Mylan-Voriconazole Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Mylan-Voriconazole (voriconazole) is indicated in the treatment of:

• Invasive aspergillosis;
• 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 TRIALS, MICROBIOLOGY).

Geriatrics

Evidence from clinical studies and experience suggests that safety and effectiveness of voriconazole are similar in geriatric and adult subjects (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION and DETAILED PHARMACOLOGY).

Pediatrics

Safety and effectiveness of voriconazole in pediatric subjects below the age of twelve years have not been established (see WARNINGS AND PRECAUTIONS, CLINICAL TRIALS and DETAILED PHARMACOLOGY).

CONTRAINDICATIONS

Mylan-Voriconazole (voriconazole) is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. For a complete listing see Dosage Forms, Composition and Packaging section of the product monograph. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing Mylan-Voriconazole to patients with hypersensitivity to other azoles.

Voriconazole is a substrate and inhibitor of cytochrome P450 isozymes CYP2C19, CYP2C9 and CYP3A4. Thus, coadministration of voriconazole is contraindicated with drugs that are highly dependent on these isozymes for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events. In addition, coadministration of voriconazole is contraindicated with drugs that significantly decrease voriconazole plasma concentrations due to induction of these isozymes (see DRUG INTERACTIONS).

Coadministration of voriconazole is contraindicated with drugs that are CYP450 substrates and for which elevated plasma levels may result in serious and/or life-threatening events. These drugs are listed in Table 1.

Coadministration of voriconazole is contraindicated with drugs that are CYP450 inducers where significantly reduced voriconazole plasma levels may be associated with the potential for serious and/or life-threatening events. These drugs are listed in Table 1.

Table 1: Drugs That Are Contraindicated with Mylan-Voriconazole

* Not marketed in Canada

** also P-gp inducer

WARNINGS AND PRECAUTIONS

General

Mylan-Voriconazole tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance.

Cardiovascular

QT Interval Prolongation

Voriconazole has been associated with prolongation of the QT interval of the electrocardiogram in some patients. Prolongation of QT interval may increase the risk of arrhythmia (see DETAILED PHARMACOLOGY). During clinical development and post- marketing surveillance, there have been rare cases of arrhythmias (including ventricular arrhythmias such as torsades de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved patients with risk factors such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.

Due to limited clinical experience, voriconazole should be administered with caution to patients with potentially proarrhythmic conditions such as cardiomyopathy (in particular when heart failure is present), existing symptomatic arrhythmias, hypokalemia, clinically significant sinus bradycardia, acute myocardial ischemia, congestive heart failure or congenital or acquired prolongation of QT.

Caution should be exercised if voriconazole is used in patients taking other drugs that may prolong the QT interval, such as antipsychotics, tricyclic antidepressants, erythromycin, Class IA (e.g. procainamide, quinidine) Class III (e.g. amiodarone, sotalol) antiarrythmic agents (see DRUG INTERACTIONS).

There is a report of a life-threatening syncopal episode in a patient receiving concomitant voriconazole and methadone (see DRUG INTERACTIONS - Effect of Voriconazole on other drugs).

Drugs metabolized by the hepatic cytochrome P450 isoenzymes CYP2C19, CYP2C9 and CYP3A4 may also affect, or be affected by, voriconazole levels, with possible resulting QT effects. Such drugs include tacrolimus, HIV protease inhibitors, and macrolide antibiotics (See DRUG INTERACTIONS).

Ophthalmologic

Voriconazole may cause visual symptoms including photophobia altered/enhanced visual perception, blurred vision and/or color vision change. The majority of visual symptoms appeared to spontaneously resolve within 60 minutes. The effect of Mylan-Voriconazole on visual function is not known if treatment continues beyond 28 days. If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored.

There has been a small number of postmarketing reports of vision loss (including decreased visual acuity or visual fields) where a relationship to voriconazole could not be excluded. These events mostly occurred in medically complex patients, where underlying disease processes and the primary infections themselves confound interpretation (see below under ADVERSE REACTIONS, DETAILED PHARMACOLOGY- Animal Pharmacology).

There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. These events occurred primarily in severely ill patients who had underlying conditions and/or concomitant medications which may have caused or contributed to these events (see POST-MARKET ADVERSE DRUG REACTIONS).

Effects on Ability to Drive and Operating Machines

Voriconazole may cause visual symptoms including blurring and/or photophobia. The majority of visual symptoms appeared to spontaneously resolve within 60 minutes. Patients on voriconazole must avoid potentially hazardous tasks, such as driving or operating machinery if they perceive any change in vision. Patients should not drive at night while taking voriconazole.

Hepatic

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.

Patients who develop abnormal liver function tests during voriconazole therapy should be monitored for the development of more severe hepatic injury. Discontinuation of voriconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole (see below under Patients with Hepatic Impairment, ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, DETAILED PHARMACOLOGY).

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. Other symptoms, including hypotension, were considered to be infusion related in the clinical trial setting.

Pancreatic

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

Renal

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.

Sensitivity and Resistance

Voriconazole does not have activity against Zygomycete spp in vitro (see MICROBIOLOGY). Cases of breakthrough zygomycosis, most fatal, have been reported in patients who had received voriconazole (see references 5, 10, 14, 26 and 27).

Skin

There have been cases of exfoliative cutaneous reactions, such as Stevens-Johnson Syndrome (uncommon), toxic epidermal necrolysis (rare) and erythema multiforme (rare) during treatment with voriconazole (see ADVERSE REACTIONS). Stevens-Johnson Syndrome and toxic epidermal necrolysis should be considered as a differential diagnosis if patients develop prodromal flu-like symptoms (fever, malaise, rhinitis, chest pain. vomiting, sore throat, cough, diarrhea, headache, myalgia and arthralgia). If a patient develops an exfoliative cutaneous reaction voriconazole should be discontinued.

Photosensitivity reactions have been observed. It is recommended that patients, including children, avoid exposure to direct sunlight during voriconazole treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF). In patients with photosensitivity skin reactions and additional risk factors, squamous cell carcinoma of the skin and melanoma have been reported during long-term therapy.

If phototoxic reactions occur, multidisciplinary advice should be sought and the patient should be referred to a dermatologist. Voriconazole discontinuation should be considered. Dermatologic evaluation should be performed on a systematic and regular basis, whenever voriconazole is continued despite the occurrence of phototoxicity-related lesions, to allow early detection and management of premalignant lesions.

If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole discontinuation should be considered.

There was a small number of post-marketing reports of squamous cell carcinoma, all of which were preceded by episodes of photosensitivity and/or phototoxicity.

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

Skeletal adverse events

Non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been reported in transplant patients. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole should be discontinued.

Special Populations

Women of Child-Bearing Potential

Women of child-bearing potential should always use effective contraception during treatment with voriconazole.

Pregnant Woman

There are no adequate and well-controlled studies in pregnant women. Voriconazole can cause fetal harm when administered to a pregnant woman. If this drug is used in pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Voriconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus.

In reproduction studies in rats, voriconazole was teratogenic (cleft palate, hydronephrosis /hydroureter) from 10 mg/kg (0.3 times the human exposure based on body surface area comparisons) and above. Plasma estradiol in pregnant rats was reduced at all dose levels. Voriconazole treatment in rats produced increased gestational length and dystocia which was associated with increased perinatal pup mortality at the 10 mg/kg dose. In rabbits, voriconazole increased embryolethality, and reduced fetal weight (see TOXICOLOGY - Reproductive Toxicology).

Nursing Woman

Breast-feeding must be stopped on initiation of treatment with voriconazole. The excretion of voriconazole in breast milk has not been investigated.

Pediatric (< 12 years)

Safety and effectiveness in pediatric subjects below the age of twelve years have not been established. A limited number of pediatric subjects have received voriconazole at doses comparable to those used in adults on a per kilogram body weight basis. There were no apparent differences in safety or efficacy of voriconazole compared to adults although post-marketing data suggest there might be a higher occurrence of skin reactions in the pediatric population compared to adults. A total of 22 patients aged 12-18 years of 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 twice daily (see DETAILED PHARMACOLOGY).

Geriatrics (> 65 years)

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 clinical pharmacology study in healthy volunteers, some differences were seen in the pharmacokinetic parameters of elderly males compared to young males, and a relationship between plasma concentrations and age was observed in the patients in therapeutic studies. However, the overall safety profile of the elderly patients appeared similar to that of the young. Therefore dosage adjustment does not appear to be required (see DETAILED PHARMACOLOGY, DOSAGE AND ADMINISTRATION).

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 A and B) receiving voriconazole (see above under Hepatic, ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, DETAILED PHARMACOLOGY).

Safety and efficacy of reduced voriconazole dosing in this setting is not established.

Due to the small number of subjects studied, close clinical monitoring is advised.

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.

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. Renal function (including serum creatinine levels and creatinine clearance) should be closely monitored in these patients, and if significant changes occur, consideration should be given to changing to oral voriconazole therapy (see DOSAGE AND ADMINISTRATION, DETAILED PHARMACOLOGY).

Monitoring and Laboratory Tests

Patient management should include periodic laboratory evaluation of renal function (particularly serum creatinine).

Patients receiving voriconazole must be carefully monitored for hepatic toxicity. Clinical management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin) at the initiation of treatment with voriconazole and at least weekly for the first month of treatment. If treatment is continued, monitoring frequency can be reduced to monthly if there are no changes in the liver function tests.

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be monitored and corrected, if necessary, prior to initiation of and during voriconazole therapy (see DOSAGE AND ADMINISTRATION).

Carcinogenesis and Mutagenesis

In patients with photosensitivity skin reactions and additional risk factors, 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 discontinuation should be considered.

Voriconazole demonstrated clastogenic activity in human lymphocyte cultures in vitro. Voriconazole did not display mutagenic activity in bacterial or mammalian cells in vitro, or clastogenic activity in vivo.

For animal data regarding carcinogenesis and mutagenesis, see TOXICOLOGY.

ADVERSE REACTIONS

Overview

The most frequently reported adverse events (all causalities) in the therapeutic trials were visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorder. The treatment-related adverse events which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances (see WARNINGS AND PRECAUTIONS, DETAILED PHARMACOLOGY).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The data described in the table below reflect exposure to voriconazole in 1655 patients in the therapeutic studies. This represents a heterogeneous population, including immunocompromised patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy volunteers 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 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 studies 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. In study 608, 403 non-neutropenic patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) for another indication in immunocompromised (primarily HIV) patients. Laboratory test abnormalities 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

*Amphotericin B followed by other licensed antifungal therapy

Visual Disturbances:

In clinical trials, voriconazole treatment-related visual disturbances were common. In these studies, approximately 21% of patients experienced altered/enhanced visual perception, blurred vision, color vision change and/or photophobia. These visual disturbances were generally mild and rarely resulted in discontinuation. Visual disturbances may be associated with higher plasma concentrations and/or doses.

The mechanism of action of the visual disturbances is unknown, although the site of action is most likely to be within the retina. The majority of visual symptoms appeared to spontaneously resolve within 60 minutes. The serious conditions of the patients treated in Phase 3 studies did not generally allow rigorous testing of visual function. In a study in healthy volunteers investigating the effect of 28 days 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 colour perception. The ERG measures electrical currents in the retina. The effects were noted early in administration and continued through the course of study drug dosing. Fourteen days after the end of dosing, ERG, visual fields and colour perception returned to normal (see WARNINGS AND PRECAUTIONS, DETAILED PHARMACOLOGY).

Dermatological Reactions:

Dermatological reactions were common in the patients treated with voriconazole. The mechanism underlying these dermatologic adverse events remains unknown. In clinical trials, rashes considered related to therapy were reported by 7% (110/1655) of voriconazole-treated patients. The majority of rashes were of mild to moderate severity. Cases of photosensitivity reactions appear to be more likely to occur with long term treatment. Patients have developed serious cutaneous reactions, including Stevens Johnson syndrome (uncommon), toxic epidermal necrolysis (rare) and erythema multiforme (rare) during treatment with voriconazole. Stevens-Johnson Syndrome and toxic epidermal necrolysis should be considered as a differential diagnosis if patients develop prodromal flu-like symptoms (fever, malaise, rhinitis, chest pain. vomiting, sore throat, cough, diarrhea, headache, myalgia and arthralgia).

Patients should be closely monitored at the first appearance of a skin rash and voriconazole should be discontinued if lesions progress. It is recommended that patients avoid strong, direct sunlight during voriconazole therapy (see WARNINGS AND PRECAUTIONS).

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: Abdomen enlarged, abdominal pain, allergic reaction, anaphylactoid reaction (see CONTRAINDICATIONS), 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: A fatal case of ventricular fibrillation occurred where a relationship to voriconazole could not be ruled out. There have been rare cases of torsades de pointes in which a causal relationship to voriconazole could not be excluded.

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 torsades de pointes).

Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, dry mouth, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, 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, melanosis, photosensitivity skin reaction, psoriasis, pruritus, pseudoporphyria, skin discoloration, skin disorder, skin dry, sweating, toxic epidermal necrolysis, urticaria.

Special Senses: abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, eye hemorrhage, hypoacusis, dry eyes, 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.

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 incidences 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.

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.

Liver function tests should be evaluated at the start of and during the course of voriconazole therapy. Patients who develop abnormal liver function tests 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, DETAILED PHARMACOLOGY).

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, 4 and 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 were randomized to either oral voriconazole or oral fluconazole to evaluate an indication other than invasive aspergillosis in immunocompromised patients. In protocol 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 - 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 - 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 - 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

Post-Market Adverse Drug Reactions

During postmarketing surveillance, cases of severe hypoglycemia have been reported in patients receiving voriconazole and glipizide (see DRUG INTERACTIONS).

During post-marketing surveillance, there have been rare cases of arrhythmias (including ventricular arrhythmias such as torsades de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved patients with risk factors such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory (see WARNINGS AND PRECAUTIONS).

There have been post-marketing reports of pancreatitis in pediatric patients (see WARNINGS AND PRECAUTIONS).

There has been a small number of post-marketing reports of vision loss (including decreased visual acuity or visual fields) where a relationship to voriconazole could not be excluded. These events mostly occurred in medically complex patients, where underlying disease processes and the primary infections themselves confound interpretation (see WARNINGS AND PRECAUTIONS).

There have been post-marketing reports of prolonged visual adverse events (see WARNINGS AND PRECAUTIONS).

During post-marketing surveillance, there have been cases of hyponatremia and rare cases of peripheral neuropathy.

DRUG INTERACTIONS

Overview

Potential for Other Drugs to Affect Voriconazole

Voriconazole is metabolised by cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4. In vitro, the affinity for CYP3A4 is 100-fold lower than that for CYP2C9 and CYP2C19. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively.

Potential for Voriconzole to Affect Other Drugs

Voriconazole inhibits the activity of cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4. Therefore, there is potential for Mylan-Voriconazole to increase the plasma concentrations of drugs metabolised by these CYP450 isoenzymes. In patients who are CYP2C19 poor metabolizers, there may be more reliance on CYP3A4 for elimination.

Drug-Drug Interactions

Interactions between voriconazole and other medicinal products are listed in Table 6 (once daily as “QD”, twice daily as “BID”, three times daily as “TID” and not determined as “ND”). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) the 80-125% range. The asterisk (*) indicates a two-way interaction. AUC_τ, AUC_t and AUC_0-∞ represent area under the curve over a dosing interval, from time zero to the time with detectable measurement and from time zero to infinity, respectively.

The interactions in the table are presented in the following order: contraindications, those requiring dose adjustment and careful clinical and/or biological monitoring, and finally those that have no significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field.

Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects using multiple dosing to steady state with oral voriconazole at 200 mg BID. These results are relevant to other populations and routes of administration.

Table 6: Summary of Drug-Drug Interactions Between Voriconazole and Other Drugs

The asterisk (*) indicates a two-way interaction.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products such as St-John’s Wort (Hypericum perforatum) significantly reduced plasma exposure of voriconazole. Because long-term use of St. John’s Wort could lead to reduced voriconazole exposure, concomitant use of voriconazole with St. John’s Wort is contraindicated (see CONTRAINDICATIONS).

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing considerations

• Therapy should be initiated with the specified loading dose regimen.
• Dosage is based on weight.
• Dose can be adjusted if patient response is inadequate or patient is unable to tolerate treatment.

• In patients with mild to moderate hepatic impairment, the maintenance dose should be

  • halved.
• In patients with moderate to severe renal insufficiency (CrCl < 50 mL/min), oral voriconazole should be used.
• When Mylan-Voriconazole is taken concomitantly with other drugs, the dosage of voriconazole or the concomitant drugs may need to be adjusted (see DRUG INTERACTIONS).

Recommended Dose and Dosage Adjustment

Dosage

Use in Adults

Therapy must be initiated with the specified loading dose regimen of oral Mylan-Voriconazole to achieve adequate plasma concentrations on Day 1. Once the patient can tolerate medication given by mouth, the oral tablet of Mylan-Voriconazole may be utilized.

Detailed information on dosage recommendations is provided in the following table.

Table 7: Voriconazole Dosage and Administration

* In clinical trials, patients with candidemia received 3 mg/kg every 12 hours as primary therapy, while patients with invasive candidiasis received 4 mg/kg as salvage therapy. Appropriate dose should be based on the severity and nature of the infection.

¹BID = twice daily (12 hours apart).

Dosage Adjustment

If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every twelve hours to 300 mg every 12 hours. For patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every twelve hours to 150 mg every 12 hours. If patients are 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).

Treatment duration depends upon the patient's clinical and mycological response.

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

Administration

Mylan-Voriconazole Tablets should be taken at least one hour before, or two hours following a meal (see DETAILED PHARMACOLOGY).

Missed dose

Patients who miss taking a dose should take their regular dose next time it is due. Patients should not take a double dose to make up for the forgotten dose.

Special Populations

Use in Geriatrics

Dosage adjustment does not appear to be required for elderly patients (see WARNINGS AND PRECAUTIONS, DETAILED PHARMACOLOGY).

Use in Pediatrics

See WARNINGS AND PRECAUTIONS, DETAILED PHARMACOLOGY

Use in Patients with Renal Impairment

The pharmacokinetics of orally administered voriconazole do not appear to be affected by renal insufficiency. Therefore, no dosage adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

Due to the small number of subjects studied, close clinical monitoring is advised.

In patients with moderate or severe renal insufficiency (creatinine clearance <50 mL/min), oral voriconazole should be administered , unless an assessment of the benefit risk to the patient justifies the use of intravenous voriconazole. Renal function (including serum creatinine levels and creatinine clearance) should be closely monitored in these patients, and, if significant changes occur, consideration should be given to changing to oral voriconazole therapy (see WARNINGS AND PRECAUTIONS, DETAILED PHARMACOLOGY).

Voriconazole is hemodialyzed with clearance of 121 mL/min. The mean amount of voriconazole removed during 4 hour hemodialysis session (8%, range 1-16%) is not enough to warrant dose adjustment.

Use in Patients with Hepatic Impairment

Hepatic impairment is likely to result in increased voriconazole plasma levels in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B).

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 A and B).

Safety and efficacy of reduced voriconazole dosing in this setting is not established.

Due to the small number of subjects studied, close clinical monitoring is advised.

Voriconazole has not been studied in patients with severe hepatic cirrhosis (Child-Pugh C). Mylan-Voriconazole should be used only if the benefit outweighs the potential risk. Patients should be carefully monitored for drug toxicity (see WARNINGS AND PRECAUTIONS, DETAILED PHARMACOLOGY).

OVERDOSAGE

There is no known antidote to voriconazole; it is recommended that treatment of overdose is symptomatic and supportive. Administration of activated charcoal may be used to aid in removal of unabsorbed drug.

EKG monitoring is recommended due to the possible prolongation of the QT interval and ensuing risk of arrhythmia.

Voriconazole is hemodialyzed with clearance of 121 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole from the body.

In clinical trials, there were three cases of accidental overdose with voriconazole. 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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Mylan-Voriconazole (voriconazole) is a triazole antifungal agent, which exhibits broad-spectrum in vitro activity and fungicidal activity against Aspergillus spp. as well as a range of other filamentous fungi (see MICROBIOLOGY). The primary mode of action of voriconazole is the inhibition of fungal cytochrome P450-mediated 14α-sterol demethylation, an essential step in ergosterol biosynthesis. The subsequent loss of normal sterols correlates with the accumulation of 14α-methyl sterols in fungi and may be responsible for its fungistatic / fungicidal activity.

The voriconazole clinical program included a total of 38 patients with Scedosporium spp. and 21 patients with Fusarium spp. This limited clinical data suggest that voriconazole may be effective against infections caused by these rare pathogens in patients intolerant of or refractory to other therapies (see CLINICAL TRIALS).

Absorption

Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations ₍C_max) achieved 1-2 hours after dosing.

Distribution

The volume of distribution at steady-state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58%.

Metabolism

In vitro studies showed that voriconazole is metabolised by the hepatic cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4.

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 in healthy subjects from 200 mg Q12h to 300 mg Q12h leads to a 2.5 fold increase in exposure (AUC) while increasing the intravenous dose from 3 mg/kg Q12h to 4 mg/kg Q12h produces a 2.3 fold increase in exposure (Table 8).

Table 8: Population Pharmacokinetic Parameters of Voriconazole in Volunteers

*Mean AUC_T are predicted values from population pharmacokinetic analysis of data from 236 volunteers

The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma.

Elimination

Voriconazole is eliminated primarily by hepatic metabolism with less than 2% of the dose excreted unchanged in the urine. The terminal half life ₍T_1/2) depends on the dose and is approximately 6 hours at 3 mg/kg (intravenously) or 200 mg (oral). Because of non-linear pharmacokinetics, the terminal half-life is not useful in predicting the accumulation or elimination of voriconazole.

STORAGE AND STABILITY

Mylan-Voriconazole Tablets should be stored at controlled room temperature, 15°C - 30ºC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability

Mylan-Voriconazole 50 mg and 200 mg tablets are supplied in HDPE bottles of 30.

Composition

Mylan-Voriconazole 50 mg tablets are white to off-white, oval shaped, film coated tablets debossed with “V26” on one side and plain on the other.

Mylan-Voriconazole 200 mg tablets are white to off-white, capsule shaped, film coated tablets debossed with “M164” on one side and plain on the other.

Mylan-Voriconazole Tablets contain 50 mg or 200 mg of voriconazole. The inactive ingredients include croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, and a coating containing hypromellose, lactose monohydrate, titanium dioxide, and triacetin.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name:	Voriconazole
Chemical Name:	(2R, 3 S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H - 1,2,4-triazol-1-yl)butan-2-ol
Structural Formula:
Molecular Formula:	C16H14F3N5O
Molecular Weight:	349.31 g/mol
pka:	Determined experimentally and found to be between 12.00 and 4.98
Description:	voriconazole drug substance is a white to off-white crystalline powder
Solubility:	0.41 mg/mL pH 1.2 (0.1N HCl)
Melting Range:	127 - 130oC

CLINICAL TRIALS

Comparative Bioavailability Studies

A double-blind, randomized, single dose, two-way crossover study investigating the bioequivalence of 1 x 200 mg Mylan-Voriconazole (voriconazole) tablets (Mylan Pharmaceuticals ULC) and 1 x 200 mg VFEND® (voriconazole) tablets (Pfizer Canada Inc.) was conducted in 28 healthy, adult, male subjects under fasting conditions.

A summary of the comparative bioavailability data is presented below.

* Mylan-Voriconazole 200 mg tablets (Mylan Pharmaceuticals ULC)

† ^PrVFEND^® tablets 200 mg (Pfizer Canada Inc.) were purchased in Canada.

§ Expressed as the median (range) only.

€ Expressed as the arithmetic mean (CV%) only.

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 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 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 BID. 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.

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 9). 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 9). Table 9 also summarizes the response (success) based on mycological confirmation and species.

Table 9: Overall Efficacy and Success by Species in the Primary Treatment of Acute Invasive Aspergillosis Study 307/602

a Assessed by independent Data Review Committee (DRC)

b Proportion of subjects alive

c Amphotericin B followed by other licensed antifungal therapy

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

e Not all mycologically confirmed specimens were speciated

f Some patients had more than one species isolated at baseline

The results of this comparative trial (Study 307/602) confirmed the results of an earlier non- comparative trial in the primary and salvage treatment of patients with acute invasive aspergillosis (Study 304).

Candidemia

Voriconazole was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open label, comparative study in non-neutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in a 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 40.72% and 40.70%, respectively) in the treatment of candidemia. 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 65.48% for voriconazole and 71.33% 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 invasive candidiasis. 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, 2 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.

Other Serious Fungal Pathogens

Scedosporium spp. and Fusarium spp.

Voriconazole clinical program included a total of 38 patients with Scedosporium spp. and 21 patients with Fusarium spp. This limited clinical data suggest that voriconazole may be effective against these rare pathogens in patients intolerant of or refractory to other therapies.

Pediatric Use

Therapeutic trials included five patients aged 12-15 years. The remaining 56 patients received voriconazole in the compassionate use programs. Thus sixty-one (61) pediatric patients aged 9 months up to 15 years who had definite or probable invasive fungal infections, were treated with voriconazole. The majority (57/61) had failed previous antifungal therapies. Underlying diseases in these patients included hematologic malignancies and aplastic anemia (27 patients) and chronic granulomatous disease (14 patients). The most commonly treated fungal infection was aspergillosis (43/61; 70%).

Table 10: Clinical Outcome by Age in Pediatric Patients with Aspergillosis Infection

DETAILED PHARMACOLOGY

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 BID for 14 days in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue), the observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-linear pharmacokinetics were similar to those observed in healthy subjects.

The pharmacokinetics of voriconazole is non-linear due to saturation of its metabolism. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg BID to 300 mg BID leads to an approximately 2.5-fold increase in exposure (AUCτ), and increasing the intravenous dose from 3 mg/kg BID to 4 mg/kg BID produces a 2.3-fold increase in exposure.

The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) achieves a voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less than 40 kg) oral maintenance dose achieves an exposure similar to 4 mg/kg IV (see table below)

Table 11: Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens ^a Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies.

AUC₁₂ = area under the curve over 12 hour dosing interval, C_max = maximum plasma concentration, C_min = minimum plasma concentration.

When the recommended intravenous or oral loading dose regimens are administered, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (e.g, 6 mg/kg IV every 12 hours on day 1 followed by 3 mg/kg IV every 12 hours; 400 mg oral every 12 hours on day 1 followed by 200 mg oral every 12 hours). Without the loading dose, accumulation occurs during twice-daily multiple dosing with steady-state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects.

Absorption

Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (C_max) achieved 1-2 hours after dosing. The oral bioavailability of voriconazole is estimated to be 96%.

When multiple doses of voriconazole are administered with high fat meals, C_max and AUCτ are reduced by 34% and 24%, respectively when administered as a tablet.

The absorption of voriconazole is not affected by changes in gastric pH.

Distribution

The volume of distribution at steady-state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58%.

Voriconazole concentrations have been determined in cerebrospinal fluid (CSF) of a few patients. The range of CSF concentrations was similar to the range of plasma voriconazole concentrations observed in the overall patient population.

Metabolism

In vitro studies showed that voriconazole is metabolised by the hepatic cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4.

The interindividual variability of voriconazole pharmacokinetics is high.

In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected to be poor metabolisers. For Caucasians and Blacks, the prevalence of poor metabolisers is 3-5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolisers have, on average, 4-fold higher voriconazole exposure (AUCτ) than their homozygous extensive metaboliser counterparts. Subjects who are heterozygous extensive metabolisers have, on average, 2-fold higher voriconazole exposure than their homozygous extensive metaboliser counterparts.

The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma. Since this metabolite has minimal antifungal activity, it does not contribute to the overall efficacy of voriconazole.

Excretion

Voriconazole is eliminated primarily by hepatic metabolism with less than 2% of the dose excreted unchanged in the urine. After administration of a radiolabelled dose of voriconazole, approximately 80% of the radioactivity is recovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral dosing. The majority (> 94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.

The terminal half life (T_1/2) depends on the dose and is approximately 6 hours at 3 mg/kg (intravenously) or 200 mg (oral). Because of non-linear pharmacokinetics, the terminal half-life is not useful in predicting the accumulation or elimination of voriconazole.

Pharmacokinetic-pharmacodynamic (PK/PD) relationships

Analysis of the median pharmacokinetic data from 10 therapeutic trials shows that the average and maximum plasma concentrations in individual subjects across the studies was 2425 ng/mL (inter-quartile range 1193 to 4380 ng/mL) and 3742 ng/mL (inter-quartile range 2027 to 6302 ng/mL), respectively. A positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy in therapeutic studies was not found.

PK/PD analyses of clinical trial data identified positive associations between plasma voriconazole concentrations and both liver function test abnormalities and visual disturbances (see ADVERSE REACTIONS).

QT Prolongation

The effect of 3 oral, single doses of voriconazole (800, 1200 and 1600 mg) and an active comparator (oral ketoconazole 800 mg) was investigated in healthy subjects(male and female, 18-65 yrs) in a randomized, single-blind, placebo-controlled 5-way crossover study. At 1600 mg voriconazole resulted in prolongation of the electrocardiogram QTcF (F=Fridericia’s correction) by a mean maximum increase of 8.23 milliseconds (90% CI 6.01 to 10.45 milliseconds). The clinical significance of this change is unknown. No subject experienced a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec. Six out of 75 subjects (8%), 6 out of 77 (7.8%) and 14 out of 74 (19%) had a prolongation of 30 to 60 milliseconds after dosing with 800, 1200 and 1600 mg voriconazole, respectively. In comparison, 12 subjects out of 75 (16%) following ketoconazole 800 mg and 1 subject out of 76 (1%) following placebo had increases of 30 to 60 msec. No subject had a QTcF prolongation of greater than 60 milliseconds. No clear relationship between plasma voriconazole concentration and QTcF was observed in this study. The effect on cardiac QTcF with multiple dosing is unknown.

Pharmacokinetics in Special Populations

Gender

In the clinical program, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female subjects appeared similar (see results below).

In a multiple oral dose study, C_max and AUCτ for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18-45 years), after tablet dosing. In the same study, no significant differences in C_max and AUCτ were observed between healthy elderly males and healthy elderly females (≥ 65 years). In a multiple oral dose study with the oral suspension, the mean AUC for healthy young females was higher than in healthy young males whereas the mean C_max was comparable between genders. The steady state trough voriconazole concentrations (C_min) seen in females were higher than in males receiving the tablet and the oral suspension.

Geriatric

In therapeutic studies, no dosage adjustment was made on the basis of age. A relationship between plasma concentrations and age was observed (see results below). However, the safety profile of voriconazole in young and elderly subjects appeared similar. Therefore, dosage adjustment does not appear to be required (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION).

In an oral multiple dose study, C_max and AUCτ in healthy elderly males (≥ 65 years) were 61% and 86% higher, respectively, than in young males (18-45 years). No significant differences in C_max and AUCτ were observed between healthy elderly females (≥ 65 years) and healthy young females (18-45 years).

Table 12: Phase 1 phamacokinetic results in groups of young and elderly, male and female subjects are indicated in the table below.

* Means are geometric for AUC, AUCt, AUCτ and Cmax, arithmetic for Tmax

Figure 1: Plasma Voriconazole Concentrations in Individual Patients by Gender and Age

Group* - Phase 2/3 Therapeutic Studies

The Phase 1 study indicates that there appears to be a significant effect of age and gender on the exposure of voriconazole with increased levels in elderly versus young and female versus males; however, the Phase 2/3 database indicates the differences in voriconazole pharmacokinetics observed in the Phase 1 study are to a large extent negated for gender and there is a reduced effect of age.

Pediatric

Preliminary pharmacokinetic data were obtained from eight immunocompromised children (aged 2 to 11 years) in a single intravenous dose study and 18 patients (fourteen aged 2 to 11 years and four aged 12 to 15 years) in the compassionate use program. Plasma concentrations in these children were similar to those in adults following administration of similar intravenous doses of voriconazole on a weight-corrected basis (3 or 4 mg/kg).

Renal Impairment

Intravenous voriconazole should be avoided in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), unless an assessment of the benefit risk to the patient justifies the use of intravenous voriconazole (see DOSAGE AND ADMINISTRATION).

In patients with moderate renal dysfunction (creatinine clearance 30 - 50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. The mean systemic exposure (AUC) and peak plasma concentrations of SBECD (C_max) were increased by 4-fold and almost 50%, respectively, in the moderately impaired group compared to the normal control group.

A pharmacokinetic study in 6 subjects with renal failure undergoing hemodialysis showed that voriconazole is dialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. The mean amount of voriconazole removed during 4 hour hemodialysis session (8%, range 1-16%) is not enough to warrant dose adjustment.

In a single oral dose (200 mg) study in 24 subjects with normal renal function and mild to severe renal impairment, sytemic exposure (AUC) and peak plasma concentration (C_max) of voriconazole were not significantly affected by renal impairment. Therefore, no dosage adjustment appears necessary for oral dosing in patients with mild to severe renal impairment.

Due to the small number of subjects studied, close clinical monitoring is advised.

In a multiple dose study of IV voriconazole (6 mg/kg IV loading dose x 2, then 3 mg/kg IV x 5.5 days) in 7 patients with moderate renal dysfunction (creatinine clearance 30-50 mL/min), the systemic exposure (AUC) and peak plasma concentrations (C_max) were not significantly different from those in 6 volunteers with normal renal function.

Hepatic Impairment

Voriconazole should not be used in severe hepatic insufficiency. Hepatic impairment is likely to result in increased voriconazole plasma levels in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B), 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 A and B) receiving voriconazole (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION).

Due to the small number of subjects studied, close clinical monitoring is advised.

After an oral single dose (200 mg), AUC was 233% higher in subjects with mild to moderate hepatic cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding of voriconazole was not affected by impaired hepatic function.

In an oral multiple dose study, AUC was similar in subjects with moderate hepatic impairment (Child-Pugh B) given a lower maintenance dose of 100 mg BID and subjects with normal hepatic function given 200 mg BID. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh C).

The results of the study are outlined in the table below.

Table 13: Summary of pharmacokinetic parameters for normal and cirrhotic subjects

^a Geometric means. ^b Arithmetic mean. ^c Cirrhotic/Normal ratios (%) are presented for AUC_t, C_max and CL/F, Cirrhotic-Normal differences are presented for T_max.

Animal Pharmacology

The pharmacological properties of voriconazole were investigated in a variety of tests designed to evaluate its effects, if any, on major organ systems, in particular the central nervous, peripheral nervous, cardiovascular, gastrointestinal, renal and respiratory systems.

In a rat symptomatology study, voriconazole was lethal following an oral dose of 300 mg/kg. A lower dose (100 mg/kg) caused a small increase in body temperature, a decrease in food intake and body weight gain, whereas 30 mg/kg was devoid of untoward effects. Thus, voriconazole is well tolerated by the rat after single oral doses up to 100 mg/kg and these data are consistent with observations in the acute toxicity studies.

Voriconazole did not affect motor co-ordination up to 30 mg/kg p.o. in the mouse. In the anaesthetised cat, voriconazole at doses up to 3 mg/kg IV did not display any sympathomimetic or ganglion stimulating or blocking activity. Furthermore, in the cat voriconazole did not block α- or β-adrenoceptors or cholinergic, histaminergic or serotonergic receptors. Voriconazole also did not affect gastrointestinal function up to 10 mg/kg p.o. or respiratory function up to 3 mg/kg IV in the rat.

In the saline-loaded female rat, voriconazole up to 10 mg/kg p.o. had no effect on renal function, however, a small reduction in the excretion of electrolytes and increase in urinary volume was observed following 30 mg/kg IV, but this was not associated with any other changes in renal function. Voriconazole concentrations up to 10 μM did not display antihistaminic activity or affinity for a range of physiological receptors and binding sites, affect oxytocin-induced uterine contractions or inhibit the key enzymes acetylcholinesterase and Na/K-activated ATPase in vitro.

However, at voriconazole concentrations greater than 10 μM slight inhibition of spontaneous contractions of the rabbit isolated ileum and acetylcholine, histamine, 5HT and barium chloride-induced contractions of the guinea pig isolated ileum were observed. In mice, a potentiation of barbiturates-induced, but not alcohol-induced sleeping times was observed with voriconazole at 3 and 10 mg/kg p.o. and 3 and 30 mg/kg IV. This is consistent with the drug's known ability to interact with cytochrome P450, a key enzyme in the metabolism of barbiturates. Also, voriconazole does not display a sedative activity as evidenced by the lack of effect on interaction with alcohol.

Administration of voriconazole (12 mg/kg for 14 days) achieved supratherapeutic free plasma concentrations (14.6 to 28.4 μg/mL) in dogs chronically instrumented to record cardiovascular parameters. Voriconazole had no effect on cardiac contractility.

Cardiovascular Activity of Voriconazole

The preclinical development of voriconazole involved three general pharmacology studies in anaesthetised dogs over a range of intravenous doses. Arrhythmias occurred in a single anaesthetised dog at very high free plasma voriconazole concentrations (42 μg/mL; approximately

7 times the highest clinical concentration of around 5 μg/mL) in one of the escalating-dose studies. There were no predisposing factors identified in this animal. Arrhythmias were not seen in the other two studies.

From all available preclinical studies it can be concluded that intravenous doses of voriconazole that are tolerated in conscious dog at the maximum tolerated dose of 6 mg/kg had no effects on the ECG, either in anaesthetised or conscious dogs. Higher intravenous doses, yielding free exposure levels of up to 4.7 μg/mL (13.3 μM) in anaesthetised dogs, caused minor inconsistent changes in QTc interval of the ECG which were not detected in the toxicology program. Plasma concentrations increased with dose, as expected. Furthermore, voriconazole had no effect in in vitro assays which may be predictive of effects on cardiac repolarisation.

Effects on Electroretinogram in the Anaesthetised Dog

In order to understand the mechanism of visual disturbances seen in patients, we investigated the effect of intravenously administered voriconazole on the electroretinogram (ERG) of anaesthetized dogs. Voriconazole had an effect on the a-wave amplitude at a free steady state plasma concentration of 2.2 μg/mL (the lowest dose examined), and an effect on the b-wave amplitude at

4.6 μg/mL. These results confirm that the site of action of voriconazole is the retina.

Ophthalmological examinations have revealed no unusual findings in rats, mice or dogs treated in toxicology studies up to 24, 24 or 12 months respectively. The histopathological examination in these studies involved all the major structures and no histopathological evidence of toxicity to the visual pathways was observed. The peak plasma concentrations of free voriconazole in dogs used in toxicology studies (5 - 7 μg/mL) exceed the exposure range expected in man (0.6 - 2.4 μg/mL).

Thus, the effects on the ERG seen in humans have also been shown in dogs at similar plasma exposures of voriconazole. Despite exposure to plasma concentrations causing an effect on the ERG of the dog, the clinical, ophthalmoscopic, morphologic and morphometric data indicate that chronic treatment of rats and dogs with voriconazole was without detectable functional or anatomical changes to the retina.

Oral absorption of voriconazole is high (>75%) in all species. The drug has a non-linear elimination profile in all species (including human), and consequently plasma clearance and volume of distribution data are of limited utility. However, apparent volume of distribution values greater than total body water indicate that voriconazole has some tissue affinity, in keeping with its moderately lipophilic nature. In addition, significant concentrations of voriconazole are obtained in CSF and CNS of guinea pigs. Clearance of voriconazole is predominantly by hepatic metabolism resulting in several oxidised and further conjugated metabolites. The major circulating metabolite in human, rat and dog is the N-oxide, UK-121,265, which has negligible therapeutic activity. The majority of dosed voriconazole was excreted over 48h, with both urine and faeces being important routes of elimination. Multiple administration of voriconazole leads to auto-induction of metabolism in most animal species, but this effect is not observed in human. A sex difference in clearance was observed in rodents only. Voriconazole metabolism in humans is mediated by CYP2C9, CYP2C19 and CYP3A4 and it has been shown to competitively inhibit the same isoenzymes. Therefore, voriconazole has the potential for clinical interactions with co-administered drugs that are substrates for CYP2C9, CYP2C19 and CYP3A4. Since CYP2C19 exhibits genetic polymorphism, it is likely that poor metabolisers will be exposed to higher concentrations of voriconazole. Toxicokinetic data for voriconazole indicate that clinical exposure at the therapeutic maintenance doses is similar to or slightly lower than that seen in both rat and dog at doses without adverse effect in the 6-month toxicology studies.

MICROBIOLOGY

Activity in vitro and in vivo

Voriconazole demonstrated in vitro activity against Aspergillus species (A. fumigatus, A. flavus, A. niger and A. terreus) and Candida species (C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis). Variable in vitro activity has also been demonstrated against a variety of fungal pathogens. The in vitro susceptible organisms and Minimum Inhibitory Concentration (MIC90) values are summarized in Table 14.

Standardized techniques for susceptibility testing of antifungal agents have only been established for yeasts. Standardized testing for the filamentous fungi are ongoing. Results of such studies do not necessarily correlate with clinical outcome.

Table 14: In vitro Voriconazole-Susceptible Organisms

^a minimal inhibitory concentration at which 90% of the strains tested are inhibited from growth

^b range is reported when >1 study is conducted to detect the MIC₉₀. MIC₉₀ used alone means that only one study was conducted or if >1 study, the MIC₉₀ values are the same.

Voriconazole is active in vivo in guinea pig models of fungal infection including various systemic infections with Aspergillus species (including itraconazole-resistant Aspergillus) in either immune normal or immune compromised animals. In addition, voriconazole exhibits fungicidal activity against Aspergillus as evidenced by 100% cures at a dose of 10 mg/kg/p.o. BID for 4 days.

Clinical and Laboratory Standards Institute (CLSI) Breakpoints

Breakpoint criteria established by CLSI

Susceptibility Testing Methods

Aspergillus species and other filamentous fungi: No interpretive criteria have been established for

Aspergillus species and other filamentous fungi.

Candida species: The interpretive standards for voriconazole against Candida species are applicable only to tests performed using Clinical and Laboratory Standards Institute (CLSI) microbroth dilution reference method M27 for MIC read at 48 hours or disk diffusion reference method M44 for zone diameter read at 24 hours.

Broth Dilution Techniques: Quantitative methods are used to determine antifungal MICs. These MICs provide estimates of the susceptibility of Candida species to antifungal agents. MICs should be determined using a standardized procedure at 48 hours. Standardized procedures are based on a dilution method (broth) with standardized inoculums concentrations and standardized concentrations of voriconazole powder. The MIC values should be interpreted according to the criteria provided in the table below.

Diffusion Techniques: Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida species to an antifungal agent. One such standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper discs impregnated with 1 microgram of voriconazole to test the susceptibility of yeasts to voriconazole. Disc diffusion interpretive criteria are also provided in the table below.

Table 15: Susceptibility Interpretive Criteria for Voriconazole

Note 1: Shown are the breakpoints (μg/ml) for voriconazole against Candida species. If MICs are measured using a scale that yields results falling between categories, the next higher category is implied. Thus, an isolate with a voriconazole MIC of 1.5 μg /ml would be placed in the S-DD category.

The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommended dosage is used for the site of infection. The susceptible-dose dependent category implies that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies.

Quality Control

Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standard voriconazole powder and 1 μg discs should provide the following range of values noted in the table below.

NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.

Table 16: Acceptable Quality Control Ranges for Voriconazole to be used in Validation of

Susceptibility Test Results

* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies.

ATCC is a registered trademark of the American Type Culture Collection.

TOXICOLOGY

Voriconazole

Acute Toxicity

The minimum lethal oral dose in mice and rats was 300 mg/kg or greater. The minimum lethal IV dose was greater than 100 mg/kg for both mice and rats. Clinical signs observed included mydriasis, titubation (loss of balance while moving), depressed behavior, prostration, partially closed eyes, and dyspnea.

Long-Term Toxicity

Long-term toxicity studies have been performed at exposures below and up to approximately the human exposure at the recommended clinical doses.

Repeat-dose oral studies in rats have shown the liver to be the target organ, with a range of adaptive and functional changes, slight increases in plasma enzyme, and at 80 mg/kg (AUC_24h=127.7 μg.h.mL) (7 times the human exposure based on AUC comparisons), evidence of toxicity (small foci of coagulative necrosis). There was no evidence of hepatotoxicity at 50 mg/kg (AUC_24h=23.3 μg.h.mL) in the 6-month study. Thyroid follicular cell hypertrophy in rats was shown to be secondary to the liver adaptive responses. Intravenous studies in rats up to doses of 20 mg/kg (AUC_24h=24.5 μg.h.mL) did not demonstrate target organ toxicity. Hepatotoxicity occurred at plasma exposures similar to those obtained at therapeutic doses in humans.

Repeat-dose studies in dogs produced a similar spectrum of adaptive, functional and plasma enzymes changes in the liver as seen in rodents. Voriconazole administered for up to 1 month had no effect on transaminase activities, except at the toxic dose of 24 mg/kg (AUC_24h=171.1 μg.h.mL) (28 times the human exposure based on AUC comparisons), where increases in AST and ALT accompanied systemic toxicity. Longer exposure to voriconazole in the 6- and 12-month studies at the high dose of 12 mg/kg (AUC_24h=56.8 and 64.1μg.h.mL, respectively) (3 times the human exposure based on AUC comparisons) produced evidence of hepatotoxicity (single cell necrosis, increases in plasma ALT and alkaline phosphatase) but this was not seen at 8 mg/kg (AUC_24h=34.6 and 35.2 μg.h.mL, respectively). Intravenous administration of voriconazole to dogs resulted in transient severe clinical signs at 10 mg/kg (AUC_24h=50.6 μg.h.mL), but not at 6 mg/kg (AUC_24h=31.3 μg.h.mL).

Reproductive Toxicology

Reproduction toxicology studies indicate that voriconazole produces adverse effects on parturition and is teratogenic in the rat.

Voriconazole prolonged the duration of gestation and labour, and produced dystocia in pregnant rats at 10 mg/kg (AUC_24h=15.4 μg.h.mL) (0.3 times the human exposure based on body surface area comparisons). These parturition disorders led to maternal mortality and a decrease in perinatal survival of pups. Similar effects (though without maternal mortality) were seen at 3 mg/kg (AUC_24h=7.8 μg.h.mL) (0.1 times the human exposure based on body surface area comparisons). There was no perinatal mortality at 1 mg/kg.

A probable mechanism for the effects on parturition in rats is the fall in maternal plasma oestradiol induced by voriconazole.

In rats, voriconazole was teratogenic (cleft palate, hydronephrosis/hydroureter) from 10 mg/kg (0.3 times the human exposure based on body surface area comparisons) and above. Other effects included reduced ossification of sacral and caudal vertebrae, skull pubic end hyoid bone, anomalies of the sternebrae and dilatation of the ureter/renal pelvis. Voriconazole treatment in rats produced increased gestational length and dystocia. These parturition disorders led to maternal mortality and a decrease in perinatal survival of pups. In rabbits, voriconazole increased embryolethality, reduced fetal weight and increased incidences of skeletal variations cervical ribs and extra sternebral ossification sites.

Possible mechanisms for the teratogenic responses to voriconazole are a reduction in maternal plasma estradiol and a direct effect on neural crest cells of the developing embryos.

Voriconazole administration induced no impairment of male or female fertility in rats at exposures similar to those obtained in humans at therapeutic doses.

Mutagenicity

Voriconazole was subjected to a complete battery of mutagenicity tests.

Voriconazole did not display mutagenic activity in bacterial or mammalian cells in vitro, or clastogenic activity in vivo, although it demonstrated clastogenic activity in human lymphocyte cultures in vitro.

Carcinogenicity

Two-year carcinogenicity studies have been performed in mice and rats at doses of 10, 30 or

100 mg/kg/day, and 6, 18 or 50 mg/kg/day, respectively. A statistically significant increase in the incidence of hepatocellular adenomas was observed in high-dose female rats; the incidence of hepatocellular carcinomas in male rats (6 and 50 mg/kg, 0.2 and 1.6 times human exposure based on body surface area comparisons) was slightly higher than both controls although the difference was not statistically significant. In mice, a spectrum of hepatic neoplastic (adenomas and carcinomas) and non-neoplastic changes (foci of cellular alteration) were observed. The incidence of hepatocellular adenomas was statistically significantly different compared to controls in male and female mice at the dose of 100 mg/kg (1.4x human exposure based on body surface area comparisons); the incidence of hepatocellular carcinomas was significantly increased in high-dose male mice (1.4x human exposure).

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