WARNINGS
Hypersensitivity
There is no information regarding cross-sensitivity between NOXAFIL® and other azole antifungal agents. Caution should be used when prescribing NOXAFIL® to patients with hypersensitivity to other azoles.
Hepatic Toxicity
In clinical trials, there were infrequent cases of hepatic reactions (eg, mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis). 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. Rarely, more severe hepatic reactions including cholestasis or hepatic failure including fatalities were reported in patients with serious underlying medical conditions (eg, hematologic malignancy) during treatment with posaconazole. These severe hepatic events were seen primarily in subjects receiving the 800 mg daily (400 mg BID or 200 mg QID) in another indication.
Monitoring of hepatic function
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.
Cyclosporine drug interaction
Cases of elevated cyclosporine levels resulting in rare serious adverse events, including nephrotoxicity and leukoencephalopathy, and death were reported in clinical efficacy studies. Dose reduction and more frequent clinical monitoring of cyclosporine, and tacrolimus, should be performed when posaconazole therapy is initiated. (See PRECAUTIONS, Drug Interactions.)
PRECAUTIONS
Arrhythmias and QT prolongation
Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. During clinical development there was one case of torsades de pointes in a patient taking posaconazole. This patient was seriously ill with multiple confounding risk factors including a history of cardiotoxic chemotherapy, hypokalemia, and concomitant medications that may have been contributory.
Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions and should not be administered with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4. (See CLINICAL PHARMACOLOGY, Electrocardiogram Evaluation ; CONTRAINDICATIONS ; and PRECAUTIONS, Drug Interactions.) Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting posaconazole.
Information for Patients
Patients should be advised to:
- Take each dose of NOXAFIL® Oral Suspension with a full meal or liquid nutritional supplement in order to enhance absorption.
- Inform their physician if they develop severe diarrhea or vomiting as these conditions may decrease the plasma concentrations of posaconazole.
- Inform their physician if they are taking other drugs or before they begin taking other drugs as certain drugs can decrease the plasma concentrations of posaconazole. (See CLINICAL PHARMACOLOGY, Drug Interactions.)
Drug Interactions
A summary of significant drug interactions with posaconazole that have been studied clinically are provided in TABLES 8 and 9. Appropriate precautions for the co-administration of these drugs with posaconazole are provided. (See CLINICAL PHARMACOLOGY/Drug Interactions, CONTRAINDICATIONS and WARNINGS.)
TABLE 8. Summary of the Effect of Co-administered Drugs on Posaconazole | Co-administered Drug | Recommendations |
|---|
| Cimetidine | Avoid concomitant use unless the benefit outweighs the risks. |
| Rifabutin | Avoid concomitant use unless the benefit outweighs the risks. |
| Phenytoin | Avoid concomitant use unless the benefit outweighs the risks. |
| Efavirenz | Avoid concomitant use unless the benefit outweighs the risks. |
Co-administration of these drugs listed in TABLE 8 with posaconazole may result in lower plasma concentrations of posaconazole.
TABLE 9. Summary of the Effect of Posaconazole on Co-administered Drugs | Co-administered Drug | Recommendations |
|---|
| Sirolimus | Co-administration of posaconazole with sirolimus is contraindicated. (See CLINICAL PHARMACOLOGY/Drug Interactions and CONTRAINDICATIONS.) |
| Cyclosporine | Increased cyclosporine concentrations resulted in cyclosporine dose reductions in heart transplant patients co-administered posaconazole. At initiation of posaconazole treatment, reduce the cyclosporine dose to approximately three fourths of the original dose. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly. |
| Tacrolimus | Posaconazole has been shown to increase Cmax and AUC of tacrolimus significantly. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly. |
| Rifabutin | Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required frequent monitoring of full blood counts and adverse events due to increased rifabutin levels (eg, uveitis, leukopenia) is recommended. |
| Midazolam | Frequent monitoring of adverse effects of benzodiazepines metabolized by CYP3A4 should be performed and dose reduction of these benzodiazepines should be considered during co-administration with posaconazole. |
| Phenytoin | Frequent monitoring of phenytoin concentrations should be performed while co-administered with posaconazole and dose reduction of phenytoin should be considered. |
| Atazanavir | Frequent monitoring of adverse effects and toxicity of atazanavir should be performed during co-administration with posaconazole. |
| Ritonavir | Frequent monitoring of adverse effects and toxicity of ritonavir should be performed during co-administration with posaconazole. |
Although not studied in vitro or in vivo, posaconazole may affect the plasma concentrations of the drugs or drug classes described in TABLE 10. Appropriate precautions for the co-administration of these drugs with posaconazole are provided. (See CONTRAINDICATIONS.)
TABLE 10. Drugs Not Studied in vitro or in vivo but Likely to Result in Significant Drug Interactions Drug or Drug Class
(CYP3A4 Substrates) | Recommendations |
|---|
| Terfenadine, Astemizole, Pimozide, Cisapride, Quinidine, Halofantrine | Increased plasma concentrations of these drugs can lead to QT prolongation with rare occurrences of torsade de pointes. Co-administration with posaconazole is contraindicated. (See CONTRAINDICATIONS.) |
| Ergot Alkaloids | Posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Co-administration of posaconazole with ergot alkaloids is contraindicated. (See CONTRAINDICATIONS.) |
| Vinca Alkaloids | Posaconazole may increase the plasma concentrations of vinca alkaloids (eg, vincristine and vinblastine) which may lead to neurotoxicity. Therefore, it is recommended that the dose adjustment of the vinca alkaloid be considered. |
HMG-CoA reductase
inhibitors (statins)
metabolized through CYP3A4 | It is recommended that dose reduction of statins be considered during co-administration. Increased statin concentrations in plasma can be associated with rhabdomyolysis. |
Calcium Channel Blockers
metabolized through CYP3A4 | Frequent monitoring for adverse events and toxicity related to calcium channel blockers is recommended during co-administration. Dose reduction of calcium channel blockers may be needed. |
| Digoxin | Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during co-administration. |
Carcinogenesis, Mutagenesis, Impairment of Fertility
No drug-related neoplasms were recorded in rats or mice treated with posaconazole for two years at doses below the maximum tolerated dose. In a two-year 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 400 mg 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 × 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 × the 400 mg BID regimen).
Pregnancy
Pregnancy Category C
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 was seen. There are no adequate and well-controlled studies in pregnant women. Posaconazole should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Posaconazole is excreted in milk of lactating rats. The excretion of posaconazole in human breast milk has not been investigated. NOXAFIL® should not be used by nursing mothers unless the benefit to the mother clearly outweighs the potential risk to the infant.
Pediatric Use
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). (See CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, Pediatric.)
Safety and effectiveness of posaconazole in pediatric patients below the age of 13 years have not been established.
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. (See CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, Geriatric.)
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