TARO-POSACONAZOLE

1 Dosing Considerations • The prescriber should follow the specific dosing instructions for each formulation. • The tablet, oral suspension and intravenous solution are not to be used interchangeably due to the differences in the dosing of each formulation.

• TARO-POSACONAZOLE Delayed‐Release Tablets may be taken with or without food. TARO-POSACONAZOLE (posaconazole) Page 6 of 50 • Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections.

• Co‐administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections (see 9 DRUG INTERACTIONS).

• Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections. 2 Recommended Dose and Dosage Adjustment Recommended Dose Table 1 ‐ Dosing for Posaconazole Delayed‐Release Tablet Indication Dose and Duration of Therapy Prophylaxis of Invasive Fungal Infections (IFIs) Loading dose of 300 mg (three 100 mg tablets) twice a day on the first day, then 300 mg (three 100 mg tablets) once a day thereafter.

Each dose may be taken without regard to food intake. The duration of therapy is based on recovery from neutropenia or immunosuppression. For patients with acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS), prophylaxis with posaconazole should start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 500 cells per mm3.

Treatment of Refractory IFIs / Intolerant Patients with IFIs Loading dose of 300 mg (three 100 mg tablets) twice a day on the first day, then 300 mg (three 100 mg tablets) once a day thereafter. Duration of therapy should be based on the severity of the underlying disease, recovery from immunosuppression, and clinical response.

TARO-POSACONAZOLE (posaconazole) Page 7 of 50 Dosage Adjustment Use in Renal Impairment The pharmacokinetics of posaconazole oral suspension are not significantly affected by renal impairment. Therefore, no dose adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

, Less Common Clinical Trial Adverse Drug Reactions (< 2%)). Dependence/Tolerance There is no known abuse potential for posaconazole. TARO-POSACONAZOLE (posaconazole) Page 11 of 50 Hematologic Rare cases of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have been reported primarily among patients who had been receiving concomitant cyclosporine or tacrolimus for management of transplant rejection or graft vs.

host disease (GVHD). , mild to moderate elevations in ALT (Alanine aminotransferase), AST (Aspartate aminotransferase), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) during treatment with posaconazole. 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.

, hematologic malignancy) during treatment with posaconazole.

Monitoring of hepatic function:

Liver function tests should be evaluated at the start of and during the course of TARO-POSACONAZOLE therapy. Patients who develop abnormal liver function tests during TARO-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 TARO-POSACONAZOLE should be considered if clinical signs and symptoms are consistent with development of worsening liver disease.

Hepatic Impairment:

TARO-POSACONAZOLE should be used with caution in patients with severe hepatic impairment. Prolonged elimination half‐life may lead to increased exposure.

Immune Patients Taking Immunosuppressant:

1 Dosing Considerations • The prescriber should follow the specific dosing instructions for each formulation. • The tablet, oral suspension and intravenous solution are not to be used interchangeably due to the differences in the dosing of each formulation.

• TARO-POSACONAZOLE Delayed‐Release Tablets may be taken with or without food. TARO-POSACONAZOLE (posaconazole) Page 6 of 50 • Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections.

• Co‐administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections (see 9 DRUG INTERACTIONS).

• Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections. 2 Recommended Dose and Dosage Adjustment Recommended Dose Table 1 ‐ Dosing for Posaconazole Delayed‐Release Tablet Indication Dose and Duration of Therapy Prophylaxis of Invasive Fungal Infections (IFIs) Loading dose of 300 mg (three 100 mg tablets) twice a day on the first day, then 300 mg (three 100 mg tablets) once a day thereafter.

Each dose may be taken without regard to food intake. The duration of therapy is based on recovery from neutropenia or immunosuppression. For patients with acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS), prophylaxis with posaconazole should start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 500 cells per mm3.

Treatment of Refractory IFIs / Intolerant Patients with IFIs Loading dose of 300 mg (three 100 mg tablets) twice a day on the first day, then 300 mg (three 100 mg tablets) once a day thereafter. Duration of therapy should be based on the severity of the underlying disease, recovery from immunosuppression, and clinical response.

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. There is no information regarding cross‐ sensitivity between posaconazole and other azole antifungal agents.

Caution should be used when prescribing TARO-POSACONAZOLE to patients with hypersensitivity to other azoles. TARO-POSACONAZOLE (posaconazole) Page 5 of 50 ______________________________________________________________________________________________ • Co‐administration of posaconazole and ergot alkaloids.

Posaconazole may increase the plasma concentrations of ergot alkaloids, which may lead to ergotism (see 9 DRUG INTERACTIONS). • Co‐administration of posaconazole and certain medicinal products metabolized through the CYP3A4 system: terfenadine, astemizole, cisapride, pimozide and quinidine.

Although not studied in vitro or in vivo, co‐administration of these CYP3A4 substrates may result in increased plasma concentrations of those medicinal products, leading to potentially serious and/or life threatening adverse events, such as QT prolongation and rare occurrences of torsade de pointes (see 9 DRUG INTERACTIONS).

• Co‐administration of posaconazole and HMG‐CoA reductase inhibitors (statins) that are primarily metabolized through CYP3A4, since increased plasma concentration of these drugs can lead to rhabdomyolysis. • Co‐administration of posaconazole and sirolimus.

Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9‐fold and can result in sirolimus toxicity.