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Astellas Pharma Co. Ltd

5 Waterside, Citywest Business Campus, Naas Road, Dublin 24,
Telephone: +353 1 467 1555
Fax: +353 1 467 1550
Summary of Product Characteristics last updated on medicines.ie: 16/03/2017
SPC Xtandi 40 mg soft capsules

When a pharmaceutical company changes an SPC or PIL, 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 16/03/2017 and displayed until Current
Reasons for adding or updating:
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   09-Mar-2017
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

Section 4.6
The following text has been added:

This medicine may cause harm to the unborn child or potential loss of pregnancy if taken by women who are pregnant (see section 5.3).

It is not known if enzalutamide is present in human milk. Enzalutamide and/or its metabolites are secreted in rat milk (see section 5.3).


Section 5.1
The pharmacotherapeutic group and ATC have now been added:
Pharmacotherapeutic group: anti-androgen, hormone antagonists and related agents, ATC code: L02BB04

Section 5.3
The results from studies performed in pregnant and breastfeeding rats have been added to this section.

Section 10
Date of revision changed to 09 March 2017
Updated on 11/05/2016 and displayed until 16/03/2017
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   01-Apr-2016
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 reflect the revised incidence of seizure following the addition of the data collected during the TERRAIN clinical study.

Section 5.1:
Addition of paragraph outlining the results of the TERRAIN study.

Section 10:
Date of revision changed to 01 April 2016
Updated on 04/12/2015 and displayed until 11/05/2016
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   30-Nov-2015
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 has been revised to include further information on the co-administration of Xtandi with CYP1A2 substrates. A seperate ssection dealing with CYP2C8 and CYP3A4 inducers has also been added.

Section 4.8, table of adverse reactions has been updated to include diarrhoea and thrombocytopaenia with frequency unknown (observed from post-marketing experience).

Section 10, date of revision has been updated to 30 November 2015
Updated on 02/07/2015 and displayed until 04/12/2015
Reasons for adding or 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 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   22-Jun-2015
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
Hepatic impairment
No dose adjustment is necessary for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C, respectively). An increased drug half-life has however been observed in patients with severe hepatic impairment (see section 4.4 and 5.2).


4.4 Special warnings and precautions for use
Severe hepatic impairment
An increased drug half-life has been observed in patients with severe hepatic impairment, possibly related to increased tissue distribution. The clinical relevance of this observation remains unknown. A prolonged time to reach steady state concentrations is however anticipated, and the time to maximum pharmacological effect as well as time for onset and decline of enzyme induction (see section 4.5) may be increased.


5.2 Pharmacokinetic properties
Hepatic impairment
Hepatic impairment did not have a pronounced effect on the total exposure to enzalutamide or its active metabolite. Drug half-life was however doubled in patients with severe hepatic impairment compared with healthy controls (10.4 days compared to 4.7 days), possibly related to an increased tissue distribution.
The pharmacokinetics of enzalutamide were examined in subjects with baseline mild (N = 6), moderate (N = 8) or severe (N=8) hepatic impairment (Child Pugh Class A , B or C, respectively) and in 22 matched control subjects with normal hepatic function. Following a single oral 160 mg dose of enzalutamide, the AUC and Cmax for enzalutamide in subjects with mild impairment increased by 5% and 24%, respectively, the AUC and Cmax of enzalutamide in subjects with moderate impairment increased by 29% and decreased by 11%, respectively, and the AUC and Cmax of enzalutamide in subjects with severe impairment increased by 5% and decreased by 41%, respectively, compared to healthy control subjects. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC and Cmax in subjects with mild impairment increased by 14% and 19%, respectively, the AUC and Cmax in subjects with moderate impairment increased by 14% and decreased by 17%, respectively, and the AUC and Cmax in subjects with severe hepatic impairment increased by 34% and decreased by 27%., respectively, compared to healthy control subjects.

The date of revision has been updated to June 2015

Updated on 09/06/2015 and displayed until 02/07/2015
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   27-May-2015
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, the following text has been added:
Hypersensitivity reactions
Hypersensitivity reactions manifested by symptoms including, but not limited to, tongue oedema, lip oedema and pharyngeal oedema have been observed with enzalutamide (see section 4.8).

Section 4.8, the following has been added:
Immune system disorders                              not known*: tongue oedema, lip oedema, pharyngeal oedema
Gastrointestinal disorders                               not known*: nausea, vomiting
Skin and subcutaneous tissue disorders           not known*: rash

Section 5.1 has been revised to include updated overall survival analysis data.

The date of revision has been updated to May 2015

Updated on 27/04/2015 and displayed until 09/06/2015
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   20-Apr-2015
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:
The following text has been added
Posterior reversible encephalopathy syndromeThere have been rare reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving Xtandi (see section 4.8). PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizure, headache, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of Xtandi in patients who develop PRES is recommended.

Section 4.8:
The following has been added

Rare cases of posterior reversible encephalopathy syndrome have been reported in enzalutamide-treated patients (see section 4.4).

Nervous system disorders

very common: headache

common: memory impairment, amnesia,

disturbance in attention, restless legs syndrome

uncommon: cognitive disorder, seizure

not known*: posterior reversibile encephalopathy syndrome

Section 10:
The date of revision has been updated to April 2015

Updated on 03/02/2015 and displayed until 27/04/2015
Reasons for adding or updating:
  • 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 4.8 - Undesirable effects
  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   16-Jan-2015
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 updated to include the following:
Androgen deprivation therapy may prolong the QT interval
In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Xtandi.

Section 4.5 updated to include the following:
Medicinal products which prolong the QT interval
Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Xtandi with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

Section 4.8 updated to include the following:
Cardiac disorders not known**: QT-prolongation (see sections 4.4 and 4.5)

Section 6.3:
Shelf life extended to 3 years

Section 10:
Date of revision of text updated to January 2015
Updated on 09/12/2014 and displayed until 03/02/2015
Reasons for adding or updating:
  • Change to section 4.1 - Therapeutic indications
  • 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 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   28-Nov-2014
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



There are updates throughout the SPC with the following sections implicated:

Section 4.1 Therapeutic indications

Addition of new indication for the treatment of adult men with metastatic castration-resistant prostate cancer who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated (see section 5.1)

Section 4.2 Posology

Added: Medical castration with an LHRH analogue should be continued during treatment of patients not surgically castrated.

Section on Paediatric population updated

4.8 Undesirable effects

Updates throughout this section resulting from new data. Updated information on risk of seizure.

5.1 Pharmacodynamic properties

Clinical efficacy and safety

Information on the Prevail study added.

Added:

Older people: Of the 1671 patients in the phase 3 trials who received enzalutamide, 1261 patients (75%) were 65 years and over and 516 patients (31%) were 75 years and over. No overall differences in safety or effectiveness were observed between these older patients and younger patients.

10. Date of Revision of the Text

Changed to November 2014
Updated on 25/11/2014 and displayed until 09/12/2014
Reasons for adding or updating:
  • Addition of black triangle
Date of revision of text on the SPC:   17-Sep-2014
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

N/A
Updated on 07/10/2014 and displayed until 25/11/2014
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
Date of revision of text on the SPC:   17-Sep-2014
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

4.8 Undesirable effects

Musculoskeletal and connective tissue disorders:
common: fractures*
not known**: myalgia, muscle spasms, muscular weakness, back pain

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 via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.
Updated on 21/02/2014 and displayed until 07/10/2014
Reasons for adding or updating:
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
Date of revision of text on the SPC:   21-Jun-2013
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company








Reporting of  suspected adverse reactions

Reporting of suspected adverse reactions after authorisation of the medicinal products 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 via,

IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

Updated on 17/12/2013 and displayed until 21/02/2014
Reasons for adding or updating:
  • New SPC for new product
Date of revision of text on the SPC:  
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

None provided

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Active Ingredients

 
   enzalutamide