VFEND (Page 4 of 13)

3 DOSAGE FORMS AND STRENGTHS

Powder for Solution for Injection

VFEND I.V. for Injection is supplied in a single-dose vial as a sterile lyophilized powder equivalent to 200 mg voriconazole and 3,200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD).

4 CONTRAINDICATIONS

  • VFEND is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between VFEND (voriconazole) and other azole antifungal agents. Caution should be used when prescribing VFEND to patients with hypersensitivity to other azoles.
  • Coadministration of pimozide, quinidine, or ivabradine with VFEND 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 VFEND with sirolimus is contraindicated because VFEND significantly increases sirolimus concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
  • Coadministration of VFEND 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 VFEND 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 VFEND with rifabutin is contraindicated since VFEND significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
  • Coadministration of VFEND with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because VFEND may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [see Drug Interactions (7)].
  • Coadministration of VFEND with naloxegol is contraindicated because VFEND may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7)].
  • Coadministration of VFEND with tolvaptan is contraindicated because VFEND may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions (7)].
  • Coadministration of VFEND 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 VFEND 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 VFEND (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 VFEND 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, VFEND 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 VFEND, 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.

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

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

5.3 Infusion Related Reactions

During infusion of the intravenous formulation of VFEND in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly. Symptoms appeared immediately upon initiating the infusion. Consideration should be given to stopping the infusion should these reactions occur.

5.4 Visual Disturbances

The effect of VFEND 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)].

5.5 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with VFEND. If a patient develops a severe cutaneous adverse reaction, VFEND should be discontinued [see Adverse Reactions (6.1), (6.2)].

5.6 Photosensitivity

VFEND has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during VFEND treatment and should use measures such as protective clothing and sunscreen with high sun protection factor (SPF). If phototoxic reactions occur, the patient should be referred to a dermatologist and VFEND discontinuation should be considered. If VFEND is continued despite the occurrence of phototoxicity-related lesions, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Squamous cell carcinoma of the skin and melanoma have been reported during long-term VFEND therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, VFEND should be discontinued. In addition, VFEND has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus. Patients should avoid strong, direct sunlight during VFEND therapy.

The frequency of phototoxicity reactions is higher in the pediatric population. Because squamous cell carcinoma has been reported in patients who experience photosensitivity reactions, stringent measures for photoprotection are warranted in children. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

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