Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most common adverse reactions are leukopenia (20.2%), thrombocytopenia (18.5%), arthralgia (13.5%), fatigue (12.4%), increased gamma-glutamyltransferase (11.2%), influenza-like illness (11.2 %), myalgia (10.7%), anaemia (9.6%), increased alanine aminotransferase (8.4%), neutropenia (7.9%), pyrexia (7.9%), increased aspartate aminotransferase (7.3%), pruritus (6.8%), pain in extremity (6.7%), alopecia (6.7%), headache (6.2%), diarrhoea (5.7%), injection site reaction (5.6%), chills (5.1%) and dizziness (5.1%).
Serious adverse reactions are depression (1.1%), atrial fibrillation (1.1%) and acute stress disorder (0.6%).

Tabulated list of adverse reactions
Following treatment-related adverse reactions were reported with ropeginterferon alfa-2b in clinical studies in 178 polycythaemia vera adult patients. Adverse reactions are listed by system organ class and frequency (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) or not known (cannot be estimated from available data).

System organ class       Frequency          Adverse reaction
Infections and           common             respiratory tract infection, influenza, rhinitis, fungal skin infestations                                infection


uncommon      oral herpes, herpes zoster, oral candidiasis, sinusitis, oesophageal candidiasis, vulvovaginal mycotic infection,
hordeolum, onychomycosis
Blood and lymphatic     very common   leukopenia, thrombocytopenia system disorders        common        pancytopenia, neutropenia, anaemia Immune system           uncommon      sarcoidosis disorders               very rare     idiopathic or thrombotic thrombocytopenic purpura# not known     Vogt-Koyanagi-Harada disease#, acute hypersensitivity reactions#**
Endocrine disorders     common        hypothyroidism, hyperthyroidism, thyroiditis uncommon      Basedow's disease, diabetes mellitus#
Metabolism and          common        hypertriglyceridaemia, decreased appetite nutrition disorders
Psychiatric disorders   common        depression, aggression#, insomnia, anxiety, mood altered, mood swings, mood disorders uncommon      suicide attempt#, suicidal ideation#, confusional state#, acute stress disorder, hallucination, emotional distress,
nervousness, nightmare, irritability rare          bipolar disorder#, mania#
Nervous system          common        headache, dizziness, hypoesthesia, somnolence, disorders                             paraesthesia uncommon      polyneuropathy, peripheral motor neuropathy,
radiculopathy, migraine, mental impairment, tremor, aura
Eye disorders           common        dry eye uncommon      retinal haemorrhage#, retinal exudates#, visual impairment, visual acuity reduced, vision blurred, ocular discomfort,
eczema eyelids rare          retinopathy#, optic neuropathy#, retinal artery occlusion#, retinal vein occlusion#,
very rare     blindness# not known     retinal detachment#
Ear and labyrinth       uncommon      deafness, tinnitus, vertigo disorders
Cardiac disorders       common        atrial fibrillation uncommon      myocardial infarction#, atrioventricular block, intracardiac thrombus, aortic valve incompetence, cardiovascular disorder rare          cardiomyopathy#, angina pectoris# very rare     myocardial ischemia#
Vascular disorders      common        microangiopathy uncommon      Raynaud's phenomenon, hypertension, haematoma,
flushing
Respiratory, thoracic   common        dyspnoea and mediastinal         uncommon      pneumonitis, cough, epistaxis, throat irritation disorders very rare     lung infiltration# not known     pulmonary fibrosis#, pneumonia#, pulmonary arterial hypertension#*
Gastrointestinal        common        diarrhoea, nausea, abdominal pain, constipation, disorders                             abdominal distension, dry mouth uncommon      gastritis, abdominal wall disorder, flatulence, frequent bowel movements, odynophagia, gingival bleeding
not known          tooth disorder#, periodontal disease#
Hepatobiliary             very common        gamma-glutamyltransferase increased disorders                 common             liver disorder, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased uncommon           hepatotoxicity, hepatitis toxic, hepatomegaly, porphyria non-acute rare               hepatic failure#
Skin and                  common             pruritus, alopecia, rash, erythema, psoriasis, xeroderma, subcutaneous tissue                          dermatitis acneiform, hyperkeratosis, hyperhidrosis, dry disorders                                    skin uncommon           photosensitivity reaction, skin exfoliation, nail dystrophy not known          skin depigmentation#
Musculoskeletal and       very common        arthralgia, myalgia connective tissue         common             Sjogren's syndrome, arthritis, pain in extremity, disorders                                    musculoskeletal pain, bone pain, muscle spasms uncommon           muscular weakness, neck pain, groin pain
Renal and urinary         uncommon           cystitis haemorrhagic, dysuria, micturition urgency, disorders                                    urinary retention
Reproductive system       uncommon           erectile dysfunction, haematospermia and breast disorders
General disorders         very common        influenza like illness, fatigue and administration site conditions           common             pyrexia, injection site reaction, asthenia, chills, general physical health deterioration, injection site erythema uncommon           injection site pain, injection site pruritus, sensitivity to weather change not known:         tongue hyperpigmentation#
Investigations            common             antithyroid antibody positive, blood thyroid stimulating hormone increased, body temperature increased,
antinuclear antibody positive, blood lactate dehydrogenase increased, weight decreased uncommon           platelet count increased, blood uric acid increased, Coombs test positive
#
Reported as adverse reactions during treatment with other interferon alfa medicinal products.
*Class label for interferon medicinal products, see below pulmonary arterial hypertension.
**e.g., urticaria, angioedema, bronchoconstriction or anaphylaxis.

Description of selected adverse reactions

Most common adverse reactions
The most common adverse reactions (including number of patients, incidence rate, severity grade, necessity for dose adaptation and outcome) reported during the ropeginterferon alfa-2b clinical development program are summarised in Table 1.

Table 1. Most common adverse reactions during ropeginterferon alfa-2b treatment.

ADR >10%                                                                                 Medicinal CTCAE             Dose                                      Recovered PT                    N (%)       IR                                    Medicinal         Product intensity       reduced
N=178                                               Product        discontinued grade ≥3 interrupted
N (%)          N (%)                                         N (%)
N (%)                N (%)
Leukopenia              36        21.2     3 (8.3)      5 (13.9)      4 (11.1)          n.r.           8 (22.2) (20.2)

Thrombo-              33            11.2     4 (12.1)        3 (9.1)         2 (6.1)             n.r.            6 (18.2) cytopenia           (18.5)
Arthralgia             24            5.2     1 (4.2)             4           3 (12.5)            1 (4.2)         15 (62.5) (13.5)                                   (16.7)

Fatigue               22            6.6      n.r.            3 (13.6)        1 (4.5)             1 (4.5)         11 (50.0) (12.4)
Gamma-              20              7.9      7 (35.0)        3 (15.0)        n.r.                n.r.            4 (20.0) glutamyl-           (11.2) transferase increased
Influenza like          20          4.9      n.r.            4 (20.0)        2 (10.0)            n.r.            10 (50.0) illness             (11.2)

Myalgia               19            3.5      n.r.            2 (10.5)        1 (5.3)             n.r.            9 (47.4) (10.7)
No CTCAE grade 5 (death) adverse reactions reported for these preferred terms; 1 AE grade 4 (life-threating or disabling) reported for Gamma-glutamyltransferase increased.
Abbreviations: CTCAE, common terminology criteria for adverse events; n.r., not reported; ADR, adverse drug reaction; PT, preferred term; IR, incidence rate of mean adverse events per 100 patients per year; N, number of patients.
N (%) number and percentage of patients with given AE


Gastrointestinal disorders
Gastrointestinal disorders have been reported with other interferon alfa medicinal products and have been reported in 15.7% of patients with ropeginterferon alfa-2b treatment. The most common gastrointestinal disorders reported in these studies were diarrhoea (5.1%; incidence rate: 2.8 [events/100 patients per year]) and nausea (4.5%; incidence rate: 1.2 events/100 patients per year]).

CNS
In the clinical development program of ropeginterferon alfa-2b, two cases of serious depression (1.1%; incidence rate: 0.4 events/100 patients per year) occurred. The patients recovered completely after permanent medicinal product discontinuation. One patient who experienced serious acute stress disorder (0.6%; incidence rate: 0.2 events/100 patients per year) with moderate intensity recovered completely after the dose of ropeginterferon alfa-2b was reduced. CNS effects including suicide attempt, suicidal ideation, aggression, bipolar disorder, mania and confusion have been reported with interferon alfa (see section 4.4).

Cardiovascular system
During ropeginterferon alfa-2b therapy, three cases of atrial fibrillation (1.1%; incidence rate: 0.3 events/100 patients per year) with intensity grade 1 to 3 occurred in two patients. Ropeginterferon alfa-2b treatment was continued, and the patients received appropriate medicinal products to treat these events. Patients recovered from the two events; one event was ongoing at the time of assessment.

Respiratory system
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa, notably in patients with risk factors for PAH (such as portal hypertension, HIV infection, cirrhosis). Events were reported at various time points typically several months after starting treatment with interferon alfa.

Visual system
Serious eye disorders have been reported with interferon alfa such as retinopathy, retinal haemorrhage, retinal exudates, retinal detachment and retinal artery or vein occlusion (see section 4.4).

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 events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/