Amphotericin B

Amphotericin B liposome for injection 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 amphotericin B liposome for injection, relapse rates were high following initial clearance of parasites (see
  DESCRIPTION OF CLINICAL STUDIES)
  .

See

Amphotericin B liposome for injection 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 amphotericin B liposome for injection; provided 

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 amphotericin B liposome for injection 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:

Unopened vials of lyophilized material are to be stored at temperatures 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

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

Amphotericin B liposome for injection should commence within 6 hours of dilution with 5% Dextrose Injection.

As with all parenteral drug products, the reconstituted amphotericin B liposome for injection 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 amphotericin B liposome for injection or in the materials specified for reconstitution and dilution.

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

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

Amphotericin B liposome for injection was well tolerated. Amphotericin B liposome for injection 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, amphotericin B liposome for injection 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 amphotericin B liposome for injection 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 amphotericin B liposome for injection 3 mg/kg, 81 patients were treated with amphotericin B liposome for injection 5 mg/kg and 78 patients were treated with amphotericin B lipid complex 5 mg/kg in Study 97-0-034, a randomized double-blind, multicenter study in febrile, neutropenic patients. Amphotericin B liposome for injection 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:

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 amphotericin B liposome for injection 3 mg/kg, 94 patients were treated with amphotericin B liposome for injection 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 multicenter 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:

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

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

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 amphotericin B liposome for injection and amphotericin B deoxycholate as initial therapy for cryptococcal meningitis, premedications to prevent infusion related reactions were permitted. Amphotericin B liposome for injection treated patients had a lower incidence of fever, chill/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 amphotericin B liposome for injection 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 amphotericin B liposome for injection 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 amphotericin B liposome for injection.

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 amphotericin B liposome for injection groups.

Less Common Adverse Events

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

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

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

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.

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

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

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

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

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

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

Conjunctivitis, dry eyes, and eye hemorrhage.

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

Postmarketing Experience

The following infrequent adverse experiences have been reported in postmarketing 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 amphotericin B liposome for injection 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 amphotericin B liposome for injection 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 amphotericin B liposome for injection group as summarized in the following table:

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

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 amphotericin B liposome for injection groups as shown in the following table:

No formal clinical studies of drug interactions have been conducted with amphotericin B liposome for injection. However, the following drugs are known to interact with amphotericin B and may interact with amphotericin B liposome for injection:

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

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.

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

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

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

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.

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.

Amphotericin B liposome for injection is a sterile, non-pyrogenic lyophilized product for intravenous infusion. Each vial contains amphotericin B, USP 50 milligrams (mg), intercalated into a liposomal membrane consisting of alpha tocopherol approximately 0.64 mg; cholesterol 52 mg; distearoylphosphatidylglycerol, sodium salt 84 mg; hydrogenated soy phosphatidylcholine 213 mg, together with disodium succinate hexahydrate 27 mg; and sucrose 900 mg. Amphotericin B liposome for injection may also contain hydrochloric acid and/or sodium hydroxide as pH adjusters. Following reconstitution with Sterile Water for Injection, the resulting pH of the suspension is between 5.0 to 6.0.

Amphotericin B liposome for injection is a true single bilayer liposomal drug delivery system. Liposomes are closed, spherical vesicles created by mixing specific proportions of amphophilic substances such as phospholipids and cholesterol so that they arrange themselves into multiple concentric bilayer membranes when hydrated in aqueous solutions. Single bilayer liposomes are then formed by microemulsification of multilamellar vesicles using a homogenizer. Amphotericin B liposome for injection consists of these unilamellar bilayer liposomes with amphotericin B intercalated within the membrane. Due to the nature and quantity of amphophilic substances used, and the lipophilic moiety in the amphotericin B molecule, the drug is an integral part of the overall structure of the Amphotericin B liposomes. Amphotericin B liposome for injection contains true liposomes that are less than 100 nm in diameter. A schematic depiction of the liposome is presented below.

Note: Liposomal encapsulation or incorporation into a lipid complex can substantially affect a drug’s functional properties relative to those of the unencapsulated drug or non-lipid associated drug. In addition, different liposomal or lipid-complex products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect the functional properties of these drug products.

Amphotericin B is a macrocyclic, polyene, antifungal antibiotic produced from a strain of 

Amphotericin B is designated chemically as: [1R-(1R*,3S*,5R*,6R*,9R*,11R*,15S*,16R*,17R*,18S*, 19E,21E,23E,25E,27E,29E,31E,33R*,35S*,36R*,37S*)]-33-[(3-Amino-3,6-dideoxy-ß-D-mannopyranosyl)oxy]-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo-[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid (CAS No.1397-89-3).

Amphotericin B has a molecular formula of C₄₇H₇₃NO₁₇ and a molecular weight of 924.09 g/mol.

The structure of amphotericin B is shown below: