AmBisome ® (amphotericin B) liposome for injection

Amphotericin B, the active ingredient of AmBisome, acts by binding to the sterol component, ergosterol, of the cell membrane of susceptible fungi. It forms transmembrane channels leading to alterations in cell permeability through which monovalent ions (NA+, K+, H+, and Cl-) leak out of the cell resulting in cell death. While amphotericin B has a higher affinity for the ergosterol component of the fungal cell membrane, it can also bind to the cholesterol component of the mammalian cell leading to cytotoxicity. AmBisome, the liposomal preparation of amphotericin B, has been shown to penetrate the cell wall of both extracellular and intracellular forms of susceptible fungi.

Mutants with decreased susceptibility to amphotericin B have been isolated from several fungal species after serial passage in culture media containing the drug, and from some patients receiving prolonged therapy. Drug combination studies in vitro and in vivo suggest that imidazoles may induce resistance to amphotericin B; however, the clinical relevance of drug resistance has not been established.

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: www.fda.gov/STIC.

The assay used to measure amphotericin B in the serum after administration of AmBisome does not distinguish amphotericin B that is complexed with the phospholipids of AmBisome from amphotericin B that is uncomplexed. The pharmacokinetic profile of amphotericin B after administration of AmBisome 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 AmBisome for 3 to 20 days.

The pharmacokinetics of amphotericin B after administration of AmBisome 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.

Distribution

Based on total amphotericin B concentrations measured within a dosing interval (24 hours) after administration of AmBisome, the mean half-life was 7-10 hours. However, based on total amphotericin B concentration measured up to 49 days after dosing of AmBisome, 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 AmBisome are not known.

Excretion

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

Renal Impairment

The effect of renal impairment on the disposition of amphotericin B after administration of AmBisome has not been studied. However, AmBisome has been successfully administered to patients with pre-existing renal impairment (see DESCRIPTION OF CLINICAL STUDIES).

Hepatic Impairment

The effect of hepatic impairment on the disposition of amphotericin B after administration of AmBisome is not known. 

Pediatric and Elderly Patients

The pharmacokinetics of amphotericin B after administration of AmBisome in pediatric and elderly patients has not been studied; however, AmBisome has been used in pediatric and elderly patients (see DESCRIPTION OF CLINICAL STUDIES).

Gender and Ethnicity

The effect of gender or ethnicity on the pharmacokinetics of amphotericin B after administration of AmBisome is not known.

Study 94-0-002, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of AmBisome (1.5-6 mg/kg/day) compared with amphotericin B deoxycholate (0.3-1.2 mg/kg/day) in the empirical treatment of 687 adult and pediatric neutropenic patients who were febrile despite having received at least 96 hours of broad spectrum antibacterial therapy. Therapeutic success required (a) resolution of fever during the neutropenic period, (b) absence of an emergent fungal infection, (c) patient survival for at least 7 days post therapy, (d) no discontinuation of therapy due to toxicity or lack of efficacy, and (e) resolution of any study-entry fungal infection.

The overall therapeutic success rates for AmBisome and the amphotericin B deoxycholate were equivalent. Results are summarized in the following table. Note: The categories presented below are not mutually exclusive.

* 8 and 10 patients, respectively, were treated as failures due to premature discontinuation alone.

This therapeutic equivalence had no apparent relationship to the use of prestudy antifungal prophylaxis or concomitant granulocytic colony-stimulating factors.

The incidence of mycologically-confirmed, and clinically-diagnosed, emergent fungal infections are presented in the following table. AmBisome and amphotericin B were found to be equivalent with respect to the total number of emergent fungal infections.

Mycologically-confirmed fungal infections at study entry were cured in 8 of 11 patients in the AmBisome group and 7 of 10 in the amphotericin B group.

Study 97-0-034, a randomized, double-blind, comparative multi-center trial, evaluated the safety of AmBisome (3 and 5 mg/kg/day) compared with amphotericin B lipid complex (5 mg/kg/day) in the empirical treatment of 202 adult and 42 pediatric neutropenic patients. One hundred and sixty-six (166) patients received AmBisome (85 patients received 3 mg/kg/day and 81 received 5 mg/kg/day) and 78 patients received amphotericin B lipid complex. The study patients were febrile despite having received at least 72 hours of broad spectrum antibacterial therapy. The primary endpoint of this study was safety. The study was not designed to draw statistically meaningful conclusions related to comparative efficacy and, in fact, Abelcet is not labeled for this indication.

Two supportive, prospective, randomized, open-label, comparative multi-center studies examined the efficacy of two dosages of AmBisome (1 and 3 mg/kg/day) compared to amphotericin B deoxycholate (1 mg/kg/day) in the treatment of neutropenic patients with presumed fungal infections. These patients were undergoing chemotherapy as part of a bone marrow transplant or had hematological disease. Study 104-10 enrolled adult patients (n = 134). Study 104-14 enrolled pediatric patients (n = 214). Both studies support the efficacy equivalence of AmBisome and amphotericin B as empirical therapy in febrile neutropenic patients.

Study 94-0-013, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of AmBisome at doses (3 and 6 mg/kg/day) compared with amphotericin B deoxycholate (0.7 mg/kg/day) for the treatment of cryptococcal meningitis in 266 adult and one pediatric HIV-positive patients (the pediatric patient received amphotericin B deoxycholate). Of the 267 treated patients, 86 received AmBisome 3 mg/kg/day, 94 received 6 mg/kg/day and 87 received amphotericin B deoxycholate; cryptococcal meningitis was documented by a positive CSF culture at baseline in 73, 85 and 76 patients, respectively. Patients received study drug once daily for an induction period of 11 to 21 days. Following induction, all patients were switched to oral fluconazole at 400 mg/day for adults and 200 mg/day for patients less than 13 years of age to complete 10 weeks of protocol-directed therapy. For mycologically evaluable patients, defined as all randomized patients who received at least one dose of study drug, had a positive baseline CSF culture, and had at least one follow-up culture, success was evaluated at week 2 (i.e., 14 ± 4 days), and was defined as CSF culture conversion. Success rates at 2 weeks for AmBisome and amphotericin B deoxycholate are summarized in the following table:

* 97.5% Confidence Interval for the difference between AmBisome and amphotericin B success rates. A negative value is in favor of amphotericin B. A positive value is in favor of AmBisome.

Success at 10 weeks was defined as clinical success at week 10 plus CSF culture conversion at or prior to week 10. Success rates at 10 weeks in patients with positive baseline culture for cryptococcus species are summarized in the following table and show that the efficacy of AmBisome 6 mg/kg/day approximates the efficacy of the amphotericin B deoxycholate regimen. These data do not support the conclusion that AmBisome 3 mg/kg/day is comparable in efficacy to amphotericin B deoxycholate. The table also presents 10-week survival rates for patients treated in this study.

* 97.5% Confidence Interval for the difference between AmBisome and amphotericin B rates. A negative value is in favor of amphotericin B. A positive value is in favor of AmBisome.

The incidence of infusion-related, cardiovascular and renal adverse events was lower in patients receiving AmBisome compared to amphotericin B deoxycholate (see ADVERSE REACTIONS section for details); therefore, the risks and benefits (advantages and disadvantages) of the different amphotericin B formulations should be taken into consideration when selecting a patient treatment regimen.

AmBisome was evaluated in a compassionate use study in hospitalized patients with systemic fungal infections. These patients either had fungal infections refractory to amphotericin B deoxycholate, were intolerant to the use of amphotericin B deoxycholate, or had pre-existing renal insufficiency. Patient recruitment involved 140 infectious episodes in 133 patients, with 53 episodes evaluable for mycological response and 91 episodes evaluable for clinical outcome. Clinical success and mycological eradication occurred in some patients with documented aspergillosis, candidiasis, and cryptococcosis.

AmBisome was studied in patients with visceral leishmaniasis who were infected in the Mediterranean basin with documented or presumed Leishmania infantum. Clinical studies have not provided conclusive data regarding efficacy against L. donovani or L. chagasi.

AmBisome achieved high rates of acute parasite clearance in immunocompetent patients when total doses of 12-30 mg/kg were administered. Most of these immunocompetent patients remained relapse-free during follow-up periods of 6 months or longer. While acute parasite clearance was achieved in most of the immunocompromised patients who received total doses of 30-40 mg/kg, the majority of these patients were observed to relapse in the 6 months following the completion of therapy. Of the 21 immunocompromised patients studied, 17 were coinfected with HIV; approximately half of the HIV-infected patients had AIDS. The following table presents a comparison of efficacy rates among immunocompetent and immunocompromised patients infected in the Mediterranean basin who had no prior treatment or remote prior treatment for visceral leishmaniasis. Efficacy is expressed as both acute parasite clearance at the end of therapy (EOT) and as overall success (clearance with no relapse) during the follow-up period (F/U) of greater than 6 months for immunocompetent and immunocompromised patients:

When followed for 6 months or more after treatment, the overall success rate among immunocompetent patients was 96.5% and the overall success rate among immunocompromised patients was 11.8% due to relapse in the majority of patients. While case reports have suggested there may be a role for long-term therapy to prevent relapses in HIV coinfected patients (Lopez-Dupla, et al. J Antimicrob Chemother 1993; 32: 657-659), there are no data to date documenting the efficacy or safety of repeat courses of AmBisome or of maintenance therapy with this drug among immunocompromised patients.

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

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

False elevations of serum phosphate may occur when samples from patients receiving AmBisome 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.

No formal clinical studies of drug interactions have been conducted with AmBisome; however, the following drugs are known to interact with amphotericin B and may interact with AmBisome:

Antineoplastic Agents

Concurrent use of antineoplastic agents may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with caution.

Corticosteroids and Corticotropin (ACTH)

Concurrent use of corticosteroids and ACTH may potentiate hypokalemia, which could predispose the patient to cardiac dysfunction. If used concomitantly, serum electrolytes and cardiac function should be closely monitored.

Digitalis Glycosides

Concurrent use may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly, serum potassium levels should be closely monitored.

Flucytosine

Concurrent use of flucytosine may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion.

Azoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.)

In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazoles may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.

Leukocyte Transfusions

Acute pulmonary toxicity has been reported in patients simultaneously receiving intravenous amphotericin B and leukocyte transfusions.

Other Nephrotoxic Medications

Concurrent use of amphotericin B and other nephrotoxic medications may enhance the potential for drug-induced renal toxicity. 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, serum potassium levels should be closely monitored.

No long-term studies in animals have been performed to evaluate carcinogenic potential of AmBisome. AmBisome 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). AmBisome did not affect fertility or days to copulation. There were no effects on male reproductive function.

There have been no adequate and well-controlled studies of AmBisome 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 AmBisome had no teratogenic potential in these species. In rats, the maternal non-toxic dose of AmBisome 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 AmBisome experienced a higher rate of spontaneous abortions than did the control groups. AmBisome should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks involved.

Many drugs are excreted in human milk; however, it is not known whether AmBisome is excreted in human milk. Due to the potential for serious adverse reactions in breastfed 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 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 AmBisome. In studies which included 302 pediatric patients administered AmBisome, there was no evidence of any differences in efficacy or safety of AmBisome compared to adults. Since pediatric patients have received AmBisome 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).

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

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). AmBisome-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:

* Day 1 body temperature increased above the temperature taken within 1 hour prior to infusion (preinfusion temperature) or above the lowest infusion value (no preinfusion temperature recorded).

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:

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 AmBisome-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 AmBisome compared with amphotericin B lipid complex. Fever, chills/rigors and hypoxia were significantly lower for each AmBisome 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 AmBisome and 1.2% of patients treated with 5 mg/kg per day AmBisome.

Day 1 body temperature increased above the temperature taken within 1 hour prior to infusion (preinfusion temperature) or above the lowest infusion value (no preinfusion temperature recorded).

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 AmBisome and amphotericin B deoxycholate as initial therapy for cryptococcal meningitis, premedications to prevent infusion-related reactions were permitted. AmBisome-treated patients had a lower incidence of fever, chills/rigors and respiratory adverse events as summarized in the following table:

There have been a few reports of flushing, back pain with or without chest tightness, and chest pain associated with AmBisome 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.

In Study 94-0-002, a significantly lower incidence of grade 3 or 4 toxicity was observed in the AmBisome 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 AmBisome.

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 AmBisome groups.

The following adverse events also have been reported in 2% to 10% of AmBisome-treated patients receiving chemotherapy or bone marrow transplantation, or who 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.

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.

The effect of AmBisome 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 AmBisome 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 AmBisome group as summarized in the following table:

The effect of AmBisome (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 AmBisome (individual dose groups and combined) compared with amphotericin B lipid complex.

Incidence of Nephrotoxicity

Empirical Therapy Study 97-0-034

The following graph shows the average serum creatinine concentrations in the compassionate use study and shows that there is a drop from pretreatment concentrations for all patients, especially those with elevated (greater than 1.7 mg/dL) pretreatment creatinine concentrations.

The incidence of nephrotoxicity in Study 94-0-013 comparative trial in cryptococcal meningitis was lower in the AmBisome groups as shown in the following table:

Read This Entire Section Carefully Before Beginning Reconstitution

AmBisome must be reconstituted using Sterile Water for Injection, USP (without a bacteriostatic agent). Vials of AmBisome containing 50 mg of amphotericin B are prepared as follows:

Reconstitution

1. 1.Aseptically add 12 mL of Sterile Water for Injection, USP to each AmBisome 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 AmBisome.
2. 2.Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the AmBisome. AmBisome forms a yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed.

Filtration and Dilution

1. 3.Calculate the amount of reconstituted (4 mg/mL) AmBisome to be further diluted.
2. 4.Withdraw this amount of reconstituted AmBisome into a sterile syringe.
3. 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 AmBisome).
4. 6.AmBisome 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.

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.

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

As with all parenteral drug products, the reconstituted AmBisome 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 AmBisome or in the materials specified for reconstitution and dilution.