Epilim Enteric 500mg Gastro-resistant Coated Tablets

Section 4.6

Pregnancy Exposure Risk related to valproate

Both valproate monotherapy and valproate polytherapy including other antiepileptics, are frequently associated with abnormal pregnancy outcomes. Available data suggest that antiepileptic polytherapy including valproate is associated with a greater risk of congenital malformations than valproate monotherapy. Valproate was shown to cross the placental barrier both in animal species and in humans (see section 5.2).

In animals: teratogenic effects have been demonstrated in mice, rats and rabbits (see section 5.3).

Congenital malformations

There are limited data on the long term outcomes.

Available data from a population based study show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately 3-fold) and childhood autism (approximately 5-fold) compared to the unexposed population in the study.

Available data from another population based study show that children exposed to valproate in utero are at increased risk of developing attention deficit/hyperactivity disorder (ADHD) (approximately 1.5 fold) compared to the unexposed population in the study.

If a Woman plans a Pregnancy

5.3       Preclinical Safety Data

Animal studies show that in utero exposure to valproate results in morphological and functional alterations of the auditory system in rats and mice.

Carcinogenesis, mutagenesis

Valproate was not mutagenic in bacteria (Ames test), or mouse lymphoma L5178Y cells at thymidine kinase locus (mouse lymphoma assay) and did not induce DNA repair activity in primary culture of rat hepatocytes. In in vivo studies, when tested at teratogenic doses, results were contradictory depending on the route of administration. After oral administration, the main route of administration in humans, valproate did not induce either chromosome aberrations in rat bone marrow, or dominant lethal effects in mice. 

After intraperitoneal exposure to valproate, increased incidences of DNA and chromosome damage (DNA strand-breaks, chromosomal aberrations or micronuclei) have been reported in rodents. However, the relevance of the results obtained with the intraperitoneal route of administration is unknown.

Statistically significant higher incidences of sister-chromatid exchange (SCE) have been observed in epileptic patients exposed to valproate as compared to healthy subjects not exposed to valproate. However, there are confounding factors and contradictory results in 2 published studies. The biological significance of an increase in SCE frequency is not known.

Non-clinical data reveal no carcinogenicity hazard for humans based on conventional carcinogenicity studies.

Reproductive toxicology

Teratogenic effects (malformations of multiple organ systems) have been demonstrated in mice, rats, and rabbits.

In published literature, behavioural abnormalities have been reported in first generation offspring of mice and rats after in utero exposure. In mice, behavioural changes have also been observed in the 2^nd and 3^rd generations, albeit less pronounced in the 3^rd generation, following an acute in utero exposure of the first generation to teratogenic doses. The underlying mechanisms of action and the relevance of these findings for humans are unknown.

Addition of QR code

4.3          Contraindications

Epilim is contraindicated in the following situations:

Treatment of epilepsy

• in pregnancy unless there is no suitable alternative treatment (see section 4.4 and 4.6).
• in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (see section 4.4 and 4.6).

All indications

• Hypersensitivity to sodium valproate
• Active liver disease
• Personal or family history of severe hepatic dysfunction, especially drug related
• Porphyria
• Valproate is contraindicated in patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome, and in children under two years of age who are suspected of having a POLG-related disorder (see section 4.4).
• Patients with known urea cycle disorders (see section 4.4)

…….

4.4          Special Warnings and Precautions for Use

Pregnancy Prevention Programme

Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders (see section 4.6).

Epilim is contraindicated in the following situations:

Treatment of epilepsy

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F

or the indication epilepsy, iIf a woman is planning to become pregnant, a specialist experienced in the management of epilepsy, must reassess valproate therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued (see section 4.4). If switching is not possible, the woman should receive further counselling regarding the valproate risks for the unborn child to support her informed decision making regarding family planning

4.8       Undesirable Effects

Nervous system disorders:

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

Renal and urinary disorders:

Common: urinary incontinence

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

Estrogen-containing products, including estrogen-containing hormonal contraceptives

Estrogens are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in valproate glucuronidation and may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see section 4.4). Consider monitoring of valproate serum levels.

On the opposite, valproate has no enzyme inducing effect; as a consequence, valproate

does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception.

Epilim usually has no enzyme-inducing effect; as a consequence, Epilim does not reduce the efficacy of oestroprogestative agents in women receiving hormonal contraception, including the oral contraceptive pill.

4.6       Fertility, pregnancy and lactation

However the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.

Women of childbearing potential

Estrogen-containing products

Estrogen-containing products, including estrogen-containing hormonal contraceptives, may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (sections 4.4 and 4.5).

Risk in the neonate

The pharmacological (or therapeutic) effects of Epilim may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.

Metabolism

The major pathway of valproate biotransformation is glucuronidation (~40%), mainly via UGT1A6, UGT1A9, and UGT2B7.

5.3       Preclinical Safety Data

Section 6.5

.  Pack sizes of 30 or 100 tablets with 10 tablets per strip and 112 tablets. 

4.2

Female children, female adolescents,and  women of childbearing potential and pregnant women

Epilim should must be initiated and supervised by a specialist experienced in the management of epilepsy or bipolar disorder. Valproate should not be used in female children and women of childbearing potential unless Treatment should only be initiated if other treatments are ineffective or not tolerated (see section 4.4 and 4.6) and the benefit and risk should be carefully reconsidered at regular treatment reviews.

Valproate is prescribed and dispensed according to the Valproate Pregnancy Prevention Programme (see section 4.3 and 4.4).

Preferably Epilim should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation to avoid high peak plasma concentrations. The daily dose should be divided into at least two single doses (see section 4.6).

.3         Contraindications

Epilim is contraindicated in the following situations:

Treatment of epilepsy

• in pregnancy unless there is no suitable alternative treatment (see section 4.4 and 4.6).
• in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (see section 4.4 and 4.6).
   
  Treatment of bipolar disorder
• in pregnancy (see section 4.4 and 4.6).
• in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled  (see section 4.4 and 4.6).
   
  All indications

• Hypersensitivity to sodium valproate
• Active liver disease
• Personal or family history of severe hepatic dysfunction, especially drug related
• Hypersensitivity to sodium valproate or to any of the excipients
• Porphyria.

4.4-Special Warnings and Special Precautions for Use- full changes

Section 4.5 interactions – this has been added

- Nimodipine

In patients concomitantly treated with sodium valproate and nimodipine the exposure to nimodipine can be increased by 50%. The nimodipine dose should therefore be decreased in case of hypotension

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.

• Extrapyramidal disorders
• Interactions with Lamotrigine
• Interactions with Felbamate
• Male infertility
• Peadiatric data in Bipolar Disorder
• Alcohol intake
• Use of contraception in women