A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Cancidas Warnings, Precautions, Pregnancy, Nursing, Abuse - Caspofungin acetate
Cancidas Warnings, Precautions, Pregnancy, Nursing, Abuse - Caspofungin acetate
WARNINGS
Concomitant use of CANCIDAS with cyclosporine is not recommended
unless the potential benefit outweighs the potential risk to the patient.
In one clinical study, 3 of 4 healthy subjects who received CANCIDAS 70 mg on
Days 1 through 10, and also received two 3 mg/kg doses of cyclosporine 12 hours
apart on Day 10, developed transient elevations of alanine transaminase (ALT)
on Day 11 that were 2 to 3 times the upper limit of normal (ULN). In a separate
panel of subjects in the same study, 2 of 8 who received CANCIDAS 35 mg daily
for 3 days and cyclosporine (two 3 mg/kg doses administered 12 hours apart)
on Day 1 had small increases in ALT (slightly above the ULN) on Day 2. In both
groups, elevations in aspartate transaminase (AST) paralleled ALT elevations,
but were of lesser magnitude (see ADVERSE REACTIONS,
Laboratory Abnormalities.) Hence, concomitant use of CANCIDAS
with cyclosporine is not recommended until multiple-dose use in patients is
studied.
PRECAUTIONS
General
The efficacy of a 70-mg dose regimen in patients with invasive aspergillosis who are not
clinically responding to the 50 mg daily dose is not known. Limited safety data
suggest that an increase in dose to 70 mg daily is well tolerated. For candidiasis, see Clinical Studies. The safety
and efficacy of doses above 70 mg have not been adequately studied.
The safety information on treatment durations longer than 2
weeks is limited, however, available data suggest that CANCIDAS continues to
be well tolerated with longer courses of therapy (74 patients received from
15 to 60 days of therapy; 14 patients received from 61 to 162 days of therapy).
Drug Interactions
Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome
P450 (CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other
drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450
enzymes.
Clinical studies in healthy volunteers show that the pharmacokinetics of CANCIDAS are not altered by
itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. CANCIDAS has no effect on the
pharmacokinetics of itraconazole, amphotericin B, or the active metabolite of mycophenolate.
CANCIDAS reduced the blood AUC0-12 of tacrolimus (FK-506, Prograf®2) by approximately 20%, peak
blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy subjects
when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS
70 mg daily, as compared to results from a control period in which tacrolimus was administered alone. For
patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate
tacrolimus dosage adjustments are recommended.
In two clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of
caspofungin by approximately 35%. CANCIDAS did not increase the plasma levels of cyclosporine. There
were transient increases in liver ALT and AST when CANCIDAS and cyclosporine were co-administered
(see WARNINGS and ADVERSE REACTIONS, REACTIONS).
A drug-drug interaction study with rifampin in healthy volunteers has shown a 30% decrease in
caspofungin trough concentrations. Patients on rifampin should receive 70 mg of CANCIDAS daily. In
addition, results from regression analyses of patient pharmacokinetic data suggest that coadministration
ofco-administration of other inducers of drug clearance (efavirenz, phenytoin, dexamethasone, or carbamazepine) with CANCIDAS may result in
clinically meaningful reductions in caspofungin concentrations. It is not known which drug clearance
mechanism involved in caspofungin disposition may be inducible. When CANCIDAS is co-administered with inducers of drug clearance, such as efavirenz,
nevirapine, phenytoin, dexamethasone, or carbamazepine, use of a daily dose of
70 mg of CANCIDAS should be considered.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of
caspofungin.
Caspofungin did not show evidence of mutagenic or genotoxic potential when evaluated in the
following in vitro assays: bacterial (Ames) and mammalian cell (V79 Chinese hamster lung fibroblasts)
mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand break test, and the chromosome
aberration assay in Chinese hamster ovary cells. Caspofungin was not genotoxic when assessed in the
mouse bone marrow chromosomal test at doses up to 12.5 mg/kg (equivalent to a human dose of
1 mg/kg based on body surface area comparisons), administered intravenously.
Fertility and reproductive performance were not affected by the intravenous administration of
caspofungin to rats at doses up to 5 mg/kg. At 5 mg/kg exposures were similar to those seen in patients
treated with the 70-mg dose.
Pregnancy
Pregnancy Category C. CANCIDAS was shown to be embryotoxic in rats and rabbits. Findings
included incomplete ossification of the skull and torso and an increased incidence of cervical rib in rats. An
increased incidence of incomplete ossifications of the talus/calcaneus was seen in rabbits. Caspofungin
also produced increases in resorptions in rats and rabbits and periimplantation losses in rats. These
findings were observed at doses which produced exposures similar to those seen in patients treated with
a 70-mg dose. Caspofungin crossed the placental barrier in rats and rabbits and was detected in the
plasma of fetuses of pregnant animals dosed with CANCIDAS. There are no adequate and well-controlled
studies in pregnant women. CANCIDAS should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Nursing Mothers
Caspofungin was found in the milk of lactating, drug-treated rats. It is not known whether caspofungin
is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised
when caspofungin is administered to a nursing woman.
Patients with Hepatic Insufficiency
Patients with mild hepatic insufficiency (Child-Pugh score 5 to 6) do not need a dosage adjustment. For
patients with esophageal and/or oropharyngeal candidiasis and moderate hepatic insufficiency
(Child-Pugh score 7 to 9), CANCIDAS 35 mg daily is recommended. For patients with invasive
aspergillosis and moderate hepatic insufficiency, after the initial 70-mg loading dose, CANCIDAS 35 mg
daily is recommended. There is no clinical experience in patients with severe hepatic insufficiency
(Child-Pugh score >9).
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of CANCIDAS did not include sufficient numbers of patients aged 65 and over to
determine whether they respond differently from younger patients. Although the number of elderly patients
was not large enough for a statistical analysis, no overall differences in safety or efficacy were observed
between these and younger patients. Plasma concentrations of caspofungin in healthy older men and
women (≥65 years of age) were increased slightly (approximately 28% in AUC) compared to young
healthy men. No dose adjustment is recommended for the elderly; however, greater sensitivity of some
older individuals cannot be ruled out.
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