1.1 Invasive Aspergillosis

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 Clinical Pharmacology (12.4)].

1.2 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 Clinical Pharmacology (12.4)]

1.3 Esophageal Candidiasis

[see Clinical Studies (14.3) and Clinical Pharmacology (12.4)]

1.4 Serious Fungal Infections Caused by Scedosporium apiospermum (Asexual Form of Pseudallescheria boydii) and Fusarium spp. Including Fusarium solani, in Patients Intolerant of, or Refractory to, Other Therapy

[see Clinical Studies (14.4) and Clinical Pharmacology (12.4)]

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.

2.1 Instructions for Use in All Patients

Voriconazole tablets should be taken at least one hour before or after a meal.

2.3 Recommended Dosing 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 on Day 1 followed by the recommended maintenance dose regimen. Intravenous treatment should be continued for at least 7 days. Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of voriconazole may be utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg IV; a 300 mg oral dose achieves an exposure similar to 4 mg/kg IV.
Switching between the intravenous and oral formulations is appropriate because of the high bioavailability of the oral formulation in adults [see Clinical Pharmacology (12)].

Candidemia in non-neutropenic patients and other deep tissue Candida infections

See Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.

Esophageal Candidiasis

See Table 1. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.

2.4 Dosage Adjustment

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 [see Drug Interactions (7)].

The maintenance dose of voriconazole should be reduced in patients with mild to moderate hepatic impairment, Child-Pugh Class A and B [see Dosage and Administration (2.7)]. 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.

2.7 Use in Patients With Hepatic Impairment

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  [see Warnings and Precautions (5.9)].

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) [see Clinical Pharmacology (12.3)].

Voriconazole tablets have 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. Voriconazole tablets have 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.

2.8 Use in Patients With Renal Impairment

The pharmacokinetics of orally administered voriconazole tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see Clinical Pharmacology (12.3)].

In patients with moderate or severe renal impairment (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 Warnings and Precautions (5.10)].

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.

5.1 Drug Interactions

See Table 6 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 7 for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [see Contraindications (4) and Drug Interactions (7)].

5.2 Hepatic Toxicity

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with voriconazole (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 Warnings and Precautions (5.9) and Adverse Reactions (6.3)].

Measure serum transaminase levels and bilirubin at the initiation of voriconazole therapy and monitor at least weekly for the first month of treatment. Monitoring frequency can be reduced to monthly during continued use if no clinically significant changes are noted. If liver function tests become markedly elevated compared to baseline, voriconazole should be discontinued unless the medical judgment of the benefit-risk of the treatment for the patient justifies continued use. [see Warnings and Precautions (5.9), Dosage and Administration (2.4, 2.7), and Adverse Reactions (6.3)].

5.3 Visual Disturbances

The effect of voriconazole 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. If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored [see Adverse Reactions (6.2)].

5.4 Embryo-Fetal Toxicity

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 8.1 (Use in Pregnancy)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.

5.5 Galactose Intolerance

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

5.6 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 potentially proarrhythmic conditions such as:
• Congenital or acquired QT-prolongation
• Cardiomyopathy, in particular when heart failure is present
• Sinus bradycardia
• Existing symptomatic arrhythmias
• Concomitant medicinal product that is known to prolong QT interval [see Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3)]

Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy [see Clinical Pharmacology (12.3)].

5.7 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.

5.8 Laboratory Tests

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

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

5.9 Patients With Hepatic Impairment

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 voriconazole [see Clinical Pharmacology (12.3) and Dosage and Administration (2.7)].

Voriconazole has not been studied in patients with severe cirrhosis (Child-Pugh Class C). 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.

5.10 Patients With Renal Impairment

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 (12.3) and Dosage and Administration (2.8)].

5.11 Monitoring of Renal Function

Acute renal failure has been observed in patients undergoing treatment with 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.

5.12 Monitoring of Pancreatic Function

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

5.13 Dermatological Reactions

Serious exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, have been reported during treatment with voriconazole. If a patient develops an exfoliative cutaneous reaction, voriconazole should be discontinued.

Voriconazole has been associated with photosensitivity skin reaction. Patients, including children, should avoid exposure to direct sunlight during voriconazole treatment and should use measures such as protective clothing and sunscreen with high sun protection factor (SPF). If phototoxic reactions occur, the patient should be referred to a dermatologist and voriconazole discontinuation should be considered. If voriconazole is continued despite the occurrence of phototoxicity-related lesions, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Squamous cell carcinoma of the skin and melanoma have been reported during long-term voriconazole therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole should be discontinued.

The frequency of phototoxicity reactions is higher in the pediatric population. Because squamous cell carcinoma has been reported in patients who experience photosensitivity reactions, stringent measures for photoprotection are warranted in children. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

5.14 Skeletal Adverse Events

Fluorosis and periostitis have been reported during long-term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole should be discontinued [see Adverse Reactions (6.4)].

6.1 Overview

The most frequently reported adverse events (all causalities) in the 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 treatment-related adverse events which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances [see Warning and Precautions (5.2, 5.3), and Adverse Reactions (6.2, 6.3)].

6.2 Clinical Trial Experience in Adults

The data described in Table 2 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. Table 2 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 <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 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.

Table 2:

 Treatment Emergent Adverse Events

Rate ≥ 2% on Voriconazole or Adverse Events of Concern in All Therapeutic Studies Population, Studies 307/602-608 Combined, or Study 305. Possibly Related to Therapy or Causality Unknown*

* Study 307/602: invasive aspergillosis; Study 608: candidemia; Study 305: esophageal candidiasis

† Amphotericin B followed by other licensed antifungal therapy

‡ See Warnings and Precautions (5.3)

Visual Disturbances

Voriconazole treatment-related visual disturbances are common. In therapeutic trials, approximately 21% of patients experienced abnormal vision, color vision change and/or photophobia. Visual disturbances may be associated with higher plasma concentrations and/or doses.

There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema [see Warnings and Precautions (5.3)].

The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. In a study in healthy subjects investigating the effect of 28-day treatment with voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude, a decrease in the visual field, and an alteration in color perception. The ERG measures electrical currents in the retina. The effects were noted early in administration of voriconazole and continued through the course of study drug dosing. Fourteen days after end of dosing, ERG, visual fields and color perception returned to normal [see Warnings and Precautions (5.7)].

Dermatological Reactions

Dermatological reactions were common in the patients treated with voriconazole. The mechanism underlying these dermatologic adverse events remains unknown.

Serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme have been reported during treatment with voriconazole. If a patient develops an exfoliative cutaneous reaction, voriconazole should be discontinued.

In addition, voriconazole has been associated with photosensitivity skin reactions. Patients should avoid strong, direct sunlight during voriconazole therapy. 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, voriconazole should be discontinued [see Warnings and Precautions (5.13)].

Less Common Adverse Events

The following adverse events occurred in <2% of all voriconazole-treated patients in all therapeutic studies (N=1655). This listing includes events where a causal relationship to voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients. The list does not include events included in Table 2 above and does not include every event reported in the voriconazole clinical program.

Body as a Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction [see Warnings and Precautions (5.6)], ascites, asthenia, back pain, chest pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multi-organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain.

Cardiovascular: atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes) [see Warnings and Precautions (5.6)].

Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema.

Endocrine: adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism.

Hemic and Lymphatic: agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen, thrombocytopenia, thrombotic thrombocytopenic purpura.

Metabolic and Nutritional: albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema, uremia.

Musculoskeletal: arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis.

Nervous System: abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, Extrapyramidal Syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo.

Respiratory System: cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration.

Skin and Appendages: alopecia, angioedema, contact dermatitis, discoid lupus erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, maculopapular rash, melanoma, melanosis, photosensitivity skin reaction, pruritus, pseudoporphyria, psoriasis, skin discoloration, skin disorder, skin dry, Stevens-Johnson syndrome, squamous cell carcinoma, sweating, toxic epidermal necrolysis, urticaria.

Special Senses: abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, eye hemorrhage, dry eyes, hypoacusis, keratitis, keratoconjunctivitis, mydriasis, night blindness, optic atrophy, optic neuritis, otitis externa, papilledema, retinal hemorrhage, retinitis, scleritis, taste loss, taste perversion, tinnitus, uveitis, visual field defect.

Urogenital: anuria, blighted ovum, creatinine clearance decreased, dysmenorrhea, dysuria, epididymitis, glycosuria, hemorrhagic cystitis, hematuria, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, metrorrhagia, nephritis, nephrosis, oliguria, scrotal edema, urinary incontinence, urinary retention, urinary tract infection, uterine hemorrhage, vaginal hemorrhage.

6.3 Clinical Laboratory Values

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 voriconazole therapy. Patients who develop abnormal liver function tests during 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 voriconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole [see Warnings and Precautions (5.2)].

Acute renal failure has been observed in severely ill patients undergoing treatment with 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 3 to 5 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.

Table 3;

Protocol 305 – Patients with Esophageal Candidiasis

Clinically Significant Laboratory Test Abnormalities

     * Without regard to baseline value

n  = number of patients with a clinically significant abnormality while on study therapy

N  = total number of patients with at least one observation of the given lab test while on study therapy

ULN = upper limit of normal

 Table 4:

Protocol 307/602 – Primary Treatment of Invasive Aspergillosis

Clinically Significant Laboratory Test Abnormalities

* Without regard to baseline value

† Amphotericin B followed by other licensed antifungal therapy

n  = number of patients with a clinically significant abnormality while on study therapy

N = total number of patients with at least one observation of the given lab test while on study therapy

ULN = upper limit of normal

LLN = lower limit of normal

Table 5:

 Protocol 608 – Treatment of Candidemia

Clinically Significant Laboratory Test Abnormalities

* Without regard to baseline value

n =   number of patients with a clinically significant abnormality while on study therapy

N =   total number of patients with at least one observation of the given lab test while on study therapy

ULN =  upper limit of normal

LLN =   lower limit of normal

6.4 Postmarketing Experience

The following adverse reactions have been identified during post approval use of voriconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skeletal: fluorosis and periostitis have been reported during long-term voriconazole therapy [see Warnings and Precautions (5.14)].

Table 7: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]

* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects

† 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

‡ Results 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 q24h)

§ Non-Steroidal Anti-Inflammatory Drug

¶ Non-Nucleoside Reverse Transcriptase Inhibitors

8.1 Pregnancy

Pregnancy Category D

Voriconazole can cause fetal harm when administered to a pregnant woman and should not be taken in pregnancy except in patients where the benefit to the mother clearly outweighs the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patients should be informed of the potential hazard to the fetus [see Warnings and Precautions (5.4)].

Animal Data

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.

8.3 Nursing Mothers

It is not known whether voriconazole is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from voriconazole, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 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 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 [see Clinical Pharmacology (12.3)].

There have been postmarketing reports of pancreatitis in pediatric patients.

8.5 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 (12.3)].

8.6 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. Monitoring for adverse events associated with oral contraceptives and voriconazole is recommended [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Voriconazole is an antifungal drug [see Microbiology (12.4)]

12.3 Pharmacokinetics

General Pharmacokinetic Characteristics

The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients.

During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue), the observed pharmacokinetic characteristics were similar to those observed in healthy subjects.

The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. The interindividual variability of voriconazole pharmacokinetics is high. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg q12h to 300 mg q12h leads to an approximately 2.5-fold increase in exposure (AUCτ); similarly, increasing the intravenous dose from 3 mg/kg q12h to 4 mg/kg q12h produces an approximately 2.5-fold increase in exposure (Table 8).

12.4 Microbiology

Mechanism of Action
Voriconazole is an azole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of voriconazole.

Drug Resistance
Voriconazole drug resistance development has not been adequately studied in vitro against Candida, Aspergillus, Scedosporium and Fusarium species. The frequency of drug resistance development for the various fungi for which this drug is indicated is not known.
Fungal isolates exhibiting reduced susceptibility to fluconazole or itraconazole may also show reduced susceptibility to voriconazole, suggesting cross-resistance can occur among these azoles. The relevance of cross-resistance and clinical outcome has not been fully characterized. Clinical cases where azole cross-resistance is demonstrated may require alternative antifungal therapy.
Activity In Vitro and In Vivo
Voriconazole has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections.
Aspergillus fumigatus
Aspergillus flavus
Aspergillus niger
Aspergillus terreus
Candida albicans
Candida glabrata (In clinical studies, the voriconazole MIC90 was 4 µg/mL)*
Candida krusei
Candida parapsilosis
Candida tropicalis
Fusarium spp. including Fusarium solani
Scedosporium apiospermum

* In clinical studies, voriconazole MIC90 for C. glabrata baseline isolates was 4 µg/mL; 13/50 (26%) C. glabrata baseline isolates were resistant (MIC ≥4 µg/mL) to voriconazole. However, based on 1054 isolates tested in surveillance studies the MIC90 was 1 µg/mL (see Table 11).

13.1 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 administration induced no impairment of male or female fertility in rats dosed at 50 mg/kg, or 1.6 times the RMD (recommended maintenance dose).

13.2 Teratogenic Effects

Pregnancy category D [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1).]

14.1 Invasive Aspergillosis

Voriconazole was studied in patients for primary therapy of invasive aspergillosis (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with invasive aspergillosis who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604).

Study 307/602 – Primary Therapy of Invasive Aspergillosis

The efficacy of voriconazole compared to amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in 277 patients treated for 12 weeks in a randomized, controlled study (Study 307/602). The majority of study patients had underlying hematologic malignancies, including bone marrow transplantation. The study also included patients with solid organ transplantation, solid tumors, and AIDS. The patients were mainly treated for definite or probable invasive aspergillosis of the lungs. Other aspergillosis infections included disseminated disease, CNS infections and sinus infections. Diagnosis of definite or probable invasive aspergillosis was made according to criteria modified from those established by the National Institute of Allergy and Infectious Diseases Mycoses Study Group/European Organisation for Research and Treatment of Cancer (NIAID MSG/EORTC).

Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of seven days. Therapy could then be switched to the oral formulation at a dose of 200 mg q12h. Median duration of IV voriconazole therapy was 10 days (range 2 -85 days). After IV voriconazole therapy, the median duration of PO voriconazole therapy was 76 days (range 2-232 days).

Patients in the comparator group received conventional amphotericin B as a slow infusion at a daily dose of 1.0-1.5 mg/kg/day. Median duration of IV amphotericin therapy was 12 days (range 1-85 days). Treatment was then continued with other licensed antifungal therapy (OLAT), including itraconazole and lipid amphotericin B formulations. Although initial therapy with conventional amphotericin B was to be continued for at least two weeks, actual duration of therapy was at the discretion of the investigator. Patients who discontinued initial randomized therapy due to toxicity or lack of efficacy were eligible to continue in the study with OLAT treatment.

A satisfactory global response at 12 weeks (complete or partial resolution of all attributable symptoms, signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of voriconazole treated patients compared to 32% of amphotericin B treated patients (Table 13). A benefit of voriconazole compared to amphotericin B on patient survival at Day 84 was seen with a 71% survival rate on voriconazole compared to 58% on amphotericin B (Table 11).

Table 11 also summarizes the response (success) based on mycological confirmation and species.

Table 11:

Overall Efficacy and Success by Species in the Primary Treatment of Acute Invasive Aspergillosis
Study 307/602

* Assessed by independent Data Review Committee (DRC)

† Proportion of subjects alive

‡ Amphotericin B followed by other licensed antifungal therapy

§ Difference and corresponding 95% confidence interval are stratified by protocol

¶ Not all mycologically confirmed specimens were speciated

# Some patients had more than one species isolated at baseline

Study 304 – Primary and Salvage Therapy of Aspergillosis

In this non-comparative study, an overall success rate of 52% (26/50) was seen in patients treated with voriconazole for primary therapy. Success was seen in 17/29 (59%) with Aspergillus fumigatus infections and 3/6 (50%) patients with infections due to non-fumigatus species [A. flavus (1/1); A. nidulans (0/2); A. niger (2/2); A. terreus (0/1)]. Success in patients who received voriconazole as salvage therapy is presented in Table 12.

Study 309/604 – Treatment of Patients with Invasive Aspergillosis who were Refractory to, or Intolerant of, other Antifungal Therapy

Additional data regarding response rates in patients who were refractory to, or intolerant of, other antifungal agents are also provided in Table 14. In this non-comparative study, overall mycological eradication for culture-documented infections due to fumigatus and non-fumigatus species of Aspergillus was 36/82 (44%) and 12/30 (40%), respectively, in voriconazole treated patients. Patients had various underlying diseases and species other than A. fumigatus contributed to mixed infections in some cases.

For patients who were infected with a single pathogen and were refractory to, or intolerant of, other antifungal agents, the satisfactory response rates for voriconazole in studies 304 and 309/604 are presented in Table 12.

Table 12:

Combined Response Data in Salvage Patients with

Single Aspergillus Species (Studies 304 and 309/604)

Nineteen patients had more than one species of Aspergillus isolated. Success was seen in 4/17 (24%) of these patients.

14.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections

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 C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%), and C. krusei (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 Candida, infected deep tissue sites negative for Candida 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 Candida species in Study 150-608 are presented in Table 13.

 Table 13:

Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up

Time Point By Baseline Pathogen*,†

* A few patients had more than one pathogen at baseline.

† Patients who did not have a 12 week assessment for any reason were considered a treatment failure.

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 Candida infections. A favorable response was seen in 4 of 7 patients with intra-abdominal 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.

14.3 Esophageal Candidiasis

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 Table 14.

Table 14:

Success Rates in Patients Treated for Esophageal Candidiasis

* Confidence Interval for the difference (Voriconazole – Fluconazole) in success rates.

† PP (Per Protocol) patients had confirmation of Candida esophagitis by endoscopy, received at least 12 days of treatment and had a repeat endoscopy at EOT (end of treatment).

‡ ITT (Intent to Treat) patients without endoscopy or clinical assessment at EOT were treated as failures.

Microbiologic success rates by Candida species are presented in Table 15.

Table 15:

Clinical and mycological outcome by baseline pathogen in patients with esophageal candidiasis (Study 150-305)

* Some patients had more than one species isolated at baseline

† Patients with endoscopic and/or mycological assessment at end of therapy

14.4 Other Serious Fungal Pathogens

In pooled analyses of patients, voriconazole was shown to be effective against the following additional fungal pathogens:

Scedosporium apiospermum - Successful response to voriconazole therapy was seen in 15 of 24 patients (63%). Three of these patients relapsed within 4 weeks, including 1 patient with pulmonary, skin and eye infections, 1 patient with cerebral disease and 1 patient with skin infection. Ten patients had evidence of cerebral disease and 6 of these had a successful outcome (1 relapse). In addition, a successful response was seen in 1 of 3 patients with mixed organism infections.

Fusarium spp. - Nine of 21 (43%) patients were successfully treated with voriconazole. Of these 9 patients, 3 had eye infections, 1 had an eye and blood infection, 1 had a skin infection, 1 had a blood infection alone, 2 had sinus infections and 1 had disseminated infection (pulmonary, skin, hepatosplenic). Three of these patients (1 with disseminated disease, 1 with an eye infection and 1 with a blood infection) had Fusarium solani and were complete successes. Two of these patients relapsed, 1 with a sinus infection and profound neutropenia and 1 post surgical patient with blood and eye infections.

16.1 How Supplied

Voriconazole Tablets are available containing 50 mg or 200 mg of voriconazole.

The 50 mg tablets are white, round, biconvex, film-coated, with "V50" debossed on one side and plain on other side.

They are available as follows:

Bottles of 30 (NDC 61748-365-30)

The 200 mg tablets are white, caplet shaped, biconvex, film-coated, with "V200" debossed on one side and plain on other side.

They are available as follows:

Bottles of 30 (NDC 61748-366-30)

16.2 Storage

Voriconazole tablets should be stored at 20° to 25°C (68° to 77°F)  [see USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.