Voriconazole Drug Information

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adults Overview The most frequently reported adverse reactions (see Table 4) in the adult therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%). The adverse reactions which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances. The data described in Table 4 reflect exposure to voriconazole in 1655 patients in nine therapeutic studies.

This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non-therapeutic studies. This patient population was 62% male, had a mean age of 46 years (range 11-90, including 51 patients aged 12-18 years), and was 78% White and 10% Black.

Five hundred sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months. Table 4 includes all adverse reactions which were reported at an incidence of ≥2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, 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 (OLAT) in the primary treatment of patients with acute IA. The rate of discontinuation from voriconazole study medication due to adverse reactions was 21.4% (42/196 patients). In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from voriconazole study medication due to adverse reactions was 19.5% out of 272 patients. Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of EC. The rate of discontinuation from voriconazole study medication in Study 305 due to adverse reactions was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.

Table 4: Adverse Reactions Rate ≥ 2% on Voriconazole or Adverse Reactions of Concern in Therapeutic Studies Population, Studies 307/602-608 Combined, or Study 305. Possibly Related to Therapy or Causality Unknown† † Study 307/602: IA; Study 608: candidemia; Study 305: EC * Studies 303, 304, 305, 307, 309, 602, 603, 604, 608 **Amphotericin B followed by other licensed antifungal therapy *** See Warnings and Precautions Therapeutic Studies* Studies 307/602 and 608 (IV/ oral therapy) Study 305 (oral therapy) Voriconazole N=1655 Voriconazole N=468 Ampho B** N=185 Ampho B→ Fluconazole N=131 Voriconazole N=200 Fluconazole N=191 N (%) N (%) N (%) N (%) N (%) N (%) Special Senses*** Abnormal vision 310 63 1 0 31 8 Photophobia 37 8 0 0 5 2 Chromatopsia 20 2 0 0 2 0 Body as a Whole Fever 94 8 25 5 0 0 Chills 61 1 36 8 1 0 Headache 49 9 8 1 0 1 Cardiovascular System Tachycardia 39 6 5 0 0 0 Digestive System Nausea 89 18 29 2 2 3 Vomiting 72 15 18 1 2 1 Liver function tests abnormal 45 15 4 1 6 2 Cholestatic jaundice 17 8 0 1 3 0 Metabolic and Nutritional Systems Alkaline phosphatase increased 59 19 4 3 10 3 Hepatic enzymes increased 30 11 5 1 3 0 SGOT increased 31 9 0 1 8 2 SGPT increased 29 9 1 2 6 2 Hypokalemia 26 3 36 16 0 0 Bilirubinemia 15 5 3 2 1 0 Creatinine increased 4 0 59 10 1 0 Nervous System Hallucinations 39 13 1 0 0 0 Skin and Appendages Rash 88 20 7 1 3 1 Urogenital Kidney function abnormal 10 6 40 9 1 1 Acute kidney failure 7 2 11 7 0 0 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.

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.

These effects were noted early in administration of voriconazole and continued through the course of study drug treatment. Fourteen days after the end of dosing, ERG, visual fields and color perception returned to normal. Dermatological Reactions Dermatological reactions were common in patients treated with voriconazole.

The mechanism underlying these dermatologic adverse reactions remains unknown. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported during treatment with voriconazole tablets. Erythema multiforme has also been reported during treatment with voriconazole tablets. . Voriconazole tablets have also been associated with additional photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus.

Less Common Adverse Reactions The following adverse reactions 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 4 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, 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 ). 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 (including cutaneous SCC in situ, or Bowen’s disease), 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. Clinical Laboratory Values in Adults The overall incidence of transaminase increases >3x upper limit of normal (not necessarily comprising an adverse reaction) was 17.7% (268/1514) in adult subjects treated with voriconazole for therapeutic use in pooled clinical trials. 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 resolved 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 tablets therapy. Patients who develop abnormal liver function tests during voriconazole tablets 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 tablets must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole tablets.

Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole tablets. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that can result in decreased renal function. It is recommended that patients are monitored for the development of abnormal renal function.

This should include laboratory evaluation of serum creatinine. Tables 5 to 7 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 EC were randomized to either oral voriconazole or oral fluconazole.

In study 307/602, patients with definite or probable IA 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 5: Protocol 305 – Patients with Esophageal CandidiasisClinically 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 AST = Aspartate aminotransferase; ALT= alanine aminotransferase ULN = upper limit of normal Criteria* Voriconazole Fluconazole n/N (%) n /N (%) T. Bilirubin >1.5x ULN 8/185 7/186 AST >3.0x ULN 38/187 15/186 ALT >3.0x ULN 20/187 12/186 Alkaline Phosphatase >3.0x ULN 19/187 14/186 Table 6: 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 AST = Aspartate aminotransferase; ALT= alanine aminotransferase ULN = upper limit of normal LLN = lower limit of normal Criteria* Voriconazole Amphotericin B** n/N (%) n/N (%) T. Bilirubin >1.5x ULN 35/180 46/173 AST >3.0x ULN 21/180 18/174 ALT >3.0x ULN 34/180 40/173 Alkaline Phosphatase >3.0x ULN 29/181 38/173 Creatinine >1.3x ULN 39/182 102/177 Potassium <0.9x LLN 30/181 70/178 Table 7: 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 AST = Aspartate aminotransferase; ALT= alanine aminotransferase ULN = upper limit of normal LLN = lower limit of normal Criteria* Voriconazole Amphotericin B followed by Fluconazole n/N (%) n/N (%) T. Bilirubin >1.5x ULN 50/261 31/115 AST >3.0x ULN 40/261 16/116 ALT >3.0x ULN 22/261 15/116 Alkaline Phosphatase >3.0x ULN 59/261 26/115 Creatinine >1.3x ULN 39/260 32/118 Potassium <0.9x LLN 43/258 35/118 Clinical Trials Experience in Pediatric Patients The safety of voriconazole was investigated in 105 pediatric patients aged 2 to less than 18 years, including 52 pediatric patients less than 18 years of age who were enrolled in the adult therapeutic studies.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In clinical studies, serious adverse reactions occurred in 46% (48/105) of voriconazole treated pediatric patients. Treatment discontinuations due to adverse reactions occurred in 12 /105 (11%) of all patients. Hepatic adverse reactions (i.e.

ALT increased; liver function test abnormal; jaundice) 6% (6/105) accounted for the majority of voriconazole treatment discontinuations. Most Common Adverse Reactions The most common adverse reactions occurring in ≥5% of pediatric patients receiving voriconazole tablets in the pooled pediatric clinical trials are displayed by body system, in Table 8. Table 8: Adverse Reactions Occurring in ≥5% of Pediatric Patients ReceivingVoriconazole tablets in the Pooled Pediatric Clinical Trials a Reflects all adverse reactions and not treatment-related only. b Pooled reports include such terms as: amaurosis (partial or total blindness without visible change in the eye); asthenopia (eye strain); chromatopsia (abnormally colored vision); color blindness; diplopia; photopsia; retinal disorder; vision blurred, visual acuity decreased, visual brightness; visual impairment. Several patients had more than one visual disturbance. c Pooled reports include such terms as: abdominal pain and abdominal pain, upper. d Pooled reports include such terms as: ALT abnormal and ALT increased. e Pooled reports include such terms as: hallucination; hallucination, auditory; hallucination, visual.

Several patients had both visual and auditory hallucinations. f Pooled reports include such terms as: renal failure and a single patient with renal impairment. g Pooled reports include such terms as: rash; rash generalized; rash macular; rash maculopapular; rash pruritic. Abbreviations: ALT = alanine aminotransferase; LFT = liver function test Body System Adverse Reaction Pooled Pediatric Data a N=105 n (%) Blood and Lymphatic Systems Disorders Thrombocytopenia 10 Cardiac Disorders Tachycardia 7 Eye Disorders Visual Disturbances b 27 Photophobia 6 Gastrointestinal Disorders Vomiting 21 Nausea 14 Abdominal pain c 13 Diarrhea 12 Abdominal distention 5 Constipation 5 General Disorders and Administration Site Conditions Pyrexia 25 Peripheral edema 9 Mucosal inflammation 6 Infections and Infestations Upper respiratory tract infection 5 Investigations ALT abnormal d 9 LFT abnormal 6 Metabolism and Nutrition Disorders Hypokalemia 11 Hyperglycemia 7 Hypocalcemia 6 Hypophosphotemia 6 Hypoalbuminemia 5 Hypomagnesemia 5 Nervous System Disorders Headache 10 Dizziness 5 Psychiatric Disorders Hallucinations e 5 Renal and Urinary Disorders Renal impairment f 5 Respiratory Disorders Epistaxis 17 Cough 10 Dyspnea 6 Hemoptysis 5 Skin and Subcutaneous Tissue Disorders Rash g 14 Vascular Disorders Hypertension 12 Hypotension 9 The following adverse reactions with incidence less than 5% were reported in 105 pediatric patients treated with voriconazole: Blood and Lymphatic System Disorders: anemia, leukopenia, pancytopenia Cardiac Disorders: bradycardia, palpitations, supraventricular tachycardia Eye Disorders: dry eye, keratitis Ear and Labyrinth Disorders: tinnitus, vertigo Gastrointestinal Disorders: abdominal tenderness, dyspepsia General Disorders and Administration Site Conditions: asthenia, catheter site pain, chills, hypothermia, lethargy Hepatobiliary Disorders: cholestasis, hyperbilirubinemia, jaundice Immune System Disorders: hypersensitivity, urticaria Infections and Infestations: conjunctivitis Laboratory Investigations: AST increased, blood creatinine increased, gamma-glutamyl transferase increased Metabolism and Nutrition Disorders: hypercalcemia, hypermagnesemia, hyperphosphatemia, hypoglycemia Musculoskeletal and Connective Tissue Disorders: arthralgia, myalgia Nervous System Disorders: ataxia, convulsion, dizziness, nystagmus, paresthesia, syncope Psychiatric Disorders: affect lability, agitation, anxiety, depression, insomnia Respiratory Disorders: bronchospasm, nasal congestion, respiratory failure, tachypnea Skin and Subcutaneous Tissue Disorders: alopecia, dermatitis (allergic, contact, and exfoliative), pruritus Vascular Disorders: flushing, phlebitis Hepatic-Related Adverse Reactions in Pediatric Patients The frequency of hepatic-related adverse reactions in pediatric patients exposed to voriconazole in therapeutic studies was numerically higher than that of adults (28.6% compared to 24.1%, respectively). The higher frequency of hepatic adverse reactions in the pediatric population was mainly due to an increased frequency of liver enzyme elevations (21.9% in pediatric patients compared to 16.1% in adults), including transaminase elevations (ALT and AST combined) 7.6% in the pediatric patients compared to 5.1% in adults. Clinical Laboratory Values in Pediatric Patients The overall incidence of transaminase increases >3x upper limit of normal was 27.2% (28/103) in pediatric and 17.7% (268/1514) in adult patients treated with voriconazole in pooled clinical trials.

The majority of abnormal liver function tests either resolved on treatment with or without dose adjustment or after voriconazole discontinuation. A higher frequency of clinically significant liver laboratory abnormalities, irrespective of baseline laboratory values (>3x ULN ALT or AST), was consistently observed in the combined therapeutic pediatric population (15.5% AST and 22.5% ALT) when compared to adults (12.9% AST and 11.6% ALT). The incidence of bilirubin elevation was comparable between adult and pediatric patients. The incidence of hepatic abnormalities in pediatric patients is shown in Table 9. Table 9: Incidence of Hepatic Abnormalities among Pediatric Subjects n = number of patients with a clinically significant abnormality while on study therapyN = total number of patients with at least one observation of the given lab test while on study therapy AST = Aspartate aminotransferase; ALT = alanine aminotransferase ULN = upper limit of normal Criteria n/N (%) Total bilirubin >1.5x ULN 19/102 AST >3.0x ULN 16/103 ALT >3.0x ULN 23/102 Alkaline Phosphatase >3.0x ULN 8/97

Postmarketing Experience in Adult and Pediatric Patients

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. Dermatological Reactions Increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with UV reactivation, was observed in postmarketing reports.

Adults Skeletal : fluorosis and periostitis have been reported during long-term voriconazole therapy . Eye disorders : prolonged visual adverse reactions, including optic neuritis and papilledema . Skin and Appendages: drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported. Endocrine disorders: adrenal insufficiency, Cushing’s syndrome (when voriconazole has been used concomitantly with corticosteroids) . Pediatric Patients There have been postmarketing reports of pancreatitis in pediatric patients.

Voriconazole is metabolized by cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Therefore, inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole is a strong inhibitor of CYP3A4, and also inhibits CYP2C19 and CYP2C9. Therefore, voriconazole may increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes. Tables 10 and Table 11 provide listings of clinically significant drug interactions, including contraindicated drugs.

Drugs listed in Table 10 and Table 11 are a guide and not considered a comprehensive list of all possible drugs and herbal products that are contraindicated or may interact with voriconazole. Table 10:Effect of Other Drugs on Voriconazole Pharmacokinetics Drug/Drug Class (Mechanism of Interaction by the Drug) Voriconazole Plasma Exposure (C max and AUC τ after 200 mg every 12 hours) Prevention or Management Recommendations * Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjects ** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects *** Non-Nucleoside Reverse Transcriptase Inhibitors Rifampin* and Rifabutin* (CYP450 Induction) Significantly Reduced Contraindicated Efavirenz (400 mg every 24 hours)** (CYP450 Induction) Efavirenz (300 mg every 24 hours)** (CYP450 Induction) Significantly Reduced Slight Decrease in AUC τ Contraindicated When voriconazole is concomitantly administered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours. High-dose Ritonavir (400 mg every 12 hours)** (CYP450 Induction) Low-dose Ritonavir (100 mg every 12 hours)** (CYP450 Induction) Significantly Reduced Reduced Contraindicated Concomitant administration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Carbamazepine (CYP450 Induction) Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction) Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated Phenytoin* (CYP450 Induction) Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg). Letermovir (CYP2C9/2C19 Induction) Reduced If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole. St. John’s Wort (CYP450 inducer; P-gp inducer) Significantly Reduced Contraindicated Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse reactions and toxicity related to voriconazole is recommended for concomitant administration with oral contraceptives.

Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole. Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) No dosage adjustment in the voriconazole dosage needed for concomitant administration with indinavir.

Frequent monitoring for adverse reactions and toxicity related to voriconazole for concomitant administration with other HIV protease inhibitors. Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to voriconazole. Careful assessment of voriconazole effectiveness.

CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust voriconazole tablets dosage and monitor for adverse reactions or lack of efficacy Voriconazole tablets may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions Phenytoin or Efavirenz: With co-administration, increase maintenance oral and intravenous dosage of voriconazole Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure (C max and AUC τ ) Prevention or Management Recommendations * 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 every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects *** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg every 24 hours) **** Non-Steroidal Anti-Inflammatory Drug ***** Non-Nucleoside Reverse Transcriptase Inhibitors Sirolimus* (CYP3A4 Inhibition) Significantly Increased Contraindicated Rifabutin* (CYP3A4 Inhibition) Significantly Increased Contraindicated Efavirenz (400 mg every 24 hours)** (CYP3A4 Inhibition) Efavirenz (300 mg every 24 hours)** (CYP3A4 Inhibition) Significantly Increased Slight Increase in AUC τ Contraindicated When voriconazole is concomitantly administered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours. High-dose Ritonavir (400 mg every 12 hours )**(CYP3A4 Inhibition) Low-dose Ritonavir (100 mg every 12 hours)** No Significant Effect of Voriconazole on Ritonavir C max or AUC τ Slight Decrease in Ritonavir C max and AUC τ Contraindicated because of significant reduction of voriconazole C max and AUC τ. Concomitant administration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C max and AUC τ ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes. Ergot Alkaloids (CYP450 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated Naloxegol (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions Contraindicated Tolvaptan (CYP3A4 Inhibition) Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan Contraindicated Lurasidone (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone Contraindicated Finerenone (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone Contraindicated Eplerenone (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Eplerenone Contraindicated Voclosporin (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Voclosporin Contraindicated Venetoclax (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Venetoclax Plasma Exposure Likely to be Significantly Increased Concomitant administration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when concomitantly administered voriconazole tablets with venetoclax.

Refer to the venetoclax prescribing information for dosing instructions. Lemborexant (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Avoid concomitant use of voriconazole tablets with lemborexant Glasdegib (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.

Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Avoid concomitant use of voriconazole tablets. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.

Cyclosporine* (CYP3A4 Inhibition) AUC τ Significantly Increased; No Significant Effect on C max When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.

Methadone*** (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended when concomitantly administered with voriconazole tablets. Dose reduction of methadone may be needed.

Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when concomitantly administered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary. Alfentanil (CYP3A4 Inhibition) Significantly Increased An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when concomitantly administered with voriconazole tablets.

Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when concomitantly administered with voriconazole tablets. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary. Oxycodone (CYP3A4 Inhibition) Significantly Increased Increased visual effects (heterophoria and miosis) of oxycodone were observed when concomitantly administered with voriconazole tablets.

Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when concomitantly administered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary. NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse reactions and toxicity related to NSAIDs.

Dose reduction of NSAIDs may be needed. Tacrolimus* (CYP3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity.

When voriconazole tablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. Phenytoin* (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** Increased Monitoring for adverse reactions related to oral contraceptives is recommended during concomitant administration.

Prednisolone and other corticosteroids (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of voriconazole tablets on Prednisolone Exposure Not Studied In vitro or In vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased No dosage adjustment for prednisolone when concomitantly administered with voriconazole tablets. Monitor for potential adrenal dysfunction when voriconazole tablets is administered with other corticosteroids. Warfarin* (CYP2C9 Inhibition) Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition) Prothrombin Time Significantly Increased Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.

Ivacaftor (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor. Eszopiclone (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone Dose reduction of eszopiclone is recommended.

Refer to the prescribing information for eszopiclone. Mavacamten (CYP2C19/3A4/2C9 Inhibition) Not Studied In Vivo or In Vitro, but Mavacamten Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Heart Failure Refer to the prescribing information for mavacamten. Omeprazole* (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with voriconazole tablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half.

The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) No dosage adjustment for indinavir when concomitantly administered with voriconazole tablets. Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors.

Other NNRTIs***** (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to NNRTI. Tretinoin (CYP3A4 Inhibition) Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia. Midazolam (CYP3A4 Inhibition) Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition) Significantly Increased In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.

HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.

Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia.

Adjustment of oral hypoglycemic drug dosage may be needed. Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.

Everolimus (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended.

Pregnancy Risk Summary Voriconazole can cause fetal harm when administered to a pregnant woman. There are no available data on the use of voriconazole in pregnant women. In animal reproduction studies, oral voriconazole was associated with fetal malformations in rats and fetal toxicity in rabbits.

Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to voriconazole during organogenesis at and above 10 mg/kg (0.3 times the RMD of 200 mg every 12 hours based on body surface area comparisons). In rabbits, embryomortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons) during organogenesis. Rats exposed to voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively. Data Animal Data Voriconazole was administered orally to pregnant rats during organogenesis (gestation days 6-17) at 10, 30, and 60 mg/kg/day.

Voriconazole was associated with increased incidences of the malformations hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the RMD based on body surface area comparisons, and cleft palate at 60 mg/kg, approximately 2 times the RMD based on body surface area comparisons. 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 were also observed at doses of 10 mg/kg or greater. There was no evidence of maternal toxicity at any dose.

Voriconazole was administered orally to pregnant rabbits during the period of organogenesis (gestation days 7-19) at 10, 40, and 100 mg/kg/day. Voriconazole was associated with increased post-implantation loss and decreased fetal body weight, in association with maternal toxicity (decreased body weight gain and food consumption) at 100 mg/kg/day (6 times the RMD based on body surface area comparisons). Fetal skeletal variations (increases in the incidence of cervical rib and extra sternebral ossification sites) were observed at 100 mg/kg/day. In a peri-and postnatal toxicity study in rats, voriconazole was administered orally to female rats from implantation through the end of lactation at 1, 3, and 10 mg/kg/day.

Voriconazole prolonged the duration of gestation and labor and produced dystocia with related increases in maternal mortality and decreases in perinatal survival of F1 pups at 10 mg/kg/day, approximately 0.3 times the RMD.

Pediatric Use The safety and effectiveness of voriconazole have been established in pediatric patients 2 years of age and older based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data. A total of 105 pediatric patients aged 2 to less than 12 and aged 12 to less than 18 from two, non-comparative Phase 3 pediatric studies and eight adult therapeutic trials provided safety information for voriconazole use in the pediatric population. Safety and effectiveness in pediatric patients below the age of 2 years has not been established.

Therefore, voriconazole is not recommended for pediatric patients less than 2 years of age. A higher frequency of liver enzyme elevations was observed in the pediatric patients. The frequency of phototoxicity reactions is higher in the pediatric population.

Squamous cell carcinoma has been reported in patients who experience photosensitivity reactions. Stringent measures for photoprotection are warranted. Sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photoaging injuries, such as lentigines or ephelides, even after treatment discontinuation.

Voriconazole has not been studied in pediatric patients with hepatic or renal impairment. Hepatic function and serum creatinine levels should be closely monitored in pediatric patients.

Voriconazole tablets are contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Refer to the prescribing information for other azole antifungal agents.

Concomittant use of voriconazole with the interacting drugs described and listed below in this section are a guide and not considered a comprehensive list of all possible drugs that may be contraindicated with voriconazole tablets. 1. Concomitant use of voriconazole is contraindicated with drugs that are highly dependent on CYP3A4 for metabolism, and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions : Eplerenone Ergot alkaloids (e.g., ergotamine, dihydroergotamine) Finerenone Ivabradine Lurasidone Naloxegol Pimozide Quinidine Rifabutin Sirolimus Tolvaptan Venetoclax: Coadministration at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome. Voclosporin 2. Concomitant use of voriconazole is contraindicated with drugs and herbal products that induce CYP2C19, CYP2C9, and/or CYP3A4 and for which significantly reduced voriconazole plasma concentrations may be associated with loss of efficacy : Carbamazepine Efavirenz Concomitant use with efavirenz dosages of 400 mg every 24 hours or higher is contraindicated..Long- acting barbiturates Rifabutin Rifampin Ritonavir Concomitant use with high-dose ritonavir (400 mg every 12 hours) is contraindicated. Concomitant use with low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

St. John’s Wort Known hypersensitivity to voriconazole or its excipients Concomitant use with drugs that are highly dependent on CYP3A4 for metabolism, and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions Concomitant use with drugs and herbal products that induce CYP2C19, CYP2C9, and/or CYP3A4 and for which significantly reduced voriconazole plasma concentrations may be associated with loss of efficacy

In clinical trials, there were three cases of accidental overdose. All occurred in pediatric patients who received up to five times the recommended intravenous dose of voriconazole. A single adverse reaction of photophobia of 10 minutes duration was reported.

There is no known antidote to voriconazole. Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min.

In an overdose, hemodialysis may assist in the removal of voriconazole and SBECD from the body.