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Vfend (Voriconazole) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

Drug Interactions

Tables 11 and 12 provide a summary of significant drug interactions with voriconazole that either have been studied in vivo (clinically) or that may be expected to occur based on results of in vitro metabolism studies with human liver microsomes. For more details, see CLINICAL PHARMACOLOGY - Drug Interactions.

Table 11: Effect of Other Drugs on Voriconazole Pharmacokinetics
Drug/Drug Class
(Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure
(Cmax and AUCτ after
200 mg Q12h)
Recommendations for Voriconazole
Dosage Adjustment/Comments
Rifampin 1, and Rifabutin
(CYP450 Induction)
Significantly Reduced Contraindicated
Efavirenz 2
(CYP450 Induction)
Significantly ReducedWhen voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION-Dosage Adjustment)
High-dose Ritonavir (400mg Q12h)
(CYP450 Induction)
Significantly Reduced Contraindicated
Low-dose Ritonavir (100mg Q12h)
(CYP450 Induction)
ReducedCoadministration of voriconazole and low-dose ritonavir (100 mg Q12h) 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 ReducedIncrease voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hrs or from 200 mg to 400 mg orally every 12 hrs (100 mg to 200 mg orally every 12 hrs in patients weighing less than 40 kg)
St. John's Wort
(CYP450 inducer; P-gp inducer)
Significantly Reduced Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)IncreasedMonitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Other HIV Protease Inhibitors
(CYP3A4 Inhibition)
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure

In 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 events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs 3
(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

1 Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg Q12h voriconazole to healthy subjects
2 Results based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for at least 2 days voriconazole to healthy subjects
3 Non-Nucleoside Reverse Transcriptase Inhibitors

Table 12: Effect of Voriconazole on Pharmacokinetics of Other Drugs
Drug/Drug Class
(Mechanism of Interaction by Voriconazole)
Drug Plasma Exposure
(Cmax and AUCτ)
Recommendations for Drug Dosage Adjustment/Comments
Sirolimus 1
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Rifabutin
(CYP3A4 Inhibition)
Significantly Increased Contraindicated
Efavirenz 2
(CYP3A4 Inhibition)
Significantly IncreasedWhen voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION-Dosage Adjustment)
High-dose Ritonavir (400 mg Q12h)(CYP3A4 Inhibition)No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of voriconazole Cmax and AUCτ
Low-dose Ritonavir (100mg Q12h)Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) 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
Terfenadine, Astemizole, 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
Cyclosporine
(CYP3A4 Inhibition)
AUCτ Significantly Increased; No Significant Effect on CmaxWhen initiating therapy with VFEND 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 VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition)IncreasedIncreased 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
Alfentanil (CYP3A4 Inhibition)Significantly IncreasedReduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary (see CLINICAL PHARMACOLOGY - Drug Interactions).
Tacrolimus
(CYP3A4 Inhibition)
Significantly IncreasedWhen initiating therapy with VFEND 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 VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin
(CYP2C9 Inhibition)
Significantly IncreasedFrequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)IncreasedMonitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin
(CYP2C9 Inhibition)
Prothrombin Time Significantly IncreasedMonitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole
(CYP2C19/3A4 Inhibition)
Significantly IncreasedWhen initiating therapy with VFEND 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 VFEND

Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs 3
(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 IncreasedFrequent 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 IncreasedFrequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
1 Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
2 Results based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for at least 2 days voriconazole to healthy subjects
3 Non-Nucleoside Reverse Transcriptase Inhibitors

OVERDOSE

In clinical trials, there were three cases of accidental overdose. All occurred in pediatric patients who received up to five times the recommended intravenous dose of voriconazole. A single adverse event of photophobia of 10 minutes duration was reported.

There is no known antidote to voriconazole.

Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole and SBECD from the body.

The minimum lethal oral dose in mice and rats was 300 mg/kg (equivalent to 4 and 7 times the recommended maintenance dose (RMD), based on body surface area). At this dose, clinical signs observed in both mice and rats included salivation, mydriasis, titubation (loss of balance while moving), depressed behavior, prostration, partially closed eyes, and dyspnea. Other signs in mice were convulsions, corneal opacification and swollen abdomen.

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 the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine with VFEND are contraindicated since increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).

Coadministration of VFEND with sirolimus is contraindicated because VFEND significantly increases sirolimus concentrations in healthy subjects (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).

Coadministration of VFEND with rifampin, carbamazepine and long-acting barbiturates is contraindicated since these drugs are likely to decrease plasma voriconazole concentrations significantly (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).

Coadministration of VFEND with high-dose ritonavir (400 mg Q12h) is contraindicated because ritonavir (400 mg Q12h) significantly decreases plasma voriconazole concentrations in healthy subjects. Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).

Coadministration of VFEND with rifabutin is contraindicated since VFEND significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).

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.

Coadministration of VFEND with St. John's Wort is contraindicated (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).

REFERENCES

  1. Clinical Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of conidium-forming filamentous fungi. Approved Standard M38-P. Clinical Laboratory Standards Institute, Villanova, Pa.
  2. Clinical Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved Standard M27-A. Clinical Laboratory Standards Institute, Villanova, Pa.
  3. Clinical Laboratory Standards Institute. Method for antifungal disk diffusion susceptibility testing of yeasts. Approved guideline M44-A. Clinical Laboratory Standards Institute, Villanova, Pa.

Rx only

LAB-0271-22.0

May 2008

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