AMPHOTERICIN-B
DESCRIPTION:
FUNGIZONE is a sterile, pyrogen-free suspension for intravenous infusion.
FUNGIZONE consists of amphotericin B complexed with two phospholipids in a 1:1
drug-to-lipid molar ratio. The two phospholipids, L-alpha-
dimyristoylphosphatidylcholine (DMPC) and L- alpha-
dimyristoylphosphatidylglycerol (DMPG), are present in a 7:3 molar ratio.
FUNGIZONE is yellow and opaque in appearance, with a pH of 5-7.
NOTE: LIPOSOMAL ENCAPSULATION OR INCORPORATION IN A LIPID COMPLEX CAN
SUBSTANTIALLY AFFECT A DRUG'S FUNCTIONAL PROPERTIES RELATIVE TO THOSE OF THE
UNENCAPSULATED OR NONLIPID-ASSOCIATED DRUG. IN ADDITION, DIFFERENT LIPOSOMAL OR
LIPID-COMPLEXED 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 FUNCTIONAL PROPERTIES OF THESE DRUG PRODUCTS.
Amphotericin B is a polyene, antifungal antibiotic produced from a strain of
Streptomyces Nodosus. Amphotericin B is designated chemically as (1R-(1R+ACo-, 3S+ACo-,
5R+ACo-, 6R+ACo-, 9R+ACo-, 11R+ACo-, 15S+ACo-, 16R+ACo-, 17R+ACo-, 18S+ACo-, 19E, 21E, 23E, 25E, 27E, 29E, 31E,
33R+ACo-, 35S+ACo-, 36R+ACo-, 37S+ACo-))-33-((3-Amino-3, 6-dideoxy-beta-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.
It has a molecular weight of 924.09 and a molecular formula of C47H73NO17.
ACTIONS/CLINICAL PHARMACOLOGY:
MICROBIOLOGY
MECHANISM OF ACTION
The active component of FUNGIZONE, amphotericin B, acts by binding to sterols
in the cell membrane of susceptible fungi, with a resultant change in the
permeability of the membrane. Mammalian cell membranes also contain sterols, and
damage to human cells is believed to occur through the same mechanism of action.
ACTIVITY IN VITRO AND IN VIVO
FUNGIZONE shows In Vitro activity against Aspergillus sp. (n+AD0-3) and Candida sp.
(n+AD0-10), with MICs generally +ADw-1 mcgm/mL. Depending upon the species and strain of
Aspergillus and Candida tested, significant In Vitro differences in
susceptibility to amphotericin B have been reported (MICs ranging from 0.1 to
+AD4-10 mcgm/mL). However, standardized techniques for susceptibility testing for
antifungal agents have not been established, and results of susceptibility
studies do not necessarily correlate with clinical outcome.
FUNGIZONE is active in animal models against Aspergillus Fumigatus, Candida
Albicans, C. Guillermondii, C. Stellatoideae, and C. Tropicalis, Cryptococcus
Sp., Coccidioidomyces Sp., Histoplasma Sp., And Blastomyces Sp. in which end-
points were clearance of microorganisms from target organ(s) and/or prolonged
survival of infected animals.
DRUG RESISTANCE
Fungal species with decreased susceptibility to amphotericin B have been
isolated after serial passage in culture media containing the drug, and from
some patients receiving prolonged therapy. Although the relevance of drug
resistance to clinical outcome has not been established, fungal species which
are resistant to amphotericin B may also be resistant to FUNGIZONE.
PHARMACOKINETICS
The assay used to measure amphotericin B in the blood after the administration
of FUNGIZONE does not distinguish amphotericin B that is complexed with the
phospholipids of FUNGIZONE from amphotericin B that is uncomplexed.
pharmacokinetics of amphotericin B after the administration of FUNGIZONE are
nonlinear. Volume of distribution and clearance from blood increase with
increasing dose of FUNGIZONE, resulting in less than proportional increases in
blood concentrations of amphotericin B over a dose range of 0.6-5 mg/kg/day. The
pharmacokinetics of amphotericin B in whole blood after the administration of
FUNGIZONE and amphotericin B desoxycholate are:
PHARMACOKINETIC PARAMETERS OF AMPHOTERICIN B IN WHOLE BLOOD IN PATIENTS ADMINISTERED
MULTIPLE DOSES OF FUNGIZONE OR AMPHOTERICIN B DESOXYCHOLATE
____________________________________________________________________________________________________________
FUNGIZONE AMPHOTERICIN B
5 MG/KG/DAY 0.6 MG/KG/DAY
FOR 5-7 DAYS FOR 42 DAYSa
PHARMACOKINETIC PARAMETER MEAN SD MEAN SD
Peak Concentration (mcgm/mL) 1.7 0.8 (n+AD0-10)b 1.1 0.2 (n+AD0-5)
Concentration at End of 0.6 0.3 (n+AD0-10)b 0.4 0.2 (n+AD0-5)
Dosing Interval (mcgm/mL)
Area Under Blood Concentration-Time 14 7 (n+AD0-14)b,c 17.1 5 (n+AD0-5)
Curve (AUC0-24h) (mcgm+ACo-h/mL)
Clearance (mL/h+ACo-kg) 436 188.5 (n+AD0-14)b,c 38 15 (n+AD0-5)
Apparent Volume of Distribution 131 57.7 (n+AD0-8)c 5 2.8 (n+AD0-5)
(Vdarea) (L/kg)
Terminal Elimination Half-Life (h) 73.4 78 (n+AD0-8)c 91.1 40.9 (n+AD0-5)
Amount Excreted in Urine Over 24 h
After Last Dose (+ACU- of dose)d 0.9 0.4 (n+AD0-8)c 9.6 2.5 (n+AD0-8)
____________________________________________________________________________________________________________
a Data from patients with mucocutaneous leishmaniasis. Infusion rate was 0.25 mg/kg/h.
____________________________________________________________________________________________________________
b Data from studies in patients with cytologically proven cancer being treated with chemotherapy or neutropenic patients with presumed or proven fungal infection. Infusion rate was 2.5 mg/kg/h.
____________________________________________________________________________________________________________
c Data from patients with mucocutaneous leishmaniasis. Infusion rate was 4 mg/kg/h.
____________________________________________________________________________________________________________
d Percentage of dose excreted in 24 hours after last dose.
____________________________________________________________________________________________________________
The large volume of distribution and high clearance from blood of amphotericin B
after the administration of FUNGIZONE probably reflect uptake by tissues. The
long terminal elimination half-life probably reflects a slow redistribution from
tissues. Although amphotericin B is excreted slowly, there is little
accumulation in the blood after repeated dosing. AUC of amphotericin B increased
approximately 34+ACU- from day 1 after the administration of FUNGIZONE 5 mg/kg/day
for 7 days. The effect of gender or ethnicity on the pharmacokinetics of
FUNGIZONE has not been studied.
Tissue concentrations of amphotericin B have been obtained at autopsy from one
heart transplant patient who received three doses of FUNGIZONE at 5.3
mg/kg/day:
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CONCENTRATION IN HUMAN TISSUES
-----------------------------------------------------------------------------------------------------------------------------------
AMPHOTERICIN B
ORGAN TISSUE CONCENTRATION (MCGM/G)
-----------------------------------------------------------------------------------------------------------------------------------
Spleen 290
Lung 222
Liver 196
Lymph Node 7.6
Kidney 6.9
Heart 5
Brain 1.6
------------------------------------------------------------------------------------------------------------------------------------
This pattern of distribution is consistent with that observed in preclinical
studies in dogs in which greatest concentrations of amphotericin B after
FUNGIZONE administration were observed in the liver, spleen, and lung+ADs- however,
the relationship of tissue concentrations of amphotericin B to its biological
activity when administered as FUNGIZONE is unknown.
SPECIAL POPULATIONS
Hepatic Impairment: The effect of hepatic impairment on the disposition of
FUNGIZONE is not known.
Renal Impairment: The effect of renal impairment on the disposition of
FUNGIZONE is not known. The effect of dialysis on the elimination of FUNGIZONE
has not been studied+ADs- however, amphotericin B is not removed by hemodialysis
when administered as amphotericin B desoxycholate.
Pediatric And Elderly Patients: The pharmacokinetics and pharmacodynamics of
pediatric patients (+ADw-/+AD0-16 years of age) and elderly patients (+AD4-/+AD0-65 years of
age) have not been studied.
INDICATIONS AND USAGE:
FUNGIZONE is indicated for the treatment of invasive fungal infections in
patients who are refractory to or intolerant of conventional amphotericin B
therapy. This is based on open- label treatment of patients judged by their
physicians to be intolerant to or failing conventional amphotericin B therapy
(See DESCRIPTION OF CLINICAL STUDIES).
DESCRIPTION OF CLINICAL STUDIES
FUNGAL INFECTIONS
Data from 473 patients were pooled from three open-label studies in which
FUNGIZONE was provided for the treatment of patients with invasive fungal
infections who were judged by their physicians to be refractory to or intolerant
of conventional amphotericin B, or who had preexisting nephrotoxicity. Results
of these studies demonstrated effectiveness of FUNGIZONE in the treatment of
invasive fungal infections as a second line therapy.
Patients were defined by their individual physician as being refractory to or
failing conventional amphotericin B therapy based on overall clinical judgement
after receiving a minimum total dose of 500 mg of amphotericin B. Nephrotoxicity
was defined as a serum creatinine that had increased to +AD4-2.5 mg/dL in adults and
+AD4-1.5 mg/dL in pediatric patients, or a creatinine clearance of +ADw-25 mL/min while
receiving conventional amphotericin B therapy.
Of the 473 patients, four were enrolled more than once+ADs- each enrollment
contributed separately to the denominator. The median age was 39 years (range of
+ADw-1 to 93 years)+ADs- 307 patients were male and 166 female. Patients were Caucasian
(381, 81+ACU-), African-American (41, 9+ACU-), Hispanic (27, 6+ACU-), Asian (10, 2+ACU-), and
various other races (14, 3+ACU-). The median baseline neutrophil count was 4,000
PMN/MM(cubed)+ADs- of these, 101 (21+ACU-) had a baseline neutrophil count
+ADw-500/MM(cubed).
Two-hundred eighty-two patients of the 473 patients were considered evaluable
for response to therapy+ADs- the other 191 patients were excluded on the basis of
unconfirmed diagnosis, confounding factors, concomitant systemic antifungal
therapy, or receiving 4 doses or less of FUNGIZONE. For evaluable patients, the
following fungal infections were treated (n+AD0-282): aspergillosis (n+AD0-111),
candidiasis (n+AD0-87), zygomycosis (n+AD0-25), cryptococcosis (n+AD0-16), and fusariosis
(n+AD0-11). There were fewer than 10 evaluable patients for each of several other
fungal species treated.
For each type of fungal infection listed above there were some patients
successfully treated. However, in the absence of controlled studies it is
unknown how response would have compared to either continuing conventional
amphotericin B therapy or the use of alternative antifungal agents.
RENAL FUNCTION: Patients with aspergillosis who initiated treatment with
FUNGIZONE when serum creatinine was above 2.5 mg/dL experienced a decline in
serum creatinine during treatment (Figure 1). Serum creatinine levels were also
lower during treatment with FUNGIZONE when compared to the serum creatinine
levels of patients treated with conventional amphotericin B in a retrospective
historical control study. Meaningful statistical testing of the differences
between these two groups is precluded since these data were obtained from two
separate studies.
In a randomized study of FUNGIZONE for the treatment of invasive candidiasis in
patients with normal baseline renal function, the incidence of nephrotoxicity
was significantly less for FUNGIZONE at a dose of 5 mg/kg/day than for
conventional amphotericin B at a dose of 0.7 mg/kg/day.
Despite generally less nephrotoxicity of FUNGIZONE observed at a dose of 5
mg/kg/day compared with conventional amphotericin B therapy at a dose range of
0.6-1 mg/kg/day, dose-limiting renal toxicity may still be observed with
FUNGIZONE. Renal toxicity of doses greater than 5 mg/kg/day of FUNGIZONE has
not been formally studied.
CONTRAINDICATIONS:
FUNGIZONE is contraindicated in patients who have shown hypersensitivity to
amphotericin B or any other component in the formulation.
WARNINGS:
Anaphylaxis has been reported with amphotericin B desoxycholate and other
amphotericin B-containing drugs. Anaphylaxis has been reported with FUNGIZONE
with an incidence rate of +ADw-0.1+ACU-. If severe respiratory distress occurs, the
infusion should be immediately discontinued. The patient should not receive
further infusions of FUNGIZONE.
PRECAUTIONS:
GENERAL: As with any amphotericin B-containing product, during the initial
dosing of FUNGIZONE, the drug should be administered under close clinical
observation by medically trained personnel.
Acute reactions including fever and chills may occur 1 to 2 hours after starting
an intravenous infusion of FUNGIZONE. These reactions are usually more common
with the first few doses of FUNGIZONE and generally diminish with subsequent
doses. Infusion has been rarely associated with hypotension, bronchospasm,
arrhythmias, and shock.
LABORATORY TESTS: Serum creatinine should be monitored frequently during
FUNGIZONE therapy (see ADVERSE REACTIONS). It is also advisable to regularly
monitor liver function, serum electrolytes (particularly magnesium and
potassium), and complete blood counts.
DRUG INTERACTIONS: No formal clinical studies of drug interactions have been
conducted with FUNGIZONE. However, when administered concomitantly, the
following drugs are known to interact with amphotericin B+ADs- therefore, the
following drugs may interact with FUNGIZONE:
Antineoplastic Agents: Concurrent use of antineoplastic agents and amphotericin
B may enhance the potential for renal toxicity, bronchospasm, and hypotension.
Antineoplastic agents should be given concomitantly with FUNGIZONE with great
caution.
Corticosteroids And Corticotropin (ACTH): Concurrent use of corticosteroids and
corticotropin (ACTH) with amphotericin B may potentiate hypokalemia which could
predispose the patient to cardiac dysfunction if used concomitantly with
FUNGIZONE, serum electrolytes and cardiac function should be closely monitored.
Cyclosporin A: Data from a prospective study of prophylactic FUNGIZONE in 22
patients undergoing bone marrow transplantation suggested that concurrent
initiation of cyclosporin A and FUNGIZONE within several days of bone marrow
ablation may be associated with increased nephrotoxicity.
Digitalis Glycosides: Concurrent use of amphotericin B may induce hypokalemia
and may potentiate digitalis toxicity. When administered concomitantly with
FUNGIZONE, serum potassium levels should be closely monitored.
Flucytosine: Concurrent use of flucytosine with amphotericin B-containing
preparations may increase the toxicity of flucytosine by possibly increasing its
cellular uptake and/or impairing its renal excretion. Flucytosine should be
given concomitantly with FUNGIZONE with caution.
Imidazoles (e.g., Ketoconazole, Miconazole, Clotrimazole, Fluconazole, Etc):
Antagonism between amphotericin B and imidazole derivatives such as miconazole
and ketoconazole, which inhibit ergosterol synthesis, has been reported in both
In Vitro and In Vivo animal studies. The clinical significance of these findings
has not been determined.
Leukocyte Transfusions: Acute pulmonary toxicity has been reported in patients
receiving intravenous amphotericin B and leukocyte transfusions. Leukocyte
transfusions and FUNGIZONE should not be given concurrently.
Other Nephrotoxic Medications: Concurrent use of amphotericin B and agents such
as aminoglycosides and pentamidine may enhance the potential for drug-induced
renal toxicity. Aminoglycosides and pentamidine should be used concomitantly
with FUNGIZONE only with great caution. 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 with FUNGIZONE, serum potassium
levels should be closely monitored.
Zidovudine: Increased myelotoxicity and nephrotoxicity were observed in dogs
when either FUNGIZONE (at doses of 0.16 or 0.5 times the recommended human
dose) or amphotericin B desoxycholate (at 0.5 times the recommended human dose)
were administered concomitantly with zidovudine for 30 days. If zidovudine is
used concomitantly with FUNGIZONE, renal hematologic function should be closely
monitored.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY: No long-term studies
in animals have been performed to evaluate the carcinogenic potential of
FUNGIZONE. The following In Vitro (with and without metabolic activation) and
In Vivo studies to assess FUNGIZONE for mutagenic potential were conducted:
bacterial reverse mutation assay, mouse lymphoma forward mutation assay,
chromosomal aberration assay in CHO cells, and In Vivo mouse micronucleus assay.
FUNGIZONE was found to be without mutagenic effects in all assay systems.
Studies demonstrated that FUNGIZONE had no impact on fertility in male and
female rats at doses up to 0.32 times the recommended human dose (based on body
surface area considerations).
PREGNANCY: There are no reports of pregnant women having been treated with
FUNGIZONE. Teratogenic Effects. Pregnancy Category B: Reproductive studies in
rats and rabbits at doses of FUNGIZONE up to 0.64 times the human dose revealed
no harm to the fetus. Because animal reproductive studies are not always
predictive of human response, and adequate and well-controlled studies have not
been conducted in pregnant women, FUNGIZONE should be used during pregnancy
only after taking into account the importance of the drug to the mother.
NURSING MOTHERS: It is not known whether FUNGIZONE is excreted in human milk.
Because many drugs are excreted in human milk, and because of the potential for
serious adverse reactions in breast-fed infants from FUNGIZONE, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
PEDIATRIC USE: One hundred eleven children (2 were enrolled twice and counted as
separate patients), age 16 years and under, of whom 11 were less than 1 year,
have been treated with FUNGIZONE at 5 mg/kg/day in two open-label studies and
one small, prospective, single-arm study. In one single-center study, 5 children
with hepatosplenic candidiasis were effectively treated with 2.5 mg/kg/day of
FUNGIZONE. No serious unexpected adverse events have been reported.
GERIATRIC USE: Forty-nine elderly patients, age 65 years or over, have been
treated with FUNGIZONE at 5 mg/kg/day in two open-label studies and one small,
prospective, single-arm study. No serious unexpected adverse events have been
reported.
DRUG INTERACTIONS:
DRUG INTERACTIONS: No formal clinical studies of drug interactions have been
conducted with FUNGIZONE. However, when administered concomitantly, the
following drugs are known to interact with amphotericin B+ADs- therefore, the
following drugs may interact with FUNGIZONE:
Antineoplastic Agents: Concurrent use of antineoplastic agents and amphotericin
B may enhance the potential for renal toxicity, bronchospasm, and hypotension.
Antineoplastic agents should be given concomitantly with FUNGIZONE with great
caution.
Corticosteroids And Corticotropin (ACTH): Concurrent use of corticosteroids and
corticotropin (ACTH) with amphotericin B may potentiate hypokalemia which could
predispose the patient to cardiac dysfunction if used concomitantly with
FUNGIZONE, serum electrolytes and cardiac function should be closely monitored.
Cyclosporin A: Data from a prospective study of prophylactic FUNGIZONE in 22
patients undergoing bone marrow transplantation suggested that concurrent
initiation of cyclosporin A and FUNGIZONE within several days of bone marrow
ablation may be associated with increased nephrotoxicity.
Digitalis Glycosides: Concurrent use of amphotericin B may induce hypokalemia
and may potentiate digitalis toxicity. When administered concomitantly with
FUNGIZONE, serum potassium levels should be closely monitored.
Flucytosine: Concurrent use of flucytosine with amphotericin B-containing
preparations may increase the toxicity of flucytosine by possibly increasing its
cellular uptake and/or impairing its renal excretion. Flucytosine should be
given concomitantly with FUNGIZONE with caution.
Imidazoles (e.g., Ketoconazole, Miconazole, Clotrimazole, Fluconazole, Etc):
Antagonism between amphotericin B and imidazole derivatives such as miconazole
and ketoconazole, which inhibit ergosterol synthesis, has been reported in both
In Vitro and In Vivo animal studies. The clinical significance of these findings
has not been determined.
Leukocyte Transfusions: Acute pulmonary toxicity has been reported in patients
receiving intravenous amphotericin B and leukocyte transfusions. Leukocyte
transfusions and FUNGIZONE should not be given concurrently.
Other Nephrotoxic Medications: Concurrent use of amphotericin B and agents such
as aminoglycosides and pentamidine may enhance the potential for drug-induced
renal toxicity. Aminoglycosides and pentamidine should be used concomitantly
with FUNGIZONE only with great caution. 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 with FUNGIZONE, serum potassium
levels should be closely monitored.
Zidovudine: Increased myelotoxicity and nephrotoxicity were observed in dogs
when either FUNGIZONE (at doses of 0.16 or 0.5 times the recommended human
dose) or amphotericin B desoxycholate (at 0.5 times the recommended human dose)
were administered concomitantly with zidovudine for 30 days. If zidovudine is
used concomitantly with FUNGIZONE, renal hematologic function should be closely
monitored.
(See Also PRECAUTIONS).
ADVERSE REACTIONS:
The total safety data base is composed of 921 patients treated with FUNGIZONE
(5 patients were enrolled twice and counted as separate patients), of whom 775
were treated with 5 mg/kg/day. Of these 775 patients, 194 patients were treated
in four comparative studies+ADs- 25 were treated in open-label, non-comparative
studies+ADs- and 556 patients were treated in an open-label, emergency-use program.
Most had underlying hematologic neoplasms, and many were receiving multiple
concomitant medications. Of the 556 patients treated with FUNGIZONE, 9+ACU-
discontinued treatment due to adverse events regardless of presumed relationship
to study drug.
In general, the adverse events most commonly reported with FUNGIZONE were
transient chills and/or fever during infusion of the drug.
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ADVERSE EVENTSa WITH AN INCIDENCE OF +AD4-/+AD0-3+ACU- (N+AD0-556)
-----------------------------------------------------------------------------------------------------------------------------------------------------
PERCENTAGE (+ACU-)
ADVERSE EVENT OF PATIENTS
------------------------------------------------------------------------------------------------------------------------------------------------------
Chills 18
Fever 14
Increased Serum Creatinine 11
Multiple Organ Failure 11
Nausea 9
Hypotension 8
Respiratory Failure 8
Vomiting 8
Dyspnea 7
Sepsis 7
Diarrhea 6
Headache 6
Heart Arrest 6
Hypertension 5
Hypokalemia 5
Infection 5
Kidney Failure 5
Pain 5
Thrombocytopenia 5
Abdominal Pain 4
Anemia 4
Bilirubinemia 4
Gastrointestinal Hemorrhage 4
Leukopenia 4
Rash 4
Respiratory Disorder 4
Chest Pain 3
Nausea and Vomiting 3
------------------------------------------------------------------------------------------------------------------------------
a The causal association between these adverse events and FUNGIZONE is
uncertain.
-------------------------------------------------------------------------------------------------------------------------------
The following adverse events have also been reported in patients using
FUNGIZONE in open- label, uncontrolled clinical studies. The causal association
between these adverse events and FUNGIZONE is uncertain.
Body As A Whole: malaise, weight loss, deafness, injection site reaction
including inflammation
Allergic: bronchospasm, wheezing, asthma, anaphylactoid and other allergic
reactions
Cardiopulmonary: cardiac failure, pulmonary edema, shock, myocardial infarction,
hemoptysis, tachypnea, thrombophlebitis, pulmonary embolus, cardiomyopathy,
pleural effusion, arrhythmias including ventricular fibrillation
Dermatological: maculopapular rash, pruritus, exfoliative dermatitis, erythema
multiforme
Gastrointestinal: acute liver failure, hepatitis, jaundice, melena, anorexia,
dyspepsia, cramping, epigastric pain, veno-occlusive liver disease, diarrhea,
hepatomegaly, cholangitis, cholecystitis
Hematologic: coagulation defects, leukocytosis, blood dyscrasias including
eosinophilia
Musculoskeletal: myasthenia, including bone, muscle, and joint pains
Neurologic: convulsions, tinnitus, visual impairment, hearing loss, peripheral
neuropathy, transient vertigo, diplopia, encephalopathy, cerebral vascular
accident, extrapyramidal syndrome and other neurologic symptoms
Urogenital: oliguria, decreased renal function, anuria, renal tubular acidosis,
impotence, dysuria
Serum Electrolyte Abnormalities: hypomagnesemia, hyperkalemia, hypocalcemia,
hypercalcemia
Liver Function Test Abnormalities: increased AST, ALT, alkaline phosphatase, LDH
Renal Function Test Abnormalities: increased BUN
Other Test Abnormalities: acidosis, hyperamylasemia, hypoglycemia,
hyperglycemia, hyperuricemia, hypophosphatemia
OVERDOSAGE:
Amphotericin B desoxycholate overdose has been reported to result in cardio-
respiratory arrest. Fifteen patients have been reported to have received one or
more doses of FUNGIZONE between 7-13 mg/kg. None of these patients had a
serious acute reaction to FUNGIZONE. If an overdose is suspected, discontinue
therapy, monitor the patient's clinical status, and administer supportive
therapy as required. FUNGIZONE is not hemodialyzable.
DOSAGE AND ADMINISTRATION:
The recommended daily dosage for adults and children is 5 mg/kg given as a
single infusion. FUNGIZONE should be administered by intravenous infusion at a
rate of 2.5 mg/kg/h. If the infusion time exceeds 2 hours, mix the contents by
shaking the infusion bag every 2 hours.
Renal toxicity of FUNGIZONE, as measured by serum creatinine levels, has been
shown to be dose dependent. Decisions about dose adjustments should be made only
after taking into account the overall clinical condition of the patient.
PREPARATION OF ADMIXTURE FOR INFUSION: Shake the vial gently until there is no
evidence of any yellow sediment at the bottom. Withdraw the appropriate dose of
FUNGIZONE from the required number of vials into one or more sterile 20 mL
syringes using an 18-gauge needle. Remove the needle from each syringe filled
with FUNGIZONE and replace with the 5-micron filter needle supplied with each
vial. Each filter needle may be used to filter the contents of up to four vials.
Insert the filter needle of the syringe into an IV bag containing 5+ACU- Dextrose
Injection USP, and empty the contents of the syringe into the bag. The final
infusion concentration should be 1 mg/mL. For pediatric patients and patients
with cardiovascular disease the drug may be diluted with 5+ACU- Dextrose Injection
to a final infusion concentration of 2 mg/mL. Before infusion, shake the bag
until the contents are thoroughly mixed. Do not use the admixture after dilution
with 5+ACU- Dextrose Injection if there is any evidence of foreign matter. Vials are
for single use. Unused material should be discarded. Aseptic technique must be
strictly observed throughout handling of FUNGIZONE, since no bacteriostatic
agent or preservative is present.
DO NOT DILUTE WITH SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR ELECTROLYTES as
the compatibility of FUNGIZONE with these materials has not been established.
An existing intravenous line should be flushed with 5+ACU- Dextrose Injection before
infusion of FUNGIZONE, or a separate infusion line should be used. DO NOT USE
AN IN-LINE FILTER.
The diluted ready-for-use admixture is stable for up to 48 hours at 2 deg to 8
deg C (36 deg to 46 deg F) and an additional 6 hours at room temperature.
CLINICAL STUDIES:
DESCRIPTION OF CLINICAL STUDIES
FUNGAL INFECTIONS
Data from 473 patients were pooled from three open-label studies in which
FUNGIZONE was provided for the treatment of patients with invasive fungal
infections who were judged by their physicians to be refractory to or intolerant
of conventional amphotericin B, or who had preexisting nephrotoxicity. Results
of these studies demonstrated effectiveness of FUNGIZONE in the treatment of
invasive fungal infections as a second line therapy.
Patients were defined by their individual physician as being refractory to or
failing conventional amphotericin B therapy based on overall clinical judgement
after receiving a minimum total dose of 500 mg of amphotericin B. Nephrotoxicity
was defined as a serum creatinine that had increased to +AD4-2.5 mg/dL in adults and
+AD4-1.5 mg/dL in pediatric patients, or a creatinine clearance of +ADw-25 mL/min while
receiving conventional amphotericin B therapy.
Of the 473 patients, four were enrolled more than once+ADs- each enrollment
contributed separately to the denominator. The median age was 39 years (range of
+ADw-1 to 93 years)+ADs- 307 patients were male and 166 female. Patients were Caucasian
(381, 81+ACU-), African-American (41, 9+ACU-), Hispanic (27, 6+ACU-), Asian (10, 2+ACU-), and
various other races (14, 3+ACU-). The median baseline neutrophil count was 4,000
PMN/MM(cubed)+ADs- of these, 101 (21+ACU-) had a baseline neutrophil count
+ADw-500/MM(cubed).
Two-hundred eighty-two patients of the 473 patients were considered evaluable
for response to therapy+ADs- the other 191 patients were excluded on the basis of
unconfirmed diagnosis, confounding factors, concomitant systemic antifungal
therapy, or receiving 4 doses or less of FUNGIZONE. For evaluable patients, the
following fungal infections were treated (n+AD0-282): aspergillosis (n+AD0-111),
candidiasis (n+AD0-87), zygomycosis (n+AD0-25), cryptococcosis (n+AD0-16), and fusariosis
(n+AD0-11). There were fewer than 10 evaluable patients for each of several other
fungal species treated.
For each type of fungal infection listed above there were some patients
successfully treated. However, in the absence of controlled studies it is
unknown how response would have compared to either continuing conventional
amphotericin B therapy or the use of alternative antifungal agents.
RENAL FUNCTION: Patients with aspergillosis who initiated treatment with
FUNGIZONE when serum creatinine was above 2.5 mg/dL experienced a decline in
serum creatinine during treatment (Figure 1). Serum creatinine levels were also
lower during treatment with FUNGIZONE when compared to the serum creatinine
levels of patients treated with conventional amphotericin B in a retrospective
historical control study. Meaningful statistical testing of the differences
between these two groups is precluded since these data were obtained from two
separate studies.
In a randomized study of FUNGIZONE for the treatment of invasive candidiasis in
patients with normal baseline renal function, the incidence of nephrotoxicity
was significantly less for FUNGIZONE at a dose of 5 mg/kg/day than for
conventional amphotericin B at a dose of 0.7 mg/kg/day.
Despite generally less nephrotoxicity of FUNGIZONE observed at a dose of 5
mg/kg/day compared with conventional amphotericin B therapy at a dose range of
0.6-1 mg/kg/day, dose-limiting renal toxicity may still be observed with
FUNGIZONE. Renal toxicity of doses greater than 5 mg/kg/day of FUNGIZONE has
not been formally studied.
(See Also INDICATIONS AND USAGE section.)