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SANOFI

Citywest Business Campus, Dublin 24, Ireland
Telephone: +353 1 4035600
Fax: +353 1 4035687
Medical Information e-mail: iemedinfo@sanofi.com
Summary of Product Characteristics last updated on medicines.ie: 21/07/2017
SPC Epilim Chrono 500mg Prolonged Release Tablets

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 21/07/2017 and displayed until Current
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   18-Jul-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Type IAIN – C.I.3.A Update the SmPCs (section 4.2) at the request of the HPRA to harmonise the location of the warning related to valproate use in female children, female adolescents, WOCBP and pregnant women to improve the clarity
Updated on 17/07/2017 and displayed until 21/07/2017
Reasons for adding or updating:
  • Improved presentation of SPC
Date of revision of text on the SPC:   01-May-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Upload of improved version
Updated on 05/06/2017 and displayed until 17/07/2017
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
Date of revision of text on the SPC:   17-May-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Type IIC – CCDS v17, 18, 20
Updated on 04/11/2016 and displayed until 05/06/2017
Reasons for adding or updating:
  • Change to section 4.3 - Contraindications
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   28-Oct-2016
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Worksharing procedure for urea cycle disorders
Updated on 12/05/2015 and displayed until 04/11/2016
Reasons for adding or updating:
  • Addition of black triangle
  • 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 4.6 - Pregnancy and lactation
  • 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:   27-Apr-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Black Triangle included.
Section 4.2: new paragraph 'Female children, female adolescents, women of childbearing potential and pregnant women'.
Section 4.3: new paragraph added regarding mitrochondrial disorders.
Section 4.4: new boxed wording titled 'Female children, female adolescents, women of childbearing potential and pregnant women'.
Paragraph title 'Women of childbearing potential' has been removed.
New information on 'Patients with known or suspected mitrochondrial disease' included.
Section 4.6: Majority of section has been updated with new paragraphs title 'Breastfeeding' and 'Fertility' added.
Section 4.8: 'Congenital malformations and development disorders' added.
Updated on 22/12/2014 and displayed until 12/05/2015
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 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   12-Dec-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: updated to include:

Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the greater risk of rhabdomyolysis when taking valproate.


Section 4.5: 4.5.3 updated to include:

Co-administration of valproate and quetiapine may increase the risk of neutropenia/leucopenia.


Section 4.6: 4.6.1 paragraph 'Risks associated with Epilim' updated:

In humans: Available data suggest an increased incidence of minor or major malformations including neural tube defects, craniofacial defects, malformation of the limbs, cardiovascular malformations and multiple anomalies involving various body systems in offspring born to mothers with epilepsy treated with valproate when compared to the incidence for certain other antiepileptic drugs.  Data from a meta-analysis (including registries and cohort studies) has shown an incidence of congenital malformations in children born to epileptic women exposed to valproate monotherapy during pregnancy at 10.73% (95% CI: 8.16 13.29).  Available data indicate dose dependency of this effect. 


'Risks in the neonate' updated:

Very rare cases of haemorrhagic syndrome have been reported in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to decreases in other coagulation factors; afibrinogenemia has also been reported and may be fatal.  These are possibly associated with a decrease of coagulation factors. However, this syndrome has to be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and other anti-epileptic enzyme inducing drugs.

Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.

 

Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during the third trimester of pregnancy.

 

Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.

 

Withdrawal syndrome (such as, in particular, agitation, irritability, hyper-excitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of pregnancy.


Section 4.8: updated as follows:

The following CIOMS frequency rating is used, when applicable:

 

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); not known (cannot be estimated from the available data).

 

Congenital, familial and genetic disorders: (see section 4.6. Fertility, Ppregnancy and Llactation)

 

Hepatobiliary disorders:

Common:  rare cases of liver injury (see section 4.4. Special warnings and precautions for use)

 

Gastrointestinal disorders:

Very common: (nausea,

Common:  vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis. abdominal pain upper, diarrhoea)

 

The above three adverse events frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking Epilim with or after food or by using Enteric Coated Epilim.

 

Uncommon:  Very rare cases of pancreatitis, sometimes lethal, have been reported (see section 4.4 Special Warnings and Special Precautions for Use).

 

Nervous system disorders:

 

Very common: tremor

Common: extrapyramidal disorder, stupor*, somnolence, convulsion*, memory impairment, headache, nystagmus,

Uncommon: coma*, encephalopathy, lethargy* (see below), reversible parkinsonism, ataxia, paresthesia.

Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorder.

 

Sedation has been reported occasionally, usually when in combination with other anticonvulsants. In monotherapy it occurred early in treatment on rare occasions and is usually transient. 

 

*Rare cases of lethargy and confusion, occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have very rarely been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation or concomitant use of other anticonvulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.  Extrapyramidal disorders.

 

Very rare cases of reversible dementia associated with reversible cerebral atrophy have been reported.

Ataxia and transient and/or dose related fine postural tremor have occasionally been reported.

 

Extrapyramidal disorder which may not be reversible, including reversible Parkinsonism.

 

Cognitive disorders.

 

An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural disorders have been reported.

 

Cases of isolated and moderate hyperammonaemia without change in liver function may occur frequently and should not cause treatment discontinuation.  However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness.  Should these symptoms occur Epilim should be discontinued.

Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4.2 Precautions). In such cases further investigations should be considered.

 

Metabolic and nutrition disorders:

Common:  hyponatraemia.

Rare:  hyperammonaemia* (see section 4.4.2 Precautions)

 

*Cases of isolated and moderate hyperammonaemia without change in liver function may occur frequently and should not cause treatment discontinuation.  However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness.  Should these symptoms occur Epilim should be discontinued.

 

Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4.2 Precautions). In such cases further investigations should be considered.

 

Very rare cases of hyponatremia have been reported.

Syndrome of Inappropriate Secretion of ADH (SIADH)

 

Endocrine Disorders:

Uncommon:  Syndrome of Inappropriate Secretion of ADH (SIADH), hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia, and/or androgen increased)

Rare:  hypothyroidism (see section 4.6 Fertility, pregnancy and lactation)

 

 

Blood and lymphatic system disorders: 

Frequent occurrence of Common:  anaemia, thrombocytopenia, rare cases of anaemia, leucopoenia or (see section 4.4.2 Precautions).

Uncommon:  pancytopenia., leucopenia.

 

The blood picture returned to normal when the drug was discontinued.

 

Rare:  Bbone marrow failure, including pure red cell aplasia.,  Aagranulocytosis, anaemia macrocytic, macrocytosis.

 

Isolated finding of a reduction in blood fibrinogen and/or increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (Epilim has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations (see also section 4.6 Fertility, Ppregnancy and Llactation).

 

           

Deficiency in Factor VIII / Von Willebrand.

 

Skin and subcutaneous tissue disorders:

Very rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme, rash.

 

Common:  hypersensitivity, Ttransient and/or dose related alopecia., has often been reported. Regrowth normally begins within six months, although the hair may become more curly than previously.

Uncommon:  angioedema, rash, hair disorder (such as hair texture abnormal, hair colour changes, hair growth abnormal)

 

Rare:  toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome.

 

Musculoskeletal and connective tissue disorders:

Uncommon:  There have been reports of decreased bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long-term therapy with Epilim. The mechanism by which Epilim affects bone metabolism has not been identified.

Rare:  systemic lupus erythematosus (see section 4.4.2 Precautions), rhabdomyolysis (see section 4.4.2 Precautions)

 

 

Reproductive system and breast disorders:

Common:  dysmenorrhea

Uncommon:  amenorrhea

Rare:  male infertility, polycystic ovaries

            Amenorrhoea and dysmenorrhea have been reported.  

 

Very rarely gynaecomastia has occurred.

Male infertility.

 

Vascular disorders:

Common: haemorrhage (see section 4.4.2 Precautions and 4.6 Fertility, pregnancy and lactation).

Uncommon:  The occurrence of vasculitis has occasionally been reported.

 

Ear and labyrinth disorders:

Common:  Deafness, either reversible or irreversible has been reported rarely.

 

Renal and urinary disorders:

Uncommon: renal failure

There have been isolated reports of a reversible Fanconi’s syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) but the mode of action is as yet unclear.

Very rRare: cases of enuresis, tubulointerstitial nephritishave been reported.

reversible Fanconi syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with Epilim therapy, but the mode of action is as yet unclear.

 

Immune system disorders:

Angioedema, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome.

Allergic reactions (ranging from rash to hypersensitivity reactions) have been reported.

 

Psychiatric disorders:

Common:  Cconfusional state, hallucinations, aggression*, agitation*, disturbance in attention*

Rare:  abnormal behaviour*, psychomotor hyperactivity*, learning disorder*

 

*These ADRs are principally observed in the paediatric population.

 

 

General disorders and administration site conditions:

Very rare cases of Uncommon: hypothermia, non-severe peripheral oedema peripheral have been reported.

 

Increase in weight may also occur. Since it is a risk factor for polycystic ovary syndrome, it should be carefully monitored (see section 4.4 Special Warnings and Special Precautions for Use).

 

Respiratory, thoracic and mediastinal disorders:

Uncommon: pleural effusion

 

Investigations:

Common:  Weight increased*

Rare:  Coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged), biotin deficiency/biotinidase deficiency.

 

*Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome (see section 4.4.2 Precautions)

 

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Rare:  myelodysplastic syndrome

 

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 IMB HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpraimb.ie; e-mail: imbpharmacovigilance@imb.iemedsafety@hpra.ie.


Section 4.9: updated as follows:

Signs of massive overdose, i.e. plasma concentration 10 to 20 times maximum therapeutic levels, usually include CNS depression or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis, hypotension and circulatory collapse/shock. 

Deaths have occurred following massive overdose; nevertheless, a favourable outcome is usual.

 

Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels (see also section 5.2 Pharmacokinetic Properties). Cases of intracranial hypertension related to cerebral oedema have been reported.

 

The presence of sodium content in the valproate formulations may lead to hypernatraemia when taken in overdose.



Updated on 01/11/2013 and displayed until 22/12/2014
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   14-Oct-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Type IB variation relating to the Bone density disorder for sodium valproate.  
Updated on 24/08/2012 and displayed until 01/11/2013
Reasons for adding or updating:
  • Change to section 7 - Marketing authorisation holder
Date of revision of text on the SPC:   26-Apr-2012
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Section 7 updated with the addition of T/A SANOFI
Updated on 13/04/2012 and displayed until 24/08/2012
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 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
Date of revision of text on the SPC:   08-Mar-2012
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Sections 4.2, 4.4, 4.5, 4.6 & 4.8 updated in line with version 13 of the Company Core Data Sheet with regard to:-
  • Extrapyramidal disorders
  • Interactions with Lamotrigine
  • Interactions with Felbamate
  • Male infertility
  • Peadiatric data in Bipolar Disorder
  • Alcohol intake
  • Use of contraception in women
Updated on 18/05/2011 and displayed until 13/04/2012
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 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   30-Dec-2010
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Addtion of information for use in manic episodes in bipolar disorder & update of undesirable effects following Article 31 approval.

Updated on 04/10/2010 and displayed until 18/05/2011
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
Date of revision of text on the SPC:   30-Jul-2010
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Update to section 4.4 & 4.5 with regard to interaction with carbapenem agents.
Updated on 08/10/2009 and displayed until 04/10/2010
Reasons for adding or updating:
  • 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 4.9 - Overdose
Date of revision of text on the SPC:   01-Sep-2009
Legal Category:   Product subject to restricted prescription (C)

Free-text change information supplied by the pharmaceutical company

Warning regarding autism spectrum disorders to section 4.6
Additional adverse events to section 4.8
Addition of rifampicin and topiramate to section 4.5
Modification of section 4.9
Updated on 05/01/2009 and displayed until 08/10/2009
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
Date of revision of text on the SPC:   12/2008
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Update to section 4.4 of SPC.
Updated on 18/07/2008 and displayed until 05/01/2009
Reasons for adding or updating:
  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   07/2008
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Update section 7, 8 and 10
Updated on 04/07/2008 and displayed until 18/07/2008
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 10 - Date of revision of the text
Date of revision of text on the SPC:   06/2008
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Update section 4.1 and 4.2, section 10.
Updated on 03/06/2008 and displayed until 04/07/2008
Reasons for adding or updating:
  • New SPC for medicines.ie

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Active Ingredients

 
   Valproic Acid
   Sodium Valproate