Voriconazole (Page 2 of 19)

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.

2.4 Recommended Dosing Regimen in Pediatric Patients

For pediatric patients 12 to 14 years of age with a body weight greater than or equal to 50 kg and those 15 years of age and above regardless of body weight, administer the adult dosing regimen of voriconazole tablets [see Dosage and Administration (2.3)] .

Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement.

Method for Adjusting the Dosing Regimen in Pediatric Patients

Pediatric Patients 12 to 14 Years of Age Weighing Greater Than or Equal to 50 kg and 15 Years of Age and Older Regardless of Body Weight

Use the optimal method for titrating dosage recommended for adults [see Dosage and Administration (2.3)] .

Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole). However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information.

2.5 Dosage Modifications in Patients With Hepatic Impairment

Adults

The maintenance dose of voriconazole tablets should be reduced in adult patients with mild to moderate hepatic impairment, Child-Pugh Class A and B. 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.

Adult patients with baseline liver function tests (ALT, AST) of up to 5 times the upper limit of normal (ULN) were included in the clinical program. Dose adjustments are not necessary for adult patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions (5.1)] .

It is recommended that the recommended voriconazole loading dose regimens be used, but that the maintenance dose be halved in adult 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 adult 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 with clinical signs of liver damage, such as jaundice. Voriconazole tablets should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity.

Pediatric Patients

Dosage adjustment of voriconazole tablets in pediatric patients with hepatic impairment has not been established [see Use in Specific Populations (8.4)] .

2.6 Dosage Modifications in Patients With Renal Impairment

Adult Patients

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) who are receiving an intravenous infusion of voriconazole, 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 (5.7)] .

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.

Pediatric Patients

Dosage adjustment of voriconazole tablets in pediatric patients with renal impairment has not been established [see Use in Specific Populations (8.4)] .

2.7 Dosage Adjustment When Co-Administered With Phenytoin or Efavirenz

The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz. Use the optimal method for titrating dosage [see Drug Interactions (7) and Dosage and Administration (2.3)] .

3 DOSAGE FORMS AND STRENGTHS

Voriconazole Tablets are available containing 50 mg or 200 mg of voriconazole, USP.

  • The 50 mg tablets are white to off-white, film coated, oval, unscored tablets debossed with V26 on one side and plain on the other.
  • The 200 mg tablets are white to off-white, film coated, capsule shaped, unscored tablets debossed with M164 on one side and plain on the other.

4 CONTRAINDICATIONS

  • Voriconazole tablets are contraindicated in patients with known hypersensitivity to voriconazole or their excipients. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing voriconazole tablets to patients with hypersensitivity to other azoles.
  • Coadministration of cisapride, pimozide or quinidine with voriconazole tablets is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
  • Coadministration of voriconazole tablets with sirolimus is contraindicated because voriconazole tablets significantly increase sirolimus concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
  • Coadministration of voriconazole tablets with rifampin, carbamazepine and long-acting barbiturates is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
  • Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg every 24 hours or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
  • Coadministration of voriconazole tablets with high-dose ritonavir (400 mg every 12 hours) is contraindicated because ritonavir (400 mg every 12 hours) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
  • Coadministration of voriconazole tablets with rifabutin is contraindicated since voriconazole tablets significantly increase rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
  • Coadministration of voriconazole tablets with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because voriconazole tablets may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
  • Coadministration of voriconazole tablets with St. John’s Wort is contraindicated because this herbal supplement may decrease voriconazole plasma concentration [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
  • Coadministration of voriconazole tablets with naloxegol is contraindicated because voriconazole tablets may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
  • Coadministration of voriconazole tablets with tolvaptan is contraindicated because voriconazole tablets may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions (7)] .

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