Tolsura (Page 4 of 7)

7.2 Effect of Other Drugs on TOLSURA

Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Some concomitant drugs have the potential to interact with TOLSURA resulting in either increased or sometimes decreased concentrations of TOLSURA. Increased concentrations may increase the risk of adverse reactions associated with TOLSURA. Decreased concentrations may reduce TOLSURA efficacy.

Table 4 lists examples of drugs that may affect itraconazole concentrations, but is not a comprehensive list. Refer to the approved product labeling to become familiar with the interaction pathways, risk potential and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with TOLSURA.

Although many of the clinical drug interactions in Table 5 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with TOLSURA.

Table 5: Drug Interactions with Other Drugs that Affect TOLSURA Concentrations
Concomitant Drug Within Class Prevention or Management
*
Based on clinical drug interaction information with itraconazole.
Drug Interactions with Other Drugs that Increase TOLSURA Concentrations and May Increase Risk of Adverse Reactions Associated with TOLSURA
Antibacterials
Ciprofloxacin * Erythromycin * Clarithromycin * Monitor for adverse reactions. TOLSURA dose reduction may be necessary.
Antineoplastics
Idelalisib Monitor for adverse reactions. TOLSURA dose reduction may be necessary. See also Table 4.
Antivirals
Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavir * Ritonavir Saquinavir Monitor for adverse reactions. TOLSURA dose reduction may be necessary. For, cobicistat, elvitegravir, indinavir, ritonavir, and saquinavir, see also Table 4.
Calcium Channel Blockers
Diltiazem Monitor for adverse reactions. TOLSURA dose reduction may be necessary. See also Table 4.
Gastrointestinal Drugs
Drugs that reduce gastric acidity e.g. acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H 2 — receptor antagonists and proton pump inhibitors (e.g., omeprazole). Co-administration of these drugs, including omeprazole, with TOLSURA increases the systemic exposure to itraconazole. Monitor for adverse reactions. TOLSURA dose reduction may be necessary [see Clinical Pharmacology (12.3)].
Drug Interactions with Other Drugs that Decrease TOLSURA Concentrations and May Reduce Efficacy of TOLSURA
Antibacterials
Isoniazid Rifampicin * Not recommended 2 weeks before and during TOLSURA treatment.
Rifabutin * Not recommended 2 weeks before, during, and 2 weeks after TOLSURA treatment. See also Table 4.
Anticonvulsants
Phenobarbital Phenytoin * Not recommended 2 weeks before and during TOLSURA treatment.
Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after TOLSURA treatment. See also Table 4.
Antivirals
Efavirenz * Nevirapine * Not recommended 2 weeks before and during TOLSURA treatment.
Miscellaneous Drugs and Other Substances
Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after TOLSURA treatment.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no data on exposure to itraconazole during pregnancy for the approved indications. Published epidemiologic studies of women exposed to short courses of treatment with itraconazole in the first trimester of pregnancy have reported no risk of major birth defects overall and inconclusive findings on the risk of miscarriage (see Data) .

In animal reproduction studies, itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately (6-25 times the maximum recommended human dose [MRHD] of 390 mg/day based on mg/kg comparisons), and in mice at dosage levels of approximately 80 mg/kg/day (12 times the MRHD).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Human Data

Published prospective and retrospective cohort studies of women exposed to short courses of treatment with itraconazole in the first trimester of pregnancy (sample size 198-687) have reported no increase in the rate of major birth defects. The most important methodological limitation of these studies is the short duration of exposure in pregnancy (mean duration 6.9 to 8.5 days), or the lack of information on treatment duration. The risk of prolonged exposure in pregnancy is not known.

Published prospective and retrospective cohort studies of pregnant women exposed to itraconazole (sample size 131-198) have reported inconsistent findings on the risk of miscarriage. Available data are inconclusive and limited by possible bias due to earlier enrollment and possible residual confounding in the exposed group compared to the unexposed group.

Animal Data

Itraconazole has been shown to cross the placenta in a rat model. In animal reproduction studies, itraconazole administration to rats and mice during organogenesis resulted in maternal toxicity, embryotoxicity and teratogenicity at and above 40 and 80 mg/kg respectively (doses equivalent to 6- and 12-times the MRHD of 390 mg/day, based on mg/kg comparisons). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.

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