HYCAMTIN 0.25 mg and 1 mg hard capsules

  • Name:

    HYCAMTIN 0.25 mg and 1 mg hard capsules

  • Company:
    info
  • Active Ingredients:

    Topotecan Hydrochloride

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 05/11/18

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Summary of Product Characteristics last updated on medicines.ie: 28/3/2019

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Novartis Ireland Limited

Novartis Ireland Limited

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 28 March 2019 SmPC

Reasons for updating

  • File format updated to PDF

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 5 November 2018 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder

Updated on 21 May 2018 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 25 January 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 25 January 2018 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision
  • Improved presentation of PIL

Updated on 21 December 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 21 December 2017 SmPC

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 8 - Marketing authorisation number(s)
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text
  • Change from individual to joint SPC

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.8 updated to add 2 new identified ADRs: GI perforation and mucosal inflammation which have been identified for Hycamtin in the post-marketing experience.
Section 6.6 updated to remove the sentence "liquid waste may be flushed with large amounts of water".
Additional changes made to bring the SmPC in line with the QRD template.
Both SmPCs were previously individual but these have now been combined into one joint SmPC and approved by EMA.

Updated on 11 October 2017 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 25 May 2016 PIL

Reasons for updating

  • Change to marketing authorisation holder

Updated on 16 November 2015 PIL

Reasons for updating

  • Previous version of PIL reinstated

Updated on 2 June 2015 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

7.       MARKETING AUTHORISATION HOLDER

Updated on 7 October 2014 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text
  • Change to section 4.9 - Overdose
  • Transfer of marketing authorisation holder

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.4 – minor typographical correction
Section 4.8 – updated Ireland ADR reporting contact details

Section 4.9 – updated with new overdose information

Updated on 6 October 2014 PIL

Reasons for updating

  • Change to date of revision
  • Addition of information on reporting a side effect.
  • Transfer of Marketing Authorisation Holder

Updated on 6 January 2014 PIL

Reasons for updating

  • Change to side-effects

Updated on 23 December 2013 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Addition of the following to section 4.2 Posology and method of administration

 

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 Clcr less than 60 ml/min have not been established (see section 4.4).

The recommended monotherapy dose of oral topotecan in patients with small cell lung carcinoma with a creatinine clearance between 30 and 49 ml/min is 1.9 mg/m2/day for five consecutive days. If well tolerated, 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 further lowering 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.

 

 

Update to the following information in section 4.4 Special warnings and precautions for use

 

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 creatinine clearance Clcr less than 6030 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.

 

Addition of the following to section 4.8 Undesirable effects:

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions preferably through the online reporting option accessible from the IMB homepage.  A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’. Alternatively, the traditional post-paid ‘yellow card’ option may also continue to be used.

 

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

 

 

Addition of the following information to 5.2 Pharmacokinetic properties

 

Results of a cross-study analysis suggest that the exposure to topotecan lactone, the active moiety following topotecan administration, increases at decreased renal functionGeometric mean topotecan lactone dose-normalized AUC(0-¥) values were 9.4, 11.1 and 12.0 ng*h/mL in subjects with creatinine 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 MDRD formula corrected for body weight. Patients with creatinine clearance >60 ml/min have been included in efficacy/safety studies of topotecan. Therefore, use of the normal starting dose in patients with a mild 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 the same degree of renal impairment.  The clinical significance of this finding is unclear.  Geometric mean topotecan lactone dose-normalized AUC(0-¥) values for Korean patients  were 7.9, 12.9 and 19.7 ng*h/mL in subjects with creatinine clearance values of more than 80 mL/min, 50 to 80 mL/min and 30 to 49 mL/min, respectively (see section 4.2 and 4.4).  There are no data from Asian patients with renal impairment other than Koreans.

 

 

 

 

 

 

 

Updated on 16 December 2013 PIL

Reasons for updating

  • Change to side-effects

Updated on 30 August 2013 PIL

Reasons for updating

  • Change of distributor details

Updated on 7 February 2011 PIL

Reasons for updating

  • Change to side-effects

Updated on 21 October 2010 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

 

 

4.2     Posology and method of administration

 

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 5five consecutive days with a 3three week interval between the start of each course. If well tolerated, treatment may continue until disease progression (see sections 4.8 and 5.1).

 

 

 

If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 x 109/l) for 7seven 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).

 

 

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 intravenous electrolytes and fluids, and interruption of topotecan therapy (see sections 4.4 and 4.8).

 

Paediatrics population

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

 

 

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.

 

 

Blood and lymphatic system disorders

 

 

Very common: febrile neutropenia, neutropenia (see Gastrointestinal disorders), thrombocytopenia, anaemia, leucopenia.

 

 

Common: pancytopenia

Not known: severe bleeding (associated with thrombocytopenia)

 

 

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

Rare: interstitial lung disease (some cases have been fatal)

 

 

 

 

 

Gastrointestinal disorders

 

 

Very common: Nnausea, vomiting and diarrhoea (all of which may be severe), which may lead to dehydration (see sections 4.2 and 4.4)

 

 

Common: abdominal pain1*, constipation, stomatitis,mucositis, dyspepsia

 

 

1*Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a

complication of topotecan-induced neutropenia (see section 4.4).

 

 

 

 

 

Skin and subcutaneous tissue disorders

 

 

Very common: alopecia.

 

 

Common: pruritis

 

 

 

 

 

Metabolism and nutrition disorders

 

 

Very common: anorexia (which may be severe).

 

 

 

 

 

Infections and infestations

 

 

Very common: infection

 

 

Common: sepsis2

2Fatalities due to sepsis have been reported in patients treated with topotecan (see section 4.4)

 

 

 

 

 

General disorders and administration site conditions

 

 

Very common: fatigue.

 

 

Common : asthenia, pyrexia, malaise.

 

 

 

 

 

Immune system disorders

 

 

Common: hypersensitivity reaction including rash

 

 

Not known: anaphylactic reaction, angioedema, urticaria.

 

 

 

 

 

Hepato-biliary disorders

 

 

Uncommon: hyperbilirubinaemia.

 

 

 

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/.

 

 

Updated on 9 April 2010 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 7.0 change in MAH name only from ‘SmithKline Beecham Plc’ to ‘SmithKline Beecham Limited’

 

Section 10.0 from dec 2008 to jan 2010

Updated on 29 January 2010 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

- Section 4.2, capsules - 'Topotecan' replaced with 'Hycamtin'

- Section 4.3, all formulations - 'less than or equal to' replaced with 'less than'

- Section 6.5, capsules - child resistant blister details added

Updated on 14 May 2009 PIL

Reasons for updating

  • Change to dosage and administration
  • Change to appearance of the medicine
  • Change to warnings or special precautions for use
  • Change to packaging
  • Change to side-effects

Updated on 21 January 2009 SmPC

Reasons for updating

  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 6.5 - Nature and contents of container
  • Change to section 4.3 - Contraindications

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

SPC amendments:

Section 3 - powder colour;

Section 4.2 - removal of GCSF;  addition of diarrhoea (oral only);

- Section 4.2, capsules - 'Topotecan' replaced with 'Hycamtin'

- Section 4.3, all formulations - 'less than or equal to' replaced with 'less than'

Section 4.4 - addition of Interstitial Lung Disease (ILD); Section4.8 - addition of ILD; Section 6.6 - powder colour; other minor administrative corrections.

- Section 6.5, capsules - child resistant blister details added

Section 6.6 - powder colour; other minor administrative corrections.

 

Updated on 29 October 2008 SmPC

Reasons for updating

  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 12 June 2008 PIL

Reasons for updating

  • New PIL for new product

Updated on 6 June 2008 SmPC

Reasons for updating

  • New SPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 6 June 2008 SmPC

Reasons for updating

  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)