Vfend Information
Vfend (Voriconazole) Indications And Usage
Vfend (Voriconazole) is indicated for use in patients 12 years of age and older in the treatment of the following fungal infections:
[].
Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.
Vfend (Voriconazole) Dosage And Administration
Vfend (Voriconazole) I.V. for Injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to administration as an infusion, at a maximum rate of 3 mg/kg per hour over 1 to 2 hours.
Do not administer as an IV bolus injection.
If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV q12h) to 300 mg every 12 hours (similar to 4 mg/kg IV q12h). For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).
If patient is unable to tolerate 4 mg/kg IV q12h, reduce the intravenous maintenance dose to 3 mg/kg q12h.
The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz [].
The maintenance dose of voriconazole should be reduced in patients with mild to moderate hepatic impairment, Child-Pugh Class A and B []. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).
Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.
In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [].
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) [].
Vfend (Voriconazole) has not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. Vfend (Voriconazole) 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 impairment if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.
The pharmacokinetics of orally administered Vfend (Voriconazole) are not significantly affected by renal impairment. Therefore, no adjustment is necessary for dosing in patients with mild to severe renal impairment [].
In patients with moderate or severe renal impairment (creatinine clearance
Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.
Vfend (Voriconazole) Warnings And Precautions
See for a listing of drugs that may significantly alter voriconazole concentrations. Also, see for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [].
Monitoring of hepatic function: Liver function tests should be evaluated at the start of and during the course of Vfend (Voriconazole) therapy. Patients who develop abnormal liver function tests during Vfend (Voriconazole) 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 (Voriconazole) must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to Vfend (Voriconazole) [].
Voriconazole can cause fetal harm when administered to a pregnant woman.
In animals, voriconazole administration was associated with teratogenicity, embryotoxicity, increased gestational length, dystocia and embryomortality. Please refer to section for additional details.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the fetus.
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 ), 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 [].
Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of Vfend (Voriconazole) therapy.
Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).
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 (Voriconazole) [].
Vfend (Voriconazole) has not been studied in patients with severe cirrhosis (Child-Pugh Class C). Vfend (Voriconazole) 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.
Acute renal failure has been observed in patients undergoing treatment with Vfend (Voriconazole) . 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.
Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Serious exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, have been reported during treatment with Vfend (Voriconazole) . If a patient develops an exfoliative cutaneous reaction, Vfend (Voriconazole) should be discontinued.
In addition Vfend (Voriconazole) has been associated with photosensitivity skin reaction. Patients should avoid intense or prolonged exposure to direct sunlight during Vfend (Voriconazole) treatment. In patients with photosensitivity skin reactions squamous cell carcinoma of the skin and melanoma have been reported during long-term therapy. If a patient develops a skin lesion consistent with squamous cell carcinoma or melanoma, Vfend (Voriconazole) should be discontinued.
Vfend (Voriconazole) Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in reflect exposure to voriconazole in 1655 patients in the therapeutic studies. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non-therapeutic studies. This patient population was 62% male, had a mean age of 46 years (range 11–90, including 51 patients aged 12–18 years), and was 78% white and 10% black. Five hundred sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months. includes all adverse events which were reported at an incidence of ≥2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, or study 305, as well as events of concern which occurred at an incidence of
In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy in the primary treatment of patients with acute invasive aspergillosis. The rate of discontinuation from voriconazole study medication due to adverse events was 21.4% (42/196 patients). In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from voriconazole study medication due to adverse events was 19.5% out of 272 patients. Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of esophageal candidiasis. The rate of discontinuation from voriconazole study medication in Study 305 due to adverse events was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.
The overall incidence of clinically significant transaminase abnormalities in all therapeutic studies was 12.4% (206/1655) of patients treated with voriconazole. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.
Voriconazole has been infrequently associated with cases of serious hepatic toxicity including cases of jaundice and rare cases of hepatitis and hepatic failure leading to death. Most of these patients had other serious underlying conditions.
Liver function tests should be evaluated at the start of and during the course of Vfend (Voriconazole) therapy. Patients who develop abnormal liver function tests during Vfend (Voriconazole) 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 (Voriconazole) must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to Vfend (Voriconazole) [].
Acute renal failure has been observed in severely ill patients undergoing treatment with Vfend (Voriconazole) . 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. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Tables 4 to 6 show the number of patients with hypokalemia and clinically significant changes in renal and liver function tests in three randomized, comparative multicenter studies. In study 305, patients with esophageal candidiasis were randomized to either oral voriconazole or oral fluconazole. In study 307/602, patients with definite or probable invasive aspergillosis were randomized to either voriconazole or amphotericin B therapy. In study 608, patients with candidemia were randomized to either voriconazole or the regimen of amphotericin B followed by fluconazole.
Vfend (Voriconazole) Use In Specific Populations
Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
A total of 22 patients aged 12 to 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 [].
There have been postmarketing reports of pancreatitis in pediatric patients.
Vfend (Voriconazole) Overdosage
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.
Vfend (Voriconazole) Description
Vfend (Voriconazole) (voriconazole), a triazole antifungal agent is available as a lyophilized powder for solution for intravenous infusion. The structural formula is:
Voriconazole is designated chemically as (2R, 3S)-2-(2, 4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1-1, 2, 4-triazol-1-yl)-2-butanol with an empirical formula of CHFNO and a molecular weight of 349.3.
Voriconazole drug substance is a white to light-colored powder.
Vfend (Voriconazole) I.V. is a white lyophilized powder containing nominally 200 mg voriconazole and 3200 mg sulfobutyl ether beta-cyclodextrin sodium in a 30 mL Type I clear glass vial.
Vfend (Voriconazole) I.V. is intended for administration by intravenous infusion. It is a single-dose, unpreserved product. Vials containing 200 mg lyophilized voriconazole are intended for reconstitution with Water for Injection to produce a solution containing 10 mg/mL Vfend (Voriconazole) and 160 mg/mL of sulfobutyl ether beta-cyclodextrin sodium. The resultant solution is further diluted prior to administration as an intravenous infusion [].
Vfend (Voriconazole) Nonclinical Toxicology
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/m 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/m 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 . 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.
Vfend (Voriconazole) Clinical Studies
Voriconazole, administered orally or parenterally, has been evaluated as primary or salvage therapy in 520 patients aged 12 years and older with infections caused by spp., spp., and spp.
Voriconazole was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open label, comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in 2:1 ratio to receive either voriconazole (n=283) or the regimen of amphotericin B followed by fluconazole (n=139). Patients were treated with randomized study drug for a median of 15 days. Most of the candidemia in patients evaluated for efficacy was caused by (46%), followed by (19%), (17%), (15%), and (1%).
An independent Data Review Committee (DRC), blinded to study treatment, reviewed the clinical and mycological data from this study, and generated one assessment of response for each patient. A successful response required all of the following: resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for , infected deep tissue sites negative for or resolution of all local signs of infection, and no systemic antifungal therapy other than study drug. The primary analysis, which counted DRC-assessed successes at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that voriconazole was comparable to the regimen of amphotericin B followed by fluconazole (response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients who did not have a 12-week assessment for any reason were considered a treatment failure.
The overall clinical and mycological success rates by species in Study 150-608 are presented in .
In a secondary analysis, which counted DRC-assessed successes at any time point (EOT, or 2, 6, or 12 weeks after EOT), the response rates were 65% for voriconazole and 71% for the regimen of amphotericin B followed by fluconazole.
In Studies 608 and 309/604 (non-comparative study in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal agents), voriconazole was evaluated in 35 patients with deep tissue infections. A favorable response was seen in 4 of 7 patients with intraabdominal infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1 patients with mixed intraabdominal and pulmonary infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection, and 0 of 1 with cervical lymph node infection.
The efficacy of oral voriconazole 200 mg twice daily compared to oral fluconazole 200 mg once daily in the primary treatment of esophageal candidiasis was demonstrated in Study 150-305, a double-blind, double-dummy study in immunocompromised patients with endoscopically-proven esophageal candidiasis. Patients were treated for a median of 15 days (range 1 to 49 days). Outcome was assessed by repeat endoscopy at end of treatment (EOT). A successful response was defined as a normal endoscopy at EOT or at least a 1 grade improvement over baseline endoscopic score. For patients in the Intent to Treat (ITT) population with only a baseline endoscopy, a successful response was defined as symptomatic cure or improvement at EOT compared to baseline. Voriconazole and fluconazole (200 mg once daily) showed comparable efficacy rates against esophageal candidiasis, as presented in .
Microbiologic success rates by species are presented in .
Vfend (Voriconazole) How Supplied/storage And Handling
Vfend (Voriconazole) I.V. for Injection unreconstituted vials should be stored at 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature]. Vfend (Voriconazole) is a single dose unpreserved sterile lyophile. From a microbiological point of view, following reconstitution of the lyophile with Water for Injection, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2° to 8°C (36° to 46°F). Chemical and physical in-use stability has been demonstrated for 24 hours at 2° to 8°C (36° to 46°F). This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used [].
LAB-0509-2.0
June 2011
Vfend (Voriconazole) Patient Counseling Information
Read the Patient Information that comes with Vfend (Voriconazole) before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your condition or treatment.
Vfend (Voriconazole) is a prescription medicine used to treat certain serious fungal infections in your blood and body. These infections are called "aspergillosis," "esophageal candidiasis," "" "" and "candidemia.".
It is not known if Vfend (Voriconazole) is safe and effective in children younger than 12 years old.
Ask your healthcare provider or pharmacist if you are not sure if you are taking any of the medicines listed above.
Do not start taking a new medicine without talking to your healthcare provider or pharmacist.
Before you take Vfend (Voriconazole) , tell your healthcare provider if you:
Vfend (Voriconazole) may affect the way other medicines work, and other medicines may affect how Vfend (Voriconazole) works.
Know what medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.
Vfend (Voriconazole) may cause serious side effects including:
Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the symptoms listed above.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Vfend (Voriconazole) . For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Vfend (Voriconazole) for a condition for which it was not prescribed. Do not give Vfend (Voriconazole) to other people, even if they have the same symptoms that you have. It may harm them.
This Patient Information leaflet summarizes the most important information about Vfend (Voriconazole) . If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about Vfend (Voriconazole) that is written for health professionals.
For more information, go to www.pfizerpro.com or call 1-800-438-1985.
Active ingredient: voriconazole
Inactive ingredients:
Vfend (Voriconazole)
Vfend (Voriconazole) Principal Display Panel - Mg Vial Carton
