DRUGS & SUPPLEMENTS

Friso Gold 3

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Friso Gold 3 uses

Friso Gold 3 consists of Adenosine Monophosphate, Alpha-Linolenic Acid, Arachidonic Acid, Beta-Carotene, Bifidobacterium Lactis, Calcium, Carbohydrates, Carotenes Mixed, Choline, Cytidine Monophosphate, Dietary Fibre, Docosahexaenoic Acid, Fat, Fatty Acids Monounsaturated, Fatty Acids Polyunsaturated, Fatty Acids Saturated, Folic Acid, Fructooligosaccharides, Galactooligosaccharides, Guanosine Monophosphate, Inosine Monophosphate, Iodine, Iron, L-Tryptophan, L-Tyrosine, Lactobacillus Paracasei, Linoleic Acid, Magnesium, Moisture, Protein, Selenium, Sialic Acid, Taurine, Trans Fatty Acids, Uridine Monophosphate, Vitamin A (Retinol), Vitamin B1, Vitamin B12, Vitamin B2, Vitamin B3 (Niacin), Vitamin B5 (Pantothenic Acid), Vitamin B6, Vitamin C, Vitamin D3, Vitamin E, Vitamin H (Biotin), Vitamin K1, Zinc.

Adenosine Monophosphate:


1 INDICATIONS AND USAGE

Friso Gold 3 (Adenosine Monophosphate) Injection, USP is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately.

Friso Gold 3 (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)

2 DOSAGE AND ADMINISTRATION

The recommended Friso Gold 3 (Adenosine Monophosphate) injection dose is 0.14 mg/kg/min infused over six minutes (total dose of 0.84 mg/kg) (Table 1).

  • Administer Friso Gold 3 (Adenosine Monophosphate) injection only as a continuous peripheral intravenous infusion
  • Inject Thallium-201 at the midpoint of the Friso Gold 3 (Adenosine Monophosphate) injection infusion (i.e., after the first three minutes of Friso Gold 3 (Adenosine Monophosphate) injection)
  • Thallium-201 is physically compatible with Friso Gold 3 (Adenosine Monophosphate) injection and may be injected directly into the Friso Gold 3 (Adenosine Monophosphate) injection infusion set
  • Inject Thallium-201 as close to the venous access as possible to prevent an inadvertent increase in the dose of Friso Gold 3 (Adenosine Monophosphate) injection (the contents of the intravenous tubing) being administered

Visually inspect Friso Gold 3 (Adenosine Monophosphate) injection for particulate matter and discoloration prior to administration. Do not administer Friso Gold 3 (Adenosine Monophosphate) injection if it contains particulate matter or is discolored.

There are no data on the safety or efficacy of alternative Friso Gold 3 (Adenosine Monophosphate) injection infusion protocols. The safety and efficacy of Friso Gold 3 (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)

formula

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3 DOSAGE FORMS AND STRENGTHS

Friso Gold 3 (Adenosine Monophosphate) Injection, USP is supplied as 20 mL and 30 mL single-dose vials containing a sterile, nonpyrogenic, clear solution of Friso Gold 3 (Adenosine Monophosphate) 3 mg per mL.

Friso Gold 3 (Adenosine Monophosphate) Injection, USP: 3 mg per mL in single-dose vials (3)

4 CONTRAINDICATIONS

Friso Gold 3 (Adenosine Monophosphate) is contraindicated in patients with:

  • Second- or third-degree AV block (except in patients with a functioning artificial pacemaker)
  • Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker)
  • Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma)
  • Known hypersensitivity to Friso Gold 3 (Adenosine Monophosphate)
  • Second- or third-degree AV block (except in patients with a functioning artificial pacemaker) (4)
  • Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker) (4)
  • Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma) (4)
  • Known hypersensitivity to Friso Gold 3 (Adenosine Monophosphate) (4)

5 WARNINGS AND PRECAUTIONS

  • Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction. Fatal cardiac events have occurred. Avoid use in patients with symptoms or signs of acute myocardial ischemia. Appropriate resuscitative measures should be available
  • Sinoatrial (SA) and Atrioventricular (AV) Nodal Block. First-, second-or third-degree AV block, or sinus bradycardia can occur. Discontinue Friso Gold 3 (Adenosine Monophosphate) if patient develops persistent or symptomatic high-grade AV block (5.2)
  • Bronchoconstriction. Can induce dyspnea, bronchoconstriction, and respiratory compromise, especially in patients with obstructive pulmonary disease. Discontinue Friso Gold 3 (Adenosine Monophosphate) if patient develops severe respiratory difficulties (5.3)
  • Hypotension. Significant hypotension can occur. Discontinue Friso Gold 3 (Adenosine Monophosphate) if patient develops persistent or symptomatic hypotension (5.4)
  • Cerebrovascular Accidents. Hemorrhagic and ischemic cerebrovascular accidents have occurred (5.5)
  • Seizures. New onset or recurrence of convulsive seizures have occurred. Use of methylxanthines (e.g., caffeine, aminophylline and theophylline) is not recommended in patients who experience a seizures in association with Friso Gold 3 (Adenosine Monophosphate) (5.6)
  • Hypersensitivity. Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. Have personnel and resuscitative equipment immediately available (5.7)
  • Atrial Fibrillation. Reported in patients with or without a history of atrial fibrillation (5.8)
  • Hypertension. Clinically significant increases in systolic and diastolic pressure have been observed (5.9)

5.1 Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction

Fatal and nonfatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and myocardial infarction have occurred following Friso Gold 3 (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 Friso Gold 3 (Adenosine Monophosphate). Appropriate resuscitative measures should be available .

5.2 Sinoatrial and Atrioventricular Nodal Block

Friso Gold 3 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 Friso Gold 3 (Adenosine Monophosphate) administration (first-degree heart block developed in 3%, second-degree in 3%, and third-degree in 0.8% of patients) .

Use Friso Gold 3 (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 Friso Gold 3 (Adenosine Monophosphate) in any patient who develops persistent or symptomatic high-grade AV block.

5.3 Bronchoconstriction

Friso Gold 3 (Adenosine Monophosphate) administration can cause dyspnea, bronchoconstriction, and respiratory compromise. Friso Gold 3 (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 Friso Gold 3 (Adenosine Monophosphate) in any patient who develops severe respiratory difficulties. Resuscitative measures should be available prior to Friso Gold 3 (Adenosine Monophosphate) administration .

5.4 Hypotension

Friso Gold 3 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 Friso Gold 3 (Adenosine Monophosphate) in any patient who develops persistent or symptomatic hypotension.

5.5 Cerebrovascular Accident

Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of Friso Gold 3 (Adenosine Monophosphate) including hypotension or hypertension can be associated with these adverse reactions .

5.6 Seizures

New-onset or recurrence of convulsive seizures has occurred following Friso Gold 3. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with Friso Gold 3 (Adenosine Monophosphate). Methylxanthine use is not recommended in patients who experience seizures in association with Friso Gold 3 (Adenosine Monophosphate) administration .

5.7 Hypersensitivity, Including Anaphylaxis

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 .

5.8 Atrial Fibrillation

Friso Gold 3 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 Friso Gold 3 (Adenosine Monophosphate), lasted for 15 seconds to 6 hours, and spontaneously converted to normal sinus rhythm .

5.9 Hypertension

Friso Gold 3 (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 .

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6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the prescribing information:

  • Fatal Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction
  • Sinoatrial and Atrioventricular Nodal Block
  • Bronchoconstriction
  • Hypotension
  • Cerebrovascular Accident
  • Seizures
  • Hypersensitivity
  • Atrial fibrillation
  • Hypertension

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 .

6.1 Clinical Trials Experience

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 Friso Gold 3 (Adenosine Monophosphate) among 1,421 patients in clinical trials. 11% of the adverse reactions occurred several hours after Friso Gold 3 (Adenosine Monophosphate) administration. 8% of the adverse reactions began with Friso Gold 3 (Adenosine Monophosphate) infusion and persisted for up to 24 hours.

The most common (incidence ≥ 10%) adverse reactions to Friso Gold 3 (Adenosine Monophosphate) are flushing, chest discomfort, shortness of breath, headache, throat, neck or jaw discomfort, gastrointestinal discomfort, and dizziness (Table 2).

Adverse Reactions Friso Gold 3 (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 Friso Gold 3 (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

6.2 Post-Marketing Experience

The following adverse reactions have been reported from marketing experience with Friso Gold 3 (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

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7 DRUG INTERACTIONS

  • Methylxanthines interfere with the activity of Friso Gold 3 (7.1, 10)
  • Nucleoside transport inhibitors such as dipyridamole can increase the activity of Friso Gold 3 (Adenosine Monophosphate) (7.1)

7.1 Effects of Other Drugs on Friso Gold 3 (Adenosine Monophosphate)

  • The vasoactive effects of Friso Gold 3 (Adenosine Monophosphate) are inhibited by Friso Gold 3 (Adenosine Monophosphate) receptor antagonists, (such as methylxanthines (e.g., caffeine, aminophylline, and theophylline). The safety and efficacy of Friso Gold 3 (Adenosine Monophosphate) in the presence of these agents has not been systematically evaluated .
  • The vasoactive effects of Friso Gold 3 (Adenosine Monophosphate) are potentiated by nucleoside transport inhibitors such as dipyridamole. The safety and efficacy of Friso Gold 3 (Adenosine Monophosphate) in the presence of dipyridamole has not been systematically evaluated.
  • Whenever possible, drugs that might inhibit or augment the effects of Friso Gold 3 (Adenosine Monophosphate) should be withheld for at least five half-lives prior to the use of Friso Gold 3 (Adenosine Monophosphate).

7.2 Effects of Friso Gold 3 on Other Drugs

Friso Gold 3 (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, Friso Gold 3 (Adenosine Monophosphate) should be used with caution in the presence of these agents .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Friso Gold 3 ; nor have studies been performed in pregnant women. Because it is not known whether Friso Gold 3 (Adenosine Monophosphate) can cause fetal harm when administered to pregnant women, Friso Gold 3 (Adenosine Monophosphate) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Friso Gold 3 (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 Friso Gold 3 (Adenosine Monophosphate) in nursing infants, the decision to interrupt nursing after administration of Friso Gold 3 (Adenosine Monophosphate) or not to administer Friso Gold 3 (Adenosine Monophosphate), should take into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of Friso Gold 3 in patients less than 18 years of age have not been established.

8.5 Geriatric Use

Clinical studies with Friso Gold 3 (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.

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10 OVERDOSAGE

The half-life of Friso Gold 3 (Adenosine Monophosphate) is less than 10 seconds and adverse reactions of Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Adenosine Monophosphate) adverse reactions in approximately 2% of patients. Methylxanthine use is not recommended in patients who experience seizures in association with Friso Gold 3 (Adenosine Monophosphate) .

11 DESCRIPTION

Friso Gold 3 (Adenosine Monophosphate) is an endogenous nucleoside and is chemically described as 6-amino-9-beta-D-ribofuranosyl-9-H-purine. Friso Gold 3 (Adenosine Monophosphate) has the following structural formula:

The molecular formula for Friso Gold 3 (Adenosine Monophosphate) is C10H13N5O4 and its molecular weight is 267.24.

Friso Gold 3 (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 Friso Gold 3 (Adenosine Monophosphate) Injection, USP vial contains a sterile, non-pyrogenic solution of Friso Gold 3 (Adenosine Monophosphate) 3 mg/mL and sodium chloride 9 mg/mL in water for injection, with pH between 4.5 and 7.5.

Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Friso Gold 3 causes cardiac vasodilation which increases cardiac blood flow. Friso Gold 3 (Adenosine Monophosphate) is thought to exert its pharmacological effects through activation of purine receptors (cell-surface A1 and A2 Friso Gold 3 (Adenosine Monophosphate) receptors). Although the exact mechanism by which Friso Gold 3 (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. Friso Gold 3 (Adenosine Monophosphate) may also lessen vascular tone by modulating sympathetic neurotransmission. The intracellular uptake of Friso Gold 3 (Adenosine Monophosphate) is mediated by a specific transmembrane nucleoside transport system. Once inside the cell, Friso Gold 3 (Adenosine Monophosphate) is rapidly phosphorylated by Friso Gold 3 (Adenosine Monophosphate) kinase to Friso Gold 3 (Adenosine Monophosphate) monophosphate, or deaminated by Friso Gold 3 (Adenosine Monophosphate) deaminase to inosine. These intracellular metabolites of Friso Gold 3 (Adenosine Monophosphate) are not vasoactive.

Myocardial uptake of thallium-201 is directly proportional to coronary blood flow. Since Friso Gold 3 (Adenosine Monophosphate) significantly increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, Friso Gold 3 (Adenosine Monophosphate) causes relatively less thallium-201 uptake in vascular territories supplied by stenotic coronary arteries i.e., a greater difference is seen after Friso Gold 3 (Adenosine Monophosphate) between areas served by normal and areas served by stenotic vessels than is seen prior to Friso Gold 3 (Adenosine Monophosphate).

12.2 Pharmacodynamics

Hemodynamic Effects

Friso Gold 3 (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 Friso Gold 3 (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 .

12.3 Pharmacokinetics

Distribution

Intravenously administered Friso Gold 3 (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 Friso Gold 3 (Adenosine Monophosphate) is metabolized either via phosphorylation to Friso Gold 3 (Adenosine Monophosphate) monophosphate by Friso Gold 3 (Adenosine Monophosphate) kinase, or via deamination to inosine by Friso Gold 3 (Adenosine Monophosphate) deaminase in the cytosol. Since Friso Gold 3 (Adenosine Monophosphate) kinase has a lower Km and Vmax than Friso Gold 3 (Adenosine Monophosphate) deaminase, deamination plays a significant role only when cytosolic Friso Gold 3 (Adenosine Monophosphate) saturates the phosphorylation pathway. Inosine formed by deamination of Friso Gold 3 (Adenosine Monophosphate) can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Friso Gold 3 (Adenosine Monophosphate) monophosphate formed by phosphorylation of Friso Gold 3 (Adenosine Monophosphate) is incorporated into the high-energy phosphate pool.

Elimination

While extracellular Friso Gold 3 (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 Friso Gold 3 (Adenosine Monophosphate) deaminase.

Specific Populations

Renal Impairment

As Friso Gold 3 (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 Friso Gold 3 (Adenosine Monophosphate) does not require hepatic function for its activation or inactivation, hepatic impairment would not be expected to alter its effectiveness or tolerability.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals have not been performed to evaluate adenosine's carcinogenic potential or potential effects on fertility. Friso Gold 3 (Adenosine Monophosphate) was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay.

Friso Gold 3 (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.

14 CLINICAL STUDIES

In two crossover comparative studies involving 319 subjects who could exercise (including 106 healthy volunteers and 213 patients with known or suspected coronary disease), Friso Gold 3 (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 Friso Gold 3 (Adenosine Monophosphate) and 64% for exercise testing. The specificity was 54% for Friso Gold 3 (Adenosine Monophosphate) and 65% for exercise testing. The 95% confidence limits for Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Adenosine Monophosphate) infusion.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Friso Gold 3 Injection, USP is supplied as 20 mL and 30 mL single-dose vials of sterile, nonpyrogenic solution in normal saline as follows:

NDC Friso Gold 3 (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

16.2 Storage and Handling

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.

17 PATIENT COUNSELING INFORMATION

  • Advise patients that they may be at increased risk of fatal and nonfatal heart attacks, abnormal heart rhythms, cardiac arrest, heart block, significant increase or decrease in blood pressure, bronchoconstriction, hypersensitivity reactions, seizures, or cerebrovascular accidents with the use of Friso Gold 3 (Adenosine Monophosphate) .
  • Advise patients with COPD or asthma to discuss their respiratory history with their clinician before scheduling a myocardial perfusion imaging study with Friso Gold 3 (Adenosine Monophosphate) .
  • Methylxanthines have the potential to impact the effects of Friso Gold 3 (Adenosine Monophosphate). Instruct patients to avoid consumption of any products containing methylxanthines, including caffeinated coffee, tea or other caffeinated beverages, caffeine-containing drug products, aminophylline, and theophylline prior to the myocardial perfusion imaging study. Question patients about a history of seizures .

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

Friso Gold 3 (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:


Friso Gold 3 (Alpha-Linolenic Acid) (ALA) is a polyunsaturated omega-3 fatty acid. It is a component of many common vegetable oils and is important to human nutrition. [Wikipedia]

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. Friso Gold 3 (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:


1 INDICATIONS AND USAGE

Friso Gold 3 (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)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Friso Gold 3 (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)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Friso Gold 3 (Calcium) acetate capsule.

- Capsule: 667 mg Friso Gold 3 (Calcium) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Friso Gold 3 acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Friso Gold 3 (Calcium) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Friso Gold 3 (Calcium), including Friso Gold 3 (Calcium) acetate. Avoid the use of Friso Gold 3 (Calcium) supplements, including Friso Gold 3 (Calcium) based nonprescription antacids, concurrently with Friso Gold 3 (Calcium) acetate.

An overdose of Friso Gold 3 (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 Friso Gold 3 (Calcium) levels twice weekly. Should hypercalcemia develop, reduce the Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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.

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

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 Friso Gold 3 (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

6.1 Clinical Trial Experience

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, Friso Gold 3 (Calcium) acetate has been generally well tolerated.

Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Calcium) acetate

N=167

N (%)


3 month, open label study of Friso Gold 3 (Calcium) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Friso Gold 3 (Calcium) acetate

N=69


Friso Gold 3 (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 Friso Gold 3 (Calcium) concentration could reduce the incidence and severity of Friso Gold 3 (Calcium) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

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 Friso Gold 3 (Calcium) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Friso Gold 3 acetate is characterized by the potential of Friso Gold 3 (Calcium) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Friso Gold 3 (Calcium) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Friso Gold 3 (Calcium) acetate and most concomitant drugs. When administering an oral medication with Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Calcium) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Friso Gold 3 (Calcium) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Friso Gold 3 acetate capsules contains Friso Gold 3 (Calcium) acetate. Animal reproduction studies have not been conducted with Friso Gold 3 (Calcium) acetate, and there are no adequate and well controlled studies of Friso Gold 3 (Calcium) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Friso Gold 3 (Calcium) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Friso Gold 3 (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. Friso Gold 3 (Calcium) acetate treatment, as recommended, is not expected to harm a fetus if maternal Friso Gold 3 (Calcium) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Friso Gold 3 (Calcium) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Friso Gold 3 Acetate Capsules contains Friso Gold 3 (Calcium) acetate and is excreted in human milk. Human milk feeding by a mother receiving Friso Gold 3 (Calcium) acetate is not expected to harm an infant, provided maternal serum Friso Gold 3 (Calcium) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Friso Gold 3 (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.

10 OVERDOSAGE

Administration of Friso Gold 3 (Calcium) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Friso Gold 3 (Calcium) acetate acts as a phosphate binder. Its chemical name is Friso Gold 3 (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 Friso Gold 3 (Calcium) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Friso Gold 3 (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.

Friso Gold 3 (Calcium) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Friso Gold 3 resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Friso Gold 3 (Calcium) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Friso Gold 3 (Calcium) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Friso Gold 3 (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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Friso Gold 3 (Calcium) acetate.

14 CLINICAL STUDIES

Effectiveness of Friso Gold 3 (Calcium) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Calcium) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Friso Gold 3 (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


Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Calcium) acetate is shown in the Table 3.


* ANOVA of Friso Gold 3 (Calcium) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Friso Gold 3 (Calcium) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Friso Gold 3 (Calcium) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Friso Gold 3 (Calcium) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Friso Gold 3 (Calcium) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Friso Gold 3 (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).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Friso Gold 3 (Calcium) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Friso Gold 3 (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 Friso Gold 3 (Calcium) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Choline:


A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism.

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). Friso Gold 3 (Choline) is also needed for gallbladder regulation, liver function and lecithin (a key lipid) formation. Friso Gold 3 (Choline) also aids in fat and cholesterol metabolism and prevents excessive fat build up in the liver. Friso Gold 3 (Choline) has been used to mitigate the effects of Parkinsonism and tardive dyskinesia. Friso Gold 3 (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.

Folic Acid:


INDICATIONS AND USAGE

Friso Gold 3 (Folic Acid)® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.

CONTRAINDICATIONS

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.

PRECAUTIONS

Friso Gold 3 (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.

ADVERSE REACTIONS

Allergic sensitization has been reported following both oral and parenteral administration of Friso Gold 3 (Folic Acid) acid.

DOSAGE AND ADMINISTRATION

One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.

HOW SUPPLIED

Friso Gold 3 (Folic Acid)® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)

KEEP OUT OF REACH OF CHILDREN.

STORAGE

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.

Friso Gold 3 (Folic Acid) and the BIFERA logo are registered trademarks and the Friso Gold 3 (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:


Friso Gold 3 Tincture 7%

Directions:


Topical Antiseptic

Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Friso Gold 3 (Iodine) with a swab.

If necessary, clip hair around the area being treated and clean with soap and water.

Apply Friso Gold 3 (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.

Friso Gold 3 Tincture 7%

image description

Iron:


1 INDICATIONS AND USAGE

Friso Gold 3 (Iron) is indicated for the treatment of Friso Gold 3 (Iron) deficiency anemia in patients with chronic kidney disease (CKD).

Friso Gold 3 (Iron) is an Friso Gold 3 (Iron) replacement product indicated for the treatment of Friso Gold 3 (Iron) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Friso Gold 3 must only be administered intravenously either by slow injection or by infusion. The dosage of Friso Gold 3 (Iron) is expressed in mg of elemental Friso Gold 3 (Iron). Each mL contains 20 mg of elemental Friso Gold 3 (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

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Friso Gold 3 (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. Friso Gold 3 (Iron) should be administered early during the dialysis session. The usual total treatment course of Friso Gold 3 (Iron) is 1000 mg. Friso Gold 3 (Iron) treatment may be repeated if Friso Gold 3 (Iron) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Friso Gold 3 (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 Friso Gold 3 (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. Friso Gold 3 (Iron) treatment may be repeated if Friso Gold 3 (Iron) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Friso Gold 3 (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 Friso Gold 3 (Iron) in a maximum of 250 mL of 0.9% NaCl. Friso Gold 3 (Iron) treatment may be repeated if Friso Gold 3 (Iron) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Friso Gold 3 (Iron) maintenance treatment

The dosing for Friso Gold 3 (Iron) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Friso Gold 3 (Iron) maintenance treatment: Administer Friso Gold 3 (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. Friso Gold 3 (Iron) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Friso Gold 3 (Iron) maintenance treatment

The dosing for Friso Gold 3 (Iron) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Friso Gold 3 (Iron) maintenance treatment: Administer Friso Gold 3 (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. Friso Gold 3 (Iron) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Friso Gold 3 (Iron) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Friso Gold 3 (Iron) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Friso Gold 3 (Iron) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Friso Gold 3 (Iron) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Friso Gold 3 (Iron) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Friso Gold 3 (Iron) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Friso Gold 3 (Iron)
  • Known hypersensitivity to Friso Gold 3 (Iron) (4)

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Friso Gold 3 administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Friso Gold 3 (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
  • Hypotension: Friso Gold 3 (Iron) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Friso Gold 3 (Iron). (5.2)
  • Friso Gold 3 (Iron) Overload: Regularly monitor hematologic responses during Friso Gold 3 (Iron) therapy. Do not administer Friso Gold 3 (Iron) to patients with Friso Gold 3 (Iron) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Friso Gold 3 (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 Friso Gold 3 (Iron) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Friso Gold 3 (Iron) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Friso Gold 3 (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Friso Gold 3 (Iron) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Friso Gold 3 may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Friso Gold 3 (Iron). Hypotension following administration of Friso Gold 3 (Iron) may be related to the rate of administration and/or total dose administered .

5.3 Friso Gold 3 (Iron) Overload

Excessive therapy with parenteral Friso Gold 3 (Iron) can lead to excess storage of Friso Gold 3 (Iron) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Friso Gold 3 (Iron) require periodic monitoring of hematologic and Friso Gold 3 (Iron) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Friso Gold 3 (Iron) to patients with evidence of Friso Gold 3 (Iron) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Friso Gold 3 (Iron) sucrose; do not perform serum Friso Gold 3 (Iron) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Friso Gold 3 are described in other sections .

  • The most common adverse reactions (≥2%) following the administration of Friso Gold 3 (Iron) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

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 .

6.1 Adverse Reactions in Clinical Trials

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 Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Friso Gold 3 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 Friso Gold 3 (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
Friso Gold 3 (Iron) Friso Gold 3 (Iron) Oral Friso Gold 3 (Iron) Friso Gold 3 (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 Friso Gold 3 (Iron) therapy and were reported to be intolerant (defined as precluding further use of that Friso Gold 3 (Iron) product). When these patients were treated with Friso Gold 3 (Iron) there were no occurrences of adverse reactions that precluded further use of Friso Gold 3 (Iron) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Friso Gold 3 (Iron) maintenance treatment with Friso Gold 3 (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 Friso Gold 3 (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving Friso Gold 3 (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving Friso Gold 3 (Iron) 2.0 mg/kg.

A total of 5 (11%) subjects in the Friso Gold 3 (Iron) 0.5 mg/kg group, 10 (21%) patients in the Friso Gold 3 (Iron) 1.0 mg/kg group, and 10 (21%) patients in the Friso Gold 3 (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%).

6.2 Adverse Reactions from Post-Marketing Experience

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 Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Iron) injection. Reactions have occurred following the first dose or subsequent doses of Friso Gold 3 (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.

7 DRUG INTERACTIONS

Drug interactions involving Friso Gold 3 (Iron) have not been studied. However, Friso Gold 3 (Iron) may reduce the absorption of concomitantly administered oral Friso Gold 3 (Iron) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Friso Gold 3 sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Friso Gold 3 (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 Friso Gold 3 (Iron) sucrose. Because animal reproductive studies are not always predictive of human response, Friso Gold 3 (Iron) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Friso Gold 3 (Iron) sucrose is excreted in human milk. Friso Gold 3 (Iron) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Friso Gold 3 (Iron) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Friso Gold 3 for Friso Gold 3 (Iron) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Friso Gold 3 (Iron) for Friso Gold 3 (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. Friso Gold 3 (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)]

Friso Gold 3 (Iron) has not been studied in patients younger than 2 years of age.

In a country where Friso Gold 3 (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 Friso Gold 3 (Iron), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Friso Gold 3 (Iron) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Friso Gold 3 (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 Friso Gold 3 (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.

10 OVERDOSAGE

No data are available regarding overdosage of Friso Gold 3 (Iron) in humans. Excessive dosages of Friso Gold 3 (Iron) may lead to accumulation of Friso Gold 3 (Iron) in storage sites potentially leading to hemosiderosis. Do not administer Friso Gold 3 (Iron) to patients with Friso Gold 3 (Iron) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Friso Gold 3 (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.

11 DESCRIPTION

Friso Gold 3 (Iron) (iron sucrose injection, USP), an Friso Gold 3 (Iron) replacement product, is a brown, sterile, aqueous, complex of polynuclear Friso Gold 3 (Iron) (III)-hydroxide in sucrose for intravenous use. Friso Gold 3 (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 Friso Gold 3 (Iron) polymerization and m is the number of sucrose molecules associated with the Friso Gold 3 (Iron) (III)-hydroxide.

Each mL contains 20 mg elemental Friso Gold 3 (Iron) as Friso Gold 3 (Iron) sucrose in water for injection. Friso Gold 3 (Iron) is available in 10 mL single-use vials (200 mg elemental Friso Gold 3 (Iron) per 10 mL), 5 mL single-use vials (100 mg elemental Friso Gold 3 (Iron) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Friso Gold 3 (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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Friso Gold 3 is an aqueous complex of poly-nuclear Friso Gold 3 (Iron) (III)-hydroxide in sucrose. Following intravenous administration, Friso Gold 3 (Iron) is dissociated into Friso Gold 3 (Iron) and sucrose and the Friso Gold 3 (Iron) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Friso Gold 3 (Iron) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Friso Gold 3 (Iron) is dissociated into Friso Gold 3 (Iron) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Friso Gold 3 (Iron) sucrose containing 100 mg of Friso Gold 3 (Iron), three times weekly for three weeks, significant increases in serum Friso Gold 3 (Iron) and serum ferritin and significant decreases in total Friso Gold 3 (Iron) binding capacity occurred four weeks from the initiation of Friso Gold 3 (Iron) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Friso Gold 3, its Friso Gold 3 (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 Friso Gold 3 (Iron) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Friso Gold 3 (Iron) containing 100 mg of Friso Gold 3 (Iron) labeled with 52Fe/59Fe in patients with Friso Gold 3 (Iron) deficiency showed that a significant amount of the administered Friso Gold 3 (Iron) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Friso Gold 3 (Iron) trapping compartment.

Following intravenous administration of Friso Gold 3 (Iron), Friso Gold 3 (Iron) sucrose is dissociated into Friso Gold 3 (Iron) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Friso Gold 3 (Iron) containing 1,510 mg of sucrose and 100 mg of Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Iron) sucrose containing 500 to 700 mg of Friso Gold 3 (Iron) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Friso Gold 3 (Iron) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Friso Gold 3 (Iron) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Friso Gold 3 (Iron), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Friso Gold 3 (Iron) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Friso Gold 3 (Iron), the half-life of total serum Friso Gold 3 (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.

Friso Gold 3 (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Friso Gold 3 (Iron) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Friso Gold 3 (Iron) sucrose.

Friso Gold 3 (Iron) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Friso Gold 3 (Iron) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Friso Gold 3 (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental Friso Gold 3 (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.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Friso Gold 3.

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Friso Gold 3 (Iron) treatment and 24 in the historical control group) with Friso Gold 3 (Iron) deficiency anemia. Eligibility criteria for Friso Gold 3 (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.

Friso Gold 3 (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 Friso Gold 3 (Iron), who were off intravenous Friso Gold 3 (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 Friso Gold 3 (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
Friso Gold 3 (Iron) (n=69 Historical Control (n=18) Friso Gold 3 (Iron)

(n=73)

Historical Control

(n=18)

Friso Gold 3 (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%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Friso Gold 3 (Iron) in 23 patients with Friso Gold 3 (Iron) deficiency and HDD-CKD who had been discontinued from Friso Gold 3 (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.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

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 Friso Gold 3 (Iron). Exclusion criteria were similar to those in studies A and B. Friso Gold 3 (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Friso Gold 3 (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.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Friso Gold 3 (Iron) versus Friso Gold 3 (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 Friso Gold 3 (Iron) (325 mg ferrous sulfate three times daily for 56 days); or Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Iron) group.

A statistically significantly greater proportion of Friso Gold 3 (Iron) subjects (35/79; 44.3%) compared to oral Friso Gold 3 (Iron) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Friso Gold 3 (Iron) to patients with PDD-CKD receiving an erythropoietin alone without Friso Gold 3 (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 Friso Gold 3 (Iron) or Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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%).

14.6 Study F: Friso Gold 3 Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Iron) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Friso Gold 3 (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 Friso Gold 3 (Iron) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Friso Gold 3 is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Friso Gold 3 (Iron), each 5 mL vial contains 100 mg elemental Friso Gold 3 (Iron), and each 2.5 mL vial contains 50 mg elemental Friso Gold 3 (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

16.2 Stability and Storage

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: Friso Gold 3 (Iron), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Friso Gold 3 (Iron) per mL, or undiluted (20 mg elemental Friso Gold 3 (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: Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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.

17 PATIENT COUNSELING INFORMATION

Prior to Friso Gold 3 (Iron) administration:

  • Question patients regarding any prior history of reactions to parenteral Friso Gold 3 (Iron) products
  • Advise patients of the risks associated with Friso Gold 3 (Iron)
  • Advise patients to report any symptoms of hypersensitivity that may develop during and following Friso Gold 3 (Iron) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Friso Gold 3 (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx® is a trademark of Premier, Inc., used under license.

PREMIERProRx®

IN2340

MG #15727

L-Tryptophan:


An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor of indole alkaloids in plants. It is a precursor of serotonin (hence its use as an antidepressant and sleep aid). It can be a precursor to niacin, albeit inefficiently, in mammals.

Indication: Tryptophan may be useful in increasing serotonin production, promoting healthy sleep, managing depression by enhancing mental and emotional well-being, managing pain tolerance, and managing weight.

Tryptophan is critical for the production of the body's proteins, enzymes and muscle tissue. It is also essential for the production of niacin, the synthesis of the neurotransmitter serotonin and melatonin. Tryptophan supplements can be used as natural relaxants to help relieve insomnia. Tryptophan can also reduce anxiety and depression and has been shown to reduce the intensity of migraine headaches. Other promising indications include the relief of chronic pain, reduction of impulsivity or mania and the treatment of obsessive or compulsive disorders. Tryptophan also appears to help the immune system and can reduce the risk of cardiac spasms. Tryptophan deficiencies may lead to coronary artery spasms. Tryptophan is used as an essential nutrient in infant formulas and intravenous feeding. Tryptophan is marketed as a prescription drug (Tryptan) for those who do not seem to respond well to conventional antidepressants. It may also be used to treat those afflicted with seasonal affective disorder (a winter-onset depression). Tryptopan serves as the precursor for the synthesis of serotonin (5-hydroxytryptamine, 5-HT) and melatonin (N-acetyl-5-methoxytryptamine).

L-Tyrosine:


A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin.

Indication: Tyrosine is claimed to act as an effective antidepressant, however results are mixed. Tyrosine has also been claimed to reduce stress and combat narcolepsy and chronic fatigue, however these claims have been refuted by some studies.

Tyrosine is a nonessential amino acid synthesized in the body from phenylalanine. Tyrosine is critical for the production of the body's proteins, enzymes and muscle tissue. Tyrosine is a precursor to the neurotransmitters norepinephrine and dopamine. It can act as a mood elevator and an anti-depressant. It may improve memory and increase mental alertness. Tyrosine aids in the production of melanin and plays a critical role in the production of thyroxin (thyroid hormones). Tyrosine deficiencies are manifested by hypothyroidism, low blood pressure and low body temperature. Supplemental tyrosine has been used to reduce stress and combat narcolepsy and chronic fatigue.

Magnesium:



Friso Gold 3 (Magnesium) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Friso Gold 3 (Magnesium) Sulfate Injection, USP is a sterile solution of Friso Gold 3 (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.

Friso Gold 3 (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.

CLINICAL PHARMACOLOGY

Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Magnesium). While there are large stores of Friso Gold 3 (Magnesium) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Friso Gold 3 (Magnesium) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Friso Gold 3 (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. Friso Gold 3 (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 Friso Gold 3 (Magnesium) levels range from 1.5 to 2.5 mEq/liter.

As plasma Friso Gold 3 (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 Friso Gold 3 (Magnesium). Serum Friso Gold 3 (Magnesium) concentrations in excess of 12 mEq/L may be fatal.

Friso Gold 3 (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 Friso Gold 3 (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. Friso Gold 3 (Magnesium) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Friso Gold 3 (Magnesium) Sulfate Injection, USP is suitable for replacement therapy in Friso Gold 3 (Magnesium) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Friso Gold 3 (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), Friso Gold 3 (Magnesium) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Friso Gold 3 (Magnesium) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Friso Gold 3 (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. Friso Gold 3 (Magnesium) sulfate should be used during pregnancy only if clearly needed. If Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Magnesium) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

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 Friso Gold 3 (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of Friso Gold 3 (Magnesium).

Because Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Magnesium) should be given until they return. Serum Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Magnesium) intoxication in eclampsia.

50% Friso Gold 3 (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

Friso Gold 3 (Magnesium) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Friso Gold 3 (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 Friso Gold 3 (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of Friso Gold 3 (Magnesium). CNS depression and peripheral transmission defects produced by Friso Gold 3 (Magnesium) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Friso Gold 3 (Magnesium) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Friso Gold 3 (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 Friso Gold 3 (Magnesium) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Friso Gold 3 (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 Friso Gold 3 (Magnesium) sulfate for more than 5 to 7 days.1-10 Friso Gold 3 (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 Friso Gold 3 (Magnesium) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Friso Gold 3 (Magnesium) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Friso Gold 3 (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 Friso Gold 3 (Magnesium) is distributed into milk during parenteral Friso Gold 3 (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 Friso Gold 3 (Magnesium) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Friso Gold 3 (Magnesium) usually are the result of Friso Gold 3 (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 Friso Gold 3 (Magnesium) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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 AND ADMINISTRATION

Dosage of Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Magnesium) Deficiency

In the treatment of mild Friso Gold 3 (Magnesium) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Friso Gold 3 (Magnesium) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Magnesium) sulfate is 20 grams/48 hours and frequent serum Friso Gold 3 (Magnesium) concentrations must be obtained. Continuous use of Friso Gold 3 (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 Friso Gold 3 (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, Friso Gold 3 (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

Friso Gold 3 (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 Friso Gold 3 (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.

HOW SUPPLIED

Friso Gold 3 (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).

REFERENCES

  • Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Friso Gold 3 (Magnesium) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
  • Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Friso Gold 3 (Magnesium) toxicity. J. Perinatol. 2006; 26(6):371-4.
  • Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Friso Gold 3 (Magnesium) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
  • Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Friso Gold 3 (Magnesium) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
  • Matsuda Y, Maeda Y, Ito M, et al. Effect of Friso Gold 3 (Magnesium) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
  • Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Friso Gold 3 (Magnesium) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
  • Santi MD, Henry GW, Douglas GL. Friso Gold 3 (Magnesium) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
  • Holcomb WL, Shackelford GD, Petrie RH. Friso Gold 3 (Magnesium) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
  • Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
  • Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Friso Gold 3 (Magnesium) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Friso Gold 3 (Magnesium) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
  • Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Friso Gold 3 (Magnesium) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Friso Gold 3 (Magnesium) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Friso Gold 3 (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

Moisture:


This medication is used to relieve dry, irritated eyes. Common causes for dry eyes include wind, sun, heating/air conditioning, computer use/reading, and certain medications. This product may contain 1 or more of the following ingredients: carboxymethylcellulose, dextran, glycerin, hypromellose, polyethylene glycol 400 (PEG 400), polysorbate, polyvinyl alcohol, povidone, or propylene glycol, among others. Eye lubricants keep the eye moist, help to protect the eye from injury and infection, and decrease symptoms of dry eyes such as burning, itching, and feeling as if something is in the eye.

Protein:


1 INDICATIONS AND USAGE

Friso Gold 3 is indicated for pediatric and adult patients with severe congenital Friso Gold 3 (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)

1.1 Severe Congenital Friso Gold 3 (Protein) C Deficiency

Friso Gold 3 (Protein) is indicated for pediatric and adult patients with severe congenital Friso Gold 3 (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.

2 DOSAGE AND ADMINISTRATION

Initiate treatment under the supervision of a physician experienced in using coagulation factors/inhibitors where monitoring of Friso Gold 3 C activity is feasible. (2.1)


Friso Gold 3 (Protein) Dosing Schedule for Acute Episodes, Short-term Prophyaxis and Long-term Prophylaxis Dosing is based upon a pivotal clinical trial of 15 patients


Initial Dose The dose regimen should be adjusted according to the pharmacokinetic profile for each individual. (2.1, 2.2)


Subsequent # Doses


Maintenance Dose


Acute Episodes, Short-term ProphyaxisFriso Gold 3 (Protein) should be continued until desired anticoagulation is achieved.


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)

2.1 General

For intravenous administration only.

Initiate treatment with Friso Gold 3 (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Friso Gold 3 (Protein) C activity is feasible.

The dose, administration frequency and duration of treatment with Friso Gold 3 (Protein) depends on the severity of the Friso Gold 3 (Protein) C deficiency, the patient's age, the clinical condition of the patient and the patient's plasma level of Friso Gold 3 (Protein) C. Therefore, adjust the dose regimen according to the pharmacokinetic profile for each individual patient. See DOSAGE AND ADMINISTRATION: Friso Gold 3 (Protein) C Activity Monitoring (2.2).

Table 1 provides the Friso Gold 3 (Protein) dosing schedule for acute episodes, short-term prophylaxis and long-term prophylaxis.

NA = Not applicable; Q = every.

Initial Dose The dose regimen should be adjusted according to the pharmacokinetic profile for each individual. (2.1, 2.2)


Subsequent 3

Doses


Maintenance

Dose


Acute Episode /

Short-term ProphylaxisFriso Gold 3 (Protein) should be continued until desired anticoagulation is achieved.


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 Friso Gold 3 (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Friso Gold 3 (Protein) C activity level above 25% for the duration of treatment.

In patients receiving prophylactic administration of Friso Gold 3 (Protein), higher peak Friso Gold 3 (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 Friso Gold 3 (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).

2.2 Friso Gold 3 C Activity Monitoring

The measurement of Friso Gold 3 (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Friso Gold 3 (Protein) C before and during treatment with Friso Gold 3 (Protein). The half-life of Friso Gold 3 (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 Friso Gold 3 (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the Friso Gold 3 (Protein) C levels to maintain the trough Friso Gold 3 (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 Friso Gold 3 (Protein) C activity levels and coagulation parameters.

2.3 Initiation of Vitamin K Antagonists

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 Friso Gold 3 C, itself a vitamin K-dependent plasma Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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.

2.4 Preparation of Friso Gold 3 (Protein) [Protein C Concentrate (Human)]

Reconstitution: Use Aseptic Technique

  • Bring the Friso Gold 3 (Protein) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
  • Remove caps from the Friso Gold 3 (Protein) and diluent vials.
  • Cleanse stoppers with germicidal solution, and allow them to dry prior to use.
  • Remove protective covering from one end of the double-ended transfer needle and insert exposed needle through the center of the diluent vial stopper.
  • Remove protective covering from the other end of the double-ended transfer needle. Invert diluent vial over the upright Friso Gold 3 (Protein) vial; then rapidly insert the free end of the needle through the Friso Gold 3 (Protein) vial stopper at its center. The vacuum in the vial will draw in the diluent. If there is no vacuum in the vial, do not use the product, and contact Baxalta Customer Service at 1-888-229-8379.
  • Disconnect the two vials by removing the needle from the diluent vial stopper. Then, remove the transfer needle from the Friso Gold 3 (Protein) vial. Gently swirl the vial until all powder is dissolved. Be sure that Friso Gold 3 (Protein) is completely dissolved; otherwise, active materials will be removed by the filter needle.

2.5 Administration of Friso Gold 3 [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

Visually inspect Friso Gold 3 (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 Friso Gold 3 (Protein) at room temperature not more than 3 hours after reconstitution.

  • Attach the filter needle to a sterile, disposable syringe and draw back the plunger to admit air into the syringe.
  • Insert the filter needle into the vial of reconstituted Friso Gold 3 (Protein).
  • Inject air into the vial and then withdraw the reconstituted Friso Gold 3 (Protein) into the syringe.
  • Remove and discard the filter needle in a hard-walled Sharps container for proper disposal. Filter needles are intended to filter the contents of a single vial of Friso Gold 3 (Protein) only.
  • Attach a suitable needle or infusion set with winged adapter, and inject intravenously as instructed below under Administration by infusion.

Record the name and batch number of the product every time Friso Gold 3 (Protein) is administered to a patient.

Administration by Infusion

Administer Friso Gold 3 (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.

3 DOSAGE FORMS AND STRENGTHS

Friso Gold 3 (Protein) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human Friso Gold 3 (Protein) C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection, respectively to provide a single dose of human Friso Gold 3 (Protein) C at a concentration of 100 IU/mL.

Friso Gold 3 (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)

4 CONTRAINDICATIONS

None known.

None known. (4)

5 WARNINGS AND PRECAUTIONS

  • Discontinue administration if symptoms of hypersensitivity/allergic reactions occur.
  • Made from pooled human plasma. The possibility of transmitting infectious agents cannot be ruled out. (5.2, 11)
  • Simultaneous administration with tPA and/or anticoagulants may increase risk of bleeding. (5.3)
  • Contains heparin. If heparin-induced thrombocytopenia is suspected, check platelet counts immediately and discontinue administration. (5.4)
  • Contains sodium >200 mg. Inform patients on a low sodium diet and/or patients with renal impairment. (5.5)

5.1 Hypersensitivity/Allergic Reactions

Friso Gold 3 (Protein) may contain traces of mouse Friso Gold 3 (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse Friso Gold 3 (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.

5.2 Transmission of Infectious Agents

Because Friso Gold 3 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.

5.3 Bleeding Episodes

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 Friso Gold 3 (Protein) further contributed to these bleeding events.

Simultaneous administration of Friso Gold 3 (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia

Friso Gold 3 (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 Friso Gold 3 (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of Friso Gold 3 (Protein).

5.5 Low Sodium Diet/Renal Impairment

Inform patients on a low sodium diet that the quantity of sodium in the maximum daily dose of Friso Gold 3 (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

The common adverse reactions related to Friso Gold 3 treatment observed were the following hypersensitivity or allergic reactions: lightheadedness and itching and rash.

  • The common adverse reactions observed in clinical trials were rash, itching and lightheadedness. (2.1, 5.1, 6)

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 .

6.1 Clinical Studies Experience

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 Friso Gold 3 (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital Friso Gold 3 (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 Friso Gold 3 (Protein).

No inhibiting antibodies to Friso Gold 3 (Protein) have been observed in clinical studies. However, the potential for developing antibodies cannot be ruled out.

6.2 Post-marketing Experience

The following adverse reactions have been identified during postapproval use of Friso Gold 3 (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.

7 DRUG INTERACTIONS

No formal drug interaction studies have been conducted.

See WARNINGS AND PRECAUTIONS: Bleeding Episodes (5.3) for information regarding simultaneous administration of Friso Gold 3 (Protein) and tissue plasminogen activator (tPA).

See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of Friso Gold 3 (Protein) and vitamin K antagonists.

  • None known. (7)

8 USE IN SPECIFIC POPULATIONS

  • Pregnancy: Not studied.
  • Labor and Delivery: Not studied. (8.2)
  • Nursing Mothers: Not studied. (8.3)
  • Pediatric Use: Recommended for neonate and pediatric use. (2.1, 8.4, 12.3)
  • Renal/Hepatic Impairment: Not studied. (8.6)

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Friso Gold 3 (Protein). It is also not known whether Friso Gold 3 (Protein) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Friso Gold 3 (Protein) should be given to pregnant women only if clearly needed.

8.2 Labor and Delivery

Friso Gold 3 has not been studied for use during labor and delivery. Use only if clearly needed.

8.3 Nursing Mothers

Friso Gold 3 (Protein) has not been studied for use in nursing mothers. Use Friso Gold 3 (Protein) only if clearly needed.

8.4 Pediatric Use

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)].

8.5 Geriatric Use

Clinical studies of Friso Gold 3 (Protein) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Renal/Hepatic Impairment

No experience in the treatment of patients with renal and/or hepatic impairment is available.

11 DESCRIPTION

Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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.


2.5Coupled with IEX. I


>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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of action

Friso Gold 3 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 Friso Gold 3 (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Protein) C is not compatible with life. A severe deficiency of this anticoagulant Friso Gold 3 (Protein) causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.

12.2 Pharmacodynamics

In clinical studies, the intravenous administration of Friso Gold 3 (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.

12.3 Pharmacokinetics

Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with Friso Gold 3 (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 Friso Gold 3 (Protein) C concentration following infusion divided by dose


The Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Protein).

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: Friso Gold 3 (Protein) C Activity Monitoring (2.2).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in Friso Gold 3 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.

Friso Gold 3 (Protein) has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test).

13.2 Animal Toxicology and/or Pharmacology

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 Friso Gold 3 (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived Friso Gold 3 (Protein). Thus, the long-term toxicity potential of Friso Gold 3 (Protein) following repeated dosing in animals is unknown.

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that Friso Gold 3 (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:

Friso Gold 3 (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).

14 CLINICAL STUDIES

14.1 Pivotal Study

This was a multi-center, open-label, non-randomized, phase 2/3 study in 3 parts which evaluated the safety and efficacy of Friso Gold 3 in subjects with severe congenital Friso Gold 3 (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.


Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Protein) C deficiency were more effectively treated with Friso Gold 3 (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 Friso Gold 3 (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.

Friso Gold 3 (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 Friso Gold 3 (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. Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Protein), as shown in Table 8. When not on prophylactic treatment and receiving Friso Gold 3 (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 Total number of episodes while subjects were On-Demand was 13


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

14.2 Retrospective Analysis

A retrospective study to capture dosing information and treatment outcome data in subjects with severe congenital Friso Gold 3 (Protein) C deficiency who were treated with Friso Gold 3 (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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Friso Gold 3 (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 Friso Gold 3 (Protein) C corresponds to the amidolytically measured activity of Friso Gold 3 (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).

Friso Gold 3 (Protein) is available in single-dose vials that contain the following nominal product strengths:

NDC 0944-4177-05

Friso Gold 3 (Protein) C

Concentrate (Human)

Friso Gold 3 (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

Friso Gold 3 (Protein) C Concentrate

(Human)

Friso Gold 3 (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

Friso Gold 3 (Protein) C

Concentrate (Human)

Friso Gold 3 (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

Friso Gold 3 (Protein) C Concentrate (Human)

Friso Gold 3 (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

DESCRIPTION

Friso Gold 3 (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 Friso Gold 3 (Selenium) 40 mcg/mL) and Water for Injection q.s. pH may be adjusted with nitric acid to 1.8 to 2.4.

CLINICAL PHARMACOLOGY

Friso Gold 3 (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 Friso Gold 3 (Selenium) deficiency symptoms which include muscle pain and tenderness. The symptoms have been reported to respond to supplementation of TPN solutions with Friso Gold 3 (Selenium).

Pediatric conditions, Keshan disease, and Kwashiorkor, have been associated with low dietary intake of Friso Gold 3 (Selenium). The conditions are endemic to geographical areas with low Friso Gold 3 (Selenium) soil content. Dietary supplementation with Friso Gold 3 (Selenium) salts has been reported to reduce the incidence of the conditions among affected children.

Normal blood levels of Friso Gold 3 (Selenium) in different human populations have been found to vary and depend on the Friso Gold 3 (Selenium) content of the food consumed. Results of surveys carried out in some countries are tabulated below:



COUNTRY


Number of

Samples

Friso Gold 3 (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 Friso Gold 3 (Selenium) levels of 0.3 and 0.9 mcg/100 mL have been reported to produce deficiency symptoms in humans.

Friso Gold 3 (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 Friso Gold 3 (Selenium) used in supplementation. Ancillary routes of elimination are lungs and skin.

INDICATIONS AND USAGE

Friso Gold 3 (Selenium) Injection is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN). Administration of Friso Gold 3 (Selenium) in TPN solutions helps to maintain plasma Friso Gold 3 (Selenium) levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

Friso Gold 3 (Selenium) Injection should not be given undiluted by direct injection into a peripheral vein because of the potential for infusion phlebitis.

WARNINGS

Friso Gold 3 (Selenium) Injection can be toxic if given in excessive amounts. Supplementation of TPN solution with Friso Gold 3 (Selenium) should be immediately discontinued if toxicity symptoms are observed. Frequent determination of plasma Friso Gold 3 (Selenium) levels during TPN support and close medical supervision is recommended.

Friso Gold 3 (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.

PRECAUTIONS

As Friso Gold 3 is eliminated in urine and feces, Friso Gold 3 (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 Friso Gold 3 (Selenium) plasma level determinations are suggested as a guideline.

In animals, Friso Gold 3 (Selenium) has been reported to enhance the action of Vitamin E and decrease the toxicity of mercury, cadmium and arsenic.

Pregnancy

Teratogenic Effects

Pregnancy Category C: Friso Gold 3 (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. Friso Gold 3 (Selenium) Injection should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

Presence of Friso Gold 3 (Selenium) in placenta and umbilical cord blood has been reported in humans.

ADVERSE REACTIONS

The amount of Friso Gold 3 (Selenium) present in Friso Gold 3 (Selenium) Injection is small. Symptoms of toxicity from Friso Gold 3 (Selenium) are unlikely to occur at the recommended dosage level.

OVERDOSAGE

Chronic toxicity in humans resulting from exposure to Friso Gold 3 (Selenium) in industrial environments, intake of foods grown in seleniferous soils, use of selenium-contaminated water, and application of cosmetics containing Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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.

DOSAGE AND ADMINISTRATION

Friso Gold 3 (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, Friso Gold 3 (Selenium) deficiency states resulting from long-term TPN support, Friso Gold 3 (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 Friso Gold 3 (Selenium) Injection to the TPN solution under laminar flow hood is recommended. Friso Gold 3 (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 Friso Gold 3 (Selenium) levels is suggested as a guideline for subsequent administration. The normal whole blood range for Friso Gold 3 (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.

HOW SUPPLIED

Friso Gold 3 (Selenium) Injection containing selenious acid 65.4 mcg/mL (equivalent to elemental Friso Gold 3 (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

Friso Gold 3 (Selenium) INJECTION

Friso Gold 3 (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

Friso Gold 3 (Selenium) INJECTION

Friso Gold 3 (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

Uridine Monophosphate:


1 INDICATIONS AND USAGE

Friso Gold 3 (Uridine Monophosphate) ® is indicated for the treatment of hereditary orotic aciduria.

Friso Gold 3 (Uridine Monophosphate) is a pyrimidine analog for Friso Gold 3 (Uridine Monophosphate) replacement indicated for the treatment of hereditary orotic aciduria. (1)

2 DOSAGE AND ADMINISTRATION

Recommended Dosage :

  • The starting dosage is 60 mg/kg once daily; the dose may be increased to120 mg/kg (not to exceed 8 grams) once daily for insufficient efficacy.
  • See the full prescribing information for 60 mg/kg and 120 mg/kg weight-based dosing tables.

Preparation and Administration (2.2)

  • 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.
  • Administer the dose with food (applesauce, pudding or yogurt) or in milk or infant formula. See full prescribing information for preparation and administration instructions.

2.1 Recommended Dosage

The recommended starting dosage of oral Friso Gold 3 (Uridine Monophosphate) is 60 mg/kg once daily. Increase the dosage of Friso Gold 3 (Uridine Monophosphate) to 120 mg/kg (not to exceed 8 grams) once daily for insufficient efficacy, such as occurrence of one of the following:

  • Levels of orotic acid in urine remain above normal or increase above the usual or expected range for the patient
  • Laboratory values (e.g., red blood cell or white blood cell indices) affected by hereditary orotic aciduria show evidence of worsening
  • Worsening of other signs or symptoms of the disease

The Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) contains approximately ¾ teaspoon of Friso Gold 3 (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.

Friso Gold 3 (Uridine Monophosphate) Daily Dose Based on Body Weight (kg)

Patient Weight Table 1: Friso Gold 3 (Uridine Monophosphate) 60 mg/kgtotal daily dose by weight category in the tables was rounded to achieve the approximate dose level Dose Level
Kilograms Dose to be Administered Using a Scale (grams) Dose in Teaspoons
up to 5 0.4
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 may use 1 entire 2 gram packet without weighing or measuring
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 3.9may use 2 entire 2 gram packets without weighing or measuring 1 ½
66-70 4 to 4.2
71-75 4.3 to 4.5
Above 75 6may use 3 entire 2 gram packets without weighing or measuring 2
Patient Weight Table 2: Friso Gold 3 (Uridine Monophosphate) 120 mg/kgtotal daily dose by weight category in the tables was rounded to achieve the approximate dose level Dose Level
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 4.2may use 2 entire 2 gram packets without weighing or measuring 1 ½
36-40 4.4 to 4.8 1 ¾
41-45 5 to 5.4 2may use 3 entire 2 gram packets without weighing or measuring
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 8may use 4 entire 2 gram packets without weighing or measuring 2 ¾
71-75 8
Above 75 8

2.2 Preparation and Administration

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 Friso Gold 3 (Uridine Monophosphate) packet, discard the unused portion of granules. Do not use any granules left in the open packet.

Administration with Food

  • Place 3 to 4 ounces of applesauce, pudding or yogurt in a small clean container.
  • Mix the measured amount of granules in the applesauce, pudding or yogurt
  • Swallow applesauce/pudding/yogurt immediately. Do not chew the granules. Do not save the applesauce/pudding/yogurt for later use.
  • Drink at least 4 ounces of water.

Administration in Milk or Infant Formula

Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate). After weighing the dose of Friso Gold 3 (Uridine Monophosphate):

  • Pour 5 mL of milk or infant formula into a 30 mL medicine cup.
  • Insert the tip of the oral syringe into the medicine cup and draw up 5 mL of milk/infant formula into the syringe.
  • Hold the syringe with the tip pointing upward. Pull down on the plunger until the plunger reaches 10 mL. This will add air to the syringe.
  • Place the cap over the tip of the syringe. Then invert the syringe so the syringe tip is pointing down, and remove the plunger.
  • Pour the measured amount of Friso Gold 3 (Uridine Monophosphate) granules into the syringe barrel and reinsert the syringe plunger. Do not push up on the plunger.
  • Gently swirl the syringe to mix the Friso Gold 3 (Uridine Monophosphate) granules with the liquid.
  • 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 5 mL mark. This will remove air from the syringe.
  • Place the tip of the syringe in the patient's mouth between the cheek and gum at the back of the mouth. Gently push the plunger all the way down.
  • Refill the syringe with another 5 mL of milk/infant formula.
  • Gently swirl the syringe to rinse any remaining Friso Gold 3 (Uridine Monophosphate) granules from the syringe barrel.
  • Place the tip of the syringe in the patient's mouth between the cheek and gum at the back of the mouth. Gently push the plunger all the way down.
  • Follow with a bottle of milk or infant formula, if desired.

3 DOSAGE FORMS AND STRENGTHS

Oral granules: 2 grams of orange-flavored oral granules (95% w/w) in single-use packets

Oral granules: 2 gram packets. (3)

4 CONTRAINDICATIONS

None

None (4)

5 WARNINGS AND PRECAUTIONS

None

None (5)

6 ADVERSE REACTIONS

No adverse reactions were reported with Friso Gold 3 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.

6.1 Clinical Trials Experience

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 Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) once daily for six weeks. The patients continued to receive Friso Gold 3 (Uridine Monophosphate) for at least 9 months at dosages of up to 120 mg/kg once daily. No adverse reactions were reported with Friso Gold 3 (Uridine Monophosphate).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on Friso Gold 3 use in pregnant women to inform a drug-associated risk. When administered orally to pregnant rats during the period of organogenesis, Friso Gold 3 (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, Friso Gold 3 (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.

8.2 Lactation

Risk Summary

There are no data on the presence of Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) and any potential adverse effects on the breastfed infant from Friso Gold 3 (Uridine Monophosphate) or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of Friso Gold 3 (Uridine Monophosphate) have been established in pediatric patients. Use of Friso Gold 3 (Uridine Monophosphate) is supported by a single open-label clinical trial of Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate), however, data are limited.

11 DESCRIPTION

Friso Gold 3 (Uridine Monophosphate) (uridine triacetate) oral granules is a pyrimidine analog indicated for Friso Gold 3 (Uridine Monophosphate) replacement therapy. Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) orange-flavored oral granules (95% w/w) contains 2 grams of Friso Gold 3 (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).

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Friso Gold 3 triacetate is an acetylated form of Friso Gold 3 (Uridine Monophosphate). Following oral administration, Friso Gold 3 (Uridine Monophosphate) triacetate is deacetylated by nonspecific esterases present throughout the body, yielding Friso Gold 3 (Uridine Monophosphate) in the circulation (Figure 1).

Figure 1: Friso Gold 3 (Uridine Monophosphate) Triacetate Conversion to Friso Gold 3 (Uridine Monophosphate)

Friso Gold 3 (Uridine Monophosphate) provides Friso Gold 3 (Uridine Monophosphate) in the systemic circulation of patients with hereditary orotic aciduria who cannot synthesize adequate quantities of Friso Gold 3 (Uridine Monophosphate) due to a genetic defect in Friso Gold 3 (Uridine Monophosphate) nucleotide synthesis.

Figure 1

12.2 Pharmacodynamics

Hereditary orotic aciduria (uridine monophosphate synthase deficiency) is a rare congenital autosomal recessive disorder of pyrimidine metabolism caused by a defect in Friso Gold 3 (Uridine Monophosphate) monophosphate synthase (UMPS). The UMPS gene encodes Friso Gold 3 (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.

Friso Gold 3 (Uridine Monophosphate) delivers Friso Gold 3 (Uridine Monophosphate) into the circulation, where it can be used by essentially all cells to make Friso Gold 3 (Uridine Monophosphate) nucleotides, compensating for the genetic deficiency in synthesis in patients with hereditary orotic aciduria. When intracellular Friso Gold 3 (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.

12.3 Pharmacokinetics

Absorption

Friso Gold 3 (Uridine Monophosphate) delivers 4- to 6-fold more Friso Gold 3 (Uridine Monophosphate) into the systemic circulation compared to equimolar doses of Friso Gold 3 (Uridine Monophosphate) itself. Maximum concentrations of Friso Gold 3 (Uridine Monophosphate) in plasma following oral Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) pharmacokinetics in 4 patients. Three of the patients were previously treated with oral Friso Gold 3 (Uridine Monophosphate). On Day 0 (baseline), these three patients received their usual daily dose of oral Friso Gold 3 (Uridine Monophosphate) as a single dose (150 to 200 mg/kg once daily) and on Day 1, initiated oral Friso Gold 3 (Uridine Monophosphate) treatment (60 mg/kg once daily). A fourth patient was enrolled who was naïve to Friso Gold 3 (Uridine Monophosphate) replacement therapy. The dose of Friso Gold 3 (Uridine Monophosphate) was increased on Day 116 to 120 mg/kg once daily in two patients (Patients 3 and 4) and plasma Friso Gold 3 (Uridine Monophosphate) concentrations were assessed on Day 160 (44 days after the dose increase).

Plasma Friso Gold 3 (Uridine Monophosphate) levels in all four patients are depicted in Figure 2. Pharmacokinetic parameters are summarized in Table 3. Mean exposure to plasma Friso Gold 3 (Uridine Monophosphate) as assessed by Cmax and AUC was greater after oral Friso Gold 3 (Uridine Monophosphate) than after oral Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) catabolite uracil were generally below the limit of quantitation in all patients.

Pharmacokinetic Parameters

(Plasma Friso Gold 3 (Uridine Monophosphate))

Day 0 (Baseline)

(Oral Friso Gold 3 (Uridine Monophosphate), 150 to 200 mg/kg once daily)

N = 3 Data shown are from patients previously treated with oral Friso Gold 3 (Uridine Monophosphate)

Day 1

(Oral Friso Gold 3 (Uridine Monophosphate), 60 mg/kg once daily)

N = 4

Day 28

(Oral Friso Gold 3 (Uridine Monophosphate), 60 mg/kg once daily)

N = 4

Day 160

(Oral Friso Gold 3 (Uridine Monophosphate), 120 mg/kg once daily)

N = 2 The dose of Friso Gold 3 (Uridine Monophosphate) was increased on Day 116 to 120 mg/kg per day. Serial plasma samples were taken on Day 160 (44 days after the dose increase) for plasma Friso Gold 3 (Uridine Monophosphate) levels.

Cmax (µM)

mean ± SD

56.0 ± 16.6 91.3 ± 32.2 88.7 ± 43.2 80.9 ± 20.0
Tmax (hours)

median (range Tmax range is expressed as the minimum and maximum values obtained )

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 Friso Gold 3 (Uridine Monophosphate) Following Oral Administration of Friso Gold 3 (Uridine Monophosphate) (Day 0) or Friso Gold 3 (Uridine Monophosphate) (Days 1, 28 and 160) in Patients with Hereditary Orotic Aciduria

Figure 2

Food Effect on Friso Gold 3 (Uridine Monophosphate) PK: A study in healthy adult subjects receiving a slightly different formulation of Friso Gold 3 (Uridine Monophosphate) triacetate granules (6 gram dose) under fed and fasted conditions showed no difference in the overall rate and extent of Friso Gold 3 (Uridine Monophosphate) exposure.

Distribution

Circulating Friso Gold 3 (Uridine Monophosphate) is taken up into mammalian cells via specific nucleoside transporters, and also crosses the blood brain barrier.

Excretion

Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) triacetate or Friso Gold 3 (Uridine Monophosphate) on CYP3A4, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In vitro enzyme induction data did not reveal an inducing effect of Friso Gold 3 (Uridine Monophosphate) triacetate or Friso Gold 3 (Uridine Monophosphate) on CYP1A2, CYP2B6, or CYP3A4.

In vitro data showed that Friso Gold 3 (Uridine Monophosphate) triacetate was a weak substrate for P-glycoprotein. Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) with orally administered P-gp substrate drugs cannot be ruled out.

In vivo data in humans are not available.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Friso Gold 3 (Uridine Monophosphate) triacetate.

Friso Gold 3 (Uridine Monophosphate) triacetate was not genotoxic in the Ames test, the mouse lymphoma assay and the mouse micronucleus test.

Orally administered Friso Gold 3 (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).

14 CLINICAL STUDIES

The efficacy of Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) and were switched at study entry to Friso Gold 3 (Uridine Monophosphate). All patients were administered Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) to oral Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) to Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) maintained normal levels 6 weeks after transitioning to Friso Gold 3 (Uridine Monophosphate). All four patients had normal urine orotidine levels at baseline which remained stable after 6 weeks of treatment with Friso Gold 3 (Uridine Monophosphate).

During an extension phase of the trial, patients continued to receive Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate). One patient, diagnosed at age 28, was not treated with exogenous Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) replacement therapy.

The effects of exogenous Friso Gold 3 (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 Friso Gold 3 (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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Friso Gold 3 (Uridine Monophosphate) orange-flavored oral granules (95% w/w) are available in single-use packets (NDC 69468-152-02) containing 2 grams of Friso Gold 3 (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).

17 PATIENT COUNSELING INFORMATION

Advise the patient or caregiver to read the FDA-approved patient labeling (Instructions for Use)

Administration

Advise the patient or caregiver:

  • To measure the prescribed 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.
  • To discard the unused portion of granules in a packet after measuring out the dose.
  • That Friso Gold 3 (Uridine Monophosphate) can be taken mixed in food (applesauce, pudding or yogurt) or mixed in milk or infant formula.
  • That the Friso Gold 3 (Uridine Monophosphate) granules should not be chewed.

Manufactured and distributed by:

Wellstat Therapeutics Corporation

Rockville, MD 20850

Friso Gold 3 (Uridine Monophosphate) ® is a registered trademark of Wellstat Therapeutics Corporation. The Wellstat logo is a registered trademark of Wellstat Therapeutics Corporation.

Instructions for Use

Friso Gold 3 ® (ZUR-uh-den)

(uridine triacetate)

oral granules

Read this Instructions for Use before you prepare Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) the right way.

Important Information

  • Take Friso Gold 3 (Uridine Monophosphate) exactly as your healthcare provider tells you to.
  • Your healthcare provider will prescribe the dose of Friso Gold 3 (Uridine Monophosphate) depending on your body weight. Your healthcare provider will tell you the right dose to take.
  • Your healthcare provider will show you how to measure the prescribed dose. The prescribed dose of Friso Gold 3 (Uridine Monophosphate) can be measured using a scale or an adjustable measuring spoon.
  • Your healthcare provider may change your dose if needed. Do not change the dose without first talking with your healthcare provider.
  • Friso Gold 3 (Uridine Monophosphate) may be taken by mixing Friso Gold 3 (Uridine Monophosphate) with 3 to 4 ounces of applesauce, pudding or yogurt or may be mixed with milk or infant formula.
  • Friso Gold 3 (Uridine Monophosphate) mixed with applesauce, pudding or yogurt should be eaten right away. Do not save the mixed applesauce, pudding or yogurt for later use.
  • Do not chew the Friso Gold 3 (Uridine Monophosphate) oral granules.

For each dose of Friso Gold 3 (Uridine Monophosphate) given in applesauce, pudding or yogurt, you will need the following :

  • paper towels
  • Friso Gold 3 (Uridine Monophosphate) packet or packets containing the medicine needed for the prescribed dose
  • 1 scale or 1 adjustable measuring spoon
  • small spoon for stirring
  • 1 small clean container (such as a small cup or bowl)
  • 3 to 4 ounces of applesauce, pudding or yogurt
  • 4 ounces of drinking water
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 Friso Gold 3 (Uridine Monophosphate) packets needed for the prescribed dose.
Step 5: Measure the dose:
  • If you are using a scale:
    • Open the packet or packets and measure out the amount needed for the prescribed dose on the scale. Follow the instructions that came with the scale for correct and accurate use.
  • If you are using an adjustable measuring spoon:
    • Open the packet or packets and use the adjustable measuring spoon to measure out the amount needed for the prescribed dose as shown.
  • Throw away any unused Friso Gold 3 (Uridine Monophosphate) in the trash. Do not use any Friso Gold 3 (Uridine Monophosphate) left in the open packet.
Step 6: Sprinkle the Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) mixture.

Friso Gold 3 (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 Friso Gold 3 (Uridine Monophosphate) given in milk or formula to children receiving up to ¾ teaspoon (2 grams of Friso Gold 3 (Uridine Monophosphate)), you will need the following :

  • paper towels
  • Friso Gold 3 (Uridine Monophosphate) packet or packets containing the medicine needed for your prescribed dose
  • 1 oral dosing syringe (10mL) with a cap
  • 1 scale or 1 adjustable measuring spoon
  • milk or infant formula (10mL)
  • 1 medicine cup (30mL)
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.
  • If using infant formula, prepare the formula according to the directions on the infant formula package.
Step 2: Wash and dry your hands.
Step 3: Open one Friso Gold 3 (Uridine Monophosphate) packet.
Step 4: Measure the dose:
  • If you are using a scale:
    • Open the packet and measure out the amount needed for the prescribed dose on the scale. Follow the instructions that came with the scale for correct and accurate use.
  • If you are using an adjustable measuring spoon:
    • Open the packet and use the adjustable measuring spoon to measure out the amount needed for the prescribed dose as shown.
  • Throw away any unused Friso Gold 3 (Uridine Monophosphate) in the trash. Do not use any Friso Gold 3 (Uridine Monophosphate) left in the open packet.
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 Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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.
  • Wash the supplies needed to measure your dose as your healthcare provider has told you.
  • Throw away the paper towel and clean the work surface.
  • Wash your hands.

How should I store Friso Gold 3 (Uridine Monophosphate)?

  • Store Friso Gold 3 (Uridine Monophosphate) at room temperature between 59° F to 86°F (15° to 30°C).
  • Keep Friso Gold 3 (Uridine Monophosphate) and all medicines out of the reach of children.

General information about the safe and effective use of Friso Gold 3 (Uridine Monophosphate)

This Instructions for Use leaflet summarizes the most important information about Friso Gold 3 (Uridine Monophosphate). If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Friso Gold 3 (Uridine Monophosphate) that is written for healthcare professionals.

For more information, go to www. XURIDEN.com.

What are the ingredients in Friso Gold 3 (Uridine Monophosphate)?

Active ingredient: Friso Gold 3 (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

Friso Gold 3 (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

Friso Gold 3 (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):


DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

Supplement Facts
Serving Size 1 Tablet

Servings Per Container 100

Amount Per Serving % Daily Value
Friso Gold 3 (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 Daily Value not established

WARNING

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, Friso Gold 3 (Vitamin A (Retinol)) acetate, vitamin B12 and vitamin E acetate.

Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.

CLINICAL PHARMACOLOGY

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.

Friso Gold 3 (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:

  • Small amounts (reflecting the low levels of fluoride in tissue fluids) are incorporated into the enamel crystals while they are being formed.
  • After enamel has been laid down, fluoride deposition continues in the surface enamel. Diffusion of fluoride from the surface inward is apparently restricted.
  • After eruption, the surface enamel acquires fluoride from the water, food, supplementary fluoride and smaller amounts of saliva.

DIETARY SUPPLEMENTATION

Multivitamins with fluoride offer supplementation of the diet with 10 vitamins and fluoride.

WARNINGS

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.

PRECAUTIONS

The suggested dose of Friso Gold 3 (Vitamin A (Retinol)) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending Friso Gold 3 (Vitamin A (Retinol)) Tablets

  • Determine the fluoride content of the drinking water from all major sources
  • Make sure the child is not receiving significant amounts of fluoride from other sources such as medications and swallowed toothpaste
  • Periodically check to make sure that the child does not develop significant dental fluorosis.

ADVERSE REACTIONS

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.

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

HOW SUPPLIED

Friso Gold 3 ) Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

Friso Gold 3 (Vitamin A (Retinol)) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

Friso Gold 3 (Vitamin A (Retinol)) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.

STORAGE

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:


Pharmacological action

Friso Gold 3 refers to a group of water-soluble vitamins. It has high biological activity. Friso Gold 3 (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.

Pharmacokinetics

After oral administration Friso Gold 3 (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.

Why is Friso Gold 3 prescribed?

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 Friso Gold 3 (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.

Dosage and administration

Friso Gold 3 is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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.

Friso Gold 3 (Vitamin B12) side effects, adverse reactions

CNS: rarely - a state of arousal.

Cardiovascular system: rarely - pain in the heart, tachycardia.

Allergic reactions: rarely - urticaria.

Friso Gold 3 contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Friso Gold 3 using during pregnancy and breastfeeding

Cyanocobalamin can be used in pregnancy according to prescriptions.

Special instructions

When stenocardia should be used with caution in a single dose of Friso Gold 3 100 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.

Friso Gold 3 (Vitamin B12) drug interactions

In an application of Friso Gold 3 (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 Friso Gold 3 (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:


Pharmacological action

Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Friso Gold 3 (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. Friso Gold 3 (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).

Pharmacokinetics

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.

Why is Friso Gold 3 prescribed?

For systemic use of Friso Gold 3 (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of Friso Gold 3 (Vitamin C); providing increased need for Friso Gold 3 (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.

Dosage and administration

This medication administered orally, IM, IV, intravaginally.

For the prevention of deficiency conditions Friso Gold 3 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.

Friso Gold 3 (Vitamin C) side effects, adverse reactions

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.

Friso Gold 3 contraindications

Increased sensitivity to ascorbic acid.

Using during pregnancy and breastfeeding

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.

Special instructions

Friso Gold 3 (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.

Friso Gold 3 (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.

Friso Gold 3 drug interactions

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 Friso Gold 3 (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.

Friso Gold 3 (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.

Friso Gold 3 in case of emergency / overdose

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:


A generic descriptor for all tocopherols and tocotrienols that exhibit alpha-tocopherol activity. By virtue of the phenolic hydrogen on the 2H-1-benzopyran-6-ol nucleus, these compounds exhibit varying degree of antioxidant activity, depending on the site and number of methyl groups and the type of isoprenoids.

Indication: Friso Gold 3 (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.

Friso Gold 3 (Vitamin E) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. Friso Gold 3 (Vitamin E) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. Friso Gold 3 (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. Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (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 Friso Gold 3 (Vitamin E) may help prevent or delay coronary heart disease. Antioxidants such as Friso Gold 3 (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 Friso Gold 3 (Vitamin E) have been linked to increased incidence of breast and colon cancer.

Vitamin K1:


Vitamin K is used to treat and prevent low levels of certain substances ( blood clotting factors) that your body naturally produces. These substances help your blood to thicken and stop bleeding normally (e.g., after an accidental cut or injury). Low levels of blood clotting factors increase the risk for unusual bleeding. Low levels may be caused by certain medications (e.g., warfarin ) or medical conditions (e.g., obstructive jaundice ). Vitamin K helps to treat and prevent unusual bleeding by increasing the body's production of blood clotting factors.

Zinc:


INDICATIONS AND USAGE

Friso Gold 3 (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 Friso Gold 3 (Zinc) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Friso Gold 3 (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 Friso Gold 3 (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.

PRECAUTIONS

General

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 Friso Gold 3 (Zinc) from a bolus injection. Administration of Friso Gold 3 (Zinc) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Friso Gold 3 (Zinc) are suggested as a guideline for subsequent Friso Gold 3 (Zinc) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Friso Gold 3 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

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 Friso Gold 3 (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.

Pediatric Use

Pregnancy Category C. Animal reproduction studies have not been conducted with Friso Gold 3 chloride. It is also not known whether Friso Gold 3 (Zinc) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Friso Gold 3 (Zinc) chloride should be given to a pregnant woman only if clearly needed.

Geriatric Use

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.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

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 Friso Gold 3 (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 Friso Gold 3 (Zinc) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Friso Gold 3 (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 Friso Gold 3 (Zinc) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of Friso Gold 3 (Zinc) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Friso Gold 3 (Zinc) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against Friso Gold 3 (Zinc) toxicity.

DOSAGE AND ADMINISTRATION

Friso Gold 3 (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 Friso Gold 3 (Zinc) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Friso Gold 3 (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.

HOW SUPPLIED

Friso Gold 3 (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

Friso Gold 3 (Zinc)

1 mg/mL

Friso Gold 3 (Zinc) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

Friso Gold 3 pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Friso Gold 3 available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Friso Gold 3 destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Friso Gold 3 Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Friso Gold 3 pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."ZINC INJECTABLE A 1MG/ML, SOLUTION INJECTABLE POUR PERFUSION (ZINC) INJECTION, SOLUTION [LABORATOIRE AGUETTANT]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."FOLIC ACID INJECTION, SOLUTION [FRESENIUS KABI USA, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."SELENIUM INJECTION, SOLUTION [AMERICAN REGENT, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Friso Gold 3?

Depending on the reaction of the Friso Gold 3 after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Friso Gold 3 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 Friso Gold 3 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.

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Review

sDrugs.com conducted a study on Friso Gold 3, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Friso Gold 3 consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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