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
Sporanox Warnings, Precautions, Pregnancy, Nursing, Abuse - Itraconazole Capsules
Sporanox Warnings, Precautions, Pregnancy, Nursing, Abuse - Itraconazole Capsules
WARNINGS
In U.S. clinical trials
prior to marketing, there have been three cases of reversible
idiosyncratic hepatitis
reported among more than 2500 patients taking Sporanox (itraconazole
capsules). One patient
outside the U.S. developed fulminant hepatitis
and died during Sporanox administration. Since this patient was
on multiple medications,
the casual association
with Sporanox is uncertain. If clinical
signs and symptoms consistent with liver
disease develop that may be attributable to itraconazole, Sporanox
should be discontinued.
Prior to U.S. marketing, there have been three cases of life-threatening
cardiac dysrhythmias and one death
reported in patients receiving terfenadine and itraconazole. (See
BOXED WARNING), CONTRAINDICATIONS,
and PRECAUTIONS
sections.
Coadministration of astemizole with Sporanox is contraindicated.
(See BOXED WARNING, CONTRAINDICATIONS,
and PRECAUTIONS
.)
Concomitant administration
of oral ketoconazole with
cisapride has resulted
in markedly elevated cisapride
plasma concentrations,
prolonged QT intervals, and has rarely been associated with ventricular
arrhythmias and torsades de pointes. Due to potent
in vitro inhibition
of the hepatic enzyme
system mainly responsible for the metabolism
of cisapride (cytochrome
P450 3A4), itraconazole is also expected to markedly raise cisapride
plasma concentrations; therefore, concomitant
use of cisapride with
Sporanox is contraindicated. (See BOXED
WARNING), CONTRAINDICATIONS,
and PRECAUTIONS
sections.
PRECAUTIONS
General
Hepatic enzyme test
values should be monitored in patients with preexisting hepatic
function abnormalities.
Hepatic enzyme test
values should be monitored periodically in all patients receiving
continuous treatment
for more than one month or at any time
a patient develops signs or symptoms suggestive
of liver dysfunction.
Sporanox (itraconazole capsules) should be administered after a
full meal. See CLINICAL PHARMACOLOGY,
Pharmacokinetics and Metabolism.
Under fasted conditions, itraconazole absorption
was decreased in the presence of decreased gastric
acidity. The absorption
of itraconazole may be decreased with the concomitant
administration
of antacids or gastric acid secretion
suppressors. Studies conducted under fasted conditions demonstrated
that administration
with 8 ounces of a cola beverage resulted in increased absorption
of itraconazole in AIDS
patients with relative or absolute
achlorhydria. This increase relative to the effects of a full meal
is unknown. (See CLINICAL PHARMACOLOGY,
Pharmacokinetics and Metabolism.)
Information for the Patient
Patients should be instructed to take
Sporanox with a full meal.
Patients should be instructed to report
any signs and symptoms that may suggest liver
dysfunction so that
the appropriate
laboratory testing
can be done. Such signs and symptoms may include unusual fatigue,
anorexia, nausea and/or vomiting,
jaundice, dark urine
or pale stool.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Itraconazole showed no evidence
of carcinogenicity potential
in mice treated orally for 23 months at dosage
levels up to 80 mg/kg/day [approximately 10x the maximum recommended
human dose
(MRHD)]. Male rats treated with 25 mg/kg/day (3.1 x MRHD) had a
slightly increased incidence
of soft tissue
sarcoma. These sarcomas may have been a consequence
of hypercholesterolemia,
which is a response
of rats, but not dogs or humans, to chronic
itraconazole administration. Female rats treated with 50 mg/kg/day
(6.25x MRHD) had an increased incidence
of squamous cell
carcinoma of the lung
(2/50) as compared to the untreated group. Although the occurrence
of squamous cell carcinoma
in the lung is extremely
uncommon in untreated rats, the increase in this study was not statistically
significant.
Itraconazole produced no
mutagenic effects when assayed in appropriate bacterial, non-mammalian
and mammalian test systems.
Itraconazole did not affect
the fertility of male
or female rats treated
orally with dosage levels
of up to 40 mg/kg/day (5x MRHD) even though parental toxicity was
present at this dosage
level. More severe signs of parental toxicity, including death,
were present in the
next higher dosage level,
160 mg/kg/day (20x MRHD).
Pregnancy
Pregnancy Category C: Teratogenic Effects: Itraconazole
was found to cause a dose-related
increase in maternal
toxicity, embryotoxicity and teratogenicity in rats at dosage
levels at approximately 40-160 mg/kg/day (5-20x MRHD) and in mice
at dosage levels of approximately
80 mg/kg/day (10x MRHD). In
rats, the teratogenicity consisted of major skeletal defects; in
mice it consisted of encephaloceles and/or macroglossia.
There are no studies in
pregnant women. Sporanox
should be used for the treatment
of systemic fungal
infections in pregnancy
only if the benefit outweighs the potential
risk. Sporanox should not be administered for the treatment of onychomycosis
to pregnant patients
or to women contemplating pregnancy. Sporanox should not be administered
to women of child-bearing potential for the treatment
of onychomycosis
unless they are taking effective measures to prevent pregnancy
and the patient begins
therapy on the second
or third day of the next normal
menstrual period. Effective contraception should be continued throughout
Sporanox therapy and
for 2 months following treatment.
Nursing Mothers
Itraconazole is excreted in human
milk; therefore, Sporanox should not be administered to nursing
women.
Pediatric Use
The efficacy and safety
of Sporanox have not been established in pediatric
patients. No pharmacokinetic data are available in children. A small
number of patients from
age 3 to 16 years have been
treated with 100 mg/day of itraconazole for systemic
fungal infections and no
serious unexpected adverse effects have been reported.
In three toxicology
studies using rats, itraconazole induced
bone defects at dosage
levels as low as 20 mg/kg/day (2.5x MRHD). The induced
defects included reduced bone
plate activity, thinning
of the zona compacta of
the large bones and increased bone
fragility. At a dosage
level of 80 mg/kg/day (10x MRHD) over one year or 160 mg/kg/day
(20x MRHD) for six months, itraconazole induced small tooth
pulp with hypocellular
appearance in some
rats.
While no such
bone toxicity
has been reported in adult
patients, the long term
effect of itraconazole
in pediatric patients
is unknown.
HIV-infected Patients
Because hypochlorhydria
has been reported in HIV-infected individuals, the absorption
of itraconazole in these patients may be decreased.
The results from a study in which eight HIV-infected individuals
were treated with zidovudine, 8 ± 0.4 mg/kg/day, showed that
the pharmacokinetics of zidovudine
were not affected during concomitant
administration
of Sporanox, 100 mg b.i.d.
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