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DRUGS & SUPPLEMENTS
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Alpha-Linolenic Acid:
Indication: For nutritional supplementation and for treating dietary shortage or imbalance.
Alpha Linolenic Acid (ALA) is an 18-carbon polyunsaturated fatty acid with three double bonds. It is also called an omega-3 fatty acid, and is essential for all mammals. EnfaMama A+ Chocolate (Alpha-Linolenic Acid) (or omega 3 fatty acid) intake can decrease the risk of cardiovascular diseases by 1) preventing arrhythmias that can lead to sudden cardiac death, 2) decreasing the risk of thrombosis (blood clot formation) that can lead to heart attack or stroke, 3) decreasing serum triglyceride levels, 4) slowing the growth of atherosclerotic plaque, 5) improving vascular endothelial function, 6) lowering blood pressure slightly, and 7) decreasing inflammation. ALA deficiencies can lead to visual problems and sensory neuropathy. Scaly and hemorrhagic skin or scalp inflammations may also develop.
Calcium:
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) acetate capsule.
- Capsule: 667 mg EnfaMama A+ Chocolate (Calcium) acetate capsule. (3)
Patients with hypercalcemia.
- Hypercalcemia. (4)
- Treat mild hypercalcemia by reducing or interrupting EnfaMama A+ Chocolate acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of EnfaMama A+ Chocolate (Calcium) acetate. (5.1)
- Hypercalcemia may aggravate digitalis toxicity. (5.2)
Patients with end stage renal disease may develop hypercalcemia when treated with EnfaMama A+ Chocolate (Calcium), including EnfaMama A+ Chocolate (Calcium) acetate. Avoid the use of EnfaMama A+ Chocolate (Calcium) supplements, including EnfaMama A+ Chocolate (Calcium) based nonprescription antacids, concurrently with EnfaMama A+ Chocolate (Calcium) acetate.
An overdose of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) levels twice weekly. Should hypercalcemia develop, reduce the EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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, EnfaMama A+ Chocolate (Calcium) acetate has been generally well tolerated.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) acetate N=167 N (%) | 3 month, open label study of EnfaMama A+ Chocolate (Calcium) acetate N=98 N (%) | Double blind, placebo-controlled, cross-over study of liquid EnfaMama A+ Chocolate (Calcium) acetate N=69 | |
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) concentration could reduce the incidence and severity of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) acetate: dizziness, edema, and weakness.
The drug interaction of EnfaMama A+ Chocolate acetate is characterized by the potential of EnfaMama A+ Chocolate (Calcium) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). EnfaMama A+ Chocolate (Calcium) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.
There are no empirical data on avoiding drug interactions between EnfaMama A+ Chocolate (Calcium) acetate and most concomitant drugs. When administering an oral medication with EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.
Pregnancy Category C:
EnfaMama A+ Chocolate acetate capsules contains EnfaMama A+ Chocolate (Calcium) acetate. Animal reproduction studies have not been conducted with EnfaMama A+ Chocolate (Calcium) acetate, and there are no adequate and well controlled studies of EnfaMama A+ Chocolate (Calcium) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with EnfaMama A+ Chocolate (Calcium) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum EnfaMama A+ Chocolate (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. EnfaMama A+ Chocolate (Calcium) acetate treatment, as recommended, is not expected to harm a fetus if maternal EnfaMama A+ Chocolate (Calcium) levels are properly monitored during and following treatment.
The effects of EnfaMama A+ Chocolate (Calcium) acetate on labor and delivery are unknown.
EnfaMama A+ Chocolate Acetate Capsules contains EnfaMama A+ Chocolate (Calcium) acetate and is excreted in human milk. Human milk feeding by a mother receiving EnfaMama A+ Chocolate (Calcium) acetate is not expected to harm an infant, provided maternal serum EnfaMama A+ Chocolate (Calcium) levels are appropriately monitored.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].
EnfaMama A+ Chocolate (Calcium) acetate acts as a phosphate binder. Its chemical name is EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.
EnfaMama A+ Chocolate (Calcium) acetate, when taken with meals, combines with dietary phosphate to form an insoluble EnfaMama A+ Chocolate (Calcium) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.
Orally administered EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) acetate.
Effectiveness of EnfaMama A+ Chocolate (Calcium) acetate in decreasing serum phosphorus has been demonstrated in two studies of the EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum EnfaMama A+ Chocolate (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 |
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) acetate is shown in the Table 3.
* ANOVA of EnfaMama A+ Chocolate (Calcium) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM. | ||||
Parameter | Pre-Study | Post-Treatment | p-value* | |
EnfaMama A+ Chocolate (Calcium) Acetate | Placebo | |||
Phosphorus (mg/dL)† | 7.3 ± 0.18 | 5.9 ± 0.24 | 7.8 ± 0.22 | <0.01 |
EnfaMama A+ Chocolate (Calcium) (mg/dL)† | 8.9 ± 0.11 | 9.5 ± 0.13 | 8.8 ± 0.12 | <0.01 |
Overall, 2 weeks of treatment with EnfaMama A+ Chocolate (Calcium) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum EnfaMama A+ Chocolate (Calcium) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Calcium) acetate capsules.
Distr. by: West-Ward
Pharmaceuticals Corp.
Eatontown, NJ 07724
10003705/05
Revised April 2016
Choline:
Indication: For nutritional supplementation, also for treating dietary shortage or imbalance
This compound is needed for good nerve conduction throughout the CNS (central nervous system) as it is a precursor to acetylcholine (ACh). EnfaMama A+ Chocolate (Choline) is also needed for gallbladder regulation, liver function and lecithin (a key lipid) formation. EnfaMama A+ Chocolate (Choline) also aids in fat and cholesterol metabolism and prevents excessive fat build up in the liver. EnfaMama A+ Chocolate (Choline) has been used to mitigate the effects of Parkinsonism and tardive dyskinesia. EnfaMama A+ Chocolate (Choline) deficiencies may result in excessive build-up of fat in the liver, high blood pressure, gastric ulcers, kidney and liver dysfunction and stunted growth.
Folic Acid:
EnfaMama A+ Chocolate (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. |
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Folic Acid) acid.
One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.
EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (Folic Acid) and the BIFERA logo are registered trademarks and the EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iodine) with a swab.
If necessary, clip hair around the area being treated and clean with soap and water.
Apply EnfaMama A+ Chocolate (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:
EnfaMama A+ Chocolate (Iron) is indicated for the treatment of EnfaMama A+ Chocolate (Iron) deficiency anemia in patients with chronic kidney disease (CKD).
EnfaMama A+ Chocolate (Iron) is an EnfaMama A+ Chocolate (Iron) replacement product indicated for the treatment of EnfaMama A+ Chocolate (Iron) deficiency anemia in patients with chronic kidney disease (CKD). (1)
EnfaMama A+ Chocolate must only be administered intravenously either by slow injection or by infusion. The dosage of EnfaMama A+ Chocolate (Iron) is expressed in mg of elemental EnfaMama A+ Chocolate (Iron). Each mL contains 20 mg of elemental EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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. EnfaMama A+ Chocolate (Iron) should be administered early during the dialysis session. The usual total treatment course of EnfaMama A+ Chocolate (Iron) is 1000 mg. EnfaMama A+ Chocolate (Iron) treatment may be repeated if EnfaMama A+ Chocolate (Iron) deficiency reoccurs.
Administer EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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. EnfaMama A+ Chocolate (Iron) treatment may be repeated if EnfaMama A+ Chocolate (Iron) deficiency reoccurs.
Administer EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) in a maximum of 250 mL of 0.9% NaCl. EnfaMama A+ Chocolate (Iron) treatment may be repeated if EnfaMama A+ Chocolate (Iron) deficiency reoccurs.
The dosing for EnfaMama A+ Chocolate (Iron) replacement treatment in pediatric patients with HDD-CKD has not been established.
For EnfaMama A+ Chocolate (Iron) maintenance treatment: Administer EnfaMama A+ Chocolate (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. EnfaMama A+ Chocolate (Iron) treatment may be repeated if necessary.
The dosing for EnfaMama A+ Chocolate (Iron) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.
For EnfaMama A+ Chocolate (Iron) maintenance treatment: Administer EnfaMama A+ Chocolate (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. EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after EnfaMama A+ Chocolate (Iron) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer EnfaMama A+ Chocolate (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous EnfaMama A+ Chocolate (Iron) preparations occur within 30 minutes of the completion of the infusion .
EnfaMama A+ Chocolate may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of EnfaMama A+ Chocolate (Iron). Hypotension following administration of EnfaMama A+ Chocolate (Iron) may be related to the rate of administration and/or total dose administered .
Excessive therapy with parenteral EnfaMama A+ Chocolate (Iron) can lead to excess storage of EnfaMama A+ Chocolate (Iron) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving EnfaMama A+ Chocolate (Iron) require periodic monitoring of hematologic and EnfaMama A+ Chocolate (Iron) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer EnfaMama A+ Chocolate (Iron) to patients with evidence of EnfaMama A+ Chocolate (Iron) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of EnfaMama A+ Chocolate (Iron) sucrose; do not perform serum EnfaMama A+ Chocolate (Iron) measurements for at least 48 hours after intravenous dosing .
The following serious adverse reactions associated with EnfaMama A+ Chocolate 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 EnfaMama A+ Chocolate 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 EnfaMama A+ Chocolate (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 | ||
EnfaMama A+ Chocolate (Iron) | EnfaMama A+ Chocolate (Iron) | Oral EnfaMama A+ Chocolate (Iron) | EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) therapy and were reported to be intolerant (defined as precluding further use of that EnfaMama A+ Chocolate (Iron) product). When these patients were treated with EnfaMama A+ Chocolate (Iron) there were no occurrences of adverse reactions that precluded further use of EnfaMama A+ Chocolate (Iron) .
Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)
In a randomized, open-label, dose-ranging trial for EnfaMama A+ Chocolate (Iron) maintenance treatment with EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving EnfaMama A+ Chocolate (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving EnfaMama A+ Chocolate (Iron) 2.0 mg/kg.
A total of 5 (11%) subjects in the EnfaMama A+ Chocolate (Iron) 0.5 mg/kg group, 10 (21%) patients in the EnfaMama A+ Chocolate (Iron) 1.0 mg/kg group, and 10 (21%) patients in the EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) injection. Reactions have occurred following the first dose or subsequent doses of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) have not been studied. However, EnfaMama A+ Chocolate (Iron) may reduce the absorption of concomitantly administered oral EnfaMama A+ Chocolate (Iron) preparations.
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, EnfaMama A+ Chocolate sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) sucrose. Because animal reproductive studies are not always predictive of human response, EnfaMama A+ Chocolate (Iron) should be used during pregnancy only if clearly needed.
It is not known whether EnfaMama A+ Chocolate (Iron) sucrose is excreted in human milk. EnfaMama A+ Chocolate (Iron) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when EnfaMama A+ Chocolate (Iron) is administered to a nursing woman.
Safety and effectiveness of EnfaMama A+ Chocolate for EnfaMama A+ Chocolate (Iron) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.
Safety and effectiveness of EnfaMama A+ Chocolate (Iron) for EnfaMama A+ Chocolate (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. EnfaMama A+ Chocolate (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)]
EnfaMama A+ Chocolate (Iron) has not been studied in patients younger than 2 years of age.
In a country where EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to EnfaMama A+ Chocolate (Iron) or any other drugs could be established.
Clinical studies of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) in humans. Excessive dosages of EnfaMama A+ Chocolate (Iron) may lead to accumulation of EnfaMama A+ Chocolate (Iron) in storage sites potentially leading to hemosiderosis. Do not administer EnfaMama A+ Chocolate (Iron) to patients with EnfaMama A+ Chocolate (Iron) overload.
Toxicities in single-dose studies in mice and rats, at intravenous EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (Iron) (iron sucrose injection, USP), an EnfaMama A+ Chocolate (Iron) replacement product, is a brown, sterile, aqueous, complex of polynuclear EnfaMama A+ Chocolate (Iron) (III)-hydroxide in sucrose for intravenous use. EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) polymerization and m is the number of sucrose molecules associated with the EnfaMama A+ Chocolate (Iron) (III)-hydroxide.
Each mL contains 20 mg elemental EnfaMama A+ Chocolate (Iron) as EnfaMama A+ Chocolate (Iron) sucrose in water for injection. EnfaMama A+ Chocolate (Iron) is available in 10 mL single-use vials (200 mg elemental EnfaMama A+ Chocolate (Iron) per 10 mL), 5 mL single-use vials (100 mg elemental EnfaMama A+ Chocolate (Iron) per 5 mL), and 2.5 mL single-use vials (50 mg elemental EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate is an aqueous complex of poly-nuclear EnfaMama A+ Chocolate (Iron) (III)-hydroxide in sucrose. Following intravenous administration, EnfaMama A+ Chocolate (Iron) is dissociated into EnfaMama A+ Chocolate (Iron) and sucrose and the EnfaMama A+ Chocolate (Iron) is transported as a complex with transferrin to target cells including erythroid precursor cells. The EnfaMama A+ Chocolate (Iron) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.
Following intravenous administration, EnfaMama A+ Chocolate (Iron) is dissociated into EnfaMama A+ Chocolate (Iron) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with EnfaMama A+ Chocolate (Iron) sucrose containing 100 mg of EnfaMama A+ Chocolate (Iron), three times weekly for three weeks, significant increases in serum EnfaMama A+ Chocolate (Iron) and serum ferritin and significant decreases in total EnfaMama A+ Chocolate (Iron) binding capacity occurred four weeks from the initiation of EnfaMama A+ Chocolate (Iron) sucrose treatment.
In healthy adults administered intravenous doses of EnfaMama A+ Chocolate, its EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating EnfaMama A+ Chocolate (Iron) containing 100 mg of EnfaMama A+ Chocolate (Iron) labeled with 52Fe/59Fe in patients with EnfaMama A+ Chocolate (Iron) deficiency showed that a significant amount of the administered EnfaMama A+ Chocolate (Iron) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible EnfaMama A+ Chocolate (Iron) trapping compartment.
Following intravenous administration of EnfaMama A+ Chocolate (Iron), EnfaMama A+ Chocolate (Iron) sucrose is dissociated into EnfaMama A+ Chocolate (Iron) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of EnfaMama A+ Chocolate (Iron) containing 1,510 mg of sucrose and 100 mg of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) sucrose containing 500 to 700 mg of EnfaMama A+ Chocolate (Iron) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the EnfaMama A+ Chocolate (Iron) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of EnfaMama A+ Chocolate (Iron) have not been studied.
Pharmacokinetics in Pediatric Patients
In a single-dose PK study of EnfaMama A+ Chocolate (Iron), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of EnfaMama A+ Chocolate (Iron) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose EnfaMama A+ Chocolate (Iron), the half-life of total serum EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) sucrose.
EnfaMama A+ Chocolate (Iron) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. EnfaMama A+ Chocolate (Iron) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.
EnfaMama A+ Chocolate (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate.
Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with EnfaMama A+ Chocolate (Iron) treatment and 24 in the historical control group) with EnfaMama A+ Chocolate (Iron) deficiency anemia. Eligibility criteria for EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron), who were off intravenous EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 | |||
EnfaMama A+ Chocolate (Iron) (n=69 | Historical Control (n=18) | EnfaMama A+ Chocolate (Iron) (n=73) | Historical Control (n=18) | EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) in 23 patients with EnfaMama A+ Chocolate (Iron) deficiency and HDD-CKD who had been discontinued from EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron). Exclusion criteria were similar to those in studies A and B. EnfaMama A+ Chocolate (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) versus EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) (325 mg ferrous sulfate three times daily for 56 days); or EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) group.
A statistically significantly greater proportion of EnfaMama A+ Chocolate (Iron) subjects (35/79; 44.3%) compared to oral EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) to patients with PDD-CKD receiving an erythropoietin alone without EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) or EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.
EnfaMama A+ Chocolate is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental EnfaMama A+ Chocolate (Iron), each 5 mL vial contains 100 mg elemental EnfaMama A+ Chocolate (Iron), and each 2.5 mL vial contains 50 mg elemental EnfaMama A+ Chocolate (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: EnfaMama A+ Chocolate (Iron), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental EnfaMama A+ Chocolate (Iron) per mL, or undiluted (20 mg elemental EnfaMama A+ Chocolate (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: EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Iron) administration:
AMERICAN
REGENT, INC.
SHIRLEY, NY 11967
EnfaMama A+ Chocolate (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.
PremierProRx® is a trademark of Premier, Inc., used under license.
PREMIERProRx®
IN2340
MG #15727
Magnesium:
EnfaMama A+ Chocolate (Magnesium) Sulfate
Injection, USP
Ansyr Plastic Syringe
Rx only
EnfaMama A+ Chocolate (Magnesium) Sulfate Injection, USP is a sterile solution of EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium). While there are large stores of EnfaMama A+ Chocolate (Magnesium) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral EnfaMama A+ Chocolate (Magnesium) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.
EnfaMama A+ Chocolate (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. EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium) levels range from 1.5 to 2.5 mEq/liter.
As plasma EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium). Serum EnfaMama A+ Chocolate (Magnesium) concentrations in excess of 12 mEq/L may be fatal.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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. EnfaMama A+ Chocolate (Magnesium) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.
EnfaMama A+ Chocolate (Magnesium) Sulfate Injection, USP is suitable for replacement therapy in EnfaMama A+ Chocolate (Magnesium) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum EnfaMama A+ Chocolate (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), EnfaMama A+ Chocolate (Magnesium) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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. EnfaMama A+ Chocolate (Magnesium) sulfate should be used during pregnancy only if clearly needed. If EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of EnfaMama A+ Chocolate (Magnesium).
Because EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium) should be given until they return. Serum EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium) intoxication in eclampsia.
50% EnfaMama A+ Chocolate (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
EnfaMama A+ Chocolate (Magnesium) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of EnfaMama A+ Chocolate (Magnesium). CNS depression and peripheral transmission defects produced by EnfaMama A+ Chocolate (Magnesium) may be antagonized by calcium.
Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral EnfaMama A+ Chocolate (Magnesium) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.
Cardiac Glycosides - EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium) toxicity.
Pregnancy
Teratogenic Effects
Pregnancy Category D (See WARNINGS and PRECAUTIONS )
See WARNINGS and PRECAUTIONS .
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium) sulfate for more than 5 to 7 days.1-10 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).
Labor and Delivery
Continuous administration of EnfaMama A+ Chocolate (Magnesium) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium) is distributed into milk during parenteral EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium) should be monitored in such patients.
The adverse effects of parenterally administered EnfaMama A+ Chocolate (Magnesium) usually are the result of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium) sulfate therapy for eclampsia has been reported.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium) Deficiency
In the treatment of mild EnfaMama A+ Chocolate (Magnesium) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of EnfaMama A+ Chocolate (Magnesium) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Magnesium) sulfate is 20 grams/48 hours and frequent serum EnfaMama A+ Chocolate (Magnesium) concentrations must be obtained. Continuous use of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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, EnfaMama A+ Chocolate (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
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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% EnfaMama A+ Chocolate (Magnesium) Sulfate 5 g/10 mL (500 mg/mL)
Rx only
NDC 0409-1754-10
10 mL Single-dose syringe
50% EnfaMama A+ Chocolate (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:
EnfaMama A+ Chocolate is indicated for pediatric and adult patients with severe congenital EnfaMama A+ Chocolate (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)
EnfaMama A+ Chocolate (Protein) is indicated for pediatric and adult patients with severe congenital EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate C activity is feasible. (2.1)
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of EnfaMama A+ Chocolate (Protein) C activity is feasible.
The dose, administration frequency and duration of treatment with EnfaMama A+ Chocolate (Protein) depends on the severity of the EnfaMama A+ Chocolate (Protein) C deficiency, the patient's age, the clinical condition of the patient and the patient's plasma level of EnfaMama A+ Chocolate (Protein) C. Therefore, adjust the dose regimen according to the pharmacokinetic profile for each individual patient. See DOSAGE AND ADMINISTRATION: EnfaMama A+ Chocolate (Protein) C Activity Monitoring (2.2).
Table 1 provides the EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough EnfaMama A+ Chocolate (Protein) C activity level above 25% for the duration of treatment.
In patients receiving prophylactic administration of EnfaMama A+ Chocolate (Protein), higher peak EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of EnfaMama A+ Chocolate (Protein) C before and during treatment with EnfaMama A+ Chocolate (Protein). The half-life of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the EnfaMama A+ Chocolate (Protein) C levels to maintain the trough EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate C, itself a vitamin K-dependent plasma EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) at room temperature not more than 3 hours after reconstitution.
Record the name and batch number of the product every time EnfaMama A+ Chocolate (Protein) is administered to a patient.
Administration by Infusion
Administer EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (Protein) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human EnfaMama A+ Chocolate (Protein) C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection, respectively to provide a single dose of human EnfaMama A+ Chocolate (Protein) C at a concentration of 100 IU/mL.
EnfaMama A+ Chocolate (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)
EnfaMama A+ Chocolate (Protein) may contain traces of mouse EnfaMama A+ Chocolate (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate 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 EnfaMama A+ Chocolate (Protein) further contributed to these bleeding events.
Simultaneous administration of EnfaMama A+ Chocolate (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of EnfaMama A+ Chocolate (Protein).
Inform patients on a low sodium diet that the quantity of sodium in the maximum daily dose of EnfaMama A+ Chocolate (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.
The common adverse reactions related to EnfaMama A+ Chocolate 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 EnfaMama A+ Chocolate (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein).
No inhibiting antibodies to EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) and tissue plasminogen activator (tPA).
See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of EnfaMama A+ Chocolate (Protein) and vitamin K antagonists.
Pregnancy Category C. Animal reproduction studies have not been conducted with EnfaMama A+ Chocolate (Protein). It is also not known whether EnfaMama A+ Chocolate (Protein) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. EnfaMama A+ Chocolate (Protein) should be given to pregnant women only if clearly needed.
EnfaMama A+ Chocolate has not been studied for use during labor and delivery. Use only if clearly needed.
EnfaMama A+ Chocolate (Protein) has not been studied for use in nursing mothers. Use EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 |
EnfaMama A+ Chocolate 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 EnfaMama A+ Chocolate (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) C is not compatible with life. A severe deficiency of this anticoagulant EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) C concentration following infusion divided by dose |
The EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein).
The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: EnfaMama A+ Chocolate (Protein) C Activity Monitoring (2.2).
Protein C contained in EnfaMama A+ Chocolate 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.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived EnfaMama A+ Chocolate (Protein). Thus, the long-term toxicity potential of EnfaMama A+ Chocolate (Protein) following repeated dosing in animals is unknown.
Local Tolerance Testing:
Investigation of route of injection tolerance demonstrated that EnfaMama A+ Chocolate (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:
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate in subjects with severe congenital EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) C deficiency were more effectively treated with EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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. EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein), as shown in Table 8. When not on prophylactic treatment and receiving EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) C deficiency who were treated with EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Protein) C corresponds to the amidolytically measured activity of EnfaMama A+ Chocolate (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).
EnfaMama A+ Chocolate (Protein) is available in single-dose vials that contain the following nominal product strengths:
NDC 0944-4177-05
EnfaMama A+ Chocolate (Protein) C
Concentrate (Human)
EnfaMama A+ Chocolate (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
EnfaMama A+ Chocolate (Protein) C Concentrate
(Human)
EnfaMama A+ Chocolate (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
EnfaMama A+ Chocolate (Protein) C
Concentrate (Human)
EnfaMama A+ Chocolate (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
EnfaMama A+ Chocolate (Protein) C Concentrate (Human)
EnfaMama A+ Chocolate (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
Sodium:
EnfaMama A+ Chocolate nitrite is indicated for sequential use with EnfaMama A+ Chocolate (Sodium) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)
EnfaMama A+ Chocolate (Sodium) Nitrite Injection is indicated for sequential use with EnfaMama A+ Chocolate (Sodium) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with EnfaMama A+ Chocolate (Sodium) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.
Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to EnfaMama A+ Chocolate nitroprusside.
The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, EnfaMama A+ Chocolate (Sodium) Nitrite Injection and EnfaMama A+ Chocolate (Sodium) Thiosulfate Injection should be administered without delay.
Symptoms | Signs |
---|---|
|
|
In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.
The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.
Smoke Inhalation
Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of EnfaMama A+ Chocolate (Sodium) Nitrite Injection, smoke-inhalation victims should be assessed for the following:
Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.
Caution should be exercised when administering cyanide antidotes, other than EnfaMama A+ Chocolate (Sodium) thiosulfate, simultaneously with EnfaMama A+ Chocolate (Sodium) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than EnfaMama A+ Chocolate (Sodium) thiosulfate, with EnfaMama A+ Chocolate (Sodium) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]
Age | Intravenous Dose of EnfaMama A+ Chocolate Nitrite and EnfaMama A+ Chocolate (Sodium) Thiosulfate |
---|---|
Adults |
|
Children |
|
Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both EnfaMama A+ Chocolate (Sodium) nitrite and EnfaMama A+ Chocolate (Sodium) thiosulfate.
Monitoring: Blood pressure must be monitored during treatment. (2.2)
Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of EnfaMama A+ Chocolate (Sodium) nitrite, followed by EnfaMama A+ Chocolate (Sodium) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer EnfaMama A+ Chocolate (Sodium) nitrite and EnfaMama A+ Chocolate (Sodium) thiosulfate.
EnfaMama A+ Chocolate (Sodium) nitrite injection and EnfaMama A+ Chocolate (Sodium) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. EnfaMama A+ Chocolate (Sodium) nitrite should be administered first, followed immediately by EnfaMama A+ Chocolate (Sodium) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.
Age | Intravenous Dose of EnfaMama A+ Chocolate (Sodium) Nitrite and EnfaMama A+ Chocolate (Sodium) Thiosulfate |
---|---|
Adults |
|
Children |
|
NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both EnfaMama A+ Chocolate (Sodium) nitrite and EnfaMama A+ Chocolate (Sodium) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of EnfaMama A+ Chocolate (Sodium) nitrite should be reduced proportionately to the hemoglobin concentration.
All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Patients should be monitored for at least 24-48 hours after EnfaMama A+ Chocolate Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.
Methemoglobin level: Administrations of EnfaMama A+ Chocolate (Sodium) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of EnfaMama A+ Chocolate (Sodium) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to EnfaMama A+ Chocolate (Sodium) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of EnfaMama A+ Chocolate (Sodium) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of EnfaMama A+ Chocolate (Sodium) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.
Chemical incompatibility has been reported between EnfaMama A+ Chocolate (Sodium) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between EnfaMama A+ Chocolate (Sodium) thiosulfate and EnfaMama A+ Chocolate (Sodium) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
EnfaMama A+ Chocolate (Sodium) Nitrite Injection consists of:
Administration of the contents of one vial constitutes a single dose.
None
Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with EnfaMama A+ Chocolate nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with EnfaMama A+ Chocolate (Sodium) nitrite whenever possible. When EnfaMama A+ Chocolate (Sodium) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of EnfaMama A+ Chocolate (Sodium) nitrite administered to an adult. EnfaMama A+ Chocolate (Sodium) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. EnfaMama A+ Chocolate (Sodium) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of EnfaMama A+ Chocolate (Sodium) nitrite, and infusion rates should be slowed if hypotension occurs.
EnfaMama A+ Chocolate (Sodium) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a EnfaMama A+ Chocolate (Sodium) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
EnfaMama A+ Chocolate nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.
Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when EnfaMama A+ Chocolate (Sodium) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.
Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with EnfaMama A+ Chocolate nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive EnfaMama A+ Chocolate (Sodium) nitrite.
EnfaMama A+ Chocolate (Sodium) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.
There have been no controlled clinical trials conducted to systematically assess the adverse events profile of EnfaMama A+ Chocolate (Sodium) nitrite.
The medical literature has reported the following adverse events in association with EnfaMama A+ Chocolate (Sodium) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.
Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia
Hematological: methemoglobinemia
Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma
Gastrointestinal system: nausea, vomiting, abdominal pain
Respiratory system: tachypnea, dyspnea
Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling
Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of EnfaMama A+ Chocolate (Sodium) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.
Most common adverse reactions are:
To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Formal drug interaction studies have not been conducted with EnfaMama A+ Chocolate (Sodium) Nitrite Injection.
Teratogenic Effects. Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. EnfaMama A+ Chocolate (Sodium) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
EnfaMama A+ Chocolate (Sodium) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of EnfaMama A+ Chocolate (Sodium) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).
The potential reproductive toxicity of EnfaMama A+ Chocolate (Sodium) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, EnfaMama A+ Chocolate (Sodium) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, EnfaMama A+ Chocolate (Sodium) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of EnfaMama A+ Chocolate (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with EnfaMama A+ Chocolate (Sodium) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of EnfaMama A+ Chocolate (Sodium) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
EnfaMama A+ Chocolate (Sodium) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.
Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to EnfaMama A+ Chocolate (Sodium) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to EnfaMama A+ Chocolate (Sodium) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.
Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, EnfaMama A+ Chocolate nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
It is not known whether EnfaMama A+ Chocolate (Sodium) nitrite is excreted in human milk. Because EnfaMama A+ Chocolate (Sodium) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following EnfaMama A+ Chocolate (Sodium) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of EnfaMama A+ Chocolate (Sodium) nitrite. In studies conducted with Long-Evans rats, EnfaMama A+ Chocolate (Sodium) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.
There are case reports in the medical literature of EnfaMama A+ Chocolate nitrite in conjunction with EnfaMama A+ Chocolate (Sodium) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of EnfaMama A+ Chocolate (Sodium) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
EnfaMama A+ Chocolate (Sodium) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.
Mortality attributed to EnfaMama A+ Chocolate (Sodium) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.
EnfaMama A+ Chocolate (Sodium) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
EnfaMama A+ Chocolate (Sodium) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Large doses of EnfaMama A+ Chocolate (Sodium) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
EnfaMama A+ Chocolate (Sodium) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to EnfaMama A+ Chocolate (Sodium) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.
Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of EnfaMama A+ Chocolate (Sodium) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.
Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.
EnfaMama A+ Chocolate (Sodium) nitrite has the chemical name nitrous acid EnfaMama A+ Chocolate (Sodium) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of EnfaMama A+ Chocolate (Sodium) Nitrite
EnfaMama A+ Chocolate (Sodium) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of EnfaMama A+ Chocolate (Sodium) nitrite injection.
EnfaMama A+ Chocolate (Sodium) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of EnfaMama A+ Chocolate (Sodium) nitrite in 10 mL solution (30 mg/mL). EnfaMama A+ Chocolate (Sodium) nitrite injection is a clear solution with a pH between 7.0 and 9.0.
Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.
The synergy resulting from treatment of cyanide poisoning with the combination of EnfaMama A+ Chocolate nitrite and EnfaMama A+ Chocolate (Sodium) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
EnfaMama A+ Chocolate (Sodium) Nitrite
EnfaMama A+ Chocolate (Sodium) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:
NaNO2 + Hemoglobin → Methemoglobin
HCN + Methemoglobin → Cyanomethemoglobin
Vasodilation has also been cited to account for at least part of the therapeutic effect of EnfaMama A+ Chocolate (Sodium) nitrite. It has been suggested that EnfaMama A+ Chocolate (Sodium) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, EnfaMama A+ Chocolate (Sodium) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
EnfaMama A+ Chocolate (Sodium) Thiosulfate
The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine. EnfaMama A+ Chocolate (Sodium) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:
Chemical Structure
EnfaMama A+ Chocolate (Sodium) Nitrite
When 4 mg/kg EnfaMama A+ Chocolate (Sodium) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of EnfaMama A+ Chocolate (Sodium) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.
Oral doses of 120 to 180 mg of EnfaMama A+ Chocolate (Sodium) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.
The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered EnfaMama A+ Chocolate (Sodium) nitrite is estimated to be 55 minutes.
EnfaMama A+ Chocolate (Sodium) Nitrite
EnfaMama A+ Chocolate (Sodium) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free EnfaMama A+ Chocolate (Sodium) nitrite in humans have not been well studied. It has been reported that approximately 40% of EnfaMama A+ Chocolate (Sodium) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.
Cyanide
The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with EnfaMama A+ Chocolate (Sodium) nitrite and EnfaMama A+ Chocolate (Sodium) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.
Thiocyanate
After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.
The potential benefit of an acute exposure to EnfaMama A+ Chocolate nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. EnfaMama A+ Chocolate (Sodium) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. EnfaMama A+ Chocolate (Sodium) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that EnfaMama A+ Chocolate (Sodium) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to EnfaMama A+ Chocolate (Sodium) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Mutagenesis
EnfaMama A+ Chocolate (Sodium) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. EnfaMama A+ Chocolate (Sodium) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. EnfaMama A+ Chocolate (Sodium) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of EnfaMama A+ Chocolate (Sodium) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, EnfaMama A+ Chocolate (Sodium) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.
Fertility
Clinical studies to evaluate the potential effects of EnfaMama A+ Chocolate (Sodium) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of EnfaMama A+ Chocolate (Sodium) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of EnfaMama A+ Chocolate (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of EnfaMama A+ Chocolate (Sodium) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of EnfaMama A+ Chocolate (Sodium) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of EnfaMama A+ Chocolate (Sodium) nitrite and EnfaMama A+ Chocolate (Sodium) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) EnfaMama A+ Chocolate (Sodium) nitrite or 1 g/kg EnfaMama A+ Chocolate (Sodium) thiosulfate alone or in sequence immediately after subcutaneous injection of EnfaMama A+ Chocolate (Sodium) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg EnfaMama A+ Chocolate (Sodium) nitrite and/or 0.5 g/kg EnfaMama A+ Chocolate (Sodium) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of EnfaMama A+ Chocolate (Sodium) cyanide required to cause death, and when administered together, EnfaMama A+ Chocolate (Sodium) nitrite and EnfaMama A+ Chocolate (Sodium) thiosulfate resulted in a synergistic effect in raising the lethal dose of EnfaMama A+ Chocolate (Sodium) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.
Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous EnfaMama A+ Chocolate (Sodium) nitrite and EnfaMama A+ Chocolate (Sodium) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of EnfaMama A+ Chocolate (Sodium) nitrite and EnfaMama A+ Chocolate (Sodium) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of EnfaMama A+ Chocolate (Sodium) nitrite, with or without EnfaMama A+ Chocolate (Sodium) thiosulfate, was found not to be effective in the same setting.
The human data supporting the use of EnfaMama A+ Chocolate (Sodium) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of EnfaMama A+ Chocolate (Sodium) thiosulfate report its use in conjunction with EnfaMama A+ Chocolate (Sodium) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
There have been no human studies to prospectively and systematically evaluate the safety of EnfaMama A+ Chocolate (Sodium) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.
Each EnfaMama A+ Chocolate (Sodium) Nitrite carton (NDC 60267-311-10) consists of the following:
Storage
Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.
(Note: EnfaMama A+ Chocolate (Sodium) Thiosulfate must be obtained separately.)
EnfaMama A+ Chocolate Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.
When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.
Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.
Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for
Hope Pharmaceuticals, Scottsdale, Arizona 85260
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
NDC 60267-311-10
Rx Only
EnfaMama A+ Chocolate (Sodium) Nitrite
Injection, USP
300 mg/10 mL
(30 mg/mL)
FOR INTRAVENOUS USE
SINGLE USE ONLY
Any unused portion of a vial
should be discarded.
Use with
EnfaMama A+ Chocolate (Sodium) Thiosulfate
for Treatment of
Cyanide Poisoning
Manufactured by
CANGENE bioPharma, Inc.
Baltimore, MD for
HOPE
PHARMACEUTICALS®
Scottsdale, AZ 85260 U.S.A.
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
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 | |
EnfaMama A+ Chocolate (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, EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.
Before recommending EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.
EnfaMama A+ Chocolate (Vitamin A) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.
EnfaMama A+ Chocolate (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 B12:
EnfaMama A+ Chocolate refers to a group of water-soluble vitamins. It has high biological activity. EnfaMama A+ Chocolate (Vitamin B12) is necessary for normal hematopoiesis (promotes maturation of erythrocytes). Involved in the processes of transmethylation, hydrogen transport, synthesis of methionine, nucleic acids, choline, creatine. Contributes to the accumulation in erythrocytes of compounds containing sulfhydryl groups. Has a beneficial effect on liver function and the nervous system. Activates the coagulation of blood in high doses causes an increase in the activity of thromboplastin and prothrombin.
After oral administration EnfaMama A+ Chocolate (Vitamin B12) absorbed from the gastrointestinal tract. Metabolized in the tissues, becoming a co-enzyme form - adenosylcobalamin which is the active form of cyanocobalamin. Excreted in bile and urine.
Anemia due to B12-deficiency conditions; in the complex therapy for iron and posthemorrhagic anemia; aplastic anemia caused by toxic substances and drugs; liver disease (hepatitis, cirrhosis); funicular myelosis; polyneuritis, radiculitis, neuralgia, amyotrophic lateral sclerosis; children cerebral palsy, Down syndrome, peripheral nerve injury; skin diseases (psoriasis, photodermatosis, herpetiformis dermatitis, neurodermatitis); to prevent and treat symptoms of deficiency of EnfaMama A+ Chocolate (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.
EnfaMama A+ Chocolate is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with EnfaMama A+ Chocolate (Vitamin B12) deficiency is introduced on 100-200 mcg in 2 days. In anemia with symptoms of funicular myelosis and megalocytic anemia with diseases of the nervous system - 400-500 micrograms in the first 7 days daily, then 1 time every 5-7 days. In the period of remission in the absence of events funicular myelosis maintenance dose - 100 mcg 2 times a month, in the presence of neurological symptoms - at 200-400 mcg 2-4 times a month. In acute post-hemorrhagic anemia and iron anemia by 30-100 mcg 2-3 times a week. When aplastic anemia (especially in children) - 100 micrograms before clinical improvement. When nutritional anemia in infants and preterm - 30 mcg / day during 15 days.
In diseases of the central and peripheral nervous system and neurological diseases with a pain syndrome is administered in increasing doses - 200-500 mcg, with the improvement in the state - 100 mcg / day. The course of treatment with EnfaMama A+ Chocolate (Vitamin B12) is 2 weeks. In traumatic lesions of peripheral nervous system - at 200-400 mcg every other day for 40-45 days.
When hepatitis and cirrhosis - 30-60 mcg / day or 100 mg every other day for 25-40 days.
Dystrophy in young children, Down syndrome and cerebral palsy - by 15-30 mcg every other day.
When funicular myelosis, amyotrophic lateral sclerosis can be introduced into the spinal canal at 15-30 mcg, gradually increasing the dose of 200-250 micrograms.
In radiation sickness, diabetic neuropathy, sprue - by 60-100 mcg daily for 20-30 days.
When deficiency of EnfaMama A+ Chocolate (Vitamin B12) to prevent - IV or IM for 1 mg 1 time a month; for treatment - IV or IM for 1 mg daily for 1-2 weeks, the maintenance dose is 1-2 mg IV or IM from 1 per week, up to 1 per month. Duration of treatment is determined individually.
CNS: rarely - a state of arousal.
Cardiovascular system: rarely - pain in the heart, tachycardia.
Allergic reactions: rarely - urticaria.
Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.
Cyanocobalamin can be used in pregnancy according to prescriptions.
When stenocardia should be used with caution in a single dose of EnfaMama A+ Chocolate 100 mcg. During treatment should regularly monitor the blood picture and coagulation. It is unacceptable to enter in the same syringe with cyanocobalamin solutions of thiamine and pyridoxine.
In an application of EnfaMama A+ Chocolate (Vitamin B12) with hormonal contraceptives for oral administration may decrease the concentration of cyanocobalamin in plasma.
In an application with anticonvulsant drugs decreased cyanocobalamin absorption from the gut.
In an EnfaMama A+ Chocolate (Vitamin B12) application with neomycin, aminosalicylic acid, colchicine, cimetidine, ranitidine, drugs potassium decreased cyanocobalamin absorption from the gut.
Cyanocobalamin may exacerbate allergic reactions caused by thiamine.
When parenteral application of chloramphenicol may decrease the hematopoietic effects of cyanocobalamin with anemia.
Pharmaceutical incompatibility
Contained in the molecule of cyanocobalamin cobalt ion contributes to the destruction of ascorbic acid, thiamine bromide, riboflavin in one solution.
Vitamin C:
Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. EnfaMama A+ Chocolate (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. EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of EnfaMama A+ Chocolate (Vitamin C); providing increased need for EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate 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.
EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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: EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (Vitamin E) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. EnfaMama A+ Chocolate (Vitamin E) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. EnfaMama A+ Chocolate (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. EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Vitamin E) may help prevent or delay coronary heart disease. Antioxidants such as EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Vitamin E) have been linked to increased incidence of breast and colon cancer.
Zinc:
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Zinc) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.
None known.
Direct intramuscular or intravenous injection of EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Zinc) from a bolus injection. Administration of EnfaMama A+ Chocolate (Zinc) in the absence of copper may cause a decrease in serum copper levels.
Periodic determinations of serum copper as well as EnfaMama A+ Chocolate (Zinc) are suggested as a guideline for subsequent EnfaMama A+ Chocolate (Zinc) administration.
Long-term animal studies to evaluate the carcinogenic potential of EnfaMama A+ Chocolate 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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate chloride. It is also not known whether EnfaMama A+ Chocolate (Zinc) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Zinc) concentration of 207 mcg/dl. Symptoms abated within three hours.
Hyperamylasemia may be a sign of impending EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Zinc) was delivered intravenously over the course of 60 hours to a 72 year old patient.
Symptoms of EnfaMama A+ Chocolate (Zinc) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum EnfaMama A+ Chocolate (Zinc) level of 4184 mcg/dl.
Calcium supplements may confer a protective effect against EnfaMama A+ Chocolate (Zinc) toxicity.
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate (Zinc) blood levels is suggested for patients receiving more than the usual maintenance dosage level of EnfaMama A+ Chocolate (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.
EnfaMama A+ Chocolate (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
EnfaMama A+ Chocolate (Zinc)
1 mg/mL
EnfaMama A+ Chocolate (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 EnfaMama A+ Chocolate after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider EnfaMama A+ Chocolate 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 EnfaMama A+ Chocolate addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology