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 Side Effects, and Drug Interactions - Itraconazole Capsules
Sporanox Side Effects, and Drug Interactions - Itraconazole Capsules
SIDE EFFECTS
In U.S. clinical trials
prior to marketing, there have been three cases of reversible
idiosyncratic hepatitis
reported among more than 2500 patients. One patient
outside the U.S. developed fulminant
hepatitis and died
during Sporanox (itraconazole capsules) administration. Because
this patient was on
multiple medications,
the causal association
with Sporanox is uncertain. (See WARNINGS.)
Onychomycosis
Adverse events in the following table
(TABLE 4) led to either temporary or permanent
discontinuation of treatment:
TABLE 4
| Body System/Adverse Event |
Incidence (%) (n=112) |
| Elevated Liver Enzymes (>2x normal
range) |
4% |
| Gastrointestinal Disorders |
4% |
| Rash |
3% |
| Hypertension |
2% |
| Orthostatic Hypotension |
1% |
| Headache |
1% |
| Malaise |
1% |
| Myalgia |
1% |
| Vasculitis |
1% |
| Vertigo |
1% |
Systemic Fungal Infections
Adverse experience
data in the following table (TABLE 5) are derived from 602 patients
treated for systemic
fungal disease in U.S. clinical
trials, who were immunocompromised
or receiving multiple concomitant
medications. Of these patients, treatment
was discontinued in 10.5% of patients due to adverse events. The
median duration
before discontinuation of therapy
was 81 days, with a range
of 2-776 days. The table (TABLE 5) lists adverse events reported
by at least 1% of patients.
TABLE 5
|
(Incidence ³1%)
|
|
Body System/Adverse Event
|
Incidence (%)
|
|
Gastrointestinal Disorders
|
|
Nausea
|
10.6 |
|
Vomiting
|
5.1 |
|
Diarrhea
|
3.3 |
|
Abdominal Pain
|
1.5 |
|
Anorexia
|
1.2 |
|
Body as a Whole
|
|
Edema
|
3.5 |
|
Fatigue
|
2.8 |
|
Fever
|
2.5 |
|
Malaise
|
1.2 |
|
Skin and Appendages
|
|
Rash
|
8.6* |
|
Pruritus
|
2.5 |
|
Central and Peripheral Nervous System
|
|
Headache
|
3.8 |
|
Dizziness
|
1.7 |
|
Psychiatric Disorders
|
|
Libido decreased
|
1.2 |
|
Somnolence
|
1.2 |
|
Cardiovascular Disorders
|
|
Hypertension
|
3.2 |
|
Metabolic and Nutritional Disorders
|
|
Hypokalemia
|
2.0 |
|
Urinary System Disorders
|
|
Albuminuria
|
1.2 |
|
Liver and Biliary System Disorders
|
|
Hepatic function
abnormal
|
2.7 |
|
Reproductive Disorders, Male Impotence
|
1.2 |
|
* Rash tends to occur more frequently in immunocompromised
patients receiving immunosuppressive medications.
|
Adverse events infrequently reported in all studies indicated:
constipation, gastritis, depression,
insomnia, tinnitus,
menstrual disorder, adrenal insufficiency, gynecomastia
and male breast
pain.
In worldwide postmarketing experience
with Sporanox, allergic
reactions including rash,
pruritus, urticaria,
angioedema and in
rare instances, anaphylaxis and Stevens-Johnson syndrome,
have been reported. Marketing experiences have also included reports
of elevated liver enzymes
and rare hepatitis. Although the causal association
with Sporanox is uncertain, rare hypertriglyceridemia
and isolated cases of neuropathy
have also been reported.
DRUG INTERACTIONS
Both itraconazole and its major metabolite,
hydroxyitraconazole, are inhibitors of the cytochrome
P450 3A4 enzyme system.
Coadministration of Sporanox and drugs primarily metabolized by
the cytochrome P450
3A4 enzyme system may result in increased plasma
concentrations of the drugs that could increase or prolong both
therapeutic and
adverse effects. Therefore, unless otherwise specified, appropriate
dosage adjustments may
be necessary.
Coadministration of terfenadine with Sporanox has led to elevated
plasma concentrations of terfenadine, resulting in rare instances
of life- threatening cardiac dysrhythmias and one death. See BOXED
WARNING, CONTRAINDICATIONS,
and WARNINGS sections.
Another oral azole antifungal,
ketoconazole, inhibits the metabolism of astemizole, resulting in
elevated plasma concentrations
of astemizole and its active metabolite
desmethylastermizole which may prolong QT intervals. In vitro
data suggest that itraconazole, when compared to ketoconazole, has
a less pronounced effect
on the biotransformation
system responsible for
the metabolism of
astemizole. Based on the chemical
resemblance of itraconazole and ketoconazole, coadministration
of astemizole with itraconazole is contraindicated. See BOXED
WARNING, CONTRAINDICATIONS,
and WARNINGS sections.
Human pharmacokinetics
data indicate that oral
ketoconazole potently inhibits the metabolism
of cisapride resulting
in an eight-fold increase in the mean
AUC of cisapride. Data suggest
that coadministration
of oral ketoconazole and cisapride
can result in prolongation of the QT interval on the ECG. In
vitro data suggest that itraconazole also markedly inhibits
the biotransformation
system mainly responsible
for the metabolism of cisapride; therefore concomitant
administration
of Sporanox with cisapride is contraindicated. See BOXED
WARNING, CONTRAINDICATIONS,
and WARNINGS sections.
Coadministration of Sporanox with oral
midazolam or triazolam has resulted in elevated plasma
concentrations of the latter two drugs. This may potentiate and
prolong hypnotic and
sedative effects. These
agents should not be used in patients treated with Sporanox. If
midazolam is administered parenterally, special precaution
is required since the sedative
effect may be prolonged.
(See CONTRAINDICATIONS.)
Coadministration of Sporanox and cyclosporine, tacrolimus or digoxin
has led to increased plasma
concentrations of the latter three drugs. Cyclosporine, tacrolimus
and digoxin concentrations
should be monitored at the initiation of Sporanox therapy
and frequently thereafter, and the dose
of these three drug products adjusted appropriately.
There have been rare reports of rhabdomyolysis
involving renal transplant
patients receiving the combination of Sporanox, cyclosporine, and
the HMG-CoA reductase inhibitors lovastatin
or simvastatin. Rhabdomyolysis has been observed in patients receiving
HMG-CoA reductase
inhibitors administered alone (at recommended dosages) or concomitantly
with immunosuppressive drugs including cyclosporine.
When Sporanox was coadministered with phenytoin, rifampin, or H2antagonists,
reduced plasma concentrations
of itraconazole were reported. The physician is advised to monitor
the plasma concentrations
of itraconazole when any of these drugs is taken concurrently, and
to increase the dose of
Sporanox if necessary. Although no
studies have been conducted, concomitant
administration of Sporanox and phenytoin
may alter the metabolism
of phenytoin; therefore, plasma concentrations of phenytoin
should also be monitored when it is given concurrently with Sporanox.
It has been reported that Sporanox enhances the anticoagulant
effect of coumarin-like drugs. Therefore, prothrombin
time should be carefully
monitored in patients receiving Sporanox and coumarin-like drugs
simultaneously.
Plasma concentrations of azole antifungal
agents are reduced when given concurrently with isoniazid. Itraconazole
plasma concentrations
should be monitored when Sporanox and isoniazid
are coadministered.
Severe hypoglycemia
has been reported in patients concomitantly receiving azole antifungal
agents and oral hypoglycemic
agents. Blood glucose
concentrations should be carefully monitored when Sporanox and oral
hypoglycemic agents are coadministered.
Tinnitus and decreased hearing
have been reported in patients concomitantly receiving Sporanox
and quinidine. Edema has been reported in patients concomitantly
receiving Sporanox and dihydropyridine calcium
channel blockers. Appropriate
dosage adjustments may be necessary.
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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