4.3     Contraindications

HYCAMTIN is contraindicated in patients who

-               have a history of severe hypersensitivity to the active substance or to any of the excipients

-               are breast feeding (see section 4.6)

-               already have severe bone marrow depression prior to starting first course, as evidenced by baseline neutrophils < 1.5 x 10⁹/l and/or a platelet count of < 100 x 10⁹/l.

4.4     Special warnings and precautions for use

Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been fatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation and use of pneumotoxic drugs and/or colony stimulating factors. Patients should be monitored for pulmonary symptoms indicative of interstitial lung diseaseILD (e.g. cough, fever, dyspnoea and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed.

Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated with clinically relevant thrombocytopenia. This should be taken into account when prescribing Hycamtin, e.g. in case patients at increased risk of tumour bleeds are considered for therapy.

A small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/dl) were given intravenous topotecan at 1.5 mg/m² for five days every three weeks. A reduction in topotecan clearance was observed. hHowever, there are insufficient data available to make a dose recommendation for this patient group. There is insufficient experience of the use of topotecan in patients with severely impaired hepatic function (serum bilirubin ³ 10 mg/dl). Topotecan is not recommended to be used in these patients.

Diarrhoea, including severe diarrhoea requiring hospitalization, has been reported during treatment with oral topotecan. Diarrhoea related to oral topotecan can occur at the same time as drug-related neutropenia and its sequelae. Communication with patients prior to drug administration regarding these side effects and proactive management of early and all signs and symptoms of diarrhoea is important. Cancer treatment-induced diarrhoea (CTID) is associated with significant morbidity and may be life-threatening. Should diarrhoea occur during treatment with oral topotecan, physicians are advised to aggressively manage diarrhoea. Clinical guidelines describing the aggressive management of CTID includes specific recommendations on patient communication and awareness, recognition of early warning signs, use of anti-diarrhoeals and antibiotics, changes in fluid intake and diet, and need for hospitalization (see section 4.2 and 4.8).

4.5     Interaction with other medicinal products and other forms of interaction

No in vivo human pharmacokinetic interaction studies have been performed.

Topotecan does not inhibit human P450 enzymes (see section 5.2). In an intravenous population study, the co-administration of granisetron, ondansetron, morphine or corticosteroids did not appear to have a significant effect on the pharmacokinetics of total topotecan (active and inactive form).

4.6     Fertility, Ppregnancy and lactation

Contraception in males and females

As with all cytotoxic chemotherapy, effective contraceptive methods must be advised when either partner is treated with topotecan.

Women of childbearing potential

Topotecan has been shown to cause embryo-foetal lethality and malformations in preclinical studies (see section 5.3). As with other cytotoxic medicinal products, topotecan may cause foetal harm and therefore women of child bearing potential should be advised to avoid becoming pregnant during therapy with topotecan.

Pregnancy

If topotecan is used during pregnancy, or if the patient becomes pregnant during therapy with topotecan, the patient must be warned of the potential hazards to the foetus.

Breastfeeding

Topotecan is contra-indicated during breast-feeding (see section 4.3).  Although it is not known whether topotecan is excreted in human breast milk, breast-feeding should be discontinued at the start of therapy.

Fertility

No effects on male or female fertility have been observed in reproductive toxicity studies in rats (see section 5.3). However, as with other cytotoxic medicinal products topotecan is genotoxic and effects on fertility, including male fertility, cannot be excluded.

4.8     Undesirable effects

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), 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.

5.1     Pharmacodynamic properties

Relapsed SCLC

A phase III trial (study 478) compared oral topotecan plus Best Supportive Care [(BSC)] [(n=71)] with BSC alone [(n=70)] in patients who had relapsed following first line therapy [(median time to progression [TTP] from first-line therapy: 84 days for oral topotecan + BSC, 90 days for BSC)] and for whom retreatment with intravenous chemotherapy was not considered appropriate. Oral topotecan plus BSC group had a statistically significant improvement in overall survival compared with the BSC alone group (Log-rank p=0.0104). The unadjusted hazard ratio for oral topotecan plus BSC group relative to BSC alone group was 0.64 (95 % CI: 0.45, 0.90). The median survival for patients treated with topotecan + BSC was 25.9 weeks [(95 % C.I. 18.3, 31.6)] compared to 13.9 weeks [(95 % C.I. 11.1, 18.6)] for patients receiving BSC alone (p=0.0104).

5.2     Pharmacokinetic properties

A major route of clearance of topotecan is by hydrolysis of the lactone ring to form the ring-opened carboxylate. Other than hydrolysis, topotecan is cleared predominantly renally, with a minor component metabolized to the N-desmethyl metabolite (SB-209780) identified in plasma, urine and faeces. Overall recovery of topotecan-related material following five daily doses of topotecan was 4149 to 7672 % (mean 57 %) of the administered oral dose. Approximately 20% was excreted as total topotecan and 2 % was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted for 33 % while faecal elimination of N-desmethyl topotecan was 1.5%. Overall, the N-desmethyl metabolite contributed a mean of less than 6 % (range 4-8 %) of the total topotecan related material accounted for in the urine and faeces. O-glucuronides of both topotecan and N-desmethyl topotecan have been identified in the urine. The mean metabolite: parent plasma AUC ratio was less than 10 % for both total topotecan and topotecan lactone.

10.     DATE OF REVISION OF THE TEXT

Jan 2010September 2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.