Voriconazole (Page 3 of 12)

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

Tablets

Voriconazole Tablets, 50 mg; white to off-white, circular biconvex film-coated tablets, debossed with “73” on one side and a “G” on the other side.

Voriconazole Tablets, 200 mg; white to off-white, oval shaped, film-coated tablets, debossed with “573” on one side and a “G” on the other side.

4 CONTRAINDICATIONS

  • Voriconazole tablets are contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing voriconazole to patients with hypersensitivity to other azoles.
  • Coadministration of pimozide, quinidine or ivabradine with voriconazole 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)] .
  • Coadministration of voriconazole with sirolimus is contraindicated because voriconazole significantly increases sirolimus concentrations [ see Drug Interactions ( 7) and Clinical Pharmacology ( 12.3) ].
  • Coadministration of voriconazole with rifampin, carbamazepine, long-acting barbiturates, and St John’s Wort 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 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 with rifabutin is contraindicated since voriconazole significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations [ see Drug Interactions ( 7) and Clinical Pharmacology ( 12.3) ].
  • Coadministration of voriconazole with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because voriconazole may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [ see Drug Interactions ( 7) ].
  • Coadministration of voriconazole with naloxegol is contraindicated because voriconazole may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions ( 7)] .
  • Coadministration of voriconazole with tolvaptan is contraindicated because voriconazole may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions ( 7)] .
  • Coadministration of voriconazole with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Drug Interactions ( 7)] .
  • Coadministration of voriconazole with lurasidone is contraindicated since it may result in significant increases in lurasidone exposure and the potential for serious adverse reactions [see Drug Interactions ( 7)] .

5 WARNINGS AND PRECAUTIONS

5.1 Hepatic Toxicity

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities ). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy [see Adverse Reactions ( 6.1)] .

A higher frequency of liver enzyme elevations was observed in the pediatric population [see Adverse Reactions ( 6.1)] . Hepatic function should be monitored in both adult and pediatric patients.

Measure serum transaminase levels and bilirubin at the initiation of voriconazole therapy and monitor at least weekly for the first month of treatment. Monitoring frequency can be reduced to monthly during continued use if no clinically significant changes are noted. If liver function tests become markedly elevated compared to baseline, voriconazole should be discontinued unless the medical judgment of the benefit/risk of the treatment for the patient justifies continued use [see Dosage and Administration ( 2.5) and Adverse Reactions ( 6.1)].

5.2 Arrhythmias and QT Prolongation

Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and post-marketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as torsade de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.

Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as:

  • Congenital or acquired QT prolongation
  • Cardiomyopathy, in particular when heart failure is present
  • Sinus bradycardia
  • Existing symptomatic arrhythmias
  • Concomitant medicinal product that is known to prolong QT interval [ see Contraindications ( 4), Drug Interactions ( 7), and Clinical Pharmacology ( 12.3) ]

Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy [see Clinical Pharmacology ( 12.3)] .

5.4 Visual Disturbances

The effect of voriconazole on visual function is not known if treatment continues beyond 28 days. There have been post-marketing reports of prolonged visual adverse reactions, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field, and color perception should be monitored [see Adverse Reactions ( 6.2)] .

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