Voriconazole (Page 5 of 12)

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.

Dermatological Reactions

Increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with UV reactivation, was observed in postmarketing reports [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)].

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.

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 (Cmax and AUCτ 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) Efavirenz (300 mg every 24 hours)** (CYP450 Induction)

Significantly Reduced Slight Decrease in AUCτ

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)** (CYP450 Induction) Low-dose Ritonavir (100 mg every 12 hours)** (CYP450 Induction)

Significantly Reduced Reduced

Contraindicated 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 ExposureIn Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)

No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir. 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) 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)

Frequent monitoring for adverse reactions and toxicity related to voriconazole. 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 (Cmax and AUCτ ) 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 for1 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) 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 Cmax or AUCτ Slight Decrease in Ritonavir Cmax and AUCτ

Contraindicated because of significant reduction of voriconazole Cmax and AUCτ. Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole Cmax and AUCτ ) 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

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 tablets 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 tablets 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 tablets. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.

Lurasidone (CYP3A4 Inhibition)

Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone

Contraindicated

Cyclosporine* (CYP3A4 Inhibition)

AUCτ Significantly Increased; No Significant Effect on Cmax

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 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 voriconazoletablets. 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 tablets. 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 reactions may be necessary.

Oxycodone (CYP3A4 Inhibition)

Significantly Increased

Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with voriconazole tablets. 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 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 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 reactions 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)Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)

Prothrombin Time Significantly IncreasedNot 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 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 ExposureIn 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 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 IncreasedIn 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.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.