Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2981
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Sporanox (Solution)
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Empiric Therapy in Febrile, Neutropenic
Patients with Suspected Fungal Infections (ETFN):: The recommended dose of SPORANOX Injection
is 200 mg b.i.d. for four doses, followed by 200 mg once daily for up to 14
days. Each intravenous dose should be infused over 1 hour. Treatment should
be continued with SPORANOX Oral Solution 200 mg (20 mL) b.i.d.
until resolution of clinically significant neutropenia. The safety and efficacy
of SPORANOX use exceeding 28 days in ETFN is not known. SPORANOX Oral
Solution is a different preparation than SPORANOX Capsules
and should not be used interchangeably.<br/>Treatment of Oropharyngeal and Esophageal
Candidiasis:: The solution should be vigorously swished in the mouth (10
mL at a time) for several seconds and swallowed. The
recommended dosage of SPORANOX (itraconazole) Oral Solution
for oropharyngeal candidiasis is 200 mg (20 mL) daily for 1 to 2 weeks. Clinical
signs and symptoms of oropharyngeal candidiasis generally resolve within several
days. For patients with oropharyngeal candidiasis unresponsive/refractory
to treatment with fluconazole tablets, the recommended dose is 100 mg (10
mL) b.i.d. For patients responding to therapy, clinical response will be seen
in 2 to 4 weeks. Patients may be expected to relapse shortly after discontinuing
therapy. Limited data on the safety of long-term use (>6 months) of SPORANOX Oral
Solution are available at this time. The recommended
dosage of SPORANOX Oral Solution for esophageal candidiasis
is 100 mg (10 mL) daily for a minimum treatment of three weeks. Treatment
should continue for 2 weeks following resolution of symptoms. Doses up to
200 mg (20 mL) per day may be used based on medical judgment of the patient's
response to therapy. SPORANOX Oral
Solution and SPORANOX Capsules should not be used interchangeably.
Patients should be instructed to take SPORANOX Oral Solution
without food, if possible. Only SPORANOX Oral Solution has
been demonstrated effective for oral and/or esophageal candidiasis.
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SPORANOX is the brand name for itraconazole,
a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture
of four diastereomers (two enantiomeric pairs), each possessing three chiral
centers. It may be represented by the following structural formula and nomenclature: (��)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-��-1,2,4-triazolin-5-one
mixture with (��)-1-[(R*)-sec-butyl]-4-[p
-[4-[p-[[(2S
*,4R*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-��-1,2,4-triazolin-5-oneor(��)-1-[(RS)-sec-butyl]-4-[p
-[4-[p-[[(2R
,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-��-1,2,4-triazolin-5-one. Itraconazole has a molecular formula of CHClNOand
a molecular weight of 705.64. It is a white to slightly yellowish powder.
It is insoluble in water, very slightly soluble in alcohols, and freely soluble
in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values
obtained from methanolic solutions) and a log (n-octanol/water) partition
coefficient of 5.66 at pH 8.1. SPORANOX (itraconazole)
Oral Solution contains 10 mg of itraconazole per mL, solubilized by hydroxypropyl-��-cyclodextrin
(400 mg/mL) as a molecular inclusion complex. SPORANOX Oral
Solution is clear and yellowish in color with a target pH of 2. Other ingredients
are hydrochloric acid, propylene glycol, purified water, sodium hydroxide,
sodium saccharin, sorbitol, cherry flavor 1, cherry flavor 2 and caramel flavor.
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Pharmacokinetics and Metabolism:: NOTE: The plasma concentrations reported below were measured
by high-performance liquid chromatography (HPLC) specific for itraconazole.
When itraconazole in plasma is measured by a bioassay, values reported may
be higher than those obtained by HPLC due to the presence of the bioactive
metabolite, hydroxyitraconazole. The
absolute bioavailability of itraconazole administered as a non-marketed solution
formulation under fed conditions was 55% in 6 healthy male volunteers. However,
the bioavailability of SPORANOX (itraconazole) Oral Solution
is increased under fasted conditions reaching higher maximum plasma concentrations
(C) in a shorter period of time. In 27 healthy male volunteers,
the steady-state area under the plasma concentration versus time curve (AUC)
of itraconazole (SPORANOX Oral Solution, 200 mg daily for
15 days) under fasted conditions was 131��30% of that obtained under
fed conditions. Therefore, unlike SPORANOX Capsules, it is
recommended that SPORANOX Oral Solution be administered without
food. Presented in the table below are the steady-state (Day 15) pharmacokinetic
parameters for itraconazole and hydroxyitraconazole (SPORANOX Oral
Solution) under fasted and fed conditions: The bioavailability of SPORANOX Oral Solution
relative to SPORANOX Capsules was studied in 30 healthy male
volunteers who received 200 mg of itraconazole as the oral solution and capsules
under fed conditions. The AUCfrom SPORANOX Oral
Solution was 149��68% of that obtained from SPORANOX Capsules;
a similar increase was observed for hydroxyitraconazole. In addition, a cross
study comparison of itraconazole and hydroxyitraconazole pharmacokinetics
following the administration of single 200 mg doses of SPORANOX Oral
Solution (under fasted conditions) or SPORANOX Capsules (under
fed conditions) indicates that when these two formulations are administered
under conditions which optimize their systemic absorption, the bioavailability
of the solution relative to capsules is expected to be increased further.
Therefore, it is recommended that SPORANOX Oral Solution
and SPORANOX Capsules not be used interchangeably. The following
table contains pharmacokinetic parameters for itraconazole and hydroxyitraconazole
following single 200 mg doses of SPORANOX Oral Solution (n=27)
or SPORANOX Capsules (n=30) administered to healthy male
volunteers under fasted and fed conditions, respectively: The plasma protein binding of itraconazole is 99.8% and
that of hydroxyitraconazole is 99.5%. Following intravenous administration,
the volume of distribution of itraconazole averaged 796��185 L. Itraconazole
is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4),
resulting in the formation of several metabolites, including hydroxyitraconazole,
the major metabolite. Results of a pharmacokinetics study suggest that itraconazole
may undergo saturable metabolism with multiple dosing. Fecal excretion of
the parent drug varies between 3-18% of the dose. Renal excretion of the parent
drug is less than 0.03% of the dose. About 40% of the dose is excreted as
inactive metabolites in the urine. No single excreted metabolite represents
more than 5% of a dose. Itraconazole total plasma clearance averaged 381��95 mL/minute following intravenous administration.<br/>Special Populations::<br/>Pediatrics:: The pharmacokinetics of SPORANOX Oral Solution
were studied in 26 pediatric patients requiring systemic antifungal therapy.
Patients were stratified by age: 6 months to 2 years (n=8), 2 to 5 years (n=7)
and 5 to 12 years (n=11), and received itraconazole oral solution 5 mg/kg
once daily for 14 days. Pharmacokinetic parameters at steady-state (Day 14)
were not significantly different among the age strata and are summarized in
the table below for all 26 patients:<br/>Renal Insufficiency:: A pharmacokinetic study using a single 200-mg dose of itraconazole
(four 50-mg capsules) was conducted in three groups of patients with renal
impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal
dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13
mL/min.��1.73 m, the bioavailability was slightly reduced
compared with normal population parameters. This study did not demonstrate
any significant effect of hemodialysis or continuous ambulatory peritoneal
dialysis on the pharmacokinetics of itraconazole (T, C,
and AUC). Plasma concentration-versus-time profiles showed wide
intersubject variation in all three groups.<br/>Hepatic Insufficiency:: Patients with impaired hepatic function should be carefully
monitored when taking itraconazole. The prolonged elimination half-life of
itraconazole observed in cirrhotic patients should be considered when deciding
to initiate therapy with other medications metabolized by CYP3A4. (See BOX WARNING, CONTRAINDICATIONS,
and PRECAUTIONS: Drug Interactions.)<br/>Decreased Cardiac Contractility:: When itraconazole was administered intravenously to anesthetized
dogs, a dose-related negative inotropic effect was documented. In a healthy
volunteer study of SPORANOX Injection (intravenous infusion),
transient, asymptomatic decreases in left ventricular ejection fraction were
observed using gated SPECT imaging; these resolved before the next infusion,
12 hours later. If signs or symptoms of congestive heart failure appear during
administration of SPORANOX Oral Solution, monitor carefully
and consider other treatment alternatives which may include discontinuation
of SPORANOX Oral Solution administration. (See WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more
information.)<br/>Cystic Fibrosis:: Seventeen cystic fibrosis patients, ages 7 to 28 years old,
were administered itraconazole oral solution 2.5 mg/kg bid for 14 days in
a pharmacokinetic study. Sixteen patients completed the study. Steady state
trough concentrations>250ng/mL were achieved in 6 out of 11 patients���16
years of age but in none of the 5 patients<16 years of age. Large variability
was observed in the pharmacokinetic data (%CV for trough concentrations =
98% and 70% for���16 and<16 years, respectively; %CV for AUC = 75%
and 58% for���16 and<16 years, respectively). If a patient with
cystic fibrosis does not respond to SPORANOX Oral Solution,
consideration should be given to switching to alternative therapy.
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Congestive Heart Failure:: SPORANOX (itraconazole) Oral Solution should
not be administered to patients with evidence of ventricular dysfunction such
as congestive heart failure (CHF) or a history of CHF except for the treatment
of life-threatening or other serious infections. (See CLINICAL
PHARMACOLOGY: Special Populations, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers,
and ADVERSE REACTIONS: Post marketing Experience.)<br/>Drug Interactions:: Concomitant administration of SPORANOX (itraconazole)
Capsules, Injection, or Oral Solution and certain drugs metabolized by the
cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma
concentrations of those drugs, leading to potentially serious and/or life-threatening
adverse events. Cisapride, oral midazolam, nisoldipine, pimozide, quinidine,
dofetilide, triazolam and levacetylmethadol (levomethadyl) are contraindicated
with SPORANOX. HMG CoA-reductase inhibitors metabolized by
CYP3A4, such as lovastatin and simvastatin, are also contraindicated with
SPORANOX. Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine,
ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine)
are contraindicated with SPORANOX. (See BOX
WARNING, and PRECAUTIONS: Drug Interactions.) SPORANOX is
contraindicated for patients who have shown hypersensitivity to itraconazole
or its excipients. There is no information regarding cross-hypersensitivity
between itraconazole and other azole antifungal agents. Caution should be
used when prescribing SPORANOX to patients with hypersensitivity
to other azoles.
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SPORANOX (itraconazole) Oral Solution is
available in 150 mL amber glass bottles (NDC 50458-295-15) containing 10 mg
of itraconazole per mL. Store at or below 25��C
(77��F). Do not freeze. Keep out of reach of children. U.S.
Patent No. 4,267,179; 5,707,975; 4,727,064Issued October 2007��Janssen
2003 Manufactured by:Janssen Pharmaceutica N.V.Beerse,
Belgium Distributed by:Ortho Biotech Products,
L.P.Raritan, NJ 08869 ���ORTHO BIOTECH
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Congestive Heart Failure: When
itraconazole was administered intravenously to dogs and healthy human volunteers,
negative inotropic effects were seen. If signs or symptoms of congestive heart
failure occur during administration of SPORANOX (itraconazole)
Oral Solution, continued SPORANOX use should be reassessed.
(See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE
REACTIONS: Post-marketing Experience for more information.) Drug Interactions: Coadministration
of cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol (levomethadyl)
with SPORANOX(itraconazole)
Capsules, Injection or Oral Solution is contraindicated. SPORANOX,
a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase
plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular
events, including QT prolongation, torsades de pointes, ventricular tachycardia,
cardiac arrest, and/or sudden death have occurred in patients usingcisapride,
pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with
SPORANOX and/or other CYP3A4 inhibitors. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug
Interactions for more information.)
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dailymed-ingredient:caramel_flavor,
dailymed-ingredient:cherry_flavor_1,
dailymed-ingredient:cherry_flavor_2,
dailymed-ingredient:hydrochloric_acid,
dailymed-ingredient:hydroxypropyl-��-cyclodextrin,
dailymed-ingredient:propylene_glycol,
dailymed-ingredient:sodium_hydroxide,
dailymed-ingredient:sodium_saccharin,
dailymed-ingredient:sorbitol,
dailymed-ingredient:water
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General:: Rare cases of serious hepatotoxicity have been observed with
SPORANOX treatment, including some cases within the first
week. In patients with elevated or abnormal liver enzymes or active liver
disease, or who have experienced liver toxicity with other drugs, treatment
with SPORANOX is strongly discouraged unless there is a serious
or life threatening situation where the expected benefit exceeds the risk.
Liver function monitoring should be done in patients with pre-existing hepatic
function abnormalities or those who have experienced liver toxicity with other
medications and should be considered in all patients receiving SPORANOX.
Treatment shouldbe stopped immediately and liver function testing should
be conducted in patients who develop signs and symptoms suggestive of liver
dysfunction. If neuropathy occurs that may be attributable
to SPORANOX Oral Solution, the treatment should be discontinued. Transient
or permanent hearing loss has been reported in patients receiving treatment
with itraconazole. Several of these reports included concurrent administration
of quinidine which is contraindicated (see BOX WARNING:
Drug Interactions, CONTRAINDICATIONS: Drug
Interactions and PRECAUTIONS: Drug Interactions).
The hearing loss usually resolves when treatment is stopped, but can persist
in some patients. Patients should be informed of this potential side effect
and advised to discontinue therapy and inform their physicians if any hearing
loss symptoms occur.<br/>Information for Patients::<br/>Drug Interactions:: Itraconazole and its major metabolite, hydroxyitraconazole,
are inhibitors of CYP3A4. Therefore, the following drug interactions may occur
(See Table 1 below and the following drug
class subheadings that follow):<br/>Antiarrhythmics:: The class IA antiarrhythmic quinidine and class III antiarrhythmic
dofetilide are known to prolong the QT interval. Coadministration of quinidine
or dofetilide with SPORANOX may increase plasma concentrations
of quinidine or dofetilide which could result in serious cardiovascular events.
Therefore, concomitant administration of SPORANOX and quinidine
or dofetilide is contraindicated. The
class IA antiarrhythmic disopyramide has the potential to increase the QT
interval at high plasma concentrations. Caution is advised when SPORANOX and
disopyramide are administered concomitantly. Concomitant
administration of digoxin and SPORANOX has led to increased
plasma concentrations of digoxin.<br/>Anticoagulants:: SPORANOX enhances the anticoagulant effect
of coumarin-like drugs, such as warfarin.<br/>Anticonvulsants:: Reduced plasma concentrations of itraconazole were reported
when SPORANOX was administered concomitantly with phenytoin.
Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although
interactions with carbamazepine and phenobarbital have not been studied, concomitant
administration of SPORANOX and these drugs would be expected
to result in decreased plasma concentrations of itraconazole. In addition,
in vivo studies have demonstrated an increase in plasma carbamazepine concentrations
in subjects concomitantly receiving ketoconazole. Although there are no data
regarding the effect of itraconazole on carbamazepine metabolism, because
of the similarities between ketoconazole and itraconazole, concomitant administration
of SPORANOX and carbamazepine may inhibit the metabolism
of carbamazepine.<br/>Antimycobacterials:: Drug interaction studies have demonstrated that plasma concentrations
of azole antifungal agents and their metabolites, including itraconazole and
hydroxyitraconazole, were significantly decreased when these agents were given
concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin
is metabolized in part by CYP3A4. SPORANOX may inhibit the
metabolism of rifabutin. Although no formal study data are available for isoniazid,
similar effects should be anticipated. Therefore, the efficacy of SPORANOX could
be substantially reduced if given concomitantly with one of these agents.
Coadministration is not recommended.<br/>Antineoplastics:: SPORANOX may inhibit the metabolism of busulfan,
docetaxel, and vinca alkaloids.<br/>Antipsychotics:: Pimozide is known to prolong the QT interval and is partially
metabolized by CYP3A4. Coadministration of pimozide with SPORANOX could
result in serious cardiovascular events. Therefore, concomitant administration
of SPORANOX and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS,
and WARNINGS.)<br/>Benzodiazepines:: Concomitant administration of SPORANOX and
alprazolam, diazepam, oral midazolam, or triazolam could lead to increased
plasma concentrations of these benzodiazepines. Increased plasma concentrations
could potentiate and prolong hypnotic and sedative effects. Concomitant administration
of SPORANOX and oral midazolam or triazolam is contraindicated.
If midazolam is administered parenterally, special precaution and patient
monitoring is required since the sedative effect may be prolonged.<br/>Calcium
Channel Blockers:: Edema has been reported in patients concomitantly receiving
SPORANOX and dihydropyridine calcium channel blockers. Appropriate
dosage adjustment may be necessary. Calcium channel
blockers can have a negative inotropic effect which may be additive to those
of itraconazole; itraconazole can inhibit the metabolism of calcium channel
blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil.
Therefore, caution should be used when co-administering itraconazole and calcium
channel blockers due to an increased risk of CHF. Concomitant administration
of SPORANOX and nisoldipine is contraindicated. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS,
and ADVERSE REACTIONS: Post-marketing Experience for
more information.)<br/>Gastric
Acid Suppressors/Neutralizers:: Reduced plasma concentrations of itraconazole were reported
when SPORANOX Capsules were administered concomitantly with
H-receptor antagonists. Studies have shown that absorption of
itraconazole is impaired when gastric acid production is decreased. Therefore,
SPORANOX should be administered with a cola beverage if the
patient has achlorhydria or is taking H-receptor antagonists or
other gastric acid suppressors. Antacids should be administered at least 1
hour before or 2 hours after administration of SPORANOX Capsules.
In a clinical study, when SPORANOX Capsules were administered
with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole
was significantly reduced. However, as itraconazole is already dissolved in
SPORANOX Oral Solution, the effect of Hantagonists
is expected to be substantially less than with the capsules. Nevertheless,
caution is advised when the two drugs are coadministered.<br/>Gastrointestinal
Motility Agents:: Coadministration of SPORANOX with cisapride
can elevate plasma cisapride concentrations which could result in serious
cardiovascular events. Therefore, concomitant administration of SPORANOX with
cisapride is contraindicated.<br/>HMG CoA-Reductase
Inhibitors:: Human pharmacokinetic data suggest that SPORANOX inhibits
the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin,
which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Concomitant administration of SPORANOX with HMG CoA-reductase
inhibitors, such as lovastatin or simvastatin is contraindicated.<br/>Immunosuppressants:: Concomitant administration of SPORANOX and
cyclosporine or tacrolimus has led to increased plasma concentrations of these
immunosuppressants. Concomitant administration of SPORANOX and
sirolimus could increase plasma concentrations of sirolimus.<br/>Macrolide
Antibiotics:: Erythromycin and clarithromycin are known inhibitors of CYP3A4
(See Table 1) and may increase plasma concentrations
of itraconazole. In a small pharmacokinetic study involving HIV infected patients,
clarithromycin was shown to increase plasma concentrations of itraconazole.
Similarly, following administration of 1 gram of erythromycin ethyl succinate
and 200 mg itraconazole as single doses, the mean Cand AUCof
itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%),
respectively.<br/>Oral Hypoglycemic
Agents:: 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.<br/>Polyenes:: Prior treatment with itraconazole, like other azoles, may
reduce or inhibit the activity of polyenes such as amphotericin B. However,
the clinical significance of this drug effect has not been clearly defined.<br/>Protease
Inhibitors:: Concomitant administration of SPORANOX and
protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, andsaquinavir, may increase plasma concentrations of these protease inhibitors.
In addition, concomitant administration of SPORANOX and indinavir
and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole.
Caution is advised when SPORANOX and protease inhibitors
must be given concomitantly.<br/>Reverse
Transcriptase Inhibitors:: Nevirapine is an inducer of CYP3A4. In vivo studies have
shown that nevirapine induces the metabolism of ketoconazole, significantly
reducing the bioavailability of ketoconazole. Studies involving nevirapine
and itraconazole have not been conducted. However, because of the similarities
between ketoconazole and itraconazole, concomitant administration of SPORANOX and
nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects
were treated concomitantly with SPORANOX Capsules 100 mg
twice daily and the nucleoside reverse transcriptase inhibitor zidovudine
8��0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected.
Other nucleoside reverse transcriptase inhibitors have not been studied.<br/>Other::<br/>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 (3.1x RHD) 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. Hydroxypropyl-��-cyclodextrin (HP-��-CD),
the solubilizing excipient used in SPORANOX Oral Solution,
was found to produce pancreatic exocrine hyperplasia and neoplasia when administered
orally to rats at doses of 500, 2000 or 5000 mg/kg/day for 25 months. Adenocarcinomas
of the exocrine pancreas produced in the treated animals were not seen in
the untreated group and are not reported in the historical controls. Development
of these tumors may be related to a mitogenic action of cholecystokinin. This
finding was not observed in the mouse carcinogenicity study at doses of 500,
2000 or 5000 mg/kg/day for 22-23 months; however, the clinical relevance of
these findings is unknown. Based on body surface area comparisons, the exposure
to humans of HP-��-CD at the recommended clinical dose of SPORANOX Oral
Solution, is approximately equivalent to 1.7 times the exposure at the lowest
dose in the rat study. Itraconazole produced no mutagenic
effects when assayed in a DNA repair test (unscheduled DNA synthesis) in primary
rat hepatocytes, in Ames tests with Salmonella
typhimurium (6 strains) and Escherichia
coli, in the mouse lymphoma gene mutation tests, in a sex-linked
recessive lethal mutation (Drosophila melanogaster
) test, in chromosome aberration tests in human lymphocytes, in
a cell transformation test with C3H/10T��C18 mouse embryo fibroblasts
cells, in a dominant lethal mutation test in male and female mice, and in
micronucleus tests in mice and rats. 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).<br/>Pregnancy: Teratogenic Effects. Pregnancy
Category C:: Itraconazole was found to cause a dose-related increase in
maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels
of 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 in pregnancy only if the benefit
outweighs the potential risk. During post-marketing
experience, cases of congenital abnormalities have been reported.<br/>Nursing Mothers:: Itraconazole is excreted in human milk; therefore, the expected
benefits of SPORANOX therapy for the mother should be weighed
against the potential risk from exposure of itraconazole to the infant. The
U.S. Public Health Service Centers for Disease Control and Prevention advises
HIV-infected women not to breast-feed to avoid potential transmission of HIV
to uninfected infants.<br/>Pediatric Use:: The efficacy and safety of SPORANOX have
not been established in pediatric patients. A pharmacokinetic study was conducted
with SPORANOX Oral Solution in 26 pediatric patients, ages
6 months to 12 years, requiring systemic antifungal treatment. Itraconazole
was dosed at 5 mg/kg once daily for two weeks and no serious unexpected adverse
events were reported. The
long-term effects of itraconazole on bone growth in children are unknown.
In three toxicology studies using rats, itraconazole induced bone defects
at dosage levels as low as 20 mg/kg/day (2.5��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
(10��MRHD) over 1 year or 160 mg/kg/day (20��MRHD) for 6 months,
itraconazole induced small tooth pulp with hypocellular appearance in some
rats. No such bone toxicity has been reported in adult patients.<br/>Renal Impairment:: Limited data are available on the use of oral itraconazole
in patients with renal impairment. Caution should be exercised when this drug
is administered in this patient population. (See CLINICAL
PHARMACOLOGY: Special Populations.)<br/>Hepatic Impairment:: Limited data are available on the use of oral itraconazole
in patients with hepatic impairment. Caution should be exercised when this
drug is administered in this patient population. (See CLINICAL
PHARMACOLOGY: Special Populations.)
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Itraconazole is not removed by dialysis. In the event of
accidental overdosage, supportive measures, including gastric lavage with
sodium bicarbonate, should be employed. There are limited
data on the outcomes of patients ingesting high doses of itraconazole. In
patients taking either 1000 mg of SPORANOX (itraconazole)
Oral Solution or up to 3000 mg of SPORANOX Capsules, the
adverse event profile was similar to that observed at recommended doses.
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itraconazole
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| dailymed-instance:fullName |
Sporanox (Solution)
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| dailymed-instance:adverseRe... |
SPORANOX has been associated with rare cases
of serious hepatotoxicity, including liver failure and death. Some of these
cases had neither pre-existing liver disease nor a serious underlying medical
condition. If clinical signs or symptoms develop that are consistent with
liver disease, treatment should be discontinued and liver function testing
performed. The risks and benefits of SPORANOX use should
be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: General and Information
for Patients.)<br/>Adverse Events Reported in Empiric
Therapy in Febrile Neutropenic (ETFN) Patients: Adverse events considered at least possibly drug related
in a clinical trial of empiric therapy in 384 febrile, neutropenic patients
(192 treated with SPORANOX and 192 with amphotericin B) with
suspected fungal infections are listed in Table 2 below.
Patients received a regimen of SPORANOX Injection followed
by SPORANOX Oral Solution. The dose of SPORANOX Injection
was 200 mg twice daily for the first two days followed by a single daily dose
of 200 mg for the remainder of the intravenous treatment period. The majority
of patients received between 7 and 14 days of SPORANOX Injection.
The dose of SPORANOX Oral Solution was 200 mg (20 mL) b.i.d.
for the remainder of therapy. The following additional adverse events considered at least
possibly related occurred in between 1 and 2% of patients who received SPORANOX Injection
and Oral Solution: constipation, hypophosphatemia, gamma-GT increased, erythematous
rash, pruritus, dizziness, tremor, and pulmonary infiltration.<br/>Adverse Events Reported in Oropharyngeal
or Esophageal Candidiasis Trials: U.S. adverse experience data are derived from 350 immunocompromised
patients (332 HIV seropositive/AIDS) treated for oropharyngeal or esophageal
candidiasis. Table 3 below lists adverse events
reported by at least 2% of patients treated with SPORANOX Oral
Solution in U.S. clinical trials. Data on patients receiving comparator agents
in these trials are included for comparison. Treated Patients in U.S. Clinical Trials (Total) Adverse events reported by less than 2% of patients in
U.S. clinical trials with SPORANOX included: adrenal insufficiency,
asthenia, back pain, dehydration, dyspepsia, dysphagia, flatulence, gynecomastia,
hematuria, hemorrhoids, hot flushes, implantation complication, infection
unspecified, injury, insomnia, male breast pain, myalgia, pharyngitis, pruritus,
rhinitis, rigors, stomatitis ulcerative, taste perversion, tinnitus, upper
respiratory tract infection, vision abnormal, and weight decrease. Edema,
hypokalemia and menstrual disorders have been reported in clinical trials
with itraconazole capsules.<br/>Post-marketing Experience: Worldwide post-marketing experiences with the use of SPORANOX (all
formulations) include very rare reports (<1/10,000) of the adverse events
listed below: There is limited information on the use of SPORANOX during
pregnancy. Cases of congenital abnormalities including skeletal, genitourinary
tract, cardiovascular and ophthalmic malformations as well as chromosomal
and multiple malformations have been reported during post-marketing experience.
A causal relationship with SPORANOX has not been established.
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SPORANOX (itraconazole) Oral Solution and
SPORANOX Capsules should not be used interchangeably. Only
SPORANOX Oral Solution has been demonstrated effective for
oral and/or esophageal candidiasis. SPORANOX Oral Solution
contains the excipient hydroxypropyl-��-cyclodextrin which produced pancreatic
adenocarcinomas in a rat carcinogenicity study. These findings were not observed
in a similar mouse carcinogenicity study. The clinical relevance of these
findings is unknown. (See Carcinogenesis, Mutagenesis,
and Impairment of Fertility.)<br/>Hepatic Effects:: SPORANOXhas been associated with rare cases of serious hepatotoxicity,
including liver failure and death. Some of these cases had neither pre-existing
liver disease nor a serious underlying medical condition and some of these
cases developed within the first week of treatment. If clinical signs or symptoms
develop that are consistent with liver disease, treatment should be discontinued
and liver function testing performed. Continued SPORANOXuse or reinstitution of treatment with SPORANOXis strongly discouraged unless there is a serious or life-threatening
situation where the expected benefit exceeds the risk. (See PRECAUTIONS:
Information for Patientsand ADVERSE REACTIONS.)<br/>Cardiac Dysrhythmias:: Life-threatening cardiac dysrhythmias and/or sudden death
have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl),
or quinidine concomitantly with SPORANOX and/or other CYP3A4
inhibitors. Concomitant administration of these drugs with SPORANOX is
contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS:
Drug Interactions.)<br/>Cardiac Disease:: SPORANOX Oral Solution should not be used
in patients with evidence of ventricular dysfunction unless the benefit clearly
outweighs the risk. For patients with risk factors for congestive heart failure,
physicians should carefully review the risks and benefits of SPORANOX therapy.
These risk factors include cardiac disease such as ischemic and valvular disease;
significant pulmonary disease such as chronic obstructive pulmonary disease;
and renal failure and other edematous disorders. Such patients should be informed
of the signs and symptoms of CHF, should be treated with caution, and should
be monitored for signs and symptoms of CHF during treatment. If signs or symptoms
of CHF appear during administration of SPORANOX Oral Solution,
monitor carefully and consider other treatment alternatives which may include
discontinuation of SPORANOX Oral Solution administration. When
itraconazole was administered intravenously to anesthetized dogs, a dose-related
negative inotropic effect was documented. In a healthy volunteer study of
SPORANOX Injection (intravenous infusion), transient, asymptomatic
decreases in left ventricular ejection fraction were observed using gated
SPECT imaging; these resolved before the next infusion, 12 hours later. SPORANOX has
been associated with reports of congestive heart failure. In post-marketing
experience, heart failure was more frequently reported in patients receiving
a total daily dose of 400 mg than among those receiving lower total daily
doses. This suggests that the risk of heart failure might increase with the
total daily dose of itraconazole. Calcium channel blockers
can have negative inotropic effects which may be additive to those of itraconazole.
In addition, itraconazole can inhibit the metabolism of calcium channel blockers.
Therefore, caution should be used when co-administering itraconazole and calcium
channel blockers due to an increased risk of CHF. Concomitant administration
of SPORANOX and nisoldipine is contraindicated. Cases
of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing
period among patients being treated for onychomycosis and/or systemic fungal
infections. (See CLINICAL PHARMACOLOGY: Special Populations, PRECAUTIONS: Drug Interactions, and ADVERSE
REACTIONS: Post-marketing Experience for more information.)<br/>Cystic Fibrosis:: If a patient with cystic fibrosis does not respond to SPORANOX Oral
Solution, consideration should be given to switching to alternative therapy
.<br/>Treatment of Severely Neutropenic
Patients:: SPORANOX Oral Solution as treatment for
oropharyngeal and/or esophageal candidiasis was not investigated in severely
neutropenic patients. Due to its pharmacokinetic properties, SPORANOX Oral
Solution is not recommended for initiation of treatment in patients at immediate
risk of systemic candidiasis. In febrile neutropenic
subjects in whom the likelihood of systemic candidiasis is considered high,
therapy should be initiated with Sporanox Intravenous formulation.
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SPORANOX (itraconazole) Injection/Oral Solution
is indicated for empiric therapy of febrile neutropenic patients with suspected
fungal infections. (NOTE: In a comparative trial, the overall response rate
for itraconazole-treated subjects was higher than for amphotericin B-treated
subjects. However, compared to amphotericin B-treated subjects, a larger number
of itraconazole-treated subjects discontinued treatment due to persistent
fever and a change in antifungal medication due to fever. Whereas, a larger
number of amphotericin B-treated subjects discontinued due to drug intolerance. SPORANOX (itraconazole)
Oral Solution is also indicated for the treatment of oropharyngeal and esophageal
candidiasis. (See CLINICAL PHARMACOLOGY:
Special Populations, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more
information.)
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Sporanox
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