Amphocil

Amphocil is indicated for the following:

• Empirical therapy for presumed fungal infection in febrile, neutropenic patients.
• Treatment of Cryptococcal Meningitis in HIV infected patients (see Description Of Clinical Studies).
• Treatment of patients with Aspergillus species, Candida species and/or Cryptococcus species infections (see above for the treatment of Cryptococcal Meningitis) refractory to amphotericin B deoxycholate, or in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate.
• Treatment of visceral leishmaniasis. In immunocompromised patients with visceral leishmaniasis treated with Amphocil, relapse rates were high following initial clearance of parasites (see Description Of Clinical Studies).

See DOSAGE AND ADMINISTRATION for recommended doses by indication.

Amphocil should be administered by intravenous infusion, using a controlled infusion device, over a period of approximately 120 minutes.

An in-line membrane filter may be used for the intravenous infusion of Amphocil; provided THE MEAN PORE DIAMETER OF THE FILTER IS NOT LESS THAN 1.0 MICRON.

NOTE: An existing intravenous line must be flushed with 5% Dextrose Injection prior to infusion of Amphocil. If this is not feasible, Amphocil must be administered through a separate line.

Infusion time may be reduced to approximately 60 minutes in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased.

The recommended initial dose of Amphocil for each indication for adult and pediatric patients is as follows:

Dosing and rate of infusion should be individualized to the needs of the specific patient to ensure maximum efficacy while minimizing systemic toxicities or adverse events.

Doses recommended for visceral leishmaniasis are presented below:

For immunocompetent patients who do not achieve parasitic clearance with the recommended dose, a repeat course of therapy may be useful.

For immunocompromised patients who do not clear parasites or who experience relapses, expert advice regarding further treatment is recommended. For additional information see Description Of Clinical Studies.

Directions for Reconstitution, Filtration and Dilution Read This Entire Section Carefully Before Beginning Reconstitution Amphocil must be reconstituted using Sterile Water for Injection, USP (without a bacteriostatic agent). Vials of Amphocil containing 50 mg of amphotericin B are prepared as follows:

Reconstitution

1. Aseptically add 12 mL of Sterile Water for Injection, USP to each Amphocil vial to yield a preparation containing 4 mg amphotericin B/mL. CAUTION: DO NOT RECONSTITUTE WITH SALINE OR ADD SALINE TO THE RECONSTITUTED CONCENTRATION, OR MIX WITH OTHER DRUGS. The use of any solution other than those recommended, or the presence of a bacteriostatic agent in the solution, may cause precipitation of Amphocil.
2. Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the Amphocil. Amphocil forms a yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed.

Filtration and Dilution

3. Calculate the amount of reconstituted (4 mg/mL) Amphocil to be further diluted.

4. Withdraw this amount of reconstituted Amphocil into a sterile syringe.

5. Attach the 5-micron filter, provided, to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% Dextrose Injection. (Use only one filter per vial of Amphocil.)

6. Amphocil must be diluted with 5% Dextrose Injection to a final concentration of 1 to 2 mg/mL prior to administration. Lower concentrations (0.2 to 0.5 mg/mL) may be appropriate for infants and small children to provide sufficient volume for infusion. DISCARD PARTIALLY USED VIALS.

Storage of Amphocil

Unopened vials of lyophilized material are to be stored at temperatures up to 25° C (77° F).

Storage of Reconstituted Product Concentrate

The reconstituted product concentrate may be stored for up to 24 hours at 2°-8° C (36°-46° F) following reconstitution with Sterile Water for Injection, USP. Do not freeze.

Storage of Diluted Product

Injection of Amphocil should commence within 6 hours of dilution with 5% Dextrose Injection.

As with all parenteral drug products, the reconstituted Amphocil should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use material if there is any evidence of precipitation or foreign matter. Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in Amphocil or in the materials specified for reconstitution and dilution.

Amphocil is contraindicated in those patients who have demonstrated or have known hypersensitivity to amphotericin B deoxycholate or any other constituents of the product unless, in the opinion of the treating physician, the benefit of therapy outweighs the risk.

WARNINGS

Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs, including Amphocil. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of Amphocil.

PRECAUTIONS

General

As with any amphotericin B-containing product the drug should be administered by medically trained personnel. During the initial dosing period, patients should be underdose clinical observation. Amphocil has been shown to be significantly less toxic than amphotericin B deoxycholate; however, adverse events may still occur.

Laboratory Tests

Patient management should include laboratory evaluation of renal, hepatic and hematopoietic function, and serum electrolytes (particularly magnesium and potassium).

Drug-Laboratory Interactions: Serum phosphate false elevation

False elevations of serum phosphate may occur when samples from patients receiving Amphocil are analyzed using the PHOSm assay (e.g. used in Beckman Coulter analyzers including the Synchron LX20). This assay is intended for the quantitative determination of inorganic phosphorus in human serum, plasma or urine samples.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long term studies in animals have been performed to evaluate carcinogenic potential of Amphocil. Amphocil has not been tested to determine its mutagenic potential. A Segment I Reproductive Study in rats found an abnormal estrous cycle (prolonged diestrus) and decreased number of corpora lutea in the high dose groups (10 and 15 mg/kg, doses equivalent to human doses of 1.6 and 2.4 mg/kg based on body surface area considerations). Amphocil did not affect fertility or days to copulation. There were no effects on male reproductive function.

Pregnancy Category B

There have been no adequate and well-controlled studies of Amphocil in pregnant women. Systemic fungal infections have been successfully treated in pregnant women with amphotericin B deoxycholate, but the number of cases reported has been small.

Segment II studies in both rats and rabbits have concluded that Amphocil had no teratogenic potential in these species. In rats, the maternal non-toxic dose of Amphocil was estimated to be 5 mg/kg (equivalent to 0.16 to 0.8 times the recommended human clinical dose range of 1 to 5 mg/kg) and in rabbits, 3 mg/kg (equivalent to 0.2 to 1 times the recommended human clinical dose range), based on body surface area correction. Rabbits receiving the higher doses, (equivalent to 0.5 to 2 times the recommended human dose) of Amphocil experienced a higher rate of spontaneous abortions than did the control groups. Amphocil should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks involved.

Nursing Mothers

Many drugs are excreted in human milk. However, it is not known whether Amphocil is excreted in human milk. Due to the potential for serious adverse reactions in breast-fed infants, a decision should be made whether to discontinue nursing or whether to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Pediatric patients, age 1 month to 16 years, with presumed fungal infection (empirical therapy), confirmed systemic fungal infections or with visceral leishmaniasis have been successfully treated with Amphocil. In studies which included 302 pediatric patients administered Amphocil, there was no evidence of any differences in efficacy or safety of Amphocil compared to adults. Since pediatric patients have received Amphocil at doses comparable to those used in adults on a per kilogram body weight basis, no dosage adjustment is required in this population. Safety and effectiveness in pediatric patients below the age of one month have not been established. (See Description Of Clinical Studies - Empirical Therapy in Febrile Neutropenic Patients and DOSAGE AND ADMINISTRATION).

Elderly Patients

Experience with Amphocil in the elderly (65 years or older) comprised 72 patients. It has not been necessary to alter the dose of Amphocil for this population. As with most other drugs, elderly patients receiving Amphocil should be carefully monitored.

The following adverse events are based on the experience of 592 adult patients (295 treated with Amphocil and 297 treated with amphotericin B deoxycholate) and 95 pediatric patients (48 treated with Amphocil and 47 treated with amphotericin B deoxycholate) in Study 94-0-002, a randomized double-blind, multi-center study in febrile, neutropenic patients. Amphocil and amphotericin B were infused over two hours.

The incidence of common adverse events (incidence of 10% or greater) occurring with Amphocil compared to amphotericin B deoxycholate, regardless of relationship to study drug, is shown in the following table:

Empirical Therapy Study 94-0-002
Common Adverse Events

Amphocil was well tolerated. Amphocil had a lower incidence of chills, hypertension, hypotension, tachycardia, hypoxia, hypokalemia, and various events related to decreased kidney function as compared to amphotericin B deoxycholate.

In pediatric patients (16 years of age or less) in this double-blind study, Amphocil compared to amphotericin B deoxycholate had a lower incidence of hypokalemia (37% versus 55%), chills (29% versus 68%), vomiting (27% versus 55%), and hypertension (10% versus 21%). Similar trends, although with a somewhat lower incidence, were observed in open-label, randomized Study 104-14 involving 205 febrile neutropenic pediatric patients (141 treated with Amphocil and 64 treated with amphotericin B deoxycholate). Pediatric patients appear to have more tolerance than older individuals for the nephrotoxic effects of amphotericin B deoxycholate.

The following adverse events are based on the experience of 244 patients (202 adult and 42 pediatric patients) of whom 85 patients were treated with Amphocil 3 mg/kg, 81 patients were treated with Amphocil 5 mg/kg and 78 patients treated with amphotericin B lipid complex 5 mg/kg in Study 97-0-034, a randomized double-blind, multi-center study in febrile, neutropenic patients. Amphocil and amphotericin B lipid complex were infused over two hours. The incidence of adverse events occurring in more than 10% of subjects in one or more arms regardless of relationship to study drug are summarized in the following table:

Empirical Therapy Study 97-0-034
Common Adverse Events

The following adverse events are based on the experience of 267 patients (266 adult patients and 1 pediatric patient) of whom 86 patients were treated with Amphocil 3 mg/kg, 94 patients were treated with Amphocil 6 mg/kg and 87 patients treated with amphotericin B deoxycholate 0.7 mg/kg in Study 94-0-013 a randomized, double-blind, comparative multi-center trial, in the treatment of cryptococcal meningitis in HIV positive patients. The incidence of adverse events occurring in more than 10% of subjects in one or more arms regardless of relationship to study drug are summarized in the following table:

Cryptococcal Meningitis Therapy Study 94-0-013
Common Adverse Events

Infusion Related Reactions In Study 94-0-002, the large, double-blind study of pediatric and adult febrile neutropenic patients, no premedication to prevent infusion related reaction was administered prior to the first dose of study drug (Day 1). Amphocil-treated patients had a lower incidence of infusion related fever (17% versus 44%), chills/rigors (18% versus 54%) and vomiting (6% versus 8%) on Day 1 as compared to amphotericin B deoxycholate-treated patients.

The incidence of infusion related reactions on Day 1 in pediatric and adult patients is summarized in the following table:

Incidence of Day 1 Infusion Related Reactions (IRR) By Patient Age

Cardiorespiratory events, except for vasodilatation (flushing), during all study drug infusions were more frequent in amphotericin B-treated patients as summarized in the following table:

Incidence of Infusion Related Cardiorespiratory Events

The percentage of patients who received drugs either for the treatment or prevention of infusion related reactions (e.g., acetaminophen, diphenhydramine, meperidine and hydrocortisone) was lower in Amphocil-treated patients compared with amphotericin B deoxycholate-treated patients.

In the empirical therapy study 97-0-034, on Day 1, where no premedication was administered, the overall incidence of infusion related events of chills/rigors was significantly lower for patients administered Amphocil compared with amphotericin B lipid complex. Fever, chills/rigors and hypoxia were significantly lower for each Amphocil group compared with the amphotericin B lipid complex group. The infusion related event hypoxia was reported for 11.5% of amphotericin B lipid complex-treated patients compared with 0% of patients administered 3 mg/kg per day Amphocil and 1.2% of patients treated with 5 mg/kg per day Amphocil.

Incidence of Day 1 Infusion Related Reactions (IRR) Chills/Rigors
Empirical Therapy Study 97-0-034

Patients were not administered premedications to prevent infusion related reactions prior to the Day 1 study drug infusion.

In Study 94-0-013, a randomized double-blind multicenter trial comparing Amphocil and amphotericin B deoxycholate as initial therapy for cryptococcal meningitis, premedications to prevent infusion related reactions were permitted. Amphocil treated patients had a lower incidence of fever, chill/rigors and respiratory adverse events as summarized in the following table:

Incidence of Infusion-Related Reactions Study 94-0-013

There have been a few reports of flushing, back pain with or without chest tightness, and chest pain associated with Amphocil administration; on occasion this has been severe. Where these symptoms were noted, the reaction developed within a few minutes after the start of infusion and disappeared rapidly when the infusion was stopped. The symptoms do not occur with every dose and usually do not recur on subsequent administrations when the infusion rate is slowed.

Toxicity and Discontinuation of Dosing

In Study 94-0-002, a significantly lower incidence of grade 3 or 4 toxicity was observed in the Amphocil group compared with the amphotericin B group. In addition, nearly three times as many patients administered amphotericin B required a reduction in dose due to toxicity or discontinuation of study drug due to an infusion related reaction compared with those administered Amphocil.

In empirical therapy study 97-0-034, a greater proportion of patients in the amphotericin B lipid complex group discontinued the study drug due to an adverse event than in the Amphocil groups.

Less Common Adverse Events

The following adverse events also have been reported in 2% to 10% of Amphocil-treated patients receiving chemotherapy or bone marrow transplantation, or had HIV disease in six comparative, clinical trials:

Body as a Whole

Abdomen enlarged, allergic reaction, cellulitis, cell mediated immunological reaction, face edema, graft versus host disease, malaise, neck pain, and procedural complication.

Cardiovascular System

Arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, cardiomegaly, hemorrhage, postural hypotension, valvular heart disease, vascular disorder, and vasodilatation (flushing).

Digestive System

Anorexia, constipation, dry mouth/nose, dyspepsia, dysphagia, eructation, fecal incontinence, flatulence, hemorrhoids, gum/oral hemorrhage, hematemesis, hepatocellular damage, hepatomegaly, liver function test abnormal, ileus, mucositis, rectal disorder, stomatitis, ulcerative stomatitis, and veno-occlusive liver disease.

Hemic & Lymphatic System

Anemia, coagulation disorder, ecchymosis, fluid overload, petechia, prothrombin decreased, prothrombin increased, and thrombocytopenia.

Metabolic & Nutritional Disorders

Acidosis, amylase increased, hyperchloremia, hyperkalemia, hypermagnesemia, hyperphosphatemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactate dehydrogenase increased, nonprotein nitrogen (NPN) increased, and respiratory alkalosis.

Musculoskeletal System

Arthralgia, bone pain, dystonia, myalgia, and rigors.

Nervous System

Agitation, coma, convulsion, cough, depression, dysesthesia, dizziness, hallucinations, nervousness, paresthesia, somnolence, thinking abnormality, and tremor.

Respiratory System

Asthma, atelectasis, hemoptysis, hiccup, hyperventilation, influenza-like symptoms, lung edema, pharyngitis, pneumonia, respiratory insufficiency, respiratory failure, and sinusitis.

Skin & Appendages

Alopecia, dry skin, herpes simplex, injection site inflammation, maculopapular rash, purpura, skin discoloration, skin disorder, skin ulcer, urticaria, and vesiculobullous rash.

Special Senses

Conjunctivitis, dry eyes, and eye hemorrhage.

Urogenital System

Abnormal renal function, acute kidney failure, acute renal failure, dysuria, kidney failure, toxic nephropathy, urinary incontinence, and vaginal hemorrhage.

Post-marketing Experience

The following infrequent adverse experiences have been reported in post-marketing surveillance, in addition to those mentioned above: angioedema, erythema, urticaria, bronchospasm, cyanosis/hypoventilation, pulmonary edema, agranulocytosis, hemorrhagic cystitis, and rhabdomyolysis.

Clinical Laboratory Values

The effect of Amphocil on renal and hepatic function and on serum electrolytes was assessed from laboratory values measured repeatedly in Study 94-0-002. The frequency and magnitude of hepatic test abnormalities were similar in the Amphocil and amphotericin B groups. Nephrotoxicity was defined as creatinine values increasing 100% or more over pretreatment levels in pediatric patients, and creatinine values increasing 100% or more over pretreatment levels in adult patients provided the peak creatinine concentration was > 1.2 mg/dL. Hypokalemia was defined as potassium levels ≤ 2.5 mmol/L any time during treatment.

Incidence of nephrotoxicity, mean peak serum creatinine concentration, mean change from baseline in serum creatinine, and, incidence of hypokalemia in the double-blind randomized study were lower in the Amphocil group as summarized in the following table:

Study 94-0-002 Laboratory Evidence of Nephrotoxicity

The effect of Amphocil (3 mg/kg/day) vs. amphotericin B (0.6 mg/kg/day) on renal function in adult patients enrolled in this study is illustrated in the following figure:

In empirical therapy study 97-0-034, the incidence of nephrotoxicity as measured by increases of serum creatinine from baseline was significantly lower for patients administered Amphocil (individual dose groups and combined) compared with amphotericin B lipid complex.

Incidence of Nephrotoxicity
Empirical Therapy Study 97-0-034

The toxicity of Amphocil due to overdose has not been defined. Repeated daily doses up to 10 mg/kg in pediatric patients and 15 mg/kg in adult patients have been administered in clinical trials with no reported dose-related toxicity.

Management

If overdosage should occur, cease administration immediately. Symptomatic supportive measures should be instituted. Particular attention should be given to monitoring renal function. Hemodialysis or peritoneal dialysis do not appear to significantly affect the elimination of Amphocil.

The assay used to measure amphotericin B in the serum after administration of Amphocil does not distinguish amphotericin B that is complexed with the phospholipids of Amphocil from amphotericin B that is uncomplexed. The pharmacokinetic profile of amphotericin B after administration of Amphocil is based upon total serum concentrations of amphotericin B. The pharmacokinetic profile of amphotericin B was determined in febrile neutropenic cancer and bone marrow transplant patients who received 1-2 hour infusions of 1 to 5 mg/kg/day Amphocil for 3 to 20 days.

The pharmacokinetics of amphotericin B after administration of Amphocil is nonlinear such that there is a greater than proportional increase in serum concentrations with an increase in dose from 1 to 5 mg/kg/day. The pharmacokinetic parameters of total amphotericin B (mean ± SD) after the first dose and at steady state are shown in the table below.

Pharmacokinetic Parameters of Amphocil

Distribution

Based on total amphotericin B concentrations measured within a dosing interval (24 hours) after administration of Amphocil, the mean half-life was 7-10 hours. However, based on total amphotericin B concentration measured up to 49 days after dosing of Amphocil, the mean half-life was 100-153 hours. The long terminal elimination half-life is probably a slow redistribution from tissues. Steady state concentrations were generally achieved within 4 days of dosing.

Although variable, mean trough concentrations of amphotericin B remained relatively constant with repeated administration of the same dose over the range of 1 to 5 mg/kg/day, indicating no significant drug accumulation in the serum.

Metabolism

The metabolic pathways of amphotericin B after administration of Amphocil are not known.

Excretion

The mean clearance at steady state was independent of dose. The excretion of amphotericin B after administration of Amphocil has not been studied.