Voriconazole

VORICONAZOLE — voriconazole tablet, film coated
Rising Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

VORICONAZOLE is indicated for use in patients 12 years of age and older in the treatment of the following fungal infections:

1.1 Invasive Aspergillosis

In clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number ofcases of culture-proven disease due to species of Aspergillus other than A. fumigatus [see Clinical Studies (14.1) and Clinical Pharmacology (12.4)].

1.2 Candidemia in Non-neutropenic Patients and the Following Candida Infections: Disseminated Infections in Skin and Infections in Abdomen, Kidney, Bladder Wall, and Wounds

[see Clinical Studies (14.2) and Clinical Pharmacology (12.4)].

1.3 Esophageal Candidiasis

[ see Clinical Studies (14.3) and Clinical Pharmacology (12.4)].

1.4 Serious Fungal Infections Caused by Scedosporium apiospermum (Asexual Form of Pseudallescheria boydii) and Fusarium spp. Including Fusarium solani, in Patients Intolerant of, or Refractory to, Other Therapy

[see Clinical Studies (14.4) and Clinical Pharmacology (12.4)].

Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

2 DOSAGE AND ADMINISTRATION

2.1 Instructions for Use in All Patients

VORICONAZOLE Tablets should be taken at least one hour before or after a meal.

2.3 Recommended Dosing in Adults

Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum

See Table 1. Therapy must be initiated with the specified loading dose regimen of intravenous VORICONAZOLE on Day 1 followed by the recommended maintenance dose (RMD) regimen. Intravenous treatment should be continued for at least 7 days. Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form of VORICONAZOLE may be utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg IV; a 300 mg oral dose achieves an exposure similar to 4 mg/kg IV. Switching between the intravenous and oral formulations is appropriate because of the high bioavailability of the oral formulation in adults [see Clinical Pharmacology (12) ].

Candidemia in non-neutropenic patients and other deep tissue Candida infections

See Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.

Esophageal Candidiasis

See Table 1. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.

Table 1: Recommended Dosing Regimen

Infection Loading dose Maintenance Dose *,†
IV IV Oral
Invasive Aspergillosis § 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h
Candidemia in nonneutropenic patients and other deep tis sue Candida infections 6 mg/kg q12h for the first 24 hours 3–4 mg/kg q12h¶ 200 mg q12h
Esophageal Candidiasis # # 200 mg q12h
Scedosporiosis and Fusariosis 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h

* Increase dose when VORICONAZOLE is co- administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.7)

† In healthy volunteer studies, the 200 mg oral q12h dose provided an exposure (AUCτ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUCτ) similar to a 4 mg/kg IV q12h dose [see Clinical Pharmacology (12) ].

‡ Adult patients who weigh less than 4 0 kg should receive half of the oral maintenance dose.

§ In a clinical study of invasive aspergillosis, the median duration of IV VORICONAZOLE therapy was 10 days (range 2–85 days). The median duration of oral VORICONAZOLE therapy was 76 days (range 2–232 days) [see Clinical Studies (14.1) ].

¶ In clinical trials, patients with candidemia received 3 mg/kg IV q12h as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg q12h as salvage therapy. Appropriate dose should be based on the severity and nature of the infection.

# Not evaluated in patients with esophageal candidiasis.

2.4 Dosage Adjustment

If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV q12h) to 300 mg every 12 hours (similar to 4 mg/kg IV q12h). For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).

If patient is unable to tolerate 4 mg/kg IV q12h, reduce the intravenous maintenance dose to 3 mg/kg q12h.

The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz [see Drug Interactions (7) ].

The maintenance dose of voriconazole should be reduced in patients with mild to moderate hepatic impairment, Child-Pugh Class A and B [see Dosage and Administration (2.7) ]. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).

Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression, and clinical response.

2.7 Use in Patients With Hepatic Impairment

In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions (5.9) ].

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology (12.3) ].

VORICONAZOLE has not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. VORICONAZOLE has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.

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