Itraconazole Oral (Page 4 of 7)

Effect of Other Drugs on Itraconazole

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 itraconazole resulting in either increased or sometimes decreased concentrations of itraconazole. Increased concentrations may increase the risk of adverse reactions associated with itraconazole. Decreased concentrations may reduce itraconazole efficacy.

The table below 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 itraconazole.

Although many of the clinical drug interactions in Table 2 below are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with itraconazole.

Table 2. Drug Interactions with Other Drugs that Affect Itraconazole Concentrations

a Based on clinical drug interaction information with itraconazole.

Concomitant Drug Within Class Prevention or Management
Drug Interactions with Other Drugs that Increase Itraconazole Concentrations and May Increase Risk of Adverse Reactions Associated with Itraconazole
Antibacterials
Ciprofloxacina Erythromycina Clarithromycina Monitor for adverse reactions. Itraconazole dose reduction may be necessary.
Antineoplastics
Idelalisib Monitor for adverse reactions. Itraconazole dose reduction may be necessary. See also Table 3.
Antivirals
CobicistatDarunavir (ritonavir-boosted)Elvitegravir (ritonavir-boosted)Fosamprenavir (ritonavir-boosted)Indinavira Ombitasvir/Paritaprevir/Ritonavir with or without DasabuvirRitonavirSaquinavir Monitor for adverse reactions. Itraconazole dose reduction may be necessary. For Boceprevir, cobicistat, elvitegravir, indinavir, ombitasvir/ paritaprevir/ritonavir with or without dasabuvir, ritonavir and saquinavir, see also Table 3.
Calcium Channel Blockers
Diltiazem Monitor for adverse reactions. Itraconazole dose reduction may be necessary. See also the table above.
Drug Interactions with Other Drugs that Decrease Itraconazole Concentrations and May Reduce Efficacy of Itraconazole
Antibacterials
IsoniazidRifampicina Not recommended 2 weeks before and during itraconazole treatment.
Rifabutina Not recommended 2 weeks before, during, and 2 weeks after itraconazole treatment. See also Table 3.
Anticonvulsants
Phenobarbital Phenytoina Not recommended 2 weeks before and during itraconazole treatment.
Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after itraconazole treatment.See also Table 3.
Antivirals
Efavirenza Nevirapinea Not recommended 2 weeks before and during itraconazole treatment.
Miscellaneous Drugs and Other Substances
Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after itraconazole treatment.

Pediatric Population

Interaction studies have only been performed in adults.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

Itraconazole

Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10 times the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1 times the 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 (6.25 times the 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.

Itraconazole produced no mutagenic effects when assayed in 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 (5 times the 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 (20 times the MRHD).

Hydroxypropyl-β-cyclodextrin (HP-β-CD)

Hydroxypropyl-β-cyclodextrin (HP-β-CD) is the solubilizing excipient used in itraconazole oral solution.

Hydroxypropyl-β-cyclodextrin (HP-β-CD) was found to produce neoplasms in the large intestine at 5,000 mg/kg/day in rat carcinogenicity study. This dose was about 6 times amount contained in the recommended clinical dose of itraconazole oral solution based on body surface area comparisons. The clinical relevance of this finding is unknown. The slightly higher incidence of adenocarcinomas in the large intestines was linked to the hypertrophic/hyperplastic and inflammatory changes in the colonic mucosa brought about by HP-β-CD-induced increased osmotic forces.

In addition, HP-β-CD was found to produce pancreatic exocrine hyperplasia and neoplasia when administered orally to rats at doses of 500, 2,000 or 5,000 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. The recommended clinical dose of itraconazole oral solution contains approximately 1.7 times the amount of HP-β-CD as was in the 500 mg/kg/day dose, based on body surface area comparisons. This finding was not observed in the mouse carcinogenicity study at doses of 500, 2,000 or 5,000 mg/kg/day for 22 to 23 months. This finding was also not observed in a 12-month toxicity study in dogs or in a 2-year toxicity study in female cynomolgus monkeys.

Since the development of the pancreatic tumors may be related to a mitogenic action of cholecystokinin and since there is no evidence that cholecystokinin has a mitogenic action in man, the clinical relevance of these findings is unknown.

HP-β-CD has no antifertile effect, and is not mutagenic.

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