Adverse reactions : תופעות לוואי

4.8   Undesirable effects
Summary of Safety Profile

The most frequent adverse drug reaction during treatment with epoetin alfa is a dose-dependent increase in blood pressure or aggravation of existing hypertension. Monitoring of the blood pressure should be performed, particularly at the start of therapy (see section 4.4).

The most frequently occurring adverse drug reactions observed in clinical trials of epoetin alfa are diarrhoea, nausea, vomiting, pyrexia and headache. Influenza-like illness may occur especially at the start of treatment.

Respiratory tract congestion, which includes events of upper respiratory tract congestion, nasal congestion and nasopharyngitis, have been reported in studies with extended interval dosing in adult patients with renal insufficiency not yet undergoing dialysis.

An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs (see section 4.4).

Tabulated List of Adverse Reactions

Of a total 3,417 subjects in 25 randomized, double-blinded, placebo or standard of care controlled studies, the overall safety profile of EPREX was evaluated in 2,094 anaemic subjects. Included were 228 epoetin alfa-treated CRF subjects in 4 chronic renal failure studies (2 studies in predialysis
[N = 131 exposed CRF subjects] and 2 in dialysis [N = 97 exposed CRF subjects]; 1,404 exposed cancer subjects in 16 studies of anaemia due to chemotherapy; 147 exposed subjects in 2 studies for autologous blood donation; 213 exposed subjects in 1 study in the perisurgical period Adverse drug reactions reported by ≥1% of subjects treated with epoetin alfa in these trials are shown in the table below.

Frequency estimate: 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).

MedDRA System Organ Classification             Adverse Reaction (Preferred              Frequency (SOC)                                   Term Level)
Blood and lymphatic system disorders            Pure red cell aplasia3,             Rare Thrombocythemia
Metabolism and nutrition disorders              Hyperkalaemia1                      Uncommon Immune system disorders                         Hypersensitivity3                   Uncommon Anaphylactic reaction3              Rare
Nervous system disorders                        Headache                            Common Convulsion                          Uncommon
Vascular disorders                              Hypertension, Venous and arterial   Common thromboses2
Hypertensive crisis3                Not known
Respiratory, thoracic and mediastinal disorders Cough                               Common Respiratory tract congestion        Uncommon
Gastrointestinal disorders                      Diarrhoea, Nausea, Vomiting         Very common Skin and subcutaneous tissue disorders          Rash                                Common Urticaria3                          Uncommon
Angioneurotic oedema3               Not known
Musculoskeletal and connective tissue disorders Arthralgia, Bone pain, Myalgia,     Common Pain in extremity
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Congenital, familial and genetic disorders            Porphyria acute3                        Rare General disorders and administration                  Pyrexia                                 Very common site conditions                                       Chills, Influenza like illness,         Common Injection site reaction,
Oedema peripheral
Drug ineffective3                       Not known
Investigations                                        Anti-erythropoeitin antibody            Rare positive
1
Common in dialysis
2
Includes arterial and venous, fatal and non fatal events, such as deep venous thrombosis, pulmonary emboli, retinal thrombosis, arterial thrombosis (including myocardial infarction), cerebrovascular accidents (including cerebral infarction and cerebral haemorrhage) transient ischaemic attacks, and shunt thrombosis (including dialysis equipment) and thrombosis within arteriovenous shunt aneurisms
3
Addressed in the subsection below and/or in section 4.4

Description of selected adverse reactions

Hypersensitivity reactions, including cases of rash (including urticaria), anaphylactic reactions, and angioneurotic oedema have been reported.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with epoetin treatment (see section 4.4).

Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have occurred also during epoetin alfa treatment in patients with previously normal or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like headaches as a possible warning signal (see section 4.4).

Antibody-mediated pure red cell aplasia has been very rarely reported in < 1/10,000 cases per patient year after months to years of treatment with EPREX (see section 4.4). More cases have been reported with subcutaneous (SC) route of administration, compared with the IV route.

Paediatric population with chronic renal failure on haemodialysis

The exposure of paediatric patients with chronic renal failure on haemodialysis in clinical trials and post-marketing experience is limited. No paediatric-specific adverse reactions not mentioned previously in the table above, or any that were not consistent with the underlying disease were reported in      this population.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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://sideeffects.health.gov.il