Voriconazole (voriconazole 50 mg) Dailymed

Recent Major Changes Section

Contraindications ( 4)     1/2021

Warnings and Precautions ( 5.5)     9/2020

Warnings and Precautions ( 5.8)     1/2021

1 Indications And Usage

Voriconazole tablets are an azole antifungal indicated for the treatment of adults and pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight with:

• Invasive aspergillosis ( 1.1)
• Candidemia in non-neutropenics and other deep tissue Candida infections ( 1.2)
• Esophageal candidiasis ( 1.3)
• Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of, or refractory to, other therapy ( 1.4)

1.1 Invasive Aspergillosis

Voriconazole is indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of invasive aspergillosis (IA). In clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus  [see Clinical Studies (14.1, 14.5) and Microbiology (12.4)] .

1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Infections

Voriconazole is indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of candidemia in non-neutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds [see Clinical Studies (14.2, 14.5) and Microbiology (12.4)] .

1.3 Esophageal Candidiasis

Voriconazole is indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of esophageal candidiasis (EC) in adults and pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight  [see Clinical Studies (14.3, 14.5) and Microbiology (12.4)] .

1.4 Scedosporiosis and Fusariosis

Voriconazole is indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) intolerant of, or refractory to, other therapy [see Clinical Studies (14.4) and Microbiology (12.4)] .

1.5Usage

Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole). However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information.

2 Dosage And Administration

• Dosage in Adults ( 2.3)

Infection	Loading Dose	Maintenance Dose
	Intravenous infusion	Intravenous infusion	Oral
Invasive Aspergillosis	6 mg/kg every 12 hours for the first 24 hours	4 mg/kg every 12 hours	200 mg every 12 hours
Candidemia in nonneutropenics and other deep tissue Candida infections		3-4 mg/kg every 12 hours	200 mg every 12 hours
Scedosporiosis and Fusariosis		4 mg/kg every 12 hours	200 mg every 12 hours
Esophageal Candidiasis	Not Evaluated	Not Evaluated	200 mg every 12 hours

• • Adult patients weighing less than 40 kg: oral maintenance dose 100 mg or 150 mg every 12 hours
  • Hepatic Impairment: Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) ( 2.5)
  • Renal Impairment: Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance < 50 mL/min) ( 2.6)

 

• Dosage in Pediatric Patients ( 2.4)
  • For pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight use adult dosage. ( 2.4)
  • Dosage adjustment of voriconazole tablets in pediatric patients with renal or hepatic impairment has not been established ( 2.5, 2.6)

2.1 Important Administration Instructions for Use in All Patients

Administer voriconazole tablets at least one hour before or after a meal.

2.3 Recommended Dosing Regimen in Adults

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

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

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

Table 1: Recommended Dosing Regimen (Adults)

Infection	Loading Dose	Maintenance Dose Increase dose when voriconazole is co-administered with phenytoin or efavirenz ( 7); Decrease dose in patients with hepatic impairment ( 2.5) In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUC τ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUC τ) similar to a 4 mg/kg intravenous infusion every 12 hours dose ( 12).
	Intravenous infusion	Intravenous infusion	Oral Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.
Invasive Aspergillosis In a clinical study of IA, the median duration of intravenous voriconazole therapy was 10 days (range 2 to 85 days). The median duration of oral voriconazole therapy was 76 days (range 2 to 232 days) ( 14.1).	6 mg/kg every 12 hours for the first 24 hours	4 mg/kg every 12 hours	200 mg every 12 hours
Candidemia in nonneutropenic patients and other deep tissue Candida infections	6 mg/kg every 12 hours for the first 24 hours	3-4 mg/kg every 12 hours In clinical trials, patients with candidemia received 3 mg/kg intravenous infusion every 12 hours as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg every 12 hours as salvage therapy. Appropriate dose should be based on the severity and nature of the infection.	200 mg every 12 hours
Esophageal Candidiasis	Not Evaluated Not evaluated in patients with EC.	Not Evaluated	200 mg every 12 hours
Scedosporiosis and Fusariosis	6 mg/kg every 12 hours for the first 24 hours	4 mg/kg every 12 hours	200 mg every 12 hours

If patient’s response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg intravenously every 12 hours) to 300 mg every 12 hours (similar to 4 mg/kg intravenously every 12 hours). For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).

If patient is unable to tolerate 4 mg/kg intravenously every 12 hours, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours.

2.4 Recommended Dosing Regimen in Pediatric Patients

For pediatric patients 12 to 14 years of age with a body weight greater than or equal to 50 kg and those 15 years of age and above regardless of body weight, administer the adult dosing regimen of voriconazole tablets [see Dosage and Administration (2.3)] .

Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement.

Use the optimal method for titrating dosage recommended for adults [see Dosage and Administration (2.3)] .

Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole). However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information.

2.5Dosage Modifications in Patients With Hepatic Impairment

The maintenance dose of voriconazole tablets should be reduced in adult patients with mild to moderate hepatic impairment, Child-Pugh Class A and B. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).

Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression, and clinical response.

Adult patients with baseline liver function tests (ALT, AST) of up to 5 times the upper limit of normal (ULN) were included in the clinical program. Dose adjustments are not necessary for adult patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions (5.1)] .

It is recommended that the recommended voriconazole loading dose regimens be used, but that the maintenance dose be halved in adult patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology (12.3)] .

Voriconazole tablets have not been studied in adult patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. Voriconazole tablets have been associated with elevations in liver function tests and with clinical signs of liver damage, such as jaundice. Voriconazole tablets should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity.

Dosage adjustment of voriconazole tablets in pediatric patients with hepatic impairment has not been established [see Use in Specific Populations (8.4)] .

2.6Dosage Modifications in Patients With Renal Impairment

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

In patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min) who are receiving an intravenous infusion of voriconazole, accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see Warnings and Precautions (5.7)] .

Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

Dosage adjustment of voriconazole tablets in pediatric patients with renal impairment has not been established [see Use in Specific Populations (8.4)] .

2.7Dosage Adjustment When Co-Administered With Phenytoin or Efavirenz

The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz. Use the optimal method for titrating dosage [see Drug Interactions (7) and Dosage and Administration (2.3)] .

• Voriconazole tablets are contraindicated in patients with known hypersensitivity to voriconazole or their excipients. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing voriconazole tablets to patients with hypersensitivity to other azoles.
• Coadministration of cisapride, pimozide or quinidine with voriconazole tablets is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole tablets with sirolimus is contraindicated because voriconazole tablets significantly increase sirolimus concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole tablets with rifampin, carbamazepine and long-acting barbiturates is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg every 24 hours or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole tablets with high-dose ritonavir (400 mg every 12 hours) is contraindicated because ritonavir (400 mg every 12 hours) significantly decreases plasma voriconazole concentrations. Coadministration 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 [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole tablets with rifabutin is contraindicated since voriconazole tablets significantly increase rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole tablets with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because voriconazole tablets may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole tablets with St. John’s Wort is contraindicated because this herbal supplement may decrease voriconazole plasma concentration [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole tablets with naloxegol is contraindicated because voriconazole tablets may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole tablets with tolvaptan is contraindicated because voriconazole tablets may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions (7)] .

• Hypersensitivity to voriconazole or its excipients ( 4)
• Coadministration with cisapride, pimozide or quinidine, sirolimus due to risk of serious adverse reactions ( 4, 7)
• Coadministration with rifampin, carbamazepine, long-acting barbiturates, efavirenz, ritonavir, rifabutin, ergot alkaloids, and St. John’s Wort due to risk of loss of efficacy ( 4, 7)
• Coadministration with naloxegol due to risk of adverse reactions ( 4, 7)
• Coadministration with tolvaptan due to risk of adverse reactions ( 4, 7)

5 Warnings And Precautions

• Hepatic Toxicity: Serious hepatic reactions reported. Evaluate liver function tests at start of and during voriconazole therapy ( 5.1)
• Arrhythmias and QT Prolongation: Correct potassium, magnesium and calcium prior to use; caution patients with proarrhythmic conditions ( 5.2)
• Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days ( 5.4)
• Severe Cutaneous Adverse Reactions: Discontinue for exfoliative cutaneous reactions ( 5.5)
• Photosensitivity: Avoid sunlight due to risk of photosensitivity ( 5.6)
• Adrenal Dysfunction: Carefully monitor patients receiving voriconazole and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after voriconazole treatment. Instruct patients to seek immediate medical care if they develop signs and symptoms of Cushing’s syndrome or adrenal insufficiency ( 5.8)
• Embryo-Fetal Toxicity: Voriconazole can cause fetal harm when administered to a pregnant woman. Inform pregnant patients of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with voriconazole ( 5.9, 8.1, 8.3)
• Skeletal Adverse Reactions: Fluorosis and periostitis with long-term voriconazole therapy. Discontinue if these adverse reactions occur ( 5.12)
• Clinically Significant Drug Interactions: Review patient’s concomitant medications ( 5.13, 7)
• Patients with Hereditary Galactose Intolerance, Lapp Lactase Deficiency or Glucose-Galactose Malabsorption: Voriconazole tablets should not be given to these patients because they contain lactose ( 5.14)

5.1Hepatic Toxicity

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities).Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy [see Adverse Reactions (6.1)] .

A higher frequency of liver enzyme elevations was observed in the pediatric population [see Adverse Reactions (6.1)] . Hepatic function should be monitored in both adult and pediatric patients.

Measure serum transaminase levels and bilirubin at the initiation of voriconazole therapy and monitor at least weekly for the first month of treatment. Monitoring frequency can be reduced to monthly during continued use if no clinically significant changes are noted. If liver function tests become markedly elevated compared to baseline, voriconazole should be discontinued unless the medical judgment of the benefit/risk of the treatment for the patient justifies continued use [see Dosage and Administration (2.5) and Adverse Reactions (6.1)] .

5.2 Arrhythmias and QT Prolongation

Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and post-marketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as torsade de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.

Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as:

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

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

5.4 Visual Disturbances

The effect of voriconazole on visual function is not known if treatment continues beyond 28 days.There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field, and color perception should be monitored [see Adverse Reactions (6.2)] .

5.5 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with voriconazole. If a patient develops a severe cutaneous adverse reaction, voriconazole should be discontinued [see Adverse Reactions (6.1, 6.2)] .

5.6 Photosensitivity

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

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

5.7 Renal Toxicity

Acute renal failure has been observed in patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that may result in decreased renal function.

Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine [see Clinical Pharmacology (12.3) and Dosage and Administration (2.6)] .

5.8Adrenal Dysfunction

Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including voriconazole. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression [see Drug Interactions (7) and Clinical Pharmacology (12.3)] . Cushing’s syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving voriconazole concomitantly with corticosteroids.

Patients receiving voriconazole and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after voriconazole treatment. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing’s syndrome or adrenal insufficiency.

5.9 Embryo-Fetal Toxicity

Voriconazole can cause fetal harm when administered to a pregnant woman.

In animals, voriconazole administration was associated with fetal malformations, embryotoxicity, increased gestational length, dystocia and embryomortality [see Use in Specific Populations (8.1)] .

If voriconazole is used during pregnancy, or if the patient becomes pregnant while taking voriconazole, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with voriconazole [see Use in Specific Populations (8.3)] .

5.10 Laboratory Tests

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

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

5.11 Pancreatitis

Pancreatitis has been observed in patients undergoing treatment with voriconazole [see Adverse Reactions (6.1, 6.2)] . Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during voriconazole treatment.

5.12 Skeletal Adverse Reactions

Fluorosis and periostitis have been reported during long-term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole should be discontinued [see Adverse Reactions (6.2)] .

5.13 Clinically Significant Drug Interactions

See Table 10 for a uling of drugs that may significantly alter voriconazole concentrations. Also, see Table 11 for a uling of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [see Contraindications (4) and Drug Interactions (7)] .

5.14 Galactose Intolerance

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

6 Adverse Reactions

The following serious adverse reactions are described elsewhere in the labeling:

Hepatic Toxicity [see Warnings and Precautions (5.1)]

Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]

Visual Disturbances [see Warnings and Precautions (5.4)]

Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]

Photosensitivity [see Warnings and Precautions (5.6)]

Renal Toxicity [see Warnings and Precautions (5.7)]

• Adult Patients: The most common adverse reactions (incidence ≥ 2%) were visual disturbances, fever, nausea, rash, vomiting, chills, headache, liver function test abnormal, tachycardia, hallucinations ( 6)

 

To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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.

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 [see Warnings and Precautions (5.1, 5.4) and Adverse Reactions (6.1)] .

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 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 EC. 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 4: Treatment Emergent Adverse Events Rate ≥ 2% on Voriconazole or Adverse Events 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

	Therapeutic Studies Studies 303, 304, 305, 307, 309, 602, 603, 604, 608	Studies 307/602 and 608 (IV/oral therapy)			Study 305 (oral therapy)
	Voriconazole N = 1655	Voriconazole N = 468	Ampho B Amphotericin B followed by other licensed antifungal therapy N = 185	Ampho B→ Fluconazole N = 131	Voriconazole N = 200	Fluconazole N = 191
	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)
Special Senses See Warnings and Precautions (5.4)
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

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 therapy. Patients who develop abnormal liver function tests during voriconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of voriconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole [see Warnings and Precautions (5.1)] .

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 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 Candidiasis Clinically Significant Laboratory Test Abnormalities

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 AST = Aspartate aminotransferase; ALT = alanine aminotransferase
	Criteria Without regard to baseline value	Voriconazole	Fluconazole
		n/N (%)	n/N (%)
T. Bilirubin	> 1.5 x ULN	8/185 (4.3)	7/186 (3.8)
AST	> 3.0 x ULN	38/187 (20.3)	15/186 (8.1)
ALT	> 3.0 x ULN	20/187 (10.7)	12/186 (6.5)
Alkaline Phosphatase	> 3.0 x ULN	19/187 (10.2)	14/186 (7.5)

Table 6: Protocol 307/602 - Primary Treatment of Invasive Aspergillosis Clinically Significant Laboratory Test Abnormalities

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 AST = Aspartate aminotransferase; ALT = alanine aminotransferase
	Criteria Without regard to baseline value	Voriconazole	Amphotericin B Amphotericin B followed by other licensed antifungal therapy
		n/N (%)	n/N (%)
T. Bilirubin	> 1.5 x ULN	35/180 (19.4)	46/173 (26.6)
AST	> 3.0 x ULN	21/180 (11.7)	18/174 (10.3)
ALT	> 3.0 x ULN	34/180 (18.9)	40/173 (23.1)
Alkaline Phosphatase	> 3.0 x ULN	29/181 (16.0)	38/173 (22.0)
Creatinine	> 1.3 x ULN	39/182 (21.4)	102/177 (57.6)
Potassium	< 0.9 x LLN	30/181 (16.6)	70/178 (39.3)

Table 7: Protocol 608 - Treatment of Candidemia Clinically Significant Laboratory Test Abnormalities

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 Without regard to baseline value	Voriconazole	Amphotericin B followed by Fluconazole
		n/N (%)	n/N (%)
T. Bilirubin	> 1.5 x ULN	50/261 (19.2)	31/115 (27.0)
AST	> 3.0 x ULN	40/261 (15.3)	16/116 (13.8)
ALT	> 3.0 x ULN	22/261 (8.4)	15/116 (12.9)
Alkaline Phosphatase	> 3.0 x ULN	59/261 (22.6)	26/115 (22.6)
Creatinine	> 1.3 x ULN	39/260 (15.0)	32/118 (27.1)
Potassium	< 0.9 x LLN	43/258 (16.7)	35/118 (29.7)

The safety of voriconazole was investigated in pediatric patients, including 52 pediatric patients less than 18 years of age who were enrolled in the adult therapeutic studies.

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.

Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole). However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information.

6.2 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.

Skeletal: fluorosis and periostitis have been reported during long-term voriconazole therapy [see Warnings and Precautions (5.12)] .

Eye Disorders: prolonged visual adverse reactions, including optic neuritis and papilledema [see Warnings and Precautions (5.4)] .

Skin and Appendages: drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)] .

Endocrine Disorders: adrenal insufficiency, Cushing’s syndrome (when voriconazole has been used concomitantly with corticosteroids) [see Warnings and Precautions (5.8)] .

There have been postmarketing reports of pancreatitis in pediatric patients.