Amphotericin B desoxycholate overdose has been reported to result in cardio-respiratory arrest. Fifteen patients have been reported to have received one or more doses of %medicine_name%® (amphotericin b) between 7-13 mg/kg. None of these patients had a serious acute reaction to %medicine_name%® (amphotericin b). If an overdose is suspected, discontinue therapy, monitor the patient's clinical status, and administer supportive therapy as required. %medicine_name%® (amphotericin b) is not hemodialyzable.
%medicine_name%® (amphotericin b) is contraindicated in patients who have shown hypersensitivity to amphotericin B or any other component in the formulation.
The total safety data base is composed of 921 patients treated with %medicine_name%® (amphotericin b) (5 patients were enrolled twice and counted as separate patients), of whom 775 were treated with 5 mg/kg/day. Of these 775 patients, 194 patients were treated in four comparative studies; 25 were treated in open-label, non-comparative studies; and 556 patients were treated in an open-label, emergency-use program. Most had underlying hematologic neoplasms, and many were receiving multiple concomitant medications. Of the 556 patients treated with %medicine_name%® (amphotericin b) , 9% discontinued treatment due to adverse events regardless of presumed relationship to study drug.
In general, the adverse events most commonly reported with %medicine_name%® (amphotericin b) were transient chills and/or fever during infusion of the drug.
Adverse Eventsa with an Incidence of ≥ 3% (N=556)
| Adverse Event | Percentage (%) of Patients |
| Chills | 18 |
| Fever | 14 |
| Increased Serum Creatinine | 11 |
| Multiple Organ Failure | 11 |
| Nausea | 9 |
| Hypotension | 8 |
| Respiratory Failure | 8 |
| Vomiting | 8 |
| Dyspnea | 7 |
| Sepsis | 7 |
| Diarrhea | 6 |
| Headache | 6 |
| Heart Arrest | 6 |
| Hypertension | 5 |
| Hypokalemia | 5 |
| Infection | 5 |
| Kidney Failure | 5 |
| Pain | 5 |
| Thrombocytopenia | 5 |
| Abdominal Pain | 4 |
| Anemia | 4 |
| Bilirubinemia | 4 |
| Gastrointestinal Hemorrhage | 4 |
| Leukopenia | 4 |
| Rash | 4 |
| Respiratory Disorder | 4 |
| Chest Pain | 3 |
| Nausea and Vomiting | 3 |
| a The causal association between these adverse events and %medicine_name%® is uncertain. | |
The following adverse events have also been reported in patients using %medicine_name%® (amphotericin b) in open-label, uncontrolled clinical studies. The causal association between these adverse events and %medicine_name%® (amphotericin b) is uncertain.
Body as a whole: malaise, weight loss, deafness, injection site reaction including inflammation
Allergic: bronchospasm, wheezing, asthma, anaphylactoid and other allergic reactions
Cardiopulmonary:cardiac failure, pulmonary edema, shock, myocardial infarction, hemoptysis, tachypnea, thrombophlebitis, pulmonary embolus, cardiomyopathy, pleural effusion, arrhythmias including ventricular fibrillation.
Dermatological: maculopapular rash, pruritus, exfoliative dermatitis, erythema multiforme
Gastrointestinal:acute liver failure, hepatitis, jaundice, melena, anorexia, dyspepsia, cramping, epigastric pain, veno-occlusive liver disease, diarrhea, hepatomegaly, cholangitis, cholecystitis
Hematologic:coagulation defects, leukocytosis, blood dyscrasias including eosinophilia
Musculoskeletal: myasthenia, including bone, muscle, and joint pains
Neurologic: convulsions, tinnitus, visual impairment, hearing loss, peripheral neuropathy, transient vertigo, diplopia, encephalopathy, cerebral vascular accident, extrapyramidal syndrome and other neurologic symptoms
Urogenital: oliguria, decreased renal function, anuria, renal tubular acidosis, impotence, dysuria
Serum electrolyte abnormalities: hypomagnesemia, hyperkalemia, hypocalcemia, hypercalcemia
Liver function test abnormalities: increased AST, ALT, alkaline phosphatase, LDH
Renal function test abnormalities: increased BUN
Other test abnormalities: acidosis, hyperamylasemia, hypoglycemia, hyperglycemia, hyperuricemia, hypophosphatemia
%medicine_name%® (amphotericin b) is indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy. This is based on open-label treatment of patients judged by their physicians to be intolerant to or failing conventional amphotericin B therapy (See Description Of Clinical Studies).
The assay used to measure amphotericin B in the blood after the administration of %medicine_name%® does not distinguish amphotericin B that is complexed with the phospholipids of %medicine_name%® from amphotericin B that is uncomplexed.
The pharmacokinetics of amphotericin B after the administration of %medicine_name%® (amphotericin b) are nonlinear. Volume of distribution and clearance from blood increase with increasing dose of %medicine_name%® (amphotericin b) , resulting in less than proportional increases in blood concentrations of amphotericin B over a dose range of 0.6-5 mg/kg/day. The pharmacokinetics of amphotericin B in whole blood after the administration of %medicine_name%® and amphotericin B desoxycholate are:
Pharmacokinetic Parameters of Amphotericin B in Whole Blood
in Patients Administered Multiple Doses of %medicine_name%® or Amphotericin B Desoxycholate
| Pharmacokinetic Parameter | %medicine_name%® (amphotericin b) 5 mg/kg/day for 5-7 days Mean ± SD |
Amphotericin B 0.6 mg/kg/day for 42 daysa Mean ± SD |
| Peak Concentration (µg/mL) | 1.7 ± 0.8 (n=10)b | 1.1 ± 0.2 (n=5) |
| Concentration at End of Dosing Interval (µg/mL) | 0.6 ± 0.3 (n=10)b | 0.4 ± 0.2 (n=5) |
| Area Under Blood Concentration-Time Curve (AUC0-24h) (ng*h/mL) | 14 ± 7 (n=14)b,c | 17.1 ± 5 (n=5) |
| Clearance (mL/h*kg) | 436 ± 188.5 (n=14)b,c | 38 ±15 (n=5) |
| Apparent Volume of Distribution (Vdarea) (L/kg) | 131 ± 57.7 (n=8)c | 5 ± 2.8 (n=5) |
| Terminal Elimination Half-Life (h) | 173.4 ± 78 (n=8)c | 91.1 ± 40.9 (n=5) |
| Amount Excreted in Urine Over 24 h After Last Dose (% of dose)d | 0.9 ± 0.4 (n=8)c | 9.6 ± 2.5 (n=8) |
| a Data from patients with mucocutaneous leishmaniasis.
Infusion rate was 0.25 mg/kg/h. b Data from studies in patients with cytologically proven cancer being treated with chemotherapy or neutropenic patients with presumed or proven fungal infection. Infusion rate was 2.5 mg/kg/h. c Data from patients with mucocutaneous leishmaniasis. Infusion rate was 4 mg/kg/h. d Percentage of dose excreted in 24 hours after last dose. |
The large volume of distribution and high clearance from blood of amphotericin B after the admistration of %medicine_name%® (amphotericin b) probably reflect uptake by tissues. The long terminal elimination half-life probably reflects a slow redistribution from tissues. Although amphotericin B is excreted slowly, there is little accumulation in the blood after repeated dosing. AUC of amphotericin B increased approximately 34% from day 1 after the administration of %medicine_name%® (amphotericin b) 5 mg/kg/day for 7 days. The effect of gender or ethnicity on the pharmacokinetics of %medicine_name%® (amphotericin b) has not been studied.
Tissue concentrations of amphotericin B have been obtained at autopsy from one heart transplant patient who received three doses of %medicine_name%® (amphotericin b) at 5.3 mg/kg/day:
Concentration in Human Tissues
| Organ | Amphotericin B Tissue Concentration (µg/g) |
| Spleen | 290 |
| Lung | 222 |
| Liver | 196 |
| Lymph Node | 7.6 |
| Kidney | 6.9 |
| Heart | 5 |
| Brain | 1.6 |
This pattern of distribution is consistent with that observed in preclinical studies in dogs in which greatest concentrations of amphotericin B after %medicine_name%® (amphotericin b) administration were observed in the liver, spleen, and lung; however, the relationship of tissue concentrations of amphotericin B to its biological activity when administered as %medicine_name%® (amphotericin b) is unknown.
There are no reports of pregnant women having been treated with %medicine_name%® (amphotericin b). Teratogenic Effects. Pregnancy Category B: Reproductive studies in rats and rabbits at doses of %medicine_name%® (amphotericin b) up to 0.64 times the human dose revealed no harm to the fetus. Because animal reproductive studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women, %medicine_name%® (amphotericin b) should be used during pregnancy only after taking into account the importance of the drug to the mother.
Single-use vials along with 5-micron filter needles are individually packaged.
100 mg of %medicine_name%® (amphotericin b) in 20 mL of suspension NDC 57665-101-41
StoragePrior to admixture, %medicine_name%® (amphotericin b) should be stored at 2° to 8°C (36° to 46°F) and protected from exposure to light. Do not freeze. %medicine_name%® (amphotericin b) should be retained in the carton until time of use.
The admixed %medicine_name%® (amphotericin b) and 5% Dextrose Injection may be stored for up to 48 hours at 2° to 8°C (36° to 46°F) and an additional 6 hours at room temperature. Do not freeze. Any unused material should be discarded.
Distributed by: ENZON Pharmaceuticals Inc., Bridgewater, NJ 08807.
Anaphylaxis has been reported with amphotericin B desoxycholate and other amphotericin B-containing drugs. Anaphylaxis has been reported with %medicine_name%® (amphotericin b) with an incidence rate of < 0.1%. If severe respiratory distress occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of %medicine_name%® (amphotericin b).
PRECAUTIONS GeneralAs with any amphotericin B-containing product, during the initial dosing of %medicine_name%® (amphotericin b) , the drug should be administered under close clinical observation by medically trained personnel.
Acute reactions including fever and chills may occur 1 to 2 hours after starting an intravenous infusion of %medicine_name%® (amphotericin b). These reactions are usually more common with the first few doses of %medicine_name%® (amphotericin b) and generally diminish with subsequent doses. Infusion has been rarely associated with hypotension, bronchospasm, arrhythmias, and shock.
Laboratory TestsSerum creatinine should be monitored frequently during %medicine_name%® therapy (see ADVERSE REACTIONS). It is also advisable to regularly monitor liver function, serum electrolytes (particularly magnesium and potassium), and complete blood counts.
Carcinogenesis, Mutagenesis, and Impairment of FertilityNo long-term studies in animals have been performed to evaluate the carcinogenic potential of %medicine_name%® (amphotericin b). The following in vitro (with and without metabolic activation) and in vivo studies to assess %medicine_name%® (amphotericin b) for mutagenic potential were conducted: bacterial reverse mutation assay, mouse lymphoma forward mutation assay, chromosomal aberration assay in CHO cells, and in vivo mouse micronucleus assay. %medicine_name%® (amphotericin b) was found to be without mutagenic effects in all assay systems. Studies demonstrated that %medicine_name%® (amphotericin b) had no impact on fertility in male and female rats at doses up to 0.32 times the recommended human dose (based on body surface area considerations).
PregnancyThere are no reports of pregnant women having been treated with %medicine_name%® (amphotericin b). Teratogenic Effects. Pregnancy Category B: Reproductive studies in rats and rabbits at doses of %medicine_name%® (amphotericin b) up to 0.64 times the human dose revealed no harm to the fetus. Because animal reproductive studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women, %medicine_name%® (amphotericin b) should be used during pregnancy only after taking into account the importance of the drug to the mother.
Nursing MothersIt is not known whether %medicine_name%® (amphotericin b) is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants from %medicine_name%® (amphotericin b) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric UseOne hundred eleven children (2 were enrolled twice and counted as separate patients), age 16 years and under, of whom 11 were less than 1 year, have been treated with %medicine_name%® (amphotericin b) at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. In one single-center study, 5 children with hepatosplenic candidiasis were effectively treated with 2.5 mg/kg/day of %medicine_name%® (amphotericin b). No serious unexpected adverse events have been reported.
Geriatric UseForty-nine elderly patients, age 65 years or over, have been treated with %medicine_name%® (amphotericin b) at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. No serious unexpected adverse events have been reported.
The recommended daily dosage for adults and children is 5 mg/kg given as a single infusion. %medicine_name%® (amphotericin b) should be administered by intravenous infusion at a rate of 2.5 mg/kg/h. If the infusion time exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours.
Renal toxicity of %medicine_name%® (amphotericin b) , as measured by serum creatinine levels, has been shown to be dose dependent. Decisions about dose adjustments should be made only after taking into account the overall clinical condition of the patient.
Preparation of Admixture for Infusion: Shake the vial gently until there is no evidence of any yellow sediment at the bottom. Withdraw the appropriate dose of %medicine_name%® (amphotericin b) from the required number of vials into one or more sterile syringes using an 18-gauge needle. Remove the needle from each syringe filled with %medicine_name%® (amphotericin b) and replace with the 5-micron filter needle supplied with each vial. Each filter needle may be used to filter the contents of up to four 100 mg vials. Insert the filter needle of the syringe into an IV bag containing 5% Dextrose Injection USP, and empty the contents of the syringe into the bag. The final infusion concentration should be 1 mg/mL. For pediatric patients and patients with cardiovascular disease the drug may be diluted with 5% Dextrose Injection to a final infusion concentration of 2 mg/mL. Before infusion, shake the bag until the contents are thoroughly mixed. Do not use the admixture after dilution with 5% Dextrose Injection if there is any evidence of foreign matter. Vials are for single use. Unused material should be discarded. Aseptic technique must be strictly observed throughout handling of %medicine_name%® (amphotericin b) , since no bacteriostatic agent or preservative is present.
DO NOT DILUTE WITH SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR ELECTROLYTES as the compatibility of %medicine_name%® (amphotericin b) with these materials has not been established. An existing intravenous line should be flushed with 5% Dextrose Injection before infusion of %medicine_name%® (amphotericin b) , or a separate infusion line should be used. DO NOT USE AN IN-LINE FILTER.
The diluted ready-for-use admixture is stable for up to 48 hours at 2° to 8°C (36° to 46°F) and an additional 6 hours at room temperature.
The total safety data base is composed of 921 patients treated with %medicine_name%® (amphotericin b) (5 patients were enrolled twice and counted as separate patients), of whom 775 were treated with 5 mg/kg/day. Of these 775 patients, 194 patients were treated in four comparative studies; 25 were treated in open-label, non-comparative studies; and 556 patients were treated in an open-label, emergency-use program. Most had underlying hematologic neoplasms, and many were receiving multiple concomitant medications. Of the 556 patients treated with %medicine_name%® (amphotericin b) , 9% discontinued treatment due to adverse events regardless of presumed relationship to study drug.
In general, the adverse events most commonly reported with %medicine_name%® (amphotericin b) were transient chills and/or fever during infusion of the drug.
Adverse Eventsa with an Incidence of ≥ 3% (N=556)
| Adverse Event | Percentage (%) of Patients |
| Chills | 18 |
| Fever | 14 |
| Increased Serum Creatinine | 11 |
| Multiple Organ Failure | 11 |
| Nausea | 9 |
| Hypotension | 8 |
| Respiratory Failure | 8 |
| Vomiting | 8 |
| Dyspnea | 7 |
| Sepsis | 7 |
| Diarrhea | 6 |
| Headache | 6 |
| Heart Arrest | 6 |
| Hypertension | 5 |
| Hypokalemia | 5 |
| Infection | 5 |
| Kidney Failure | 5 |
| Pain | 5 |
| Thrombocytopenia | 5 |
| Abdominal Pain | 4 |
| Anemia | 4 |
| Bilirubinemia | 4 |
| Gastrointestinal Hemorrhage | 4 |
| Leukopenia | 4 |
| Rash | 4 |
| Respiratory Disorder | 4 |
| Chest Pain | 3 |
| Nausea and Vomiting | 3 |
| a The causal association between these adverse events and %medicine_name%® is uncertain. | |
The following adverse events have also been reported in patients using %medicine_name%® (amphotericin b) in open-label, uncontrolled clinical studies. The causal association between these adverse events and %medicine_name%® (amphotericin b) is uncertain.
Body as a whole: malaise, weight loss, deafness, injection site reaction including inflammation
Allergic: bronchospasm, wheezing, asthma, anaphylactoid and other allergic reactions
Cardiopulmonary:cardiac failure, pulmonary edema, shock, myocardial infarction, hemoptysis, tachypnea, thrombophlebitis, pulmonary embolus, cardiomyopathy, pleural effusion, arrhythmias including ventricular fibrillation.
Dermatological: maculopapular rash, pruritus, exfoliative dermatitis, erythema multiforme
Gastrointestinal:acute liver failure, hepatitis, jaundice, melena, anorexia, dyspepsia, cramping, epigastric pain, veno-occlusive liver disease, diarrhea, hepatomegaly, cholangitis, cholecystitis
Hematologic:coagulation defects, leukocytosis, blood dyscrasias including eosinophilia
Musculoskeletal: myasthenia, including bone, muscle, and joint pains
Neurologic: convulsions, tinnitus, visual impairment, hearing loss, peripheral neuropathy, transient vertigo, diplopia, encephalopathy, cerebral vascular accident, extrapyramidal syndrome and other neurologic symptoms
Urogenital: oliguria, decreased renal function, anuria, renal tubular acidosis, impotence, dysuria
Serum electrolyte abnormalities: hypomagnesemia, hyperkalemia, hypocalcemia, hypercalcemia
Liver function test abnormalities: increased AST, ALT, alkaline phosphatase, LDH
Renal function test abnormalities: increased BUN
Other test abnormalities: acidosis, hyperamylasemia, hypoglycemia, hyperglycemia, hyperuricemia, hypophosphatemia
DRUG INTERACTIONSNo formal clinical studies of drug interactions have been conducted with %medicine_name%® (amphotericin b). However, when administered concomitantly, the following drugs are known to interact with amphotericin B; therefore, the following drugs may interact with %medicine_name%® (amphotericin b) :
Antineoplastic agents: Concurrent use of antineoplastic agents and amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with %medicine_name%® (amphotericin b) with great caution.
Corticosteroids and corticotropin (ACTH): Concurrent use of corticosteroids and corticotropin (ACTH) with amphotericin B may potentiate hypokalemia which could predispose the patient to cardiac dysfunction. If used concomitantly with %medicine_name%® (amphotericin b) , serum electrolytes and cardiac function should be closely monitored.
Cyclosporin A: Data from a prospective study of prophylactic %medicine_name%® (amphotericin b) in 22 patients undergoing bone marrow transplantation suggested that concurrent initiation of cyclosporin A and %medicine_name%® (amphotericin b) within several days of bone marrow ablation may be associated with increased nephrotoxicity.
Digitalis glycosides: Concurrent use of amphotericin B may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly with %medicine_name%® (amphotericin b) , serum potassium levels should be closely monitored.
Flucytosine: Concurrent use of flucytosine with amphotericin B-containing preparations may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Flucytosine should be given concomitantly with %medicine_name%® (amphotericin b) with caution.
Imidazoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.): Antagonism between amphotericin B and imidazole derivatives such as miconazole and ketoconazole, which inhibit ergosterol synthesis, has been reported in both in vitro and in vivo animal studies. The clinical significance of these findings has not been determined.
Leukocyte transfusions: Acute pulmonary toxicity has been reported in patients receiving intravenous amphotericin B and leukocyte transfusions. Leukocyte transfusions and %medicine_name%® (amphotericin b) should not be given concurrently.
Other nephrotoxic medications: Concurrent use of amphotericin B and agents such as aminoglcosides and pentamidine may enhance the potential for drug-induced renal toxicity. Aminoglycosides and pentamidine should be used concomitantly with %medicine_name%® (amphotericin b) only with great caution. Intensive monitoring of renal function is recommended in patients requiring any combination of nephrotoxic medications.
Skeletal muscle relaxants: Amphotericin B-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g., tubocurarine) due to hypokalemia. When administered concomitantly with %medicine_name%® (amphotericin b) , serum potassium levels should be closely monitored.
Zidovudine: Increased myelotoxicity and nephrotoxicity were observed in dogs when either %medicine_name%® (amphotericin b) (at doses 0.16 or 0.5 times the recommended human dose) or amphotericin B desoxycholate (at 0.5 times the recommended human dose) were administered concomitantly with zidovudine for 30 days. If zidovudine is used concomitantly with %medicine_name%® (amphotericin b) , renal and hematologic function should be closely monitored.
