Orfiril

Sodium valproate is used in the:

- treatment of all forms of epilepsy.

- treatment of manic episode in bipolar disorder when lithium is contraindicated or not tolerated. The continuation of treatment after manic episode could be considered in patients who have responded to sodium valproate for acute mania.

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

Orfiril^® should be initiated and supervised by a specialist experienced in the management of epilepsy or bipolar disorder. Treatment should only be initiated if other treatments are ineffective or not tolerated and the benefit and risk should be carefully reconsidered at regular treatment reviews. Preferably Orfiril^® should 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.

Posology

Treatment in all forms of epilepsy:

Dosage requirements vary according to age and body weight and should be adjusted individually to achieve adequate seizure control. The daily dosage should be given in 1 - 2 single doses.

Monotherapy

Usual requirements are as follows:

Adults

Dosage should start at 600mg daily increasing by 150-300mg at three day intervals until control is achieved. This is generally within the dosage range of 1000mg to 2000mg per day i.e. 20-30mg/kg body weight daily. Where adequate control is not achieved within this range the dose may be further increased to a maximum of 2500mg per day.

Children over 20kg

Initial dosage should be 300mg/day increasing until control is achieved. This is usually within the range 20-30mg/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 20kg

20mg/kg body weight per day; in severe cases this may be increased up to 40mg/kg/day.

Elderly

Care should be taken when adjusting dosage in the elderly since the pharmacokinetics of sodium valproate are modified. 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. Dosage should be determined by seizure control.

In patients with renal insufficiency

It may be necessary to decrease dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading.

In patients with hepatic insufficiency

Salicylates should not be used concomitantly with sodium valproate since they employ the same metabolic pathway.

Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid.

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

Combined Therapy

When starting Orfiril^® in patients already on anticonvulsants, these should be tapered slowly; initiation of Orfiril^® treatment 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 to 10mg/kg/day when used in combination with liver enzyme inducing drugs such as phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of Orfiril^®.

When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.

N.B. 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.

Manic episodes in bipolar disorder

Adults

The daily dosage should be established and controlled individually by the treating physician. The initial recommended daily dose is 750 mg. In addition, in clinical trials a starting dose of 20 mg sodium valproate/kg body weight has also shown an acceptable safety profile. Prolonged-release formulations can be given once or twice daily. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect. The daily dose should be adapted to the clinical response to establish the lowest effective dose for the individual patient. The mean daily dose usually ranges between 1,000 and 2,000 mg sodium valproate. Patients receiving daily doses higher than 45 mg/kg/day body weight should be carefully monitored.

Continuation of treatment of manic episodes in bipolar disorder should be adapted individually using the lowest effective dose.

Children and adolescents

The safety and efficacy of Orfiril^® for the treatment of manic episodes in bipolar disorder have not been evaluated in patients aged less than 18 years.

Method of administration

For oral administration.

The contents of the sachet may be sprinkled or stirred into soft food or drinks and swallowed immediately without chewing, or crushing the prolonged- release granules. The food or drink should be cold or at room temperature. A mixture of the granules with liquid or soft food should not be stored for future use. If the contents of the sachet are taken in a drink, as some granules may stick to the glass after the drink has been finished, the glass should be rinsed with a small amount of water and this water swallowed as well. The prolonged-release granules should not be given in babies' bottles as they can block the teat.

When changing from sodium valproate enteric coated tablets to Orfiril^® it is recommended to keep the same daily dose.

-

- Active liver disease.

- Personal or family history of severe hepatic dysfunction, especially drug related.

- Porphyria.

- Patients with known urea cycle disorders.

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.

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of antiepileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for sodium valproate.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

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.

The concomitant use of sodium valproate and carbapenem is not recommended.

Aggravated convulsions:

As with other antiepileptic drugs, some patients may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately.

Hepatic dysfunction

Conditions of occurrence

Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported. Experience in epilepsy has indicated that patients most at risk, especially in cases of multiple anticonvulsants therapy, are infants and in particular young children under the age of 3 and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation. After the age of 3, the incidence of occurrence is significantly reduced and progressively decreases with age. The concomitant use of salicylates should be avoided in children under 3 due to the risk liver toxicity. Additionally, salicylates should not be used in children under 16 years of age (see aspirin/salicylate product information on Reye's syndrome).

Monotherapy is recommended in children under the age of 3 years when prescribing Orfiril^®, but the potential benefit of Orfiril^® should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy.

In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2 - 12 weeks.

Suggestive signs

Clinical symptoms are essential for early diagnosis. In particular the following conditions, which may precede jaundice, should be taken into consideration, especially in patients at risk (see above: Conditions of occurrence):

- non-specific symptoms, usually of sudden onset, such as asthenia, malaise, anorexia, lethargy, oedema and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain.

- in patients with epilepsy, recurrence of seizures

These are an indication for immediate withdrawal of the drug.

Patients (or their carers), should be instructed to report immediately any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.

Detection

Liver function should be measured before and then periodically monitored during the first 6 months of therapy, especially in those who seem at risk, and those with a prior history of liver disease. Amongst usual investigations, tests which reflect protein synthesis, particularly prothrombin rate, are most relevant. Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decreases in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) require cessation of Orfiril^® therapy.

As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.

As with most antiepileptic drugs, increased liver enzymes are common, particularly at the beginning of therapy; they are also transient.

More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary.

Pancreatitis

Pancreatitis, which may be severe and result in fatalities, has been very rarely reported. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase).

Young children are at particular risk; this risk decreases with increasing age. Severe seizures and severe neurological impairment with combination anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, Orfiril^® should be discontinued.

Haematological

Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding..

Renal insufficiency

In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring.

Systemic lupus erythematosus

Although immune disorders have only rarely been noted during the use of sodium valproate, the potential benefit of Orfiril^® should be weighed against its potential risk in patients with systemic lupus erythematosus.

Hyperammonaemia

When urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of risk of hyperammonaemia with sodium valproate.

Weight gain

Sodium valproate very commonly causes weight gain, which may be marked and progressive. Patients should be warned of the risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimise it.

Patients with known or suspected mitochondrial disease

Valproate may trigger or worsen clinical signs of underlying mitochondrial diseases caused by mutations of mitochondrial DNA as well as the nuclear encoded POLG gene. In particular, valproate-induced acute liver failure and liver-related deaths have been reported at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the gene for the mitochondrial enzyme polymerase γ (POLG),e.g. Alpers-Huttenlocher Syndrome.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders.

Diabetic patients

Sodium valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies: this may give false positive results in the urine testing of possible diabetics.

Alcohol

Alcohol intake is not recommended during treatment with valproate.

Granules in stools

The prolonged-release granules are surrounded by an indigestible cellulose shell through which the sodium valproate is released and these shells will be seen as white residues in the stools of the patient. There are no safety issues concerning such residues.

Use of Orfiril^® may provide seizure control such that the patient may be eligible to hold a driving licence.

At the start of treatment with sodium valproate, at higher dosages or with a combination of other centrally acting drugs, reaction time may be altered to an extent that affects the ability to drive or to operate machinery, irrespective of the effect on the primary disease being treated. Patients should be warned of the risk of transient drowsiness. This is especially the case when taken during anticonvulsant polytherapy, concomitant use of benzodiazepines or in combination with alcohol.

Frequency categories are defined using the following convention:

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

Congenital malformations and developmental disorders.

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 occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have uncommonly 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.

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

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

Hyperammonaemia associated with neurological symptoms has also been reported. In such cases further investigations should be considered.

Isolated findings of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (Orfiril^® has an inhibitory effect on the second phase of platelet aggregation).).).

*Weight increase should be carefully monitored since it is a factor for polycystic ovary 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 the national reporting system (see details below).

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Cases of accidental and deliberate overdosage with oral therapy have been reported. At plasma concentrations of up to 5 to 6 times the maximum therapeutic levels, there are unlikely to be any symptoms other than nausea, vomiting and dizziness. In massive overdose, 10 to 20 times the maximum therapeutic levels, there may be serious CNS depression or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis. A favourable outcome is usual, however some deaths have occurred following massive overdose.

The symptoms may however be variable and seizures have been reported in the presence of very high plasma levels. Cases of intracranial hypertension related to cerebral oedema have been reported. A number of deaths have occurred following large overdoses.

Hospital management of overdose includes induced vomiting, gastric lavage, assisted ventilation and other supportive measures. Haemodialysis and haemoperfusion have been used successfully. Intravenous naloxone has also been used sometimes in association with activated charcoal given orally.

Pharmacotherapeutic Group: Fatty acid derivatives

ATC code: N03AG01

The mode of action of valproic acid is not fully understood but may involve an elevation of gamma-amino butyric acid levels in the brain.

In certain in-vitro studies, it was reported that sodium valproate could stimulate HIV replication, but studies on peripheral blood mononuclear cells from HIV-infected subjects show that sodium valproate does not have a mitogen-like effect on inducing HIV replication. Indeed, the effect of sodium valproate on HIV replication ex-vivo is highly variable, modest in quantity, appears to be unrelated to the dose and has not been documented in man.

The increased expression of drug efflux transporters at the blood-brain barrier can results in lower concentrations of their respective substrate, i. e. the active substance, in the brain compared to its free concentration in plasma, and thereby reduce the concentration of antiepileptics at the site of action. This can lead to pharmacoresistance and thus to the development of a treatment-resistant status epilepticus or treatment-resistant epilepsy. However, in vitro data suggest that sodium valproate is not a substrate for transporters such as ATP-binding cassette (ABC) transporters (e. g. P-glycoprotein (Pgp)) or multidrug resistance-associated proteins (MRP1, MRP2 and MRP5). The development of pharmacoresistance against valproate by these transporters is therefore considered unlikely.

With peroral administration 90-100 % of the dose is rapidly absorbed.

Maximal plasma concentration is achieved with Orfiril^® within 6.5 ± 3.3 hours. The half-life is 12-16 h in most patients but can in exceptional cases be considerably lower. Impaired renal function prolongs the half-life. In infants under 2 months the half-life can be prolonged up to 60 hours but in older children it is the same as in adults.

Steady-state concentration is normally achieved after treatment in 3-5 days. A satisfactory effect is most often achieved at 50-100 µg/mL, but the patient's overall situation must be considered.

The relation between the dose and effect, and between plasma concentrations and effect, has not been fully clarified.

The cerebrospinal fluid concentration is up to 10 % of the plasma concentration. About 90 % of sodium valproate is bound to plasma protein (mainly to albumin), which may entail a risk of clinically significant interactions with other antiepileptics, primarily phenytoin. Protein binding decreases at higher dosages. Plasma protein binding is lower in elderly patients and in patients with kidney or liver dysfunction. In one study, elevated levels of the free drug (8.5 % up to more than 20 %) were observed in patients with significantly reduced renal function.

However, if hypoproteinaemia is present, the total concentration of valproic acid (free and protein-bound substance) can be essentially unchanged, although it may also be reduced due to the increased metabolism of the free portion.

Sodium valproate is metabolised to a great extent and is excreted in the urine as conjugated metabolites. Sodium valproate crosses the placental barrier and concentrations of foetal plasma are comparable to those in the mother.

Valproic acid passes into breast milk but is not likely to influence the child when therapeutic doses are used.

Testicular atrophy, degeneration of the vas deferens and inadequate spermatogenesis as well as changes to the lungs and prostate gland have been observed in chronic toxicity studies with high oral dosages (250 mg/kg in rats and 90 mg/kg in the dog).

Mutagenicity tests in bacteria, rats and mice yielded no evidence of mutagenic potential.

Long-term studies have been conducted in rats and mice. At very high doses, the rate of subcutaneous fibrosarcomas was increased in male rats. Animal studies have shown valproic acid to be teratogenic.

None known

No special requirements