Adverse reactions : תופעות לוואי

4.8 Undesirable effects
In clinical studies involving patients with relapsed small cell lung cancer, the dose-limiting toxicity of oral topotecan monotherapy was found to be haematological. Toxicity was predictable and reversible.
There were no signs of cumulative haematological or non-haematological toxicity.

The frequencies associated with the haematological and non-haematological adverse events presented are for adverse events considered to be related/possibly related to oral topotecan therapy.

Adverse reactions are listed below, by system organ class and absolute frequency (all reported events).
Frequencies are defined 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), and not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations
Very common           Infection
Common                Sepsis1
Blood and lymphatic system disorders
Very common           Febrile neutropenia, neutropenia (see “Gastrointestinal disorders”), thrombocytopenia, anaemia, leucopenia
Common                Pancytopenia
Not known             Severe bleeding (associated with thrombocytopenia) Immune system disorders
Common                Hypersensitivity reaction including rash
Rare                  Anaphylactic reaction, angioedema, urticaria
Metabolism and nutrition disorders
Very common           Anorexia (which may be severe)
Respiratory, thoracic and mediastinal disorders
Rare                  Interstitial lung disease (some cases have been fatal) Gastrointestinal disorders
Very common           Nausea, vomiting and diarrhoea (all of which may be severe), which may lead to dehydration (see sections 4.2 and 4.4)
Common                Abdominal pain2, constipation, mucositis, dyspepsia Not known             Gastrointestinal perforation
Hepatobiliary disorders
Common                Hyperbilirubinaemia
Skin and subcutaneous tissue disorders
Very common           Alopecia
Common                Pruritus
General disorders and administration site conditions
Very common           Fatigue
Common                Asthenia, pyrexia, malaise
Not known             Mucosal inflammation
1
Fatalities due to sepsis have been reported in patients treated with topotecan (see section 4.4).
2
Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a complication of topotecan-induced neutropenia (see section 4.4)

The adverse events listed above have the potential to occur with a higher frequency in patients who have a poor performance status (see section 4.4).

Safety data are presented based on an integrated data set of 682 patients with relapsed lung cancer administered 2,536 courses of oral topotecan monotherapy (275 patients with relapsed SCLC and 407 with relapsed non-SCLC).
Haematological

Neutropenia
Severe neutropenia (Grade 4 - neutrophil count < 0.5 x 109/l) occurred in 32 % of patients in 13 % of courses. Median time to onset of severe neutropenia was day 12 with a median duration of 7 days. In 34 % of courses with severe neutropenia, the duration was > 7 days. In course 1 the incidence was 20 %, by course 4 the incidence was 8 %. Infection, sepsis and febrile neutropenia occurred in 17 %,
2 %, and 4 % of patients, respectively. Death due to sepsis occurred in 1 % of patients. Pancytopenia has been reported. Growth factors were administered to 19 % of patients in 8 % of courses.

Thrombocytopenia
Severe thrombocytopenia (Grade 4 - platelets <10 x 109/l) occurred in 6 % of patients in 2 % of courses. Median time to onset of severe thrombocytopenia was day 15 with a median duration of 2.5 days. In 18 % of courses with severe thrombocytopenia the duration was > 7 days. Moderate thrombocytopenia (Grade 3 - platelets between 10.0 and 50.0 x 109/l) occurred in 29 % of patients in 14 % of courses. Platelet transfusions were given to 10 % of patients in 4 % of courses. Reports of significant sequelae associated with thrombocytopenia including fatalities due to tumour bleeds have been infrequent.

Anaemia
Moderate to severe anaemia (Grade 3 and 4 – Hb ≤ 8.0 g/dl) occurred in 25 % of patients (12 % of courses). Median time to onset of moderate to severe anaemia was day 12 with a median duration of 7 days. In 46 % of courses with moderate to severe anaemia, the duration was > 7 days. Red blood cell transfusions were given in 30 % of patients (13 % of courses). Erythropoietin was administered to 10 % of patients in 8 % of courses.

Non-haematological
The most frequently reported non-haematological effects were nausea (37 %), diarrhoea (29 %), fatigue (26 %), vomiting (24 %), alopecia (21 %) and anorexia (18 %). All cases were irrespective of associated causality. For severe cases (CTC Grade 3/4) reported as related / possibly related to topotecan administration the incidence was diarrhoea 5 % (see section 4.4), fatigue 4 %, vomiting 3 %, nausea 3 % and anorexia 2 %.

The overall incidence of drug-related diarrhoea was 22 %, including 4 % with Grade 3 and 0.4 % with Grade 4. Drug-related diarrhoea was more frequent in patients ≥65 years of age (28 %) compared to those less than 65 years of age (19 %).

Complete alopecia related/possibly related to topotecan administration was observed in 9 % of patients and partial alopecia related/possibly related to topotecan administration in 11 % of patients.

Therapeutic interventions associated with non-haematological effects included anti-emetic agents, given to 47 % of patients in 38 % of courses and anti-diarrhoeal agents, given to 15 % of patients in 6 % of courses. A 5-HT3 antagonist was administered to 30 % of patients in 24 % of courses.
Loperamide was administered to 13 % of patients in 5 % of courses. The median time to onset of Grade 2 or worse diarrhoea was 9 days.

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.