VORICONAZOLE Drug Interactions: What You Need to Know
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Drug Interactions (FDA Label)
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 )].
7 DRUG INTERACTIONS Voriconazole is metabolized by cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Therefore, inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole is a strong inhibitor of CYP3A4, and also inhibits CYP2C19 and CYP2C9. Therefore, voriconazole may increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes.
Tables
10 and 11 provide the clinically significant interactions between voriconazole and other medical products.
Table
10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology ( 12.3 )]
Drug/Drug
Class (Mechanism of Interaction by the Drug)
Voriconazole Plasma
Exposure (C max and AUC τ after 200 mg every 12 hours) Recommendations for Voriconazole Dosage Adjustment/Comments Rifampin * and Rifabutin * (CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (400 mg every 24 hours) ** (CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz (300 mg every 24 hours) ** (CYP450 Induction)
Slight
Decrease in AUC τ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours. High-dose Ritonavir (400 mg every 12 hours) ** (CYP450 Induction)
Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) ** (CYP450 Induction)
Reduced
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. Carbamazepine (CYP450 Induction)
Not Studied In
Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)
Not Studied In
Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Phenytoin * (CYP450 Induction)
Significantly Reduced
Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg). Letermovir (CYP2C9/2C19 Induction) Reduced If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole. St. John's Wort (CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated Oral
Contraceptives ** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)
Increased
Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives. Fluconazole ** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)
Significantly Increased
Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole. Other HIV Protease Inhibitors (CYP3A4 Inhibition)
In Vivo Studies Showed No
Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir.
In Vitro Studies Demonstrated
Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors. Other NNRTIs *** (CYP3A4 Inhibition or CYP450 Induction)
In Vitro Studies Demonstrated
Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to voriconazole. A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness. * Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjects ** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects *** Non-Nucleoside Reverse Transcriptase Inhibitors Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology ( 12.3 )] * Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects Drug/Drug Class (Mechanism of Interaction by Voriconazole)
Drug Plasma
Exposure (C max and AUC τ ) Recommendations for Drug Dosage Adjustment/Comments Sirolimus * (CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin * (CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz (400 mg every 24 hours) ** (CYP3A4 Inhibition) Efavirenz (300 mg every 24 hours) ** (CYP3A4 Inhibition)
Significantly Increased Slight
Increase in AUC τ Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours. High-dose Ritonavir (400 mg every 12 hours) ** (CYP3A4 Inhibition) Low-dose Ritonavir (100 mg every 12 hours) ** No Significant Effect of Voriconazole on Ritonavir C max or AUC τ Slight Decrease in Ritonavir C max and AUC τ Contraindicated because of significant reduction of voriconazole C max and AUC τ . Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C max and AUC τ ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)
Not Studied In
Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes.
Ergot
Alkaloids (CYP450 Inhibition)
Not Studied In
Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Contraindicated Naloxegol (CYP3A4 Inhibition)
Not Studied In
Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions Contraindicated Tolvaptan (CYP3A4 Inhibition)
Although Not Studied
Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan Contraindicated Lurasidone (CYP3A4 Inhibition)
Not Studied In
Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone Contraindicated Finerenone (CYP3A4 Inhibition)
Not Studied In
Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone Contraindicated Venetoclax (CYP3A4 Inhibition)
Not Studied In
Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering voriconazole with venetoclax. Refer to the venetoclax prescribing information for dosing instructions. Lemborexant (CYP3A4 Inhibition)
Not Studied In
Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Avoid concomitant use of voriconazole with lemborexant. Glasdegib (CYP3A4 Inhibition)
Not Studied In
Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation. Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)
Not Studied In
Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Avoid concomitant use of voriconazole. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product. Cyclosporine * (CYP3A4 Inhibition) AUC τ Significantly Increased; No Significant Effect on C max When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. Methadone *** (CYP3A4 Inhibition)
Increased
Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed. Fentanyl (CYP3A4 Inhibition)
Increased
Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary. Alfentanil (CYP3A4 Inhibition)
Significantly
Increased An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with voriconazole. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary. Oxycodone (CYP3A4 Inhibition)
Significantly Increased
Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with voriconazole. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary. NSAIDs **** including. ibuprofen and diclofenac (CYP2C9 Inhibition)
Increased
Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. Tacrolimus * (CYP3A4 Inhibition)
Significantly Increased
When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. Phenytoin * (CYP2C9 Inhibition)
Significantly Increased
Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral
Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) ** Increased Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration. Prednisolone and other corticosteroids (CYP3A4 Inhibition)
In Vivo Studies Showed No
Significant Effects of voriconazole on Prednisolone Exposure Not Studied In vitro or In vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased No dosage adjustment for prednisolone when coadministered with voriconazole [see Clinical Pharmacology (12.3)]. Monitor for potential adrenal dysfunction when voriconazole is administered with other corticosteroids [see Warnings and Precautions (5.8)]. Warfarin * (CYP2C9 Inhibition)
Other Oral Coumarin
Anticoagulants (CYP2C9/3A4 Inhibition)
Prothrombin Time Significantly Increased Not
Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly. Ivacaftor (CYP3A4 Inhibition)
Not Studied In
Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor Eszopiclone (CYP3A4 Inhibition)
Not Studied In
Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone. Omeprazole * (CYP2C19/3A4 Inhibition)
Significantly Increased
When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. Other HIV Protease Inhibitors (CYP3A4 Inhibition)
In Vivo Studies Showed No
Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with voriconazole.
In Vitro Studies Demonstrated
Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors. Other NNRTIs ***** (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to NNRTI. Tretinoin (CYP3A4 Inhibition)
Although Not
Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia. Midazolam (CYP3A4 Inhibition) Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)
Significantly Increased In Vitro Studies
Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details. HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)
In Vitro Studies Demonstrated
Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel
Blockers (CYP3A4 Inhibition)
In Vitro Studies Demonstrated
Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral
Hypoglycemics (CYP2C9 Inhibition)
Not Studied In
Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca
Alkaloids (CYP3A4 Inhibition)
Not Studied In
Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options. Everolimus (CYP3A4 Inhibition)
Not Studied In
Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended. ** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects *** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg every 24 hours) **** Non-Steroidal Anti-Inflammatory Drug ***** Non-Nucleoside Reverse Transcriptase Inhibitors
- CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust voriconazole tablets dosage and monitor for adverse reactions or lack of efficacy ( 4 , 7 )
- Voriconazole tablets may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions ( 4 , 7 )
- Phenytoin or Efavirenz: With co-administration, increase maintenance oral and intravenous dosage of voriconazole tablets ( 2.3 , 2.7 , 7 )
Contraindications
Hypersensitivity to voriconazole or its excipients ( 4 ) Coadministration with pimozide, quinidine, sirolimus or ivabradine due to risk of serious adverse reactions ( 4 , 7 ) Coadministration with rifampin, carbamazepine, long-acting barbiturates, efavirenz, ritonavir, rifabutin, ergot alkaloids, and St. John's Wort due to risk of loss of efficacy ( 4 , 7 ) Coadministration with naloxegol, tolvaptan, and lurasidone due to risk of adverse reactions ( 4 , 7 ) Coadministration of voriconazole with venetoclax at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to increased risk of adverse reactions ( 4 , 7 ) Voriconazole is 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 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 ) and Clinical Pharmacology ( 12.3 )] . 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 )].
Related Warnings
AND PRECAUTIONS Hepatic Toxicity : Serious hepatic reactions reported. Evaluate liver function tests at start of and during Voriconazole for injection therapy ( 5.1 ) Arrhythmias and QT Prolongation : Correct potassium, magnesium and calcium prior to use; caution patients with proarrhythmic conditions ( 5.2 )
Infusion Related
Reactions (including anaphylaxis) : Stop the infusion ( 5.3 )
Visual
Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days ( 5.4 )
Severe Cutaneous Adverse
Reactions : Discontinue for exfoliative cutaneous reactions ( 5.5 ) Photosensitivity : Avoid sunlight due to risk of photosensitivity ( 5.6 )
Adrenal
Dysfunction : Carefully monitor patients receiving Voriconazole for injection and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after Voriconazole for injection treatment. Instruct patients to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency ( 5.8 ) Embryo-Fetal Toxicity : Voriconazole can cause fetal harm when administered to a pregnant woman. Inform pregnant patients of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with Voriconazole for injection ( 5.9 , 8.1 , 8.3 )
Skeletal Adverse
Reactions : Fluorosis and periostitis with long-term voriconazole therapy. Discontinue if these adverse reactions occur ( 5.12 )
Clinically Significant Drug
Interactions : Review patient's concomitant medications ( 5.13 , 7 )
5.1 Hepatic Toxicity In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with Voriconazole for injection (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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . A higher frequency of liver enzyme elevations was observed in the pediatric population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Hepatic function should be monitored in both adult and pediatric patients. Measure serum transaminase levels and bilirubin at the initiation of Voriconazole for injection 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 for injection should be discontinued unless the medical judgment of the benefit/risk of the treatment for the patient justifies continued use <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) , and Adverse Reactions (6.1) ]</span> .
5.2 Arrhythmias and QT Prolongation Some azoles, including Voriconazole for injection, 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 for injection. 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 for injection 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 <span class="opacity-50 text-xs">[see Contraindications (4) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ]</span> Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.
5.3 Infusion Related Reactions During infusion of the intravenous formulation of Voriconazole for injection 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 Voriconazole for injection 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .
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 Voriconazole for injection. If a patient develops a severe cutaneous adverse reaction, Voriconazole for injection should be discontinued <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 , 6.2) ]</span>.
5.6 Photosensitivity Voriconazole for injection has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during Voriconazole for injection 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 Voriconazole for injection discontinuation should be considered.
If
Voriconazole for injection 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 (including cutaneous SCC in situ , or Bowen's disease) and melanoma have been reported during long-term Voriconazole for injection therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, Voriconazole for injection should be discontinued. In addition, Voriconazole for injection has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus, as well as increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with ultraviolet (UV) reactivation. There is the potential for this risk to be observed with other drugs associated with UV reactivation. Patients should avoid strong, direct sunlight during Voriconazole for injection 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.
5.7 Renal Toxicity Hydroxypropyl-β-cyclodextrin (HPβCD), the intravenous vehicle of Voriconazole for injection, is eliminated through glomerular filtration. Therefore, in patients with moderate to severe renal dysfunction (creatinine clearance <50 mL/min), accumulation of HPβCD occurs. Serum creatinine (Scr) levels should be closely monitored in patients with renal impairment. If increases in Scr occur, consideration should be given to changing to alternate antifungal therapy with similar coverage, unless an assessment of the benefit/risk to the patient justifies the continued use of intravenous Voriconazole for injection <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ]</span> . Acute renal failure has been observed in patients undergoing treatment with Voriconazole for injection. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that may result in decreased renal function. Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) and Dosage and Administration (2.6) ]</span> .
5.8 Adrenal Dysfunction Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including Voriconazole for injection. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression <span class="opacity-50 text-xs">[see Drug Interactions (7) and Clinical Pharmacology (12.3) ]</span> . Cushing's syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving Voriconazole for injection concomitantly with corticosteroids. Patients receiving Voriconazole for injection and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after Voriconazole for injection treatment. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency.
5.9 Embryo-Fetal Toxicity Voriconazole can cause fetal harm when administered to a pregnant woman. In animals, voriconazole administration was associated with fetal malformations, embryotoxicity, increased gestational length, dystocia and embryomortality <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> .
If
Voriconazole for injection is used during pregnancy, or if the patient becomes pregnant while taking Voriconazole for injection, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with Voriconazole for injection [see Use in Specific Populations (8.3) ] .