HYCAMTIN 1mg capsules medication leaflet

HYCAMTIN 0.25 mg hard capsules

HYCAMTIN 1 mg hard capsules

HYCAMTIN 0.25 mg hard capsules

Each capsule contains 0.25 mg of topotecan (as hydrochloride).

HYCAMTIN 1 mg hard capsules

Each capsule contains 1 mg of topotecan (as hydrochloride).

For the full list of excipients, see section 6.1.

Hard capsule.

HYCAMTIN 0.25 mg hard capsules

The capsules are opaque, white to yellowish white and imprinted with “HYCAMTIN” and “0.25 mg”.

HYCAMTIN 1 mg hard capsules

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 relapsedsmall cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not consideredappropriate (see section 5.1).

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

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

Initial dose

The recommended dose of HYCAMTIN capsules is 2.3 mg/m2 body surface area per day administeredfor 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).

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 withother medicinal products (e.g. G-CSF) or to reduce the dose 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 whohave had treatment delayed due to neutropenia, the dose should be reduced by 0.4 mg/m2/day to1.9 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 studies,topotecan was discontinued if the dose needed to be reduced below 1.5 mg/m2/day.

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

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

The recommended monotherapy dose of oral topotecan in patients with small cell lung carcinoma withcreatinine clearance between 30 and 49 ml/min is 1.9 mg/m2/day for five consecutive days. If welltolerated, the dose may be increased to 2.3 mg/m2/day in subsequent cycles (see section 5.2).

Limited data in Korean patients with creatinine clearance less than 50 ml/min suggest a furtherlowering of dose may be required (see section 5.2).

Insufficient data are available to make a recommendation for patients with a creatinine clearance<30 ml/min.

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

Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posologycan be made.

No overall differences in effectiveness were observed between patients aged over 65 years andyounger adult patients. However in the two studies in which both oral and intravenous topotecan wereadministered, patients over 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).

− Severe hypersensitivity to the active substance or to any of the excipients.− Breast-feeding (see section 4.6).− Severe bone marrow depression prior to starting first course, as evidenced by baselineneutrophils <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 determinedregularly (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 treatedwith topotecan (see section 4.8).

Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis havebeen reported in clinical studies with topotecan. In patients presenting with fever, neutropenia and acompatible 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 beenfatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer,thoracic exposure to radiation and use of pneumotoxic substances and/or colony stimulating factors.

Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoeaand/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 withclinically relevant thrombocytopenia. This should be taken into account when prescribing

HYCAMTIN, e.g. if patients at increased risk of tumour bleeds are considered for therapy.

As would be expected, patients with poor performance status (PS >1) have a lower response rate andan increased incidence of complications such as fever, infection and sepsis (see section 4.8). Accurateassessment of performance status at the time therapy is given is important, to ensure that patients havenot deteriorated to PS 3.

Topotecan is partly eliminated via renal excretion and renal impairment might lead to increasedexposure to topotecan. Dosing recommendations for patients receiving oral topotecan with creatinineclearance less than 30 ml/min have not been established. Use of topotecan in these patients is notrecommended (see section 4.2).

A small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/dl) weregiven intravenous topotecan at 1.5 mg/m2/day for five days every three weeks. A reduction intopotecan clearance was observed. However, there are insufficient data available to make a doserecommendation for this patient group. There is insufficient experience of the use of topotecan inpatients with severely impaired hepatic function (serum bilirubin ≥10 mg/dl). Use of topotecan inthese patients is not recommended (see section 4.2).

Diarrhoea, including severe diarrhoea requiring hospitalisation, has been reported during treatmentwith oral topotecan. Diarrhoea related to oral topotecan can occur at the same time as drug-relatedneutropenia and its sequelae. Communication with patients prior to drug administration regardingthese side effects and proactive management of early and all signs and symptoms of diarrhoea isimportant. Cancer treatment-induced diarrhoea (CTID) is associated with significant morbidity andmay be life-threatening. Should diarrhoea occur during treatment with oral topotecan, physicians areadvised to aggressively manage diarrhoea. Clinical guidelines describing the aggressive managementof CTID include specific recommendations on patient communication and awareness, recognition ofearly warning signs, use of anti-diarrhoeals and antibiotics, changes in fluid intake and diet, and needfor hospitalisation (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 altergastrointestinal 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 a population study using theintravenous route, the co-administration of granisetron, ondansetron, morphine or corticosteroids didnot appear to have a significant effect on the pharmacokinetics of total topotecan (active and inactiveform).

Topotecan is a substrate for both ABCB1 (P-glycoprotein) and ABCG2 (BCRP). Inhibitors of ABCB1and 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 oraltopotecan increased topotecan AUC to approximately 2-2.5-fold of control.

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

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

The pharmacokinetics of topotecan were generally unchanged when co-administered with ranitidine.

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 andtherefore women of childbearing potential should be advised to avoid becoming pregnant duringtherapy with topotecan.

As with all cytotoxic chemotherapy, patients being treated with topotecan must be advised that they ortheir partner must use an effective method of contraception.

Women of childbearing potential should use effective contraceptive measures while beingtreated with topotecan and for 6 months following completion of treatment.

Men are recommended to use effective contraceptive measures and to not father a child whilereceiving topotecan and for 3 months following completion of treatment.

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

Topotecan is contraindicated during breast-feeding (see section 4.3). Although it is not known whethertopotecan is excreted in human breast milk, breast-feeding should be discontinued at the start oftherapy.

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

No studies of 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 studies involving patients with relapsed small cell lung cancer, the dose-limiting toxicity oforal 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 presentedare 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 (cannotbe estimated from the available data).

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

Very common Infection

Common Sepsis1

Very common Febrile neutropenia, neutropenia (see “Gastrointestinal disorders”),thrombocytopenia, anaemia, leucopenia

Common Pancytopenia

Not known Severe bleeding (associated with thrombocytopenia)

Common Hypersensitivity reaction including rash

Rare Anaphylactic reaction, angioedema, urticaria

Very common Anorexia (which may be severe)

Rare Interstitial lung disease (some cases have been fatal)

Very common Nausea, vomiting and diarrhoea (all of which may be severe), which may leadto dehydration (see sections 4.2 and 4.4)

Common Abdominal pain2, constipation, mucositis, dyspepsia

Not known Gastrointestinal perforation

Common Hyperbilirubinaemia

Very common Alopecia

Common Pruritus

Very common Fatigue

Common Asthenia, pyrexia, malaise

Not known Mucosal inflammation1 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 acomplication of topotecan-induced neutropenia (see section 4.4)

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

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

Haematological

Severe neutropenia (Grade 4 - neutrophil count <0.5 x 109/l) occurred in 32% of patients in 13% ofcourses. Median time to onset of severe neutropenia was day 12 with a median duration of 7 days. In34% 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%, and4% of patients, respectively. Death due to sepsis occurred in 1% of patients. Pancytopenia has beenreported. Growth factors were administered to 19% of patients in 8% of courses.

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. In18% 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 sequelaeassociated with thrombocytopenia including fatalities due to tumour bleeds have been infrequent.

Moderate to severe anaemia (Grade 3 and 4 - Hb ≤8.0 g/dl) occurred in 25% of patients (12% ofcourses). Median time to onset of moderate to severe anaemia was day 12 with a median duration of7 days. In 46% of courses with moderate to severe anaemia, the duration was >7 days. Red blood celltransfusions 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 associatedcausality. For severe cases (CTC Grade 3/4) reported as related/possibly related to topotecanadministration 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 tothose less than 65 years of age (19%).

Complete alopecia related/possibly related to topotecan administration was observed in 9% of patientsand 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. Loperamidewas administered to 13% of patients in 5% of courses. The median time to onset of Grade 2 or worsediarrhoea was 9 days.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdoses have been reported in patients being treated with topotecan capsules (up to 5 fold of therecommended dose) and intravenous topotecan (up to 10 fold of the recommended dose). The signsand symptoms observed following overdose were consistent with the known undesirable eventsassociated with topotecan (see section 4.8). The primary complications of overdose are bone marrowsuppression and mucositis. In addition, elevated hepatic enzymes have been reported with intravenoustopotecan overdose.

There is no known antidote for topotecan overdose. Further management should be as clinicallyindicated or as recommended by the national poisons centre, where available.

Pharmacotherapeutic group: antineoplastic agents, plant alkaloids and other natural products, ATCcode: L01CE01.

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

Relapsed SCLC

A Phase III study (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 toprogression [TTP] from first-line therapy: 84 days for oral topotecan plus BSC, 90 days for BSCalone) and for whom re-treatment with intravenous chemotherapy was not considered appropriate. Inthe oral topotecan plus BSC group there was a statistically significant improvement in overall survivalcompared with the BSC alone group (Log-rank p = 0.0104). The unadjusted hazard ratio for the oraltopotecan plus BSC group relative to the BSC alone group was 0.64 (95% CI: 0.45, 0.90). Mediansurvival in patients treated with oral topotecan plus BSC was 25.9 weeks (95% CI: 18.3, 31.6)compared to 13.9 weeks (95% CI: 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 forsymptom benefit for oral topotecan plus BSC.

One Phase II study (Study 065) and one Phase III study (Study 396) were conducted to evaluate theefficacy of oral topotecan versus intravenous topotecan in patients who had relapsed ≥90 days aftercompletion of one prior regimen of chemotherapy (see Table 1). Oral and intravenous topotecan wereassociated 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 patientstreated with oral or intravenous topotecan

Study 065 Study 396

Oral Intravenous Oral Intravenoustopotecan topotecan topotecan topotecan(N = 52) (N = 54) (N = 153) (N = 151)

Median survival (weeks) 32.3 25.1 33.0 35.0(95% CI) (26.3, 40.9) (21.1, 33.0) (29.1, 42.4) (31.0, 37.1)

Hazard ratio (95% CI) 0.88 (0.59, 1.31) 0.88 (0.7, 1.11)

Response rate (%) 23.1 14.8 18.3 21.9(95% CI) (11.6, 34.5) (5.3, 24.3) (12.2, 24.4) (15.3, 28.5)

Difference in response 8.3 (-6.6, 23.1) -3.6 (-12.6, 5.5)rate (95% CI)

Median time to 14.9 13.1 11.9 14.6progression (weeks)(95% CI) (8.3, 21.3) (11.6, 18.3) (9.7, 14.1) (13.3, 18.9)

Hazard ratio (95% CI) 0.90 (0.60, 1.35) 1.21 (0.96, 1.53)

N = total number of patients treated

CI = confidence interval

The 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 patientsfollowing doses of 1.2 to 3.1 mg/m2/day and 4 mg/m2/day administered daily for 5 days. Thebioavailability of oral topotecan (total and lactone) in humans is approximately 40%. Plasmaconcentrations of total topotecan (i.e. lactone and carboxylate forms) and topotecan lactone (activemoiety) peak at approximately 2.0 hours and 1.5 hours, respectively, and decline bi-exponentially withmean terminal half-life of approximately 3.0 to 6.0 hours. Total exposure (AUC) increasesapproximately proportionally with dose. There is little or no accumulation of topotecan with repeateddaily dosing and there is no evidence of a change in pharmacokinetics after multiple doses. Preclinicalstudies indicate plasma protein binding of topotecan is low (35%) and distribution between blood cellsand plasma was fairly homogeneous.

A major route of clearance of topotecan is by hydrolysis of the lactone ring to form the ring-openedcarboxylate. Other than hydrolysis, topotecan is cleared predominantly renally, with a minorcomponent metabolised to the N-desmethyl metabolite (SB-209780) identified in plasma, urine andfaeces.

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 and2% was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecanaccounted 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-relatedmaterial accounted for in the urine and faeces. O-glucuronides of both topotecan and N-desmethyltopotecan have been identified in the urine. The mean metabolite: parent plasma AUC ratio was lessthan 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 enzymesdihydropyrimidine or xanthine oxidase.

Following co-administration of the ABCB1 (P-gp) and ABCG2 (BCRP) inhibitor, elacridar(GF120918) at 100 to 1000 mg with oral topotecan, the AUC0-∞ of topotecan lactone and totaltopotecan 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 topotecanincreased the dose normalised AUC0-24h of topotecan lactone and total topotecan approximately2.0- and 2.5-fold, respectively (see section 4.5).

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

The pharmacokinetics of oral topotecan have not been studied in patients with hepatic impairment (seesection 4.2 and 4.4).

Results of a cross-study analysis suggest that the exposure to topotecan lactone, the active moietyfollowing topotecan administration, increases with decreased renal function. Geometric meantopotecan lactone dose-normalised AUC(0-∞) values were 9.4, 11.1 and 12.0 ng*h/ml in subjects withcreatinine clearance values of more than 80 ml/min, 50 to 80 ml/min and 30 to 49 ml/min,respectively. In this analysis, creatinine clearance was calculated using the Cockcroft-Gault method.

Similar results were obtained if glomerular filtration rate (ml/min) was estimated using the MDRDformula corrected for body weight. Patients with creatinine clearance >60 ml/min have been includedin efficacy/safety studies of topotecan. Therefore, use of the normal starting dose in patients with amild decrease in renal function is considered established (see section 4.2).

Korean patients with renal impairment had generally higher exposure than non-Asian patients with thesame degree of renal impairment. The clinical significance of this finding is unclear. Geometric meantopotecan lactone dose-normalised AUC(0-∞) values for Korean patients were 7.9, 12.9 and19.7 ng*h/ml in subjects with creatinine clearance values of more than 80 ml/min, 50 to 80 ml/minand 30 to 49 ml/min, respectively (see section 4.2 and 4.4). There are no data from Asian patients withrenal impairment other than Koreans.

A cross-study analysis in 217 patients with advanced solid tumours indicated that gender did not affectthe pharmacokinetics of HYCAMTIN capsules to a clinically relevant extent.

Resulting from its mechanism of action, topotecan is genotoxic to mammalian cells (mouse lymphomacells and human lymphocytes) in vitro and mouse bone marrow cells in vivo. Topotecan was alsoshown 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.

HYCAMTIN 0.25 mg hard capsules

Hydrogenated vegetable oil

Glyceryl monostearate

Gelatin

Titanium dioxide (E171)

Sealing band

Gelatin

Black ink

Black iron oxide (E172)

Shellac

Anhydrous ethanol - see leaflet for further information

Isopropyl alcohol

Butanol

Concentrated ammonia solution

Potassium hydroxide

HYCAMTIN 1 mg hard capsules

Hydrogenated vegetable oil

Glyceryl monostearate

Gelatin

Titanium dioxide (E171)

Red iron oxide (E172)

Sealing band

Gelatin

Black ink

Black iron oxide (E172)

Shellac

Anhydrous ethanol - see leaflet for further information

Isopropyl alcohol

Butanol

Concentrated ammonia solution

Potassium hydroxide

Not applicable.

3 years.

Store in a refrigerator (2ºC - 8ºC).

Do not freeze.

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

White polyvinyl chloride/polychlorotrifluoroethylene blister sealed with aluminium /

Polyethylenterephtalate (PET)/paper foil lidding. The blisters are sealed with a peel-push childresistant opening feature.

Each blister contains 10 capsules.

HYCAMTIN capsules should not be opened or crushed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sandoz Pharmaceuticals d.d.

Verovškova ulica 571000 Ljubljana

Slovenia

HYCAMTIN 0.25 mg hard capsules

EU/1/96/027/006

HYCAMTIN 1 mg hard capsules

EU/1/96/027/007

Date of first authorisation: 12 November 1996

Date of latest renewal: 20 November 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/