Central Nervous System

Therapeutic indications

Treatment of generalised, partial or other epilepsy.

POSOLOGY AND METHOD OF ADMINISTRATION

Syrup is for oral administration. Daily dosage requirements vary according to age and body weight. Epilim Syrup may be given twice daily. If it is necessary to dilute Epilim Syrup, the recommended diluent is Syrup BP, but syrup containing SO2 as a preservative should not be used. The diluted product will have a 14-day shelf life.

Epilim 200 Gastro-resistant tablets are for oral administration.Daily dosage requirements vary according to age and body weight. Epilim tablets may be given twice daily. Tablets should be swallowed whole and not crushed or chewed.

Epilim Chrono is a prolonged release formulation of Epilim which reduces peak concentration and ensures more even plasma concentrations throughout the day. Epilim Chrono may be given once or twice daily. The tablets should be swallowed whole and not crushed or chewed. Daily dosage requirements vary according to age and body weight.
In patients where adequate control has been achieved Epilim Chrono formulations are interchangeable with other Epilim conventional or prolonged release formulations on an equivalent daily dosage basis.

Dosage

Usual requirements are as follows:

Adults: Dosage should start at 600 mg daily increasing by 200 mg at three-day intervals until control is achieved. This is generally within the dosage range 1000 – 2000 mg per day, i.e. 20 – 30mg/kg/day body weight. Where adequate control is not achieved within this range the dose may be further increased to 2500 mg per day.

Children over 20 kg: Initial dosage should be 400 mg/day (irrespective of weight) with spaced increases until control is achieved; this is usually within the range 20 – 30 mg/kg body weight per day. Where adequate control is not achieved within this range the dose may be increased to 35 mg/kg body weight per day.

Children under 20 kg: An alternative formulation of Epilim should be used in this group of patients, due to the tablet size and need for dose titration. Epilim Liquid (sugar-free) or Epilim Syrup are alternatives.

Elderly: Although the pharmacokinetics of Epilim are modified in the elderly, they have limited clinical significance and dosage should be determined by seizure control. The volume of distribution is increased in the elderly and because of decreased binding to serum albumin, the proportion of free drug is increased. This will affect the clinical interpretation of plasma valproic acid levels.

In patients with renal insufficiency: It may be necessary to decrease the dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading (see section 5.2).

In patients with hepatic insufficiency: Salicylates should not be used concomitantly with Epilim since they employ the same metabolic pathway (see sections 4.4 and 4.8). Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid (see sections 4.3 and 4.4).

Salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye’s syndrome). In addition, in conjunction with Epilim, concomitant use in children under 3 years can increase the risk of liver toxicity (see section 4.4.1).

Female children and women of childbearing potential: Valproate must be initiated and supervised by a specialist experienced in the management of epilepsy. Valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated (see sections 4.3, 4.4 and 4.6). Valproate is prescribed and dispensed according to the Valproate Pregnancy Prevention Programme (see sections 4.3 and 4.4). The benefits and risks should be carefully reconsidered at regular treatment reviews (see section 4.4).

Valproate should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation. The daily dose should be divided into at least two single doses (see section 4.6).

Combined Therapy: When starting Epilim in patients already on other anti-convulsants, these should be tapered slowly; initiation of Epilim therapy should then be gradual, with target dose being reached after about 2 weeks. In certain cases, it may be necessary to raise the dose by 5 – 10 mg/kg/day when used in combination with anti-convulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of Epilim. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.

NB: In children requiring doses higher than 40 mg/kg/day clinical chemistry and haematological parameters should be monitored.
Optimum dosage is mainly determined by seizure control and routine measurement of plasma levels is unnecessary. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected (see section 5.2).

Method of administration: Epilim Chrono Controlled Release Tablets are for oral administration.

In view of the sustained release process and the nature of the excipients in the formula, the inert matrix of the tablet is not absorbed by the digestive tract; it is eliminated in the stools after the active substances have been released.

CONTRA-INDICATIONS

Epilim is contraindicated in the following situations:
• In pregnancy unless there is no suitable alternative treatment (see sections 4.4 and 4.6).
• In women of childbearing potential unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.4 and 4.6).
• Active liver disease.
• Personal or family history of severe hepatic dysfunction, especially drug related.
• Patients with known urea cycle disorders (see section 4.4).
• Hypersensitivity to sodium valproate.
• 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 whoare suspected of having a POLG-related disorder (see section 4.4).

SPECIAL WARNINGS ANDSPECIAL PRECAUTIONS FOR USE

Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally only be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms. NICE has advised that generic switching of valproate preparations is not normally recommended due to the clinical implications of possible variations in plasma concentrations.

INTERACTIONS

Effects of Epilim on other drugs

- Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines: Epilim may potentiate the effect of other psychotropics such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate. In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g. neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder and somnolence.

- Lithium: Epilim has no effect on serum lithium levels.

- Olanzapine: Valproic acid may decrease the olanzapine plasma concentration.

- Phenobarbital: Epilim increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.

- Primidone: Epilim increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.

- Phenytoin: Epilim decreases phenytoin total plasma concentration. Moreover, Epilim increases phenytoin free form with possible overdose symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.

- Carbamazepine: Clinical toxicity has been reported when Epilim was administered with carbamazepine as Epilim may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.

- Lamotrigine: Epilim reduces the metabolism of lamotrigine and increases the lamotrigine mean half-life by nearly to fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore, clinical monitoring is recommended, and dosages should be adjusted (lamotrigine dosage decreased) when appropriate.

- Felbamate: Valproic acid may decrease the felbamate mean clearance by up to 16%.

- Rufinamide: Valproic acid may lead to an increase in plasma levels of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.

- Propofol: Valproic acid may lead to an increased blood level of propofol. When co-administered with valproate, a reduction of the dose of propofol should be considered.

- Zidovudine: Epilim may raise zidovudine plasma concentration leading to increased zidovudine toxicity.

- 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.

- Temozolomide: Co-administration of temozolomide and Epilim may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.

Effects of other drugs on Epilim

- Anti-epileptics: Anti-epileptics with enzyme inducing effect (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy. Valproic acid metabolite levels may be increased in the case of concomitant use with phenytoin or phenobarbital. Therefore, patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonaemia. On the other hand, combination of felbamate and Epilim decreases valproic acid clearance by 22 – 50% and consequently increase the valproic acid plasma concentrations. Epilim dosage should be monitored.

- Anti-malarial agents: Mefloquine and chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore, epileptic seizures may occur in cases of combined therapy. Accordingly, the dosage of Epilim may need adjustment.

- Highly protein bound agents: In case of concomitant use of Epilim and highly protein bound agents (e.g. aspirin), free valproic acid plasma levels may be increased.

- Vitamin K-dependent factor anticoagulants: The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored.

- Cimetidine or erythromycin: Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.

- Carbapenem antibiotics (such as imipenem panipenem and meropenem): Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60 – 100% decrease in valproic acid levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided (section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood levels should be performed.

- Rifampicin: Rifampicin may decrease the valproic acid blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.

Others

Caution is advised when using Epilim in combination with newer anti-epileptics whose pharmacodynamics may not be well established.
Concomitant administration of valproate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring of signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.
- Quetiapine: Co-administration of Epilim and quetiapine may increase the risk of neutropenia/leucopenia.

PREGNANCY AND LACTATION

• Valproate is contraindicated as treatment for epilepsy during pregnancy unless there is no suitable alternative to treat epilepsy.
• Valproate is contraindicated for use in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled.

UNDESIRABLE EFFECTS

Hepatobiliary disorders:

Common: liver injury (see section 4.4.1). Severe liver damage, including hepatic failure sometimes resulting in death, has been reported (see sections 4.2, 4.3 and 4.4.1). Increased liver enzymes are common, particularly early in treatment, and may be transient (see section 4.4.1).

Gastrointestinal disorders:

Very common: nausea.
Common: vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, gastralgia, diarrhoea.

The above 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.

Very common: tremor.
Common: extrapyramidal disorder, stupor*, somnolence, convulsion*, memory impairment, headache, nystagmus
Common:confusional state, hallucinations, aggression*, agitation*, disturbance in attention*

Metabolism and nutrition disorders:

Common: hyponatraemia, weight increased* *Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome.
Common: anaemia, thrombocytopenia,
Common: hypersensitivity, transient and/or dose related alopecia (hair loss), nail and nail bed disorders. Regrowth normally begins within six months, although the hair may become more curly than previously.
Common: dysmenorrhea
Common: haemorrhage (see sections 4.4.2 and 4.6)

Ear and labyrinth disorders:

Common: deafness, a cause and effect relationship has not been established.

Renal and urinary disorders:

Common: urinary incontinence.

For uncommon, rare and very rare side effects see full prescribing information

OVERDOSE

Hospital management of overdose should be symptomatic, including cardio-respiratory monitoring. Gastric lavage may be useful up to 10 – 12 hours following ingestion. Haemodialysis and haemoperfusion have been used successfully. Naloxone has been successfully used in a few isolated cases, sometimes in association with activated charcoal given orally.
In case of massive overdose, haemodialysis and haemoperfusion have been used successfully.

PHARMACODYNAMIC PROPERTIES

Sodium valproate and valproic acid are anti-convulsants

Date of SmPC text revision: 23^rd March 2020;
Date of abbreviated prescribing information: December 2020
More detailed Information on request:
Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

Sanofi Office, 2nd Floor Yekeima Square,
No_ 6 George Walker Bush Highway Dzorwulu, Accra.
Tel: +233 302 734772;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.