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Cardiac effects: In a healthy volunteer study with SPORANOX IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion. The clinical relevance of these findings to the oral formulations is unknown.
Itraconazole has been shown to have a negative inotropic effect and SPORANOX has been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400 mg total daily dose than among those of lower total daily doses, suggesting that the risk of heart failure might increase with the total daily dose of itraconazole.
SPORANOX should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk. This individual benefit/risk assessment should take into consideration factors such as the severity of the indication, the dosing regimen (e.g., total daily dose), and individual risk factors for congestive heart failure. 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 congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment; if such signs or symptoms do occur during treatment, SPORANOX should be discontinued.
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.
Interaction potential: Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in Interactions.
Cross-hypersensitivity: There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing SPORANOX to patients with hypersensitivity to other azoles.
Neuropathy: If neuropathy occurs that may be attributable to SPORANOX, the treatment should be discontinued.
Hearing loss: 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 Contraindications and Drugs that may have their plasma concentrations increased by itraconazole under Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
Cross-resistance: In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence it is recommended to have their sensitivity tested before the start of itraconazole therapy.
Interchangeability: It is not recommended that SPORANOX capsules and SPORANOX oral solution be used interchangeably. This is because drug exposure is greater with the oral solution than with the capsules when the same dose of drug is given.
Hepatic effects: Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of SPORANOX. Most of these cases involved patients who, had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. Some patients had no obvious risk factors for liver disease. Some of these cases were observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving SPORANOX treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted.
Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. It is recommended that patients with impaired hepatic function be carefully monitored when taking itraconazole. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4.
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. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications. (See Pharmacology: Pharmacokinetics: Special Populations: Hepatic impairment under Actions.)
Renal impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.
Cystic fibrosis: In cystic fibrosis patients, variability in therapeutic levels of itraconazole was observed with steady state dosing of itraconazole oral solution using 2.5 mg/kg bid. Steady state concentrations of > 250 ng/mL were achieved in approximately 50% of subjects greater than 16 years of age, but in none of the patients less than 16 years of age. If a patient does not respond to SPORANOX capsules, consideration should be given to switching to alternative therapy.
Capsule: Reduced gastric acidity: Absorption of itraconazole from SPORANOX capsules is impaired when gastric acidity is reduced. In patients with reduced gastric acidity, whether from disease (e.g. patients with achlorhydria) or from concomitant medication (e.g. patients taking drugs that reduce gastric acidity), it is advisable to administer SPORANOX capsules with an acidic beverage (such as non-diet cola). The antifungal activity should be monitored and the itraconazole dose increased as deemed necessary. (See Drugs that may decrease itraconazole plasma concentrations under Interactions and Pharmacology: Pharmacokinetics: Absorption under Actions.)
Immunocompromised patients: In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the oral bioavailability of SPORANOX capsules may be decreased. Therefore, the dose should be adjusted based on the clinical response in these patients.
Patients with immediately life-threatening systemic fungal infections: Due to the pharmacokinetic properties (See Pharmacology: Pharmacokinetics under Actions), SPORANOX capsules are not recommended for initiation of treatment in patients with immediately life-threatening systemic fungal infections.
Patients with AIDS: In patients with AIDS who have received treatment for a systemic fungal infection with SPORANOX capsules and who are considered at risk for relapse, the treating physician should evaluate the need for a maintenance treatment.
Oral solution: Treatment of severely neutropenic patients: SPORANOX Oral Solution as treatment for oral and/or esophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties (see Pharmacology: Pharmacokinetics under Actions), SPORANOX Oral Solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidosis.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss (See Adverse Reactions.), which may occur in some instances, must be taken into account.
Use in Children: Clinical data on the use of SPORANOX capsules in pediatric patients are limited. The use of SPORANOX in pediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks.
Use in Elderly: Clinical data on the use of SPORANOX capsules in elderly patients are limited. It is advised to use SPORANOX in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
