Adverse reactions : תופעות לוואי

4.8   Undesirable effects

See ribavirin SPC for ribavirin-related undesirable effects if Intron A is to be administered in combination with ribavirin in patients with chronic hepatitis C.

In clinical trials conducted in a broad range of indications and at a wide range of doses (from 6 MIU/m2/week in hairy cell leukaemia up to 100 MIU/m2/week in melanoma), the most commonly reported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue were often reversible within 72 hours of interruption or cessation of treatment.

In clinical trials conducted in the hepatitis C population, patients were treated with Intron A alone or in combination with ribavirin for one year. All patients in these trials received 3 MIU of Intron A three times a week. In Table 1 the frequency of patients reporting (treatment related) undesirable effects is presented from clinical trials in naïve patients treated for one year. Severity was generally mild to moderate. The adverse reactions listed in Table 1 are based on experience from clinical trials and post-marketing. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rarely (≥1/10,000 to <1/1,000); very rarely (<1/10,000); not known.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1 Adverse reactions reported during clinical trials or following the marketing use of Intron A alone or in combination with ribavirin
System Organ Class                                Adverse Reactions
Infections and infestations
Very common:                                      Pharyngitis*, infection viral* Common:                                           Bronchitis, sinusitis, herpes simplex (resistance), rhinitis
Uncommon:                                         Bacterial infection Rarely:                                           Pneumonia§, sepsis Not known:                                        Hepatitis B reactivation in HCV/HBV co- infected patients
Blood and lymphatic system disorders
Very common:                                      Leukopaenia
Common:                                           Thrombocytopaenia, lymphadenopathy, lymphopenia
Very rarely:                                      Aplastic anaemia

Not known:                           Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura
Immune system disorders§
Very rarely:                         Sarcoidosis, exacerbation of sarcoidosis Not known:                           Systemic lupus erythematosus, vasculitis, rheumatoid arthritis (new or aggravated), Vogt-
Koyanagi-Harada syndrome, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction,
anaphylaxis§
Endocrine disorders
Common:                              Hypothyroidism§, hyperthyroidism§ Very rarely:                         Diabetes, aggravated diabetes
Metabolism and nutrition disorders
Very common:                         Anorexia
Common:                              Hypocalcaemia, dehydration, hyperuricemia, thirst
Very rarely:                         Hyperglycaemia, hypertriglyceridaemia§, increased appetite
Psychiatric disorders§
Very common:                         Depression, insomnia, anxiety, emotional lability*, agitation, nervousness
Common:                              Confusion, sleep disorder, libido decreased Rarely:                              Suicide ideation
Very rarely:                         Suicide, suicide attempts, aggressive behavior (sometimes directed against others), psychosis including hallucinations
Not known:                           Homicidal ideation, mental status change§, mania, bipolar disorders
Nervous system disorders§
Very common:                         Dizziness, headache, concentration impaired, mouth dry
Common:                              Tremor, paresthesia, hypoesthesia, migraine, flushing, somnolence, taste perversion
Uncommon:                            Peripheral neuropathy
Very rarely:                         Cerebrovascular haemorrhage,
cerebrovascular ischaemia, seizure, impaired consciousness, encephalopathy
Not known:                           Mononeuropathies, coma§
Eye disorders
Very common:                         Vision blurred
Common:                              Conjunctivitis, vision abnormal, lacrimal gland disorder, eye pain
Rarely:                              Retinal haemorrhages§, retinopathies (including macular oedema), retinal artery or vein obstruction§, optic neuritis, papilloedema,
loss of visual acuity or visual field, cotton-wool spots§
Not known:                           Serous retinal detachment
Ear and labyrinth
Common:                              Vertigo, tinnitus
Very rarely:                         Hearing loss, hearing disorder


Cardiac disorders
Common:                                 Palpitation, tachycardia
Uncommon:                               Pericarditis
Rarely:                                 Cardiomyopathy
Very rarely:                            Myocardial infarction, cardiac ischaemia Not known:                              Congestive heart failure, pericardial effusion, arrhythmia
Vascular disorders
Common:                                 Hypertension
Very rarely:                            Peripheral ischaemia, hypotension§ Respiratory, thoracic and mediastinal disorders
Very common:                            Dyspnoea*, coughing*
Common:                                 Epistaxis, respiratory disorder, nasal congestion, rhinorrhea, cough nonproductive
Very rarely:                            Pulmonary infiltrates§, pneumonitis§, Not known:                              Pulmonary fibrosis, Pulmonary arterial # hypertension
Gastrointestinal disorders
Very common:                            Nausea/vomiting, abdominal pain, diarrhoea, stomatitis, dyspepsia
Common:                                 Stomatitis ulcerative, right upper quadrant pain, glossitis, gingivitis, constipation, loose stools
Very rarely:                            Pancreatitis, ischaemic colitis, ulcerative colitis, gingival bleeding
Not known:                              Periodontal disorder NOS, dental disorder NOS, tongue pigmentation §
Hepatobiliary disorders
Common:                                 Hepatomegaly
Very rarely:                            Hepatotoxicity, (including fatality) Skin and subcutaneous tissue disorders
Very common:                            Alopecia, pruritus*, skin dry*, rash*, sweating increased
Common:                                 Psoriasis (new or aggravated) §, rash maculopapular, rash erythematous, eczema,
erythema, skin disorder
Very rarely:                            Stevens Johnson syndrome, toxic epidermal necrolysis, erythema multiforme
Musculoskeletal and connective tissue disorders
Very common:                            Myalgia, arthralgia, musculoskeletal pain Common:                                 Arthritis
Very rarely:                            Rhabdomyolysis, myositis, leg cramps, back pain
Renal and urinary disorders
Common:                                 Micturition frequency
Very rarely:                            Renal failure, renal insufficiency, nephrotic syndrome
Reproductive system and breast disorders
Common:                                 Amenorrhea, breast pain, dysmenorrhea, menorrhagia, menstrual disorder, vaginal
disorder
General disorders and administration site conditions
Very common:                                             Injection site inflammation, injection site reaction*, fatigue, rigors, pyrexia§, flu-like symptoms§, asthenia, irritability, chest pain,
malaise
Common:                                                  Injection site pain Very rarely:                                             Injection site necrosis, face oedema Investigations
Very common:                                             Weight decrease *These events were only common with Intron A alone
§
See section 4.4
#
Class label for interferon products, see below Pulmonary arterial hypertension 
These undesirable effects have also been reported with Intron A alone.

The undesirable effects seen with hepatitis C are representative of those reported when Intron A is administered in other indications, with some anticipated dose- related increases in incidence. For example, in a trial of high-dose adjuvant Intron A treatment in patients with melanoma, incidences of fatigue, pyrexia, myalgia, neutropaenia/anaemia, anorexia, nausea and vomiting, diarrhoea, chills, flu-like symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis C trials. Severity also increased with high dose therapy (WHO Grade 3 and 4, in 66 % and 14 % of patients, respectively), in comparison with the mild to moderate severity usually associated with lower doses. Undesirable effects were usually managed by dose adjustment.

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, that may be reversible upon discontinuation of interferon alfa, has been reported rarely in patients without prior evidence of cardiac disease (see section 4.4).

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, 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.

A wide variety of autoimmune and immune-mediated disorders have been reported with alfa interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including mononeuropathies (see also section 4.4).

Clinically significant laboratory abnormalities, most frequently occurring at doses greater than 10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases in haemoglobin level and platelet count; increases in alkaline phosphatase, LDH, serum creatinine and serum urea nitrogen levels. Moderate and usually reversible pancytopenia has been reported. Increase in serum ALT/AST (SGPT/SGOT) levels have been noted as an abnormality in some non-hepatitis subjects and also in some patients with chronic hepatitis B coincident with clearance of viral DNAp.


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://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffe ctMedic@moh.gov.il or by email (adr@MOH.HEALTH.GOV.IL)