Voriconazole

Trade Names:
Vfend
- Tablets 50 mg
- Tablets 200 mg
- Powder for injection, lyophilized 200 mg
- Powder for oral suspension 45 g (40 mg/mL after reconstitution)

Pharmacology

User Reviews & Ratings As a treatment for... Avg User Ratings [?] Systemic Fungal Infection Be the first to rate it 0 reviews Fungal Pneumonia Be the first to rate it 0 reviews Aspergillosis, Invasive Be the first to rate it 0 reviews Showing 3 of 13 conditions - Show All... Compare with other drugs.

Inhibition of fungal CYP-450–mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis.

Pharmacokinetics

Absorption

Oral bioavailability is 96%. T _max is 1 to 2 h. AUC decreases 24% (tablet) and 37% (oral suspension) with high-fat meal. C _max decreases 34% (tablet) and 58% (oral suspension) with high-fat meal.

Distribution

Vd is 4.6 L/kg, suggesting extensive distribution into tissue. About 58% protein bound.

Metabolism

Nonlinear because of saturation of metabolism. Metabolized by CYP450 enzymes CYP2C19, CYP2C9, and CYP3A4, with CYP2C19 significantly involved; this enzyme also exhibits genetic polymorphism. Major metabolite, N-oxide, accounts for 72% of the circulating radiolabelled metabolites in the plasma but has minimal antifungal activity.

Elimination

Eliminated by hepatic metabolism with less than 2% of the dose excreted unchanged in the urine. Terminal t _½ is dose-dependent and is not useful in predicting accumulation or elimination.

Special Populations

AUC and C _max not significantly affected by renal impairment. No dosage adjustment necessary for oral dosing in patients with mild to severe renal impairment. Accumulation of the IV vehicle, SEBCD (sulfobutyl ether beta-cyclodextrin sodium), occurs in patients with moderate renal impairment (CrCl 30 to 50 mL/min).

AUC 3.2-fold higher in patients with mild to moderate hepatic impairment (Child-Pugh class A and B).

Indications and Usage

Treatment of invasive aspergillosis; treatment of Scedosporium apiospermum and Fusarium spp., including Fusarium solani , in patients intolerant of or refractory to other therapy; treatment of esophageal candidiasis; candidemia in nonneutropenic patients.

Contraindications

Hypersensitivity to voriconazole or any of it excipients; coadministration of carbamazepine, cisapride, efavirenz, ergot derivatives (eg, ergotamine, dihydroergotamine), long-acting barbiturates, pimozide, quinidine, rifabutin, rifampin, ritonavir, sirolimus.

Dosage and Administration

IV Loading dose of 6 mg/kg every 12 h for 2 doses, followed by a maintenance dose of 4 mg/kg every 12 h. If patients are unable to tolerate treatment, reduce IV maintenance dose to 3 mg/kg every 12 h. PO Once an oral dose can be tolerated, patients weighing more than 40 kg should receive 200 mg every 12 h. If response is inadequate, the oral dose may be increased to 300 mg every 12 h. If patients are unable to tolerate 300 mg every 12 h, reduce the oral dose by 50 mg increments to a minimum of 200 mg every 12 h. Patients weighing less than 40 kg should receive 100 mg every 12 h. If response is inadequate, the oral dose may be increased to 150 mg every 12 h. If patients weighing less than 40 kg are unable to tolerate 150 mg every 12 h, reduce the oral dose by 50 mg increments to a minimum of 100 mg every 12 h.

PO For patients weighing 40 kg or more, the recommended dosing regimen is 200 mg every 12 h. If response is inadequate, the dose may be increased to 300 mg every 12 h. If patients are unable to tolerate 300 mg every 12 h, reduce the oral dose by 50 mg increments to a minimum of 200 mg every 12 h. In patients weighing less than 40 kg, the recommended dose is 100 mg every 12 h. If response is inadequate, the dose may be increased to 150 mg every 12 h. If patients weighing less than 40 kg are unable to tolerate 150 mg every 12 h, reduce oral dose to 100 mg every 12 h. Treat for a minimum of 14 days and for at least 7 days after resolution of symptoms.

IV Loading dose of 6 mg/kg every 12 h for 2 doses, followed by a maintenance dose of 3 to 4 mg/kg every 12 h. If patients are unable to tolerate treatment, reduce IV maintenance dose to 3 mg/kg every 12 h. PO Once an oral dose can be tolerated, patients weighing more than 40 kg should receive 200 mg every 12 h. If response is inadequate, the oral dose may be increased to 300 mg every 12 h. If patients are unable to tolerate 300 mg every 12 h, reduce the oral dose by 50 mg increments to a minimum of 200 mg every 12 h. Patients weighing less than 40 kg should receive 100 mg every 12 h. If response is inadequate, the oral dose may be increased to 150 mg every 12 h. If patients weighing less than 40 kg are unable to tolerate 150 mg every 12 h, reduce the oral dose by 50 mg increments to a minimum of 100 mg every 12 h. Treat for a minimum of 14 days following resolution of symptoms or following last positive culture, whichever is longer.

IV or PO 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 function impairment (Child-Pugh class A and B).

Increase the IV maintenance dose of voriconazole to 5 mg/kg every 12 h, or the oral maintenance dose from 200 to 400 mg every 12 h. In patients weighing less than 40 kg, increase oral maintenance dose from 100 to 200 mg every 12 h.

General Advice

• Tablets and oral suspension
• Tablets and oral suspension are bioequivalent and can be interchanged on a mg-to-mg basis.
• Administer every 12 h, at least 1 h before or 1 h after a meal.
• Shake reconstituted oral suspension for approximately 10 sec before measuring dose. Administer using the supplied oral dispenser only.
• Do not mix reconstituted oral suspension with any other medication or flavoring agent or further dilute with water or other vehicles.

• Injection
• For IV infusion only. Not for intradermal, subcutaneous, IM, IV bolus, or intra-arterial administration.
• Reconstitute powder for injection with 19 mL water for injection. Discard vial if vacuum does not pull the diluent into the vial. Shake the vial until all the powder is dissolved. Reconstituted concentrate contains voriconazole 10 mg/mL.
• Further dilute reconstituted concentrate in compatible IV infusion solution to a final concentration of not less than 0.5 mg/mL nor greater than 5 mg/mL.
• Do not administer if solution is cloudy, discolored, or contains particulate matter.
• Discard any unused reconstituted concentrate. Do not save for future use.
• Administer loading doses and maintenance doses at a max rate of 3 mg/kg/h over 1 to 2 h.
• Do not administer concomitantly with other drug infusions or blood products.

Do not infuse voriconazole into the same line or cannula with other drug infusions, including parenteral nutrition (eg, Aminofusin 10% Plus ); do not infuse with blood products or electrolyte supplementations; do not dilute with 4.2% sodium bicarbonate infusion.

Storage/Stability

Store powder for oral suspension in refrigerator (36° to 46°F) before reconstitution. Store tablets and reconstituted oral suspension at controlled room temperature (59° to 86°F). Do not refrigerate or freeze reconstituted oral suspension. Discard any remaining reconstituted oral suspension 14 days after reconstitution. Store powder for injection at controlled room temperature (59° to 86°F). Reconstituted injection should be used immediately. If not used immediately, may be stored in refrigerator (36°to 46°F) for up to 24 h. Discard any unused solution or solution stored for more than 24 h.

Drug Interactions

Plasma exposure to these agents may be increased by voriconazole, increasing the pharmacologic and adverse effects.

Coadministration of these agents with voriconazole is contraindicated.

May decrease voriconazole plasma levels, reducing the pharmacologic effect.

May elevate voriconazole plasma levels, increasing the pharmacologic and adverse effect.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Tachycardia (2%); atrial arrhythmia, atrial fibrillation, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, CHF, complete AV block, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, MI, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolongation, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia including torsades de pointes (less than 2%).

CNS

Headache (3%); hallucinations (2%); abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, decreased libido, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, extrapyramidal syndrome, grand mal convulsion, Guillain-Barré, hypertonia, hypesthesia, insomnia, intracranial hypertension, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo (less than 2%).

Dermatologic

Rash (5%); alopecia, angioedema, contact dermatitis, discoid lupus erythematosus, dry skin, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, maculopapular rash, melanosis, photosensitivity skin reaction, pruritus, psoriasis, skin discoloration, skin disorder, Stevens-Johnson syndrome, sweating, toxic epidermal necrolysis, urticaria (less than 2%).

EENT

Abnormal vision (19%); photophobia (2%); chromatopsia (1%); abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, dry eyes, ear pain, epistaxis, eye hemorrhage, eye pain, hypoacusis, keratitis, keratoconjunctivitis, mydriasis, night blindness, optic atrophy, optic neuritis, otitis externa, papilledema, pharyngitis, retinal hemorrhage, retinitis, rhinitis, scleritis, taste loss, tinnitus, uveitis, visual field defect (less than 2%).

Endocrine

Adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism (less than 2%).

GI

Nausea (5%); vomiting (4%); anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, elevated gamma-glutamyl transpeptidase/LDH, esophageal ulcer, esophagitis, flatulence, gastroenteritis, GI hemorrhage, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, taste perversion, tongue edema (less than 2%).

Genitourinary

Abnormal kidney function (1%); anuria, blighted ovum, decreased CrCl, dysmenorrhea, dysuria, epididymitis, glycosuria, hematuria, hemorrhagic cystitis, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, metrorrhagia, nephritis, nephrosis, oliguria, scrotal edema, urinary incontinence, urinary retention, uterine hemorrhage, UTI, vaginal hemorrhage (less than 2%).

Hematologic-Lymphatic

Agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, cyanosis, DIC, ecchymosis, enlarged spleen, eosinophilia, hemolytic anemia, hypervolemia, increased bleeding time, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechiae, purpura, thrombocytopenia, thrombotic thrombocytopenic purpura (less than 2%).

Hepatic

Abnormal LFTs (3%); cholestatic jaundice (1%); enlarged liver, jaundice (less than 2%).

Local

Injection site pain, infection, and inflammation (less than 2%).

Metabolic-Nutritional

Increased alkaline phosphatase (4%); increased ALT, AST, hypokalemia (2%); bilirubinemia (1%); albuminuria, decreased glucose tolerance, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, increased BUN and creatine phosphokinase, uremia (less than 2%).

Musculoskeletal

Arthralgia, arthritis, back pain, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis (less than 2%).

Respiratory

Increased cough, dyspnea, hemoptysis, hypoxia, lung edema, pleural effusion, pneumonia, respiratory disorder, RDS, respiratory tract infection, sinusitis, voice alteration (less than 2%).

Miscellaneous

Fever (6%); chills (4%); abdominal pain, allergic reaction, anaphylactoid reaction, ascites, asthenia, bacterial infection, chest pain, cellulitis, edema, enlarged abdomen, facial edema, flank pain, flu syndrome, fungal infection, graft versus host reaction, granuloma, infection, mucous membrane disorder, multiorgan failure, pain, pelvic pain, peripheral edema, peritonitis, sepsis, substernal chest pain (less than 2%).

Precautions

Pregnancy

Category D . Women of childbearing potential should use effective contraception during treatment.

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 12 yr of age.

Renal Function

Use oral voriconazole in patients with moderate to severe renal impairment (CrCl less than 50 mL/min) unless an assessment of benefit/risk to patient justifies the use of IV voriconazole and accumulation of the IV vehicle, SEBCD. Monitor serum creatinine closely and, if increases occur, consider changing to oral voriconazole.

Hepatic Function

Reduce maintenance dose in patients with mild to moderate hepatic function impairment (Child-Pugh class A and B). Use in patients with severe hepatic function impairment (Child-Pugh class C) only if benefit outweighs risk and monitor patient carefully for drug toxicity.

Photosensitivity

Has occurred, especially during long-term therapy.

Arrhythmias and QT prolongation

Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias (including ventricular arrhythmias, cardiac arrests, and sudden deaths). Use with caution in patients with proarrhythmic conditions. Correct hypokalemia, hypomagnesemia, and hypocalcemia before initiating therapy.

Dermatologic reactions

Serious cutaneous reactions, such as Steven-Johnson syndrome, have occurred rarely. Closely monitor patients who develop a rash; consider discontinuing therapy.

Fructose intolerance

Oral suspension contains sucrose and should not be given to patients with hereditary problems of fructose intolerance, sucrase-isomaltase deficiency, or glucose-galactose malabsorption.

Galactose intolerance

The tablets contain lactose and should not be given to patients with hereditary galactose intolerance, Lapp lactose deficiency, or glucose-galactose malabsorption.

Hepatic toxicity

Cases of serious hepatic reactions (clinical hepatitis, cholestasis, and fulminant hepatic failure, including fatalities) have been reported. Consider discontinuing therapy if clinical signs and symptoms consistent with liver disease develop.

Infusion-related reactions

Anaphylactoid reactions (chest tightness, dyspnea, faintness, fever, flushing, nausea, pruritus, rash, sweating, tachycardia) have appeared immediately upon initiating infusion. Consider stopping the infusion if these reactions occur.

Visual disturbances

Effect of voriconazole on visual function is not known if treatment continues beyond 28 days.

Overdosage

Symptoms

Photophobia.

Patient Information

• Advise patient or caregiver that injectable form of drug will be prepared and administered by health care professional in a medical facility.
• Explain need for prolonged therapy and for close monitoring during course of therapy.
• Advise patient to take tablets or oral suspension every 12 h at least 1 h before or 1 h after a meal.
• Advise patient or caregiver using oral suspension to shake suspension for approximately 10 sec before measuring dose and to only use the oral dispenser supplied with the medication.
• Advise patient to report any of the following to health care provider: chills; dark urine; fever; injection site reaction; persistent diarrhea, nausea, or vomiting; persistent headache; rash; swelling of the feet, ankles, or calves; visual disturbances; yellowing of skin or eyes.
• Advise patient that medication may cause photosensitivity (sensitivity to sunlight), to avoid unnecessary exposure to sunlight or tanning lamps, and to use sunscreens and wear protective clothing to avoid photosensitivity reactions.
• Caution patient not to drive at night while taking this medication because it may cause changes in vision including blurring and sensitivity to bright light.
• Advise patient that drug may cause visual changes and to avoid driving or operating machinery if they perceive any change in vision.
• Instruct women of childbearing potential to use effective contraception while taking voriconazole.

Link to Page

Print Page

Email Page

Add to List