Voriconazole

FDA Drug Information • Also known as: Vfend, Voriconazole

Brand Names: Vfend, Voriconazole
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION Voriconazole for injection, an azole antifungal is available as a sterile lyophilized cake or 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 H -1,2,4-triazol-1-yl)-2-butanol with an empirical formula of C 16 H 14 F 3 N 5 O and a molecular weight of 349.3. Voriconazole drug substance is a white or almost white powder. Voriconazole for injection is a white to off white lyophilized cake or powder containing nominally 200 mg voriconazole and 3200 mg hydroxypropyl β-cyclodextrin (HPβCD) in a 30 mL Type I clear glass vial. Voriconazole for injection is intended for administration by intravenous infusion. It is an unpreserved product in a single dose vial. Vials containing 200 mg lyophilized voriconazole are intended for reconstitution with Water for Injection to produce a solution containing 10 mg/mL Voriconazole for injection and 160 mg/mL of hydroxypropyl β-cyclodextrin (HPβCD). The resultant solution is further diluted prior to administration as an intravenous infusion [see Dosage and Administration (2) ] . Chemical Structure

What Is Voriconazole Used For?

1 INDICATIONS AND USAGE Voriconazole for injection is an azole antifungal indicated for use in the treatment of adults and pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight with: Invasive aspergillosis ( 1.1 ) Candidemia in non-neutropenics and other deep tissue Candida infections ( 1.2 ) Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani , in patients intolerant of, or refractory to, other therapy ( 1.3 ) 1.1 Invasive Aspergillosis Voriconazole for injection is indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of invasive aspergillosis (IA). In clinical trials, the majority of isolates recovered were Aspergillus fumigatus . There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus [see Clinical Studies (14.1) and Microbiology (12.4) ]. 1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections Voriconazole for injection is indicated in adult and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of candidemia in non-neutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds [see Clinical Studies (14.2) and Microbiology (12.4) ]. 1.3 Scedosporiosis and Fusariosis Voriconazole for injection is indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii ) and Fusarium spp . including Fusarium solani , in adult and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) intolerant of, or refractory to, other therapy [see Clinical Studies (14.3) and Microbiology (12.4) ] . 1.4 Usage 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. Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Dosage in Adults ( 2.3 ) Infection Loading dose Maintenance Dose Intravenous infusion Intravenous infusion Invasive Aspergillosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours Candidemia in nonneutropenics and other deep tissue Candida infections 3–4 mg/kg every 12 hours Scedosporiosis and Fusariosis 4 mg/kg every 12 hours Hepatic Impairment : Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) ( 2.5 ) Renal Impairment : Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) ( 2.6 ) Dosage in Pediatric Patients ( 2.4 ) For pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight use adult dosage. ( 2.4 ) Dosage adjustment of Voriconazole for injection in pediatric patients with renal or hepatic impairment has not been established. ( 2.5 , 2.6 ) See full prescribing information for instructions on reconstitution of Voriconazole for injection lyophilized powder for intravenous use ( 2.8 ) 2.1 Important Administration Instructions for Use in All Patients Voriconazole 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 3 hours. Administer diluted Voriconazole for injection by intravenous infusion over 1 to 3 hours only. Do not administer as an IV bolus injection. 2.2 Use of Voriconazole for injection With Other Parenteral Drug Products Blood products and concentrated electrolytes Voriconazole for injection must not be infused concomitantly with any blood product or short-term infusion of concentrated electrolytes, even if the two infusions are running in separate intravenous lines (or cannulas). Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during Voriconazole for injection therapy [see Warnings and Precautions (5.10) ] . Intravenous solutions containing (non-concentrated) electrolytes Voriconazole for injection can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line. Total parenteral nutrition (TPN) Voriconazole for injection can be infused at the same time as total parenteral nutrition, but must be infused in a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for Voriconazole for injection. 2.3 Recommended Dosing Regimen in Adults Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum See Table 1 . Therapy must be initiated with the specified loading dose regimen of intravenous Voriconazole for injection on Day 1 followed by the recommended maintenance dose...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Hepatic Toxicity [see Warnings and Precautions (5.1) ] Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2) ] Infusion Related Reactions [see Warnings and Precautions (5.3) ] Visual Disturbances [see Warnings and Precautions (5.4) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) ] Photosensitivity [see Warnings and Precautions (5.6) ] Renal Toxicity [see Warnings and Precautions (5.7) ] Adult patients : The most common adverse reactions (incidence ≥2%): were visual disturbances, fever, nausea, rash, vomiting, chills, headache, liver function test abnormal, tachycardia, hallucinations ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Xellia Pharmaceuticals USA, LLC at 1-833-295-6953, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. Clinical Trials Experience in Adults Overview The most frequently reported adverse reactions (see Table 3 ) in the adult therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%). The adverse reactions which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances [see Warning and Precautions (5.1 , 5.4) , and Adverse Reactions (6.1) ] . The data described in Table 3 reflect exposure to voriconazole in 1655 patients in the nine 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. Table 3 includes all adverse reactions which were reported at an incidence of ≥2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, as well as events of concern which occurred at an incidence of <2%. 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 (OLAT) in the primary treatment of patients with acute IA. The rate of discontinuation from voriconazole study medication due to adverse reactions 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 reactions was 19.5% out of 272 patients. Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below. Table 3: Adverse Reactions Rate ≥ 2% on Voriconazole or Adverse Reactions of Concern in Therapeutic Studies Population, Studies 307/602-608 Combined, Possibly Related to Therapy or Causality Unknown Study 307/602: IA; Study 608: candidemia Therapeutic Studies Studies 303, 304, 307, 309, 602, 603, 604, 608 Studies 307/602 and 608 Voriconazole N=1655 Voriconazole N=468 Ampho B Amphotericin B followed by other licensed antifungal therapy N=185 Ampho B→ Fluconazole N=131 N (%) N (%) N (%) N (%) Special Senses See Warnings and Precautions...

Drug Interactions

7 DRUG INTERACTIONS Voriconazole is metabolized by cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Therefore, inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole is a strong inhibitor of CYP3A4, and also inhibits CYP2C19 and CYP2C9. Therefore, voriconazole may increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes. Tables 6 and 7 provide the clinically significant interactions between voriconazole and other medical products. Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3) ] Drug/Drug Class (Mechanism of Interaction by the Drug) Voriconazole Plasma Exposure (C max and AUC τ after 200 mg every 12 hours) Recommendations for Voriconazole Dosage Adjustment/Comments Rifampin and Rifabutin (CYP450 Induction) Significantly Reduced Contraindicated Efavirenz (400 mg every 24 hours) (CYP450 Induction) Significantly Reduced Contraindicated High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction) Significantly Reduced Contraindicated Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) 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 (e.g., phenobarbital, mephobarbital) (CYP450 Induction) Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Phenytoin (CYP450 Induction) Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every12 hours Letermovir (CYP2C9/2C19 Induction) Reduced If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole. St. John's Wort (CYP450 inducer; P-gp inducer) Significantly Reduced Contraindicated Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir. In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to voriconazole when...

Contraindications

4 CONTRAINDICATIONS Voriconazole for injection is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between Voriconazole for injection (voriconazole) and other azole antifungal agents. Caution should be used when prescribing Voriconazole for injection to patients with hypersensitivity to other azoles. Coadministration of pimozide, quinidine or ivabradine with Voriconazole for injection is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes [see Drug Interactions (7) ] . Coadministration of Voriconazole for injection with sirolimus is contraindicated because Voriconazole for injection significantly increases sirolimus concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Coadministration of Voriconazole for injection with rifampin, carbamazepine, long-acting barbiturates and St. John's Wort is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg every 24 hours or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Coadministration of Voriconazole for injection with high-dose ritonavir (400 mg every 12 hours) is contraindicated because ritonavir (400 mg every 12 hours) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole [see Drug Interactions (7) and...

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Voriconazole can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Voriconazole for injection in pregnant women. In animal reproduction studies, oral voriconazole was associated with fetal malformations in rats and fetal toxicity in rabbits. Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to voriconazole during organogenesis at and above 10 mg/kg (0.3 times the RMD of 200 mg every 12 hours based on body surface area comparisons). In rabbits, embryomortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons) during organogenesis. Rats exposed to voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose [see Data ] . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus [see Warnings and Precautions (5.9) ] . The background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively. Data Animal Data Voriconazole was administered orally to pregnant rats during organogenesis (gestation days 6-17) at 10, 30, and 60 mg/kg/day. Voriconazole was associated with increased incidences of the malformations in hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the recommended human dose (RMD) based on body surface area comparisons, and cleft palate at 60 mg/kg, approximately 2 times the RMD based on body surface area comparisons....

Overdosage

10 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, HPβCD, is hemodialyzed with clearance of 37.5±24 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole and HPβCD from the body.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Voriconazole for injection is supplied in a single dose-vial as a sterile white to off white lyophilized cake or powder equivalent to 200 mg voriconazole and 3,200 mg hydroxypropyl β-cyclodextrin (HPβCD). It does not contain preservatives and is not made with natural rubber latex. Individually packaged vials of Voriconazole for injection, 200 mg, NDC 70594-067-01. 16.2 Storage Powder for Injection: Voriconazole for injection unreconstituted vials should be stored at 20°C – 25°C (68°F – 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Reconstituted Drug Solution: 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°C to 8°C (36° to 46°F). Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C (36° to 46°F). Discard Unused Portion [see Dosage and Administration (2.8) ] . Further Diluted Drug Solution for Infusion: Once the reconstituted product is further diluted for infusion, it should be used immediately. Discard Unused Portion [see Dosage and Administration (2.8) ] . This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used [see Dosage and Administration (2.8) ] . 16.1 How Supplied Voriconazole for injection is supplied in a single dose-vial as a sterile white to off white lyophilized cake or powder equivalent to 200 mg voriconazole and 3,200 mg hydroxypropyl β-cyclodextrin (HPβCD). It does not contain preservatives and is not made with natural rubber latex. Individually packaged vials of Voriconazole for injection, 200 mg, NDC 70594-067-01.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.