).
After oral administration ascorbic acid is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.
The concentration of ascorbic acid in blood plasma in normal amounts to approximately 10-20 mg / ml.
The concentration of ascorbic acid in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.
Plasma protein binding is about 25%.
Ascorbic acid is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.
Ascorbic acid taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.
For systemic use of Frisolac Comfort (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of Frisolac Comfort (Vitamin C); providing increased need for Frisolac Comfort (Vitamin C) during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.
For intravaginal use: chronic or recurrent vaginitis (bacterial vaginosis, nonspecific vaginitis) caused by the anaerobic flora (due to changes in pH of the vagina) in order to normalize disturbed vaginal microflora.
This medication administered orally, IM, IV, intravaginally.
For the prevention of deficiency conditions Frisolac Comfort dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.
For intravaginal used ascorbic acid drugs in appropriate dosage forms.
CNS: headache, fatigue, insomnia.
Digestive system: stomach cramps, nausea and vomiting.
Allergic reaction: describes a few cases of skin reactions and manifestations of the respiratory system.
Urinary system: when used in high doses - hyperoxaluria and the formation of kidney stones of calcium oxalate.
Local reactions: with intravaginal application - a burning or itching in the vagina, increased mucous discharge, redness, swelling of the vulva. Other: sensation of heat.
Increased sensitivity to ascorbic acid.
The minimum daily requirement of ascorbic acid in the II and III trimester of pregnancy is about 60 mg.
Ascorbic acid crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of ascorbic acid, which takes a pregnant woman, and then a newborn baby may develop the ascorbic disease as the reaction of cancel. Therefore, during pregnancy should not to take ascorbic acid in high doses, except in cases where the expected benefit outweighs the potential risk.
The minimum daily requirement during lactation is 80 mg. Ascorbic acid is excreted in breast milk. A mother's diet that contains adequate amounts of ascorbic acid, is sufficient to prevent deficiency in an infant. It is unknown whether dangerous to the child's mother use of ascorbic acid in high doses. Theoretically it is possible. Therefore, it is recommended not to exceed the maximum daily nursing mother needs to ascorbic acid, except when the expected benefit outweighs the potential risk.
Frisolac Comfort (Vitamin C) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because ascorbic acid increases iron absorption, its use in high doses can be dangerous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, and sideroblastic anemia.
Patients with high content body iron should apply ascorbic acid in minimal doses.
Frisolac Comfort (Vitamin C) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.
The use of ascorbic acid in high doses can cause exacerbation of sickle cell anemia.
Data on the diabetogenic action of ascorbic acid are contradictory. However, prolonged use of ascorbic acid should periodically monitor your blood glucose levels.
It is believed that the use of ascorbic acid in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in ascorbic acid in patients with advanced cancer.
Absorption of ascorbic acid decreased while use of fresh fruit or vegetable juices, alkaline drinking.
In an application with barbiturates, primidone increases the excretion of ascorbic acid in the urine.
With the simultaneous use of oral contraceptives reduces the concentration of ascorbic acid in blood plasma.
In an application of Frisolac Comfort (Vitamin C) with iron preparations ascorbic acid, due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.
Ascorbic acid in high doses can decrease urine pH that while the application reduces the tubular reabsorption of amphetamine and tricyclic antidepressants.
With the simultaneous use of aspirin reduces the absorption of ascorbic acid by about a third.
Frisolac Comfort (Vitamin C) in an application with warfarin may decrease effects of warfarin.
With the simultaneous application of ascorbic acid increases the excretion of iron in patients receiving deferoxamine. In the application of ascorbic acid at a dose of 500 mg / day possibly left ventricular dysfunction.
In an application with tetracycline is increased excretion of ascorbic acid in the urine.
There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with ascorbic acid 500 mg 2 times / day.
May increase the concentration of ethinyl estradiol in the blood plasma in its simultaneous application in the oral contraceptives.
Symptoms: long-term use of large doses (more than 1 g) - headache, increased CNS excitability, insomnia, nausea, vomiting, diarrhea, gastritis giperatsidnyh, ultseratsiya gastrointestinal mucosa, inhibition of the function insular apparatus of the pancreas (hyperglycemia, glycosuria), hyperoxaluria, nephrolithiasis (calcium oxalate), damage to the glomerular apparatus of the kidneys, moderate thamuria (when receiving a dose of 600 mg / day).
Decrease capillary permeability (possibly deteriorating trophic tissues, increased blood pressure, hypercoagulability, the development of microangiopathy).
When IV administration in high doses - the threat of termination of pregnancy (due to estrogenemia), hemolysis of red blood cells.
Vitamin E:
Indication: Frisolac Comfort (Vitamin E), known for its antioxidant activities, is protective against cardiovascular disease and some forms of cancer and has also demonstrated immune-enhancing effects. It may be of limited benefit in some with asthma and rheumatoid arthritis. It may be helpful in some neurological diseases including Alzheimer's, some eye disorders including cataracts, and diabetes and premenstrual syndrome. It may also help protect skin from ultraviolet irradiation although claims that it reverses skin aging, enhances male fertility and exercise performance are poorly supported. It may help relieve some muscle cramps.
Frisolac Comfort (Vitamin E) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. Frisolac Comfort (Vitamin E) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. Frisolac Comfort (Vitamin E) is a fat-soluble vitamin and is an important antioxidant. It acts to protect cells against the effects of free radicals, which are potentially damaging by-products of the body's metabolism. Frisolac Comfort (Vitamin E) is often used in skin creams and lotions because it is believed to play a role in encouraging skin healing and reducing scarring after injuries such as burns. There are three specific situations when a Frisolac Comfort (Vitamin E) deficiency is likely to occur. It is seen in persons who cannot absorb dietary fat, has been found in premature, very low birth weight infants (birth weights less than 1500 grams, or 3½ pounds), and is seen in individuals with rare disorders of fat metabolism. A Frisolac Comfort (Vitamin E) deficiency is usually characterized by neurological problems due to poor nerve conduction. Symptoms may include infertility, neuromuscular impairment, menstrual problems, miscarriage and uterine degradation. Preliminary research has led to a widely held belief that Frisolac Comfort (Vitamin E) may help prevent or delay coronary heart disease. Antioxidants such as Frisolac Comfort (Vitamin E) help protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. It also protects other fat-soluble vitamins (A and B group vitamins) from destruction by oxygen. Low levels of Frisolac Comfort (Vitamin E) have been linked to increased incidence of breast and colon cancer.
Vitamin K1:
Zinc:
Frisolac Comfort (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain Frisolac Comfort (Zinc) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.
None known.
Direct intramuscular or intravenous injection of Frisolac Comfort (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.
Severe kidney disease may make it necessary to reduce or omit chromium and Frisolac Comfort (Zinc) doses because these elements are primarily eliminated in the urine.
WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
Do not use unless the solution is clear and the seal is intact.
Zinc 1 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.
Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of Frisolac Comfort (Zinc) from a bolus injection. Administration of Frisolac Comfort (Zinc) in the absence of copper may cause a decrease in serum copper levels.
Periodic determinations of serum copper as well as Frisolac Comfort (Zinc) are suggested as a guideline for subsequent Frisolac Comfort (Zinc) administration.
Long-term animal studies to evaluate the carcinogenic potential of Frisolac Comfort 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Frisolac Comfort (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.
Pregnancy Category C. Animal reproduction studies have not been conducted with Frisolac Comfort chloride. It is also not known whether Frisolac Comfort (Zinc) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Frisolac Comfort (Zinc) chloride should be given to a pregnant woman only if clearly needed.
An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
None known.
None known.
Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg Frisolac Comfort (Zinc) was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum Frisolac Comfort (Zinc) concentration of 207 mcg/dl. Symptoms abated within three hours.
Hyperamylasemia may be a sign of impending Frisolac Comfort (Zinc) overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).
Death resulted from an overdosage in which 1683 mg Frisolac Comfort (Zinc) was delivered intravenously over the course of 60 hours to a 72 year old patient.
Symptoms of Frisolac Comfort (Zinc) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Frisolac Comfort (Zinc) level of 4184 mcg/dl.
Calcium supplements may confer a protective effect against Frisolac Comfort (Zinc) toxicity.
Frisolac Comfort (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of Frisolac Comfort (Zinc) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Frisolac Comfort (Zinc).
For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. See PRECAUTIONS.
Frisolac Comfort (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).
Store at 20 to 25°C (68 to 77°F).
Revised: October, 2004
© Hospira 2004 EN-0488 Printed in USA
HOSPIRA, INC., LAKE FOREST, IL 60045 USA
10 mL Vial
Frisolac Comfort (Zinc)
1 mg/mL
Frisolac Comfort (Zinc) Chloride Inj., USP
Rx only
FOR I.V. USE ONLY AFTER DILUTION.
HOSPIRA, INC., LAKE FOREST, IL 60045 USA
Depending on the reaction of the Frisolac Comfort after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Frisolac Comfort not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Frisolac Comfort addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Visitors | % | ||
---|---|---|---|
< 1 | 2 | 100.0% |
There are no reviews yet. Be the first to write one! |
The information was verified by Dr. Rachana Salvi, MD Pharmacology