|
|||
DRUGS & SUPPLEMENTS
|
How long you have been taking the medicine? |
Calcium:
Zimaron Granules (Calcium) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).
- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)
The recommended initial dose of Zimaron Granules (Calcium) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.
- Starting dose is 2 capsules with each meal. (2)
- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)
Capsule: 667 mg Zimaron Granules (Calcium) acetate capsule.
- Capsule: 667 mg Zimaron Granules (Calcium) acetate capsule. (3)
Patients with hypercalcemia.
- Hypercalcemia. (4)
- Treat mild hypercalcemia by reducing or interrupting Zimaron Granules acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Zimaron Granules (Calcium) acetate. (5.1)
- Hypercalcemia may aggravate digitalis toxicity. (5.2)
Patients with end stage renal disease may develop hypercalcemia when treated with Zimaron Granules (Calcium), including Zimaron Granules (Calcium) acetate. Avoid the use of Zimaron Granules (Calcium) supplements, including Zimaron Granules (Calcium) based nonprescription antacids, concurrently with Zimaron Granules (Calcium) acetate.
An overdose of Zimaron Granules (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 Zimaron Granules (Calcium) levels twice weekly. Should hypercalcemia develop, reduce the Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Calcium) acetate; all cases resolved upon lowering the dose or discontinuing treatment.
Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg2/dL2.
Hypercalcemia may aggravate digitalis toxicity.
Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].
- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)
- In clinical studies, patients have occasionally experienced nausea during Zimaron Granules (Calcium) acetate therapy. (6)
To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In clinical studies, Zimaron Granules (Calcium) acetate has been generally well tolerated.
Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Calcium) acetate N=167 N (%) | 3 month, open label study of Zimaron Granules (Calcium) acetate N=98 N (%) | Double blind, placebo-controlled, cross-over study of liquid Zimaron Granules (Calcium) acetate N=69 | |
Zimaron Granules (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 Zimaron Granules (Calcium) concentration could reduce the incidence and severity of Zimaron Granules (Calcium) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.
The following additional adverse reactions have been identified during post-approval of Zimaron Granules (Calcium) acetate: dizziness, edema, and weakness.
The drug interaction of Zimaron Granules acetate is characterized by the potential of Zimaron Granules (Calcium) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Zimaron Granules (Calcium) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.
There are no empirical data on avoiding drug interactions between Zimaron Granules (Calcium) acetate and most concomitant drugs. When administering an oral medication with Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Calcium) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.
Pregnancy Category C:
Zimaron Granules acetate capsules contains Zimaron Granules (Calcium) acetate. Animal reproduction studies have not been conducted with Zimaron Granules (Calcium) acetate, and there are no adequate and well controlled studies of Zimaron Granules (Calcium) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Zimaron Granules (Calcium) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Zimaron Granules (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. Zimaron Granules (Calcium) acetate treatment, as recommended, is not expected to harm a fetus if maternal Zimaron Granules (Calcium) levels are properly monitored during and following treatment.
The effects of Zimaron Granules (Calcium) acetate on labor and delivery are unknown.
Zimaron Granules Acetate Capsules contains Zimaron Granules (Calcium) acetate and is excreted in human milk. Human milk feeding by a mother receiving Zimaron Granules (Calcium) acetate is not expected to harm an infant, provided maternal serum Zimaron Granules (Calcium) levels are appropriately monitored.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of Zimaron Granules (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 Zimaron Granules (Calcium) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].
Zimaron Granules (Calcium) acetate acts as a phosphate binder. Its chemical name is Zimaron Granules (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 Zimaron Granules (Calcium) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Zimaron Granules (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.
Zimaron Granules (Calcium) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.
Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Zimaron Granules resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.
Zimaron Granules (Calcium) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Zimaron Granules (Calcium) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.
Orally administered Zimaron Granules (Calcium) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.
No carcinogenicity, mutagenicity, or fertility studies have been conducted with Zimaron Granules (Calcium) acetate.
Effectiveness of Zimaron Granules (Calcium) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Calcium) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Zimaron Granules (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 |
Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Calcium) acetate is shown in the Table 3.
* ANOVA of Zimaron Granules (Calcium) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM. | ||||
Parameter | Pre-Study | Post-Treatment | p-value* | |
Zimaron Granules (Calcium) Acetate | Placebo | |||
Phosphorus (mg/dL)† | 7.3 ± 0.18 | 5.9 ± 0.24 | 7.8 ± 0.22 | <0.01 |
Zimaron Granules (Calcium) (mg/dL)† | 8.9 ± 0.11 | 9.5 ± 0.13 | 8.8 ± 0.12 | <0.01 |
Overall, 2 weeks of treatment with Zimaron Granules (Calcium) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Zimaron Granules (Calcium) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.
Zimaron Granules (Calcium) Acetate Capsules
667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.
NDC 0615-2303-39: Blistercards of 30 Capsules
NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules
STORAGE
Store at 20° to 25°C (68° to 77°F).
Inform patients to take Zimaron Granules (Calcium) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Zimaron Granules (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 Zimaron Granules (Calcium) acetate capsules.
Distr. by: West-Ward
Pharmaceuticals Corp.
Eatontown, NJ 07724
10003705/05
Revised April 2016
Fiber Natural:
Folic Acid:
Zimaron Granules (Folic Acid)® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.
This product is contraindicated in patients with a known hypersensitivity to any of the ingredients. Hemochromatosis and hemosiderosis are contraindications to iron therapy.
WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately. |
Zimaron Granules (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 Zimaron Granules (Folic Acid) acid.
One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.
Zimaron Granules (Folic Acid)® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)
KEEP OUT OF REACH OF CHILDREN.
Store at controlled room temperature 20°-25°C (68°-77°F). Excursions permitted to 15°-30°C (59°-86°F).
Dispense in a tight, light-resistant container to protect from light and moisture.
To report SUSPECTED ADVERSE REACTIONS contact Meda Pharmaceuticals Inc. at 1-888-349-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch
Distributed by:
Meda Pharmaceuticals Inc.
Somerset New Jersey 08873-4120
© 2014 Meda Pharmaceuticals Inc.
U.S. Patent Nos. 7,585,527 and 8,080,520
Proferrin® is a registered trademark of Colorado BioLabs, Inc., Cozad, NE.
Zimaron Granules (Folic Acid) and the BIFERA logo are registered trademarks and the Zimaron Granules (Folic Acid) logo is a trademark of Alaven Pharmaceutical LLC, used under license by Meda Pharmaceuticals Inc.
MEDA PHARMACEUTICALS mark and logo are trademarks of Meda AB.
IN-6885-02 Rev 6/2014
Iodine:
Directions:
Topical Antiseptic
Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Zimaron Granules (Iodine) with a swab.
If necessary, clip hair around the area being treated and clean with soap and water.
Apply Zimaron Granules (Iodine) Tincture 7% only once daily. Dilute product 3 to 1 if repeating application.
Do not apply under bandage.
Irritation may occur if used on tender skin areas. If redness, irritation, or swelling persists or increases, discontinue use and consult a veterinarian.
Storage:
Store at 2-30 degrees C (36-86 degrees F).
Keep container away from heat and out of sunlight. Rinse empty container thoroughly and discard.
DANGER - Poison
Caution:
If swallowed, give starch paste, milk, bread, egg white, or
activated charcoal. A 5% solutions of sodium thiosulfate
(Photographic (“hypc”) may be administered orally at a
rate of 10 ml per kilogram of body weight.
Eye irritant: Use only as directed. Avoid contact with eyes. In case of contact, flush eyes immediately with tepid water for at least 15 minutes. Consult a physician.
Avoid contamination of food.
Not for use on burns, deep cuts, or body cavities.
image description
Iron:
Zimaron Granules (Iron) is indicated for the treatment of Zimaron Granules (Iron) deficiency anemia in patients with chronic kidney disease (CKD).
Zimaron Granules (Iron) is an Zimaron Granules (Iron) replacement product indicated for the treatment of Zimaron Granules (Iron) deficiency anemia in patients with chronic kidney disease (CKD). (1)
Zimaron Granules must only be administered intravenously either by slow injection or by infusion. The dosage of Zimaron Granules (Iron) is expressed in mg of elemental Zimaron Granules (Iron). Each mL contains 20 mg of elemental Zimaron Granules (Iron).
Population | Dose | |
Adult patients | Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1) | 100 mg slow intravenous injection or infusion |
Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2) | 200 mg slow intravenous injection or infusion | |
Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) | 300 mg or 400 mg intravenous infusion | |
Pediatric patients | HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5) | 0.5 mg/kg slow intravenous injection or infusion |
Administer Zimaron Granules (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. Zimaron Granules (Iron) should be administered early during the dialysis session. The usual total treatment course of Zimaron Granules (Iron) is 1000 mg. Zimaron Granules (Iron) treatment may be repeated if Zimaron Granules (Iron) deficiency reoccurs.
Administer Zimaron Granules (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 Zimaron Granules (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. Zimaron Granules (Iron) treatment may be repeated if Zimaron Granules (Iron) deficiency reoccurs.
Administer Zimaron Granules (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 Zimaron Granules (Iron) in a maximum of 250 mL of 0.9% NaCl. Zimaron Granules (Iron) treatment may be repeated if Zimaron Granules (Iron) deficiency reoccurs.
The dosing for Zimaron Granules (Iron) replacement treatment in pediatric patients with HDD-CKD has not been established.
For Zimaron Granules (Iron) maintenance treatment: Administer Zimaron Granules (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. Zimaron Granules (Iron) treatment may be repeated if necessary.
The dosing for Zimaron Granules (Iron) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.
For Zimaron Granules (Iron) maintenance treatment: Administer Zimaron Granules (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. Zimaron Granules (Iron) treatment may be repeated if necessary.
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Zimaron Granules (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 Zimaron Granules (Iron) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Zimaron Granules (Iron) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Zimaron Granules (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Zimaron Granules (Iron) preparations occur within 30 minutes of the completion of the infusion .
Zimaron Granules may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Zimaron Granules (Iron). Hypotension following administration of Zimaron Granules (Iron) may be related to the rate of administration and/or total dose administered .
Excessive therapy with parenteral Zimaron Granules (Iron) can lead to excess storage of Zimaron Granules (Iron) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Zimaron Granules (Iron) require periodic monitoring of hematologic and Zimaron Granules (Iron) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Zimaron Granules (Iron) to patients with evidence of Zimaron Granules (Iron) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Zimaron Granules (Iron) sucrose; do not perform serum Zimaron Granules (Iron) measurements for at least 48 hours after intravenous dosing .
The following serious adverse reactions associated with Zimaron Granules are described in other sections .
To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.
Adverse Reactions in Adult Patients with CKD
The frequency of adverse reactions associated with the use of Zimaron Granules 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 Zimaron Granules (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 | ||
Zimaron Granules (Iron) | Zimaron Granules (Iron) | Oral Zimaron Granules (Iron) | Zimaron Granules (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 Zimaron Granules (Iron) therapy and were reported to be intolerant (defined as precluding further use of that Zimaron Granules (Iron) product). When these patients were treated with Zimaron Granules (Iron) there were no occurrences of adverse reactions that precluded further use of Zimaron Granules (Iron) .
Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)
In a randomized, open-label, dose-ranging trial for Zimaron Granules (Iron) maintenance treatment with Zimaron Granules (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 Zimaron Granules (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving Zimaron Granules (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving Zimaron Granules (Iron) 2.0 mg/kg.
A total of 5 (11%) subjects in the Zimaron Granules (Iron) 0.5 mg/kg group, 10 (21%) patients in the Zimaron Granules (Iron) 1.0 mg/kg group, and 10 (21%) patients in the Zimaron Granules (Iron) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.
The following adverse reactions have been identified during post-approval use of Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Iron) injection. Reactions have occurred following the first dose or subsequent doses of Zimaron Granules (Iron). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.
Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.
Drug interactions involving Zimaron Granules (Iron) have not been studied. However, Zimaron Granules (Iron) may reduce the absorption of concomitantly administered oral Zimaron Granules (Iron) preparations.
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Zimaron Granules sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Zimaron Granules (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 Zimaron Granules (Iron) sucrose. Because animal reproductive studies are not always predictive of human response, Zimaron Granules (Iron) should be used during pregnancy only if clearly needed.
It is not known whether Zimaron Granules (Iron) sucrose is excreted in human milk. Zimaron Granules (Iron) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Zimaron Granules (Iron) is administered to a nursing woman.
Safety and effectiveness of Zimaron Granules for Zimaron Granules (Iron) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.
Safety and effectiveness of Zimaron Granules (Iron) for Zimaron Granules (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. Zimaron Granules (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)]
Zimaron Granules (Iron) has not been studied in patients younger than 2 years of age.
In a country where Zimaron Granules (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 Zimaron Granules (Iron), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Zimaron Granules (Iron) or any other drugs could be established.
Clinical studies of Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Iron) in humans. Excessive dosages of Zimaron Granules (Iron) may lead to accumulation of Zimaron Granules (Iron) in storage sites potentially leading to hemosiderosis. Do not administer Zimaron Granules (Iron) to patients with Zimaron Granules (Iron) overload.
Toxicities in single-dose studies in mice and rats, at intravenous Zimaron Granules (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.
Zimaron Granules (Iron) (iron sucrose injection, USP), an Zimaron Granules (Iron) replacement product, is a brown, sterile, aqueous, complex of polynuclear Zimaron Granules (Iron) (III)-hydroxide in sucrose for intravenous use. Zimaron Granules (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 Zimaron Granules (Iron) polymerization and m is the number of sucrose molecules associated with the Zimaron Granules (Iron) (III)-hydroxide.
Each mL contains 20 mg elemental Zimaron Granules (Iron) as Zimaron Granules (Iron) sucrose in water for injection. Zimaron Granules (Iron) is available in 10 mL single-use vials (200 mg elemental Zimaron Granules (Iron) per 10 mL), 5 mL single-use vials (100 mg elemental Zimaron Granules (Iron) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Zimaron Granules (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.
Zimaron Granules is an aqueous complex of poly-nuclear Zimaron Granules (Iron) (III)-hydroxide in sucrose. Following intravenous administration, Zimaron Granules (Iron) is dissociated into Zimaron Granules (Iron) and sucrose and the Zimaron Granules (Iron) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Zimaron Granules (Iron) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.
Following intravenous administration, Zimaron Granules (Iron) is dissociated into Zimaron Granules (Iron) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Zimaron Granules (Iron) sucrose containing 100 mg of Zimaron Granules (Iron), three times weekly for three weeks, significant increases in serum Zimaron Granules (Iron) and serum ferritin and significant decreases in total Zimaron Granules (Iron) binding capacity occurred four weeks from the initiation of Zimaron Granules (Iron) sucrose treatment.
In healthy adults administered intravenous doses of Zimaron Granules, its Zimaron Granules (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 Zimaron Granules (Iron) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Zimaron Granules (Iron) containing 100 mg of Zimaron Granules (Iron) labeled with 52Fe/59Fe in patients with Zimaron Granules (Iron) deficiency showed that a significant amount of the administered Zimaron Granules (Iron) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Zimaron Granules (Iron) trapping compartment.
Following intravenous administration of Zimaron Granules (Iron), Zimaron Granules (Iron) sucrose is dissociated into Zimaron Granules (Iron) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Zimaron Granules (Iron) containing 1,510 mg of sucrose and 100 mg of Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Iron) sucrose containing 500 to 700 mg of Zimaron Granules (Iron) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Zimaron Granules (Iron) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Zimaron Granules (Iron) have not been studied.
Pharmacokinetics in Pediatric Patients
In a single-dose PK study of Zimaron Granules (Iron), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Zimaron Granules (Iron) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Zimaron Granules (Iron), the half-life of total serum Zimaron Granules (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.
Zimaron Granules (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Zimaron Granules (Iron) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).
Carcinogenicity studies have not been performed with Zimaron Granules (Iron) sucrose.
Zimaron Granules (Iron) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Zimaron Granules (Iron) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.
Zimaron Granules (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental Zimaron Granules (Iron) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.
Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Zimaron Granules.
Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Zimaron Granules (Iron) treatment and 24 in the historical control group) with Zimaron Granules (Iron) deficiency anemia. Eligibility criteria for Zimaron Granules (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.
Zimaron Granules (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 Zimaron Granules (Iron), who were off intravenous Zimaron Granules (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 Zimaron Granules (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 | |||
Zimaron Granules (Iron) (n=69 | Historical Control (n=18) | Zimaron Granules (Iron) (n=73) | Historical Control (n=18) | Zimaron Granules (Iron) (n=71) | Historical Control (n=15) | |
Hemoglobin (g/dL) | 1.0 ± 0.12** | 0.0 ± 0.21 | 1.3 ± 0.14** | -0.6 ± 0.24 | 1.2 ± 0.17* | -0.1 ± 0.23 |
Hematocrit (%) | 3.1 ± 0.37** | -0.3 ± 0.65 | 3.6 ± 0.44** | -1.2 ± 0.76 | 3.3 ± 0.54 | 0.2 ± 0.86 |
Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).
Study B was a multicenter, open label study of Zimaron Granules (Iron) in 23 patients with Zimaron Granules (Iron) deficiency and HDD-CKD who had been discontinued from Zimaron Granules (Iron) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.
All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.
Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Zimaron Granules (Iron). Exclusion criteria were similar to those in studies A and B. Zimaron Granules (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Zimaron Granules (Iron) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.
The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.
Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Zimaron Granules (Iron) versus Zimaron Granules (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 Zimaron Granules (Iron) (325 mg ferrous sulfate three times daily for 56 days); or Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Iron) group.
A statistically significantly greater proportion of Zimaron Granules (Iron) subjects (35/79; 44.3%) compared to oral Zimaron Granules (Iron) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).
Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Zimaron Granules (Iron) to patients with PDD-CKD receiving an erythropoietin alone without Zimaron Granules (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 Zimaron Granules (Iron) or Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Iron) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).
Study F was a randomized, open-label, dose-ranging study for Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Iron) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Zimaron Granules (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 Zimaron Granules (Iron) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.
Zimaron Granules is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Zimaron Granules (Iron), each 5 mL vial contains 100 mg elemental Zimaron Granules (Iron), and each 2.5 mL vial contains 50 mg elemental Zimaron Granules (Iron) (20 mg/mL).
NDC-0517-2310-05 | 200 mg/10 mL Single-Use Vial | Packages of 5 |
NDC-0517-2310-10 | 200 mg/10 mL Single-Use Vial | Packages of 10 |
NDC-0517-2340-01 | 100 mg/5 mL Single-Use Vial | Individually Boxed |
NDC-0517-2340-10 | 100 mg/5 mL Single-Use Vial | Packages of 10 |
NDC-0517-2340-25 | 100 mg/5 mL Single-Use Vial | Packages of 25 |
NDC-0517-2340-99 | 100 mg/5 mL Single-Use Vial | Packages of 10 |
NDC-0517-2325-10 | 50 mg/2.5 mL Single-Use Vial | Packages of 10 |
NDC-0517-2325-25 | 50 mg/2.5 mL Single-Use Vial | Packages of 25 |
Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.
Syringe Stability: Zimaron Granules (Iron), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Zimaron Granules (Iron) per mL, or undiluted (20 mg elemental Zimaron Granules (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: Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Iron) with other medications or add to parenteral nutrition solutions for intravenous infusion.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.
Prior to Zimaron Granules (Iron) administration:
AMERICAN
REGENT, INC.
SHIRLEY, NY 11967
Zimaron Granules (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.
PremierProRx® is a trademark of Premier, Inc., used under license.
PREMIERProRx®
IN2340
MG #15727
Lysine:
Pharmacy Bulk Package
Not For Direct Infusion
Zimaron Granules (Lysine)® 15% Amino Acids Injection in a Pharmacy Bulk Package is a sterile, clear, nonpyrogenic solution of essential and nonessential amino acids for intravenous infusion in parenteral nutrition following appropriate dilution.
Zimaron Granules (Lysine)® 15% in a Pharmacy Bulk Package is not for direct infusion. It is a sterile dosage from which contains several single doses for use in a pharmacy admixture program in the preparation of intravenous parenteral fluids.
Each 100 mL contains:
Essential Amino Acids | ||
Zimaron Granules (Lysine) (from Zimaron Granules (Lysine) Acetate, USP)……………………………………...1.18 | g | |
Leucine, USP……………………………………………………………...1.04 | g | |
Phenylalanine, USP……………………………………...1.04 | g | |
Valine, USP……………………………………………………………...960 | mg | |
Isoleucine, USP………………………………………...749 | mg | |
Methionine, USP………………………………………...749 | mg | |
Threonine, USP………………………………………...749 | mg | |
Tryptophan, USP………………………………………...250 | mg | |
Nonessential Amino Acids | ||
Alanine, USP…………………………………………...2.17 | g | |
Arginine, USP…………………………………………...1.47 | g | |
Glycine, USP…………………………………………...1.04 | g | |
Histidine, USP…………………………………………...894 | mg | |
Proline, USP……………………………………………………………...894 | mg | |
Glutamic Acid…………………………………………...749 | mg | |
Serine, USP……………………………………………...592 | mg | |
Aspartic Acid, USP……………………………………...434 | mg | |
Tyrosine, USP…………………………………………...39 | mg | |
Sodium Metabisulfite, NF added……………………………………………...30 | mg | |
Water for Injection, USP……………………………………………………... | qs | |
Essential Amino Acids………………………………………………………...6.7 | g | |
Nonessential Amino Acids…………………………………………………...8.3 | g | |
Total Amino Acids…………………………………………………………...15.0 | g | |
Total Nitrogen………………………………………………………………...2.37 | g | |
Acetate*……………………………………………………...151 | mEq/L | |
Osmolarity (calculated)……………………………………...1388 | mOsmol/L | |
pH……………………………………………………………………………...5.6(5.2-6.0) | ||
*Acetate from Zimaron Granules (Lysine) Acetate, USP and acetic acid used for pH adjustment. |
The formulas for the individual amino acids are as follows:
Formulas for individual amino acids
Zimaron Granules (Lysine)® 15% Amino Acids Injection providesseventeen crystalline amino acids. This completely utilizable substrate promotesprotein synthesis and wound healing and reduces the rate of protein catabolism.
A.Total Parenteral Nutrition (Central Infusion)
When enteralfeeding is inadvisable, Zimaron Granules (Lysine)® 15% given by central venousinfusion in combination with energy sources, vitamins, trace elements andelectrolytes, will completely satisfy the requirements for weight maintenanceor weight gain, depending upon the dose selected. The energy component inparenteral nutrition by central infusion may be derived solely from dextroseor may be provided by a combination of dextrose and intravenous fat emulsion. The addition of intravenous fat emulsion provides essential fatty acids andpermits a dietary balance of fat and carbohydrate, at the same time offeringthe option of reducing the dextrose load and/or increasing the total caloricinput. An adequate energy supply is essential for optimal utilization of aminoacids.
B. Total Parenteral Nutrition (Peripheral Infusion)
Zimaron Granules (Lysine)® 15%can also be administered as part of a total parenteral nutrition program byperipheral vein when the enteral route is inadvisable and use of the centralvenous catheter is contraindicated.
Reduction of proteinloss can be achieved by use of diluted Zimaron Granules (Lysine)® 15% in combinationwith dextrose or with dextrose and intravenous fat emulsion by peripheralinfusion. Complete peripheral intravenous nutrition can be achieved in patientswith low caloric requirements by a Zimaron Granules (Lysine)®15%-dextrose-fatregimen.
Zimaron Granules (Lysine)® 15% is indicated as an amino acid(nitrogen) source in parenteral nutrition regimens. This use is appropriatewhen the enteral route is inadvisable, inadequate or not possible, as when:
-Gastrointestinal absorption is impaired by obstruction, inflammatory diseaseor its complications, or antineoplastic therapy;
-Bowel rest is needed because of gastrointestinal surgery or its complicationssuch as ileus, fistulae or anastomotic leaks;
-Tube feeding methods alone cannot provide adequate nutrition.
This solution should not be used in patients in hepatic coma,severe renal failure, metabolic disorders involving impaired nitrogen utilizationor hypersensitivity to one or more amino acids.
Administration of amino acids solutions at excessive ratesor to patients with hepatic insufficiency may result in plasma amino acidimbalances, hyperammonemia, prerenal azotemia, stupor and coma. Conservativedoses of amino acids should be given to these patients, dictated by the nutritionalstatus of the patient. Should symptoms of hyperammonemia develop, amino acidadministration should be discontinued and the patient’s clinical statusre-evaluated.
Contains sodium metabisulfite, a sulfitethat may cause allergic-type reactions including anaphylactic symptoms andlife-threatening or less severe asthmatic episodes in certain susceptiblepeople. The overall prevalence of sulfite sensitivity in the general populationis unknown and probably low.
Sulfite sensitivity isseen more frequently in asthmatic than in nonasthmatic people.
WARNING: This product contains aluminum that maybe toxic. Aluminum may reach toxic levels with prolonged parenteral administrationif kidney function is impaired. Premature neonates are particularly at riskbecause their kidneys are immature, and they require large amounts of calciumand phosphate solutions, which contain aluminum.
Researchindicates that patients with impaired kidney function, including prematureneonates, who receive parenteral levels of aluminum at greater than 4 to 5mcg/kg/day accumulate aluminum at levels associated with central nervous systemand bone toxicity. Tissue loading may occur at even lower rates of administration.
A. GENERAL
It is essential to provide adequate calories concurrently if parenterally administered amino acids are to be retained by the body and utilized for protein synthesis.
The administration of Zimaron Granules (Lysine)® 15% Amino Acids Injection as part of total parenteral nutrition (TPN) with large volumes of hyperosmotic fluids requires periodic monitoring of the patient for signs of hyperosmolarity, hyperglycemia, glycosuria and hypertriglyceridemia.
During parenteral nutrition with concentrated dextrose and amino acids solutions, essential fatty acid deficiency syndrome may develop but may not be clinically apparent. Early demonstration of this condition can only be accomplished by gas liquid chromatographic analysis of plasma lipids. The syndrome may be prevented or corrected by appropriate treatment with intravenous fat emulsions.
For complete nutritional support, TPN regimens must also include multiple vitamins and trace elements. Potentially incompatible ions such as calcium and phosphate may be added to alternate infusate bottles to avoid precipitation. Although the metabolizable acetate ion in Zimaron Granules (Lysine)® 15% diminishes the risk of acidosis, the physician must be alert to the potential appearance of this disorder.
Initiation and termination of infusions of TPN fluids must be gradual to permit adjustment of endogenous insulin release.
Undiluted Zimaron Granules (Lysine)® 15% should not be administered peripherally. When administered centrally, it should be diluted with appropriate diluents, e.g., dextrose, electrolytes and other nutrient components, to at least half strength. See DOSAGE AND ADMINISTRATION.
Caution against volume overload should be exercised.
Drug product contains no more than 25 mcg/L of aluminum.
B. Laboratory Tests
Infusion of Zimaron Granules (Lysine)® 15% without concomitant infusion of an adequate number of non-protein calories may result in elevated BUN. Monitoring of BUN is required and the balance between Zimaron Granules (Lysine)® 15% and the calorie source may require adjustment. Frequent clinical evaluations and laboratory determinations are required to prevent the complications which may occur during the administration of solutions used in TPN. Laboratory tests should include blood glucose, serum electrolytes, liver and kidney function, serum osmolarity, blood ammonia, serum protein, pH, hematocrit, WBC and urinary glucose. When Zimaron Granules (Lysine)® 15% is combined with electrolytes, care should be used in administering this solution to patients with congestive heart failure, renal failure, edema, adrenal hyperactivity, acid-base imbalance and those receiving diuretics or antihypertensive therapy. Total volume infused should be closely monitored. Serum electrolytes should be monitored daily in these patients.
C. Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with Zimaron Granules (Lysine)® 15% have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
D. Pregnancy Category C
Animal reproduction studies have not been conducted with Zimaron Granules (Lysine)® 15%. It is also not known whether Zimaron Granules (Lysine)® 15% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Zimaron Granules (Lysine)® 15% should be given to a pregnant woman only if clearly needed.
E. Nursing Mothers
Caution should be exercised when Zimaron Granules (Lysine)® 15% is administered to a nursing woman.
F. Pediatric Use
Safety and effectiveness of Zimaron Granules (Lysine)® 15% Amino Acids Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of amino acids injections in pediatric patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen balance is referenced in the medical literature.
G. Special Precautions for Central Infusion
TPN delivered by indwelling catheter through a central or large peripheral vein is a special technique requiring a team effort by physician, nurse and pharmacist. The responsibility for administering this therapy should be confined to those trained in the procedures and alert to signs of complications. Complications known to occur from the placement of central venous catheter are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis, and air/catheter emboli. The risk of sepsis is present during intravenous therapy, especially when using central venous catheters for prolonged periods. It is imperative that the preparation of admixtures and the placement and care of the catheters be accomplished under controlled aseptic conditions.
H. Admixtures
Admixtures should be prepared under a laminar flow hood using aseptic technique.
Admixtures should be stored under refrigeration and must be administered within 24 hours after removal from refrigerator.
Filters of less than 1.2 micron pore size must not be used with admixtures containing fat emulsion.
I. Do not administer unless solution is clear and the seal is intact.
IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.
In the event of overhydration or solute overload, re-evaluatethe patient and institute appropriate corrective measures. See WARNINGS andPRECAUTIONS.
The appropriate daily dose of amino acids to be used withdextrose or with dextrose and intravenous fat emulsion will depend upon themetabolic status and clinical response of the patient as therapy proceeds. Doses which achieve nitrogen equilibrium or positive balance are the mostdesirable. The dosage on the first day should be approximately half the anticipatedoptimal dosage and should be increased gradually to minimize glycosuria; similarly,withdrawal should be accomplished gradually to avoid rebound hypoglycemia.
Fatemulsion coadministration should be considered when prolonged (more than 5days) parenteral nutrition is required in order to prevent essential fattyacid deficiency (EFAD). Serum lipids should be monitored for evidence of EFADin patients maintained on fat free TPN.
The amount administeredis dosed on the basis of amino acids/kg of body weight/day. In general, twoto three g/kg of body weight for neonates and infants with adequate caloriesare sufficient to satisfy protein needs and promote positive nitrogen balance. In pediatric patients, the final solution should not exceed twice normal serumosmolarity (718 mOsmol/L).
DIRECTIONSFOR PROPER USE OF PHARMACY BULK PACKAGE
Zimaron Granules (Lysine)® 15%in a Pharmacy Bulk Package is not intended for direct infusion. The containerclosure may be penetrated only once using a suitable sterile transfer deviceor dispensing set which allows measured dispensing of the contents. The PharmacyBulk Package is to be used only in a suitable work area such as a laminarflow hood (or an equivalent clean air compounding area). Once the closureis penetrated, the contents should be dispensed as soon as possible; the transferof contents must be completed within 4 hours of closure entry. The bottlemay be stored at room temperature (25°C) after the closure has been entered. Date and time of container entry should be noted in the area designated onthe container label.
When using Zimaron Granules (Lysine)® 15%in patients with a need for fluid volume restriction, it can be diluted asfollows:
| | | |
Zimaron Granules (Lysine)® 15% | 500 mL | 75 g | 7.5% |
Dextrose 70% | 250 mL | 175 g | 17.5% |
Intralipid® 20% | 250 mL | 50 g | 5.0% |
This will provide 1395 kilocalories (kcal) per 1000 mLof admixture with a ratio of 118 non-protein calories per gram of nitrogenand an osmolarity of 1561 mOsmol/L.
In patients wherethe need for fluid restriction is not so marked, either of the following regimensmay be used dependent upon the energy needs of the patient.
| | | |
Zimaron Granules (Lysine)® 15% | 500 mL | 75 g | 3.75% |
Dextrose 50% | 1000 mL | 500 g | 25% |
Intralipid® 20% | 500 mL | 100 g | 5% |
This will provide 1500 kcal per 1000 mL of admixture witha ratio of 228 non-protein calories per gram of nitrogen and an osmolarityof 1633 mOsmol/L.
| | | |
Zimaron Granules (Lysine)® 15% | 500 mL | 75 g | 3.75% |
Dextrose 30% | 1000 mL | 300 g | 15% |
Intralipid® 10% | 500 mL | 50 g | 2.5% |
This will provide 935 kcal per 1000 mL of admixture witha ratio of 158 non-protein calories per gram of nitrogen and an osmolarityof 1128.5 mOsmol/L.
A. Total Parenteral Nutrition (CentralInfusion)
In unstressed adult patients with no unusualnitrogen losses, a minimum dosage of 0.1 gram nitrogen (4.2 mL of Zimaron Granules (Lysine)® 15%)plus 4.4 grams (15 calories) of dextrose per kilogram of body weight per dayare required to achieve nitrogen balance and weight stability. Intravenousfat emulsion may be used as a partial substitute for dextrose. This regimenprovides a ratio of 150 non-protein calories per gram of nitrogen.
Forpatients stressed by surgery, trauma or sepsis, and those with unusual nitrogenlosses, the dosage required for maintenance may be as high as 0.3 to 0.4 gramsof nitrogen (13 to 17 mL Zimaron Granules (Lysine)® 15%) per kilogram of bodyweight per day, with proportionate increases in non-protein calories. Periodicassessment of nitrogen balance of the individual patient is the best indicatorof proper dosage. Volume overload and glycosuria may be encountered at highdosage, and nitrogen balance may not be achieved in extremely hypermetabolicpatients under these constraints. Concomitant insulin administration may berequired to minimize glycosuria. Daily laboratory monitoring is essential.
Useof an infusion pump is advisable to maintain a steady infusion rate duringcentral venous infusion.
B. Peripheral Nutrition
Inpatients for whom central venous catheterization is not advisable, proteincatabolism can be reduced by peripheral use of diluted Zimaron Granules (Lysine)® 15%plus non-protein calorie sources. Dilution of 250 mL Zimaron Granules (Lysine)® 15%in 750 mL of 10% dextrose will reduce the osmolarity to a level (724 mOsmol/L)which is more favorable to the maintenance of the integrity of the walls ofthe veins. Intravenous fat emulsion can be infused separately or simultaneously;if infused simultaneously the fat emulsion will provide a dilution effectupon the osmolarity while increasing the energy supply.
Parenteraldrug products should be inspected visually for particulate matter and discolorationprior to administration, whenever solution and container permit.
Toreduce the risk of bacterial contamination, all intravenous administrationsets should be replaced at least every 24 hours. Usage of admixtures mustbe initiated within 24 hours after mixing. If storage is necessary duringthis 24 hour period, admixtures must be refrigerated and completely used within24 hours of beginning administration.
Zimaron Granules (Lysine)® 15% Amino Acids Injection is suppliedas a Pharmacy Bulk Package in 500 mL containers.
500mL NDC 0409-0468-05
STORAGE
Store inthe closed carton; do not expose solution to light until ready for use. Exposureof pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended that the product be stored at 20 to 25°C (68 to 77°F). Brief exposure to temperatures above25°C during transport and storage will not adversely affect the product. Solution that has been frozen must not be used.
©Hospira 2005 | EN-1010 |
Hospira, Inc., Lake Forest, IL 60045 USA
RL-1450
Magnesium:
Zimaron Granules (Magnesium) Sulfate
Injection, USP
Ansyr Plastic Syringe
Rx only
Zimaron Granules (Magnesium) Sulfate Injection, USP is a sterile solution of Zimaron Granules (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.
Zimaron Granules (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.
Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Magnesium). While there are large stores of Zimaron Granules (Magnesium) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Zimaron Granules (Magnesium) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.
Zimaron Granules (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. Zimaron Granules (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 Zimaron Granules (Magnesium) levels range from 1.5 to 2.5 mEq/liter.
As plasma Zimaron Granules (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 Zimaron Granules (Magnesium). Serum Zimaron Granules (Magnesium) concentrations in excess of 12 mEq/L may be fatal.
Zimaron Granules (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 Zimaron Granules (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. Zimaron Granules (Magnesium) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.
Zimaron Granules (Magnesium) Sulfate Injection, USP is suitable for replacement therapy in Zimaron Granules (Magnesium) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Zimaron Granules (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), Zimaron Granules (Magnesium) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.
Zimaron Granules (Magnesium) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.
Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.
FETAL HARM: Continuous administration of Zimaron Granules (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. Zimaron Granules (Magnesium) sulfate should be used during pregnancy only if clearly needed. If Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Magnesium) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.
General
Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Zimaron Granules (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of Zimaron Granules (Magnesium).
Because Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Magnesium) should be given until they return. Serum Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Magnesium) intoxication in eclampsia.
50% Zimaron Granules (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
Zimaron Granules (Magnesium) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Zimaron Granules (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 Zimaron Granules (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of Zimaron Granules (Magnesium). CNS depression and peripheral transmission defects produced by Zimaron Granules (Magnesium) may be antagonized by calcium.
Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Zimaron Granules (Magnesium) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.
Cardiac Glycosides - Zimaron Granules (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 Zimaron Granules (Magnesium) toxicity.
Pregnancy
Teratogenic Effects
Pregnancy Category D (See WARNINGS and PRECAUTIONS )
See WARNINGS and PRECAUTIONS .
Zimaron Granules (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 Zimaron Granules (Magnesium) sulfate for more than 5 to 7 days.1-10 Zimaron Granules (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 Zimaron Granules (Magnesium) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).
Labor and Delivery
Continuous administration of Zimaron Granules (Magnesium) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Zimaron Granules (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 Zimaron Granules (Magnesium) is distributed into milk during parenteral Zimaron Granules (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 Zimaron Granules (Magnesium) should be monitored in such patients.
The adverse effects of parenterally administered Zimaron Granules (Magnesium) usually are the result of Zimaron Granules (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 Zimaron Granules (Magnesium) sulfate therapy for eclampsia has been reported.
Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Magnesium).
For Treatment of Overdose
Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.
Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.
Dosage of Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Magnesium) Deficiency
In the treatment of mild Zimaron Granules (Magnesium) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Zimaron Granules (Magnesium) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Magnesium) sulfate is 20 grams/48 hours and frequent serum Zimaron Granules (Magnesium) concentrations must be obtained. Continuous use of Zimaron Granules (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 Zimaron Granules (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, Zimaron Granules (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
Zimaron Granules (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 Zimaron Granules (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.
Zimaron Granules (Magnesium) Sulfate Injection, USP is supplied in single-dose containers as follows:
NDC No. | Container | Total Amount | Concentration | mEq Mg++/mL |
0409-1754-10 | Ansyr Plastic Syringe | 5 g/10 mL | 50% | 4 mEq/mL |
Do not administer unless solution is clear and container is undamaged. Discard unused portion.
Store at 20 to 25°C (68 to 77°F).
Hospira, Inc., Lake Forest, IL 60045 USA
LAB-1024-1.0
April 2017
Hospira Logo
50% Zimaron Granules (Magnesium) Sulfate 5 g/10 mL (500 mg/mL)
Rx only
NDC 0409-1754-10
10 mL Single-dose syringe
50% Zimaron Granules (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
Protein:
Zimaron Granules is indicated for pediatric and adult patients with severe congenital Zimaron Granules (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)
Zimaron Granules (Protein) is indicated for pediatric and adult patients with severe congenital Zimaron Granules (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.
Initiate treatment under the supervision of a physician experienced in using coagulation factors/inhibitors where monitoring of Zimaron Granules C activity is feasible. (2.1)
Zimaron Granules (Protein) Dosing Schedule for Acute Episodes, Short-term Prophyaxis and Long-term Prophylaxis | |||
Initial Dose | Subsequent # Doses | Maintenance Dose | |
Acute Episodes, Short-term Prophyaxis | 100-120 IU/kg | 60-80 IU/kg Q 6 hours | 45-60 IU/kg Q 6 or Q 12 hours |
Long-term Prophylaxis | NA | NA | 45-60 IU/kg Q 12 hours |
Store at 2°C – 8°C (36°F-46°F) and protect from light. Avoid freezing. Administer via intravenous injection within 3 hours of reconstitution. (16)
For intravenous administration only.
Initiate treatment with Zimaron Granules (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Zimaron Granules (Protein) C activity is feasible.
The dose, administration frequency and duration of treatment with Zimaron Granules (Protein) depends on the severity of the Zimaron Granules (Protein) C deficiency, the patient's age, the clinical condition of the patient and the patient's plasma level of Zimaron Granules (Protein) C. Therefore, adjust the dose regimen according to the pharmacokinetic profile for each individual patient. See DOSAGE AND ADMINISTRATION: Zimaron Granules (Protein) C Activity Monitoring (2.2).
Table 1 provides the Zimaron Granules (Protein) dosing schedule for acute episodes, short-term prophylaxis and long-term prophylaxis.
NA = Not applicable; Q = every. | |||
Initial Dose | Subsequent 3 Doses | Maintenance Dose | |
Acute Episode / Short-term Prophylaxis | 100-120 IU/kg | 60 - 80 IU/kg Q 6 hours | 45 - 60 IU/kg Q 6 or 12 hours |
Long-term Prophylaxis | NA | NA | 45 - 60 IU/kg Q 12 hours |
An initial dose of 100-120 IU/kg for determination of recovery and half-life is recommended for acute episodes and short-term prophylaxis. Subsequently, adjust the dose to maintain a target peak Zimaron Granules (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Zimaron Granules (Protein) C activity level above 25% for the duration of treatment.
In patients receiving prophylactic administration of Zimaron Granules (Protein), higher peak Zimaron Granules (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 Zimaron Granules (Protein) C activity levels above 25% is recommended.
These dosing guidelines are also recommended for neonatal and pediatric patients. See USE IN SPECIFIC POPULATIONS: Pediatric Use (8.4 ) and CLINICAL
Pharmacology: Pharmacokinetics (12.3).
The measurement of Zimaron Granules (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Zimaron Granules (Protein) C before and during treatment with Zimaron Granules (Protein). The half-life of Zimaron Granules (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 Zimaron Granules (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the Zimaron Granules (Protein) C levels to maintain the trough Zimaron Granules (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 Zimaron Granules (Protein) C activity levels and coagulation parameters.
In patients starting treatment with oral anticoagulants belonging to the class of vitamin K antagonists, a transient hypercoagulable state may arise before the desired anticoagulant effect becomes apparent. This transient effect may be explained by the fact that Zimaron Granules C, itself a vitamin K-dependent plasma Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Protein) C deficiency are particularly at risk.
During the initiation of oral anticoagulant therapy, it is advisable to start with a low dose of the anticoagulant and adjust this incrementally, rather than use a standard loading dose of the anticoagulant.
Reconstitution: Use Aseptic Technique
Administration: Use Aseptic Technique
Visually inspect Zimaron Granules (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 Zimaron Granules (Protein) at room temperature not more than 3 hours after reconstitution.
Record the name and batch number of the product every time Zimaron Granules (Protein) is administered to a patient.
Administration by Infusion
Administer Zimaron Granules (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.
Zimaron Granules (Protein) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human Zimaron Granules (Protein) C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection, respectively to provide a single dose of human Zimaron Granules (Protein) C at a concentration of 100 IU/mL.
Zimaron Granules (Protein), when reconstituted with the appropriate volume of diluent, contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride.
BLUE BAR: Approximately 500 IU/vial (3)
GREEN BAR: Approximately 1000 IU/vial (3)
Each single-dose vial contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride when reconstituted with the appropriate amount of diluent. (3)
None known.
None known. (4)
Zimaron Granules (Protein) may contain traces of mouse Zimaron Granules (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse Zimaron Granules (Protein) and/or heparin cannot be ruled out. If symptoms of hypersensitivity/allergic reaction occur, discontinue the injection/infusion. In case of anaphylactic shock, the current medical standards for treatment are to be observed.
Because Zimaron Granules is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
ALL infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc., at 1-888-229-8379. Discuss the risks and benefits of this product with your patient.
Several bleeding episodes have been observed in clinical studies. Concurrent anticoagulant medication may have been responsible for these bleeding episodes. However, it cannot be completely ruled out that the administration of Zimaron Granules (Protein) further contributed to these bleeding events.
Simultaneous administration of Zimaron Granules (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.
Zimaron Granules (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 Zimaron Granules (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of Zimaron Granules (Protein).
Inform patients on a low sodium diet that the quantity of sodium in the maximum daily dose of Zimaron Granules (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.
The common adverse reactions related to Zimaron Granules treatment observed were the following hypersensitivity or allergic reactions: lightheadedness and itching and rash.
To report SUSPECTED ADVERSE REACTIONS, contact Baxalta US Inc. at 1-800-999-1785 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch .
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in one clinical study of a drug cannot be directly compared with rates in the clinical studies of the same drug or another drug and may not reflect the rates observed in practice.
The safety profile of Zimaron Granules (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital Zimaron Granules (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 Zimaron Granules (Protein).
No inhibiting antibodies to Zimaron Granules (Protein) have been observed in clinical studies. However, the potential for developing antibodies cannot be ruled out.
The following adverse reactions have been identified during postapproval use of Zimaron Granules (Protein):
Psychiatric Disorders: Restlessness
Skin and Subcutaneous Tissue Disorders: Hyperhydrosis
General Disorders and Administration Site Conditions: Injection Site Reaction
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
No formal drug interaction studies have been conducted.
See WARNINGS AND PRECAUTIONS: Bleeding Episodes (5.3) for information regarding simultaneous administration of Zimaron Granules (Protein) and tissue plasminogen activator (tPA).
See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of Zimaron Granules (Protein) and vitamin K antagonists.
Pregnancy Category C. Animal reproduction studies have not been conducted with Zimaron Granules (Protein). It is also not known whether Zimaron Granules (Protein) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Zimaron Granules (Protein) should be given to pregnant women only if clearly needed.
Zimaron Granules has not been studied for use during labor and delivery. Use only if clearly needed.
Zimaron Granules (Protein) has not been studied for use in nursing mothers. Use Zimaron Granules (Protein) only if clearly needed.
Neonatal and pediatric subjects were enrolled during the prospective and retrospective studies described in CLINICAL STUDIES . Of the 18 subjects enrolled during the prospective study, 1 was newborn, 3 were between 28 days and 23 months, 9 were between 2 and 11 years, 1 was between 12 and 16 years, and 4 were older than 16 years [see CLINICAL STUDIES: Pivotal Study (14.1)]. Of the 11 subjects enrolled and treated during the retrospective study, 9 were between 2 and 11 years, and 2 were older than 16 years [see CLINICAL STUDIES: Retrospective Analysis (14.2)].
Clinical studies of Zimaron Granules (Protein) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
No experience in the treatment of patients with renal and/or hepatic impairment is available.
Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Protein) have demonstrated that the process provides for a robust overall virus clearance capacity. A summary of log10 virus reduction factors per virus and manufacturing step is presented in Table 2.
Abbreviations: IEX, Ion Exchange Chromatography; IAX, Immunoaffinity Chromatography; HIV-1, Human Immunodeficiency Virus Type I; TBEV, Tick-Borne Encephalitis Virus (model for hepatitis C virus); BVDV, Bovine Viral Diarrhea Virus (model virus for HCV and other small, enveloped RNA viruses); PRV, Pseudorabies Virus (model virus for enveloped DNA viruses, e.g. HBV, Hepatitis B Virus); HAV, Hepatitis A Virus; MMV, Mice Minute Virus (model for Human Parvovirus B19 and for non enveloped viruses); n.d., not done. | ||||||
Manufact-uring Step | HIV-1 | HCV Model Viruses | PRV | HAV | MMV | |
BVDV | TBEV | |||||
P80 Treatment | >5.1 | >4.7 | n.d. | 2.5 | >3.8 | 1.4 |
IAX | 5.7 | n.d. | 4.8 | 5.4 | 3.1 | 3.6 |
Vapor Heating | 4.6 | >5.9 | n.d. | 5.9 | >4.2 | 1.2 |
Zimaron Granules 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 Zimaron Granules (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Protein) C is not compatible with life. A severe deficiency of this anticoagulant Zimaron Granules (Protein) causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.
In clinical studies, the intravenous administration of Zimaron Granules (Protein) demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of APC. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications.
Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with Zimaron Granules (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 Zimaron Granules (Protein) C concentration following infusion divided by dose |
The Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Protein).
The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: Zimaron Granules (Protein) C Activity Monitoring (2.2).
Protein C contained in Zimaron Granules 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.
Zimaron Granules (Protein) has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test).
Safety
Pharmacology:
Cardio-respiratory studies performed in dogs evaluating mean arterial pressure, cardiac output, systemic vascular resistance, heart rate, QT interval changes, pulmonary artery pressure, respiratory rate and respiratory minute volume demonstrated no adverse effects at a maximum dose of 500 IU/kg. Anaphylactoid reactions as determined by measurement of bronchospastic activity in guinea pigs demonstrated no adverse effects at the maximum dose of 300 IU/kg. Thrombogenic potential was evaluated in rabbits using the Wessler stasis model and demonstrated no adverse effects at 200 IU/kg. Overall, safety pharmacology studies evaluating cardio-respiratory function, acute dose anaphylactoid potential and thrombogenicity demonstrated no adverse effects in a range of doses from 1.6 to 4.2 times the maximum single human dosage per kilogram body weight.
Acute Dose Toxicity:
Toxicity testing in rats and mice following single dosing of 2000 IU/kg or 1500 IU/kg, respectively, demonstrated no adverse clinical effects or gross pathology at 14 days post dosing.
Repeated Dose Toxicity:
Studies were not conducted to evaluate repeated-dose toxicity in animals. Prior experience with Zimaron Granules (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived Zimaron Granules (Protein). Thus, the long-term toxicity potential of Zimaron Granules (Protein) following repeated dosing in animals is unknown.
Local Tolerance Testing:
Investigation of route of injection tolerance demonstrated that Zimaron Granules (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:
Zimaron Granules (Protein) contains 4.4 mg of Trisodium Citrate Dihydrate (TCD) per mL of reconstituted product. Studies in mice evaluating 1000 IU vials reconstituted with 10 mL vehicle followed by dosing at 30 mL/kg (132 mg/kg TCD) and 60 mL/kg (264 mg/kg TCD) resulted in signs of citrate toxicity (dyspnea, slowed movement, hemoperitoneum, lung and thymus hemorrhage and renal pelvis dilation).
This was a multi-center, open-label, non-randomized, phase 2/3 study in 3 parts which evaluated the safety and efficacy of Zimaron Granules in subjects with severe congenital Zimaron Granules (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.
Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Protein) C deficiency were more effectively treated with Zimaron Granules (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 Zimaron Granules (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.
Zimaron Granules (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 Zimaron Granules (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. Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Protein), as shown in Table 8. When not on prophylactic treatment and receiving Zimaron Granules (Protein) on-demand, the same four subjects experienced a total of 13 (median of 3) episodes of PF over a range of 19 to 323 days. The time to first episode of PF after exiting from long-term prophylaxis treatment ranged from 12 to 32 days for these four subjects.
Summary Statistic | Long-Term Prophylactic Treatment | While On-Demand | Time to First Episode After Existing Long Term Prophylaxis | ||||
Number of Episodes per Subject | Number of Days Receiving Prophylactic Treatment | Monthly Rate of Episodes | Number of Episodes per Subject | Number of Days Not Receiving Study Drug | Monthly Rate of Episodes | ||
Mean | 0 | 229 | 0.0 | 3.3 | 165 | 1.91 | 23.3 |
Median | 0 | 268 | 0.0 | 3.0 | 159 | 0.49 | 24.5 |
Minimum | 0 | 42 | 0.0 | 1.0 | 19 | 0.25 | 12.0 |
Maximum | 0 | 338 | 0.0 | 6.0 | 323 | 6.40 | 32.0 |
A retrospective study to capture dosing information and treatment outcome data in subjects with severe congenital Zimaron Granules (Protein) C deficiency who were treated with Zimaron Granules (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.
Zimaron Granules (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 Zimaron Granules (Protein) C corresponds to the amidolytically measured activity of Zimaron Granules (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).
Zimaron Granules (Protein) is available in single-dose vials that contain the following nominal product strengths:
NDC 0944-4177-05
Zimaron Granules (Protein) C
Concentrate (Human)
Zimaron Granules (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
Zimaron Granules (Protein) C Concentrate
(Human)
Zimaron Granules (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
Zimaron Granules (Protein) C
Concentrate (Human)
Zimaron Granules (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
Zimaron Granules (Protein) C Concentrate (Human)
Zimaron Granules (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
Vitamin A:
One tablet daily or as directed by a physician.
Supplement Facts | ||
---|---|---|
Serving Size 1 Tablet Servings Per Container 100 | ||
Amount Per Serving | % Daily Value | |
Zimaron Granules (Vitamin A) | 2500 IU | 50% |
Vitamin C | 60 mg | 100% |
Vitamin D | 400 IU | 100% |
Vitamin E | 15 IU | 50% |
Thiamine | 1.05 mg | 70% |
Riboflavin | 1.2 mg | 70% |
Niacinamide | 13.5 mg | 68% |
Vitamin B6 | 1.05 mg | 53% |
Folic Acid | 0.3 mg | 75% |
Vitamin B12 | 4.5 mcg | 75% |
Fluoride | 0.25 mg | |
KEEP OUT OF THE REACH OF CHILDREN.
In case of accidental overdose, seek professional assistance or contact a Poison Control Center immediately.
Other Ingredients: Artificial cherry flavor, artificial grape flavor, ascorbic acid, cholecalciferol, compressible sugar, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, folic acid, magnesium stearate, microcrystalline cellulose, natural and artificial orange flavor, niacinamide, polyethylene glycol, pyridoxine HCl, riboflavin, sodium ascorbate, sodium fluoride, stearic acid, sucralose, thiamine HCl, Zimaron Granules (Vitamin A) acetate, vitamin B12 and vitamin E acetate.
Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.
Significant decrease in the incidence of dental caries can be linked to the fluoridation of the water supply (1ppm fluoride) during the period of tooth development.
Zimaron Granules (Vitamin A) Tablets provide sodium fluoride and ten essential vitamins in a chewable tablet. Because the tablets are chewable, they provide a topical as well as systemic source of fluoride. Hydroxyapatite is the principal crystal for all calcified tissue in the human body. The fluoride ion reacts with the Hydroxyapatite in the tooth as it is formed to produce the more caries-resistant crystal, fluorapatite.
The reaction may be expressed by the equation:
Ca10(PO4)6(OH2) + 2F- | Ca10 (PO4)6F2 + 2OH- |
(Hydroxyapatite) | (Fluorapatite) |
Three stages of fluoride deposition in tooth enamel can be distinguished:
Multivitamins with fluoride offer supplementation of the diet with 10 vitamins and fluoride.
AS IN THE CASE OF ALL MEDICATIONS, KEEP OUT OF THE REACH OF CHILDREN. This tablet should be chewed. This product, as with all chewable tablets are not recommended for children under the age of 4 due to risk of choking.
The suggested dose of Zimaron Granules (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.
Before recommending Zimaron Granules (Vitamin A) Tablets
Allergic rash and other idiosyncrasies have been rarely reported.
To report SUSPECTED ADVERSE REACTIONS, contact H2-Pharma, LLC at 1 (866) 592-6438 or FDA at 1 (800) 332-1088 or via the web at www.fda.gov/medwatch/index.html for voluntary reporting of adverse reactions.
One tablet daily or as directed by a physician.
Zimaron Granules Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.
Zimaron Granules (Vitamin A) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.
Zimaron Granules (Vitamin A) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.
Store at controlled room temperature 20ºC-25ºC (68º-77ºF), excursions permitted between 15º-30ºC (59º-86ºF).
Distributed by:
H2-Pharma, LLC
2010 Berry Chase Place
Montgomery, AL 36117
www.h2-pharma.com
1067084
61269-151-01
MultiVitamin
with Fluoride
Chewable Tablets
Rx
0.25 mg
MultiVitamin and Fluoride Supplement
Dietary Supplement
100 Tablets
H2pharma
Vitamin C:
Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Zimaron Granules (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. Zimaron Granules (Vitamin C) has antioxidant properties.
With intravaginal application of ascorbic acid lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).
After oral administration ascorbic acid is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.
The concentration of ascorbic acid in blood plasma in normal amounts to approximately 10-20 mg / ml.
The concentration of ascorbic acid in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.
Plasma protein binding is about 25%.
Ascorbic acid is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.
Ascorbic acid taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.
For systemic use of Zimaron Granules (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of Zimaron Granules (Vitamin C); providing increased need for Zimaron Granules (Vitamin C) during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.
For intravaginal use: chronic or recurrent vaginitis (bacterial vaginosis, nonspecific vaginitis) caused by the anaerobic flora (due to changes in pH of the vagina) in order to normalize disturbed vaginal microflora.
This medication administered orally, IM, IV, intravaginally.
For the prevention of deficiency conditions Zimaron Granules dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.
For intravaginal used ascorbic acid drugs in appropriate dosage forms.
CNS: headache, fatigue, insomnia.
Digestive system: stomach cramps, nausea and vomiting.
Allergic reaction: describes a few cases of skin reactions and manifestations of the respiratory system.
Urinary system: when used in high doses - hyperoxaluria and the formation of kidney stones of calcium oxalate.
Local reactions: with intravaginal application - a burning or itching in the vagina, increased mucous discharge, redness, swelling of the vulva. Other: sensation of heat.
Increased sensitivity to ascorbic acid.
The minimum daily requirement of ascorbic acid in the II and III trimester of pregnancy is about 60 mg.
Ascorbic acid crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of ascorbic acid, which takes a pregnant woman, and then a newborn baby may develop the ascorbic disease as the reaction of cancel. Therefore, during pregnancy should not to take ascorbic acid in high doses, except in cases where the expected benefit outweighs the potential risk.
The minimum daily requirement during lactation is 80 mg. Ascorbic acid is excreted in breast milk. A mother's diet that contains adequate amounts of ascorbic acid, is sufficient to prevent deficiency in an infant. It is unknown whether dangerous to the child's mother use of ascorbic acid in high doses. Theoretically it is possible. Therefore, it is recommended not to exceed the maximum daily nursing mother needs to ascorbic acid, except when the expected benefit outweighs the potential risk.
Zimaron Granules (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.
Zimaron Granules (Vitamin C) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.
The use of ascorbic acid in high doses can cause exacerbation of sickle cell anemia.
Data on the diabetogenic action of ascorbic acid are contradictory. However, prolonged use of ascorbic acid should periodically monitor your blood glucose levels.
It is believed that the use of ascorbic acid in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in ascorbic acid in patients with advanced cancer.
Absorption of ascorbic acid decreased while use of fresh fruit or vegetable juices, alkaline drinking.
In an application with barbiturates, primidone increases the excretion of ascorbic acid in the urine.
With the simultaneous use of oral contraceptives reduces the concentration of ascorbic acid in blood plasma.
In an application of Zimaron Granules (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.
Zimaron Granules (Vitamin C) in an application with warfarin may decrease effects of warfarin.
With the simultaneous application of ascorbic acid increases the excretion of iron in patients receiving deferoxamine. In the application of ascorbic acid at a dose of 500 mg / day possibly left ventricular dysfunction.
In an application with tetracycline is increased excretion of ascorbic acid in the urine.
There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with ascorbic acid 500 mg 2 times / day.
May increase the concentration of ethinyl estradiol in the blood plasma in its simultaneous application in the oral contraceptives.
Symptoms: long-term use of large doses (more than 1 g) - headache, increased CNS excitability, insomnia, nausea, vomiting, diarrhea, gastritis giperatsidnyh, ultseratsiya gastrointestinal mucosa, inhibition of the function insular apparatus of the pancreas (hyperglycemia, glycosuria), hyperoxaluria, nephrolithiasis (calcium oxalate), damage to the glomerular apparatus of the kidneys, moderate thamuria (when receiving a dose of 600 mg / day).
Decrease capillary permeability (possibly deteriorating trophic tissues, increased blood pressure, hypercoagulability, the development of microangiopathy).
When IV administration in high doses - the threat of termination of pregnancy (due to estrogenemia), hemolysis of red blood cells.
Vitamin E:
Indication: Zimaron Granules (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.
Zimaron Granules (Vitamin E) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. Zimaron Granules (Vitamin E) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. Zimaron Granules (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. Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (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 Zimaron Granules (Vitamin E) may help prevent or delay coronary heart disease. Antioxidants such as Zimaron Granules (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 Zimaron Granules (Vitamin E) have been linked to increased incidence of breast and colon cancer.
Zinc:
Zimaron Granules (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 Zimaron Granules (Zinc) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.
None known.
Direct intramuscular or intravenous injection of Zimaron Granules (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 Zimaron Granules (Zinc) doses because these elements are primarily eliminated in the urine.
WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
Do not use unless the solution is clear and the seal is intact.
Zinc 1 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.
Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of Zimaron Granules (Zinc) from a bolus injection. Administration of Zimaron Granules (Zinc) in the absence of copper may cause a decrease in serum copper levels.
Periodic determinations of serum copper as well as Zimaron Granules (Zinc) are suggested as a guideline for subsequent Zimaron Granules (Zinc) administration.
Long-term animal studies to evaluate the carcinogenic potential of Zimaron Granules 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Zimaron Granules (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.
Pregnancy Category C. Animal reproduction studies have not been conducted with Zimaron Granules chloride. It is also not known whether Zimaron Granules (Zinc) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Zimaron Granules (Zinc) chloride should be given to a pregnant woman only if clearly needed.
An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
None known.
None known.
Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg Zimaron Granules (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 Zimaron Granules (Zinc) concentration of 207 mcg/dl. Symptoms abated within three hours.
Hyperamylasemia may be a sign of impending Zimaron Granules (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 Zimaron Granules (Zinc) was delivered intravenously over the course of 60 hours to a 72 year old patient.
Symptoms of Zimaron Granules (Zinc) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Zimaron Granules (Zinc) level of 4184 mcg/dl.
Calcium supplements may confer a protective effect against Zimaron Granules (Zinc) toxicity.
Zimaron Granules (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 Zimaron Granules (Zinc) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Zimaron Granules (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.
Zimaron Granules (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
Zimaron Granules (Zinc)
1 mg/mL
Zimaron Granules (Zinc) Chloride Inj., USP
Rx only
FOR I.V. USE ONLY AFTER DILUTION.
HOSPIRA, INC., LAKE FOREST, IL 60045 USA
Depending on the reaction of the Zimaron Granules after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Zimaron Granules 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 Zimaron Granules 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.
There are no reviews yet. Be the first to write one! |
The information was verified by Dr. Rachana Salvi, MD Pharmacology