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DRUGS & SUPPLEMENTS
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Bebelac FL
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Bebelac FL uses
Bebelac FL consists of Beta-Carotene, Carbohydrates, Chloride, Choline, Copper, Fat, Folic Acid, Inositol, Iodine, Iron, L-Carnitine, L-Cystine Hydrochloride, Manganese, Moisture, Phosphorus, Potassium, Protein, Sodium, Taurine, Vitamin A, Vitamin B1, Vitamin B12, Vitamin B2, Vitamin B3 (Niacinamide), Vitamin B5 (Pantothenic Acid), Vitamin B6, Vitamin C, Vitamin D3, Vitamin E (Alpha Tocopherol), Vitamin H (Biotin), Vitamin K1, Zinc.Choline:
A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism.
Indication: For nutritional supplementation, also for treating dietary shortage or imbalance
This compound is needed for good nerve conduction throughout the CNS (central nervous system) as it is a precursor to acetylcholine (ACh). Bebelac FL (Choline) is also needed for gallbladder regulation, liver function and lecithin (a key lipid) formation. Bebelac FL (Choline) also aids in fat and cholesterol metabolism and prevents excessive fat build up in the liver. Bebelac FL (Choline) has been used to mitigate the effects of Parkinsonism and tardive dyskinesia. Bebelac FL (Choline) deficiencies may result in excessive build-up of fat in the liver, high blood pressure, gastric ulcers, kidney and liver dysfunction and stunted growth.
Copper:
Water-Resistant Protection Without Bandaging
Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Bebelac FL (Copper) Naphthenate.
For Animal Use Only.
INDICATIONS:
ThrushTox® is indicated in the treatment of thrush in horses and ponies.
GENERAL DIRECTIONS:
Clean the hoof thoroughly, removing debris and necrotic material prior to application of Bebelac FL (Copper)®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Bebelac FL (Copper)® onto hair since contact with Bebelac FL (Copper)® may cause some hair loss. Do not contaminate feed.
NOTE: Bebelac FL (Copper)® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.
CONTAINS FOIL SEAL – REMOVE BEFORE USE.
SHAKE WELL BEFORE USE.
To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.
ACTIVE INGREDIENT:
Bebelac FL (Copper) Naphthenate...37.5% w/w
INACTIVE INGREDIENTS:
Inert Ingredients...62.5% w/w
Total... 100.0%
CAUTION:
Do not use in horses intended for human consumption.
CAUTION: COMBUSTIBLE MIXTURE.
Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.
If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.
KEEP OUT OF REACH OF CHILDREN AND PETS.
STORAGE:
Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.
Manufactured for:
Aspen Veterinary Resources,® Ltd.
Liberty, MO 64068, USA
FC163FP 11/13
Manufactured by:
First Priority, Inc.
Elgin, IL 60123-1146, USA
NET CONTENTS:
16 OZ (473 mL)
ANADA 200-304, Approved by FDA
Image of 473 mL bottle/case label
Folic Acid:
- Indications and usage
- Contraindications
- Precautions
- Adverse reactions
- Dosage and administration
- How supplied
- Storage
INDICATIONS AND USAGE
Bebelac FL (Folic Acid)® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.
CONTRAINDICATIONS
This product is contraindicated in patients with a known hypersensitivity to any of the ingredients. Hemochromatosis and hemosiderosis are contraindications to iron therapy.
| WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately. |
PRECAUTIONS
Bebelac FL (Folic Acid) acid when administered as a single agent in doses above 0.1 mg daily may obscure pernicious anemia in that hematological remission can occur while neurological manifestations remain progressive. While prescribing this nutritional supplement for pregnant women, nursing mothers, or for women prior to conception, their medical condition and other drugs, herbs, and/or supplements consumption should be considered.
ADVERSE REACTIONS
Allergic sensitization has been reported following both oral and parenteral administration of Bebelac FL (Folic Acid) acid.
DOSAGE AND ADMINISTRATION
One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.
HOW SUPPLIED
Bebelac FL (Folic Acid)® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)
KEEP OUT OF REACH OF CHILDREN.
STORAGE
Store at controlled room temperature 20°-25°C (68°-77°F). Excursions permitted to 15°-30°C (59°-86°F).
Dispense in a tight, light-resistant container to protect from light and moisture.
To report SUSPECTED ADVERSE REACTIONS contact Meda Pharmaceuticals Inc. at 1-888-349-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch
Distributed by:
Meda Pharmaceuticals Inc.
Somerset New Jersey 08873-4120
© 2014 Meda Pharmaceuticals Inc.
U.S. Patent Nos. 7,585,527 and 8,080,520
Proferrin® is a registered trademark of Colorado BioLabs, Inc., Cozad, NE.
Bebelac FL (Folic Acid) and the BIFERA logo are registered trademarks and the Bebelac FL (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
Inositol:
Niacin is used with a proper diet and exercise program to help lower "bad" cholesterol and fats ( LDL, triglycerides ) and raise "good" cholesterol (HDL) in the blood. It is generally used after non-drug treatments have not been fully successful at lowering cholesterol. Niacin is also known as vitamin B-3 ( nicotinic acid ), one of the B-complex vitamins. It may be used with or without other medications. Lowering "bad" cholesterol/triglycerides and raising "good" cholesterol helps prevent strokes and heart attacks. Lowering fats may also help reduce the risk of pancreas problems ( pancreatitis ) in people at risk. In addition to eating a proper diet (such as a low-cholesterol/low-fat diet), other lifestyle changes that may help this medication work better include exercising, losing weight if overweight, and stopping smoking. Consult your doctor for more details.
Iodine:
Bebelac FL Tincture 7%
Directions:
Topical Antiseptic
Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Bebelac FL (Iodine) with a swab.
If necessary, clip hair around the area being treated and clean with soap and water.
Apply Bebelac FL (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.
Bebelac FL Tincture 7%
image description
Iron:
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Overdosage
- Description
- Clinical pharmacology
- Nonclinical toxicology
- Clinical studies
- How supplied/storage and handling
- Patient counseling information
1 INDICATIONS AND USAGE
Bebelac FL (Iron) is indicated for the treatment of Bebelac FL (Iron) deficiency anemia in patients with chronic kidney disease (CKD).
Bebelac FL (Iron) is an Bebelac FL (Iron) replacement product indicated for the treatment of Bebelac FL (Iron) deficiency anemia in patients with chronic kidney disease (CKD). (1)
2 DOSAGE AND ADMINISTRATION
Bebelac FL must only be administered intravenously either by slow injection or by infusion. The dosage of Bebelac FL (Iron) is expressed in mg of elemental Bebelac FL (Iron). Each mL contains 20 mg of elemental Bebelac FL (Iron).
| Population | Dose | |
| Adult patients | Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1) | 100 mg slow intravenous injection or infusion |
| Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2) | 200 mg slow intravenous injection or infusion | |
| Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) | 300 mg or 400 mg intravenous infusion | |
| Pediatric patients | HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5) | 0.5 mg/kg slow intravenous injection or infusion |
2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
Administer Bebelac FL (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. Bebelac FL (Iron) should be administered early during the dialysis session. The usual total treatment course of Bebelac FL (Iron) is 1000 mg. Bebelac FL (Iron) treatment may be repeated if Bebelac FL (Iron) deficiency reoccurs.
2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease
Administer Bebelac FL (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 Bebelac FL (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. Bebelac FL (Iron) treatment may be repeated if Bebelac FL (Iron) deficiency reoccurs.
2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease
Administer Bebelac FL (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 Bebelac FL (Iron) in a maximum of 250 mL of 0.9% NaCl. Bebelac FL (Iron) treatment may be repeated if Bebelac FL (Iron) deficiency reoccurs.
2.4 Pediatric Patients with HDD-CKD for Bebelac FL (Iron) maintenance treatment
The dosing for Bebelac FL (Iron) replacement treatment in pediatric patients with HDD-CKD has not been established.
For Bebelac FL (Iron) maintenance treatment: Administer Bebelac FL (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. Bebelac FL (Iron) treatment may be repeated if necessary.
2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Bebelac FL (Iron) maintenance treatment
The dosing for Bebelac FL (Iron) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.
For Bebelac FL (Iron) maintenance treatment: Administer Bebelac FL (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. Bebelac FL (Iron) treatment may be repeated if necessary.
3 DOSAGE FORMS AND STRENGTHS
- 10 mL single-use vial / 200 mg elemental Bebelac FL (Iron) (20 mg/mL)
- 5 mL single-use vial / 100 mg elemental Bebelac FL (Iron) (20 mg/mL)
- 2.5 mL single-use vial / 50 mg elemental Bebelac FL (Iron) (20 mg/mL)
- 10 mL single-use vial / 200 mg elemental Bebelac FL (Iron) (20 mg/mL) (3)
- 5 mL single-use vial / 100 mg elemental Bebelac FL (Iron) (20 mg/mL) (3)
- 2.5 mL single-use vial / 50 mg elemental Bebelac FL (Iron) (20 mg/mL) (3)
4 CONTRAINDICATIONS
- Known hypersensitivity to Bebelac FL (Iron)
- Known hypersensitivity to Bebelac FL (Iron) (4)
5 WARNINGS AND PRECAUTIONS
- Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Bebelac FL administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Bebelac FL (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
- Hypotension: Bebelac FL (Iron) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Bebelac FL (Iron). (5.2)
- Bebelac FL (Iron) Overload: Regularly monitor hematologic responses during Bebelac FL (Iron) therapy. Do not administer Bebelac FL (Iron) to patients with Bebelac FL (Iron) overload. (5.3)
5.1 Hypersensitivity Reactions
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Bebelac FL (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 Bebelac FL (Iron) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Bebelac FL (Iron) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Bebelac FL (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Bebelac FL (Iron) preparations occur within 30 minutes of the completion of the infusion .
5.2 Hypotension
Bebelac FL may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Bebelac FL (Iron). Hypotension following administration of Bebelac FL (Iron) may be related to the rate of administration and/or total dose administered .
5.3 Bebelac FL (Iron) Overload
Excessive therapy with parenteral Bebelac FL (Iron) can lead to excess storage of Bebelac FL (Iron) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Bebelac FL (Iron) require periodic monitoring of hematologic and Bebelac FL (Iron) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Bebelac FL (Iron) to patients with evidence of Bebelac FL (Iron) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Bebelac FL (Iron) sucrose; do not perform serum Bebelac FL (Iron) measurements for at least 48 hours after intravenous dosing .
6 ADVERSE REACTIONS
The following serious adverse reactions associated with Bebelac FL are described in other sections .
- The most common adverse reactions (≥2%) following the administration of Bebelac FL (Iron) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Adverse Reactions in Clinical Trials
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.
Adverse Reactions in Adults Patients with CKD
Adverse Reactions in Adult Patients with CKD
The frequency of adverse reactions associated with the use of Bebelac FL 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 Bebelac FL (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 | ||
| Bebelac FL (Iron) | Bebelac FL (Iron) | Oral Bebelac FL (Iron) | Bebelac FL (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 Bebelac FL (Iron) therapy and were reported to be intolerant (defined as precluding further use of that Bebelac FL (Iron) product). When these patients were treated with Bebelac FL (Iron) there were no occurrences of adverse reactions that precluded further use of Bebelac FL (Iron) .
Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)
Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)
In a randomized, open-label, dose-ranging trial for Bebelac FL (Iron) maintenance treatment with Bebelac FL (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 Bebelac FL (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving Bebelac FL (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving Bebelac FL (Iron) 2.0 mg/kg.
A total of 5 (11%) subjects in the Bebelac FL (Iron) 0.5 mg/kg group, 10 (21%) patients in the Bebelac FL (Iron) 1.0 mg/kg group, and 10 (21%) patients in the Bebelac FL (Iron) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).
6.2 Adverse Reactions from Post-Marketing Experience
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.
The following adverse reactions have been identified during post-approval use of Bebelac FL (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 Bebelac FL (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 Bebelac FL (Iron) injection. Reactions have occurred following the first dose or subsequent doses of Bebelac FL (Iron). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.
Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.
7 DRUG INTERACTIONS
Drug interactions involving Bebelac FL (Iron) have not been studied. However, Bebelac FL (Iron) may reduce the absorption of concomitantly administered oral Bebelac FL (Iron) preparations.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Bebelac FL sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Bebelac FL (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 Bebelac FL (Iron) sucrose. Because animal reproductive studies are not always predictive of human response, Bebelac FL (Iron) should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
It is not known whether Bebelac FL (Iron) sucrose is excreted in human milk. Bebelac FL (Iron) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Bebelac FL (Iron) is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of Bebelac FL for Bebelac FL (Iron) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.
Safety and effectiveness of Bebelac FL (Iron) for Bebelac FL (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. Bebelac FL (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)]
Bebelac FL (Iron) has not been studied in patients younger than 2 years of age.
In a country where Bebelac FL (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 Bebelac FL (Iron), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Bebelac FL (Iron) or any other drugs could be established.
8.5 Geriatric Use
Clinical studies of Bebelac FL (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 Bebelac FL (Iron), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
10 OVERDOSAGE
No data are available regarding overdosage of Bebelac FL (Iron) in humans. Excessive dosages of Bebelac FL (Iron) may lead to accumulation of Bebelac FL (Iron) in storage sites potentially leading to hemosiderosis. Do not administer Bebelac FL (Iron) to patients with Bebelac FL (Iron) overload.
Toxicities in single-dose studies in mice and rats, at intravenous Bebelac FL (Iron) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.
11 DESCRIPTION
Bebelac FL (Iron) (iron sucrose injection, USP), an Bebelac FL (Iron) replacement product, is a brown, sterile, aqueous, complex of polynuclear Bebelac FL (Iron) (III)-hydroxide in sucrose for intravenous use. Bebelac FL (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 Bebelac FL (Iron) polymerization and m is the number of sucrose molecules associated with the Bebelac FL (Iron) (III)-hydroxide.
Each mL contains 20 mg elemental Bebelac FL (Iron) as Bebelac FL (Iron) sucrose in water for injection. Bebelac FL (Iron) is available in 10 mL single-use vials (200 mg elemental Bebelac FL (Iron) per 10 mL), 5 mL single-use vials (100 mg elemental Bebelac FL (Iron) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Bebelac FL (Iron) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Bebelac FL is an aqueous complex of poly-nuclear Bebelac FL (Iron) (III)-hydroxide in sucrose. Following intravenous administration, Bebelac FL (Iron) is dissociated into Bebelac FL (Iron) and sucrose and the Bebelac FL (Iron) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Bebelac FL (Iron) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.
12.2 Pharmacodynamics
Following intravenous administration, Bebelac FL (Iron) is dissociated into Bebelac FL (Iron) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Bebelac FL (Iron) sucrose containing 100 mg of Bebelac FL (Iron), three times weekly for three weeks, significant increases in serum Bebelac FL (Iron) and serum ferritin and significant decreases in total Bebelac FL (Iron) binding capacity occurred four weeks from the initiation of Bebelac FL (Iron) sucrose treatment.
12.3 Pharmacokinetics
In healthy adults administered intravenous doses of Bebelac FL, its Bebelac FL (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 Bebelac FL (Iron) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Bebelac FL (Iron) containing 100 mg of Bebelac FL (Iron) labeled with 52Fe/59Fe in patients with Bebelac FL (Iron) deficiency showed that a significant amount of the administered Bebelac FL (Iron) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Bebelac FL (Iron) trapping compartment.
Following intravenous administration of Bebelac FL (Iron), Bebelac FL (Iron) sucrose is dissociated into Bebelac FL (Iron) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Bebelac FL (Iron) containing 1,510 mg of sucrose and 100 mg of Bebelac FL (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 Bebelac FL (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 Bebelac FL (Iron) sucrose containing 500 to 700 mg of Bebelac FL (Iron) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Bebelac FL (Iron) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Bebelac FL (Iron) have not been studied.
Pharmacokinetics in Pediatric Patients
Pharmacokinetics in Pediatric Patients
In a single-dose PK study of Bebelac FL (Iron), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Bebelac FL (Iron) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Bebelac FL (Iron), the half-life of total serum Bebelac FL (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.
Bebelac FL (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Bebelac FL (Iron) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been performed with Bebelac FL (Iron) sucrose.
Bebelac FL (Iron) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Bebelac FL (Iron) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.
Bebelac FL (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental Bebelac FL (Iron) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.
14 CLINICAL STUDIES
Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Bebelac FL.
14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)
Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Bebelac FL (Iron) treatment and 24 in the historical control group) with Bebelac FL (Iron) deficiency anemia. Eligibility criteria for Bebelac FL (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.
Bebelac FL (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 Bebelac FL (Iron), who were off intravenous Bebelac FL (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 Bebelac FL (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 | |||
| Bebelac FL (Iron) (n=69 | Historical Control (n=18) | Bebelac FL (Iron) (n=73) | Historical Control (n=18) | Bebelac FL (Iron) (n=71) | Historical Control (n=15) | |
| Hemoglobin (g/dL) | 1.0 ± 0.12** | 0.0 ± 0.21 | 1.3 ± 0.14** | -0.6 ± 0.24 | 1.2 ± 0.17* | -0.1 ± 0.23 |
| Hematocrit (%) | 3.1 ± 0.37** | -0.3 ± 0.65 | 3.6 ± 0.44** | -1.2 ± 0.76 | 3.3 ± 0.54 | 0.2 ± 0.86 |
Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).
14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease
Study B was a multicenter, open label study of Bebelac FL (Iron) in 23 patients with Bebelac FL (Iron) deficiency and HDD-CKD who had been discontinued from Bebelac FL (Iron) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.
All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.
14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease
Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Bebelac FL (Iron). Exclusion criteria were similar to those in studies A and B. Bebelac FL (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Bebelac FL (Iron) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.
The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.
14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease
Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Bebelac FL (Iron) versus Bebelac FL (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 Bebelac FL (Iron) (325 mg ferrous sulfate three times daily for 56 days); or Bebelac FL (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 Bebelac FL (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 Bebelac FL (Iron) group.
A statistically significantly greater proportion of Bebelac FL (Iron) subjects (35/79; 44.3%) compared to oral Bebelac FL (Iron) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).
14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease
Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Bebelac FL (Iron) to patients with PDD-CKD receiving an erythropoietin alone without Bebelac FL (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 Bebelac FL (Iron) or Bebelac FL (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 Bebelac FL (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 Bebelac FL (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 Bebelac FL (Iron) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).
14.6 Study F: Bebelac FL Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease
Study F was a randomized, open-label, dose-ranging study for Bebelac FL (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 Bebelac FL (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 Bebelac FL (Iron) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Bebelac FL (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 Bebelac FL (Iron) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.
16 HOW SUPPLIED/storage and handling
16.1 How Supplied
Bebelac FL is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Bebelac FL (Iron), each 5 mL vial contains 100 mg elemental Bebelac FL (Iron), and each 2.5 mL vial contains 50 mg elemental Bebelac FL (Iron) (20 mg/mL).
| NDC-0517-2310-05 | 200 mg/10 mL Single-Use Vial | Packages of 5 |
| NDC-0517-2310-10 | 200 mg/10 mL Single-Use Vial | Packages of 10 |
| NDC-0517-2340-01 | 100 mg/5 mL Single-Use Vial | Individually Boxed |
| NDC-0517-2340-10 | 100 mg/5 mL Single-Use Vial | Packages of 10 |
| NDC-0517-2340-25 | 100 mg/5 mL Single-Use Vial | Packages of 25 |
| NDC-0517-2340-99 | 100 mg/5 mL Single-Use Vial | Packages of 10 |
| NDC-0517-2325-10 | 50 mg/2.5 mL Single-Use Vial | Packages of 10 |
| NDC-0517-2325-25 | 50 mg/2.5 mL Single-Use Vial | Packages of 25 |
16.2 Stability and Storage
Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.
Syringe Stability: Bebelac FL (Iron), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Bebelac FL (Iron) per mL, or undiluted (20 mg elemental Bebelac FL (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: Bebelac FL (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 Bebelac FL (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 Bebelac FL (Iron) with other medications or add to parenteral nutrition solutions for intravenous infusion.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.
17 PATIENT COUNSELING INFORMATION
Prior to Bebelac FL (Iron) administration:
- Question patients regarding any prior history of reactions to parenteral Bebelac FL (Iron) products
- Advise patients of the risks associated with Bebelac FL (Iron)
- Advise patients to report any symptoms of hypersensitivity that may develop during and following Bebelac FL (Iron) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]
AMERICAN
REGENT, INC.
SHIRLEY, NY 11967
Bebelac FL (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.
PremierProRx® is a trademark of Premier, Inc., used under license.
PREMIERProRx®
IN2340
MG #15727
L-Carnitine:
Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias.
Indication: For treatment of primary systemic carnitine deficiency, a genetic impairment of normal biosynthesis or utilization of levocarnitine from dietary sources, or for the treatment of secondary carnitine deficiency resulting from an inborn error of metabolism such as glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency. Used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. Parenteral levocarnitine is indicated for the prevention and treatment of carnitine deficiency in patients with end-stage renal disease.
Levocarnitine is a carrier molecule in the transport of long chain fatty acids across the inner mitochondrial membrane. It also exports acyl groups from subcellular organelles and from cells to urine before they accumulate to toxic concentrations. Lack of carnitine can lead to liver, heart, and muscle problems. Carnitine deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20 µmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. Only the L isomer of carnitine (sometimes called vitamin BT) affects lipid metabolism. The "vitamin BT" form actually contains D,L-carnitine, which competitively inhibits levocarnitine and can cause deficiency. Levocarnitine can be used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias.
L-Cystine Hydrochloride:
A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine.
Indication: It has been claimed that L-cysteine has anti-inflammatory properties, that it can protect against various toxins, and that it might be helpful in osteoarthritis and rheumatoid arthritis. More research will have to be done before L-cysteine can be indicated for any of these conditions. Research to date has mostly been in animal models.
Bebelac FL (L-Cystine Hydrochloride) is a covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. Cystine is a chemical substance which naturally occurs as a deposit in the urine, and can form a calculus (hard mineral formation) when deposited in the kidney. The compound produced when two cysteine molecules linked by a disulfide (S-S) bond. Cystine is required for proper vitamin B6 utilization and is also helpful in the healing of burns and wounds, breaking down mucus deposits in illnesses such as bronchitis as well as cystic fibrosis. Cysteine also assists in the supply of insulin to the pancreas, which is needed for the assimilation of sugars and starches. It increases the level of glutathione in the lungs, liver, kidneys and bone marrow, and this may have an anti-aging effect on the body by reducing age-spots etc.
Manganese:
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Drug abuse and dependence
- Overdosage
- Dosage and administration
- How supplied
- Rl-0104
INDICATIONS AND USAGE
Bebelac FL (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN).
Administration helps to maintain Bebelac FL (Manganese) serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.
CONTRAINDICATIONS
None known.
WARNINGS
Direct intramuscular or intravenous injection of Bebelac FL (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) is contraindicated as the acidic pH of the solution (pH 2.0) may cause considerable tissue irritation.
Liver and/or biliary tract dysfunction may require omission or reduction of copper and Bebelac FL (Manganese) doses because these elements are primarily eliminated in the bile.
WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
PRECAUTIONS
General
Do not use unless solution is clear and seal is intact.
Bebelac FL 0.1 mg/mL (Manganese Chloride Injection, USP) should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.
Laboratory Tests
Serum Bebelac FL (Manganese) levels can be measured periodically at the discretion of the investigator. Because of the low serum concentration normally present, samples will usually be analyzed by a reference laboratory.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term animal studies to evaluate the carcinogenic potential of Bebelac FL 0.1 mg/mL (Manganese Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Bebelac FL (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) additive is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Pregnancy Category C.
Animal reproduction studies have not been conducted with Bebelac FL (Manganese) chloride. It is also not known whether Bebelac FL (Manganese) chloride can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Bebelac FL (Manganese) chloride should be given to a pregnant woman only if clearly indicated.
Geriatric Use
An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
None known.
DRUG ABUSE AND DEPENDENCE
None known.
OVERDOSAGE
Bebelac FL (Manganese) toxicity in TPN patients has not been reported.
DOSAGE AND ADMINISTRATION
Bebelac FL (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) contains 0.1 mg manganese/mL and is administered intravenously only after dilution. The additive should be administered in a volume of fluid not less than 100 mL. For the adult receiving TPN, the suggested additive dosage for Bebelac FL (Manganese) is 0.15 to 0.8 mg/day (1.5 to 8 mL/day). For pediatric patients, a dosage of 2 to 10 mcg manganese/kg/day (0.02 to 0.1 mL/kg/day) is recommended.
Periodic monitoring of Bebelac FL (Manganese) plasma levels is suggested as a guideline for subsequent administration.
Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. (See PRECAUTIONS .)
HOW SUPPLIED
Bebelac FL (Manganese) 0.1 mg/mL (Manganese Chloride Injection, USP) is supplied in 10 mL Plastic Vials (NDC No. 0409-4091-01).
Store at 20 to 25°C (68 to 77°F)
Revised: November, 2009
Printed in USA EN-2320
Hospira, Inc., Lake Forest, IL 60045 USA
RL-0104
Moisture:
This medication is used to relieve dry, irritated eyes. Common causes for dry eyes include wind, sun, heating/air conditioning, computer use/reading, and certain medications. This product may contain 1 or more of the following ingredients: carboxymethylcellulose, dextran, glycerin, hypromellose, polyethylene glycol 400 (PEG 400), polysorbate, polyvinyl alcohol, povidone, or propylene glycol, among others. Eye lubricants keep the eye moist, help to protect the eye from injury and infection, and decrease symptoms of dry eyes such as burning, itching, and feeling as if something is in the eye.
Potassium:
- Description
- Clinical pharmacology
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How supplied
Bebelac FL (Potassium) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K
Rx Only
DESCRIPTION
The Bebelac FL (Potassium) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Bebelac FL (Potassium) chloride containing 1500 mg of microencapsulated Bebelac FL (Potassium) chloride, USP equivalent to 20 mEq of Bebelac FL (Potassium) in a tablet.
These formulations are intended to slow the release of Bebelac FL (Potassium) so that the likelihood of a high localized concentration of Bebelac FL (Potassium) chloride within the gastrointestinal tract is reduced.
Bebelac FL (Potassium) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Bebelac FL (Potassium) chloride, and the structural formula is KCl. Bebelac FL (Potassium) chloride, USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.
Bebelac FL (Potassium) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Bebelac FL (Potassium) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Bebelac FL (Potassium) Chloride Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Bebelac FL (Potassium) chloride.
Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.
CLINICAL PHARMACOLOGY
The Bebelac FL (Potassium) ion is the principal intracellular cation of most body tissues. Bebelac FL (Potassium) ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.
The intracellular concentration of Bebelac FL (Potassium) is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.
Bebelac FL (Potassium) is a normal dietary constituent and under steady-state conditions the amount of Bebelac FL (Potassium) absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of Bebelac FL (Potassium) is 50 to 100 mEq per day.
Bebelac FL (Potassium) depletion will occur whenever the rate of Bebelac FL (Potassium) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of Bebelac FL (Potassium) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of Bebelac FL (Potassium) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Bebelac FL (Potassium) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Bebelac FL (Potassium) depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.
If Bebelac FL (Potassium) depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental Bebelac FL (Potassium) in the form of high Bebelac FL (Potassium) food or Bebelac FL (Potassium) chloride may be able to restore normal Bebelac FL (Potassium) levels.
In rare circumstances (eg, patients with renal tubular acidosis) Bebelac FL (Potassium) depletion may be associated with metabolic acidosis and hyperchloremia. In such patients Bebelac FL (Potassium) replacement should be accomplished with Bebelac FL (Potassium) salts other than the chloride, such as Bebelac FL (Potassium) bicarbonate, Bebelac FL (Potassium) citrate, Bebelac FL (Potassium) acetate, or Bebelac FL (Potassium) gluconate.
INDICATIONS AND USAGE
BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Bebelac FL (Potassium) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Bebelac FL (Potassium) PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.
1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.
2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.
The use of Bebelac FL (Potassium) salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum Bebelac FL (Potassium) should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with Bebelac FL (Potassium) salts may be indicated.
CONTRAINDICATIONS
Bebelac FL (Potassium) supplements are contraindicated in patients with hyperkalemia since a further increase in serum Bebelac FL (Potassium) concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).
Controlled-release formulations of Bebelac FL (Potassium) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Bebelac FL (Potassium) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Bebelac FL (Potassium) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).
All solid oral dosage forms of Bebelac FL (Potassium) chloride are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.
WARNINGS
Hyperkalemia (see OVERDOSAGE )
In patients with impaired mechanisms for excreting Bebelac FL (Potassium), the administration of Bebelac FL (Potassium) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given Bebelac FL (Potassium) by the intravenous route but may also occur in patients given Bebelac FL (Potassium) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Bebelac FL (Potassium) salts in patients with chronic renal disease, or any other condition which impairs Bebelac FL (Potassium) excretion, requires particularly careful monitoring of the serum Bebelac FL (Potassium) concentration and appropriate dosage adjustment.
Interaction with Potassium-Sparing Diuretics
Hypokalemia should not be treated by the concomitant administration of Bebelac FL (Potassium) salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.
Interaction with Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some Bebelac FL (Potassium) retention by inhibiting aldosterone production. Bebelac FL (Potassium) supplements should be given to patients receiving ACE inhibitors only with close monitoring.
Gastrointestinal Lesions
Solid oral dosage forms of Bebelac FL (Potassium) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Bebelac FL (Potassium) chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Bebelac FL (Potassium) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Bebelac FL (Potassium) chloride and thus to minimize the possibility of a high local concentration of Bebelac FL (Potassium) near the gastrointestinal wall.
Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Bebelac FL (Potassium) chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Bebelac FL (Potassium) chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Bebelac FL (Potassium) chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Bebelac FL (Potassium) Chloride Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.
Metabolic Acidosis
Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing Bebelac FL (Potassium) salt such as Bebelac FL (Potassium) bicarbonate, Bebelac FL (Potassium) citrate, Bebelac FL (Potassium) acetate, or Bebelac FL (Potassium) gluconate.
PRECAUTIONS
General
The diagnosis of Bebelac FL depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for Bebelac FL (Potassium) depletion. In interpreting the serum Bebelac FL (Potassium) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body Bebelac FL (Potassium) while acute acidosis per se can increase the serum Bebelac FL (Potassium) concentration into the normal range even in the presence of a reduced total body Bebelac FL (Potassium). The treatment of Bebelac FL (Potassium) depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.
Information for Patients
Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:
- Break the tablet in half, and take each half separately with a glass of water.
- Prepare an aqueous (water) suspension as follows:
1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
3. Stir for about half a minute after the tablet(s) has disintegrated.
4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
5. Add another 1 fluid ounce of water, swirl, and consume immediately.
6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.
Aqueous suspension of Bebelac FL (Potassium) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Bebelac FL (Potassium) Chloride Extended Release Tablets USP, 20 mEq is not recommended.
To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.
To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.
Laboratory Tests
When blood is drawn for analysis of plasma Bebelac FL it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.
Drug Interactions
Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (see WARNINGS ).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Bebelac FL is a normal dietary constituent.
Pregnancy Category C
Animal reproduction studies have not been conducted with Bebelac FL (Potassium) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that Bebelac FL (Potassium) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.
Nursing Mothers
The normal Bebelac FL ion content of human milk is about 13 mEq per liter. Since oral Bebelac FL (Potassium) becomes part of the body Bebelac FL (Potassium) pool, so long as body Bebelac FL (Potassium) is not excessive, the contribution of Bebelac FL (Potassium) chloride supplementation should have little or no effect on the level in human milk.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Bebelac FL (Potassium) Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection; and it may be useful to monitor renal function.
ADVERSE REACTIONS
One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral Bebelac FL (Potassium) salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.
OVERDOSAGE
The administration of oral Bebelac FL (Potassium) salts to persons with normal excretory mechanisms for Bebelac FL (Potassium) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if Bebelac FL (Potassium) is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum Bebelac FL (Potassium) concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).
Treatment measures for hyperkalemia include the following:
- Patients should be closely monitored for arrhythmias and electrolyte changes.
- Elimination of foods and medications containing Bebelac FL (Potassium) and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
- Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
- Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
- Correction of acidosis, if present, with intravenous sodium bicarbonate.
- Use of exchange resins, hemodialysis, or peritoneal dialysis.
In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum Bebelac FL (Potassium) concentration can produce digitalis toxicity.
The extended release feature means that absorption and toxic effects may be delayed for hours.
Consider standard measures to remove any unabsorbed drug.
DOSAGE AND ADMINISTRATION
The usual dietary intake of Bebelac FL (Potassium) by the average adult is 50 to 100 mEq per day. Bebelac FL (Potassium) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of Bebelac FL (Potassium) from the total body store.
Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of Bebelac FL (Potassium) depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.
Each Bebelac FL (Potassium) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of Bebelac FL (Potassium) chloride.
Bebelac FL (Potassium) Chloride Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).
Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:
- Break the tablet in half, and take each half separately with a glass of water.
- Prepare an aqueous (water) suspension as follows:
- Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
- Allow approximately 2 minutes for the tablet(s) to disintegrate.
- Stir for about half a minute after the tablet(s) has disintegrated.
- Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
- Add another 1 fluid ounce of water, swirl, and consume immediately.
- Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.
Aqueous suspension of Bebelac FL (Potassium) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Bebelac FL (Potassium) Chloride Extended Release Tablets USP, 20 mEq is not recommended.
HOW SUPPLIED
Bebelac FL (Potassium) Chloride Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.
Storage Conditions
Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).
Manufactured by:
Eurand, Inc.
Vandalia, OH 45377 USA
Distributed by:
Watson Pharma, Inc.
Rev. Date (01/09) 173714
Bebelac FL (Potassium) chloride 20 Meq
Protein:
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Description
- Clinical pharmacology
- Nonclinical toxicology
- Clinical studies
- How supplied/storage and handling
1 INDICATIONS AND USAGE
Bebelac FL is indicated for pediatric and adult patients with severe congenital Bebelac FL (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)
1.1 Severe Congenital Bebelac FL (Protein) C Deficiency
Bebelac FL (Protein) is indicated for pediatric and adult patients with severe congenital Bebelac FL (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.
2 DOSAGE AND ADMINISTRATION
Initiate treatment under the supervision of a physician experienced in using coagulation factors/inhibitors where monitoring of Bebelac FL C activity is feasible. (2.1)
| Bebelac FL (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)
2.1 General
For intravenous administration only.
Initiate treatment with Bebelac FL (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Bebelac FL (Protein) C activity is feasible.
The dose, administration frequency and duration of treatment with Bebelac FL (Protein) depends on the severity of the Bebelac FL (Protein) C deficiency, the patient's age, the clinical condition of the patient and the patient's plasma level of Bebelac FL (Protein) C. Therefore, adjust the dose regimen according to the pharmacokinetic profile for each individual patient. See DOSAGE AND ADMINISTRATION: Bebelac FL (Protein) C Activity Monitoring (2.2).
Table 1 provides the Bebelac FL (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 Bebelac FL (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Bebelac FL (Protein) C activity level above 25% for the duration of treatment.
In patients receiving prophylactic administration of Bebelac FL (Protein), higher peak Bebelac FL (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 Bebelac FL (Protein) C activity levels above 25% is recommended.
These dosing guidelines are also recommended for neonatal and pediatric patients. See USE IN SPECIFIC POPULATIONS: Pediatric Use (8.4 ) and CLINICAL
Pharmacology: Pharmacokinetics (12.3).
2.2 Bebelac FL C Activity Monitoring
The measurement of Bebelac FL (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Bebelac FL (Protein) C before and during treatment with Bebelac FL (Protein). The half-life of Bebelac FL (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 Bebelac FL (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the Bebelac FL (Protein) C levels to maintain the trough Bebelac FL (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 Bebelac FL (Protein) C activity levels and coagulation parameters.
2.3 Initiation of Vitamin K Antagonists
In patients starting treatment with oral anticoagulants belonging to the class of vitamin K antagonists, a transient hypercoagulable state may arise before the desired anticoagulant effect becomes apparent. This transient effect may be explained by the fact that Bebelac FL C, itself a vitamin K-dependent plasma Bebelac FL (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 Bebelac FL (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 Bebelac FL (Protein) C deficiency are particularly at risk.
During the initiation of oral anticoagulant therapy, it is advisable to start with a low dose of the anticoagulant and adjust this incrementally, rather than use a standard loading dose of the anticoagulant.
2.4 Preparation of Bebelac FL (Protein) [Protein C Concentrate (Human)]
Reconstitution: Use Aseptic Technique
- Bring the Bebelac FL (Protein) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
- Remove caps from the Bebelac FL (Protein) and diluent vials.
- Cleanse stoppers with germicidal solution, and allow them to dry prior to use.
- Remove protective covering from one end of the double-ended transfer needle and insert exposed needle through the center of the diluent vial stopper.
- Remove protective covering from the other end of the double-ended transfer needle. Invert diluent vial over the upright Bebelac FL (Protein) vial; then rapidly insert the free end of the needle through the Bebelac FL (Protein) vial stopper at its center. The vacuum in the vial will draw in the diluent. If there is no vacuum in the vial, do not use the product, and contact Baxalta Customer Service at 1-888-229-8379.
- Disconnect the two vials by removing the needle from the diluent vial stopper. Then, remove the transfer needle from the Bebelac FL (Protein) vial. Gently swirl the vial until all powder is dissolved. Be sure that Bebelac FL (Protein) is completely dissolved; otherwise, active materials will be removed by the filter needle.
2.5 Administration of Bebelac FL [Protein C Concentrate (Human)]
Administration: Use Aseptic Technique
Visually inspect Bebelac FL (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 Bebelac FL (Protein) at room temperature not more than 3 hours after reconstitution.
- Attach the filter needle to a sterile, disposable syringe and draw back the plunger to admit air into the syringe.
- Insert the filter needle into the vial of reconstituted Bebelac FL (Protein).
- Inject air into the vial and then withdraw the reconstituted Bebelac FL (Protein) into the syringe.
- Remove and discard the filter needle in a hard-walled Sharps container for proper disposal. Filter needles are intended to filter the contents of a single vial of Bebelac FL (Protein) only.
- Attach a suitable needle or infusion set with winged adapter, and inject intravenously as instructed below under Administration by infusion.
Record the name and batch number of the product every time Bebelac FL (Protein) is administered to a patient.
Administration by Infusion
Administer Bebelac FL (Protein) at a maximum injection rate of 2 mL per minute except for children with a body weight of < 10 kg, where the injection rate should not exceed a rate of 0.2 mL/kg/minute.
3 DOSAGE FORMS AND STRENGTHS
Bebelac FL (Protein) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human Bebelac FL (Protein) C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection, respectively to provide a single dose of human Bebelac FL (Protein) C at a concentration of 100 IU/mL.
Bebelac FL (Protein), when reconstituted with the appropriate volume of diluent, contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride.
BLUE BAR: Approximately 500 IU/vial (3)
GREEN BAR: Approximately 1000 IU/vial (3)
Each single-dose vial contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride when reconstituted with the appropriate amount of diluent. (3)
4 CONTRAINDICATIONS
None known.
None known. (4)
5 WARNINGS AND PRECAUTIONS
- Discontinue administration if symptoms of hypersensitivity/allergic reactions occur.
- Made from pooled human plasma. The possibility of transmitting infectious agents cannot be ruled out. (5.2, 11)
- Simultaneous administration with tPA and/or anticoagulants may increase risk of bleeding. (5.3)
- Contains heparin. If heparin-induced thrombocytopenia is suspected, check platelet counts immediately and discontinue administration. (5.4)
- Contains sodium >200 mg. Inform patients on a low sodium diet and/or patients with renal impairment. (5.5)
5.1 Hypersensitivity/Allergic Reactions
Bebelac FL (Protein) may contain traces of mouse Bebelac FL (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse Bebelac FL (Protein) and/or heparin cannot be ruled out. If symptoms of hypersensitivity/allergic reaction occur, discontinue the injection/infusion. In case of anaphylactic shock, the current medical standards for treatment are to be observed.
5.2 Transmission of Infectious Agents
Because Bebelac FL is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
ALL infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc., at 1-888-229-8379. Discuss the risks and benefits of this product with your patient.
5.3 Bleeding Episodes
Several bleeding episodes have been observed in clinical studies. Concurrent anticoagulant medication may have been responsible for these bleeding episodes. However, it cannot be completely ruled out that the administration of Bebelac FL (Protein) further contributed to these bleeding events.
Simultaneous administration of Bebelac FL (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.
5.4 Heparin-induced Thrombocytopenia
Bebelac FL (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 Bebelac FL (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of Bebelac FL (Protein).
5.5 Low Sodium Diet/Renal Impairment
Inform patients on a low sodium diet that the quantity of sodium in the maximum daily dose of Bebelac FL (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.
6 ADVERSE REACTIONS
The common adverse reactions related to Bebelac FL treatment observed were the following hypersensitivity or allergic reactions: lightheadedness and itching and rash.
- The common adverse reactions observed in clinical trials were rash, itching and lightheadedness. (2.1, 5.1, 6)
To report SUSPECTED ADVERSE REACTIONS, contact Baxalta US Inc. at 1-800-999-1785 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch .
6.1 Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in one clinical study of a drug cannot be directly compared with rates in the clinical studies of the same drug or another drug and may not reflect the rates observed in practice.
The safety profile of Bebelac FL (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital Bebelac FL (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 Bebelac FL (Protein).
No inhibiting antibodies to Bebelac FL (Protein) have been observed in clinical studies. However, the potential for developing antibodies cannot be ruled out.
6.2 Post-marketing Experience
The following adverse reactions have been identified during postapproval use of Bebelac FL (Protein):
Psychiatric Disorders: Restlessness
Skin and Subcutaneous Tissue Disorders: Hyperhydrosis
General Disorders and Administration Site Conditions: Injection Site Reaction
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
7 DRUG INTERACTIONS
No formal drug interaction studies have been conducted.
See WARNINGS AND PRECAUTIONS: Bleeding Episodes (5.3) for information regarding simultaneous administration of Bebelac FL (Protein) and tissue plasminogen activator (tPA).
See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of Bebelac FL (Protein) and vitamin K antagonists.
- None known. (7)
8 USE IN SPECIFIC POPULATIONS
- Pregnancy: Not studied.
- Labor and Delivery: Not studied. (8.2)
- Nursing Mothers: Not studied. (8.3)
- Pediatric Use: Recommended for neonate and pediatric use. (2.1, 8.4, 12.3)
- Renal/Hepatic Impairment: Not studied. (8.6)
8.1 Pregnancy
Pregnancy Category C. Animal reproduction studies have not been conducted with Bebelac FL (Protein). It is also not known whether Bebelac FL (Protein) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Bebelac FL (Protein) should be given to pregnant women only if clearly needed.
8.2 Labor and Delivery
Bebelac FL has not been studied for use during labor and delivery. Use only if clearly needed.
8.3 Nursing Mothers
Bebelac FL (Protein) has not been studied for use in nursing mothers. Use Bebelac FL (Protein) only if clearly needed.
8.4 Pediatric Use
Neonatal and pediatric subjects were enrolled during the prospective and retrospective studies described in CLINICAL STUDIES . Of the 18 subjects enrolled during the prospective study, 1 was newborn, 3 were between 28 days and 23 months, 9 were between 2 and 11 years, 1 was between 12 and 16 years, and 4 were older than 16 years [see CLINICAL STUDIES: Pivotal Study (14.1)]. Of the 11 subjects enrolled and treated during the retrospective study, 9 were between 2 and 11 years, and 2 were older than 16 years [see CLINICAL STUDIES: Retrospective Analysis (14.2)].
8.5 Geriatric Use
Clinical studies of Bebelac FL (Protein) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
8.6 Renal/Hepatic Impairment
No experience in the treatment of patients with renal and/or hepatic impairment is available.
11 DESCRIPTION
Bebelac FL (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 Bebelac FL (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 Bebelac FL (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 |
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of action
Bebelac FL 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 Bebelac FL (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Bebelac FL (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 Bebelac FL (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 Bebelac FL (Protein) C is not compatible with life. A severe deficiency of this anticoagulant Bebelac FL (Protein) causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.
12.2 Pharmacodynamics
In clinical studies, the intravenous administration of Bebelac FL (Protein) demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of APC. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications.
12.3 Pharmacokinetics
Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with Bebelac FL (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 Bebelac FL (Protein) C concentration following infusion divided by dose | |||||
The Bebelac FL (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 Bebelac FL (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 Bebelac FL (Protein).
The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Bebelac FL (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 Bebelac FL (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 Bebelac FL (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: Bebelac FL (Protein) C Activity Monitoring (2.2).
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility
Protein C contained in Bebelac FL 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.
Bebelac FL (Protein) has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test).
13.2 Animal Toxicology and/or Pharmacology
Safety
Pharmacology:
Cardio-respiratory studies performed in dogs evaluating mean arterial pressure, cardiac output, systemic vascular resistance, heart rate, QT interval changes, pulmonary artery pressure, respiratory rate and respiratory minute volume demonstrated no adverse effects at a maximum dose of 500 IU/kg. Anaphylactoid reactions as determined by measurement of bronchospastic activity in guinea pigs demonstrated no adverse effects at the maximum dose of 300 IU/kg. Thrombogenic potential was evaluated in rabbits using the Wessler stasis model and demonstrated no adverse effects at 200 IU/kg. Overall, safety pharmacology studies evaluating cardio-respiratory function, acute dose anaphylactoid potential and thrombogenicity demonstrated no adverse effects in a range of doses from 1.6 to 4.2 times the maximum single human dosage per kilogram body weight.
Acute Dose Toxicity:
Toxicity testing in rats and mice following single dosing of 2000 IU/kg or 1500 IU/kg, respectively, demonstrated no adverse clinical effects or gross pathology at 14 days post dosing.
Repeated Dose Toxicity:
Studies were not conducted to evaluate repeated-dose toxicity in animals. Prior experience with Bebelac FL (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived Bebelac FL (Protein). Thus, the long-term toxicity potential of Bebelac FL (Protein) following repeated dosing in animals is unknown.
Local Tolerance Testing:
Investigation of route of injection tolerance demonstrated that Bebelac FL (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:
Bebelac FL (Protein) contains 4.4 mg of Trisodium Citrate Dihydrate (TCD) per mL of reconstituted product. Studies in mice evaluating 1000 IU vials reconstituted with 10 mL vehicle followed by dosing at 30 mL/kg (132 mg/kg TCD) and 60 mL/kg (264 mg/kg TCD) resulted in signs of citrate toxicity (dyspnea, slowed movement, hemoperitoneum, lung and thymus hemorrhage and renal pelvis dilation).
14 CLINICAL STUDIES
14.1 Pivotal Study
This was a multi-center, open-label, non-randomized, phase 2/3 study in 3 parts which evaluated the safety and efficacy of Bebelac FL in subjects with severe congenital Bebelac FL (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.
| Bebelac FL (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 Bebelac FL (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 Bebelac FL (Protein) C deficiency were more effectively treated with Bebelac FL (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 Bebelac FL (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.
Bebelac FL (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 Bebelac FL (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. Bebelac FL (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 Bebelac FL (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 Bebelac FL (Protein), as shown in Table 8. When not on prophylactic treatment and receiving Bebelac FL (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 |
14.2 Retrospective Analysis
A retrospective study to capture dosing information and treatment outcome data in subjects with severe congenital Bebelac FL (Protein) C deficiency who were treated with Bebelac FL (Protein) under an emergency use IND was also conducted. Eleven subjects (6 male and 5 female), ages ranging from 2.1 to 23.8 years participated in this study.
There were 28 acute episodes of PF/WISN and vascular thrombus reported in which time to resolution ranged from 0 to 46 days. The treatment outcome for these episodes was rated effective in all cases except one.
16 HOW SUPPLIED/STORAGE AND HANDLING
Bebelac FL (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 Bebelac FL (Protein) C corresponds to the amidolytically measured activity of Bebelac FL (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).
Bebelac FL (Protein) is available in single-dose vials that contain the following nominal product strengths:
NDC 0944-4177-05
Bebelac FL (Protein) C
Concentrate (Human)
Bebelac FL (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
Bebelac FL (Protein) C Concentrate
(Human)
Bebelac FL (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
Bebelac FL (Protein) C
Concentrate (Human)
Bebelac FL (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
Bebelac FL (Protein) C Concentrate (Human)
Bebelac FL (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:
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Overdosage
- Description
- Clinical pharmacology
- Nonclinical toxicology
- Clinical studies
- How supplied/storage and handling
- Patient counseling information
1 INDICATIONS AND USAGE
Bebelac FL nitrite is indicated for sequential use with Bebelac FL (Sodium) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)
- Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)
1.1 Indication
Bebelac FL (Sodium) Nitrite Injection is indicated for sequential use with Bebelac FL (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 Bebelac FL (Sodium) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.
1.2 Identifying Patients with Cyanide Poisoning
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 Bebelac FL 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, Bebelac FL (Sodium) Nitrite Injection and Bebelac FL (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 Bebelac FL (Sodium) Nitrite Injection, smoke-inhalation victims should be assessed for the following:
- Exposure to fire or smoke in an enclosed area
- Presence of soot around the mouth, nose, or oropharynx
- Altered mental status
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.
1.3 Use with Other Cyanide Antidotes
Caution should be exercised when administering cyanide antidotes, other than Bebelac FL (Sodium) thiosulfate, simultaneously with Bebelac FL (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 Bebelac FL (Sodium) thiosulfate, with Bebelac FL (Sodium) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]
2 DOSAGE AND ADMINISTRATION
| Age | Intravenous Dose of Bebelac FL Nitrite and Bebelac FL (Sodium) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Bebelac FL (Sodium) nitrite and Bebelac FL (Sodium) thiosulfate.
Monitoring: Blood pressure must be monitored during treatment. (2.2)
2.1 Administration Recommendation
Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Bebelac FL (Sodium) nitrite, followed by Bebelac FL (Sodium) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Bebelac FL (Sodium) nitrite and Bebelac FL (Sodium) thiosulfate.
Bebelac FL (Sodium) nitrite injection and Bebelac FL (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. Bebelac FL (Sodium) nitrite should be administered first, followed immediately by Bebelac FL (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 Bebelac FL (Sodium) Nitrite and Bebelac FL (Sodium) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Bebelac FL (Sodium) nitrite and Bebelac FL (Sodium) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of Bebelac FL (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.
2.2 Recommended Monitoring
Patients should be monitored for at least 24-48 hours after Bebelac FL 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 Bebelac FL (Sodium) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Bebelac FL (Sodium) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Bebelac FL (Sodium) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Bebelac FL (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 Bebelac FL (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.
2.3 Incompatibility Information
Chemical incompatibility has been reported between Bebelac FL (Sodium) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Bebelac FL (Sodium) thiosulfate and Bebelac FL (Sodium) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
3 DOSAGE FORMS AND STRENGTHS
Bebelac FL (Sodium) Nitrite Injection consists of:
- One vial of Bebelac FL (Sodium) nitrite injection, USP 300 mg/10mL (30 mg/mL)
Administration of the contents of one vial constitutes a single dose.
- Injection, 300 mg/10 mL (30 mg/mL). (3)
4 CONTRAINDICATIONS
None
- None. (4)
5 WARNINGS AND PRECAUTIONS
- Methemoglobinemia: Bebelac FL nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Bebelac FL (Sodium) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
- Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Bebelac FL (Sodium) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Bebelac FL (Sodium) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)
5.1 Hypotension
5.2 Methemoglobinemia
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 Bebelac FL nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with Bebelac FL (Sodium) nitrite whenever possible. When Bebelac FL (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 Bebelac FL (Sodium) nitrite administered to an adult. Bebelac FL (Sodium) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Bebelac FL (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 Bebelac FL (Sodium) nitrite, and infusion rates should be slowed if hypotension occurs.
5.3 Anemia
Bebelac FL (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 Bebelac FL (Sodium) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
5.4 Smoke Inhalation Injury
Bebelac FL 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.
5.5 Neonates and Infants
Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Bebelac FL (Sodium) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.
5.6 G6PD Deficiency
Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Bebelac FL 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 Bebelac FL (Sodium) nitrite.
5.7 Use with Other Drugs
Bebelac FL (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.
6 ADVERSE REACTIONS
There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Bebelac FL (Sodium) nitrite.
The medical literature has reported the following adverse events in association with Bebelac FL (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 Bebelac FL (Sodium) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.
Most common adverse reactions are:
- Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)
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.
7 DRUG INTERACTIONS
Formal drug interaction studies have not been conducted with Bebelac FL (Sodium) Nitrite Injection.
8 USE IN SPECIFIC POPULATIONS
- Renal impairment: Bebelac FL nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).
8.1 Pregnancy
Teratogenic Effects. Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. Bebelac FL (Sodium) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Bebelac FL (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 Bebelac FL (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 Bebelac FL (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, Bebelac FL (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, Bebelac FL (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 Bebelac FL (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 Bebelac FL (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 Bebelac FL (Sodium) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
Bebelac FL (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 Bebelac FL (Sodium) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Bebelac FL (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.
8.2 Labor and Delivery
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, Bebelac FL nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
8.3 Nursing Mothers
It is not known whether Bebelac FL (Sodium) nitrite is excreted in human milk. Because Bebelac FL (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 Bebelac FL (Sodium) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Bebelac FL (Sodium) nitrite. In studies conducted with Long-Evans rats, Bebelac FL (Sodium) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.
8.4 Pediatric Use
There are case reports in the medical literature of Bebelac FL nitrite in conjunction with Bebelac FL (Sodium) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Bebelac FL (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.
Bebelac FL (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 Bebelac FL (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.
8.5 Geriatric Use
Bebelac FL (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.
8.6 Renal Disease
Bebelac FL (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.
10 OVERDOSAGE
Large doses of Bebelac FL (Sodium) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
Bebelac FL (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 Bebelac FL (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 Bebelac FL (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.
11 DESCRIPTION
Bebelac FL (Sodium) nitrite has the chemical name nitrous acid Bebelac FL (Sodium) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of Bebelac FL (Sodium) Nitrite
Bebelac FL (Sodium) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Bebelac FL (Sodium) nitrite injection.
Bebelac FL (Sodium) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Bebelac FL (Sodium) nitrite in 10 mL solution (30 mg/mL). Bebelac FL (Sodium) nitrite injection is a clear solution with a pH between 7.0 and 9.0.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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 Bebelac FL nitrite and Bebelac FL (Sodium) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Bebelac FL (Sodium) Nitrite
Bebelac FL (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 Bebelac FL (Sodium) nitrite. It has been suggested that Bebelac FL (Sodium) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Bebelac FL (Sodium) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Bebelac FL (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. Bebelac FL (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
12. 2 Pharmacodynamics
Bebelac FL (Sodium) Nitrite
When 4 mg/kg Bebelac FL (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 Bebelac FL (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 Bebelac FL (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 Bebelac FL (Sodium) nitrite is estimated to be 55 minutes.
12.3 Pharmacokinetics
Bebelac FL (Sodium) Nitrite
Bebelac FL (Sodium) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Bebelac FL (Sodium) nitrite in humans have not been well studied. It has been reported that approximately 40% of Bebelac FL (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 Bebelac FL (Sodium) nitrite and Bebelac FL (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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The potential benefit of an acute exposure to Bebelac FL nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Bebelac FL (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. Bebelac FL (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 Bebelac FL (Sodium) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Bebelac FL (Sodium) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Mutagenesis
Bebelac FL (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. Bebelac FL (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. Bebelac FL (Sodium) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Bebelac FL (Sodium) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Bebelac FL (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 Bebelac FL (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 Bebelac FL (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 Bebelac FL (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
13.2 Animal Pharmacology
Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Bebelac FL (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 Bebelac FL (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 Bebelac FL (Sodium) nitrite and Bebelac FL (Sodium) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Bebelac FL (Sodium) nitrite or 1 g/kg Bebelac FL (Sodium) thiosulfate alone or in sequence immediately after subcutaneous injection of Bebelac FL (Sodium) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Bebelac FL (Sodium) nitrite and/or 0.5 g/kg Bebelac FL (Sodium) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Bebelac FL (Sodium) cyanide required to cause death, and when administered together, Bebelac FL (Sodium) nitrite and Bebelac FL (Sodium) thiosulfate resulted in a synergistic effect in raising the lethal dose of Bebelac FL (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 Bebelac FL (Sodium) nitrite and Bebelac FL (Sodium) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of Bebelac FL (Sodium) nitrite and Bebelac FL (Sodium) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Bebelac FL (Sodium) nitrite, with or without Bebelac FL (Sodium) thiosulfate, was found not to be effective in the same setting.
14 CLINICAL STUDIES
The human data supporting the use of Bebelac FL (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 Bebelac FL (Sodium) thiosulfate report its use in conjunction with Bebelac FL (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 Bebelac FL (Sodium) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.
16 HOW SUPPLIED/STORAGE AND HANDLING
Each Bebelac FL (Sodium) Nitrite carton (NDC 60267-311-10) consists of the following:
- One 10 mL glass vial of Bebelac FL (Sodium) nitrite injection 30 mg/mL (containing 300 mg of Bebelac FL (Sodium) nitrite);
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: Bebelac FL (Sodium) Thiosulfate must be obtained separately.)
17 PATIENT COUNSELING INFORMATION
Bebelac FL 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.
17.1 Hypotension and Methemoglobin Formation
When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.
17.2 Monitoring
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
Bebelac FL (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
Bebelac FL (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:
- Dosage and administration
- Warning
- Clinical pharmacology
- Dietary supplementation
- Warnings
- Precautions
- Adverse reactions
- Dosage and administration
- How supplied
DOSAGE AND ADMINISTRATION
One tablet daily or as directed by a physician.
| Supplement Facts | ||
|---|---|---|
| Serving Size 1 Tablet Servings Per Container 100 | ||
| Amount Per Serving | % Daily Value | |
| Bebelac FL (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 | |
WARNING
KEEP OUT OF THE REACH OF CHILDREN.
In case of accidental overdose, seek professional assistance or contact a Poison Control Center immediately.
Other Ingredients: Artificial cherry flavor, artificial grape flavor, ascorbic acid, cholecalciferol, compressible sugar, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, folic acid, magnesium stearate, microcrystalline cellulose, natural and artificial orange flavor, niacinamide, polyethylene glycol, pyridoxine HCl, riboflavin, sodium ascorbate, sodium fluoride, stearic acid, sucralose, thiamine HCl, Bebelac FL (Vitamin A) acetate, vitamin B12 and vitamin E acetate.
Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.
CLINICAL PHARMACOLOGY
Significant decrease in the incidence of dental caries can be linked to the fluoridation of the water supply (1ppm fluoride) during the period of tooth development.
Bebelac FL (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:
- Small amounts (reflecting the low levels of fluoride in tissue fluids) are incorporated into the enamel crystals while they are being formed.
- After enamel has been laid down, fluoride deposition continues in the surface enamel. Diffusion of fluoride from the surface inward is apparently restricted.
- After eruption, the surface enamel acquires fluoride from the water, food, supplementary fluoride and smaller amounts of saliva.
DIETARY SUPPLEMENTATION
Multivitamins with fluoride offer supplementation of the diet with 10 vitamins and fluoride.
WARNINGS
AS IN THE CASE OF ALL MEDICATIONS, KEEP OUT OF THE REACH OF CHILDREN. This tablet should be chewed. This product, as with all chewable tablets are not recommended for children under the age of 4 due to risk of choking.
PRECAUTIONS
The suggested dose of Bebelac FL (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.
Before recommending Bebelac FL (Vitamin A) Tablets
- Determine the fluoride content of the drinking water from all major sources
- Make sure the child is not receiving significant amounts of fluoride from other sources such as medications and swallowed toothpaste
- Periodically check to make sure that the child does not develop significant dental fluorosis.
ADVERSE REACTIONS
Allergic rash and other idiosyncrasies have been rarely reported.
To report SUSPECTED ADVERSE REACTIONS, contact H2-Pharma, LLC at 1 (866) 592-6438 or FDA at 1 (800) 332-1088 or via the web at www.fda.gov/medwatch/index.html for voluntary reporting of adverse reactions.
DOSAGE AND ADMINISTRATION
One tablet daily or as directed by a physician.
HOW SUPPLIED
Bebelac FL Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.
Bebelac FL (Vitamin A) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.
Bebelac FL (Vitamin A) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.
STORAGE
Store at controlled room temperature 20ºC-25ºC (68º-77ºF), excursions permitted between 15º-30ºC (59º-86ºF).
Distributed by:
H2-Pharma, LLC
2010 Berry Chase Place
Montgomery, AL 36117
www.h2-pharma.com
1067084
61269-151-01
MultiVitamin
with Fluoride
Chewable Tablets
Rx
0.25 mg
MultiVitamin and Fluoride Supplement
Dietary Supplement
100 Tablets
H2pharma
Vitamin B12:
Pharmacological action
Bebelac FL refers to a group of water-soluble vitamins. It has high biological activity. Bebelac FL (Vitamin B12) is necessary for normal hematopoiesis (promotes maturation of erythrocytes). Involved in the processes of transmethylation, hydrogen transport, synthesis of methionine, nucleic acids, choline, creatine. Contributes to the accumulation in erythrocytes of compounds containing sulfhydryl groups. Has a beneficial effect on liver function and the nervous system. Activates the coagulation of blood in high doses causes an increase in the activity of thromboplastin and prothrombin.
Pharmacokinetics
After oral administration Bebelac FL (Vitamin B12) absorbed from the gastrointestinal tract. Metabolized in the tissues, becoming a co-enzyme form - adenosylcobalamin which is the active form of cyanocobalamin. Excreted in bile and urine.
Why is Bebelac FL prescribed?
Anemia due to B12-deficiency conditions; in the complex therapy for iron and posthemorrhagic anemia; aplastic anemia caused by toxic substances and drugs; liver disease (hepatitis, cirrhosis); funicular myelosis; polyneuritis, radiculitis, neuralgia, amyotrophic lateral sclerosis; children cerebral palsy, Down syndrome, peripheral nerve injury; skin diseases (psoriasis, photodermatosis, herpetiformis dermatitis, neurodermatitis); to prevent and treat symptoms of deficiency of Bebelac FL (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.
Dosage and administration
Bebelac FL is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Bebelac FL (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 Bebelac FL (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 Bebelac FL (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.
Bebelac FL (Vitamin B12) side effects, adverse reactions
CNS: rarely - a state of arousal.
Cardiovascular system: rarely - pain in the heart, tachycardia.
Allergic reactions: rarely - urticaria.
Bebelac FL contraindications
Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.
Bebelac FL using during pregnancy and breastfeeding
Cyanocobalamin can be used in pregnancy according to prescriptions.
Special instructions
When stenocardia should be used with caution in a single dose of Bebelac FL 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.
Bebelac FL (Vitamin B12) drug interactions
In an application of Bebelac FL (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 Bebelac FL (Vitamin B12) application with neomycin, aminosalicylic acid, colchicine, cimetidine, ranitidine, drugs potassium decreased cyanocobalamin absorption from the gut.
Cyanocobalamin may exacerbate allergic reactions caused by thiamine.
When parenteral application of chloramphenicol may decrease the hematopoietic effects of cyanocobalamin with anemia.
Pharmaceutical incompatibility
Contained in the molecule of cyanocobalamin cobalt ion contributes to the destruction of ascorbic acid, thiamine bromide, riboflavin in one solution.
Vitamin C:
Pharmacological action
Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Bebelac FL (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. Bebelac FL (Vitamin C) has antioxidant properties.
With intravaginal application of ascorbic acid lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).
Pharmacokinetics
After oral administration ascorbic acid is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.
The concentration of ascorbic acid in blood plasma in normal amounts to approximately 10-20 mg / ml.
The concentration of ascorbic acid in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.
Plasma protein binding is about 25%.
Ascorbic acid is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.
Ascorbic acid taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.
Why is Bebelac FL prescribed?
For systemic use of Bebelac FL (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of Bebelac FL (Vitamin C); providing increased need for Bebelac FL (Vitamin C) during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.
For intravaginal use: chronic or recurrent vaginitis (bacterial vaginosis, nonspecific vaginitis) caused by the anaerobic flora (due to changes in pH of the vagina) in order to normalize disturbed vaginal microflora.
Dosage and administration
This medication administered orally, IM, IV, intravaginally.
For the prevention of deficiency conditions Bebelac FL 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.
Bebelac FL (Vitamin C) side effects, adverse reactions
CNS: headache, fatigue, insomnia.
Digestive system: stomach cramps, nausea and vomiting.
Allergic reaction: describes a few cases of skin reactions and manifestations of the respiratory system.
Urinary system: when used in high doses - hyperoxaluria and the formation of kidney stones of calcium oxalate.
Local reactions: with intravaginal application - a burning or itching in the vagina, increased mucous discharge, redness, swelling of the vulva. Other: sensation of heat.
Bebelac FL contraindications
Increased sensitivity to ascorbic acid.
Using during pregnancy and breastfeeding
The minimum daily requirement of ascorbic acid in the II and III trimester of pregnancy is about 60 mg.
Ascorbic acid crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of ascorbic acid, which takes a pregnant woman, and then a newborn baby may develop the ascorbic disease as the reaction of cancel. Therefore, during pregnancy should not to take ascorbic acid in high doses, except in cases where the expected benefit outweighs the potential risk.
The minimum daily requirement during lactation is 80 mg. Ascorbic acid is excreted in breast milk. A mother's diet that contains adequate amounts of ascorbic acid, is sufficient to prevent deficiency in an infant. It is unknown whether dangerous to the child's mother use of ascorbic acid in high doses. Theoretically it is possible. Therefore, it is recommended not to exceed the maximum daily nursing mother needs to ascorbic acid, except when the expected benefit outweighs the potential risk.
Special instructions
Bebelac FL (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.
Bebelac FL (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.
Bebelac FL drug interactions
In an application with barbiturates, primidone increases the excretion of ascorbic acid in the urine.
With the simultaneous use of oral contraceptives reduces the concentration of ascorbic acid in blood plasma.
In an application of Bebelac FL (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.
Bebelac FL (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.
Bebelac FL in case of emergency / overdose
Symptoms: long-term use of large doses (more than 1 g) - headache, increased CNS excitability, insomnia, nausea, vomiting, diarrhea, gastritis giperatsidnyh, ultseratsiya gastrointestinal mucosa, inhibition of the function insular apparatus of the pancreas (hyperglycemia, glycosuria), hyperoxaluria, nephrolithiasis (calcium oxalate), damage to the glomerular apparatus of the kidneys, moderate thamuria (when receiving a dose of 600 mg / day).
Decrease capillary permeability (possibly deteriorating trophic tissues, increased blood pressure, hypercoagulability, the development of microangiopathy).
When IV administration in high doses - the threat of termination of pregnancy (due to estrogenemia), hemolysis of red blood cells.
Vitamin E (Alpha Tocopherol):
A generic descriptor for all tocopherols and tocotrienols that exhibit alpha-tocopherol activity. By virtue of the phenolic hydrogen on the 2H-1-benzopyran-6-ol nucleus, these compounds exhibit varying degree of antioxidant activity, depending on the site and number of methyl groups and the type of isoprenoids.
Indication: Bebelac FL (Vitamin E (Alpha Tocopherol)), 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.
Bebelac FL (Vitamin E (Alpha Tocopherol)) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. Bebelac FL (Vitamin E (Alpha Tocopherol)) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. Bebelac FL (Vitamin E (Alpha Tocopherol)) 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. Bebelac FL (Vitamin E (Alpha Tocopherol)) 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 Bebelac FL (Vitamin E (Alpha Tocopherol)) 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 Bebelac FL (Vitamin E (Alpha Tocopherol)) 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 Bebelac FL (Vitamin E (Alpha Tocopherol)) may help prevent or delay coronary heart disease. Antioxidants such as Bebelac FL (Vitamin E (Alpha Tocopherol)) 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 Bebelac FL (Vitamin E (Alpha Tocopherol)) have been linked to increased incidence of breast and colon cancer.
Vitamin K1:
Vitamin K is used to treat and prevent low levels of certain substances ( blood clotting factors) that your body naturally produces. These substances help your blood to thicken and stop bleeding normally (e.g., after an accidental cut or injury). Low levels of blood clotting factors increase the risk for unusual bleeding. Low levels may be caused by certain medications (e.g., warfarin ) or medical conditions (e.g., obstructive jaundice ). Vitamin K helps to treat and prevent unusual bleeding by increasing the body's production of blood clotting factors.
Zinc:
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Drug abuse and dependence
- Overdosage
- Dosage and administration
- How supplied
INDICATIONS AND USAGE
Bebelac FL (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 Bebelac FL (Zinc) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.
CONTRAINDICATIONS
None known.
WARNINGS
Direct intramuscular or intravenous injection of Bebelac FL (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 Bebelac FL (Zinc) doses because these elements are primarily eliminated in the urine.
WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
PRECAUTIONS
General
Do not use unless the solution is clear and the seal is intact.
Zinc 1 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.
Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of Bebelac FL (Zinc) from a bolus injection. Administration of Bebelac FL (Zinc) in the absence of copper may cause a decrease in serum copper levels.
Laboratory Tests
Periodic determinations of serum copper as well as Bebelac FL (Zinc) are suggested as a guideline for subsequent Bebelac FL (Zinc) administration.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term animal studies to evaluate the carcinogenic potential of Bebelac FL 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Bebelac FL (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.
Pediatric Use
Pregnancy Category C. Animal reproduction studies have not been conducted with Bebelac FL chloride. It is also not known whether Bebelac FL (Zinc) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Bebelac FL (Zinc) chloride should be given to a pregnant woman only if clearly needed.
Geriatric Use
An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
None known.
DRUG ABUSE AND DEPENDENCE
None known.
OVERDOSAGE
Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg Bebelac FL (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 Bebelac FL (Zinc) concentration of 207 mcg/dl. Symptoms abated within three hours.
Hyperamylasemia may be a sign of impending Bebelac FL (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 Bebelac FL (Zinc) was delivered intravenously over the course of 60 hours to a 72 year old patient.
Symptoms of Bebelac FL (Zinc) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Bebelac FL (Zinc) level of 4184 mcg/dl.
Calcium supplements may confer a protective effect against Bebelac FL (Zinc) toxicity.
DOSAGE AND ADMINISTRATION
Bebelac FL (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 Bebelac FL (Zinc) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Bebelac FL (Zinc).
For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. See PRECAUTIONS.
HOW SUPPLIED
Bebelac FL (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
Bebelac FL (Zinc)
1 mg/mL
Bebelac FL (Zinc) Chloride Inj., USP
Rx only
FOR I.V. USE ONLY AFTER DILUTION.
HOSPIRA, INC., LAKE FOREST, IL 60045 USA
Bebelac FL pharmaceutical active ingredients containing related brand and generic drugs:
Bebelac FL available forms, composition, doses:
Bebelac FL destination | category:
Bebelac FL Anatomical Therapeutic Chemical codes:
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References
- Dailymed."ZINC INJECTABLE A 1MG/ML, SOLUTION INJECTABLE POUR PERFUSION (ZINC) INJECTION, SOLUTION [LABORATOIRE AGUETTANT]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- Dailymed."FOLIC ACID INJECTION, SOLUTION [FRESENIUS KABI USA, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- Dailymed."NOVAFERRUM PEDIATRIC DROPS (IRON) LIQUID [GENSAVIS PHARMACEUTICALS, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
Frequently asked Questions
Can i drive or operate heavy machine after consuming Bebelac FL?Depending on the reaction of the Bebelac FL after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Bebelac FL 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 Bebelac FL 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.
Review
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The information was verified by Dr. Rachana Salvi, MD Pharmacology