Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Summary of safety profile
The safety profile of voriconazole in adults is based on an integrated safety database of more than 2,000 subjects (including 1,603 adult patients in therapeutic trials) and an additional 270 adults in prophylaxis trials. This represents a heterogeneous 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.

The most commonly reported adverse reactions were visual impairment, 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.

Tabulated list of adverse reactions
In the table below, since the majority of the studies were of an open nature, all causality adverse reactions and their frequency categories in 1,873 adults from pooled therapeutic (1,603) and prophylaxis (270) studies, by system organ class, 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:
System Organ      Very common            Common               Uncommon                Rare           Frequency Class            ≥ 1/10               ≥ 1/100            ≥ 1/1,000 to <      ≥ 1/10,000 to <     not known to < 1/10               1/100               1/1,000         (cannot be estimated from available data)

Infections and                     sinusitis              pseudomembranous infestations                                              colitis
Neoplasms                          squamous cell benign,                            carcinoma malignant and                      (including unspecified                        cutaneous SCC in
(including                         situ, or Bowen’s cysts and                          disease)* polyps)
Blood and                          agranulocytosis1,      bone marrow            disseminated lymphatic                          pancytopenia,          failure,               intravascular system                             thrombocytopenia2,     lymphadenopathy,       coagulation disorders                          leukopenia,            eosinophilia anaemia
Immune                                                    hypersensitivity       anaphylactoid system                                                                           reaction disorders
Endocrine                                                 adrenal                hyperthyroidism disorders                                                 insufficiency, hypothyroidism
Metabolism       oedema            hypoglycaemia,
and nutrition    peripheral        hypokalaemia,
disorders                          hyponatraemia

System Organ       Very common           Common                 Uncommon                Rare          Frequency Class             ≥ 1/10              ≥ 1/100              ≥ 1/1,000 to <      ≥ 1/10,000 to <    not known to < 1/10                 1/100               1/1,000        (cannot be estimated from available data)

Psychiatric                         depression,
disorders                           hallucination,
anxiety, insomnia,
agitation,
confusional state
Nervous            headache         convulsion,             brain oedema,          hepatic system                              syncope, tremor,        encephalopathy4,       encephalopathy, disorders                           hypertonia3,            extrapyramidal         Guillain-Barre paraesthesia,           disorder5,             syndrome,
somnolence,             neuropathy             nystagmus dizziness               peripheral, ataxia,
hypoaesthesia,
dysgeusia
Eye disorders      visual           retinal                 optic nerve            optic atrophy, impairment6      haemorrhage             disorder7,             corneal opacity papilloedema8,
oculogyric crisis,
diplopia, scleritis,
blepharitis
Ear and                                                     hypoacusis, labyrinth                                                   vertigo, tinnitus disorders
Cardiac                             arrhythmia              ventricular            torsades de disorders                           supraventricular,       fibrillation,          pointes, tachycardia,            ventricular            atrioventricular bradycardia             extrasystoles,         block complete,
ventricular            bundle branch tachycardia,           block, nodal electrocardiogram      rhythm
QT prolonged,
supraventricular tachycardia
Vascular                            hypotension,            thrombophlebitis, disorders                           phlebitis               lymphangitis 
Respiratory,       respiratory      acute respiratory thoracic and       distress9        distress syndrome,
mediastinal                         pulmonary oedema disorders
Gastrointestina    diarrhoea,       cheilitis, dyspepsia,   peritonitis, l disorders        vomiting,        constipation,           pancreatitis, abdominal        gingivitis              swollen tongue,
pain, nausea                             duodenitis,
gastroenteritis,
glossitis

System Organ       Very common             Common                 Uncommon                  Rare            Frequency Class             ≥ 1/10                ≥ 1/100              ≥ 1/1,000 to <        ≥ 1/10,000 to <      not known to < 1/10                 1/100                 1/1,000          (cannot be estimated from available data)

Hepatobiliary      liver function    jaundice, jaundice       hepatic failure, disorders          test abnormal     cholestatic,             hepatomegaly, hepatitis10              cholecystitis,
cholelithiasis
Skin and           rash              dermatitis               Stevens-Johnson         toxic epidermal      cutaneous subcutaneous                         exfoliative,             syndrome8,              necrolysis8, drug    lupus tissue                               alopecia, rash           purpura, urticaria,     reaction with        erythemato disorders                            maculo-papular,          dermatitis allergic,    eosinophilia and     sus*, pruritus, erythema,      rash papular, rash      systemic             ephelides*, phototoxicity**          macular, eczema         symptoms             lentigo* (DRESS)8,
angioedema,
actinic keratosis*,
pseudoporphyria
, erythema multiforme,
psoriasis, drug eruption
Musculoskeletal                      back pain                arthritis, and connective                                                periostitis*,** tissue disorders


Renal and                            renal failure acute,     renal tubular urinary                              haematuria               necrosis, disorders                                                     proteinuria, nephritis
General            pyrexia           chest pain, face         infusion site disorders and                        oedema11, asthenia,      reaction, influenza administration                       chills                   like illness site conditions
Investigations                       blood creatinine         blood urea increased                increased, blood cholesterol increased
*ADR identified post-marketing
**Frequency category is based on an observational study utilising real-world data from secondary data sources in Sweden
1
Includes febrile neutropenia and neutropenia.
2
Includes immune thrombocytopenic purpura.
3
Includes nuchal rigidity and tetany.
4
Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.
5
Includes akathisia and parkinsonism.
6
See “Visual impairments” paragraph in section 4.8.
7
Prolonged optic neuritis has been reported post-marketing. See section 4.4.
8
See section 4.4.
9
Includes dyspnoea and dyspnoea exertional.
10
Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity.
11
Includes periorbital oedema, lip oedema, and oedema mouth.

Description of selected adverse reactions
Altered taste perception
In the combined data from three bioequivalence studies using the powder for oral suspension formulation, treatment related taste perversion was recorded in 12 (14%) of subjects.

Visual impairments
In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia, chromatopsia, colour 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 and no clinically significant long-term visual effects were observed. 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 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 section 4.4).

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 medicinal products. The majority of rashes were of mild to moderate severity. Patients have developed severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) (uncommon), toxic epidermal necrolysis (TEN) (rare), drug reaction with eosinophilia and systemic symptoms (DRESS) (rare) and erythema multiforme (rare) during treatment with VFEND (see section 4.4).

If a patient develops a rash they should be monitored closely and VFEND discontinued if lesions progress. Photosensitivity reactions such as ephelides, lentigo and actinic keratosis have been reported, especially during long-term therapy (see section 4.4).

There have been reports of squamous cell carcinoma of the skin (including cutaneous SCC in situ, or Bowen’s disease) in patients treated with VFEND for long periods of time; the mechanism has not been established (see section 4.4).

Liver function tests
The overall incidence of transaminase increases >3 xULN (not necessarily comprising an adverse event) in the voriconazole clinical programme was 18.0% (319/1,768) in adults and 25.8% (73/283) in paediatric subjects who received voriconazole for pooled therapeutic and prophylaxis use. 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 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 (see section 4.4).
Infusion-related reactions
During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnoea, faintness, nausea, pruritus and rash have occurred. Symptoms appeared immediately upon initiating the infusion (see section 4.4).

Prophylaxis
In an open-label, comparative, multicenter study comparing voriconazole and itraconazole as primary prophylaxis in adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI, permanent discontinuation of voriconazole due to AEs was reported in 39.3% of subjects versus 39.6% of subjects in the 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 288 paediatric patients aged 2 to <12 years (169) and 12 to <18 years (119) who received voriconazole for prophylaxis (183) and therapeutic use (105) in clinical trials. The safety of voriconazole was also investigated in 158 additional paediatric patients aged 2 to <12 years in compassionate use programs. Overall, the safety profile of voriconazole in paediatric population was similar to that in adults. However, a trend towards a higher frequency of liver enzyme elevations, reported as adverse events in clinical trials was observed in paediatric patients as compared to adults (14.2% transaminases increased in paediatrics compared to 5.3% 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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse event should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/