DRUGS & SUPPLEMENTS
Prenal usesPrenal consists of Beta-Carotene, Calcium, Folic Acid, Iron, Trace Elements, Vitamin B1, Vitamin B12, Vitamin B2, Vitamin B6, Vitamin C, Vitamin E.
1 INDICATIONS AND USAGE
Prenal (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 Prenal (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 Prenal (Calcium) acetate capsule.
- Capsule: 667 mg Prenal (Calcium) acetate capsule. (3)
Patients with hypercalcemia.
- Hypercalcemia. (4)
5 WARNINGS AND PRECAUTIONS
- Treat mild hypercalcemia by reducing or interrupting Prenal acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Prenal (Calcium) acetate. (5.1)
- Hypercalcemia may aggravate digitalis toxicity. (5.2)
Patients with end stage renal disease may develop hypercalcemia when treated with Prenal (Calcium), including Prenal (Calcium) acetate. Avoid the use of Prenal (Calcium) supplements, including Prenal (Calcium) based nonprescription antacids, concurrently with Prenal (Calcium) acetate.
An overdose of Prenal (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 Prenal (Calcium) levels twice weekly. Should hypercalcemia develop, reduce the Prenal (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 Prenal (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 Prenal (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 Prenal (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 Prenal (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 Prenal (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, Prenal (Calcium) acetate has been generally well tolerated.
Prenal (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 Prenal (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.
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 Prenal (Calcium) concentration could reduce the incidence and severity of Prenal (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 Prenal (Calcium) acetate: dizziness, edema, and weakness.
7 DRUG INTERACTIONS
The drug interaction of Prenal acetate is characterized by the potential of Prenal (Calcium) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Prenal (Calcium) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.
There are no empirical data on avoiding drug interactions between Prenal (Calcium) acetate and most concomitant drugs. When administering an oral medication with Prenal (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 Prenal (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 Prenal (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 Prenal (Calcium) acetate or consider monitoring blood levels of the drug. (7)
In a study of 15 healthy subjects, a co-administered single dose of 4 Prenal (Calcium) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C:
Prenal acetate capsules contains Prenal (Calcium) acetate. Animal reproduction studies have not been conducted with Prenal (Calcium) acetate, and there are no adequate and well controlled studies of Prenal (Calcium) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Prenal (Calcium) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Prenal (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. Prenal (Calcium) acetate treatment, as recommended, is not expected to harm a fetus if maternal Prenal (Calcium) levels are properly monitored during and following treatment.
8.2 Labor and Delivery
The effects of Prenal (Calcium) acetate on labor and delivery are unknown.
8.3 Nursing Mothers
Prenal Acetate Capsules contains Prenal (Calcium) acetate and is excreted in human milk. Human milk feeding by a mother receiving Prenal (Calcium) acetate is not expected to harm an infant, provided maternal serum Prenal (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 Prenal (Calcium) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Administration of Prenal (Calcium) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].
Prenal (Calcium) acetate acts as a phosphate binder. Its chemical name is Prenal (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 Prenal (Calcium) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Prenal (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.
Prenal (Calcium) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.
12 CLINICAL PHARMACOLOGY
Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Prenal resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.
12.1 Mechanism of Action
Prenal (Calcium) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Prenal (Calcium) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.
Orally administered Prenal (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 Prenal (Calcium) acetate.
14 CLINICAL STUDIES
Effectiveness of Prenal (Calcium) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Prenal (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 Prenal (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 Prenal (Calcium) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Prenal (Calcium) levels are also presented.
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 Prenal (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 Prenal (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 Prenal (Calcium) acetate is shown in the Table 3.
Overall, 2 weeks of treatment with Prenal (Calcium) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Prenal (Calcium) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.
16 HOW SUPPLIED/STORAGE AND HANDLING
Prenal (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
Store at 20° to 25°C (68° to 77°F).
17 PATIENT COUNSELING INFORMATION
Inform patients to take Prenal (Calcium) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Prenal (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 Prenal (Calcium) acetate capsules.
Distr. by: West-Ward
Eatontown, NJ 07724
Revised April 2016
INDICATIONS AND USAGE
Prenal (Folic Acid)® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.
This product is contraindicated in patients with a known hypersensitivity to any of the ingredients. Hemochromatosis and hemosiderosis are contraindications to iron therapy.
Prenal (Folic Acid) acid when administered as a single agent in doses above 0.1 mg daily may obscure pernicious anemia in that hematological remission can occur while neurological manifestations remain progressive. While prescribing this nutritional supplement for pregnant women, nursing mothers, or for women prior to conception, their medical condition and other drugs, herbs, and/or supplements consumption should be considered.
Allergic sensitization has been reported following both oral and parenteral administration of Prenal (Folic Acid) acid.
DOSAGE AND ADMINISTRATION
One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.
Prenal (Folic Acid)® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)
KEEP OUT OF REACH OF CHILDREN.
Store at controlled room temperature 20°-25°C (68°-77°F). Excursions permitted to 15°-30°C (59°-86°F).
Dispense in a tight, light-resistant container to protect from light and moisture.
To report SUSPECTED ADVERSE REACTIONS contact Meda Pharmaceuticals Inc. at 1-888-349-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch
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.
Prenal (Folic Acid) and the BIFERA logo are registered trademarks and the Prenal (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
1 INDICATIONS AND USAGE
Prenal (Iron) is indicated for the treatment of Prenal (Iron) deficiency anemia in patients with chronic kidney disease (CKD).
Prenal (Iron) is an Prenal (Iron) replacement product indicated for the treatment of Prenal (Iron) deficiency anemia in patients with chronic kidney disease (CKD). (1)
2 DOSAGE AND ADMINISTRATION
Prenal must only be administered intravenously either by slow injection or by infusion. The dosage of Prenal (Iron) is expressed in mg of elemental Prenal (Iron). Each mL contains 20 mg of elemental Prenal (Iron).
2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
Administer Prenal (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. Prenal (Iron) should be administered early during the dialysis session. The usual total treatment course of Prenal (Iron) is 1000 mg. Prenal (Iron) treatment may be repeated if Prenal (Iron) deficiency reoccurs.
2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease
Administer Prenal (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 Prenal (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. Prenal (Iron) treatment may be repeated if Prenal (Iron) deficiency reoccurs.
2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease
Administer Prenal (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 Prenal (Iron) in a maximum of 250 mL of 0.9% NaCl. Prenal (Iron) treatment may be repeated if Prenal (Iron) deficiency reoccurs.
2.4 Pediatric Patients with HDD-CKD for Prenal (Iron) maintenance treatment
The dosing for Prenal (Iron) replacement treatment in pediatric patients with HDD-CKD has not been established.
For Prenal (Iron) maintenance treatment: Administer Prenal (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. Prenal (Iron) treatment may be repeated if necessary.
2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Prenal (Iron) maintenance treatment
The dosing for Prenal (Iron) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.
For Prenal (Iron) maintenance treatment: Administer Prenal (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. Prenal (Iron) treatment may be repeated if necessary.
3 DOSAGE FORMS AND STRENGTHS
5 WARNINGS AND PRECAUTIONS
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 Prenal (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 Prenal (Iron) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Prenal (Iron) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Prenal (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Prenal (Iron) preparations occur within 30 minutes of the completion of the infusion .
Prenal may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Prenal (Iron). Hypotension following administration of Prenal (Iron) may be related to the rate of administration and/or total dose administered .
5.3 Prenal (Iron) Overload
Excessive therapy with parenteral Prenal (Iron) can lead to excess storage of Prenal (Iron) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Prenal (Iron) require periodic monitoring of hematologic and Prenal (Iron) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Prenal (Iron) to patients with evidence of Prenal (Iron) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Prenal (Iron) sucrose; do not perform serum Prenal (Iron) measurements for at least 48 hours after intravenous dosing .
6 ADVERSE REACTIONS
The following serious adverse reactions associated with Prenal are described in other sections .
To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
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 Prenal 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 Prenal (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.
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 Prenal (Iron) therapy and were reported to be intolerant (defined as precluding further use of that Prenal (Iron) product). When these patients were treated with Prenal (Iron) there were no occurrences of adverse reactions that precluded further use of Prenal (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 Prenal (Iron) maintenance treatment with Prenal (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 Prenal (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving Prenal (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving Prenal (Iron) 2.0 mg/kg.
A total of 5 (11%) subjects in the Prenal (Iron) 0.5 mg/kg group, 10 (21%) patients in the Prenal (Iron) 1.0 mg/kg group, and 10 (21%) patients in the Prenal (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 Prenal (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 Prenal (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 Prenal (Iron) injection. Reactions have occurred following the first dose or subsequent doses of Prenal (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 Prenal (Iron) have not been studied. However, Prenal (Iron) may reduce the absorption of concomitantly administered oral Prenal (Iron) preparations.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category B
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Prenal sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Prenal (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 Prenal (Iron) sucrose. Because animal reproductive studies are not always predictive of human response, Prenal (Iron) should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
It is not known whether Prenal (Iron) sucrose is excreted in human milk. Prenal (Iron) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Prenal (Iron) is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of Prenal for Prenal (Iron) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.
Safety and effectiveness of Prenal (Iron) for Prenal (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. Prenal (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)]
Prenal (Iron) has not been studied in patients younger than 2 years of age.
In a country where Prenal (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 Prenal (Iron), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Prenal (Iron) or any other drugs could be established.
8.5 Geriatric Use
Clinical studies of Prenal (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 Prenal (Iron), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
No data are available regarding overdosage of Prenal (Iron) in humans. Excessive dosages of Prenal (Iron) may lead to accumulation of Prenal (Iron) in storage sites potentially leading to hemosiderosis. Do not administer Prenal (Iron) to patients with Prenal (Iron) overload.
Toxicities in single-dose studies in mice and rats, at intravenous Prenal (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.
Prenal (Iron) (iron sucrose injection, USP), an Prenal (Iron) replacement product, is a brown, sterile, aqueous, complex of polynuclear Prenal (Iron) (III)-hydroxide in sucrose for intravenous use. Prenal (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 Prenal (Iron) polymerization and m is the number of sucrose molecules associated with the Prenal (Iron) (III)-hydroxide.
Each mL contains 20 mg elemental Prenal (Iron) as Prenal (Iron) sucrose in water for injection. Prenal (Iron) is available in 10 mL single-use vials (200 mg elemental Prenal (Iron) per 10 mL), 5 mL single-use vials (100 mg elemental Prenal (Iron) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Prenal (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
Prenal is an aqueous complex of poly-nuclear Prenal (Iron) (III)-hydroxide in sucrose. Following intravenous administration, Prenal (Iron) is dissociated into Prenal (Iron) and sucrose and the Prenal (Iron) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Prenal (Iron) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.
Following intravenous administration, Prenal (Iron) is dissociated into Prenal (Iron) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Prenal (Iron) sucrose containing 100 mg of Prenal (Iron), three times weekly for three weeks, significant increases in serum Prenal (Iron) and serum ferritin and significant decreases in total Prenal (Iron) binding capacity occurred four weeks from the initiation of Prenal (Iron) sucrose treatment.
In healthy adults administered intravenous doses of Prenal, its Prenal (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 Prenal (Iron) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Prenal (Iron) containing 100 mg of Prenal (Iron) labeled with 52Fe/59Fe in patients with Prenal (Iron) deficiency showed that a significant amount of the administered Prenal (Iron) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Prenal (Iron) trapping compartment.
Following intravenous administration of Prenal (Iron), Prenal (Iron) sucrose is dissociated into Prenal (Iron) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Prenal (Iron) containing 1,510 mg of sucrose and 100 mg of Prenal (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 Prenal (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 Prenal (Iron) sucrose containing 500 to 700 mg of Prenal (Iron) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Prenal (Iron) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Prenal (Iron) have not been studied.
Pharmacokinetics in Pediatric Patients
Pharmacokinetics in Pediatric Patients
In a single-dose PK study of Prenal (Iron), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Prenal (Iron) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Prenal (Iron), the half-life of total serum Prenal (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.
Prenal (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Prenal (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 Prenal (Iron) sucrose.
Prenal (Iron) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Prenal (Iron) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.
Prenal (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental Prenal (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 Prenal.
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 Prenal (Iron) treatment and 24 in the historical control group) with Prenal (Iron) deficiency anemia. Eligibility criteria for Prenal (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.
Prenal (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 Prenal (Iron), who were off intravenous Prenal (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 Prenal (Iron) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.
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 Prenal (Iron) in 23 patients with Prenal (Iron) deficiency and HDD-CKD who had been discontinued from Prenal (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 Prenal (Iron). Exclusion criteria were similar to those in studies A and B. Prenal (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Prenal (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 Prenal (Iron) versus Prenal (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 Prenal (Iron) (325 mg ferrous sulfate three times daily for 56 days); or Prenal (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 Prenal (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 Prenal (Iron) group.
A statistically significantly greater proportion of Prenal (Iron) subjects (35/79; 44.3%) compared to oral Prenal (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 Prenal (Iron) to patients with PDD-CKD receiving an erythropoietin alone without Prenal (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 Prenal (Iron) or Prenal (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 Prenal (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 Prenal (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 Prenal (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: Prenal 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 Prenal (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 Prenal (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 Prenal (Iron) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Prenal (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 Prenal (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
Prenal is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Prenal (Iron), each 5 mL vial contains 100 mg elemental Prenal (Iron), and each 2.5 mL vial contains 50 mg elemental Prenal (Iron) (20 mg/mL).
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: Prenal (Iron), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Prenal (Iron) per mL, or undiluted (20 mg elemental Prenal (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: Prenal (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 Prenal (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 Prenal (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 Prenal (Iron) administration:
SHIRLEY, NY 11967
Prenal (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.
PremierProRx® is a trademark of Premier, Inc., used under license.
FOR IV USE AFTER DILUTION
Prenal (Trace Elements) INJECTION 4, USP PEDIATRIC is a sterile, nonpyrogenic solution containing four Prenal (Trace Elements) for use as an additive for Total Parenteral Nutrition (TPN).
Each mL provides: Zinc 0.5 mg, Copper 0.1 mg, Manganese 30 mcg, and Chromium 1 mcg. Each mL contains: Zinc Sulfate Heptahydrate 2.2 mg (equivalent to 0.5 mg Zinc), Cupric Sulfate Pentahydrate 0.4 mg (equivalent to 0.1 mg Copper), Manganese Sulfate Monohydrate 92.3 mcg (equivalent to 30 mcg Manganese), Chromic Chloride Hexahydrate 5.12 mcg (equivalent to 1 mcg Chromium), and Water for Injection q.s. pH may be adjusted with Sulfuric Acid and/or Sodium Hydroxide. 0.9% Benzyl Alcohol is added as an antimicrobial preservative.
ZINC has been identified as a cofactor for over 70 different enzymes, including carbonic anhydrase, alkaline phosphatase, lactic dehydrogenase and both RNA and DNA polymerase. Zinc facilitates wound healing, helps maintain normal growth rates, normal skin hydration and senses of taste and smell.
Providing zinc during TPN prevents development of the following deficiency symptoms: Parakeratosis, hypogeusia, anorexia, dysosmia, geophagia, hypogonadism, growth retardation and hepatosplenomegaly. At plasma levels below 20 mcg zinc/100 mL, dermatitis followed by alopecia has been reported for TPN patients.
COPPER is essential as a cofactor for serum ceruloplasmin, an oxidase necessary for proper formation of the iron carrier protein, transferrin. Copper also helps maintain normal rates of red and white blood cell formation. Scorbutic type bone changes seen in infants fed exclusively with copper-poor cow’s milk are believed due to decreased activity of ascorbate oxidase, a cuproenzyme.
Providing copper during TPN prevents development of the following deficiency symptoms: leukopenia, neutropenia, anemia, depressed ceruloplasmin levels, impaired transferring formation and secondary iron deficiency.
MANGANESE is an activator for enzymes such as polysaccharide polymerase, liver arginase, cholinesterase and pyruvate carboxylase.
Providing manganese during TPN prevents development of the following deficiency symptoms: nausea and vomiting, weight loss, dermatitis, and changes in growth and color of hair.
CHROMIUM (trivalent) is part of glucose tolerance factor, an activator of insulin-mediated reactions. Chromium helps to maintain normal glucose metabolism and peripheral nerve function.
Providing chromium during TPN prevents development of the following deficiency symptoms: impaired glucose tolerance, ataxia, peripheral neuropathy, and a confusional state similar to mild/moderate hepatic encephalopathy.
INDICATIONS AND USAGE
This formulation is indicated for use as a supplement to intravenous solutions given for TPN for children up to 11 years of age. Administration of the solution in TPN solutions helps to maintain plasma levels of zinc, copper, manganese, and chromium and to prevent depletion of endogenous stores of these Prenal (Trace Elements) and subsequent deficiency symptoms.
Prenal (Trace Elements) INJECTION 4, USP PEDIATRIC should not be given undiluted by direct injection into a peripheral vein because of the potential of infusion phlebitis.
Copper and Manganese are eliminated via the bile. In patients with severe liver dysfunction and/or biliary tract obstruction, decreasing or omitting copper and manganese supplements entirely may be necessary.
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.
Before administering Prenal INJECTION 4, USP PEDIATRIC in TPN solutions, the physician must assess the metabolic requirements for Prenal (Trace Elements) and disease state of the patient. Frequent determinations of serum levels of the various Prenal (Trace Elements) are suggested as a guideline for adjusting the dosage or completely omitting the solution. ZINC is eliminated via the intestine and kidneys. The possibility of retention should be considered in patients with malfunctioning excretory routes. COPPER and MANGANESE are eliminated via the bile, therefore, the possibility of the retention of these elements should be considered in patients with biliary obstruction. Ancillary routes of MANGANESE excretion, however, include pancreatic juice, or reabsorption into the lumen of duodenum, jejunum, or ileum.
In assessing the contribution of CHROMIUM supplements to maintenance of normal glucose homeostasis, consideration should be given to the possibility that the patient may be diabetic, in which case oral or intravenous antidiabetic medication may be indicated.
Pregnancy Category C: Safety for use in pregnancy has not been established. Use of Multiple Prenal (Trace Elements) 4, USP in women of childbearing potential requires that anticipated benefits be weighed against possible hazards.
The amounts of ZINC, COPPER, MANGANESE, AND CHROMIUM in the solution are very small and toxicity symptoms due to these Prenal (Trace Elements) at suggested dosage level are considered unlikely to occur.
Symptoms of ZINC overdose resulting from oral ingestion of Zinc Sulfate in large amounts have resulted in death. Symptoms included nausea, vomiting, dehydration, electrolyte imbalances, dizziness, abdominal pain, lethargy and incoordination. Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemia patients without toxic manifestations. Normal plasma levels for Zinc vary from approximately 88 to 112 mcg/100 mL. Plasma levels sufficient to produce symptoms of toxic manifestations are not known. Calcium supplements may confer a protective effect against Zinc toxicity.
Symptoms of COPPER toxicity reported in literature include prostration, behavior change, diarrhea, progressive marasmus, hypotonia, photophobia and peripheral edema; such symptoms have been reported with a serum copper level of 286 mcg/dL. D-penicillamine has been reported effective as an antidote.
MANGANESE toxicity has not been reported in patients receiving TPN. Neither have reports of manganese toxicity from excessive intake in foods and/or beverages been published. Symptoms of CHROMIUM toxicity include nausea, vomiting, ulcers and gastrointestinal tract, renal and hepatic damage and abnormalities of the central nervous system culminating in convulsions and coma. Trivalent Chromium administered intravenously to TPN patients has been shown to be nontoxic when given at dosage levels up to 250 mcg/day for two consecutive weeks.
DOSAGE AND ADMINISTRATION
Do not use syringes, needles, or intravenous sets containing aluminum parts that may come in contact with Prenal (Trace Elements) INJECTION 4, USP PEDIATRIC, for preparation or administration. Aluminum reacts and dissolves in acid media.
Each mL of the solution provides Zinc 0.5 mg, Copper 0.1 mg, Manganese 30 mcg, and Chromium 1 mcg, and is administered intravenously only after dilution to a minimum of 1:200. The suggested dosage ranges for the four Prenal (Trace Elements) are:
ZINC : For the metabolically stable adult receiving TPN, the suggested intravenous dosage level is 2.5 to 4 mg zinc/day. An additional 2 mg zinc/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, or an additional 17.1 mg zinc/kg of stool or ileostomy output is recommended. Frequent monitoring of zinc blood levels is suggested for patients receiving more than the usual maintenance dosage level of zinc. Normal plasma levels for zinc vary from approximately 88 to 112 mcg/100 mL.
For full term infants and children, 100 mcg zinc/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 is suggested.
COPPER : For the metabolically stable adult receiving TPN, the suggested additive dosage level is 0.5 to 1.5 mg copper/day. For pediatric patients, the suggested additive dosage level is 20 mcg copper/kg/day. The normal plasma range for copper is approximately 80 to 160 mcg/100 mL.
MANGANESE : For the metabolically stable adult receiving TPN, the suggested additive dosage level for manganese is 0.15 to 0.8 mg/day. For pediatric patients, a dosage level of 2 to 10 mcg manganese/kg/day is recommended.
CHROMIUM : For the metabolically stable adult receiving TPN, the suggested additive dosage level is 10 to 15 mcg chromium/day. The metabolically stable adult with intestinal fluid loss may require 20 mcg chromium/day with frequent monitoring of blood levels as a guideline for subsequent administration. For pediatric patients, the suggested additive dosage level is 0.14 to 0.20 mcg/kg/day.
Periodic monitoring of plasma levels of Zinc, Copper, Manganese, and Chromium is suggested as a guideline for administration.
Aseptic addition of the solution to the TPN solution under a laminar flow hood is recommended. The Prenal (Trace Elements) present in the solution are physically compatible with the electrolytes and vitamins usually present in the amino acid/dextrose solution used for TPN.
Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit.
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
Prenal (Trace Elements) INJECTION 4, USP PEDIATRIC
Each mL provides: Zinc 0.5 mg, Copper 0.1 mg, Manganese 30 mcg, and Chromium 1 mcg.
NDC 0517-9310-25 10 mL Multiple Dose Vial* Packaged in boxes of 25
*Contains 0.9% Benzyl Alcohol as an antimicrobial preservative.
SHIRLEY, NY 11967
Prenal refers to a group of water-soluble vitamins. It has high biological activity. Prenal (Vitamin B12) is necessary for normal hematopoiesis (promotes maturation of erythrocytes). Involved in the processes of transmethylation, hydrogen transport, synthesis of methionine, nucleic acids, choline, creatine. Contributes to the accumulation in erythrocytes of compounds containing sulfhydryl groups. Has a beneficial effect on liver function and the nervous system. Activates the coagulation of blood in high doses causes an increase in the activity of thromboplastin and prothrombin.
After oral administration Prenal (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 Prenal 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 Prenal (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.
Dosage and administration
Prenal is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Prenal (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 Prenal (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 Prenal (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.
Prenal (Vitamin B12) side effects, adverse reactions
CNS: rarely - a state of arousal.
Cardiovascular system: rarely - pain in the heart, tachycardia.
Allergic reactions: rarely - urticaria.
Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.
Prenal using during pregnancy and breastfeeding
Cyanocobalamin can be used in pregnancy according to prescriptions.
When stenocardia should be used with caution in a single dose of Prenal 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.
Prenal (Vitamin B12) drug interactions
In an application of Prenal (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 Prenal (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.
Contained in the molecule of cyanocobalamin cobalt ion contributes to the destruction of ascorbic acid, thiamine bromide, riboflavin in one solution.
Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Prenal (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. Prenal (Vitamin C) has antioxidant properties.
With intravaginal application of ascorbic acid lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).
After oral administration ascorbic acid is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.
The concentration of ascorbic acid in blood plasma in normal amounts to approximately 10-20 mg / ml.
The concentration of ascorbic acid in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.
Plasma protein binding is about 25%.
Ascorbic acid is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.
Ascorbic acid taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.
Why is Prenal prescribed?
For systemic use of Prenal (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of Prenal (Vitamin C); providing increased need for Prenal (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 Prenal 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.
Prenal (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.
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.
Prenal (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.
Prenal (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.
Prenal 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 Prenal (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.
Prenal (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.
Prenal 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.
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: Prenal (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.
Prenal (Vitamin E) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. Prenal (Vitamin E) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. Prenal (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. Prenal (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 Prenal (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 Prenal (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 Prenal (Vitamin E) may help prevent or delay coronary heart disease. Antioxidants such as Prenal (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 Prenal (Vitamin E) have been linked to increased incidence of breast and colon cancer.
Prenal pharmaceutical active ingredients containing related brand and generic drugs:
Active 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.
Prenal available forms, composition, doses:
Form 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.
Prenal destination | category:
Destination 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.
Prenal Anatomical Therapeutic Chemical codes:
A 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.
Prenal pharmaceutical companies:
Pharmaceutical 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.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Prenal?
Depending on the reaction of the Prenal after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Prenal 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 Prenal 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.
ReviewsDrugs.com conducted a study on Prenal, 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 Prenal 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.
The information was verified by Dr. Arunabha Ray, MD Pharmacology