Summary of safety profile: The safety profile of voriconazole is based on an integrated safety database of more than 2,000 subjects (including 1,655 patients in therapeutic trials and 279 in prophylaxis trials). This represents a heterogenous population, containing patients with haematological malignancy, HIV-infected patients with oesophageal candidiasis and refractory fungal infections, non-neutropenic patients with candidaemia or aspergillosis and healthy volunteers. Seven hundred and five (705) patients had a duration of voriconazole therapy of greater than 12 weeks, with 164 patients receiving voriconazole for over 6 months.
The most commonly reported adverse reactions were visual disturbances, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema, liver function test abnormal, respiratory distress and abdominal pain.
The severity of the adverse reactions was generally mild to moderate. No clinically significant differences were seen when the safety data were analysed by age, race, or gender.
List of adverse reactions: In the list below, since the majority of the studies were of an open nature, all causality adverse reactions, by system organ class and frequency, are listed.
Frequency categories are expressed as: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Undesirable effects reported in subjects receiving voriconazole: Infections and Infestation: Common: Gastroenteritis, sinusitis, gingivitis.
Uncommon: Pseudomembranous colitis, lymphangitis, peritonitis.
Neoplasms Beningn, Malignant and Unspecified (including cysts and polyps): Not known: Squamous cell carcinoma*.
Blood and lympatic system disorders: Common: Agranulocytosis, pancytopenia, thrombocytopenia, anaemia.
Uncommon: Disseminated intravascular coagulation, bone marrow failure, leukopenia, lymphadenopathy, eosinophilia.
Immune system disorders: Common: Hypersensitivity. Uncommon: Anaphylactoid reaction.
Endocrine disorders: Uncommon: Adrenal insufficiency, hypothyroidism.
Metabolism and nutrition disorders: Very common: Peripheral oedema.
Common: Hypoglycaemia, hypokalaemia, hyponatraemia.
Psychiatric disorders: Common: Depression, hallucination, anxiety, insomnia, agitation, confusional state.
Nervous system disorders: Very common: Headache.
Common: Convulsion, tremor, paraesthesia, hypertonia, somnolence, syncope, dizziness.
Uncommon: Brain oedema, encephalopathy, extrapyramidal disorder, peripheral neuropathy, ataxia, hypoasthesia, dysgeusia, nystagmus.
Rare: Hepatic encephalopathy, Guillain-Barre syndrome.
Eye disorders: Very common: Visual impairment (including blurred vision [see Precautions], chromotopsia and photophobia).
Common: Retinal haemorrhage.
Uncommon: Oculogyric crisis, optic nerve disorder (including optic neuritis, see Precautions), papilloedema (see Precautions), scleritis, blepharitis, diplopia.
Rare: Optic neuropathy, corneal opacity.
Ear and labyrinth disorders: Uncommon: Hypoacusis, vertigo, tinnitus.
Cardiac disorders: Common: Supraventricular arrythmia, tachycaria, bradycardia.
Uncommon: Ventricular fibrillation, ventricular extrasystoles, supraventricular tachycardia, ventricular tachycardia.
Rare: Torsades de pointes, complete atrioventricular block, bundle branch block, nodal rhythm.
Vascular disorders: Common: Hypotension, phlebitis.
Respiratory, thoracic and mediastinal disorders: Very common: Respiratory distress.
Common: Acute respiratory distress syndrome, pulmonary oedema.
Gastrointestinal disorders: Very common: Abdominal pain, nausea, vomiting, diarrhoea.
Common: Dyspepsia, constipation, cheilitis.
Uncommon: Pancreatitis, duodenitis, glossitis, swollen tongue.
Hepatobiliary disorders: Very common: Abnormal liver function test (including AST, ALT, alkaline phosphatase, gamma-glutamyl transpeptidase [GGT], lactate dehydrogenase [LDH], bilirubin).
Common: Jaundice, cholestatic jaundice, hepatitis.
Uncommon: Hepatic failure, hepatomegaly, cholecystitis, cholelithiasis.
Skin and subcutaneous tissue disorders: Very common: Rash.
Common: Exfoliative dermatitis, maculo-papular rash, pruritis, alopecia, erythema multiforme, angioedema, psoriasis, urticaria, allergic dermatitis, phototoxicity, macular rash, papular rash, purpura, eczema.
Rare: Pseudoporphyria, fixed drug eruption.
Not known: Cutaneous lupus erythematosis*.
Musculoskeletal and connective tissue disorders: Common: Back pain.
Not known: Periostitis*.
Renal and urinary disorders: Common: Acute renal failure, haematuria.
Common: Renal tubular necrosis, proteinuria, nephritis.
General disorders and administration site conditions: Very common: Pyrexia.
Common: Chest pain, face oedema, asthenia, influenza like illness, chills.
Investigations: Common: Blood creatinine increased.
Uncommon: Electrocardiogram QTc prolonged, blood urea increased, blood cholesterol increased.
*Undesirable events identified during post-approval use.
Description of selective adverse reactions: Visual disturbances: In clinical trials, visual impairments with voriconazole were very common. In therapeutic studies, voriconazole treatment-related visual disturbances were very common. In these studies, short-term as well as long-term treatment, approximately 21% of subjects experienced altered/enhanced visual perception, blurred vision, colour vision change or photophobia. These visual disturbances were transient and fully reversible, with the majority spontaneously resolving within 60 minutes and no clinically significantly long-term visual effects were observed. There was evidence of attenuation with repeated doses of voriconazole. The visual disturbances were generally mild, rarely resulted in discontinuation and were not associated with long-term sequalae. Visual disturbances may be associated with higher plasma concentrations and/or doses.
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 treatment and were fully reversible on withdrawal of voriconazole.
There have been post-marketing reports of prolonged visual adverse events (see Precautions).
Dermatological reactions: Dermatological reactions were common in patients treated with voriconazole in clinical trials, but these patients had serious underlying disases and were receiving multiple concomitant medicinal products. The majority of rashes were of mild to moderate severity. Patients have rarely developed serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme during treatment with voriconazole.
If a patients develops a rash they should be monitored closely and voriconazole discontinued if lesion progress.
Photosensitivity reactions have been reported, especially during long-term therapy (see Precautions).
There have been reports of squamous cell carcinoma of the skin in patients treated with voriconazole for a long periods of time; the mechanism has not been established (see Precautions).
Liver function tests: The overall incidence of clinically significant transaminase abnormalities in the voriconazole clinical programme was 13.5% (258/1918) of subjects treated with voriconazole. Liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.
Voriconazole has ben infrequently associated with cases pf serious hepatic toxicity in patient with other serious underlying conditions. This includes cases of jaundice, and rare cases of hepatitis and hepatic failure leading to death (see Precautions).
Prophylaxis: In an open-label, comparative, multicenter study comparing voriconazole and itraconazole as primary prophylaxis in adult and adolescent allogenic HSCT recipients without prior proven or probable IFI, permanent discontinuation of voriconazole due to AEs wa reported in 39.3% of subjects versus 39.6% of subjects in itraconazole arm. Treatment-emergent hepatic AEs resulted in permanent discontinuation of study medication for 50 subjects (21.4%) treated with voriconazole and for 18 subjects (7.1%) treated with itraconazole.
Paediatric population: The safety of voriconazole was investigated in 285 paediatric patients aged 2 to <12 years who were treated with voriconazole in pharmacokinetic studies (127 paediatric patients) and in compassionate use programmes (158 paediatric patients). The adverse reaction profile of these 285 paediatric patients was similar to that in adults. Post-marketing data suggest there might be a higher occurrence of skin reactions (especially erythema) in the paediatric population compared to adults. In the 22 patients less than 2 years old who received voriconazole in a compassionate use programme, the following adverse reactions (for which a relationship to voriconazole could not be excluded) were reported; photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), blood bilirubin increased (1), hepatic enzymes increased (1), rash (1) and papilloedema (1).
There have been post-marketing reports of pancreatitis in paediatric patients.