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Active ingredient: Voriconazole - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

  • Antifungals

Dosage Forms

  • Tablet
  • Oral suspension
  • IV injection

Brands / Synonyms

VCZ; Vfend; VFEND

Indications

For the treatment of esophageal candidiasis, invasive pulmonary aspergillosis, and serious fungal infections caused by Scedosporium apiospermum and Fusarium spp.

Pharmacology

Voriconazole is a triazole antifungal agent indicated for use in the treatment of fungal infections including invasive aspergillosis, esophageal candidiasis, and serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani. Fungal plasma membranes are similar to mammalian plasma membranes, differing in having the nonpolar sterol ergosterol, rather than cholesterol, as the principal sterol. Membrane sterols such as ergosterol provide structure, modulation of membrane fluidity, and possibly control of some physiologic events. Voriconazole effects the formation of the fungal plasma membrane by indirectly inhibiting the biosynthesis of ergosterol. This results in plasma membrane permeability changes and inhibition of growth.

Mechanism of Action

Voriconazole binds and inhibits ergosterol synthesis by inhibiting CYP450-dependent 14-alpha sterol demethylase. The inhibition of 14-alpha sterol demethylase results in a depletion of ergosterol in fungal cell membrane.

Absorption

The oral bioavailability is estimated to be 96% (CV 13%).

Toxicity

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.

Biotrnasformation / Drug Metabolism

Hepatic. The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma. Since this metabolite has minimal antifungal activity, it does not contribute to the overall efficacy of voriconazole.

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.

Coadministration of VFEND with sirolimus is contraindicated because VFEND significantly increases sirolimus concentrations in healthy subjects.

Coadministration of VFEND with rifampin, carbamazepine and long-acting barbiturates is contraindicated since these drugs are likely to decrease plasma voriconazole concentrations significantly.

Coadministration of VFEND with ritonavir (400 mg Q12h) is contraindicated because ritonavir (400 mg Q12h) significantly decreases plasma voriconazole concentrations in healthy subjects. The effect of ritonavir (100 mg Q12h as used to inhibit CYP3A and increase concentrations of other antiretroviral drugs) on voriconazole concentrations has not been studied.

Coadministration of VFEND with efavirenz is contraindicated because efavirenz significantly decreases voriconazole plasma concentrations while VFEND also significantly increases efavirenz plasma concentrations.

Coadministration of VFEND with rifabutin is contraindicated since VFEND significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations.

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.

Drug Interactions

Tables 9 and 10 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 9
Effect of Other Drugs on Voriconazole Pharmacokinetics

Drug/Drug Class (Mechanism of Interaction by the Drug)
Voriconazole Plasma Exposure (Cmax and AUCt after 200 mg Q12h)
Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin*, Efavirenz** and Rifabutin*(CYP450 Induction)
Significantly Reduced
Contraindicated
Ritonavir (400mg Q12h HIV ProteaseInhibitor)** (CYP450 Induction)
Significantly Reduced

Contraindicated

The effect of ritonavir (100 mg Q12h asused to inhibit CYP3A and increaseconcentrations of other antiretroviraldrugs) on voriconazole concentrationshas not been studied.

Carbamazepine(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likelyto Result in Significant Reduction
Contraindicated
Long Acting Barbiturates(CYP450 Induction)
Not Studied In Vivo or In Vitro, but Likelyto Result in Significant Reduction
Contraindicated
Phenytoin*(CYP450 Induction)
Significantly Reduced
Increase voriconazole maintenance dosefrom 4 mg/kg to 5 mg/kg IV every 12hrs or from 200 mg to 400 mg orallyevery 12 hrs (100 mg to 200 mg orallyevery 12 hrs in patients weighing lessthan 40 kg)
Other HIV Protease Inhibitors(CYP3A4 Inhibition)
In Vivo Studies Showed No SignificantEffects of Indinavir on VoriconazoleExposure
No dosage adjustment in thevoriconazole dosage needed whencoadministered with indinavir
In Vitro Studies Demonstrated Potential forInhibition of Voriconazole Metabolism(Increased Plasma Exposure)
Frequent monitoring for adverse eventsand toxicity related to voriconazolewhen coadministered with other HIVprotease inhibitors
Other NNRTIs***(CYP3A4 Inhibition or CYP450Induction)
In Vitro Studies Demonstrated Potential forInhibition of Voriconazole Metabolism byDelavirdine and Other NNRTIs (IncreasedPlasma Exposure)
Frequent monitoring for adverse eventsand toxicity related to voriconazole
A Voriconazole-Efavirenz Drug InteractionStudy Demonstrated the Potential for theMetabolism of Voriconazole to be Inducedby Efavirenz and Other NNRTIs(Decreased Plasma Exposure)
Careful assessment of voriconazoleeffectiveness

*Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg Q12h voriconazole to healthy subjects

**Results based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 8 days voriconazole to healthy subjects

*** Non-Nucleoside Reverse Transcriptase Inhibitors

Table 10
Effect of Voriconazole on Pharmacokinetics of Other Drugs

Drug/Drug Class
(Mechanism of Interaction by
Voriconazole)
Drug Plasma Exposure
(Cmax and AUCt )
Recommendations for Drug Dosage
Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)
Significantly Increased
Contraindicated
Rifabutin* and Efavirenz** (CYP3A4 Inhibition)
Significantly Increased
Contraindicated
Ritonavir (400 mg Q12h HIV Protease Inhibitor)**(CYP3A4 Inhibition)
No significant effect of voriconazole on ritonavir Cmax or AUCt
Contraindicated because of significant reduction of voriconazole Cmax and AUCt
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)
AUCt Significantly Increased; No Significant Effect on Cmax
When 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.
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
Tacrolimus* (CYP3A4 Inhibition)
Significantly Increased
When 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 Increased
Frequent monitoring of phenytoin
plasma concentrations and frequent
monitoring of adverse effects related to
phenytoin.
Warfarin*
(CYP2C9 Inhibition)
Prothrombin Time Significantly Increased
Monitor PT or other suitable anti-
coagulation tests. Adjustment of
warfarin dosage may be needed.
Omeprazole*
(CYP2C19/3A4 Inhibition)
Significantly Increased
When 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
No dosage adjustment for indinavir
when coadministered with VFEND
In Vitro Studies Demonstrate Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
Frequent monitoring for adverse events
and toxicity related to other HIV
protease inhibitors
Other NNRTIs****
(CYP3A4 Inhibition)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrates 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 Demonstrate 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 Demonstrate 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 Demonstrate 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. Adjustment of vinca
alkaloid dosage may be needed.

*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 Q12h for 1 day, then 200 mg Q12h for 8 days voriconazole to healthy subjects

*** Results 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)

**** Non-Nucleoside Reverse Transcriptase Inhibitors

Patients with Hepatic Insufficiency

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) receiving VFEND.

VFEND has not been studied in patients with severe cirrhosis (Child-Pugh Class C). VFEND has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic insufficiency if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.

Patients with Renal Insufficiency

In patients with moderate to severe renal dysfunction (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and if increases occur, consideration should be given to changing to oral voriconazole therapy.

Renal Adverse Events

Acute renal failure has been observed in severely ill patients undergoing treatment with VFEND. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function.

Monitoring of Renal Function

Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

Dermatological Reactions

Patients have rarely developed serious cutaneous reactions, such as Stevens-Johnson syndrome, during treatment with VFEND. If patients develop a rash, they should be monitored closely and consideration given to discontinuation of VFEND. VFEND has been infrequently associated with photosensitivity skin reaction, especially during long-term therapy. It is recommended that patients avoid strong, direct sunlight during VFEND therapy.

 

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