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Included as part of the PRECAUTIONS section.

Calcineurin-Inhibitor Drug Interactions

Concomitant administration of NOXAFIL (posaconazole oral suspension) with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurininhibitors [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]. Nephrotoxicity and leukoencephalopathy (including isolated deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.

Arrhythmias and QT Prolongation

Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, rare cases of torsades de pointes have been reported in patients taking posaconazole.

Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of age) administered posaconazole 400 mg BID with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc (F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc (F) interval change from baseline was < 0 msec (–8 msec). No healthy subject administered posaconazole had a QTc (F) interval ≥ 500 msec or an increase ≥ 60 msec in their QTc (F) interval from baseline.

Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see CONTRAINDICATIONS and DRUG INTERACTIONS]. Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting posaconazole.

Hepatic Toxicity

Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption and rarely required drug discontinuation. Isolated cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the 800 mg daily (400 mg BID or 200 mg QID) in clinical trials.

Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.

Use with Midazolam

Concomitant administration of NOXAFIL (posaconazole oral suspension) with midazolam increases the midazolam plasma concentrations by approximately 5 fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Patient Counseling Information

See FDA-Approved Patient Labeling.

Administration with Food

Take each dose of NOXAFIL (posaconazole oral suspension) Oral Suspension during or immediately (i.e. within 20 minutes) following a full meal. In patients who cannot eat a full meal each dose of NOXAFIL (posaconazole oral suspension) should be administered with a liquid nutritional supplement or an acidic carbonated beverage (e.g. ginger ale) in order to enhance absorption.

Drug Interactions

Patients should be advised to inform their physician immediately if they:

• develop severe diarrhea or vomiting.
• are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.
• are currently taking a cyclosporine or tacrolimus, or if you notice swelling of one leg or shortness of breath.
• are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole.

Serious and Potentially Serious Adverse Reactions

Patients should be advised to inform their physician immediately if they:

• notice a change in heart rate or heart rhythm, or have a heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions are pregnant, plan to become pregnant, or are nursing.
• have liver disease or you develop itching, your eyes or skin turn yellow, you feel more tired than usual or feel like you have the flu.
• have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.

See Accompanying FDA-Approved Patient Labeling

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9 or 3.5 times the exposure achieved with a 400-mg BID regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400-mg BID regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8 times the exposure achieved with a 400mg BID regimen.

Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study.

Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 x the 400-mg BID regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 x the 400-mg BID regimen).

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. NOXAFIL (posaconazole oral suspension) should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Posaconazole has been shown to cause skeletal malformations (cranial malformations and missing ribs) in rats when given in doses ≥ 27 mg/kg ( ≥ 1.4 times the 400 mg BID regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400-mg BID regimen. No malformations were seen in rabbits at doses up to 80 mg/kg. In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg, 2.9 or 5.2 times the exposure achieved with the 400-mg BID regimen, caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.

Nursing Mothers

Posaconazole is excreted in milk of lactating rats. It is not known whether NOXAFIL (posaconazole oral suspension) is excreted in human milk. Because of the potential for serious adverse reactions from NOXAFIL (posaconazole oral suspension) in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of posaconazole have been established in the age groups 13 to 17 years of age. The safety and effectiveness of posaconazole in pediatric patients below the age of 13 years have not been established. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adults with additional data.

A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) for prophylaxis of invasive fungal infections. The safety profile in these patients < 18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state average posaconazole concentration (Cav) was similar between these patients and adults ( ≥ 18 years of age).

A total of 16 patients 8 to 17 years of age were treated with 800 mg/day (400 mg twice a day or 200 mg four times a day) in a study for another indication. Based on pharmacokinetic data in 12 of these pediatric patients, the mean steady-state average posaconazole concentration (Cav) was similar between these patients and adults ( ≥ 18 years of age).

In the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) was similar among ten adolescents (13 to 17 years of age) and adults ( ≥ 18 years of age). This is consistent with pharmacokinetic data from another study in which mean steady-state posaconazole Cav from 12 adolescent patients (8-17 years of age) was similar to that in the adults ( ≥ 18 years of age).

Geriatric Use

Of the 605 patients randomized to posaconazole in the prophylaxis clinical trials, 63 (10%) were ≥ 65 years of age. In addition, 48 patients treated with ≥ 800-mg/day posaconazole in another indication were ≥ 65 years of age. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.

The pharmacokinetics of posaconazole are comparable in young and elderly subjects ( ≥ 65 years of age). No adjustment in the dosage of NOXAFIL (posaconazole oral suspension) is necessary in elderly patients ( ≥ 65 years of age) based on age.

No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.

Renal Insufficiency

Following single-dose administration of 400 mg of the oral suspension, there was no significant effect of mild (CLcr: 50-80 mL/min/1.73m², n=6) and moderate (CLcr: 20-49 mL/min/1.73m², n=6) renal insufficiency on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal insufficiency (CLcr: < 20 mL/min/1.73m²), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (CLcr: > 80 mL/min/1.73m²); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal insufficiency as compared to that in the other renal impairment groups (CV < 40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see DOSAGE AND ADMINISTRATION].

Hepatic Insufficiency

After a single oral dose of posaconazole 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), and severe (Child-Pugh Class C, N=6) hepatic insufficiency, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, and severe hepatic insufficiency, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, and severe hepatic insufficiency, respectively, compared to subjects with normal hepatic function. The elimination half-life (t½) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, and severe hepatic insufficiency, respectively.

It is recommended that no dose adjustment of NOXAFIL (posaconazole oral suspension) is needed in patients with mild to severe hepatic insufficiency (Child-Pugh Class A, B, and C) [see DOSAGE AND ADMINISTRATION, and WARNINGS AND PRECAUTIONS].

Gender

The pharmacokinetics of posaconazole are comparable in men and women. No adjustment in the dosage of NOXAFIL (posaconazole oral suspension) is necessary based on gender.

Race

The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of NOXAFIL (posaconazole oral suspension) is necessary based on race.

Last reviewed on RxList: 10/12/2010
This monograph has been modified to include the generic and brand name in many instances.