Drug Criteria and Outcomes: Voriconazole formulary evaluation
By Stacey Breeding,
PharmD candidate
Samford University
Birmingham, AL
Voriconazole is a new broad-spectrum triazole antifungal. Other drugs in the triazole class are fluconazole and itraconazole.
Mechanism of action
Voriconazole acts primarily by inhibiting the fungal cytochrome P-450-dependent enzyme 14-alpha-sterol demethylase. This is an essential step in the ergosterol biosynthesis pathway that is necessary for the production of a functional cell wall and sustained growth of the fungi.
Pharmacokinetics
General. Voriconazole displays non-linear pharmacokinetics due to the saturation of its metabolism. Increasing the dose correlates with disproportionate rises in plasma concentrations.
Recommended loading-dose schedules reach steady-state concentrations at 24 hours. Without a loading dose, voriconazole concentrations do not reach steady state until day six of the twice-daily dosing regimen.
Absorption. The intravenous-to-oral dosing bioavailability is approximately 96%. Maximum plasma concentrations can be achieved one to two hours after administration.
Distribution. The volume of distribution for voriconazole at steady-state concentration is 4.6 L/kg. Protein binding is independent of plasma concentrations and estimated to be 58%.
Metabolism. Voriconazole is significantly metabolized by the human hepatic cytochrome P-450 enzyme CYP2C19, which exhibits genetic polymorphism. The enzymes CYP2C9 and CYP3A4 also are involved in the drug’s metabolism. The major metabolite, an N-oxide derivative, has minimal antifungal activity.
Elimination. Due to extensive hepatic metabolism, less than 2% of the dose is excreted unchanged in the urine.
The half-life of voriconazole is dose-dependent and cannot be used to predict the accumulation or elimination of the drug.
Indications. Voriconazole is indicated for use in the treatment of invasive aspergillosis. It also is indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum and Fusarium spp., including F. solani, in patients intolerant of or refractory to other therapy.
Dosage
Intravenous (IV) voriconazole should be administered with a loading dose of 6 mg/kg every 12 hours for two doses, followed by a maintenance dose of 4 mg/kg every 12 hours. If patients are intolerant of treatment, the maintenance dose may be reduced to 3 mg/kg. The intravenous dose should be given over one to two hours and should not exceed 3 mg/kg per hour.
Due to the drug’s 96% bioavailability, switching from IV to PO therapy is appropriate when clinically indicated.
If initiated as oral therapy, a loading dose of 400 mg every 12 hours should be given on day one. The oral maintenance dose of voriconazole is 200 mg every 12 hours for patients who weigh more than 40 kg. For patients who weigh less than 40 kg, a maintenance dose of 100 mg every 12 hours should be given. If a patient experiences an inadequate response, increase the 200 mg every 12 hours dosage to 300 mg every 12 hours, and increase the 100 mg every 12 hours dosage to 150 mg every 12 hours. If patients are unable to tolerate therapy, reduce the dose in 50 mg increments to 200 mg every 12 hours or 100 mg every 12 hours for patients who weigh less than 40 kg.
The dosing of voriconazole is equivalent for all indications.
Voriconazole tablets should be taken at least one hour before or one hour after meals. When multiple doses of voriconazole are administered with high-fat meals, the mean Cmax and area under the curve are reduced by 34% and 24%, respectively.
Clinical studies
Treatment of candidiasis. Esophageal candidiasis is a common problem in immunocompromised patients. Up to 50% of AIDS patients acquire the infection during their illness. Due to severe morbidity and possible dissemination of this infection, prompt treatment with a systemic antifungal is required. Fluconazole is first-line therapy in the treatment of esophageal candidiasis because of its tolerability and rapid resolution of symptoms. However, approximately 5% of oral and esophageal candidiasis in patients with advanced AIDS is now becoming refractory to fluconazole.
Study: Ally R, Schurmann D, Kreisel W, et al. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect Dis 2001; 33:1447-1454.
Purpose: To compare the efficacy, safety, and tolerability of voriconazole and fluconazole in immunocompromised patients with proven esophageal candidiasis.
Study design: Randomized, double-blind, double-dummy, multicenter, comparative, non-inferiority study.
Methods:
- 487 patients screened for inclusion.
- 391 patients randomized: 200 voriconazole patients, 191 fluconazole patients.
- Patients had to be diagnosed with esophagitis confirmed by esophagoscopy, plus positive microscopy and mycological culture from a brush or tissue biopsy of esophageal lesions before receiving antifungal therapy.
- Patients received either voriconazole 200 mg bid or fluconazole 400 mg (day 1), then 200 mg every day.
- Treatment was continued for seven days following resolution of all clinical signs and symptoms, but did not exceed 42 days of therapy.
- Primary endpoint was to prove non-inferiority based on treatment response assessed by esophagoscopy on day 43 or at the end of treatment.
- Voriconazole was considered not to be inferior if the lower limit of the approximate two-sided 95% confidence interval (CI) for the difference in success rates (cured + improved) between the two groups at the end of treatment did not fall below -0.15 (-15%).
- Secondary efficacy endpoints included the resolution of symptoms and the time to clinical cure determined by symptomatic assessments.
Results: The success rate (cured + improved) for esophageal candidiasis as assessed by esophagoscopy was 98.3% for voriconazole and 95.1% for fluconazole with a difference of -3.2% (95% CI for a difference of -1.0 to 7.5). Because the lower limit is above the predefined non-inferiority margin, voriconazole was shown as not inferior to fluconazole in this study. (See Table 1, below.)
Safety: Treatment-related adverse events occurred in 60 patients (30%) taking voriconazole as compared to 27 patients (14%) in the fluconazole group. In the voriconazole group, five patients (2.5%) discontinued the drug due to treatment-related adverse events, as opposed to one patient (0.5%) in the fluconazole group. Eighty percent of voriconazole discontinuations were due to mild-to-moderate visual disturbances. Seven patients (3.5%) in the voriconazole group vs. two patients (1%) taking fluconazole discontinued therapy due to lab abnormalities.
Conclusion: Voriconazole is at least as effective as fluconazole in the treatment of proven esophageal candidiasis in immunocompromised patients. However, more treatment-related adverse events occurred in the voriconazole group (30% vs. 14%), which may limit use for this indication.
Strengths:
- Randomized, double-blind, double-dummy, multicenter trial.
- Well-defined inclusion criteria.
- Specific guidelines for esophagoscopy assessments of primary endpoint.
Limitations:
- Small sample size.
- Patients did not receive a loading dose of voriconazole.
- The exact method of deriving statistical significance was not stated for the primary endpoint.
- The intention-to-treat population was not included in primary endpoint analysis.
Treatment of aspergillosis. Invasive aspergillosis is a devastating infection that develops mostly in immunocompromised patients. The incidence of infection occurs in 5% to more than 20% of patients in high-risk groups. Amphotericin B deoxycholate (amp B) is considered first-line therapy, but the response rate is less than 40%, and treatment can be limited by poor tolerability and nephrotoxicity. The lipid formulations of Amp B are equally effective and less nephrotoxic, but more costly.
Study: Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347:408-415.
Purpose: To compare efficacy, safety, and tolerability of voriconazole with those of amp B for the primary therapy of acute aspergillosis in immunocompromised patients.
Study design: Randomized, unblended, comparative trial.
Methods:
- 277 patients randomized: 144 in the voriconazole group, 133 in the amphotericin B group.
- No significant differences in baseline characteristics of patients.
- Patients must be immunocompromised and diagnosed with probable or definite invasive aspergillosis.
- Definite invasive aspergillosis was defined as a clinically compatible illness plus one or more of the following: isolation of aspergillus species from a normally sterile site; hyphae consistent with the presence of aspergillus in a biopsy specimen or aspirate, plus culture of aspergillus from the same organ; radiologic evidence of pulmonary lesions that were not attributable to other factors and a culture of bronchoalveolar-lavage fluid that was positive for aspergillus; or tracheobronchial lesions confirmed by bronchoscopy, with a positive culture for aspergillus.
- Probable invasive aspergillosis was defined as a clinically compatible illness plus one or more of the following: hyphae consistent with the presence of aspergillus in a biopsy specimen or aspirate but without culture; the presence of a halo or an air-crescent sign on a CT scan of the lung; radiologic evidence of new pulmonary lesions not attributable to other factors with either hyphae consistent with the presence of aspergillus in bronchoalveolar-lavage fluid or sputum or a sputum culture that was positive for aspergillus; clinical evidence of sinusitis, opacification of a sinus on CT or MRI, and positive histopathological examination or culture of aspergillus from a lesion in the nose or paranasal sinus; or tracheobronchial lesions confirmed by bronchoscopy and a positive finding on histopathological or microscopic examination of a biopsy specimen or bronchoalveolar-lavage fluid.
- Patients received either intravenous voriconazole (two doses of 6 mg/kg on day 1, then 4 mg/ kg twice daily for at least seven days, after which patients could be switched to 200 mg orally twice daily) or intravenous amp B (1-1.5 mg/kg/d).
- Duration of therapy was 12 weeks.
- Primary endpoint was to prove non-inferiority of voriconazole to amp B in relation to successful outcomes (complete + partial response) at 12 weeks.
- Voriconazole was considered not to be inferior to amp B if the lower limit of the voriconazole response rate minus the difference in amp B response rate was above -20 percentage points.
- A blinded data review committee assessed the adverse events, lab abnormalities, and global response at week 12.
Results: The successful outcome (complete + partial response) at week 12 in the voriconazole group was significantly better than the amp B group. The absolute difference was 21.2%, with a 95% CI for the difference of 10.4-32.9 percentage points. The lower limit of the CI was above zero, indicating voriconazole to be associated with a more successful outcome. The medium duration of voriconazole therapy was 77 days, vs. 10 days in the amp B group. (See Table 2, below.)
Other licensed antifungal therapy was given to 52 patients in the voriconazole group. The first other licensed antifungal therapy was amp B deoxycholate in 20 patients, a lipid formulation of amp B in 14 patients, itraconazole in 17 patients, and a combination in one patient. Other licensed antifungal therapy was given to 107 patients in the amp B group. The first other licensed antifungal therapy was a lipid formulation of amp B in 47 patients, itraconazole in 38 patients, and another antifungal drug or a combination of drugs in 22 patients.
Safety: Treatment-related adverse events occurred less frequently in the voriconazole group (343 events) than in the amp B group (421 events), P = 0.02. Visual disturbances were most common in the voriconazole group (44.8%). These disturbances were described as blurred vision, altered visual perception, altered color perception, and photophobia. All were transient and resolved without intervention. Severe adverse events developed in 26 patients (13.4%) in the voriconazole group in contrast to 45 (24.3%) in the amp B group. The most common severe adverse events were renal impairment (19 patients, 10%) in the amp B group and liver function abnormalities (7 patients, 4%) in the voriconazole group.
Conclusion: Voriconazole demonstrated non-inferiority to amp B as initial treatment for invasive aspergillosis.
Strengths:
- Clearly defined guidelines for inclusion in study.
- Blinded review committee performed inclusion data and successful outcome interpretation.
Limitations:
- Small sample size.
- Study was unblended.
- Researchers employed by or have consulted for Pfizer.
- Patients who displayed intolerance or lack of response to either initial therapy could be switched to other antifungal therapy and be included in the results.
Study: Denning DW, Ribaud P, Milpied N, et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 2002; 34:563-571.
Purpose: To evaluate the efficacy and safety of voriconazole in immunocompromised patients with proven invasive aspergillosis (IA).
Study Design: Open, noncomparative, multicenter study.
Methods:
- 137 patients received at least one dose of drug.
- 137 patients were included in the safety analysis, and 116 patients were included in the efficacy analysis.
- Patients were diagnosed with either probable or definite IA.
- Definite IA required histopathologic evidence of tissue invasion with hyphae morphologically consistent with aspergillus species or positive culture of aspergillus from a sterile site obtained by an invasive procedure.
- Probable IA required radiologic evidence suggestive of acute IA.
- Intravenous therapy started initially with a loading dose of 6 mg/kg every 12 hours on day 1, followed by 3 mg/kg every 12 hours lasting six to 27 days. IV therapy then could be switched to oral voriconazole 200 mg every 12 hours for four to 24 weeks. Doses could be increased to 250 mg after one week and then to 300 mg twice daily if the response was inadequate.
- Primary endpoint was to compare response rates according to underlying disease, site of infection, and whether patient received primary or salvage therapy.
- Each patient was assessed on the basis of a case report form, copies of imaging investigations (x-ray, CT scan, and MRI scans, if available), and bronchoscopy results.
Results: Voriconazole was given as primary therapy to 60 (52%) of 116 patients. Thirty-one patients (25%) had received prior prophylactic antifungal therapy for less than one week. Salvage therapy was given to 56 patients (48%). Out of 116 patients, 16 (14%) had a complete response to voriconazole therapy, 40 (34%) had a partial response, and 24 (21%) had a stable response. (See Table 3.) Treatment failures occurred in 36 patients (31%). Death occurred during or 90 days following treatment in 67 (58%) of patients. Of these patients, 31 (59%) died as a result of IA, 21 (40%) died as the result of another cause with IA, and one died without IA.
Safety: During the study, investigators noted 95 (15%) adverse events. The most common were rash (12 patients), visual disturbances (15 patients), and elevated liver function tests (20 patients). All 20 patients with elevated liver function tests and four patients with rashes discontinued therapy.
Conclusion: Overall, the infections of 48% of patients had a complete or partial response, and 31% failed to respond to therapy. The greatest benefit was seen in hematology patients (58% response rate vs. 27% failure rate). In other studies, amp B had a response rate of 35% in the same patient population. In the highest-risk group (allogenic hematopoietic stem cell transplant), the failure rate was 35% in comparison to 85% failure rates with amp B therapy according to other studies. Voriconazole was shown to be more efficacious as primary rather than salvage therapy.
Limitations:
- Small sample size.
- Noncomparative, open-label study.
- Financially supported by Pfizer.
- Patients on previous antifungal therapy were included in the study, and reasons or circumstances for switching therapy were not stated in the report.
- IV maintenance dose given was 3 mg/kg twice daily (normal maintenance dose is 4 mg/kg twice daily).
Empiric therapy in neutropenic patients. Prolonged neutropenia often develops in patients during cancer chemotherapy and organ transplantation. In patients with persistent or relapsing fevers, clinicians commonly suspect a fungal infection and thus treat it empirically. Amphotericin B is the drug of choice in this patient population.
Study: Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2001; 346:225-234.
Purpose: To determine non-inferiority of voriconazole to liposomal amp B in overall success rates of empiric antifungal therapy.
Study Design: Open-label, prospective, multicenter, international comparative trial.
Methods:
- 837 patients in the modified intention-to-treat population.
- 415 voriconazole patients and 422 liposomal amp B patients.
- Patients must be neutropenic and febrile for more than 96 hours while on antibiotic therapy.
- Patients must have undergone cancer chemotherapy or organ transplantation.
- On day 1, patients received a loading dose of 6 mg/kg every 12 hours X two doses, then a maintenance dose of 3 mg/kg every 12 hours (or 200 mg every 12 hours at least three days after IV therapy). Liposomal amp B was given at 3 mg/kg IV every day. Voriconazole could be increased to 4 mg/kg every 12 hours IV or 300 mg every 12 hours orally if warranted. Liposomal amp B could be increased to 6 mg/ kg/day or decreased to 1.5 mg/kg/day.
- Patients continued therapy for up to three days after neutrophil recovery or a maximum of 12 weeks of therapy
- The primary endpoint was to determine non-inferiority of response rates. Non-inferiority was defined as the difference in success rates between treatment groups of no more than 10 percentage points. Secondary endpoints were the five components of the composite outcome score. The composite outcome score included lack of breakthrough fungal infection, survival of seven days post-therapy, therapy not discontinued prematurely, resolution of fever during neutropenia, and successful treatment of any baseline fungal infection.
Results: The overall success rates for voriconazole did not meet the requirements for non-inferiority. (See Table 4, above.) The 95% CI falls just outside the predefined lower limit of -10 percentage points. Of the secondary endpoints, the only significant difference was in the documented breakthrough fungal infections. Documented breakthrough fungal infection developed in eight patients receiving voriconazole and 21 patients receiving liposomal amphotericin B (P = 0.02). The reduction in invasive fungal infections was particularly apparent in the stratified cohort of patients at high risk (those with allogeneic transplants or relapsed leukemia). Among these patients, those receiving voriconazole had fewer documented breakthrough fungal infections than those receiving liposomal amp B (2 of 143 [1.4%] vs. 13 of 141 [9.2%], P = 0.03).
Safety: There were no significant differences between treatment groups in hepatotoxicity or rise in serum creatinine levels (more than 2X baseline). Twenty-two percent of patients in the voriconazole group developed visual disturbances. Nineteen patients (0.05%) in the voriconazole and 23 (0.05%) in the amp B group discontinued therapy due to toxic effects.
Conclusion: Voriconazole did not meet the predefined requirements of non-inferiority of response for use as empiric antifungal therapy in neutropenic patients. The safety profiles of voriconazole and liposomal amp B were comparable, except for the visual disturbances in the voriconazole group.
Limitations:
- Open label.
- Results of a subgroup analysis (number of breakthrough fungal infections) were reported as significant in favor of voriconazole, when there was no statistically significant evidence of efficacy in the primary endpoint of the trial. Some experts believe primary endpoints must show significance before a subgroup analysis can be evaluated and the results interpreted.
Drug interactions
Of all the antifungals, voriconazole and itraconazole have the most clinically significant drug interactions. Voriconazole is contraindicated in patients taking sirolimus, rifampin, ergot alkaloids, carbamazepine, long-acting barbiturates, pimozide, and quinidine. Many of these drugs are taken by the patient population most likely to acquire a serious fungal infection. The most notable are rifampin for HIV and transplant patients, immunosuppressants for solid organ and bone marrow transplantations, chemotherapeutic agents, and antiretroviral agents.
Adverse reactions
The most common adverse event for voriconazole is visual disturbances. (See Table 5.) In all studies involving voriconazole, this event occurred in approximately 30% of patients. The events were reported to be transient and mild-to-moderate in severity.
Warnings/precautions for voriconazole
- Visual disturbances have been noted in approximately 30% of patients. If treatment continues past 28 days of therapy, visual acuity, visual field, and color perception tests should be performed.
- Hepatic toxicity has occurred during clinical trials. The effects normally are reversible upon discontinuation of voriconazole.
- Pregnancy category D.
- Voriconazole tablets contain lactose and should not be given in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
- Anaphylactoid-like reactions can develop during intravenous therapy.
- Use caution when administering IV therapy to patients with CrCl < 50 mL/min due to the accumulation of the intravenous vehicle, SBECD. If warranted, these patients could be switched to oral maintenance therapy.
- Patients should not drive at night while taking voriconazole.
- In patients with mild-to-moderate hepatic cirrhosis (Child-Pugh Class A and B), the standard loading dose should be used, but the maintenance dose should be halved.
Monitoring of voriconazole
Liver function tests (baseline and during therapy), renal function tests, serum electrolytes (especially potassium), and visual testing (after 28 days of therapy).
Summary and recommendations
In the only clinical trial published comparing fluconazole to voriconazole in the treatment of oral candidiasis, voriconazole did not prove to be significantly more efficacious. Voriconazole has more drug interactions, adverse effects, and monitoring requirements and is more costly. Some in vitro studies show voriconazole to be efficacious in treating fluconazole-resistant non-albicans Candida infections. A small trial involving 12 advanced HIV patients with fluconazole-refractory oroesophageal candidiasis showed favorable clinical responses in 10 of the patients. More studies will need to be performed to use voriconazole for fluconazole-resistant Candida species. Clinical trials are now under way for the treatment of voriconazole in invasive candidiasis.
Conventional amp B is first-line therapy in the treatment of invasive aspergillosis, but is limited by its nephrotoxicity. Patients on conventional amp B who experience nephrotoxicity then are switched to an expensive lipid formulation. In the only published study comparing conventional amp B to voriconazole in the treatment of aspergillosis, the response rates were significantly greater in the voriconazole group (52.8% vs. 31.6%). A noncomparative study showed a 48% response rate to voriconazole therapy. Although further studies need to be conducted or published before changes are made to standard therapy guidelines, voriconazole shows the most benefit in the treatment of aspergillosis.
Voriconazole can be used as first-line therapy in the treatment of invasive pulmonary and extrapulmonary aspergillosis. The drug also may be used as salvage therapy in patients refractory to or intolerant of amp B or lipid forms of amp B in the treatment of invasive aspergillosis. It should be used as a second-line agent in the treatment of esophageal candidiasis in patients refractory to or intolerant of azoles. Lastly, it can be used in the treatment of serious fungal infections caused by Scedosporium apiospermum and Fusarium spp., including F. solani, and in patients intolerant of or refractory to amp B.
Voriconazole is a new broad-spectrum triazole antifungal. Other drugs in the triazole class are fluconazole and itraconazole.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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