HYCAMTIN 0.25 mg and 1 mg hard capsules

Each capsule contains topotecan hydrochloride equivalent to 0.25 mg or 1 mg of topotecan.

For a full list of excipients, see section 6.1.

Hard capsule.

0.25 mg: the capsules are opaque white to yellowish white and imprinted with 'HYCAMTIN' and '0.25 mg'.

1 mg: the capsules are opaque pink and imprinted with 'HYCAMTIN' and '1 mg'.

HYCAMTIN capsules are indicated as monotherapy for the treatment of adult patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate (see section 5.1).

Method of administration

HYCAMTIN capsules should only be prescribed and therapy supervised by a physician experienced in the use of chemotherapeutic agents.

Posology

Initial dose

The recommended dose of HYCAMTIN capsules is 2.3 mg/m² body surface area/day administered for five consecutive days with a three week interval between the start of each course. If well tolerated, treatment may continue until disease progression (see sections 4.8 and 5.1).

The capsule(s) must be swallowed whole, and must not be chewed crushed or divided.

Hycamtin capsules may be taken with or without food (see section 5.2).

Prior to administration of the first course of topotecan, patients must have a baseline neutrophil count of 1.5 x 10⁹/l, a platelet count of 100 x 10⁹/l and a haemoglobin level of 9 g/dl (after transfusion if necessary)

Subsequent doses

Topotecan should not be re-administered unless the neutrophil count is 1 x 10⁹/l, the platelet count is 100 x 10⁹/l, and the haemoglobin level is 9 g/dl (after transfusion if necessary).

Standard oncology practice for the management of neutropenia is either to administer topotecan with other medications (e.g. G-CSF) or to dose reduce to maintain neutrophil counts.

If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 x 10⁹/l) for seven days or more, or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 0.4 mg/m²/day to 1.9 mg/m²/day (or subsequently down to 1.5 mg/m²/day if necessary).

Doses should be similarly reduced if the platelet count falls below 25 x 10⁹/l. In clinical trials, topotecan was discontinued if the dose needed to be reduced below 1.5 mg/m².

For patients who experience Grade 3 or 4 diarrhoea, the dose should be reduced by 0.4 mg/m2/day for subsequent courses (see section 4.4). Patients with Grade 2 diarrhoea may need to follow the same dose modification guidelines.

Proactive management of diarrhoea with anti-diarrhoeal agents is important. Severe cases of diarrhoea may require administration of oral or intravenous electrolytes and fluids, and interruption of topotecan therapy (see sections 4.4 and 4.8).

Dosage in renally impaired patients

Patients with small cell lung carcinoma who participated in oral topotecan clinical trials had a serum creatinine less than or equal to 1.5 mg/dl (133 µmol/l) or a creatinine clearance of greater than or equal to 60 ml/min. Dosing recommendations for patients receiving oral topotecan with Cl_cr less than 60 ml/min have not been established (see section 4.4).

Dosage in hepatically impaired patients

Pharmacokinetics of HYCAMTIN capsules have not been specifically studied in patients with impaired hepatic function. There are insufficient data available with HYCAMTIN capsules to make a dose recommendation for this patient group (see section 4.4).

Paediatric population

The experience in children is limited, therefore no recommendation for treatment of paediatric patients with HYCAMTIN can be given (see section 5.1).

Elderly

No overall differences in effectiveness were observed between patients over 65 years and younger adult patients. However in the two studies administering both oral and intravenous topotecan, patients older than 65 years old receiving oral topotecan experienced an increase in drug related diarrhoea compared to those younger than 65 years of age (see section 4.4 and 4.8).

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.

Haematological toxicity is dose-related and full blood count including platelets should be monitored regularly (see section 4.2).

As with other cytotoxic medicinal products, topotecan can cause severe myelosuppression. Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated with topotecan (see section 4.8).

Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical trials with topotecan. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered.

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 ILD (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.

As expected, patients with poor performance status (PS>1) have a lower response rate and an increased incidence of complications such as fever, infection and sepsis (see section 4.8). Accurate assessment of performance status at the time therapy is given is important, to ensure that patients have not deteriorated to performance status 3.

Topotecan is partly eliminated via renal excretion and renal impairment might lead to increased exposure to topotecan. Dosing recommendations for patients receiving oral topotecan with Cl_cr less than 60 ml/min have not been established. There is insufficient experience of the use of oral or intravenous topotecan in patients with severely impaired renal function (creatinine clearance < 20 ml/min). Topotecan is not recommended to be used in these patients.

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. However, 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 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 sections 4.2 and 4.8).

Intravenous topotecan should be considered in the following clinical situations: uncontrolled emesis, swallowing disorders, uncontrolled diarrhoea, clinical conditions and medication that may alter gastrointestinal motility and drug absorption.

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).

Topotecan is a substrate for both ABCB1 (P-glycoprotein) and ABCG2 (BCRP). Inhibitors of ABCB1 and ABCG2 administered with oral topotecan have been shown to increase topotecan exposure.

Cyclosporin A (an inhibitor of ABCB1, ABCC1 [MRP-1], and CYP3A4) administered with oral topotecan increased topotecan AUC to approximately 2 - 2.5-fold of control.

Patients should be carefully monitored for adverse reactions when oral topotecan is administered with a drug known to inhibit ABCB1 or ABCG2 (see section 5.2).

In combining topotecan with other chemotherapy agents, reduction of the doses of each medicinal product may be required to improve tolerability. However, in combining with platinum agents, there is a distinct sequence-dependent interaction depending on whether the platinum agent is given on day 1 or 5 of the topotecan dosing. If either cisplatin or carboplatin is given on day 1 of the topotecan dosing, a lower dose of each agent must be given to improve tolerability compared to the dose of each agent which can be given if the platinum agent is given on day 5 of the topotecan dosing. Currently there is only limited experience in combining oral topotecan with other chemotherapy agents.

The pharmacokinetics of topotecan was generally unchanged when coadministered with ranitidine.

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 childbearing 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.

No studies on the effects on the ability to drive and use machines have been performed. However, caution should be observed when driving or operating machines if fatigue and asthenia persist.

In clinical trials 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), 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.

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).

Safety data are presented based on an integrated data set of 682 patients with relapsed lung cancer administered 2536 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 courses 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 less than 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.

There is no known antidote for topotecan overdose. The primary complications of overdose are anticipated to be bone marrow suppression and mucositis.

Pharmacotherapeutic group: Other antineoplastic agents: ATC code: L01XX17.

The anti-tumour activity of topotecan involves the inhibition of topoisomerase-I, an enzyme intimately involved in DNA replication as it relieves the torsional strain introduced ahead of the moving replication fork. Topotecan inhibits topoisomerase-I by stabilising the covalent complex of enzyme and strand-cleaved DNA which is an intermediate of the catalytic mechanism. The cellular sequela of inhibition of topoisomerase-I by topotecan is the induction of protein-associated DNA single-strand breaks.

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).

Patient self-reports of symptoms using an unblinded assessment showed a consistent trend for symptom benefit for oral topotecan + BSC.

One Phase 2 study (Study 065) and one Phase 3 study (Study 396) were conducted to evaluate the efficacy of oral topotecan versus intravenous topotecan in patients who had relapsed 90 days after completion of one prior regimen of chemotherapy (see Table 1). Oral and intravenous topotecan were associated with similar symptom palliation in patients with relapsed sensitive SCLC in patient self-reports on an unblinded symptom scale assessment in each of these two studies.

Table 1. Summary of survival, response rate, and time to progression in SCLC patients treated with oral HYCAMTIN or intravenous HYCAMTIN

N = total number of patients treated.

CI = Confidence interval.

Paediatrics

Safety and effectiveness of oral topotecan in paediatric patients have not been established.

The pharmacokinetics of topotecan after oral administration have been evaluated in cancer patients following doses of 1.2 to 3.1 mg/m²/day and 4 mg/m²/day administered daily for 5 days. The bioavailability of oral topotecan (total and lactone) in humans is approximately 40 %. Plasma concentrations of total topotecan (i.e. lactone and carboxylate forms) and topotecan lactone (active moiety) peak at approximately 2.0 hours and 1.5 hours, respectively, and decline bi-exponentially with mean terminal half-life of approximately 3.0 to 6.0 hour. Total exposure (AUC) increases approximately proportionally with dose. There is little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change in the PK after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low (35 %) and distribution between blood cells and plasma was fairly homogeneous.

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 49 to 72 % (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.

In vitro, topotecan did not inhibit human P450 enzymes CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A nor did it inhibit the human cytosolic enzymes dihydropyrimidine or xanthine oxidase.

Following coadministration of the ABCB1 (P-gp) and ABCG2 (BCRP) inhibitor, elacridar (GF120918) at 100 to 1,000 mg with oral topotecan, the AUC0- of topotecan lactone and total topotecan increased approximately 2.5-fold (see section 4.5 for guidance).

Administration of oral cyclosporine A (15 mg/kg), an inhibitor of transporters ABCB1 (P-gp) and ABCC1 (MRP-1) as well as the metabolising enzyme CYP3A4, within 4 hours of oral topotecan increased the dose normalised AUC0-24h of topotecan lactone and total topotecan approximately 2.0- and 2.5-fold, respectively (see section 4.5).

The extent of exposure was similar following a high fat meal and fasted state while tmax was delayed from 1.5 to 3 hours (topotecan lactone) and from 3 to 4 hours (total topotecan).

The pharmacokinetics of oral topotecan has not been studied in patients with renal or hepatic impairment (see section 4.2 and 4.4).

A cross-study analysis in 217 patients with advanced solid tumours indicated that gender did not affect the pharmacokinetics of HYCAMTIN capsules to a clinically relevant extent. There are insufficient data to determine an effect of race on pharmacokinetics of oral topotecan.

Resulting from its mechanism of action, topotecan is genotoxic to mammalian cells (mouse lymphoma cells and human lymphocytes) in vitro and mouse bone marrow cells in vivo. Topotecan was also shown to cause embryo-foetal lethality when given to rats and rabbits.

In reproductive toxicity studies with topotecan in rats there was no effect on male or female fertility; however, in females super-ovulation and slightly increased pre-implantation loss were observed.

The carcinogenic potential of topotecan has not been studied.

Capsule contents (0.25 mg and 1 mg):

Hydrogenated vegetable oil

Glyceryl monostearate

Capsule shell (0.25 mg):

Gelatin

Titanium dioxide (E171)

Capsule shell (1 mg):

Gelatin,

Titanium dioxide (E171),

red iron oxide (E172)

Sealing band (0.25 mg and 1 mg):

Gelatin

Black ink comprising:

black iron oxide (E172)

shellac

anhydrous ethanol – see leaflet for further information

propylene glycol

isopropyl alcohol

butanol

concentrated ammonia solution

potassium hydroxide

Not applicable

3 years.

Store in a refrigerator (2°C - 8°C).

Keep the blister card in the outer carton in order to protect from light.

Do not freeze.

White polyvinyl chloride / polychlorotrifluoroethylene blister sealed with aluminium / Polyethylenterephtalate (PET) / paper foil lidding.

The blisters are sealed with a peel-push child resistant opening feature.

Each blister card contains 10 capsules.

HYCAMTIN capsules should not be opened or crushed.

Any unused product or waste material should be disposed of in accordance with local requirements.

SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom.

Date of first authorisation: 12/11/1996

Date of latest renewal: 12/11/2006

28 October 2010

POM

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