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Shire Pharmaceuticals Ireland Limited

5 Riverwalk, Citywest Business Campus, Dublin 24, Ireland,
Telephone: +353 1 429 7700
Fax: +353 1 429 7701
Medical Information Direct Line: 1 800 818 016
Medical Information e-mail: medinfoemea@shire.com
Customer Care direct line: +44 (0)1256 894 107
Summary of Product Characteristics last updated on medicines.ie: 14/07/2017
SPC Xagrid 0.5mg hard capsule

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 14/07/2017 and displayed until Current
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   21-Jun-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

4.4 (special warnings and precautions for use) - addition of Pulmonary hypertension

4.8 (undesirable effects) - re-classification of ‘Pulmonary Hypertension’ from “rare” to “uncommon”
Updated on 17/05/2017 and displayed until 14/07/2017
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 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   11-May-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Section 4.4:

Platelets

The platelet count will increase within 4 days of stopping treatment with anagrelide and will return to pre-treatment levels within 10 to 14 days, possibly rebounding above baseline values. Therefore platelets should be monitored frequently..

Section 4.5

Effects of other active substances on anagrelide

·               In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the pharmacokinetic properties of anagrelide. 

CYP1A2 inhibitors

·               Anagrelide is primarily metabolised by CYP1A2. It is known that CYP1A2 is inhibited by several medicinal products, including fluvoxamine and enoxacin, and such medicinal products could theoretically adversely influence the clearance of anagrelide.

·                  In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the pharmacokinetic properties of anagrelide.

CYP1A2 inducers

·         CYP1A2 inducers (such as omeprazole) could decrease the exposure of anagrelide increasing its main active metabolite. The consequences on the safety and efficacy profile of anagrelide are not established. Therefore, clinical and biological monitoring is recommended in patients taking concomitant CYP1A2 inducers. If needed, anagrelide dose adjustment could be made.

Section 5.1

Mechanism of action

The precisespecific mechanism of action by which anagrelide reduces blood platelet count is  not yet fully understood although it has been confirmed that anagrelide is platelet selective from in vitro and in vivo study informationunknown. In cell culture studies, anagrelide suppressed expression of transcription factors including GATA-1 and FOG-1 required for megakaryocytopoiesis, ultimately leading to reduced platelet production.

 and a corresponding update to Section 10

Updated on 07/05/2015 and displayed until 17/05/2017
Reasons for adding or updating:
  • Change to section 4.6 - Pregnancy and lactation
  • 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:   23-Apr-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Update of section 4.6 of the SmPC with new information regarding breast-feeding and fertility.
Update of section 5.3 of the SmPC based on new non-clinical data.
Update of section 10. Date of revision of the text to April 2015.
In addition, Shire took the opportunity to make editorial changes in the SmPC and to update the contact details of the local representatives in the Package Leaflet.

Updated on 24/11/2014 and displayed until 07/05/2015
Reasons for adding or updating:
  • Change to paediatric information
  • 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 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.1 - List of excipients
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   07-Nov-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



The following sections have been updated to include new information on use in the paediatric population in line with the completed Paediatric Investigation Plan (PIP).  See the relevant ‘Paediatric population’ sub-section under  -  

 

4.2 Posology and method of administration

4.4 Special warnings and precautions for use

4.8 Undesirable effects

5.1 Pharmacodynamic properties

5.2 Pharmacokinetic properties

 

Other

 

4.4 Special warnings and precautions for use – update regarding monitoring for evidence of cardiovascular effects.

 

Minor text updates in line with the latest version of the Quality Review Document (QRD) template throughout the SmPC.

 

Updated on 31/07/2014 and displayed until 24/11/2014
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.2 - Pharmacokinetic properties
Date of revision of text on the SPC:   18-Jul-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Section 4.4 has been updated with the following statement:
Use of concomitant anagrelide and acetylsalicylic acid has been associated with major haemorrhagic events (see section 4.5).

Section 5.2 has been updated with the appropriate QRD sub-headings.
Updated on 04/12/2013 and displayed until 31/07/2014
Reasons for adding or updating:
  • Addition of black triangle
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
Date of revision of text on the SPC:   21-Nov-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



In line with QRD9 addition of Black Triangle and associated text.
In section 4.2 (Posology and method of administration) and 5.2 (Pharmacokinetic properties), QRD9 template update to wording re the elderly.
In section 4.4 (Special warnings and precautions for use), updates to Monitoring and Cardiovascular subsections following the results of a thorough QT/QTc study.
In section 4.5 (Interactions), reference to omeprozole replaced with enoxacin.
In section 4.8 (Undesirable effects) addition of torsade de pointes, in line with updates in section 4.4. QRD9 updates regarding reporting of suspected adverse events.
In Section 5.1 (Pharmacodynamic properties), new section added as result of the QT/QTc study.

Updated on 03/06/2013 and displayed until 04/12/2013
Reasons for adding or updating:
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.3 - Contraindications
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   16-May-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



QRD 8.2 amendments as follows:
In section 2, Excipients header changed to Excipient(s) with known effect.
In section 4.3 crossreference to section 6.1 added
In section 5.1, 'm' added to SmPC
In section 9 - reference to month changed from numbers to letters ie November
In section 10 - revision date amended.

Updated on 23/01/2013 and displayed until 03/06/2013
Reasons for adding or updating:
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic 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:   14-Jan-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company


  • Changes to SmPC:
  • QRD version 8 template changes.
  • Section 4.2 (Posology and method of administration), Paediatric population, Renal and Hepatic impairment sections re-worded.
  • Section 4.4 (Special warnings and precautions for use, cardiovascular), updated with serious cardiac side effects added from section 4.8 Please notification form for more details.
  • Section 4.5 (Interaction with other medicinal products and other forms of interaction), paediatric population added to this section.
  • Section 4.6 (Fertility, pregnancy and lactation), section re-worded.
  • Section 4.8 (Undesirable effects), section reformatted and two new terms added to Respiratory SOC “Pneumonitis and Interstitial Lung Disease”, these are used in addition/interchangeably to allergic alveolitis.
  • Section 4.9 (Overdose), has been re-ordered.
Updated on 18/05/2011 and displayed until 23/01/2013
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Date of revision of text on the SPC:   01-May-2011
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



Section 4.5 …..

 

Drug interactions: effects of anagrelide on other substances

·               Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction with other co-administered medicinal products sharing that clearance mechanism e.g. theophylline.

·               Anagrelide is an inhibitor of PDE III. The effects of medicinal products with similar properties such as the inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be exacerbated by anagrelide.

·               In vivo interaction studies in humans have demonstrated that anagrelide does not affect the pharmacokinetic properties of digoxin or warfarin.

·               At the doses recommended for use in the treatment of essential thrombocythaemia, anagrelide may theoretically potentiate the effects of other medicinal products that inhibit or modify platelet function e.g. acetylsalicylic acid.

·               A clinical interaction study performed in healthy subjects showed that co-administration of repeat-dose anagrelide 1 mg once daily and acetylsalicylic acid 75 mg once daily may enhance the anti-platelet aggregation effects of each drug compared with administration of acetylsalicylic acid alone. In some ET patients concomitantly treated by acetylsalicylic acid and anagrelide, major haemorrhages occurred. Therefore, due to the lack of data in ET patients, the potential risks of the concomitant use of anagrelide with acetylsalicylic acid should be assessed, particularly in patients with a high risk profile for haemorrhage before treatment is initiated.

·               Anagrelide may cause intestinal disturbance in some patients and compromise the absorption of hormonal oral contraceptives.

Food interactions

·               Food delays the absorption of anagrelide, but does not significantly alter systemic exposure.

·The effects of food on bioavailability are not considered clinically relevant to the use of anagrelide.

...........

 

Updated on 07/12/2010 and displayed until 18/05/2011
Reasons for adding or updating:
  • 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:   26-Nov-2010
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 Undesirable Effects: was amended to add ' Tubulointerstitial nephritis' to the subsection, 'Renal and urinary disorders'. The incidence rate is not known.

Section 10 Date of Revision of the Text: was amended to reflect the approval date of 11/10.

Updated on 27/05/2010 and displayed until 07/12/2010
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:   01-May-2010
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



4.4        Special warnings and special precautions for use

 

...

 

GeneralMonitoring

Therapy requires close clinical supervision of the patient which will include a full blood count (haemoglobin and white blood cell and platelet counts), and assessment of liver function (ALT and AST) and renal function (serum creatinine and urea) tests.

...

4.8    Undesirable effects

 

Hepatobiliary disorders

Uncommon:      Hepatic enzymes increased

Not known:       Hepatitis




10. DATE OF REVISION OF THE TEXT

 

04/201005/2010

 

 

Updated on 11/05/2010 and displayed until 27/05/2010
Reasons for adding or updating:
  • Change to section 6.3 - Shelf life
Date of revision of text on the SPC:   20-Apr-2010
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

In section 6.3, the shelf-life has been changed from 3 to 4 years.
Updated on 01/12/2009 and displayed until 11/05/2010
Reasons for adding or updating:
  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4 - Clinical particulars
  • Change to section 5 - Pharmacological properties
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   30-Oct-2009
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

Renewal. EC Decision 30-Oct-2009. Administrative updates to Annex I (SmPC) and Annex III (Labelling and Package Leaflet) in line with comments from QRD during renewal assessment.
Updated on 09/03/2009 and displayed until 01/12/2009
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to MA holder contact details
Date of revision of text on the SPC:   02/2009
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Due to clinical trial publication, interactions with aspirin updated. Also new address details for contacts.
Updated on 10/12/2008 and displayed until 09/03/2009
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 5.2 - Pharmacokinetic properties
Date of revision of text on the SPC:   11/2008
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Section 4.2
Elderly
 
Delete: No specific pharmacokinetic studies have been conducted in this patient population.
Add: The observed pharmacokinetic differences between elderly and young patients with ET (see section5.2) do not warrant using a different starting regimen or different dose titration step to achieve an individual patient-optimised anagrelide regimen.
 
Section 5.2
Add
Elderly: Pharmacokinetic data from fasting elderly patients with ET (age range 65-75 years) compared tofasting adult patients (age range 22-50 years) indicate that the Cmax and AUC of anagrelide were 36% and 61% higher respectively in elderly patients, but that the Cmax and AUC of the active metabolite, 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline, were 42% and 37% lower respectively in the elderly patients. These differences were likely to be caused by lower presystemic metabolism of anagrelide to 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline in the elderly patients.
 
Updated on 18/02/2008 and displayed until 10/12/2008
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.3 - Preclinical safety data
Date of revision of text on the SPC:   01/2008
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Section 4.2 Posology and method of administration:  QRD statement re use in children and adolescents added.
Section 5.1 Pharmacodynamic properties:  Full ATC code included
Section 5.3 Preclinical safety data:  Mutagenic and carcinogenic potential section updated with the findings from a 2 year carcinogenicity study.
Updated on 02/04/2007 and displayed until 18/02/2008
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Correction of spelling/typing errors
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   03/2007
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Section 4.4:  Addition of lactose warning statement
Section 4.8:  Addition of 'allergic alveolitis'
Minor typographical/spelling corrections throughout text
Section 10:  Date of revision updated to 28 March 2007
Updated on 16/08/2006 and displayed until 02/04/2007
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
Date of revision of text on the SPC:   08/2006
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Section 4.2:  Posology and method of administration:  deletion of last two sentences under the Renal Impairment subheading concerning dose titration and administration to patients with mild to severe renal impairment
 
Section 4.8:   Undesirable effects:  Addition of 'pulmonary hypertension' and 'hepatic enzymes increased'.  Correction to placing of 'migraine' so that it is under 'Nervous system disorders'
 
Section 4.9:  Update to overdose statement
 
Section 5.1:  Deletion of 'Proposed' in relation to ATC code
Updated on 09/03/2006 and displayed until 16/08/2006
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
Updated on 25/11/2005 and displayed until 09/03/2006
Reasons for adding or updating:
  • Change to section 4.3 - Contraindications
  • Change to section 5.2 - Pharmacokinetic properties
Updated on 29/09/2005 and displayed until 25/11/2005
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
Updated on 01/07/2005 and displayed until 29/09/2005
Reasons for adding or updating:
  • Correction of spelling/typing errors
Updated on 04/03/2005 and displayed until 01/07/2005
Reasons for adding or updating:
  • New SPC for new product

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Active Ingredients

 
   Anagrelide hydrochloride