Adverse reactions : תופעות לוואי

4.8   Undesirable effects

In dose-finding studies involving 523 patients with relapsed ovarian cancer and 631 patients with relapsed small cell lung cancer, the dose-limiting toxicity of topotecan monotherapy was found to be haematological. Toxicity was predictable and reversible. There were no signs of cumulative haematological or non-haematological toxicity.

The safety profile of topotecan when given in combination with cisplatin in the cervical cancer clinical studies is consistent with that seen with topotecan monotherapy. The overall haematological toxicity is lower in patients treated with topotecan in combination with cisplatin compared to topotecan monotherapy, but higher than with cisplatin alone.

Additional adverse events were seen when topotecan was given in combination with cisplatin; however, these events were seen with cisplatin monotherapy and were not attributable to topotecan.
The prescribing information for cisplatin should be consulted for a full list of adverse events associated with cisplatin use.

The integrated safety data for topotecan monotherapy are presented below.

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), constipation, abdominal pain2, mucositis
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           Pyrexia, asthenia, fatigue
Common                Malaise
Very rare             Extravasation3
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).
3
Reactions have been mild and have not generally required specific therapy.


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).

The frequencies associated with the haematological and non-haematological adverse events listed below represent the adverse event reports considered to be related/possibly related to topotecan therapy.

Haematological

Neutropenia
Severe (neutrophil count < 0.5 x 109/l) during course 1 in 55 % of patients, with duration ≥ seven days in 20 % and overall in 77 % of patients (39 % of courses). In association with severe neutropenia, fever or infection occurred in 16 % of patients during course 1 and overall in 23 % of patients (6 % of courses). Median time to onset of severe neutropenia was nine days and the median duration was seven days. Severe neutropenia lasted beyond seven days in 11 % of courses overall. Among all patients treated in clinical studies (including both those with severe neutropenia and those who did not develop severe neutropenia), 11 % (4 % of courses) developed fever and 26 % (9 % of courses) developed infection. In addition, 5 % of all patients treated (1 % of courses) developed sepsis (see section 4.4).

Thrombocytopenia
Severe (platelets ≤25 x 109/l) in 25 % of patients (8 % of courses); moderate (platelets between 25.0 and 50.0 x 109/l) in 25 % of patients (15 % of courses). Median time to onset of severe thrombocytopenia was day 15 and the median duration was five days. Platelet transfusions were given in 4 % of courses. Reports of significant sequelae associated with thrombocytopenia, including fatalities due to tumour bleeds, have been infrequent.

Anaemia
Moderate to severe (Hb ≤ 8.0 g/dl) in 37 % of patients (14 % of courses). Red cell transfusions were given in 52 % of patients (21 % of courses).

Non-haematological
Frequently reported non-haematological effects were gastrointestinal, such as nausea (52 %), vomiting (32 %), diarrhoea (18 %), constipation (9 %) and mucositis (14 %). The incidence of severe (Grade 3 or 4) nausea, vomiting, diarrhoea and mucositis was 4, 3, 2 and 1 %, respectively.
Mild abdominal pain was reported in 4 % of patients.

Fatigue was observed in approximately 25 % and asthenia in 16 % of patients receiving topotecan.
Severe (Grade 3 or 4) fatigue and asthenia both occurred with an incidence of 3 %.

Total or pronounced alopecia was observed in 30 % of patients and partial alopecia in 15 % of patients.

Other severe events that were recorded as related or possibly related to topotecan treatment were anorexia (12 %), malaise (3 %) and hyperbilirubinaemia (1 %).

Hypersensitivity reactions including rash, urticaria, angioedema and anaphylactic reactions have been reported rarely. In clinical studies, rash was reported in 4 % of patients and pruritus in 1.5 % of patients.

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/