Voriconazole

Voriconazole Manufacturers

• Major Pharmaceuticals
  

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  Voriconazole | Major Pharmaceuticals

  

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  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 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 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 Dosea,b

   

  IV

   

  IV

   

  Oralc

   

  Invasive Aspergillosisd

   

  6 mg/kg q12h for the first 24 hours

   

  4 mg/kg q12h

   

  200 mg q12h

   

  Candidemia in nonneutropenic patients and other deep tissue Candida infections

   

  6 mg/kg q12h for the first 24 hours

   

  3 to 4 mg/kg q12h

   

  200 mg q12h

   

  Esophageal Candidiasis

   

  f

   

  f

   

  200 mg q12h

   

  Scedosporiosis and Fusariosis

   

  6 mg/kg q12h for the first 24 hours

   

  4 mg/kg q12h

   

  200 mg q12h

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

  bIn 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)].

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

  d In a clinical study of invasive aspergillosis, 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) [see CLINICAL STUDIES (14.1)].

  e 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

  f 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 tablets have 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 tablets have 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.

  2.8 Use in Patients With Renal Impairment

  The pharmacokinetics of orally administered voriconazole tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see CLINICAL PHARMACOLOGY (12.3)].

  In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see WARNINGS AND PRECAUTIONS (5.10)].

  Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

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• Mckesson Packaging Services A Business Unit Of Mckesson Corporation
  

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  Voriconazole | Mckesson Packaging Services A Business Unit Of Mckesson Corporation

  

  ---

  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 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 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 Dosea,b

  IV

  IV

  Oralc

  Invasive Aspergillosisd

  6 mg/kg q12h for the first 24 hours

  4 mg/kg q12h

  200 mg q12h

  Candidemia in nonneutropenic patients and other deep tissue Candida infections

  6 mg/kg q12h for the first 24 hours

  3 to 4 mg/kg q12h

  200 mg q12h

  Esophageal Candidiasis

  f

  f

  200 mg q12h

  Scedosporiosis and Fusariosis

  6 mg/kg q12h for the first 24 hours

  4 mg/kg q12h

  200 mg q12h

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

  bIn 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)].

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

  d In a clinical study of invasive aspergillosis, 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) [see CLINICAL STUDIES (14.1)].

  e 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

  f 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 tablets have 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 tablets have 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.

  2.8 Use in Patients With Renal Impairment

  The pharmacokinetics of orally administered voriconazole tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see CLINICAL PHARMACOLOGY (12.3)].

  In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see WARNINGS AND PRECAUTIONS (5.10)].

  Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

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• Greenstone Llc
  

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  Voriconazole | Greenstone Llc

  

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  2.1 Instructions for Use in All Patients

  Voriconazole Tablets or Oral Suspension should be taken at least one hour before or after a meal.

  2.2 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 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 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‡ * Increase dose when voriconazole is co-administered with phenytoin or efavirenz ( 7); Decrease dose in patients with hepatic impairment ( 2.5) † In healthy volunteer studies, the 200 mg oral q12h dose provided an exposure (AUC τ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUC τ) similar to a 4 mg/kg IV q12h dose [see Clinical Pharmacology (12)]. ‡ Adult patients who weigh less than 40 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.         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 tissue 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 2.3 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 (2.5)]. 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.

  2.4 Oral Suspension

  Reconstitution

  Tap the bottle to release the powder. Add 46 mL of water to the bottle. Shake the closed bottle vigorously for about 1 minute. Remove child-resistant cap and push bottle adaptor into the neck of the bottle. Replace the cap. Write the date of expiration of the reconstituted suspension on the bottle label (the shelf-life of the reconstituted suspension is 14 days at controlled room temperature 15-30°C [59-86°F]).

  Instructions for use

  Shake the closed bottle of reconstituted suspension for approximately 10 seconds before each use. The reconstituted oral suspension should only be administered using the oral dispenser supplied with each pack.

  Incompatibilities

  Voriconazole for Oral Suspension and the 40 mg/mL reconstituted oral suspension should not be mixed with any other medication or additional flavoring agent. It is not intended that the suspension be further diluted with water or other vehicles.

  2.5 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.

  2.6 Use in Patients With Renal Impairment

  The pharmacokinetics of orally administered voriconazole are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see Clinical Pharmacology (12.3)].

  In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see Warnings and Precautions (5.10)].

  Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

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• Cardinal Health
  

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  Voriconazole | Cardinal Health

  

  ---

  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 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 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 nonneutropenic 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 * Increase dose when voriconazole is coadministered 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 (AUC τ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUC τ) similar to a 4 mg/kg IV q12h dose [ see Clinical Pharmacology (12)] ‡ Adult patients who weigh less than 40 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 to 90 days). The median duration of oral voriconazole therapy was 76 days (range 2 to 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. 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 non-neutropenic patients and other deep tissue Candida infections 6 mg/kg q12h for the first 24 hours 3 to 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

   

  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 coadministered 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 tablets have 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 tablets have 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.

  2.8 Use in Patients with Renal Impairment

  The pharmacokinetics of orally administered voriconazole are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see Clinical Pharmacology (12.3)].

  In patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see Warnings and Precautions (5.10)].

  Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

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• Mylan Pharmaceuticals Inc.
  

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  Voriconazole | Mylan Pharmaceuticals Inc.

  

  ---

  2.1 Instructions for Use in All Patients

  Voriconazole for oral suspension 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 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 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 * Increase dose when voriconazole is coadministered 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 (AUC τ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUC τ) similar to a 4 mg/kg IV q12h dose [see Clinical Pharmacology (12)]. ‡ Adult patients who weigh less than 40 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 to 85 days). The median duration of oral voriconazole therapy was 76 days (range 2 to 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.

  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 non-neutropenic patients and other deep tissue Candida infections

  6 mg/kg q12h for the first 24 hours

  3 to 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

  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 coadministered 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.

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

  2.6 Oral Suspension Reconstitution

  Tap the bottle to release the powder. Add 46 mL of water to the bottle. Shake the closed bottle vigorously for about one minute. Remove child-resistant cap and push bottle adaptor into the neck of the bottle. Replace the cap. Write the date of expiration of the reconstituted suspension on the bottle label (the shelf life of the reconstituted suspension is 14 days at controlled room temperature 20° to 25°C (68° to 77°F).

  Instructions for Use

  Shake the closed bottle of reconstituted suspension for approximately 10 seconds before each use. The reconstituted oral suspension should only be administered using the oral dispenser supplied with each pack.

  Incompatibilities

  Voriconazole for oral suspension and the 40 mg/mL reconstituted oral suspension should not be mixed with any other medication or additional flavoring agent. It is not intended that the suspension be further diluted with water or other vehicles.

  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 for oral suspension 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 for oral suspension 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.

  2.8 Use in Patients with Renal Impairment

  The pharmacokinetics of orally administered voriconazole for oral suspension are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see Clinical Pharmacology (12.3)].

  In patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see Warnings and Precautions (5.10)].

  Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

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  DIRECTIONS

  SHAKE WELL BEFORE USE APPLY LIBERALLY 15 MINUTES BEFORE SUN EXPOSURE REAPPLY: AFTER 80 MINUTES OF SWIMMING, SWEATING OR EXPOSURE TO WATER IMMEDIATELY AFTER TOWEL DRYING AT LEAST EVERY 2 HOURS

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  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 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 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 * Increase dose when voriconazole is coadministered 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 (AUC τ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUC τ) similar to a 4 mg/kg IV q12h dose [ see Clinical Pharmacology (12)]. ‡ Adult patients who weigh less than 40 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 to 85 days). The median duration of oral voriconazole therapy was 76 days (range 2 to 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.

  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 tissue Candida infections

  6 mg/kg q12h for the first 24 hours

  3 to 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

   

  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 coadministered 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 tablets have 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 tablets have 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.

  2.8 Use in Patients with Renal Impairment

  The pharmacokinetics of orally administered voriconazole tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see Clinical Pharmacology (12.3)].

  In patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see Warnings and Precautions (5.10)].

  Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

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  2.1 How to Take Drospirenone and Ethinyl Estradiol Tablets

  Take one tablet by mouth at the same time every day. The failure rate may increase when pills are missed or taken incorrectly.

  To achieve maximum contraceptive effectiveness, drospirenone and ethinyl estradiol tablets must be taken as directed, in the order directed on the blister pack. Single missed pills should be taken as soon as remembered.

  2.2 How to Start Drospirenone and Ethinyl Estradiol Tablets

  Instruct the patient to begin taking drospirenone and ethinyl estradiol tablets either on the first day of her menstrual period (Day 1 Start) or on the first Sunday after the onset of her menstrual period (Sunday Start).

  Day 1 Start

  During the first cycle of drospirenone and ethinyl estradiol tablets use, instruct the patient to take one yellow drospirenone and ethinyl estradiol tablets daily, beginning on Day 1 of her menstrual cycle. (The first day of menstruation is Day 1.) She should take one yellow drospirenone and ethinyl estradiol tablet daily for 21 consecutive days, followed by one white to off-white tablet daily on Days 22 through 28. Drospirenone and ethinyl estradiol tablets should be taken in the order directed on the package at the same time each day, preferably after the evening meal or at bedtime with some liquid, as needed. Drospirenone and ethinyl estradiol tablets can be taken without regard to meals. If Drospirenone and ethinyl estradiol tablets are first taken later than the first day of the menstrual cycle, drospirenone and ethinyl estradiol tablets should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered.

  Sunday Start

  During the first cycle of drospirenone and ethinyl estradiol tablets use, instruct the patient to take one yellow drospirenone and ethinyl estradiol tablet daily, beginning on the first Sunday after the onset of her menstrual period. She should take one yellow drospirenone and ethinyl estradiol tablet daily for 21 consecutive days, followed by one white to off-white tablet daily on Days 22 through 28. Drospirenone and ethinyl estradiol tablets should be taken in the order directed on the package at the same time each day, preferably after the evening meal or at bedtime with some liquid, as needed. Drospirenone and ethinyl estradiol tablets can be taken without regard to meals. Drospirenone and ethinyl estradiol tablets should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered.

  The patient should begin her next and all subsequent 28-day regimens of drospirenone and ethinyl estradiol tablets on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her yellow tablets on the next day after ingestion of the last white to off-white tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of drospirenone and ethinyl estradiol tablets is started later than the day following administration of the last white to off-white tablet, the patient should use another method of contraception until she has taken a yellow drospirenone and ethinyl estradiol tablets daily for seven consecutive days.

  When Switching from a Different Birth Control Pill

  When switching from another birth control pill, drospirenone and ethinyl estradiol tablets should be started on the same day that a new pack of the previous oral contraceptive would have been started.

  When Switching from a Method Other Than a Birth Control Pill

  When switching from a transdermal patch or vaginal ring, drospirenone and ethinyl estradiol tablets should be started when the next application would have been due. When switching from an injection, drospirenone and ethinyl estradiol tablets should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, drospirenone and ethinyl estradiol tablets should be started on the day of removal.

  Withdrawal bleeding usually occurs within 3 days following the last yellow tablet. If spotting or breakthrough bleeding occurs while taking drospirenone and ethinyl estradiol tablets, instruct the patient to continue taking drospirenone and ethinyl estradiol tablets by the regimen described above. Counsel her that this type of bleeding is usually transient and without significance; however, advise her that if the bleeding is persistent or prolonged, she should consult her healthcare provider.

  Although the occurrence of pregnancy is low if drospirenone and ethinyl estradiol tablets are taken according to directions, if withdrawal bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue drospirenone and ethinyl estradiol tablets if pregnancy is confirmed.

  The risk of pregnancy increases with each active yellow tablet missed. For additional patient instructions regarding missed pills, see the "What to Do if You Miss Pills"  section in the FDA Approved Patient Labeling. If breakthrough bleeding occurs following missed tablets, it will usually be transient and of no consequence. If the patient misses one or more white to off-white tablets, she should still be protected against pregnancy provided she begins taking a new cycle of yellow tablets on the proper day.

  For postpartum women who do not breastfeed or after a second trimester abortion, start drospirenone and ethinyl estradiol tablets no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts drospirenone and ethinyl estradiol tablets postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken drospirenone and ethinyl estradiol tablets for 7 consecutive days.

  2.3 Advice in Case of Gastrointestinal Disturbances

  In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after tablet-taking, this can be regarded as a missed tablet.

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  2.1 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.

  Do not administer as an IV 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 (5.8)].

  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 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 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 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 Loading dose Maintenance Dose*,† Infection IV IV Oral‡ * 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 40 kg should receive half of the oral maintenance dose. § In a clinical study of invasive aspergillosis, the median duration of intravenous voriconazole therapy was 10 days (range 2-85 days). The median duration of oral voraconazole therapy was 76 days (range 2 to 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.

  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 tissue 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

  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.

  2.5 Intravenous Administration

  Reconstitution

  The powder is reconstituted with 19 mL of Water For Injection to obtain an extractable volume of 20 mL of clear concentrate containing 10 mg/mL of voriconazole. It is recommended that a standard 20 mL (non-automated) syringe be used to ensure that the exact amount (19 mL) of Water for Injection is dispensed. Discard the vial if a vacuum does not pull the diluent into the vial. Shake the vial until all the powder is dissolved.

  Dilution

  Voriconazole for injection must be infused over 1 to 2 hours, at a concentration of 5 mg/mL or less. Therefore, the required volume of the 10 mg/mL voriconazole for injection concentrate should be further diluted as follows (appropriate diluents listed below):

  1. Calculate the volume of 10 mg/mL voriconazole for injection concentrate required based on the patient’s weight (see Table 2). 2. In order to allow the required volume of voriconazole for injection concentrate to be added, withdraw and discard at least an equal volume of diluent from the infusion bag or bottle to be used. The volume of diluent remaining in the bag or bottle should be such that when the 10 mg/mL voriconazole for injection concentrate is added, the final concentration is not less than 0.5 mg/mL nor greater than 5 mg/mL. 3. Using a suitable size syringe and aseptic technique, withdraw the required volume of voriconazole for injection concentrate from the appropriate number of vials and add to the infusion bag or bottle. Discard Partially Used Vials.

  The final voriconazole for injection solution must be infused over 1 to 2 hours at a maximum rate of 3 mg/kg per hour.

  Table 2. Required Volumes of 10 mg/mL Voriconazole for Injection Concentrate Volume of Voriconazole for Injection Concentrate (10 mg/mL) required for: Body Weight (kg) 3 mg/kg dose (number of vials) 4 mg/kg dose (number of vials) 6 mg/kg dose (number of vials)

  30

  9 mL (1)

  12 mL (1)

  18 mL (1)

  35

  10.5 mL (1)

  14 mL (1)

  21 mL (2)

  40

  12 mL (1)

  16 mL (1)

  24 mL (2)

  45

  13.5 mL (1)

  18 mL (1)

  27 mL (2)

  50

  15 mL (1)

  20 mL (1)

  30 mL (2)

  55

  16.5 mL (1)

  22 mL (2)

  33 mL (2)

  60

  18 mL (1)

  24 mL (2)

  36 mL (2)

  65

  19.5 mL (1)

  26 mL (2)

  39 mL (2)

  70

  21 mL (2)

  28 mL (2)

  42 mL (3)

  75

  22.5 mL (2)

  30 mL (2)

  45 mL (3)

  80

  24 mL (2)

  32 mL (2)

  48 mL (3)

  85

  25.5 mL (2)

  34 mL (2)

  51 mL (3)

  90

  27 mL (2)

  36 mL (2)

  54 mL (3)

  95

  28.5 mL (2)

  38 mL (2)

  57 mL (3)

  100

  30 mL (2)

  40 mL (2)

  60 mL (3)

  Voriconazole for injection is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2° to 8°C (36° to 46°F). This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used.

  The reconstituted solution can be diluted with:

  9 mg/mL (0.9%) Sodium Chloride USP

  Lactated Ringers USP

  5% Dextrose and Lactated Ringers USP

  5% Dextrose and 0.45% Sodium Chloride USP

  5% Dextrose USP

  5% Dextrose and 20 mEq Potassium Chloride USP

  0.45% Sodium Chloride USP

  5% Dextrose and 0.9% Sodium Chloride USP

  The compatibility of voriconazole for injection with diluents other than those described above is unknown (see Incompatibilities below).

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Incompatibilities

  Voriconazole for injection must not be diluted with 4.2% Sodium Bicarbonate Infusion. The mildly alkaline nature of this diluent caused slight degradation of voriconazole after 24 hours storage at room temperature. Although refrigerated storage is recommended following reconstitution, use of this diluent is not recommended as a precautionary measure. Compatibility with other concentrations is unknown.

  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.

  2.8 Use in Patients With Renal Impairment

  The pharmacokinetics of orally administered voriconazole are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see CLINICAL PHARMACOLOGY (12.3 )].

  In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see WARNINGS AND PRECAUTIONS (5.10)].

  Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

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  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 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 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 Dosea,b

  IV

  IV

  Oralc

  Invasive Aspergillosisd

  6 mg/kg q12h for the first 24 hours

  4 mg/kg q12h

  200 mg q12h

  Candidemia in nonneutropenic patients and other deep tissue Candida infections

  6 mg/kg q12h for the first 24 hours

  3 to 4 mg/kg q12he

  200 mg q12h

  Esophageal Candidiasis

  f

  f

  200 mg q12h

  Scedosporiosis and Fusariosis

  6 mg/kg q12h for the first 24 hours

  4 mg/kg q12h

  200 mg q12h

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

  bIn 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)].

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

  d In a clinical study of invasive aspergillosis, 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) [see CLINICAL STUDIES (14.1)].

  e 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

  f 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 tablets have 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 tablets have 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.

  2.8 Use in Patients With Renal Impairment

  The pharmacokinetics of orally administered voriconazole tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see CLINICAL PHARMACOLOGY (12.3)].

  In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see WARNINGS AND PRECAUTIONS (5.10)].

  Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

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