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



Infections and                        sinusitis               pseudomembranous colitis infestations
Neoplasms                                                                                                         squamous benign, malignant                                                                                                 cell and unspecified                                                                                                   carcinoma* (including cysts and polyps)


Blood and                             agranulocytosis1,       bone marrow failure,         disseminated lymphatic system                      pancytopenia,           lymphadenopathy,             intravascular disorders                             thrombocytopenia2,      eosinophilia                 coagulation leukopenia, anaemia



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



Immune system                                                 hypersensitivity               anaphylactoid disorders                                                                                    reaction 
Endocrine                                                     adrenal insufficiency,         hyperthyroidism disorders                                                     hypothyroidism 
Metabolism and        oedema        hypoglycaemia,
nutrition disorders   peripheral    hypokalaemia,
hyponatraemia
Psychiatric                         depression,
disorders                           hallucination, anxiety,
insomnia, agitation,
confusional state

Nervous system        headache      convulsion, syncope,      brain oedema,                  hepatic disorders                           tremor, hypertonia3,      encephalopathy4,               encephalopathy, paraesthesia,             extrapyramidal disorder5,      Guillain-Barre somnolence, dizziness     neuropathy peripheral,         syndrome, nystagmus ataxia, hypoaesthesia,
dysgeusia


Eye disorders         visual        retinal                   optic nerve disorder7,         optic atrophy, corneal impairment6   haemorrhage               papilloedema8, oculogyric      opacity crisis, diplopia, scleritis,
blepharitis


Ear and labyrinth                                             hypoacusis, vertigo, disorders                                                     tinnitus 


Cardiac disorders                   arrhythmia                ventricular fibrillation,      torsades de pointes, supraventricular,         ventricular extrasystoles,     atrioventricular tachycardia,              ventricular tachycardia,       block complete, bradycardia               electrocardiogram QT           bundle branch prolonged,                     block, nodal rhythm supraventricular tachycardia



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



Vascular                           hypotension,            thrombophlebitis, disorders                          phlebitis               lymphangitis 
Respiratory,        respiratory    acute    respiratory thoracic and        distress9      distress syndrome,
mediastinal                        pulmonary oedema disorders
Gastrointestinal    diarrhoea,     cheilitis, dyspepsia,   peritonitis, pancreatitis, disorders           vomiting,      constipation,           swollen tongue, abdominal      gingivitis              duodenitis,
pain, nausea                           gastroenteritis, glossitis


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


Renal and                          renal failure acute,    renal tubular necrosis, urinary disorders                  haematuria              proteinuria, nephritis 

General disorders pyrexia          chest pain, face        infusion site reaction, and                                oedema11, asthenia,     influenza like illness administration                     chills site conditions

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



Investigations                      blood creatinine         blood urea increased, increased                blood cholesterol increased

*ADR identified post-marketing
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 voriconazole (see section 4.4).

If a patient develops a rash they should be monitored closely and voriconazole 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 in patients treated with voriconazole 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.