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Vfend

Side Effects
Interactions

SIDE EFFECTS

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.

Overview

The most frequently reported adverse events (all causalities) in the therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%). The treatment-related adverse events which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances [see WARNINGS AND PRECAUTIONS].

Clinical Trial Experience In Adults

The data described in Table 3 reflect exposure to voriconazole in 1655 patients in the therapeutic studies. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non-therapeutic studies. This patient population was 62% male, had a mean age of 46 years (range 11-90, including 51 patients aged 12-18 years), and was 78% White and 10% Black. Five hundred sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months. Table 3 includes all adverse events which were reported at an incidence of ≥ 2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, or study 305, as well as events of concern which occurred at an incidence of < 2%.

In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy in the primary treatment of patients with acute invasive aspergillosis. The rate of discontinuation from voriconazole study medication due to adverse events was 21.4% (42/196 patients). In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from voriconazole study medication due to adverse events was 19.5% out of 272 patients. Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of esophageal candidiasis. The rate of discontinuation from voriconazole study medication in Study 305 due to adverse events was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.

Table 3: 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†

All 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 (18.7) 63 (13.5) 1 (0.5) 0 31 (15.5) 8 (4.2)
Photophobia 37 (2.2) 8 (1.7) 0 0 5 (2.5) 2 (1.0)
Chromatopsia 20 (1.2) 2 (0.4) 0 0 2 (1.0) 0
Body as a Whole
Fever 94 (5.7) 8 (1.7) 25 (13.5) 5 (3.8) 0 0
Chills 61 (3.7) 1 (0.2) 36 (19.5) 8 (6.1) 1 (0.5) 0
Headache 49 (3.0) 9 (1.9) 8 (4.3) 1 (0.8) 0 1 (0.5)
Cardiovascular System
Tachycardia 39 (2.4) 6 (1.3) 5 (2.7) 0 0 0
Digestive System
Nausea 89 (5.4) 18 (3.8) 29 (15.7) 2 (1.5) 2 (1.0) 3 (1.6)
Vomiting 72 (4.4) 15 (3.2) 18 (9.7) 1 (0.8) 2 (1.0) 1 (0.5)
Liver function tests abnormal 45 (2.7) 15 (3.2) 4 (2.2) 1 (0.8) 6 (3.0) 2 (1.0)
Cholestatic jaundice 17 (1.0) 8 (1.7) 0 1 (0.8) 3 (1.5) 0
Metabolic and Nutritional Systems
Alkaline phosphatase increased 59 (3.6) 19 (4.1) 4 (2.2) 3 (2.3) 10 (5.0) 3 (1.6)
Hepatic enzymes increased 30 (1.8) 11 (2.4) 5 (2.7) 1 (0.8) 3 (1.5) 0
SGOT increased 31 (1.9) 9 (1.9) 0 1 (0.8) 8 (4.0) 2 (1.0)
SGPT increased 29 (1.8) 9 (1.9) 1 (0.5) 2 (1.5) 6 (3.0) 2 (1.0)
Hypokalemia 26 (1.6) 3 (0.6) 36 (19.5) 16 (12.2) 0 0
Bilirubinemia 15 (0.9) 5 (1.1) 3 (1.6) 2 (1.5) 1 (0.5) 0
Creatinine increased 4 (0.2) 0 59 (31.9) 10 (7.6) 1 (0.5) 0
Nervous System
Hallucinations 39 (2.4) 13 (2.8) 1 (0.5) 0 0 0
Skin and Appendages
Rash 88 (5.3) 20 (4.3) 7 (3.8) 1 (0.8) 3 (1.5) 1 (0.5)
Urogenital
Kidney function abnormal 10 (0.6) 6 (1.3) 40 (21.6) 9 (6.9) 1 (0.5) 1 (0.5)
Acute kidney failure 7 (0.4) 2 (0.4) 11 (5.9) 7 (5.3) 0 0
† Study 307/602: invasive aspergillosis; Study 608: candidemia; Study 305: esophageal candidiasis
* Amphotericin B followed by other licensed antifungal therapy
**See WARNINGS AND PRECAUTIONS

Visual Disturbances

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

There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema [see WARNINGS AND PRECAUTIONS].

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

Dermatological Reactions

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

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

In addition, VFEND has been associated with photosensitivity skin reactions. Patients should avoid strong, direct sunlight during VFEND therapy. In patients with photosensitivity skin reactions, squamous cell carcinoma of the skin and melanoma have been reported during long-term therapy. If a patient develops a skin lesion consistent with squamous cell carcinoma or melanoma, VFEND should be discontinued [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 5 above and does not include every event reported in the voriconazole clinical program.

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

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

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

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

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

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

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

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

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

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

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

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

Clinical Laboratory Values

The overall incidence of clinically significant transaminase abnormalities in all therapeutic studies was 12.4% (206/1655) of patients treated with voriconazole. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.

Voriconazole has been infrequently associated with cases of serious hepatic toxicity including cases of jaundice and rare cases of hepatitis and hepatic failure leading to death. Most of these patients had other serious underlying conditions.

Liver function tests should be evaluated at the start of and during the course of VFEND therapy. Patients who develop abnormal liver function tests during VFEND 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 VFEND must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to VFEND [see WARNINGS AND PRECAUTIONS].

Acute renal failure has been observed in severely ill patients undergoing treatment with VFEND. 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 4 to 6 show the number of patients with hypokalemia and clinically significant changes in renal and liver function tests in three randomized, comparative multicenter studies. In study 305, patients with esophageal candidiasis were randomized to either oral voriconazole or oral fluconazole. In study 307/602, patients with definite or probable invasive aspergillosis were randomized to either voriconazole or amphotericin B therapy. In study 608, patients with candidemia were randomized to either voriconazole or the regimen of amphotericin B followed by fluconazole.

Table 4: Protocol 305 – Patients with Esophageal Candidiasis Clinically Significant Laboratory Test Abnormalities

Criteria* Voriconazole
n/N (%)
Fluconazole
n /N (%)
T. Bilirubin > 1.5x ULN 8/185 (4.3) 7/186 (3.8)
AST > 3.0x ULN 38/187 (20.3) 15/186 (8.1)
ALT > 3.0x ULN 20/187 (10.7) 12/186 (6.5)
Alk phos > 3.0x ULN 19/187 (10.2) 14/186 (7.5)
* 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 5: Protocol 307/602 – Primary Treatment of Invasive Aspergillosis Clinically Significant Laboratory Test Abnormalities

Criteria* Voriconazole
n/N (%)
Amphotericin B**
n/N (%)
T. Bilirubin > 1.5x ULN 35/180 (19.4) 46/173 (26.6)
AST > 3.0x ULN 21/180 (11.7) 18/174 (10.3)
ALT > 3.0x ULN 34/180 (18.9) 40/173 (23.1)
Alk phos > 3.0x ULN 29/181 (16.0) 38/173 (22.0)
Creatinine > 1.3x ULN 39/182 (21.4) 102/177 (57.6)
Potassium < 0.9x LLN 30/181 (16.6) 70/178 (39.3)
* 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 6: Protocol 608 – Treatment of Candidemia Clinically Significant Laboratory Test Abnormalities

Criteria* Voriconazole
n/N (%)
Amphotericin B followed by Fluconazole
n/N (%)
T. Bilirubin > 1.5x ULN 50/261 (19.2) 31/115 (27.0)
AST > 3.0x ULN 40/261 (15.3) 16/116 (13.8)
ALT > 3.0x ULN 22/261 (8.4) 15/116 (12.9)
Alk phos > 3.0x ULN 59/261 (22.6) 26/115 (22.6)
Creatinine > 1.3x ULN 39/260 (15.0) 32/118 (27.1)
Potassium < 0.9x LLN 43/258 (16.7) 35/118 (29.7)
* 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

Postmarketing Experience

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

Skeletal: fluorosis and periostitis have been reported during long-term voriconazole therapy [see WARNINGS AND PRECAUTIONS].

Read the Vfend (voriconazole) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see CLINICAL PHARMACOLOGY]

Drug/Drug Class (Mechanism of Interaction by the Drug) Voriconazole Plasma Exposure (Cmax and AUCι after 200 mg q12h) Recommendations for Voriconazole Dosage Adjustment/ Comments
Rifampin* and Rifabutin* (CYP450 Induction) Significantly Reduced Contraindicated
Efavirenz (400 mg q24h)** (CYP450 Induction) Significantly Reduced Contraindicated
Efavirenz (300 mg q24h)** (CYP450 Induction) Slight Decrease in AUCι When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction) Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) 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 (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 q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
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 events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered 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 events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects
**Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
***Non-Nucleoside Reverse Transcriptase Inhibitors

Table 8: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see CLINICAL PHARMACOLOGY]

Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure (Cmax and AUCι) Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition) Significantly Increased Contraindicated
Rifabutin* (CYP3A4 Inhibition) Significantly Increased Contraindicated
Efavirenz (400 mg q24h)** (CYP3A4 Inhibition) Significantly Increased Contraindicated
Efavirenz (300 mg q24h)** (CYP3A4 Inhibition) Slight Increase in AUCι When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir Cmax or AUCι Contraindicated because of significant reduction of voriconazole Cmax and AUCι
Low-dose Ritonavir (100 mg q12h)** Slight Decrease in Ritonavir Cmax and AUCι Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCι) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (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
Cyclosporine* (CYP3A4 Inhibition) AUCι Significantly Increased; No Significant Effect on Cmax When initiating therapy with VFEND 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 VFEND is 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 events and toxicity related to methadone is recommended during coadministration. 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 coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary.
Alfentanil (CYP3A4 Inhibition) Significantly Increasedc Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary.
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary.
NSAIDs**** including. ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus* (CYP3A4 Inhibition) Significantly Increased When initiating therapy with VFEND 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 VFEND is 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 events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with VFEND 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 coadministered with VFEND
Frequent monitoring for adverse events 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 events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events 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 events 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 events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
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.
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
**Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
***Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg q24h)
****Non-Steroidal Anti-Inflammatory Drug
*****Non-Nucleoside Reverse Transcriptase Inhibitors

Read the Vfend Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 4/18/2014
This monograph has been modified to include the generic and brand name in many instances.

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