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SPORANOX® (itraconazole) Injection contains the excipient hydroxypropylβ-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 PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.)
SPORANOX® (itraconazole injection) 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, 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 SPORANOX® (itraconazole injection) use or reinstitution of treatment with SPORANOX® (itraconazole injection) is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: INFORMATION FOR PATIENTS and ADVERSE REACTIONS.)
Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with SPORANOX® (itraconazole injection) and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX® is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: DRUG INTERACTIONS.)
SPORANOX® (itraconazole injection) Injection 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® (itraconazole injection) 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® (itraconazole injection) Injection, monitor carefully and consider other treatment alternatives which may include discontinuation of SPORANOX® Injection administration.
Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX® (itraconazole injection) 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® (itraconazole injection) 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 although there were also cases reported among those receiving lower total daily doses.
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® (itraconazole injection) 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.)
Rare cases of serious hepatotoxicity have been observed with SPORANOX® (itraconazole injection) 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® (itraconazole injection) 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® (itraconazole injection) . Treatment should be 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® (itraconazole injection) Injection, 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.
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 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.
Hydroxypropyl-β-cyclodextrin (HP-β-CD), the solubilizing excipient used in SPORANOX® (itraconazole injection) Injection and 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-β-CD at the recommended clinical dose of SPORANOX® (itraconazole injection) Oral Solution, is approximately equivalent to 1.7 times the exposure at the lowest dose in the rat study. The relevance of the findings with orally administered HP-β-CD to potential carcinogenic effects for SPORANOX® Injection is uncertain.
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/10T½ 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).
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® (itraconazole injection) should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.
Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX® (itraconazole injection) 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.
The efficacy and safety of SPORANOX® (itraconazole injection) have not been established in pediatric patients. No pharmacokinetic data on SPORANOX® (itraconazole injection) Capsules or Injection are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse effects have been reported. SPORANOX® (itraconazole injection) Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26, ages 6 months to 12 years) for 2 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 (2.5x 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 1 year or 160 mg/kg/day (20x 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.
Clinical studies of SPORANOX® (itraconazole injection) Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Transient or permanent hearing loss has been reported in elderly 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). Itraconazole should be used with care in elderly patients (see PRECAUTIONS).
Hydroxypropyl-β-cyclodextrin, when administered intravenously, is eliminated through glomerular filtration. Therefore, in patients with severe renal impairment defined as creatinine clearance below 30 mL/min, SPORANOX IV is contraindicated (see CONTRAINDICATIONS).
In patients with mild (defined as creatinine clearance 50-80 mL/min) and moderate (defined as creatinine clearance 30-49 mL/min) renal impairment, SPORANOX IV should be used with caution. Serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to modifying the antifungal regimen to an alternate medication with similar antimycotic coverage. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, and DOSAGE AND ADMINISTRATION for further information.).
Studies have not been conducted with intravenous itraconazole in patients with 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, WARNINGS, and DOSAGE AND ADMINISTRATION.)This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 5/18/2009
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