voriconazole 50 mg tablet generic vfend

Uses

Aspergillosis

Voriconazole is used for the treatment of invasive aspergillosis. Voriconazole has been evaluated in clinical studies for primary and salvage therapy of invasive aspergillosis, including treatment of invasive aspergillosis in patients intolerant of, or whose disease was refractory to, other antifungals. In these studies, the majority of isolates were Aspergillus fumigatus.

The Infectious Diseases Society of America (IDSA) considers voriconazole the drug of choice for primary treatment of invasive aspergillosis in most patients and IV amphotericin B the preferred alternative. For salvage therapy in patients refractory to or intolerant of primary antifungal therapy, IDSA recommends amphotericin B, caspofungin, micafungin, posaconazole, or itraconazole. For empiric or preemptive therapy of presumed aspergillosis, IDSA recommends amphotericin B, caspofungin, itraconazole, or voriconazole.

For the treatment of invasive aspergillosis in adults and adolescents with human immunodeficiency virus (HIV) infection, the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and IDSA recommend voriconazole as the drug of choice; IV amphotericin B, IV echinocandins (caspofungin, micafungin, anidulafungin), and oral posaconazole are recommended as alternatives. Voriconazole also is considered the drug of choice for treatment of invasive aspergillosis in HIV-infected children; IV amphotericin B and IV caspofungin are alternatives.

Clinical Experience

Efficacy of voriconazole as primary or salvage therapy for invasive aspergillosis was evaluated in an open-label, noncomparative study in 116 patients 18-79 years of age with definite or probable invasive aspergillosis. A complete or partial response was achieved in 48% of patients in this study, but lower response rates observed in patients with definite disease (38%) than in those with probable disease (58%).

In a randomized, nonblinded study of voriconazole as primary therapy for invasive aspergillosis, 277 patients 12-79 years of age with definite or probable invasive aspergillosis received voriconazole (6 mg/kg IV twice daily for 2 doses and then 4 mg/kg IV twice daily for at least 7 days followed by oral voriconazole 200 mg twice daily) or amphotericin B (1-1.5 mg/kg IV once daily) for up to 12 weeks. At the end of the study, a complete or partial response was achieved in 53% of patients randomized to receive voriconazole compared with 32% of those randomized to receive amphotericin B and the survival rate at the end of the study was 71 or 58%, respectively. Pooled analysis of data from this study and an additional study in patients intolerant of, or whose disease was refractory to, other antifungals indicate a response rate of 44 or 40% in patients with invasive infections caused by A. fumigatus or other Aspergillus species, respectively,

Candidemia and Disseminated Candida Infections

Voriconazole is used for the treatment of candidemia in nonneutropenic patients and for the treatment of disseminated Candida infections involving the skin, abdomen, kidney, bladder wall, or wounds. The drug has been effective in Candida albicans, C. tropicalis, C. parapsilosis, C. glabrata, and C. krusei infections.

For the treatment of candidemia in nonneutropenic patients or for empiric treatment of suspected invasive candidiasis in such patients, the IDSA recommends fluconazole or an echinocandin (caspofungin, micafungin, anidulafungin) for initial therapy; amphotericin B is the preferred alternative. These experts state that voriconazole offers little advantage over fluconazole and generally has been reserved for step-down oral therapy for treatment of C. krusei candidiasis or for treatment of fluconazole-resistant, voriconazole-susceptible C. glabrata infections. Although an echinocandin is preferred for initial treatment of C. glabrata infections, if the patient initially received fluconazole or voriconazole, continuation of the azole antifungal until treatment completion is reasonable if the patient is clinically improved and follow-up culture results are negative.

For the treatment of candidemia in neutropenic patients, the IDSA recommends an echinocandin (caspofungin, micafungin, anidulafungin) or amphotericin B for initial therapy; fluconazole is a reasonable alternative in those who are less critically ill or have not recently received an azole; voriconazole can be used as an alternative when broader antifungal coverage is required. An echinocandin is preferred for C. glabrata infections; fluconazole or amphotericin B is preferred for C. parapsilosis infections; an echinocandin, amphotericin B, or voriconazole is recommended for C. krusei infections. Although an echinocandin is preferred for initial treatment of C. glabrata infections, if the patient initially received fluconazole or voriconazole, continuation of the azole antifungal until treatment completion is reasonable if the patient is clinically improved and follow-up culture results are negative. For initial empiric treatment of suspected invasive candidiasis in neutropenic patients, amphotericin B, caspofungin, or voriconazole is recommended; alternatives are fluconazole or itraconazole.

Voriconazole has been used prophylactically to reduce the incidence of candidiasis in patients at risk, including hematopoietic stem cell transplant recipients.

Clinical Experience

Efficacy of voriconazole for the treatment of candidemia and other disseminated or invasive infections caused by Candida was evaluated in an open-label comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized to receive IV voriconazole (followed by oral voriconazole) or IV amphotericin B (followed by oral fluconazole); antifungal therapy was continued for a median of 15 days. In patients evaluated for efficacy, most infections were caused by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%), and C. krusei (1%). Analysis at 12 weeks after the end of therapy indicates that voriconazole is as effective as IV amphotericin B followed by oral fluconazole. A successful response (defined as resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, or infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drugs) was observed in 41% of patients in each group.

Voriconazole has resulted in a favorable response in patients with invasive fungal infections (intra-abdominal infection, kidney and bladder wall infection, deep tissue abscess or wound infection, pneumonia/pleural space infection, skin lesions, suppurative phlebitis, hepatosplenic infection) caused by Candida whose disease was refractory to, or who were intolerant of, other antifungals.

Oropharyngeal Candidiasis

Voriconazole has been used for the treatment of oropharyngeal candidiasis refractory to other antifungals.

For the treatment of mild oropharyngeal candidiasis, the IDSA recommends topical treatment with clotrimazole lozenges or nystatin oral suspension; oral fluconazole is recommended for moderate to severe disease. For refractory oropharyngeal candidiasis, including fluconazole-refractory infections, itraconazole oral solution, oral posaconazole, or oral voriconazole is recommended. An IV echinocandin (caspofungin, micafungin, anidulafungin) or IV amphotericin B also are recommended as alternatives for refractory infections.

For the treatment of oropharyngeal candidiasis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend oral fluconazole as the drug of choice for initial episodes; if topical therapy is used for the treatment of mild to moderate episodes, the drugs of choice are miconazole buccal tablets or clotrimazole lozenges. Alternatives for systemic treatment of oropharyngeal candidiasis in HIV-infected adults and adolescents are itraconazole oral solution or oral posaconazole; nystatin oral suspension is an alternative if topical treatment is used. For fluconazole-refractory oropharyngeal infections in HIV-infected adults and adolescents, oral posaconazole is preferred; itraconazole oral solution is an alternative.

Although routine long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse or recurrence is not usually recommended in patients adequately treated for oropharyngeal candidiasis, patients with frequent or severe recurrences (including HIV-infected adults, adolescents, and children) may benefit from secondary prophylaxis with oral fluconazole or itraconazole oral solution; however, the potential for azole resistance should be considered.

Esophageal Candidiasis

Voriconazole is used for the treatment of esophageal candidiasis. The drug has been effective in immunocompromised patients with esophageal candidiasis caused by C. albicans, C. glabrata, or C. krusei.

Esophageal candidiasis requires treatment with a systemic antifungal (not a topical antifungal).

The IDSA recommends oral fluconazole as the preferred drug of choice for the treatment of esophageal candidiasis; if oral therapy is not tolerated, IV fluconazole, IV amphotericin B, or an IV echinocandin (caspofungin, micafungin, anidulafungin) is recommended. For fluconazole-refractory infections, preferred alternatives are itraconazole oral solution, oral posaconazole, or oral or IV voriconazole; other alternatives are an IV echinocandin or IV amphotericin B.

For the treatment of esophageal candidiasis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend oral or IV fluconazole as the drug of choice and itraconazole oral solution as the preferred alternative. Other alternatives include oral or IV voriconazole, oral posaconazole, IV echinocandins (caspofungin, micafungin, anidulafungin), or IV amphotericin B. For refractory esophageal candidiasis, including fluconazole-refractory infections, in HIV-infected adults and adolescents, oral posaconazole is preferred; alternatives include itraconazole oral solution, IV amphotericin B, IV echinocandins (caspofungin, micafungin, anidulafungin), or oral or IV voriconazole.

Although routine long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse or recurrence is not usually recommended in patients adequately treated for esophageal candidiasis, patients with frequent or severe recurrences (including HIV-infected adults, adolescents, and children) may benefit from secondary prophylaxis with oral fluconazole or oral posaconazole; however, the potential for azole resistance should be considered.

Clinical Experience

Efficacy of voriconazole has been evaluated in a comparative study in immunocompromised patients with esophageal candidiasis documented by endoscopy. Patients were randomized to receive oral voriconazole (200 mg twice daily) or oral fluconazole (200 mg once daily); antifungals were given for a median of 15 days. A successful response (defined as normal endoscopy at end of treatment or at least a 1 grade improvement over baseline endoscopic score) occurred in 98% of those who received voriconazole and in 95% of those who received fluconazole. In voriconazole-treated patients, mycologic eradication was achieved in 84% of those with C. albicans infection, in 57% of those with C. glabrata infection, and in the single patient with C. krusei infection.

Coccidioidomycosis

Voriconazole has been used for the treatment of coccidioidomycosis caused by Coccidioides immitis or C. posadasii, and is recommended as an alternative for the treatment or prevention of these infections.

Antifungal treatment may not be necessary in patients with mild, uncomplicated coccidioidal pneumonia since such infections often are self-limited and may resolve spontaneously. However, antifungal treatment is recommended for patients with more severe or rapidly progressing coccidioidal infections, those with chronic pulmonary or disseminated infections, and immunocompromised or debilitated individuals (e.g., HIV-infected individuals, organ transplant recipients, those receiving immunosuppressive therapy, those with diabetes or cardiopulmonary disease).

The IDSA and others state that an oral azole (fluconazole or itraconazole) usually is recommended for initial treatment of symptomatic pulmonary coccidioidomycosis and chronic fibrocavitary or disseminated (extrapulmonary) coccidioidomycosis. However, IV amphotericin B is recommended as an alternative and is preferred for initial treatment of severely ill patients who have hypoxia or rapidly progressing disease, for immunocompromised individuals, or when azole antifungals have been ineffective or cannot be used (e.g., pregnant women).

For the treatment of clinically mild coccidioidomycosis (e.g., focal pneumonia) in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend initial therapy with oral fluconazole or oral itraconazole. These experts state that, although clinical data are limited, oral voriconazole or oral posaconazole may be used as an alternative for the treatment of clinically mild coccidioidomycosis that has not responded to fluconazole or itraconazole.

HIV-infected individuals who have been adequately treated for coccidioidomycosis should receive long-term (usually life-long) secondary prophylaxis to prevent recurrence or relapse. Although oral fluconazole or oral itraconazole are the drugs of choice recommended by the CDC, NIH, and IDSA for secondary prophylaxis to prevent recurrence or relapse of coccidioidomycosis in HIV-infected adults and adolescents, these experts state that oral voriconazole or oral posaconazole can be used as an alternative for secondary prophylaxis of coccidioidomycosis if the patient did not initially respond to fluconazole or itraconazole.

Exserohilum Infections

Amphotericin B has been used for the treatment of infections known or suspected to be caused by Exserohilum rostratum.

Exserohilum is a common mold found in soil and on plants, especially grasses, and thrives in warm and humid climates.E. rostratum is considered an opportunistic human pathogen and rarely has been involved in human infections, including cutaneous and subcutaneous infections or keratitis, typically as the result of skin or eye trauma. More invasive infections (e.g., infections involving the sinuses, heart, lungs, or bones) and life-threatening infections also have been reported rarely, usually in immunocompromised individuals. In addition, E. rostratum was identified as the predominant pathogen in the 2012-2013 multistate outbreak of fungal meningitis and other fungal infections that occurred in the US in patients who received contaminated preservative-free methylprednisolone acetate injections prepared by a compounding pharmacy.Exserohilum infections cannot be transmitted person-to-person.

Although data are limited and the clinical relevance of in vitro testing remains uncertain, in vitro studies indicate that Exserohilum is inhibited by some triazole antifungals (e.g., voriconazole, itraconazole, posaconazole) and amphotericin B. Echinocandins (e.g., caspofungin, micafungin) have variable in vitro activity and fluconazole has poor in vitro activity against the fungus.

Exserohilum Infections Related to Contaminated Injections

In September 2012, the CDC and US Food and Drug Administration (FDA) initiated investigations in response to fungal CNS infections (including some fatalities) reported in patients who received epidural injections of contaminated extemporaneously prepared methylprednisolone acetate injections from the New England Compounding Center (NECC). Subsequently, there were reports of joint infections and osteomyelitis in some patients who received intra-articular injections of methylprednisolone acetate from NECC, as well as infections possibly related to other NECC products.

Out of an abundance of caution at that time, the FDA recommended that health-care professionals and consumers not use any product that was produced by NECC, and the company recalled all products that were compounded at and distributed from its facility in Framingham, Massachusetts. Recall information is available at http://www.neccrx.com.

The predominant pathogen identified in samples taken from patients who received contaminated products from NECC has been E. rostratum;Aspergillus also was identified in an index patient and Cladosporium cladosporioides was recovered from several other patients. The presence of E. rostratum was confirmed in recalled lots of the contaminated products. Other organisms identified in unopened vials from these recalled lots were C. cladosporioides, Bacillus subtilis, B. pumilus, Paecilomyces formosus, Rhodotorula laryngis, and Rhizopus stolonifer;Rhodotorula and Rhizopus are not known to cause human disease and do not grow at human body temperature.

CDC data indicate that, as of September 6, 2013, there were a total of 750 cases of fungal infections (including 64 deaths) reported in 20 states that have been linked to 3 specific lots of contaminated methylprednisolone acetate injections. Although the majority of initial cases involved fungal meningitis (some with stroke), subsequent reports involved localized spinal or paraspinal infections (e.g., epidural abscess). More than 6 months after the outbreak related to contaminated products was first identified, the CDC continued to receive reports of patients presenting with localized spinal and paraspinal infections (e.g., epidural abscess, phlegmon, discitis, vertebral osteomyelitis, arachnoiditis, or other complications at or near the site of injection). These localized infections have occurred in patients with or without a diagnosis of fungal meningitis. In some patients being treated for fungal meningitis who had no previous evidence of localized infections, such infections were found at the site of injection using magnetic resonance imaging (MRI) studies. Some cases have occurred in patients without any previous evidence of infection or in those with persistent, worsening, or new symptoms.

Patients with meningitis generally presented 1-4 weeks or longer after receiving contaminated methylprednisolone acetate injections; the greatest risk for development of fungal meningitis appeared to be during the first 6 weeks after an epidural or paraspinal injection. Data from one group of patients indicate that the median time from the last injection with contaminated product to the date of the first MRI finding indicative of infection was 50 days (range 12-121 days) for all patients with a spinal or paraspinal infection, and the median time from the first positive lumbar puncture finding to the first positive MRI finding was 21 days for those with meningitis and spinal or paraspinal infections.

Clinicians treating fungal infections in patients who received contaminated methylprednisolone acetate injections from NECC should consult an infectious disease expert to assist with diagnosis, management, and follow-up, which may be complex and prolonged. A clinical consultant network for clinicians can be reached by calling CDC at 800-232-4636. Because of evidence of latent disease, the CDC cautions clinicians to maintain a high index of suspicion and remain vigilant for fungal infections in patients who received the contaminated methylprednisolone acetate injections, especially in those who have mild or baseline symptoms, and to consider MRI evaluation if clinically warranted.

In October 2012, the CDC released interim treatment guidance documents containing recommendations for empiric antifungal treatment of CNS and parameningeal infections and osteoarticular infections associated with the contaminated methylprednisolone acetate products. As additional information became available, these treatment guidance documents were updated and revised several times. Although the following information regarding the CDC recommendations for treatment of these fungal infections was current at the time the voriconazole monograph was finalized for publication, these recommendations may change and the most recent CDC guidance documents at http://www.cdc.gov/hai/outbreaks/meningitis.html should be consulted for the most current recommendations for selection of antifungal agents and the appropriate dosages and duration of treatment.

For the treatment of CNS infections (including meningitis, stroke, and arachnoiditis) and/or parameningeal infections (epidural or paraspinal abscess, discitis or osteomyelitis, and sacroiliac infection) in adults who received the contaminated methylprednisolone acetate injections, the CDC recommends voriconazole. In most patients with these CNS or parameningeal infections, voriconazole should be given IV initially and a transition to oral voriconazole considered only after the patient is clinically stable or improving. Initial treatment with oral voriconazole should be considered only in patients with mild disease who can be monitored closely. Use of IV amphotericin B liposomal in addition to IV voriconazole should be strongly considered in patients who present with severe disease and in patients who do not improve or experience clinical deterioration or manifest new sites of disease activity while receiving voriconazole monotherapy. IV amphotericin B liposomal also is an alternative in patients who are unable to tolerate voriconazole. IV amphotericin B liposomal is preferred over other lipid formulations of amphotericin B because of better CNS penetration. Because of limited data and associated toxicities, routine use of intrathecal amphotericin B is not recommended. Although posaconazole or itraconazole has been used in some patients who could not tolerate voriconazole or amphotericin B, efficacy of these drugs for the treatment of infections associated with the contaminated methylprednisolone acetate injections has not been established. Expert consultation is advised when making decisions regarding alternative regimens.

For the treatment of osteoarticular infections (discitis, vertebral osteomyelitis, and epidural abscess or osteoarticular infections not involving the spine) in adults who received intra-articular injections of contaminated methylprednisolone acetate, the CDC recommends voriconazole. Voriconazole should be given IV initially in those with more severe osteoarticular infections, clinical instability, discitis, vertebral osteomyelitis, or epidural abscess; a transition to oral voriconazole should be considered only after the patient is clinically stable or improving. Initial treatment with oral voriconazole should be considered only in patients with mild osteoarticular infections not involving the spine who can be monitored closely. Use of a lipid formulation of IV amphotericin B in addition to IV voriconazole should be considered in patients with severe osteoarticular infection and/or clinical instability. A lipid formulation of IV amphotericin B, posaconazole, or itraconazole are alternatives in patients who cannot tolerate voriconazole. Expert consultation is advised when making decisions regarding alternative regimens.

Adequate duration of antifungal treatment for Exserohilum infections associated with contaminated methylprednisolone acetate injections is unknown, but prolonged therapy is required.(See Exserohilum Infections under Dosage and Administration: Dosage.) In addition, close follow-up monitoring after completion of treatment is essential in all patients to detect potential relapse.

The CDC website at http://www.cdc.gov/hai/outbreaks/meningitis.html and FDA website at http://www.fda.gov/Drugs/DrugSafety/ucm322734.htm should be consulted for the most recent information regarding the contaminated NECC products and associated infections. The CDC website includes specific information regarding case definitions and diagnostic testing as well as management and treatment of these infections.

Fusarium and Scedosporium Infections

Voriconazole is used for the treatment of serious fungal infections caused by Fusarium (including F. solani) or Scedosporium apiospermum (asexual form of Pseudallescheria boydii) in patients intolerant of, or whose disease is refractory to, other antifungals.

For the treatment of fusariosis, the most appropriate antifungal should be selected based on in vitro susceptibility testing. Amphotericin B may be preferred for infections caused by F. solani or F. verticillioides; either voriconazole or amphotericin B are recommended for infections caused by other Fusarium.

For the treatment of scedosporiosis, some clinicians consider voriconazole the drug of choice and posaconazole the preferred alternative.

Histoplasmosis

Voriconazole has been used for the treatment of histoplasmosis caused by Histoplasma capsulatum.

The drugs of choice for the treatment of histoplasmosis are IV amphotericin B or oral itraconazole. IV amphotericin B is preferred for initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients such as those with HIV infection. Oral itraconazole generally is used for initial treatment of less severe disease (e.g., mild to moderate acute pulmonary histoplasmosis, chronic cavitary pulmonary histoplasmosis) and as follow-up therapy in the treatment of severe infections after a response has been obtained with IV amphotericin B. Other azole antifungals (fluconazole, ketoconazole, posaconazole, voriconazole) are considered second-line alternatives to oral itraconazole.

For the treatment of less severe disseminated histoplasmosis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend initial treatment with oral itraconazole. These experts state that, although clinical data are limited, oral voriconazole or oral posaconazole may be used as an alternative for the treatment of less severe disseminated histoplasmosis in patients intolerant of itraconazole who are only moderately ill.

HIV-infected individuals who have been adequately treated for histoplasmosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse. Oral itraconazole is the drug of choice for secondary prophylaxis of histoplasmosis in HIV-infected adults and adolescents. The role of voriconazole for secondary prophylaxis of histoplasmosis in HIV-infected patients has not been evaluated to date.

Penicilliosis

Voriconazole is used for treatment of penicilliosis caused by Penicillium marneffei.

For the treatment of severe acute penicilliosis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend an initial regimen of IV amphotericin B liposomal followed by oral itraconazole. These experts state that a voriconazole regimen (IV initially, then oral) can be used as an alternative in patients with severe penicilliosis, including those who fail to respond to a regimen of amphotericin B followed by itraconazole.

For the treatment of mild penicilliosis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend oral itraconazole as the drug of choice and oral voriconazole as an alternative.

HIV-infected patients who have been treated for penicilliosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole to prevent recurrence or relapse. An optimal voriconazole regimen for secondary prophylaxis of penicilliosis has not been identified to date.

Empiric Therapy in Febrile Neutropenic Patients

Voriconazole also has been used for empiric therapy of presumed fungal infections in febrile neutropenic patients.

Clinical Experience

Efficacy of voriconazole for empiric therapy in febrile neutropenic patients has been evaluated in an open-label, randomized, multicenter study in patients 12-82 years of age who were neutropenic following chemotherapy or stem cell transplantation. In this study, patients received voriconazole or amphotericin B liposomal for up to 3 days following neutrophil recovery, or for a maximum of 12 weeks. A response (based on a composite assessment including no breakthrough infections within 7 days of the completion of therapy, survival for 7 days following completion of therapy, discontinuance of the drug because of toxicity or lack of efficacy prior to recovery from neutropenia, resolution of fever during neutropenia, and complete or partial response in patients with baseline fungal infections by the completion of therapy) was obtained in 26 or 31% of patients receiving voriconazole or amphotericin B liposomal, respectively. The composite results failed to meet protocol-defined statistical criteria for concluding that voriconazole was not inferior to amphotericin B liposomal. Exploratory analyses of the individual elements of the composite measure suggested that breakthrough infections occurred in a smaller proportion of patients receiving voriconazole (1.9%) compared with amphotericin B liposomal (5%); exploratory analyses of the other individual elements of the composite measure failed to identify other substantial differences between the 2 regimens.

Dosage and Administration

Administration

Voriconazole is administered orally or by slow IV infusion.

The IV route usually is used for initial treatment of systemic fungal infections, but may be switched to oral treatment when clinically indicated.

Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia) should be corrected prior to initiation of voriconazole.(See IV Infusion under Dosage and Administration: Administration and see Cardiovascular Effects under Warnings/Precautions: General Precautions, in Cautions.)

Oral Administration

Voriconazole film-coated tablets or oral suspension should be given at least 1 hour before or 1 hour after meals.

Reconstituted voriconazole oral suspension should be administered using the oral dispenser provided by the manufacturer and should not be mixed with other drugs or flavoring agents. Prior to withdrawal of each dose, the reconstituted oral suspension should be shaken for 10 seconds.

If a dose is missed, the missed dose should be taken as soon as possible; however, if it has been more than 6 hours since the missed dose, the next scheduled dose should be taken at the appropriate time. A double dose should not be taken.

Reconstitution

Voriconazole powder for oral suspension is reconstituted by adding 46 mL of water to the bottle containing 45 g of voriconazole to provide a suspension containing 40 mg/mL. The bottle should be shaken vigorously for about 1 minute.

The oral suspension should not be mixed with other drugs or additional flavoring agents. The reconstituted oral suspension should not be further diluted with water or any other vehicle and is stable for 14 days at 15-30°C.

IV Infusion

Voriconazole IV solutions should not be administered concomitantly with short-term infusions of concentrated electrolytes, even if the 2 infusions are running in separate IV lines or cannulas. Voriconazole IV solutions may be administered at the same time as other IV solutions containing nonconcentrated electrolytes; however, the drug must be infused through a separate line.

Voriconazole IV solutions should not be administered concomitantly with any blood product, even if the 2 infusions are running in separate IV lines or cannulas.

Voriconazole IV solutions may be administered at the same time as total parenteral nutrition (TPN); however, the drug must be infused through a separate IV line. If infused through a multiple-lumen catheter, TPN must be administered using a different port from the one used for voriconazole.

Reconstitution and Dilution

For IV infusion, the contents of a single-use vial labeled as containing 200 mg of voriconazole should be reconstituted with exactly 19 mL of sterile water for injection to prepare a solution containing 10 mg/mL of the drug. The vial should be shaken until all the powder is dissolved. Reconstituted voriconazole solutions must be further diluted in a compatible IV infusion solution prior to administration. The reconstituted solutions should be used immediately since they contain no preservative; if not used immediately, reconstituted solutions should be stored for no longer than 24 hours at 2-8°C before being diluted and used.

To dilute reconstituted voriconazole solutions, calculate the volume of reconstituted solution required to administer the appropriate weight-based dose and then withdraw and discard a volume of diluent from the final infusion container that equals or exceeds that volume. The volume of diluent remaining in the container should be such that a final concentration of at least 0.5 mg/mL but not greater than 5 mg/mL will be achieved following addition of the reconstituted solution. The appropriate dose should then be withdrawn from the required number of reconstituted vials and added to the infusion container. Any unused portion of reconstituted solution should be discarded.

Rate of Administration

IV infusions of voriconazole should be given over 1-2 hours at a maximum rate of 3 mg/kg per hour. The drug should not be administered by rapid IV infusion.

Dosage

In adults, the voriconazole 200-mg tablet and 40-mg/mL oral suspension are bioequivalent when administered using a loading dose regimen (400 mg every 12 hours) followed by maintenance dosage (200 mg every 12 hours).

In adults, an oral voriconazole dosage of 200 mg every 12 hours results in an area under the plasma-concentration time curve (AUC) similar to that achieved with an IV dosage of 3 mg/kg every 12 hours; an oral dosage of 300 mg every 12 hours results in an AUC similar to that reported with an IV dosage of 4 mg/kg every 12 hours.

Aspergillosis

Adult Dosage

For the treatment of invasive aspergillosis, adults should receive an initial loading dose regimen of 6 mg/kg of voriconazole by IV infusion every 12 hours for 2 doses, followed by a maintenance dosage of 4 mg/kg by IV infusion every 12 hours for at least 7 days until the patient is clinically improved and can be switched to oral voriconazole. If this IV maintenance dosage cannot be tolerated, the maintenance dosage can be decreased to 3 mg/kg IV every 12 hours.

After an initial IV regimen, the recommended oral maintenance dosage of voriconazole in patients with invasive aspergillosis is 200 mg every 12 hours in patients weighing 40 kg or more or 100 mg every 12 hours in adults weighing less than 40 kg; if the therapeutic response is not adequate, the dosage may be increased to 300 mg every 12 hours in patients weighing 40 kg or more or 150 mg every 12 hours in those weighing less than 40 kg. If this dosage cannot be tolerated, the dosage may be decreased by increments of 50 mg to a minimum of 200 mg every 12 hours in those weighing 40 kg or more or 100 mg every 12 hours in adults weighing less than 40 kg.

The total duration of IV and oral therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and response to the drug. The optimal duration of therapy for aspergillosis is uncertain. In a clinical study in patients with invasive aspergillosis, the median duration of initial IV therapy was 10 days (range 2-90 days) and the median duration of maintenance oral therapy was 76 days (range 2-232 days). The Infectious Diseases Society of America (IDSA) recommends that treatment of invasive pulmonary aspergillosis be continued for at least 6-12 weeks and continued throughout the period of immunosuppression.

For the treatment of invasive aspergillosis in adults with human immunodeficiency virus (HIV) infection, the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and IDSA recommend an initial loading dose regimen of 6 mg/kg by IV infusion every 12 hours on day 1, followed by a maintenance dosage of 4 mg/kg by IV infusion every 12 hours. After clinical improvement, an oral dosage of 200 mg every 12 hours is recommended. The optimal duration of therapy in these patients has not been established, but antifungal therapy should be continued at least until the CD4 T-cell count increases to 200/mm as a result of potent antiretroviral therapy and there is evidence that aspergillosis has resolved.

Pediatric Dosage

In children 12 years of age or older, an IV regimen of voriconazole that consists of a loading dose regimen of 6 mg/kg every 12 hours for 2 doses, followed by an IV maintenance regimen of 4 mg/kg every 12 hours has been recommended; the IV maintenance dosage should be decreased to 3 mg/kg every 12 hours if higher dosage is not tolerated.

In children 12 years of age or older weighing less than 40 kg, an oral regimen of voriconazole that consists of a loading dose regimen of 200 mg every 12 hours for 2 doses, followed by a maintenance dosage of 100 mg every 12 hours has been recommended; if the response is inadequate, the dosage may be increased to 150 mg every 12 hours. In children 12 years of age or older weighing 40 kg or more, an oral regimen of 400 mg every 12 hours for 2 doses, followed by a maintenance dosage of 200 mg every 12 hours has been recommended; if the response is inadequate, the dosage may be increased to 300 mg every 12 hours.

The IDSA recommends that pediatric patients receive 5-7 mg/kg IV every 12 hours for the treatment of invasive aspergillosis.

For the treatment of invasive aspergillosis in HIV-infected adolescents, some clinicians recommend an initial loading dose regimen of 6 mg/kg by IV infusion twice daily on day 1, followed by a maintenance dosage of 4 mg/kg by IV infusion twice daily. After clinical improvement, an oral dosage of 200 mg twice daily is recommended. The optimal duration of therapy in these patients has not been established, but antifungal therapy should be continued at least until the CD4 T-cell count increases to 200/mm as a result of potent antiretroviral therapy and there is evidence of clinical response.

For the treatment of invasive aspergillosis in HIV-infected children, some clinicians recommend an initial loading dose regimen of 8 mg/kg (maximum 400 mg) orally twice daily on day 1, followed by a maintenance dosage of 7 mg/kg (maximum 200 mg) orally twice daily. Alternatively, an initial loading dose regimen of 6-8 mg/kg given by IV infusion twice daily on day 1, followed by a maintenance dosage of 7 mg/kg (maximum 200 mg) given by IV infusion twice daily has been recommended. Treatment should be continued for at least 12 weeks; however, treatment duration should be individualized according to clinical response.

Candidemia and Disseminated Candida Infections

Adult Dosage

The usual initial dosage of voriconazole for the treatment of candidemia and disseminated Candida infections in nonneutropenic adults is 6 mg/kg by IV infusion every 12 hours for 2 doses, followed by a maintenance dosage of 3-4 mg/kg by IV infusion every 12 hours until the patient can be switched to oral voriconazole. In clinical studies, patients with candidemia received 3 mg/kg every 12 hours and those with deep tissue infections received 4 mg/kg every 12 hours as salvage therapy. Dosage generally should be based on the nature and severity of the infection. If the patient cannot tolerate a dosage of 4 mg/kg, the dosage can be decreased to 3 mg/kg every 12 hours.

After an initial IV regimen, the usual oral dosage of voriconazole in nonneutropenic adults with candidemia and disseminated Candida infections is 200 mg every 12 hours in patients weighing 40 kg or more or 100 mg every 12 hours in those weighing less than 40 kg; if the therapeutic response is not adequate, the dosage may be increased to 300 mg every 12 hours in patients weighing 40 kg or more or 150 mg every 12 hours in adults weighing less than 40 kg. If this dosage is not tolerated, the dosage may be decreased by increments of 50 mg to a minimum of 200 mg every 12 hours in patients weighing 40 kg or more or 100 mg every 12 hours in adults weighing less than 40 kg.

If voriconazole is used for the treatment of candidemia in neutropenic adults, the IDSA recommends an initial dosage of 6 mg/kg by IV infusion every 12 hours for 2 doses, followed by a maintenance dosage of 3 mg/kg by IV infusion every 12 hours.

The manufacturer recommends that treatment of candidemia be continued for at least 14 days after symptoms have resolved or the last positive culture, whichever is longer. The IDSA and others recommend that antifungal treatment for candidemia (without persistent fungemia or metastatic complications) be continued for 14 days after the first negative blood culture and resolution of signs and symptoms of candidemia.

Pediatric Dosage

In children 12 years of age or older, an IV regimen that consists of a loading dose regimen of 6 mg/kg every 12 hours for 2 doses, followed by an IV maintenance regimen of 4 mg/kg every 12 hours has been recommended; the IV maintenance dosage should be decreased to 3 mg/kg every 12 hours if higher dosage is not tolerated.

In children 12 years of age or older weighing less than 40 kg, an oral regimen of 200 mg every 12 hours for 2 doses, followed by a maintenance dosage of 100 mg every 12 hours has been recommended; if the response is inadequate, the dosage may be increased to 150 mg every 12 hours. In children 12 years of age or older weighing 40 kg or more, an oral regimen of 400 mg every 12 hours for 2 doses, followed by a maintenance dosage of 200 mg every 12 hours has been recommended; if the response is inadequate, the dosage may be increased to 300 mg every 12 hours.

The manufacturer recommends that treatment of candidemia be continued for at least 14 days after symptoms have resolved or the last positive culture, whichever is longer. The IDSA and others recommend that antifungal treatment for candidemia (without persistent fungemia or metastatic complications) be continued for 14 days after the first negative blood culture and resolution of signs and symptoms of candidemia.

Oropharyngeal Candidiasis

Adult Dosage

For the treatment of oropharyngeal candidiasis refractory to other antifungals, the IDSA and others recommend an oral voriconazole dosage of 200 mg twice daily.

The IDSA and others recommend that antifungal treatment for oropharyngeal candidiasis be continued for 7-14 days.

Esophageal Candidiasis

Adult Dosage

The usual adult oral dosage of voriconazole for the treatment of esophageal candidiasis is 200 mg every 12 hours in patients weighing 40 kg or more or 100 mg every 12 hours in adults weighing less than 40 kg; if the therapeutic response is not adequate, the dosage may be increased to 300 mg every 12 hours in patients weighing 40 kg or more or 150 mg every 12 hours in adults weighing less than 40 kg. If this dosage is not tolerated, the dosage may be decreased by increments of 50 mg to a minimum of 200 mg every 12 hours in patients weighing 40 kg or more or 100 mg every 12 hours in adults weighing less than 40 kg.

For the treatment of esophageal candidiasis in HIV-infected adults, some clinicians recommend a voriconazole dosage of 200 mg twice daily given orally or by IV infusion.

The manufacturer recommends that treatment of esophageal candidiasis be continued for at least 14 days and for at least 7 days after symptoms resolve. The IDSA and others recommend that antifungal treatment of esophageal candidiasis be continued for 14-21 days after clinical improvement.

Pediatric Dosage

For the treatment of esophageal candidiasis in children 12 years of age or older weighing less than 40 kg, an oral regimen of 100 mg every 12 hours has been recommended. For children 12 years of age or older weighing 40 kg or more, an oral regimen of 200 mg every 12 hours has been recommended.

For the treatment of esophageal candidiasis in HIV-infected adolescents, some clinicians recommend a voriconazole dosage of 200 mg twice daily given orally or by IV infusion.

The manufacturer recommends that treatment of esophageal candidiasis be continued for at least 14 days and for at least 7 days after symptoms resolve. The IDSA and others recommend that antifungal treatment of esophageal candidiasis be continued for 14-21 days after clinical improvement.

Coccidioidomycosis

If oral voriconazole is used as an alternative for the treatment of clinically mild coccidioidomycosis (e.g., focal pneumonia) in HIV-infected adults and adolescents, a dosage of 200 mg twice daily is recommended by the CDC, NIH, and IDSA.

If oral voriconazole is used as an alternative for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse or recurrence of coccidioidomycosis in HIV-infected adults and adolescents who have completed initial treatment of the disease, a dosage of 200 mg twice daily is recommended by the CDC, NIH, and IDSA. In HIV-infected patients who were treated for focal coccidioidal pneumonia and are receiving effective antiretroviral therapy, consideration can be given to discontinuing secondary prophylaxis against coccidioidomycosis after 12 months if CD4 T-cell counts are 250/mm or higher, provided the patient is monitored for recurrence (e.g., serial chest radiographs, coccidioidal serology). HIV-infected patients who were treated for diffuse pulmonary, disseminated, or meningeal coccidioidomycosis usually require life-long secondary prophylaxis.

Exserohilum Infections

Adult Dosage

For the treatment of CNS and/or parameningeal infections known or suspected to be caused by Exserohilum rostratum in adults who received injections of contaminated methylprednisolone acetate (see Uses: Exserohilum Infections), the CDC recommends that voriconazole be given in a dosage of 6 mg/kg every 12 hours. In most patients with these CNS or parameningeal infections, voriconazole should be given IV initially and a transition to oral voriconazole should be considered only after the patient is clinically stable or improving. Initial treatment with oral voriconazole should be considered only in those with mild disease who can be monitored closely.

For the treatment of osteoarticular infections known or suspected to be caused by E. rostratum in adults who received intra-articular injections of contaminated methylprednisolone acetate (see Uses: Exserohilum Infections), the CDC recommends that voriconazole be given in a dosage of 6 mg/kg every 12 hours. For osteoarticular infections that do not involve the spine, voriconazole can be given in a dosage of 6 mg/kg every 12 hours for 2 doses, followed by 4 mg/kg every 12 hours. In most patients with osteoarticular infections, voriconazole should be given IV initially and a transition to oral voriconazole should be considered only after the patient is clinically stable or improving. Initial treatment with oral voriconazole should be considered only in those with mild infections who can be monitored closely.

Serum voriconazole concentrations should be measured in all patients on treatment day 5 and dosage adjusted if needed, aiming for trough concentrations of 2-5 mcg/mL. Serum concentrations should be monitored once weekly during the initial 4-6 weeks of treatment and whenever dosage changes are made, maintaining trough voriconazole concentrations of 2-5 mcg/mL. Voriconazole serum concentrations greater than 5 mcg/mL should be avoided because of the risk of neurotoxicity and other adverse effects.

Adequate duration of antifungal treatment for these E. rostratum infections is unknown, but prolonged treatment is required and should be based on disease severity and clinical response. A treatment duration of 6-12 months is probably necessary in patients who have severe CNS disease with complications (arachnoiditis, stroke), persistent CSF abnormalities, or underlying immunosuppression. In those with parameningeal infection, a minimum treatment duration of 3-6 months should be considered, and at least 6 months or longer probably is required for more severe disease (e.g., discitis, osteomyelitis) and in those with underlying immunosuppression or complications not amenable to surgical treatment. In those with osteoarticular infections, a minimum treatment duration of 3 months should be considered, and longer than 3 months is probably necessary in those with severe disease, bone infections, or underlying immunosuppression. After completion of treatment, close follow-up monitoring is essential in all patients to detect potential relapse.

An infectious disease expert and the most recent guidelines from the CDC should be consulted for information regarding the management of fungal infections in patients who received injections of potentially contaminated products. Clinicians should consult the CDC website at http://www.cdc.gov/hai/outbreaks/meningitis.html for the most recent recommendations regarding the drugs of choice, dosage, and duration of treatment of these infections.

Fusarium and Scedosporium Infections

Adult Dosage

The recommended initial adult IV dosage of voriconazole for the treatment of infections caused by Fusarium or Scedosporium apiospermum is 6 mg/kg by IV infusion every 12 hours for 2 doses, followed by a maintenance dosage of 4 mg/kg by IV infusion every 12 hours until the patient can be switched to oral voriconazole. If this dosage is not tolerated, the IV maintenance dosage can be decreased to 3 mg/kg every 12 hours.

After an initial IV regimen, the usual oral dosage of voriconazole in patients with infections caused by Fusarium or Scedosporium apiospermum is 200 mg every 12 hours in those weighing 40 kg or more or 100 mg every 12 hours in adults weighing less than 40 kg; if the therapeutic response is not adequate, the dosage may be increased to 300 mg every 12 hours in those weighing 40 kg or more or 150 mg every 12 hours in adults weighing less than 40 kg. If this dosage cannot be tolerated, the dosage may be decreased by increments of 50 mg to a minimum of 200 mg every 12 hours in those weighing 40 kg or more or 100 mg every 12 hours in adults weighing less than 40 kg.

Total duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and response to the drug.

Pediatric Dosage

In children 12 years of age of older, an IV regimen of voriconazole that consists of a loading dose regimen of 6 mg/kg every 12 hours for 2 doses, followed by an IV maintenance regimen of 4 mg/kg every 12 hours has been recommended the IV maintenance dosage should be decreased to 3 mg/kg every 12 hours if higher dosage is not tolerated.

In children 12 years of age or older weighing less than 40 kg, an oral regimen of voriconazole that consists of a loading dose regimen of 200 mg every 12 hours for 2 doses, followed by a maintenance dosage of 100 mg every 12 hours has been recommended; if the response is inadequate, the dosage may be increased to 150 mg every 12 hours. In children 12 years of age or older weighing 40 kg or more, an oral regimen of 400 mg every 12 hours for 2 doses, followed by a maintenance dosage of 200 mg every 12 hours has been recommended; if the response is inadequate, the dosage may be increased to 300 mg every 12 hours.

Total duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and response to the drug.

Histoplasmosis

If oral voriconazole is used as an alternative for the treatment of less severe disseminated histoplasmosis in HIV-infected adults and adolescents who are only moderately ill (see Uses: Histoplasmosis), the CDC, NIH, and IDSA recommend a dosage of 400 mg twice daily for 2 doses followed by 200 mg twice daily.

Penicilliosis

If voriconazole is used as an alternative for the treatment of severe acute penicilliosis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend an initial IV regimen of 6 mg/kg every 12 hours for 2 doses, followed by 4 mg/kg IV every 12 hours for at least 3 days, then an oral regimen of 200 mg twice daily for a maximum of 12 weeks.

If oral voriconazole is used as an alternative for the treatment of mild penicilliosis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend a dosage of 400 mg twice daily for 2 doses, followed by 200 mg twice daily for a maximum of 12 weeks.

Special Populations

Hepatic Impairment

In adults with mild-to-moderate hepatic cirrhosis (Child-Pugh class A or B), usual IV or oral loading dosages of voriconazole should be used, but IV or oral maintenance dosages should be decreased by 50%.

Voriconazole should be used in patients with severe hepatic impairment only if benefits outweigh risks; the drug has not been studied in patients with severe hepatic cirrhosis (Child-Pugh class C) or with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.(See Hepatic Effects under Cautions: Warnings/Precautions.)

Renal Impairment

Adjustment of oral voriconazole dosage is not necessary in patients with mild to severe renal impairment.

Because of potential accumulation of the IV vehicle (sulfobutyl ether β-cyclodextrin sodium [SBECD]), IV voriconazole should be avoided in patients with moderate or severe renal impairment (creatinine clearance less than 50 mL/minute); voriconazole should be administered orally in these patients unless potential benefits of the IV route outweigh risks. If IV voriconazole is used in patients with creatinine clearance less than 50 mL/minute, serum creatinine should be monitored closely; if increases occur, switching to oral voriconazole should be considered.

Geriatric Patients

Dosage adjustment based on age is not necessary in geriatric adults.

Cautions

Contraindications

Known hypersensitivity to voriconazole or any ingredient in the formulation.

Concomitant use with astemizole or terfenadine (drugs no longer commercially available in the US), carbamazepine, cisapride (currently commercially available in the US only under a limited-access protocol), ergot alkaloids (e.g., ergotamine, dihydroergotamine), pimozide, quinidine, rifabutin, rifampin, sirolimus, St. John's wort (Hypericum perforatum), or long-acting barbiturates (e.g., phenobarbital, mephobarbital).(See Drug Interactions.)

Concomitant use with ritonavir (400 mg every 12 hours) is contraindicated. Concomitant use with low-dose ritonavir (100 mg every 12 hours) should be avoided, unless potential benefits outweigh risks.(See HIV Protease Inhibitors under Drug Interactions: Antiretroviral Agents.)

Warnings/Precautions

Sensitivity Reactions

Anaphylactoid reactions (e.g., flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus, rash) occurring immediately after initiation of voriconazole IV infusions have been reported rarely. Clinician should consider stopping the infusion if these reactions occur.

Serious cutaneous reactions (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis) and photosensitivity reactions have been reported rarely in patients receiving voriconazole.(See Dermatologic Effects under Warnings/Precautions: General Precautions, in Cautions.)

Data regarding cross-sensitivity with other azole antifungals are not available. Voriconazole should be used with caution in patients hypersensitive to other azoles.

Hepatic Effects

Serious hepatic effects, including hepatitis, cholestasis, and fulminant hepatic failure, have been reported rarely in clinical trials. Hepatic effects (including hepatitis and jaundice) have occurred in patients with no identifiable risk factors.

Hepatic effects usually are reversible when voriconazole is discontinued; however, fatalities have occurred.

If abnormal liver function test results occur during voriconazole therapy, the patient should be monitored for the development of more severe hepatic injury using appropriate laboratory evaluations (particularly liver function tests and bilirubin). Discontinuance of voriconazole must be considered if signs and symptoms consistent with liver disease develop.

Ocular Effects

Visual disturbances (e.g., abnormal vision, blurred vision, color vision change, photophobia) have been reported and may be related to high dosage and high plasma voriconazole concentrations.

There have been postmarketing reports of prolonged visual disturbances, including optic neuritis and papilledema, in patients receiving voriconazole.

Effect of voriconazole on visual function is unknown if duration of therapy exceeds 28 days. Monitor visual function (visual acuity, visual field, and color perception) if duration of therapy exceeds 28 days.

Fetal/Neonatal Morbidity and Mortality

Voriconazole can cause fetal harm. Teratogenicity, embryotoxicity, and embryomortality have been demonstrated in animals.

If voriconazole is used during pregnancy or if the patient becomes pregnant while receiving voriconazole, clinicians should advise the patient of the potential hazard to the fetus.(See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Pregnancy should be avoided. Women of childbearing potential should use effective contraception during voriconazole treatment.(See Drug Interactions: Estrogens and Progestins.)

Fructose or Galactose Intolerance

Patients with a history of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not be given voriconazole tablets since lactose is used in the manufacture of the tablets.

Patients with fructose intolerance, sucrase-isomaltase deficiency, or glucose-galactose malabsorption should not be given voriconazole oral suspension since the suspension contains sucrose.

Cardiovascular Effects

Similar to other azole antifungals, voriconazole has been associated with prolongation of the QT interval. Arrhythmias (e.g., torsades de pointes), cardiac arrest, and sudden death have occurred rarely in patients receiving voriconazole. Most reported cases involved patients with multiple confounding risk factors (e.g., prior cardiotoxic chemotherapy, cardiomyopathy, hypokalemia, concomitant drugs) that may have been contributory.

Voriconazole should be used with caution in patients with potentially proarrhythmic conditions. Rigorous attempts should be made to correct electrolyte imbalances (i.e., potassium, magnesium, calcium) before initiating voriconazole therapy.

Laboratory Monitoring

Hepatic function (liver function tests and bilirubin) should be evaluated prior to and during voriconazole therapy.

Serum electrolytes (i.e., potassium, magnesium, calcium) should be evaluated and any electrolyte abnormalities corrected prior to initiation of voriconazole therapy.

Renal function (e.g., serum creatinine concentrations) should be monitored in patients receiving voriconazole.

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 therapy.

Dermatologic Effects

Serious exfoliative cutaneous reactions (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis) have occurred rarely in patients receiving voriconazole. If an exfoliative cutaneous reaction occurs, voriconazole should be discontinued.

Photosensitivity skin reactions have been reported in patients receiving voriconazole. Patients receiving the drug should avoid intense or prolonged exposure to direct sunlight.

Squamous cell carcinoma of the skin and melanoma have been reported during long-term voriconazole therapy in patients with photosensitivity reactions. If a skin lesion consistent with squamous cell carcinoma or melanoma develops, voriconazole should be discontinued.

Renal Effects

Acute renal failure has been reported in severely ill patients with other factors predisposing to impaired renal function (e.g., underlying conditions, concomitant nephrotoxic drugs).

Skeletal Effects

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.

Specific Populations

Pregnancy

Category D.

Because voriconazole can cause fetal harm, it should not be used during pregnancy except when benefits for the mother clearly outweigh potential risks for the fetus.

In rats, voriconazole was teratogenic (cleft palates, hydronephrosis/hydroureter) at a dosage of 10 mg/kg (0.3 times the recommended human maintenance dosage [RMD] based on mg/m). Other effects in rats included reduced ossification of sacral and caudal vertebrae, skull, and pubic and hyoid bone; supernumerary ribs; anomalies of sternebrae; and dilatation of the ureter/renal pelvis. Reduced plasma estradiol concentrations in pregnant rats, increased gestational length, and dystocia (associated with increased perinatal pup mortality at a dosage of 10 mg/kg) also were reported. In rabbits, voriconazole was embryotoxic at a dosage of 100 mg/kg (6 times the RMD); increased embryomortality, reduced fetal weight, and increased incidence of skeletal variations, cervical ribs, and extrasternebral ossification sites also were reported.

Lactation

It is not known whether voriconazole is distributed into milk.

Because many drugs are distributed into human milk and because of the potential for serious adverse reactions to voriconazole in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and efficacy of voriconazole have not been established in children younger than 12 years of age.

Voriconazole has been recommended for the treatment of fungal infections in children. Some clinicians consider voriconazole the drug of choice for the treatment of invasive aspergillosis in HIV-infected children, but state that data are insufficient to recommend use of the drug for the treatment of candidemia or esophageal candidiasis in these children.

In one study, a limited number of pediatric patients 9 months to 15 years of age whose disease was refractory to, or who were intolerant of, other antifungals have received voriconazole for the treatment of aspergillosis, candidiasis, infections caused by Scedosporium, or other invasive fungal infections. At the completion of therapy, 45% of pediatric patients receiving voriconazole had a complete or partial response. Adverse effects in children receiving voriconazole were similar to those reported in adults.

There have been postmarketing reports of pancreatitis in pediatric patients receiving voriconazole. Children with risk factors for acute pancreatitis (e.g., recent chemotherapy, HSCT) should be monitored for the development of pancreatitis during voriconazole therapy.

In a population pharmacokinetic analysis of voriconazole concentrations in children 2 through 12 years of age who received various dosage regimens, systemic exposures of the drug (areas under the concentration-time curve [AUCs]) achieved with an IV dosage of 7 mg/kg twice daily or an oral dosage of 200 mg twice daily (oral suspension) were comparable to values observed in adults receiving usual dosages of the drug. Data from this study also indicated that loading doses do not appear to reduce the length of time required to reach steady-state in children 2 through 11 years of age and appear to offer little benefit in this age group. Based on a comparison of pharmacokinetic data from pediatric patients (2 years to less than 12 years of age) with data from adults, the manufacturer states that the predicted steady-state plasma voriconazole concentrations were similar in pediatric patients or adults (median concentration of 1.19 or 1.16 mcg/mL, respectively) at a maintenance IV dosage of 4 mg/kg every 12 hours in children or 3 mg/kg every 12 hours in adults.

Geriatric Use

Clinical experience with voriconazole in geriatric patients is limited. Plasma voriconazole concentrations are increased, but overall safety profile is similar to that in younger adults.

Hepatic Impairment

Patients with hepatic impairment should be monitored carefully for voriconazole toxicity, including hepatic effects.(See Hepatic Effects under Warnings/Precautions: Warnings, in Cautions.)

Voriconazole has not been evaluated in patients with severe hepatic cirrhosis (Child-Pugh class C) or with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

Voriconazole should be used in patients with severe hepatic impairment only if benefits outweigh risks.(See Dosage and Administration: Special Populations.)

Renal Impairment

IV voriconazole contains sulfobutyl ether β-cyclodextrin sodium (SBECD) which may accumulate in patients with moderate or severe renal impairment (creatinine clearance less than 50 mL/minute).

IV voriconazole should not be used in patients with creatinine clearance less than 50 mL/minute unless potential benefits outweigh risks. If IV voriconazole is used in these patients, serum creatinine concentrations should be monitored closely; if increases occur, consideration should be given to switching to oral voriconazole.(See Dosage and Administration: Special Populations.)

Common Adverse Effects

Common adverse effects include visual disturbances (e.g., abnormal vision, blurred vision, color vision change, photophobia), GI effects (nausea, vomiting, diarrhea, abdominal pain), fever, rash, chills, headache, abnormalities in liver function test results, tachycardia, and hallucinations. The most commonly reported adverse effects resulting in discontinuance of voriconazole therapy include elevated liver function test results, rash, and visual disturbances.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors or inducers of cytochrome P-450 (CYP) isoenzymes 2C9, 2C19, or 3A4 may increase or decrease plasma voriconazole concentrations, respectively. Voriconazole and its major metabolite inhibit the metabolic activity of CYP2C9, 2C19, and 3A4 and may increase plasma concentrations of other drugs metabolized by these hepatic enzymes. Voriconazole appears to be a less potent inhibitor of CYP3A4 than some other azoles (e.g., itraconazole, ketoconazole).

Because carbamazepine, long-acting barbiturates (e.g., phenobarbital, mephobarbital), ergot alkaloids, rifabutin, rifampin, ritonavir (400 mg every 12 hours), sirolimus, and St. John's wort (Hypericum perforatum) are inducers, inhibitors, and/or substrates of CYP isoenzymes, concomitant use with voriconazole is contraindicated.

Drugs that Prolong the QT Interval

Potential pharmacokinetic interaction with CYP3A4 substrates that prolong the QT interval (e.g., cisapride [currently commercially available in the US only under a limited-access protocol], pimozide, quinidine, terfenadine [no longer commercially available in the US], astemizole [no longer commercially available in the US]). Potential increased plasma concentrations of the concomitantly administered CYP3A4 substrate, which can result in QT interval prolongation and rarely, torsades de pointes. Concomitant use of these drugs that prolong the QT interval and voriconazole is contraindicated.

Alfentanil

Pharmacokinetic interaction (6- and 4-fold increase in mean area under the plasma concentration-time curve [AUC] and elimination half-life, respectively, of alfentanil) when voriconazole was administered concomitantly with alfentanil (patients also received and naloxone). Concomitant administration also resulted in an increased incidence of delayed and persistent alfentanil-induced nausea and vomiting.

If voriconazole is administered concomitantly with alfentanil or other opiate agonists metabolized by CYP3A4 (e.g., sufentanil), decreased dosage of the opiate agonist and extended close monitoring for opiate-related adverse events (e.g., respiratory depression) may be necessary.

Antifungal Agents

Fluconazole

Pharmacokinetic interaction with fluconazole (substantially increased plasma concentrations and AUC of voriconazole).

Concomitant use of fluconazole and voriconazole should be avoided. Patients should be monitored for voriconazole-related adverse effects if the drug is initiated within 24 hours after the last dose of fluconazole.

Antiretroviral Agents

HIV Entry Inhibitors

Possible pharmacokinetic interaction with maraviroc (increased maraviroc plasma concentrations). If used concomitantly, consider reducing the maraviroc dosage to 150 mg twice daily.

HIV Integrase Inhibitor

Elvitegravir

Potential pharmacokinetic interaction with the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (increased concentrations of voriconazole, elvitegravir, and/or cobicistat).

Voriconazole and the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate should not be used concomitantly unless potential benefits outweigh risks. If used concomitantly, consideration should be given to monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly.

Raltegravir

Pharmacokinetic interaction with raltegravir unlikely; dosage adjustments not needed.

HIV Protease Inhibitors

Pharmacokinetic interactions are likely if voriconazole is used in patients receiving HIV protease inhibitors (PIs) (e.g., atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir), especially if ritonavir-boosted PI regimens are used. Concomitant use may result in altered serum concentrations of the PIs and/or the antifungal.

Atazanavir

Possible pharmacokinetic interaction with atazanavir (increased plasma concentrations of voriconazole and atazanavir); possible pharmacokinetic interaction with ritonavir-boosted atazanavir (decreased voriconazole concentrations).

If voriconazole is used concomitantly with atazanavir (without low-dose ritonavir), monitor for toxicities. Concomitant use with ritonavir-boosted atazanavir should be avoided unless benefits outweigh risks; if used concomitantly, consideration should be given to monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly.

Darunavir

Possible pharmacokinetic interaction with ritonavir-boosted darunavir (decreased voriconazole concentrations).

Concomitant use with ritonavir-boosted darunavir should be avoided unless benefits outweigh risks; if used concomitantly, consideration should be given to monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly.

Fosamprenavir

Possible pharmacokinetics interaction with fosamprenavir (increased fosamprenavir concentrations and/or increased voriconazole concentrations); possible pharmacokinetic interaction with ritonavir-boosted fosamprenavir (decreased voriconazole concentrations).

If voriconazole is used concomitantly with fosamprenavir (without low-dose ritonavir), monitor for toxicities. Concomitant use with ritonavir-boosted fosamprenavir should be avoided unless benefits outweigh risks; if used concomitantly, consideration should be given to monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly.

Indinavir

Concomitant use of multiple doses of indinavir and voriconazole does not affect pharmacokinetics of either drug; dosage adjustments are not needed for either drug.

Possible pharmacokinetic interactions with ritonavir-boosted indinavir (decreased voriconazole concentrations). Concomitant use with ritonavir-boosted indinavir should be avoided unless benefits outweigh risks; if used concomitantly, consideration should be given to monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly.

Lopinavir

Possible pharmacokinetic interaction with lopinavir/ritonavir (decreased voriconazole concentrations). Concomitant use should be avoided unless benefits outweigh risks; if used concomitantly, consideration should be given to monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly.

Nelfinavir

Possible pharmacokinetic interaction with nelfinavir (increased nelfinavir concentrations and/or increased voriconazole concentrations) (without low-dose ritonavir); possible pharmacokinetic interactions with ritonavir-boosted nelfinavir (decreased voriconazole concentrations).

If voriconazole is used concomitantly with nelfinavir (without low-dose ritonavir), monitor for toxicities. Concomitant use with ritonavir-boosted nelfinavir should be avoided unless benefits outweigh risks; if used concomitantly, consideration should be given to monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly.

Ritonavir

Pharmacokinetic interaction with full-dose ritonavir (400 mg every 12 hours) (mean 66% decrease in steady-state peak plasma voriconazole concentrations and mean 82% decrease in voriconazole AUC; no clinically important effect on ritonavir pharmacokinetics). Concomitant use of voriconazole and full-dose ritonavir (400 mg every 12 hours) is contraindicated.

Pharmacokinetic interaction with low-dose ritonavir (100 mg every 12 hours) (mean 24% decrease in steady-state peak plasma voriconazole concentrations and mean 39% decrease in voriconazole AUC; 24% decrease in steady-state peak ritonavir concentrations and 14% decrease in ritonavir AUC) . Concomitant use of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided unless benefits of such therapy outweigh risks; if used concomitantly, consideration should be given to monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly.

Saquinavir

Possible pharmacokinetic interactions with saquinavir (increased saquinavir concentrations and/or increased voriconazole concentrations); possible pharmacokinetic interaction with ritonavir-boosted saquinavir (decreased voriconazole concentrations).

If voriconazole is used concomitantly with saquinavir (without low-dose ritonavir), monitor for toxicities. Concomitant use with ritonavir-boosted saquinavir should be avoided unless benefits outweigh risks; if used concomitantly, consideration should be given to monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly.

Tipranavir

Possible pharmacokinetic interaction with ritonavir-boosted tipranavir (decreased voriconazole concentrations). Concomitant use with ritonavir-boosted tipranavir should be avoided unless benefits outweigh risks; if used concomitantly, consideration should be given to monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly.

Nonnucleoside Reverse Transcriptase Inhibitors

Delavirdine

Potential pharmacokinetic interaction with delavirdine (increased voriconazole concentrations). Monitor patients for voriconazole toxicities and clinical response.

Efavirenz

Concomitant use of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) and usual dosage of efavirenz (400 mg once daily for 9 days) reduced voriconazole peak plasma concentrations and AUC by 61 and 77%, respectively, and increased efavirenz peak plasma concentrations and AUC by 38 and 44%, respectively. When a lower dosage of voriconazole (400 mg once daily) was used concomitantly with a lower dosage of efavirenz (300 mg once daily), voriconazole peak plasma concentration was increased 23%, voriconazole AUC was decreased 7%, and efavirenz AUC was increased by 17%.

If concomitant use of efavirenz and voriconazole is necessary, voriconazole maintenance dosage should be increased to 400 mg every 12 hours and efavirenz dosage decreased to 300 mg once daily. After voriconazole therapy is discontinued, the initial dosage of efavirenz should be restored.

Etravirine

Possible pharmacokinetic interaction with etravirine (substantially increased etravirine plasma concentrations, increased voriconazole plasma concentrations). Because of limited data regarding the safety of increased etravirine concentrations, the manufacturer of etravirine states that caution is advised when the drug is administered concomitantly with voriconazole.

Although dosage adjustment is not needed for either drug, some experts state that consideration should be given to monitoring plasma concentrations of voriconazole.

Nevirapine

Potential pharmacokinetic interaction with nevirapine (decreased voriconazole concentrations, increased nevirapine concentrations). Monitor patients for nevirapine toxicity and monitor clinical response to voriconazole and/or voriconazole plasma concentrations.

Rilpivirine

Potential pharmacokinetic interaction (increased rilpivirine concentrations, unknown effect on voriconazole concentrations). Rilpivirine dosage adjustments are not needed; however, patients should be monitored for breakthrough fungal infections.

Barbiturates

Potential pharmacokinetic interaction (decreased plasma voriconazole concentrations) with long-acting barbiturates (e.g., phenobarbital, mephobarbital) and risk of prolonged sedative effects. Concomitant use of long-acting barbiturates and voriconazole is contraindicated.

Benzodiazepines

Potential pharmacokinetic interaction (increased plasma benzodiazepine concentrations and AUC) with benzodiazepines that are metabolized by CYP3A4 isoenzyme (e.g., diazepam, midazolam, triazolam, alprazolam). Monitor patient for manifestations of benzodiazepine toxicity and adjust benzodiazepine dosage as necessary.

Calcium-channel Blocking Agents

Potential pharmacokinetic interaction (increased plasma concentrations of calcium-channel blocker) with calcium-channel blocking agents that are metabolized by CYP3A4 isoenzyme (e.g., felodipine). Monitor patient for manifestations of calcium-channel blocker toxicity and adjust dosage of the calcium-channel blocker as necessary.

Carbamazepine

Potential pharmacokinetic interaction (decreased plasma voriconazole concentrations) with carbamazepine. Concomitant use of carbamazepine and voriconazole is contraindicated.

Cimetidine

Pharmacokinetic interaction (increased voriconazole concentrations and AUC) with cimetidine; not considered clinically important and dosage adjustments not needed.

Clopidogrel

Possible pharmacokinetic interaction (decreased plasma concentrations of the active metabolite of clopidogrel) and reduced antiplatelet effects of clopidogrel.

Concomitant use of clopidogrel and CYP2C19 inhibitors should be avoided since clopidogrel is metabolized to its active metabolite by CYP2C19; in vitro studies indicate voriconazole inhibits CYP2C19.

Coumarin Anticoagulants

Pharmacokinetic interaction (increased prothrombin time) with coumarin anticoagulant. Monitor prothrombin time or other appropriate tests closely if a coumarin anticoagulant (e.g., warfarin) is used concomitantly with voriconazole; reduction of anticoagulant dosage may be necessary.

Digoxin

No clinically important pharmacokinetic interaction; no dosage adjustments needed.

Ergot Alkaloids

Potential pharmacokinetic interaction (increased plasma concentrations of ergot alkaloid). Concomitant use of ergot alkaloids (e.g., ergotamine, dihydroergotamine) and voriconazole is contraindicated.

Estrogens and Progestins

Pharmacokinetic interaction with oral contraceptives containing ethinyl estradiol and norethindrone (increased peak plasma concentrations and AUC of ethinyl estradiol and norethindrone; increased peak plasma concentrations and AUC of voriconazole).

The manufacturer of voriconazole states that this pharmacokinetic interaction is unlikely to affect efficacy of the oral contraceptive. If concomitant therapy is necessary, monitor for oral contraceptive-related and voriconazole-related adverse events.

Fentanyl

Pharmacokinetic interaction with IV fentanyl (decreased mean plasma fentanyl clearance and increased fentanyl AUC). If voriconazole is used concomitantly with IV, oral, or transdermal fentanyl, extended and frequent monitoring for respiratory depression and other fentanyl-associated adverse effects is recommended and fentanyl dosage should be reduced if warranted.

HCV Protease Inhibitors

Boceprevir

Potential pharmacokinetic interaction with boceprevir (increased voriconazole plasma concentrations).

Telaprevir

Potential pharmacokinetic interaction with telaprevir (altered voriconazole plasma concentrations, increased telaprevir plasma concentrations). Although clinically important changes in the QT interval corrected for rate (QT_c) have not been reported with telaprevir, QT interval prolongation and torsades de pointes have been reported with voriconazole.

Voriconazole should be used in patients receiving telaprevir only if potential benefits outweigh risks. If the drugs are used concomitantly, caution is warranted and patients should be monitored clinically.

HMG-CoA Reductase Inhibitors

Potential pharmacokinetic interaction (increased plasma concentrations of antilipemic agent) with HMG-CoA reductase inhibitors (i.e., statins) that are metabolized by CYP3A4 isoenzyme (e.g., lovastatin). Monitor patient for toxicities associated with HMG-CoA reductase inhibitors and adjust dosage of the antilipemic agent as necessary.

Immunosuppressive Agents

Cyclosporine

Pharmacokinetic interaction (increased plasma concentrations and AUC of cyclosporine).

When initiating voriconazole therapy in patients currently receiving cyclosporine, dosage of cyclosporine should be reduced by 50%. When voriconazole is discontinued, plasma concentrations of cyclosporine should be monitored frequently and dosage of the immunosuppressive agent adjusted as necessary.

Sirolimus

Pharmacokinetic interaction (increased plasma concentrations and AUC of sirolimus).

Concomitant use of sirolimus and voriconazole is contraindicated.

Tacrolimus

Pharmacokinetic interaction (increased plasma concentrations of tacrolimus).

When initiating voriconazole therapy in patients currently receiving tacrolimus, dosage of tacrolimus should be reduced to 33% of the original dose; plasma concentrations of tacrolimus should be monitored frequently. When voriconazole is discontinued, plasma concentrations of tacrolimus should be monitored frequently and dosage of the immunosuppressive agent adjusted as necessary.

Macrolides

Concomitant use of voriconazole and azithromycin or erythromycin does not have a clinically important effect on voriconazole pharmacokinetics; effects on macrolide pharmacokinetics are not known. Dosage adjustments not needed.

Methadone

Pharmacokinetic interaction (increased AUC and peak plasma concentrations of pharmacologically active R-methadone) and risk of toxicity (e.g., QT prolongation). Monitor patient for manifestation of methadone toxicity; adjust methadone dosage if necessary.

Mycophenolic Acid

No clinically important effect on pharmacokinetics of mycophenolic acid or its major metabolite (mycophenolic acid glucuronide); dosage adjustments not needed.

Nonsteroidal Anti-inflammatory Agents

If voriconazole is used concomitantly with a nonsteroidal anti-inflammatory agent (NSAIA) that is metabolized by CYP2C9 (e.g., celecoxib, diclofenac, ibuprofen, naproxen, lornoxicam [not commercially available in the US], meloxicam), increased plasma concentrations of the NSAIA are possible. Patients receiving voriconazole concomitantly with an NSAIA should be monitored closely for NSAIA-related adverse effects and toxicity and dosage of the NSAIA reduced if warranted.

Diclofenac

Pharmacokinetic interaction with diclofenac (114% increase in peak plasma diclofenac concentrations and 78% increase in diclofenac AUC). If voriconazole is used concomitantly, reduced dosage of diclofenac may be necessary; patients should be monitored closely for NSAIA-related adverse effects and toxicity.

Ibuprofen

Pharmacokinetic interaction (20% increase in peak plasma concentrations and 100% increase in AUC of the pharmacologically active isomer of ibuprofen). If voriconazole is used concomitantly, reduced dosage of ibuprofen may be necessary; patients should be monitored closely for NSAIA-related adverse effects and toxicity.

Oxycodone

Pharmacokinetic interaction (increased peak plasma concentration, AUC, and elimination half-life of oxycodone); increased oxycodone-associated adverse visual effects (heterophoria, miosis). If voriconazole is used concomitantly with oxycodone, extended and frequent monitoring for oxycodone-associated adverse effects is recommended and reduced oxycodone dosage may be necessary to avoid opiate-related adverse effects.

Phenytoin

Pharmacokinetic interaction (substantially decreased plasma voriconazole concentrations) with voriconazole 200 mg every 12 hours. Increasing the voriconazole dosage to 400 mg every 12 hours in patients receiving concomitant phenytoin results in plasma voriconazole concentrations that are essentially the same as those in patients receiving usual dosages of voriconazole (200 mg every 12 hours) without phenytoin. Pharmacokinetic interaction (increased plasma phenytoin concentrations) with voriconazole 400 mg every 12 hours.

When phenytoin and voriconazole are used concomitantly, increase IV maintenance dosage of voriconazole to 5 mg/kg every 12 hours and increase oral maintenance dosage of the drug to 400 mg every 12 hours in patients weighing 40 kg or more or 200 mg every 12 hours in those weighing less than 40 kg. Plasma phenytoin concentrations should be monitored frequently and the patient observed for potential phenytoin adverse effects.

Pimozide

Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., cardiac arrhythmias). Concomitant use of pimozide and voriconazole is contraindicated.

Prednisolone

Pharmacokinetic interaction (increased concentration and AUC of prednisolone); no dosage adjustments needed.

Proton-pump Inhibitors

Pharmacokinetic interaction (substantially increased plasma omeprazole concentrations and AUC, clinically unimportant increases in plasma voriconazole concentrations, GI absorption of voriconazole not affected) with omeprazole. In patients currently receiving omeprazole in dosages of 40 mg or more daily, reduce omeprazole dosage by one-half when voriconazole therapy is initiated. Adjustment of voriconazole dosage not needed.

Potential increased plasma concentrations of other proton-pump inhibitors that are metabolized by CYP2C19 isoenzyme.

Quinidine

Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., cardiac arrhythmias). Concomitant use of quinidine and voriconazole is contraindicated.

Ranitidine

No pharmacokinetic interaction with ranitidine; dosage adjustments not needed.

Rifampin and Rifabutin

Pharmacokinetic interaction with rifampin (substantially decreased plasma voriconazole concentrations and AUC). Pharmacokinetic interaction with rifabutin (clinically important decreased plasma voriconazole concentrations and decreased AUC of voriconazole, substantially increased plasma rifabutin concentrations and AUC).

Concomitant use of rifampin or rifabutin and voriconazole is contraindicated.

St. John's Wort

Pharmacokinetic interaction (59% decrease in mean voriconazole AUC) following multiple doses of St. John's wort (Hypericum perforatum); no clinically important effect on voriconazole AUC when a single dose of St. John's wort and a single dose of voriconazole are used concomitantly. Because long-term use of St. John's wort could result in decreased voriconazole exposure, concomitant use of voriconazole and St. John's wort is contraindicated.

Sulfonylurea Antidiabetic Agents

Potential pharmacokinetic interaction (increased plasma concentrations of antidiabetic agent) with sulfonylurea antidiabetic agents (e.g., tolbutamide, glipizide, glyburide). Monitor blood glucose concentrations and monitor patient for signs and symptoms of hypoglycemia; adjust dosage of antidiabetic agent as necessary.

Venlafaxine

Pharmacokinetic interaction (increased venlafaxine AUC); if used concomitantly, monitor for venlafaxine-associated toxicity.

Vinca Alkaloids

Potential pharmacokinetic interaction (increased plasma concentrations of vinca alkaloid). Monitor patient for manifestations of vinca alkaloid toxicity (i.e., neurotoxicity) and adjust dosage as necessary.

Zolpidem

Pharmacokinetic interaction (increased peak plasma concentration and AUC of zolpidem and prolonged zolpidem half-life); monitor for zolpidem-associated toxicity and adjust dosage as necessary.