Voriconazole (Page 5 of 10)

6.2 Postmarketing Experience in Adult and Pediatric Patients

The following adverse reactions have been identified during post-approval use of voriconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adults

Skeletal: fluorosis and periostitis have been reported during long-term voriconazole therapy [ see Warnings and Precautions (5.12)].

Eye disorders: prolonged visual adverse reactions, including optic neuritis and papilledema [see Warnings and Precautions (5.4)] .

Skin and Appendages: drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]

Endocrine disorders: adrenal insufficiency, Cushing’s syndrome (when voriconazole has been used concomitantly with corticosteroids) [see Warnings and Precautions (5.8)].

Pediatric Patients

There have been postmarketing reports of pancreatitis in pediatric patients.

To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Voriconazole is metabolized by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to 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 after 200 mg every 12 hours) Recommendations for Voriconazole Dosage Adjustment/Comments
* 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

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 AUCτ

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 (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 events 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 events 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 events 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 events 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

Table 11:Effect of Voriconazole on Pharmacokinetics of Other Drugs [ see Clinical Pharmacology ( 12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure (C max and AUC τ ) Recommendations for Drug Dosage Adjustment/Comments
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID 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 *** 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 (30-100 mg every 24 hours) **** Non-Steroidal Anti-Inflammatory Drug ***** Non-Nucleoside Reverse Transcriptase Inhibitors

Sirolimus* (CYP3A4 Inhibition)

Significantly Increased

Contraindicated

Rifabutin* (CYP3A4 Inhibition)

Significantly Increased

Contraindicated

Efavirenz (400 mg every 24 hours)** (CYP3A4 Inhibition)

Significantly Increased

Contraindicated

Efavirenz (300 mg every 24 hours)**

(CYP3A4 Inhibition)

Slight Increase 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)**

(CYP3A4 Inhibition)

No Significant Effect of Voriconazole on Ritonavir C max or AUC τ

Contraindicated because of significant reduction of voriconazole C max and AUCτ

Low-dose Ritonavir (100 mg every 12 hours)**

Slight Decrease in Ritonavir C max and AUCτ

Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C max and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole

Cisapride, Pimozide, Quinidine (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

Cyclosporine* (CYP3A4 Inhibition)

AUC τ Significantly Increased; No Significant Effect on C max

When initiating therapy with voriconazole tablets 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 tablets are 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 events 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 tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ see Drug Interactions (7) ]

Alfentanil (CYP3A4 Inhibition)

Significantly Increased

Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablets. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ see Drug Interactions (7) ].

Oxycodone (CYP3A4 Inhibition)

Significantly Increased

Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ see Drug Interactions (7) ].

NSAIDs**** including. ibuprofen and diclofenac (CYP2C9 Inhibition)

Increased

Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ see Drug Interactions (7) ].

Tacrolimus* (CYP3A4 Inhibition)

Significantly Increased

When initiating therapy with voriconazole tablets 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 tablets are 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 events related to oral contraceptives is recommended during coadministration

Prednisolone and other corticosteroids (CYP3A4 Inhibition)

In Vivo Studies Showed No Significant Effects of voriconazole tablets 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 tablets [see Clinical Pharmacology (12.3)]. Monitor for potential adrenal dysfunction when voriconazole tablets is administered with other corticosteroids [See Warnings and Precautions (5.8)].

Warfarin* (CYP2C9 Inhibition)

Prothrombin Time Significantly Increased

Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.

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

Omeprazole* (CYP2C19/3A4 Inhibition)

Significantly Increased

When initiating therapy with voriconazole tablets 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

In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)

No dosage adjustment for indinavir when coadministered with voriconazole tablets

Frequent monitoring for adverse events 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 events and toxicity related to NNRTI

Benzodiazepines (CYP3A4 Inhibition)

In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.

HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)

In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)

Frequent monitoring for adverse events 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 events 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 events 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.

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