Amphotec

Amphotericin B cholesteryl complex is an antifungal medicine. It is used to help the body overcome serious infections, such as aspergillosis, that are caused by fungus.

This medicine is available only with your doctor's prescription.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

This medicine has been tested in children and, in effective doses, has not been shown to cause different side effects or problems than it does in adults.

Geriatric

This medicine has been tested in a limited number of patients 65 years of age or older and has not been shown to cause different side effects or problems in older people than it does in younger adults.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Cyclosporine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of amphotericin B cholesteryl complex. Make sure you tell your doctor if you have any other medical problems.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

• Chills
• fever
• headache
• nausea

• Difficulty in breathing
• dizziness or fainting
• increased heartbeat
• unusual bleeding or bruising

• Difficulty in swallowing
• hives
• itching, especially of feet or hands
• reddening of skin, especially around ears
• swelling of eyes, face, or inside of nose
• unusual tiredness or weakness (sudden and severe)

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat fungal infections.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Pharmacokinetics

The pharmacokinetics of amphotericin B, administered as Amphotec, were studied in 51 bone marrow transplant patients with systemic fungal infections. The median (range) age and weight of those patients were 32 (3 to 52) years and 69.5 (14 to 116) kg, respectively. Amphotec doses ranged from 0.5 to 8.0 mg/kg/day. The assay used in this study to measure amphotericin B in plasma does not distinguish amphotericin B that is complexed with cholesteryl sulfate from uncomplexed amphotericin B. A population modeling approach was used to estimate pharmacokinetic parameters (see table). The pharmacokinetics of amphotericin B, administered as Amphotec, were best described by an open, two compartment structural model. The pharmacokinetics of amphotericin B, administered as Amphotec, were nonlinear. Steady state volume of distribution (Vss) and total plasma clearance (CLt) increased with escalating doses, resulting in less than proportional increases in plasma concentration over a dose range of 0.5 to 8.0 mg/kg/day. The increased volume of distribution probably reflected uptake by tissues. The covariates of body weight and dose level accounted for a substantial portion of the variability of the pharmacokinetic estimates between patients. The unexplained variability in clearance was 26%. Based on the population model developed for these patients, pharmacokinetic parameters were predicted for two doses of Amphotec and are provided in the following table:

In addition, the pharmacokinetics of amphotericin B, administered as amphotericin B deoxycholate, were studied in 15 patients in whom amphotericin B deoxycholate was administered for the treatment of aspergillus infections or empirical therapy. The median (range) age and weight for these patients were 21 (4 to 66) years and 60 (19 to 117) kg, respectively. A population modeling approach was used to estimate the pharmacokinetic parameters. The pharmacokinetics of amphotericin B, administered as amphotericin B deoxycholate, was best described as an open, two-compartment model with linear elimination.

The predicted pharmacokinetic parameters are provided in the following table:

An analytical assay that is able to distinguish between amphotericin B in the Amphotec complex and amphotericin B which is not complexed to cholesteryl sulfate was used to analyze samples from a study of 25 patients who were either immunocompromised with aspergillosis or both febrile and neutropenic. Following a 1 mg/kg/hour infusion, 25 ± 18% (mean ± SD) of the total amphotericin B concentration measured in plasma was in the Amphotec complex, dropping to 9.3 ± 7.9% at 1 hour and 7.5 ± 9.3% at 24 hours after the end of the infusion.

Pharmacokinetics in Special Populations

A population modeling approach was used to assess the effect of renal function, hepatic function, and age on the pharmacokinetics of Amphotec in 51 patients receiving bone marrow transplants as described earlier.

Renal Impairment: The pharmacokinetics of amphotericin B, administered as Amphotec, were not related to baseline serum creatinine clearance in the population studied; the median (range) creatinine clearance for this population was 74.0 (range: 35 - 202) mL/min/70 kg. The effect of more severe renal impairment on the pharmacokinetics of Amphotec has not been studied.

Hepatic Impairment: The pharmacokinetics of amphotericin B, administered as Amphotec, were not related to baseline liver function, as determined by liver enzymes and total bilirubin. For the population tested, the mean ± SD values for AST and total Bilirubin were 59.4 ± 70.0 IU/mL and 3.5 ± 3.7 mg/dL, respectively. The effect of more severe hepatic impairment on the pharmacokinetics of Amphotec has not been studied.

Age: The pharmacokinetics of amphotericin B, administered as Amphotec, were not related to the age of the patient. The median (range) age for the population in this study was 32 (3 to 52) years.

Clinical Studies in Aspergillosis

Data from 161 patients with proven or probable aspergillus infection were pooled from 5 non-comparative open label studies, one of which included emergency use patients. The patients were treated with Amphotec because of failure to respond to amphotericin B deoxycholate (n=49), development of nephrotoxicity while receiving amphotericin B deoxycholate (n=62), preexisting renal impairment (n=25), or other reasons (n=25).

The median age of these 161 patients (92 males and 69 females) was 41 years (range 2 months to 85 years). For the 155 patients with baseline neutrophil data, 33 patients (21%) had neutrophil counts of < 500/mm3. The underlying diseases included bone marrow transplant, 69 (43%); hematological malignancy, 51(32%); solid organ transplant, 25 (15%); solid tumor, 3 (2%); and other diagnoses, 13 (8%) including surgery, 4; HIV infection, 3; immunosuppression for autoimmune disease, 3; diabetes, 2; and no known underlying disease, 1. Pulmonary involvement was the primary infection site, 118 patients (73%), followed by sinus, 14 (9%), CNS, 9 (6%), skin/wound, 9 (6%), and others, 10 (6%) including 3 with bone involvement, 2 with hepatic involvement, 2 with disseminated disease and 1 each with endocarditis, ophthalmitis, otitis, and involvement of the hard palate. The 49 patients enrolled due to failure to respond to amphotericin B had received amphotericin B deoxycholate prior to Amphotec for ≤ 7 days (11 patients), 8 - 14 days (16 patients), and > 14 days (22 patients).

Patients were defined by their physicians as being refractory to amphotericin B deoxycholate therapy based on overall clinical judgment after receiving either a minimum of 7 days of amphotericin B deoxycholate or a minimum total dose of 15 mg/kg of amphotericin B deoxycholate. Nephrotoxicity was defined as a serum creatinine that had doubled from baseline, increased by ≥ 1.5 mg/dL or increased to ≥ 2.0 mg/dL. Preexisting renal impairment was defined as a serum creatinine that had increased to ≥ 2.0 mg/dL due to reasons other than amphotericin B deoxycholate administration.

Classifications of diagnosis and response were based on the definitions previously developed by the Mycoses Study Group.1 A retrospective response analysis was conducted in which a “complete response” was defined as resolution of all attributable symptoms, signs, and radiographic abnormalities present at enrollment, and a “partial response” was defined as major improvement of the abovementioned parameters. The total number of responders was the sum of the number of “complete” and “partial” responses.

Of the 161 patients, 80 were considered evaluable for response. Eighty-one (81) were excluded on the basis of inadequate diagnosis, confounding factors, or receiving ≤ 4 doses of Amphotec. In the evaluable patients, the median daily dose was 4 mg/kg/day (range 0.73 - 7.5 mg/kg/day) and the cumulative median dose was 6.3 g (range 0.36 - 34.4 grams). Median duration of treatment was 24 days (range 5 - 129 days).

There is no directly comparable control group for the patients described in the above table to be certain whether similar patients would have responded had amphotericin B deoxycholate therapy been continued. A randomized study comparing Amphotec with amphotericin B deoxycholate for therapy of invasive aspergillosis is currently undergoing analysis.

Renal Function

The subset of patients with aspergillosis from the above five noncomparative open label studies, who initiated treatment with Amphotec when their serum creatinine was ≥ 2.0 mg/dL (n = 47) experienced a mean decline in serum creatinine during treatment. In part, this decline may be attributed to patient dropout over time from this group. A historical control group was selected by reviewing medical charts of patients from January 1990 to June 1994 at 6 medical centers ( M.D. Anderson Cancer Center, Fred Hutchinson Cancer Research Center, H. Lee Moffitt Cancer Center, University of Pittsburgh, Memorial Sloan-Kettering Cancer Center, and Bone Marrow Transplant Program at Emory  University). The mean change in serum creatinine was evaluated for similar cohorts of patients from this historical control group, with the baseline for assessing change being the day each patient’s serum creatinine reached ≥ 2.0 mg/dL. As shown in the figure, serum creatinine levels were lower during treatment with Amphotec when compared to the serum creatinine levels of amphotericin B deoxycholate patients in the historical control group. There is no directly comparable group to be certain whether this decline is significantly better than the results of serum creatinine levels in patients who had continued on amphotericin B deoxycholate. Since these data were obtained from two separate studies, no statistical testing of the differences between these two groups was performed.

Changes in Mean Serum Creatinine Over Time in Patients with
Aspergillosis and Baseline Serum Creatinine ≥ 2.0 mg/dL [a]

[a] These curves do not represent the clinical course of a given patient, but that of an openlabel cohort of patients.

[b] Administered as amphotericin B deoxycholate.

In a randomized, double-blind, multicenter study, 213 febrile neutropenic patients were given empirically either 4 mg/kg/day of Amphotec or 0.8 mg/kg/day of amphotericin B deoxycholate for a maximum of 14 days. This study was primarily designed to compare the safety profiles of these two treatments. NOTE: Amphotec is NOT approved for empirical treatment in febrile neutropenic patients.

In the above study, patients had largely normal renal function at baseline; median serum creatinine levels were 0.8 mg/dL for both treatment groups. The mean change in serum creatinine was evaluated for patients with baseline creatinine ≤ 1.5 mg/dL. As shown in the graph, patients in both treatment groups showed an increase in serum creatinine while on study, however Amphotec patients experienced significantly less creatinine increase at each time point.

Changes in Mean Serum Creatinine Over Time in Patients with Febrile
Neutropenia, and Baseline Serum Creatinine ≤ 1.5 mg/dL [a]

[a] These curves do not represent the clinical course of a given patient, but that of a cohort of patients.

[b] Administered as amphotericin B deoxycholate.

Hypokalemia

In the same empiric study, significantly more amphotericin B deoxycholate patients had at least one laboratory result of serum potassium < 3.0 mEq/L at least one time in the study compared with Amphotec patients (23% vs. 7%), although concomitant supplemental potassium was allowed in the study design. Both groups received approximately equal amounts of potassium supplementation.

Hypomagnesemia

In the same empiric study, there was no overall trend for decreasing serum magnesium in either group.

Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs. Immediate treatment of anaphylaxis or anaphylactoid reactions is required. Epinephrine, oxygen, intravenous steroids, and airway management should be administered as indicated. If severe respiratory distress occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of Amphotec.

The following adverse events are based on the experience of 572 Amphotec patients from 5 open studies of patients with systemic fungal infections, of whom 526 were treated with a daily dose of 3 - 6 mg/kg. Additionally, comparative adverse event data from 150 Amphotec (4 or 6 mg/kg/day) and 146 amphotericin B deoxycholate (0.8 or 1 mg/kg/day) patients in prospectively randomized doubleblinded studies of empiric treatment of febrile and neutropenic patients or treatment of aspergillosis are also provided.

Infusion-related adverse events: Infusion-related adverse events (1 to 3 hours after starting intravenous infusion) occurred most frequently in association with the first infusion of Amphotec. Their frequency and severity decreased with subsequent dosing. Based on the combined non-comparative studies, 35% (197/569) of the patients reported chills or chills and fever, possibly or probably related to Amphotec, on the first day of dosing, compared to 14% (58/422) by the seventh dose. In the comparative studies, a similar decreasing trend was noted for Amphotec and amphotericin B deoxycholate.

Adverse events that were considered to be possibly or probably related to Amphotec and that occurred in 5% or more of the patients are summarized in the table below:

Additionally, the following adverse events also occurred in 5% or more of Amphotec patients; however, the causal relationship of these adverse events is uncertain:

Abdomen enlarged, abdominal pain, back pain, chest pain, face edema, injection site inflammation, mucous membrane disorder, pain, sepsis

Cardiovascular disorder, hemorrhage, postural hypotension

Diarrhea, dry mouth, hematemesis, jaundice, stomatitis

Anemia, coagulation disorder, prothrombin decreased

Edema, generalized edema, hypocalcemia, hypophosphatemia, peripheral edema, weight gain

Confusion, dizziness, insomnia, somnolence, thinking abnormal, tremor

Apnea, asthma, cough increased, epistaxis, hyperventilation, lung disorder, rhinitis

Maculopapular rash, pruritis, rash, sweating

Eye hemorrhage

Hematuria

The following adverse events occurred in 1% to less than 5% of Amphotec patients. The causal association between these adverse events and Amphotec is uncertain.

Accidental injury, allergic reaction, asthenia, death, hypothermia, immune system disorder, infection, injection site pain, injection site reaction, neck pain

Arrhythmia, atrial fibrillation, bradycardia, congestive heart failure, heart arrest, phlebitis, shock, supraventricular tachycardia, syncope, vasodilatation, venoocclusive liver disease, ventricular extrasystoles

Anorexia, bloody diarrhea, constipation, dyspepsia, fecal incontinence, gamma glutamyl transpeptidase increased, gastrointestinal disorder, gastrointestinal hemorrhage, gingivitis, glossitis, hepatic failure, melena, mouth ulceration, oral moniliasis, rectal disorder

Ecchymosis, fibrinogen increased, hypochromic anemia, leukocytosis, leukopenia, petechia, thromboplastin decreased

Acidosis, BUN increased, dehydration, hyponatremia, hyperkalemia, hyperlipemia, hypernatremia, hypervolemia, hypoglycemia, hypoproteinemia, lactic dehydrogenase increased, AST (SGOT) increased, ALT (SGPT) increased, weight loss

Arthralgia, myalgia

Agitation, anxiety, convulsion, depression, hallucinations, hypertonia, nervousness, neuropathy, paresthesia, psychosis, speech disorder, stupor

Hemoptysis, lung edema, pharyngitis, pleural effusion, respiratory disorder, sinusitis

Acne, alopecia, petechial rash, skin discoloration, skin disorder, skin nodule, skin ulcer, urticaria, vesiculobullous rash

Amblyopia, deafness, ear disorder, tinnitus

Albuminuria, dysuria, glycosuria, kidney failure, oliguria, urinary incontinence, urinary retention, urinary tract disorder

Amphotec is not dialyzable. Amphotericin B deoxycholate overdose has been reported to result in cardio-respiratory arrest.