POTACTASOL 4mg powder for concentrate infusion solution medication leaflet

Potactasol 1 mg powder for concentrate for solution for infusion

Potactasol 4 mg powder for concentrate for solution for infusion

Potactasol 1 mg powder for concentrate for solution for infusion

Each vial contains 1 mg topotecan (as hydrochloride).

After reconstitution, 1 ml concentrate contains 1 mg topotecan.

Each vial contains 0.52 mg (0.0225 mmol) sodium.

Potactasol 4 mg powder for concentrate for solution for infusion

Each vial contains 4 mg topotecan (as hydrochloride).

After reconstitution, 1 ml concentrate contains 1 mg topotecan.

Each vial contains 2.07 mg (0.09 mmol) sodium.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

Yellow lyophilisate.

Topotecan monotherapy is indicated for the treatment of:

- patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy

- patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-lineregimen is not considered appropriate (see section 5.1).

Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervixrecurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure tocisplatin require a sustained treatment free interval to justify treatment with the combination (seesection 5.1).

The use of topotecan should be confined to units specialised in the administration of cytotoxicchemotherapy. Topotecan should only be administered under the supervision of a physicianexperienced in the use of chemotherapy (see section 6.6).

When topotecan is used in combination with cisplatin, the full prescribing information for cisplatinshould be consulted.

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 transfusionif necessary).

Ovarian and small cell lung carcinoma

Initial dose

The recommended dose of topotecan is 1.5 mg/m2 body surface area per day administered byintravenous infusion over 30 minutes daily for five consecutive days with a three week intervalbetween the start of each course. If well tolerated, treatment may continue until disease progression(see sections 4.8 and 5.1).

Topotecan should not be re-administered unless the neutrophil count is ≥ 1 x 109/l, the platelet countis ≥ 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 (neutrophilcount < 0.5 x 109/l) for seven days or more, or severe neutropenia associated with fever or infection, orwho have had treatment delayed due to neutropenia, the dose should be reduced by 0.25 mg/m2/day to1.25 mg/m2/day (or subsequently down to 1.0 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 had been reduced to 1.0 mg/m2/day and a further dosereduction was required to manage adverse effects.

Cervical carcinoma

Initial dose

The recommended dose of topotecan is 0.75 mg/m2/day administered as a 30-minute intravenousinfusion on days 1, 2 and 3. Cisplatin is administered as an intravenous infusion on day 1 at a dose of50 mg/m2/day and following the topotecan dose. This treatment schedule is repeated every 21 days forsix courses or until progressive disease.

Topotecan should not be re-administered unless the neutrophil count is ≥ 1.5 x 109/l, the platelet countis ≥ 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 20 % to 0.60 mg/m2/dayfor subsequent courses (or subsequently down to 0.45 mg/m2/day if necessary).

Doses should be similarly reduced if the platelet count falls below 25 x 109/l.

Monotherapy (ovarian and small cell lung carcinoma)

There is insufficient experience with the use of topotecan in patients with severely impaired renalfunction (creatinine clearance <20 ml/min). Use of topotecan in this group of patients is notrecommended (see section 4.4).

Limited data indicate that the dose should be reduced in patients with moderate renal impairment. Therecommended monotherapy dose of topotecan in patients with ovarian or small cell lung carcinomaand a creatinine clearance between 20 and 39 ml/min is 0.75 mg/m2/day for five consecutive days.

Combination therapy (cervical carcinoma)

In clinical studies with topotecan in combination with cisplatin for the treatment of cervical cancer,therapy was only initiated in patients with serum creatinine less than or equal to 1.5 mg/dl. If, duringtopotecan/cisplatin combination therapy serum creatinine exceeds 1.5 mg/dl, it is recommended thatthe full prescribing information be consulted for any advice on cisplatin dose reduction/continuation.

If cisplatin is discontinued, there are insufficient data regarding continuing monotherapy withtopotecan in patients with cervical cancer.

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 (see section 4.4).

There is insufficient experience with the use of topotecan in patients with severely impaired hepaticfunction (serum bilirubin ≥ 10 mg/dl) due to cirrhosis. Topotecan is not recommended to be used inthis 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.

Potactasol is for intravenous infusion after reconstitution and dilution. It must be reconstituted andfurther diluted before use (see section 6.6).

Reconstitution and dilution of the medicinal product must be performed by trained personnel. Thepreparation should be performed in a designated area under aseptic conditions.

Adequate protective disposable gloves, goggles, gown and mask should be worn. Precautions shouldbe taken to avoid the medicinal product accidentally coming into contact with the eyes. In the event ofcontact with the eyes, irrigate with large amounts of water. Then seek medical evaluation by aphysician. In case of skin contact, thoroughly wash the affected area with large amount of water.

Always wash hands after removing gloves. See section 6.6.

Pregnant staff should not handle the cytotoxic preparation.

- Severe hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- 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 topotecan,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.

There is insufficient experience of the use of topotecan in patients with severely impaired renalfunction (creatinine clearance < 20 ml/min) or severely impaired hepatic function (serumbilirubin ≥ 10 mg/dl) due to cirrhosis. Use of topotecan in these patient groups is not recommended(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 (see section 4.2).

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-free’.

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).

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.

When topotecan (0.75 mg/m2/day for 5 consecutive days) and cisplatin (60 mg/m2/day on day 1) wereadministered in 13 patients with ovarian cancer, a slight increase in AUC (12 %, n = 9) and

Cmax (23 %, n = 11) was noted on day 5. This increase is considered unlikely to be of clinicalrelevance.

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 thatthey or their partner must use an effective method of contraception.

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

The safety profile of topotecan when given in combination with cisplatin in the cervical cancer clinicalstudies is consistent with that seen with topotecan monotherapy. The overall haematological toxicity islower in patients treated with topotecan in combination with cisplatin compared to topotecanmonotherapy, 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 eventsassociated 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 notknown (cannot be 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 neutropenianeutropenia (see Gastrointestinal disorders below)thrombocytopeniaanaemialeucopenia

Common: pancytopenia

Not known: severe bleeding (associated with thrombocytopenia)

Common: hypersensitivity reaction including rash

Rare: anaphylactic reactionangioedemaurticaria

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)constipationabdominal pain2mucositis

Not known: gastrointestinal perforation

Common: hyperbilirubinaemia

Very common: alopecia

Common: pruritus

Very common: pyrexiaastheniafatigue

Common: malaise

Very rare: extravasation3

Not known: mucosal inflammation1 Fatalities due to sepsis have been reported in patients treated with topotecan (seesection 4.4)2 Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur asa 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 whohave a poor performance status (see section 4.4).

The frequencies associated with the haematological and non-haematological adverse events listedbelow represent the adverse event reports considered to be related/possibly related to topotecantherapy.

Haematological

Neutropenia: Severe (neutrophil count < 0.5 x 109/l) during course 1 in 55 % of patients, withduration ≥ seven days in 20 % and overall in 77 % of patients (39 % of courses). In association withsevere 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 medianduration 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 thosewho did not develop severe neutropenia), 11 % (4 % of courses) developed fever and 26 % (9 % ofcourses) 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 onsetof severe thrombocytopenia was day 15 and the median duration was five days. Platelet transfusionswere given in 4 % of courses. Reports of significant sequelae associated with thrombocytopeniaincluding 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 celltransfusions 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 % ofpatients.

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

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

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 intravenous topotecan (up to 10 fold ofthe recommended dose) and topotecan capsules (up to 5 fold of the recommended dose). The signs andsymptoms observed following overdose were consistent with the known undesirable events associatedwith topotecan (see section 4.8). The primary complications of overdose are bone marrow suppressionand mucositis. In addition, elevated hepatic enzymes have been reported with intravenous topotecanoverdose.

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 ovarian cancer

In a comparative study of topotecan and paclitaxel in patients previously treated for ovarian carcinomawith platinum based chemotherapy (n = 112 and 114, respectively), the response rate (95 % CI) was20.5 % (13 %, 28 %) versus 14 % (8 %, 20 %) and median time to progression 19 weeks versus15 weeks (hazard ratio 0.7 [0.6, 1.0]), for topotecan and paclitaxel, respectively. Median overallsurvival was 62 weeks for topotecan versus 53 weeks for paclitaxel (hazard ratio 0.9 [0.6, 1.3]).

The response rate in the whole ovarian carcinoma programme (n = 392, all previously treated withcisplatin or cisplatin and paclitaxel) was 16 %. The median time to response in clinical studies was7.6-11.6 weeks. In patients refractory to, or relapsing within 3 months after cisplatin therapy (n = 186),the response rate was 10 %.

These data should be evaluated in the context of the overall safety profile of the medicinal product, inparticular of the significant haematological toxicity (see section 4.8).

A supplementary retrospective analysis was conducted on data from 523 patients with relapsedovarian cancer. Overall, 87 complete and partial responses were observed, with 13 of these occurringduring cycles 5 and 6 and 3 occurring thereafter. Of the patients who received more than 6 cycles oftherapy, 91 % completed the study as planned or were treated until disease progression with only 3 %withdrawn for adverse events.

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 patients treatedwith 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.

In another randomised Phase III study which compared intravenous (IV) topotecan tocyclophosphamide, doxorubicin and vincristine (CAV) in patients with relapsed, sensitive SCLC, theoverall response rate was 24.3 % for topotecan compared to 18.3 % for the CAV group. Median timeto progression was similar in the two groups (13.3 weeks and 12.3 weeks, respectively). Mediansurvivals for the two groups were 25.0 and 24.7 weeks respectively. The hazard ratio for survival with

IV topotecan relative to CAV was 1.04 (95 %, CI 0.78 -1.40).

The response rate to topotecan in the combined small cell lung cancer programme (n = 480) forpatients with relapsed disease sensitive to first-line therapy, was 20.2 %. Median survival was30.3 weeks (95 % CI: 27.6, 33.4).

In a population of patients with refractory SCLC (those not responding to first-line therapy), theresponse rate to topotecan was 4.0 %.

Cervical carcinoma

In a randomised, comparative Phase III study conducted by the Gynecologic Oncology Group (GOG0179), topotecan plus cisplatin (n = 147) was compared with cisplatin alone (n = 146) for the treatmentof histologically confirmed persistent, recurrent or Stage IVB carcinoma of the cervix where curativetreatment with surgery and/or radiation was not considered appropriate. Topotecan plus cisplatin had astatistically significant benefit in overall survival relative to cisplatin monotherapy after adjusting forinterim analyses (Log-rank p = 0.033).

Table 2. Study results Study GOG-0179

ITT population

Cisplatin 50 mg/m2 on day 1, Cisplatin 50 mg/m2 on day 1, +every 21 days Topotecan 0,75 mg/m2 ondays 1-3, every 21 days

Survival (months) (n = 146) (n = 147)

Median (95 % CI) 6.5 (5.8, 8.8) 9.4 (7.9, 11.9)

Hazard ratio (95 % CI) 0.76 (0.59, 0.98)

Log rank p-value 0.033

Patients without prior cisplatin chemoradiotherapy

Cisplatin Topotecan/Cisplatin

Survival (months) (n = 46) (n = 44)

Median (95 % CI) 8.8 (6.4, 11.5) 15.7 (11.9, 17.7)

Hazard ratio (95 % CI) 0.51 (0.31, 0.82)

Patients with prior cisplatin chemoradiotherapy

Cisplatin Topotecan/Cisplatin

Survival (months) (n = 72) (n = 69)

Median (95 % CI) 5.9 (4.7, 8.8) 7.9 (5.5, 10.9)

Hazard ratio (95 % CI) 0.85 (0.59, 1.21)

In patients (n = 39) with recurrence within 180 days after chemoradiotherapy with cisplatin, themedian survival in the topotecan plus cisplatin arm was 4.6 months (95 % CI: 2.6, 6.1) versus4.5 months (95 % CI: 2.9, 9.6) for the cisplatin arm with a hazard ratio of 1.15 (0.59, 2.23). In thosepatients (n = 102) with recurrence after 180 days, median survival in the topotecan plus cisplatin armwas 9.9 months (95 % CI: 7, 12.6) versus 6.3 months (95 % CI: 4.9, 9.5) for the cisplatin arm with ahazard ratio of 0.75 (0.49, 1.16).

Topotecan was also evaluated in the paediatric population; however, only limited data on efficacy andsafety are available.

In an open-label study involving children (n = 108, age range: infant to 16 years) with recurrent orprogressive solid tumours, topotecan was administered at a starting dose of 2.0 mg/m2 given as a30 minute infusion for 5 days repeated every 3 weeks for up to one year depending on response totherapy. Tumour types included were Ewing's sarcoma/primitive neuroectodermal tumour,neuroblastoma, osteoblastoma, and rhabdomyosarcoma. Anti-tumour activity was demonstratedprimarily in patients with neuroblastoma. Toxicities of topotecan in paediatric patients with recurrentand refractory solid tumours were similar to those historically seen in adult patients. In this study,forty-six (43 %) patients received G-CSF over 192 (42.1 %) courses; sixty-five (60 %) receivedtransfusions of packed red blood cells and fifty (46 %) of platelets over 139 and 159 courses (30.5 %and 34.9 %), respectively. Based on the dose-limiting toxicity of myelosuppression, the maximumtolerated dose (MTD) was established at 2.0 mg/m2/day with G-CSF and 1.4 mg/m2/day without

G-CSF in a pharmacokinetic study in paediatric patients with refractory solid tumours (seesection 5.2).

Following intravenous administration of topotecan at doses of 0.5 to 1.5 mg/m2 as a 30 minuteinfusion daily for five days, topotecan demonstrated a high plasma clearance of 62 l/h (SD 22),corresponding to approximately 2/3 of liver blood flow. Topotecan also had a high volume ofdistribution, about 132 l, (SD 57), and a relatively short half-life of 2-3 hours. Comparison ofpharmacokinetic parameters did not suggest any change in pharmacokinetics over the 5 days ofdosing. Area under the curve increased approximately in proportion to the increase in dose. There islittle or no accumulation of topotecan with repeated daily dosing and there is no evidence of a changein the pharmacokinetics after multiple doses. Preclinical studies indicate plasma protein binding oftopotecan is low (35 %) and distribution between blood cells and plasma was fairly homogeneous.

The elimination of topotecan has only been partly investigated in man. A major route of clearance oftopotecan was by hydrolysis of the lactone ring to form the ring-opened carboxylate.

Metabolism accounts for < 10 % of the elimination of topotecan. An N-desmethyl metabolite, whichwas shown to have similar or less activity than the parent in a cell-based assay, was found in urine,plasma, and faeces. The mean metabolite:parent AUC ratio was < 10 % for both total topotecan andtopotecan lactone. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has beenidentified in the urine.

Overall recovery of topotecan-related material following five daily doses of topotecan was 71 to 76 %of the administered IV dose. Approximately 51 % was excreted as total topotecan and 3 % wasexcreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted for18 % while faecal elimination of N-desmethyl topotecan was 1.7 %. Overall, the N-desmethylmetabolite contributed a mean of less than 7 % (range 4-9 %) of the total topotecan-related materialaccounted for in the urine and faeces. The topotecan-O-glucuronide and N-desmethyltopotecan-O-glucuronide in the urine were less than 2.0 %.

In vitro data using human liver microsomes indicate the formation of small amounts of

N-demethylated topotecan. In vitro, topotecan did not inhibit human P450 enzymes CYP1A2,

CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A or CYP4A nor did it inhibit the humancytosolic enzymes dihydropyrimidine or xanthine oxidase.

When given in combination with cisplatin (cisplatin day 1, topotecan days 1 to 5), the clearance oftopotecan was reduced on day 5 compared to day 1 (19.1 l/h/m2 compared to 21.3 l/h/m2 [n = 9]) (seesection 4.5).

Plasma clearance in patients with hepatic impairment (serum bilirubin between 1.5 and 10 mg/dl)decreased to about 67 % when compared with a control group of patients. Topotecan half-life wasincreased by about 30 % but no clear change in volume of distribution was observed. Plasma clearanceof total topotecan (active and inactive form) in patients with hepatic impairment only decreased byabout 10 % compared with the control group of patients.

Plasma clearance in patients with renal impairment (creatinine clearance 41-60 ml/min.) decreased toabout 67 % compared with control patients. Volume of distribution was slightly decreased and thushalf-life only increased by 14 %. In patients with moderate renal impairment topotecan plasmaclearance was reduced to 34 % of the value in control patients. Mean half-life increased from 1.9 hoursto 4.9 hours.

Age/weight

In a population study, a number of factors including age, weight and ascites had no significant effecton clearance of total topotecan (active and inactive form).

The pharmacokinetics of topotecan given as a 30-minute infusion for 5 days were evaluated in twostudies. One study included a dose range of 1.4 to 2.4 mg/m2 in children (aged 2 up to 12 years,n = 18), adolescents (aged 12 up to 16 years, n = 9) and young adults (aged 16 to 21 years, n = 9) withrefractory solid tumours. The second study included a dose range of 2.0 to 5.2 mg/m2 in children(n = 8), adolescents (n = 3) and young adults (n = 3) with leukaemia. In these studies, there were noapparent differences in the pharmacokinetics of topotecan among children, adolescents, and youngadult patients with solid tumours or leukaemia, but data are too limited to draw definite conclusions.

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.

Mannitol (E421)

Tartaric acid (E334)

Sodium hydroxide

Hydrochloric acid (E507)

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Vials4 years.

Reconstituted and diluted solution

Chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C innormal light conditions, and for 24 hours at 2°C to 8°C when protected from light.

Chemical and physical stability of the solution obtained after dilution of the concentrate in sodiumchloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) glucose solution for infusion hasbeen demonstrated for 4 hours at 25 ± 2°C, in normal lighting conditions. The concentrates tested werestored at 25 ± 2°C for 12 hours and 24 hours respectively after reconstitution, and then diluted.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution/dilution has takenplace in controlled and validated aseptic conditions.

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

For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.

Potactasol 1 mg powder for concentrate for solution for infusion

Type I colourless glass vial (5 ml) with grey bromobutylic stopper and aluminium seal with plasticflip-off cap containing 1 mg topotecan.

Potactasol 4 mg powder for concentrate for solution for infusion

Type I colourless glass vial (8 ml), with grey bromobutylic stopper and aluminium seal with plasticflip-off cap containing 4 mg topotecan.

Vials may or may not be sheathed in a protective sleeve.

Potactasol is available in cartons containing 1 vial.

Potactasol 1 mg powder for concentrate for solution for infusion

Potactasol 1 mg vials must be reconstituted with 1.1 ml water for injections. The clear concentrate ispale yellow in colour and provides 1 mg per ml of topotecan, as Potactasol 1 mg contains a 10 %overage of fill.

Further dilution of the appropriate volume of the reconstituted solution with either sodium chloride 9mg/ml (0.9 %) or 5 % w/v glucose is required to give a final concentration of between 25 and50 microgram/ml.

Potactasol 4 mg powder for concentrate for solution for infusion

Potactasol 4 mg vials must be reconstituted with 4 ml water for injections. The clear concentrate ispale yellow in colour and provides 1 mg per ml of topotecan.

Further dilution of the appropriate volume of the reconstituted solution with either sodium chloride 9mg/ml (0.9 %) or 5 % w/v glucose is required to give a final concentration of between 25 and50 microgram/ml.

The normal procedures for proper handling and disposal of anticancer medicinal products should beadopted, namely:

− Personnel should be trained to reconstitute and dilute the the medicinal product.− Pregnant staff should be excluded from working with this medicinal product.− Personnel handling this medicinal product during reconstitution and dilution should wearprotective clothing including mask, goggles and gloves.− Accidental contact with the skin or eyes should be treated immediately with copious amounts ofwater.− All items for administration or cleaning, including gloves, should be placed in high-risk, wastedisposal bags for high-temperature incineration.

Actavis Group PTC ehf.

Reykjavíkurvegi 76-78

IS-220 Hafnarfjörður

Iceland

Potactasol 1 mg powder for concentrate for solution for infusion

EU/1/10/660/001

Potactasol 4 mg powder for concentrate for solution for infusion

EU/1/10/660/002

Date of first authorisation: 6 January 2011

Date of latest renewal: 5 October 2015

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

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