DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Vfend (Voriconazole) - Warnings and Precautions

 
 



WARNINGS

VISUAL DISTURBANCES

The effect of VFEND on visual function is not known if treatment continues beyond 28 days. There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. These events occurred primarily in severely ill patients who had underlying conditions and/or concomitant medications which may have caused or contributed to these events. If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored (see PRECAUTIONS – Information for Patients and ADVERSE REACTIONS – Visual Disturbances).

HEPATIC TOXICITY

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with VFEND (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 PRECAUTIONS – Laboratory Tests and ADVERSE REACTIONS – Clinical Laboratory Values).

Monitoring of hepatic function

Liver function tests should be evaluated at the start of and during the course of VFEND therapy. Patients who develop abnormal liver function tests during VFEND therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of VFEND must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to VFEND (see PRECAUTIONS - Laboratory Tests, DOSAGE AND ADMINISTRATION - Dosage Adjustment, ADVERSE REACTIONS - Clinical Laboratory Tests).

Pregnancy Category D

Voriconazole can cause fetal harm when administered to a pregnant woman.

Voriconazole was teratogenic in rats (cleft palates, hydronephrosis/hydroureter) from 10 mg/kg (0.3 times the recommended maintenance dose (RMD) on a mg/m2 basis) and embryotoxic in rabbits at 100 mg/kg (6 times the RMD). Other effects in rats included reduced ossification of sacral and caudal vertebrae, skull, pubic and hyoid bone, supernumerary ribs, anomalies of the sternebrae and dilatation of the ureter/renal pelvis. Plasma estradiol in pregnant rats was reduced at all dose levels. Voriconazole treatment in rats produced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose. The effects seen in rabbits were an increased embryomortality, reduced fetal weight and increased incidences of skeletal variations, cervical ribs and extrasternebral ossification sites.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Galactose intolerance

VFEND tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

PRECAUTIONS

General

(See WARNINGS, DOSAGE AND ADMINISTRATION)

Arrhythmias and QT Prolongation

Some azoles, including voriconazole, 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. 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 should be administered with caution to patients with these potentially proarrhythmic conditions.

Rigorous attempts to correct potassium, magnesium and calcium should be made before starting voriconazole (see CLINICAL PHARMACOLOGY- Pharmacokinetic-Pharmacodynamic Relationships - Electrocardiogram).

Infusion Related Reactions

During infusion of the intravenous formulation of voriconazole 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.

Information for Patients

Patients should be advised:

  • that VFEND Tablets or Oral Suspension should be taken at least one hour before, or one hour following, a meal.
  • that they should not drive at night while taking VFEND. VFEND may cause changes to vision, including blurring and/or photophobia.
  • that they should avoid potentially hazardous tasks, such as driving or operating machinery if they perceive any change in vision.
  • that strong, direct sunlight should be avoided during VFEND therapy.
  • that VFEND for Oral Suspension contains sucrose and is not recommended for patients with rare hereditary problems of fructose intolerance, sucrase-isomaltase deficiency or glucose-galactose malabsorption.

Laboratory Tests

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of VFEND therapy.

Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).

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

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 (see CLINICAL PHARMACOLOGY - Hepatic Insufficiency, DOSAGE and ADMINISTRATION - Hepatic Insufficiency).

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 (see CLINICAL PHARMACOLOGY - Renal Insufficiency, DOSAGE AND ADMINISTRATION - Renal Insufficiency).

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.

Monitoring of Pancreatic Function

Adults and children with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during VFEND treatment.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were conducted in rats and mice. Rats were given oral doses of 6, 18 or 50 mg/kg voriconazole, or 0.2, 0.6, or 1.6 times the recommended maintenance dose (RMD) on a mg/m2 basis. Hepatocellular adenomas were detected in females at 50 mg/kg and hepatocellular carcinomas were found in males at 6 and 50 mg/kg. Mice were given oral doses of 10, 30 or 100 mg/kg voriconazole, or 0.1, 0.4, or 1.4 times the RMD on a mg/m2 basis. In mice, hepatocellular adenomas were detected in males and females and hepatocellular carcinomas were detected in males at 1.4 times the RMD of voriconazole.

Voriconazole demonstrated clastogenic activity (mostly chromosome breaks) in human lymphocyte cultures in vitro. Voriconazole was not genotoxic in the Ames assay, CHO assay, the mouse micronucleus assay or the DNA repair test (Unscheduled DNA Synthesis assay).

Voriconazole produced a reduction in the pregnancy rates of rats dosed at 50 mg/kg, or 1.6 times the RMD. This was statistically significant only in the preliminary study and not in a larger fertility study.

Teratogenic Effects

Pregnancy category D (see WARNINGS).

Women of Childbearing Potential

Women of childbearing potential should use effective contraception during treatment. The coadministration of voriconazole with the oral contraceptive, Ortho-Novum® (35 mcg ethinyl estradiol and 1 mg norethindrone), results in an interaction between these two drugs, but is unlikely to reduce the contraceptive effect. (see CLINICAL PHARMACOLOGY-Drug Interactions-Oral Contraceptives; PRECAUTIONS-Drug Interactions)

Nursing Mothers

The excretion of voriconazole in breast milk has not been investigated. VFEND should not be used by nursing mothers unless the benefit clearly outweighs the risk.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

A total of 22 patients aged 12–18 years with invasive aspergillosis were included in the therapeutic studies. Twelve out of 22 (55%) patients had successful response after treatment with a maintenance dose of voriconazole 4 mg/kg Q12h .

Sparse plasma sampling for pharmacokinetics in adolescents was conducted in the therapeutic studies (see CLINICAL PHARMACOLOGY - Pharmacokinetics, General Pharmacokinetic Characteristics).

There have been postmarketing reports of pancreatitis in pediatric patients.

Geriatric Use

In multiple dose therapeutic trials of voriconazole, 9.2% of patients were ≥ 65 years of age and 1.8% of patients were ≥ 75 years of age. In a study in healthy subjects, the systemic exposure (AUC) and peak plasma concentrations (Cmax) were increased in elderly males compared to young males. Pharmacokinetic data obtained from 552 patients from 10 voriconazole therapeutic trials showed that voriconazole plasma concentrations in the elderly patients were approximately 80% to 90% higher than those in younger patients after either IV or oral administration. However, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended (see CLINICAL PHARMACOLOGY - Pharmacokinetics in Special Populations).

Page last updated: 2008-05-22

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2012