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
Table 12
Effect of Voriconazole on Pharmacokinetics of Other Drugs
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).