Noxafil Special Precautions

Hypersensitivity: There is no information regarding cross-sensitivity between posaconazole and other azole antifungal agents. Caution should be used when prescribing posaconazole to patients with hypersensitivity to other azoles. Subjects with severe or serious reactions to azoles were excluded from key studies of posaconazole.
Hepatic toxicity: Hepatic reactions (e.g., mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported during treatment with posaconazole. Elevated liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalized without interruption of therapy. Rarely, more severe hepatic reactions with fatal outcomes have been reported.
Posaconazole should be used with caution in patients with severe hepatic impairment. In these patients, the prolonged elimination half-life may lead to increased exposure.
QT prolongation: Some azoles have been associated with prolongation of the QT_c interval. Posaconazole must not be administered with medicines that are substrates for CYP3A4 and are known to prolong the QT_c interval (see Contraindications, Interactions, Pharmacology: Pharmacodynamics: Clinical Trials: Electrocardiogram Evaluation under Actions). Noxafil should be administered with caution to patients with pro-arrhythmic conditions such as: Congenital or acquired QT_c prolongation; Cardiomyopathy, especially in the presence of cardiac failure; Sinus bradycardia; Existing symptomatic arrhythmias; Concomitant use with medicinal products known to prolong the QT_c interval.
Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.
Vincristine Toxicity: Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options (see Interactions).
Venetoclax Toxicity: Concomitant administration of posaconazole with venetoclax (a CYP3A4 substrate) may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS) and neutropenia (see Effects of Posaconazole on Other Drugs under Interactions). Refer to the venetoclax prescribing information for detailed guidance.
Effects on Adrenal Steroid Hormones: As observed with other azole antifungal agents, effects related to inhibition of adrenal steroid hormone synthesis were seen in repeat-dose toxicity studies with posaconazole. Adrenal suppressive effects were observed in toxicity studies in rats and dogs at exposures equal to or greater than those obtained at therapeutic doses in humans.
Carcinogenicity: Posaconazole caused an increase in hepatocellular adenomas in mice at plasma exposure levels ~7-times higher than anticipated in humans at the maximum recommended clinical dose. This finding is considered to have occurred secondary to liver toxicity in the species, and mice are known to be particularly susceptible to this neoplastic change.
Rats treated with posaconazole at exposure levels ≥2.4-times that of humans developed adrenal cortical cell adenomas and/or carcinomas and phaeochromocytomas. The cortical tumours are consistent with endocrinological disruption following chronic impairment of adrenal steroidogenesis. The increase in phaeochromocytomas is considered to be a rat-specific phenomenon that follows changes in calcium homeostasis. Altered calcium homeostasis has not been observed in humans receiving posaconazole. The results of animal studies indicate little carcinogenic risk for posaconazole in clinical use.
Genotoxicity: Posaconazole has been tested for genotoxicity in a series of in vitro assays (bacterial mutation, mammalian mutation and human lymphocyte chromosomal aberration) and an in vivo mouse micronucleus test. Under the conditions of these assays, posaconazole did not cause genetic damage.
Effects on Fertility: Posaconazole had no effect on the fertility of male rats at doses up to 180 mg/kg/day (1.6 times the maximum recommended clinical dose (RCD) based on AUC at steady state in healthy volunteers fed a high fat meal). Like other azoles, male dogs administered oral posaconazole had findings consistent with reduced plasma testosterone levels, including spermatic giant cells (relative exposure 4.2).
Posaconazole administered to female rats at doses up to 45 mg/kg/day (relative exposure 2.0) for 2 weeks prior to mating did not affect fertility, but disruption of oestrus cycling was seen in female rats treated for 4 weeks.
Use in Pregnancy: See Use in Pregnancy & Lactation section for further information.
Use in Lactation: See Use in Pregnancy & Lactation section for further information.
Use in the Elderly: No dosage adjustment is recommended for geriatric patients (See Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations: Elderly under Actions).