Adverse reactions : תופעות לוואי

4.8    Undesirable effects

In dose-finding trials 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 adverse event profile for topotecan when given in combination with cisplatin in the cervical cancer clinical trials is consistent with that seen with topotecan monotherapy. The  overall haemtological 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 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, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (<1/10,000), including isolated reports and not known (cannot be estimated from the available data).

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

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)

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), 1 constipation, abdominal pain and mucositis.
1
Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a complication of topotecan-induced neutropenia (see section 4.4).

Skin and subcutaneous tissue disorders
Very common: alopecia.
Common: pruritus.

Metabolism and nutrition disorders
Very common: anorexia (which may be severe).
Infections and infestations
Very common: infection.
2
Common: sepsis .
2
Fatalities due to sepsis have been reported in patients treated with topotecan (see section        4.4).

General disorders and administration site conditions
Very common: pyrexia, asthenia, fatigue.
Common: malaise.

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Very rare: extravasation
3
Extravasation has been reported very rarely. Reactions have been mild and have not generally required specific therapy.

Immune system disorders
Common: hypersensitivity reaction including rash.
Rare: anaphylactic reaction, angioedema, urticaria.

Hepato-biliary disorders
Common: hyperbilirubinaemia.
The incidence of 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 was seen in 55% of the patients and with duration ≥ 7 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 9 days and the median duration was 7 days. Severe neutropenia lasted beyond 7 days in 11% of courses overall. Among all patients treated in clinical trials (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 less than 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 5 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%), and diarrhoea (18%), constipation (9%) and mucositis (15%).
Severe (grade 3 or 4) nausea, vomiting, diarrhoea and mucositis incidence was 4, 3, 2 and 1% respectively.
Mild abdominal pain was also reported amongst 4% of patients.

Fatigue was observed in approximately 25% and asthenia in 16% of patients whilst receiving topotecan. Severe (grade 3 or 4) fatigue and asthenia incidence was 3 and 3% respectively.


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

Other severe events occuring in patients 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 trials, 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. Healthcare professionals are asked to report any suspected adverse reactions 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@mo h.health.gov.il or by email (adr@MOH.HEALTH.GOV.IL ).