Amphotericin B

AmBisome for Injection is available as single cartons (equivalent to 50mg amphotericin B) and in packs often individual vial cartons (NDC 0469-3051-30).

Each carton contains one pre-packaged, disposable sterile 5 micron filter.

References

1. Clinical and Laboratory Standards Institute (CLSI). Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard -3rd edition. CLSI document M27- A3. CLSI, 940 West Valley Rd. Suite 1400, Wayne, PA 19087-1898, 2008.

2. CLSI. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeast; 3rd Informational Supplement. CLSI document M27-S3, 2008.

3. CLSI. Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts; Approved Guideline- 2nd edition. CLSI document M44-A2, 2009.

4. CLSI Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi; Approved Standard - 2nd edition. CLSI document M38-A2, 2008.

5. CLSI. Method for Antifungal Disk Diffusion Susceptibility Testing of Nondermatophyte Filamentous Fungi; Approved Guideline. CLSI document M51-A, 2010.

Marketed by: Astellas Pharma US, Inc. Deerfield, IL 60015-2548. Manufactured by: Gilead Sciences, Inc. San Dimas, CA91773. AmBisome is a registered trademark of Gilead Sciences, Inc. Abelcet® is a registered trademark of The Liposome Company, Inc.

This medicine is for serious, life-threatening fungal infections. It is not for use in treating a minor fungal infection (yeast infection) of the mouth, esophagus, or vagina.

Do not use amphotericin B in larger amounts than recommended. An overdose can cause death.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of amphotericin B can be fatal.

The pharmacokinetics of amphotericin B vary substantially depending on whether the drug is administered as conventional amphotericin B, amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, or amphotericin B liposomal.135 201 202 203 205 210 332 Pharmacokinetic parameters reported for one formulation should not be used to predict pharmacokinetics of any other formulation.135 201 202 203 205 210 332

Absorption

Bioavailability

Amphotericin B is poorly absorbed from the GI tract and must be given parenterally.b

In general, usual dosages of amphotericin B cholesteryl sulfate complex203 208 210 338 or amphotericin B lipid complex201 206 207 210 265 333 result in lower serum concentrations and greater volumes of distribution than those reported for conventional amphotericin B.

Plasma concentrations attained with amphotericin B liposomal generally are higher and the volume of distribution is lower than those reported for conventional amphotericin B.202 205 209 210 269 332

Distribution

Extent

Information on distribution of amphotericin B is limited; distribution appears to be multicompartmental.b

To achieve fungistatic CSF concentrations, conventional amphotericin B must usually be administered intrathecally†.b

Crosses the placenta.135 Not known whether distributed into milk.201 202 203

Plasma Protein Binding

>90% bound to plasma proteins, mainly lipoproteins.135

Elimination

Metabolism

Metabolic fate has not been fully elucidated.b

Elimination Route

Conventional amphotericin B is eliminated very slowly by the kidneys.135

Half-life

Conventional amphotericin B: Following IV administration, initial plasma half-life is approximately 24 hours.135 After the first 24 hours, the rate at which amphotericin B is eliminated decreases and an elimination half-life of approximately 15 days has been reported.135

Amphotericin B cholesteryl sulfate complex: Distribution half-life of 3.5 minutes and elimination half-life of 27.5–28.2 hours.203

Amphotericin B lipid complex: Terminal elimination half-life is 173 hours.201

Amphotericin B liposomal: Mean terminal elimination half-life is 100–153 hours.202

Special Populations

Amphotericin B cholesteryl sulfate complex: Pharmacokinetics not affected by hepatic impairment or renal impairment (Clcr ≥35 ml/minute); not evaluated in those with more severe hepatic or renal impairment.203

Storage

Parenteral

Conventional amphotericin B: 2–8°C.135 417 Reconstituted colloidal dispersions should be protected from light and are stable for 24 hours at room temperature or 1 week when refrigerated at 2–8°C.135 417

Amphotericin B cholesteryl sulfate complex (Amphotec): 15–30°C.203 Following reconstitution with sterile water for injection, the colloidal dispersion should be refrigerated at 2–8°C and used within 24 hours; do not freeze.203 Reconstituted amphotericin B cholesteryl sulfate complex that has been further diluted in 5% dextrose injection should be stored at 2–8°C and used within 24 hours; any partially used vials should be discarded.203

Amphotericin B liposomal (AmBisome): 2–8°C.202 Following reconstitution with sterile water for injection, solutions containing 4 mg/mL may be stored for up to 24 hours at 2–8°C; do not freeze.202 IV infusions should be initiated within 6 hours after dilution in 5% dextrose injection;202 any partially used vials should be discarded.202

Amphotericin B lipid complex (Abelcet): 2–8°C; protect from light.201 Following dilution in 5% dextrose injection, stable for up to 48 hours at 2–8°C and for an additional 6 hours at room temperature.201 Do not freeze; any unused solutions should be discarded.201

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed.

• Importance of advising patients of other important precautionary information. (See Cautions.)

This drug should be used primarily for treatment of patients with progressive and potentially life-threatening fungal infections; it should not be used to treat noninvasive forms of fungal disease such as oral thrush, vaginal candidiasis and esophageal candidiasis in patients with normal neutrophil counts.

Amphotericin B for Injection should no be given in doses greater than 1.5 mg/kg.

EXERCISE CAUTION to prevent inadvertent overdosage, which may result in potentially fatal cardiac or cardiopulmonary arrest (see WARNINGS, OVERDOSAGE and DOSAGE AND ADMINISTRATION). Verify the product name and dosage pre-administration, especially if dose exceeds 1.5 mg/kg.

Microbiology

Amphotericin B shows a high order of in vitro activity against many species of fungi. Histoplasma capsulatum, Coccidioides immitis, Candida species, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, and Aspergillus fumigatus are all inhibited by concentrations of Amphotericin B ranging from 0.03 to 1.0 mcg/mL in vitro. While Candida albicans is generally quite susceptible to Amphotericin B, non-albicans species may be less susceptible. Pseudallescheria boydii and Fusarium sp. are often resistant to Amphotericin B. The antibiotic is without effect on bacteria, rickettsiae, and viruses.

Susceptibility Testing

Standardized techniques for susceptibility testing for antifungal agents have not been established and results of susceptibility studies have not been correlated with clinical outcomes.

PHARMACOKINETICS

Amphotericin B is fungistatic or fungicidal depending on the concentration obtained in body fluids and the susceptibility of the fungus. The drug acts by binding to sterols in the cell membrane of susceptible fungi with a resultant change in membrane permeability allowing leakage of intracellular components. Mammalian cell membranes also contain sterols and it has been suggested that the damage to human cells and fungal cells may share common mechanisms.

An initial intravenous infusion of 1 to 5 mg of Amphotericin B per day, gradually increased to 0.4 to 0.6 mg/kg daily, produces peak plasma concentrations ranging from approximately 0.5 to 2 mcg/mL. Following a rapid initial fall, plasma concentrations plateau at about 0.5 mcg/mL. An elimination half-life of approximately 15 days follows an initial plasma half-life of about 24 hours. Amphotericin B circulating in plasma is highly bound (>90%) to plasma proteins and is poorly dialyzable. Approximately two thirds of concurrent plasma concentrations have been detected in fluids from inflamed pleura, peritoneum, synovium, and aqueous humor. Concentrations in the cerebrospinal fluid seldom exceed 2.5% of those in the plasma. Little Amphotericin B penetrates into vitreous humor or normal amniotic fluid. Complete details of tissue distribution are not known.

Amphotericin B is excreted very slowly (over weeks to months) by the kidneys with 2 to 5% of a given dose being excreted in the biologically active form. Details of possible metabolic pathways are not known. After treatment is discontinued, the drug can be detected in the urine for at least 7 weeks due to the slow disappearance of the drug. The cumulative urinary output over a 7 day period amounts to approximately 40% of the amount of drug infused.

To make sure you can safely receive amphotericin B liposomal, tell your doctor if you have kidney or liver disease, or if you are allergic to amphotericin B (Abelcet, AmBisome, Amphotec, or Fungizone).

Amphotericin B liposomal may need to be given for up to several weeks or months, depending on the infection being treated.

Some people receiving a amphotericin B liposomal injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, nauseated, light-headed, sweaty, hot or cold, or if you have a fast heartbeat, chest tightness, or trouble breathing.

To make sure you can safely receive amphotericin B liposomal, tell your doctor if you are allergic to amphotericin B (Abelcet, AmBisome, Amphotec, or Fungizone), or if you have:

• kidney disease; or
• liver disease.

FDA pregnancy category B. Amphotericin B liposomal is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether amphotericin B liposomal passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using amphotericin B liposomal.

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

The incidence of common adverse events (incidence of 10% or greater) occurring with AmBisome 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

AmBisome was well tolerated. AmBisome 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, AmBisome 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 AmBisome 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 AmBisome 3 mg/kg, 81 patients were treated with AmBisome 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. AmBisome 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 AmBisome 3 mg/kg, 94 patients were treated with AmBisome 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). 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:

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 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.

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 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, 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 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.

Toxicity and Discontinuation of Dosing

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.

Less Common Adverse Events

The following adverse events also have been reported in 2% to 10% of AmBisome-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 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:

Study 94-0-002 Laboratory Evidence of Nephrotoxicity

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:

Laboratory Evidence of Nephrotoxicity Study 94-0-013

Read the entire FDA prescribing information for Ambisome (Amphotericin B)