Adverse reactions : תופעות לוואי

4.8      Undesirable effects

Combination therapy with ribavirin: Also see ribavirin labelling if interferon alfa-2a is to be administered in combination with ribavirin in patients with chronic hepatitis C.

The following data on adverse reactions are based on information derived from the treatment of cancer patients with a wide variety of malignancies and often refractory to previous therapy and suffering from advanced disease, patients with chronic hepatitis B, and patients with chronic hepatitis C.
Approximately two thirds of cancer patients experienced anorexia and one half nausea.
Cardiovascular and pulmonary disorders were seen in about one fifth of cancer patients and consisted of transient hypotension, hypertension, oedema, cyanosis, arrhythmias, palpitations and chest pain.
Most cancer patients received doses that were significantly higher than the dose now recommended and may explain the higher frequency and severity of adverse reactions in this patient group compared with patients with hepatitis B where adverse reactions are usually transient, and patients return to pre-treatment status within 1 to 2 weeks after the end of therapy. Cardiovascular disorders were very rarely seen in patients with hepatitis B. In hepatitis B patients, changes in transaminases usually signal an improvement in the clinical state of the patient.

The majority of the patients experienced flu-like symptoms such as fatigue, pyrexia, rigors, decreased appetite, myalgia, headache, arthralgia and diaphoresis. These acute side-effects can usually be reduced or eliminated by concurrent administration of paracetamol and tend to diminish with continued therapy or dose modification although continuing therapy can lead to lethargy, asthenia and fatigue.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: 
Body system         Very common            Common           Uncommon             Rare              Very rare       Not known ( 1/10)       ( 1/100 to < 1/10)   ( 1/1,000 to   ( 1/10,000 to        (< 1/10,000)      (cannot be < 1/100)      < 1/1,000)                            estimated from the available data)
Infections and                                                                Pneumonia infestations                                                                  Herpes simplex1 Blood and             Leukopenia        Thrombocytopenia                      Agranulocytosis     Idiopathic        Neutropenia lymphatic system                        Anaemia                               Haemolytic          thrombocyto- disorders2                                                                    anaemia             penic purpura Immune system                                                                 Autoimmune          Sarcoidosis       Graft disorders                                                                     disorder                              rejections† Acute hypersensitivity reactions3
Endocrine                                                                     Hypothyroidism disorders                                                                     Hyperthyroidism Thyroid dysfunction
Metabolism and        Anorexia                                Dehydration     Diabetes mellitus   Hyper- nutrition disorders   Nausea                                  Electrolyte     Hyper-glycaemia     triglyceridemia Inconsequential                         imbalance                           Hyperlipidaemia hypocalcaemia
Psychiatric                                                   Depression      Suicide disorders                                                     Anxiety         Suicide attempt Mental status   Suicidal ideation changes         Mania
Confusional state
Abnormal behaviour
Nervousness
Memory impairment
Sleep disorder
Nervous system        Headache          Dysgeusia             Neuropathy      Coma                Encephalopathy disorders                                                     Dizziness       Cerebrovascular Hypoesthesia    accident
Paraesthesia    Convulsions

Body system       Very common             Common            Uncommon             Rare                Very rare         Not known ( 1/10)        ( 1/100 to < 1/10)    ( 1/1,000 to   ( 1/10,000 to          (< 1/10,000)        (cannot be < 1/100)      < 1/1,000)                                estimated from the available data)
Tremor           Transient erectile
Somnolence       dysfunction
Eye disorders                                                 Visual           Ischaemic            Retinal artery disturbance      retinopathy          thrombosis
Conjunctivitis                        Optic neuropathy
Retinal haemorrhage
Retinal vein thrombosis
Retinal exudates
Retinopathy
Papilloedema
Ear and labyrinth                                             Vertigo                                                    Hearing disorders                                                                                                                impairment Cardiac disorders                       Arrhythmias4                           Cardiorespiratory Palpitations                           arrest
Cyanosis                               Myocardial infarction
Congestive heart failure
Pulmonary oedema
Vascular disorders                                            Hypertension     Vasculitis Hypotension
Respiratory,                                                                   Dyspnoea                                  Pulmonary thoracic and                                                                   Cough                                     arterial mediastinal                                                                                                              hypertension* disorders
Gastrointestinal     Diarrhoea          Vomiting                               Pancreatitis         Reactivation of disorders                               Abdominal pain                         Intestinal           peptic ulcer         Ischemic colitis Nausea                                 hypermotility        Gastrointestinal     ulcerative colitis Dry mouth                              Constipation         bleeding (non-life Dyspepsia            threatening)
Flatulence
Hepato-biliary                                                                 Hepatic failure disorders                                                                      Hepatitis Hepatic dysfunction
Skin and             Alopecia5                                Psoriasis6       Rash                                      Skin subcutaneous         Sweating                                 Pruritus         Dry skin                                  depigmentation tissue disorders     increased                                                 Epistaxis Mucosal dryness
Rhinorrhoea
Musculoskeletal,     Myalgia                                                   Systemic lupus connective tissue    Arthralgia                                                erythematosus and bone                                                                       Arthritis disorders
Renal and urinary                                             Proteinuria      Acute renal disorders                                                     Increased cell   failure7 count in urine   Renal impairment
General disorders    Flu like illness   Chest pain                                                  Injection site and administration   Appetite           Oedema                                                      necrosis site conditions      decreased                                                                      Injection site Pyrexia                                                                        reaction Rigors
Fatigue
Investigations                          Weight loss           Increased        Increased blood ALT              creatinine
Increased        Increased blood transaminase     urea
Increased        Increased blood blood alkaline   bilirubin phosphatase      Increased blood uric acid
Increased blood
LDH
(including exacerbations of herpes labialis)
1


2
In myelosuppressed patients, thrombocytopenia and decreased haemoglobin occurred more frequently. Recovery of severe haematological deviations to pre-treatment levels usually occurred within seven to ten days after discontinuing Roferon-A treatment.
3
(e.g. urticaria, angioedema, bronchospasm and anaphylaxis)
4 including atrioventricular block
5
(reversible upon discontinuation; increased hair loss may continue for several weeks after end of treatment) 6 exacerbation of, or provocation of psoriasis
7
(mainly in cancer patients with renal disease)
† Identified in postmarketing experience

*Class label for interferon products, see below Pulmonary arterial hypertension 
Rarely, alpha interferons including Roferon-A used alone or in combination with ribavirin, may be associated with pancytopenia, and very rarely, aplastic anaemia has been reported.

Neutralizing antibodies to interferons may form in some patients. In certain clinical conditions (cancer, systemic lupus erythematosus, herpes zoster) antibodies to human leukocyte interferon may also occur spontaneously in patients who have never received exogenous interferons. The clinical significance of the development of antibodies has not been fully clarified.

In clinical trials where lyophilized Roferon-A which had been stored at 25°C was used, neutralizing antibodies to Roferon-A have been detected in approximately one fifth of patients. In patients with hepatitis C, a trend for responding patients who develop neutralizing antibodies to lose response while still on treatment and to lose it earlier than patients who do not develop such antibodies, has been seen.
No other clinical sequelae of the presence of antibodies to Roferon-A have been documented. The clinical significance of the development of antibodies has not been fully clarified.

No data on neutralizing antibodies yet exist from clinical trials in which lyophilized Roferon-A or Roferon- A solution for injection which is stored at 4°C has been used. In a mouse model, the relative immunogenicity of lyophilized Roferon-A increases with time when the material is stored at 25°C - no such increase in immunogenicity is observed when lyophilized Roferon-A is stored at 4°C, the recommended storage conditions.

Pulmonary arterial hypertension
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 at several months after starting treatment with interferon alfa.

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 http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il