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In addition, the safety of voriconazole was investigated in 279 patients (including 270 adults) who were treated with voriconazole in prophylaxis studies. The adverse event profile in these prophylaxis studies was similar to the established safety profile from 2,000 subjects in voriconazole clinical trials.
The table as follows includes all causality adverse reactions in 1,873 adults from pooled therapeutic (1,603) and prophylaxis (270) studies. The most commonly reported adverse events were visual impairment, liver function test abnormal, pyrexia, rash, vomiting, nausea, diarrhea, headache, peripheral edema and abdominal pain. The severity of the adverse events was generally mild to moderate. No clinically significant differences were seen when the safety data were analyzed by age, race, or gender. (See Table 8.)
Click on icon to see table/diagram/imageVisual Impairments: In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia, chromatopsia, color blindness, cyanopsia, eye disorder, halo vision, night blindness, oscillopsia, photopsia, scintillating scotoma, visual acuity reduced, visual brightness, visual field defect, vitreous floaters, and xanthopsia) with voriconazole were very common.
These visual impairments were transient and fully reversible, with the majority spontaneously resolving within 60 minutes. There was evidence of attenuation with repeated doses of voriconazole. The visual impairments were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. Visual impairments may be associated with higher plasma levels and/or doses.
There have been post-marketing reports of prolonged visual adverse events (see Precautions).
The mechanism of action is unknown, although the site of action is most likely to be within the retina.
In a study in healthy volunteers investigating the impact of voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG measures electrical currents in the retina. The ERG changes did not progress over 29 days of administration and were fully reversible on withdrawal of voriconazole.
The long-term effect of voriconazole (median 169 days; range 5-353 days) on visual function was evaluated in subjects with paracoccidioidomycosis. Voriconazole had no clinically relevant effect on visual function as assessed by testing of visual acuity, visual fields, color vision and contrast sensitivity. There were no signs of retinal toxicity. 17/35 voriconazole subjects experienced visual adverse events. These events did not lead to discontinuation, were generally mild, occurred during the first week of therapy and resolved during continued voriconazole therapy.
Dermatological Reactions: Dermatological reactions were very common in patients treated with voriconazole in clinical trials, but these patients had serious underlying diseases and were receiving multiple concomitant medications. The majority of rashes were of mild to moderate severity. Patients have developed severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (uncommon), toxic epidermal necrolysis (rare), drug reaction with eosinophilia and systemic symptoms (DRESS) which was reported post-marketing (not known), and erythema multiforme (rare) during treatment with voriconazole (see Precautions).
If patients develop a rash they should be monitored closely and voriconazole discontinued if lesions progress. Patients receiving long-term voriconazole therapy have developed photosensitive skin reactions (see Precautions).
Dermatological adverse reactions potentially related to phototoxicity (pseudoporphyria, cheilitis, and cutaneous lupus erythematosus) are also reported with voriconazole. Sun avoidance and photoprotection are recommended for all patients. If phototoxicity occurs, voriconazole discontinuation and dermatological evaluation should be considered (see Precautions).
Liver Function Tests: The overall incidence of transaminase increases >3 x ULN (not necessarily comprising an adverse event) in the voriconazole clinical program was 18.0% (319/1,768) in adults and 25.8% (73/283) in pediatric subjects who received voriconazole for pooled therapeutic and prophylaxis use. Liver function test abnormalities may be associated with higher plasma levels and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.
Voriconazole has been associated with cases of serious hepatic toxicity, in patients with other serious underlying conditions. This includes cases of jaundice, hepatitis and hepatic failure leading to death.
Pediatric Use: The safety of voriconazole was investigated in 288 pediatric patients aged 2 to <12 years (169) and 12 to <18 years (119) who received voriconazole for prophylaxis (183) and therapeutic use (105). The adverse event profile in these 288 pediatric patients was similar to that in adults. A higher frequency of liver enzyme elevations reported as adverse events (14.2% transaminases increased in pediatrics compared to 5.3% in adults) was observed in pediatric patients as compared to adults. The safety of voriconazole was investigated in additional pediatric patients aged 2 to <12 years who were observed in compassionate use programs (158 pediatric patients). The adverse event profile in these pediatric patients was similar to that observed in adults.
Post-marketing data suggest there might be a higher occurrence of skin reactions in the pediatric population compared to adults.
There have been post-marketing reports of pancreatitis in pediatric patients.
Infusion-related Reactions: During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash have occurred. Symptoms appeared immediately upon initiating the infusion (see Precautions).
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