VORICONAZOLE

VORICONAZOLE — voriconazole injection, powder, lyophilized, for solution
Zydus Pharmaceuticals USA Inc.

1 INDICATIONS AND USAGE

1.1 Invasive Aspergillosis

Voriconazole for injection is indicated in adults and pediatric patients (2 years of age and older) for the treatment of invasive apergillosis (IA). In clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus [see Clinical Studies (14.1)14.5 and Microbiology (12.4)].

1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections

Voriconazole for injection is indicated in adults and pediatric patients (2 years of age and older) for the treatment of 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, 14.5) and Microbiology (12.4)].

1.3 Esophageal Candidiasis

Voriconazole for injection is indicated in adults and pediatric patients (2 years of age and older) for the treatment of esophageal candidiasis (EC) in adults and pediatric patients 2 years of age and older [see Clinical Studies (14.3, 14.5) and Microbiology (12.4)].

1.4 Scedosporiosis and Fusariosis

Voriconazole for injection is indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in adults and pediatric patients (2 years of age and older) intolerant of, or refractory to, other therapy [see Clinical Studies (14.4) and Microbiology (12.4)].

1.5 Usage

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 Important Administration Instructions for Use in All Patients

Voriconazole for injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to administration as an infusion, at a maximum rate of 3 mg/kg per hour over 1 to 2 hours.

Administer diluted voriconazole for injection by intravenous infusion over 1 to 2 hours only. Do not administer as an intravenous bolus injection.

2.2 Use of Voriconazole for Injection With Other Parenteral Drug Products

Blood products and concentrated electrolytes

Voriconazole for injection must not be infused concomitantly with any blood product or short-term infusion of concentrated electrolytes, even if the two infusions are running in separate intravenous lines (or cannulas).

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during voriconazole therapy [see Warnings and Precautions (5.9) ].

Intravenous solutions containing (non-concentrated) electrolytes

Voriconazole for injection can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line.

Total parenteral nutrition (TPN)

Voriconazole for injection can be infused at the same time as total parenteral nutrition, but must be infused in a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for voriconazole for injection.

2.3 Recommended Dosing Regimen 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 or oral suspension form of voriconazole may be utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg intravenously; a 300 mg oral dose achieves an exposure similar to 4 mg/kg intravenously.

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 (Adults)

a Increase dose when voriconazole is coadministered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.5)

b In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUCτ ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUCτ ) similar to a 4 mg/kg intravenous infusion every 12 hours dose (12).

c Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.

d In a clinical study of IA, the median duration of intravenous voriconazole therapy was 10 days (range 2 to 85 days). The median duration of oral voriconazole therapy was 76 days (range 2 to 232 days) (14.1).

e In clinical trials, patients with candidemia received 3 mg/kg intravenous infusion every 12 hours as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg every 12 hours as salvage therapy. Appropriate dose should be based on the severity and nature of the infection.

f Not evaluated in patients with EC.

Infection Loading dose Maintenance Dosea,b
Intravenous infusion Intravenous infusion Oralc
Invasive Aspergillosisd 6 mg/kg 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every hours
Candidemia in nonneutropenic patients and other deep tissue Candida infections 6 mg/kg every 12 hours for the first 24 hours 3 to 4 mg/kg every 12 hourse 200 mg every 12 hours
Esophageal Candidiasis Not Evaluatedf Not Evaluatedf 200 mg every 12 hours
Scedosporiosis and Fusariosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every 12 hours

Method for Adjusting the Dosing Regimen in Adults

If patient’s response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg intravenously every 12 hours) to 300 mg every 12 hours (similar to 4 mg/kg intravenously every 12 hours). 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 intravenously every 12 hours, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours.

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