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1. Valprotek Cr 300 Mg (Prolonged Release) Tablets
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SUMMARY OF PRODUCT CHARACTERISTICS ▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

Valprotek CR 300 mg (prolonged release) tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Valprotek CR 300 mg (prolonged release) tablets

Each prolonged-release tablet contains 200 mg sodium valproate and 87 mg valproic acid (equivalent to a total of 300 mg sodium valproate).

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet

White, oblong film coated tablet with break marks at both faces. The tablet can be divided into equal halves.

4    Clinical particulars

4.1    Therapeutic indications

For the treatment of:

-    generalised seizures in the form of absences, myoclonic and tonic-clonic seizures

-    focal and secondary generalised seizures

and in the combination treatment of other forms of seizures, e.g. focal seizures with simple and complex symptoms and focal seizures with secondary generalisation, if these forms of seizures do not respond to the usual antiepileptic treatment.

Note:

In small children up to and including 3 years, antiepileptics containing valproic acid are only in exceptional cases therapy of first choice.

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 valproate for acute mania

4.2 Posology and method of administration

Note:

When changing from pretreatment with (non-prolonged release) pharmaceutical forms to Valprotek CR, it must be ensured that adequate serum valproic acid levels are maintained.

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

Valproic acid 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 (see section 4.4 and 4.6) and the benefit and risk should be carefully reconsidered at regular treatment reviews. Preferably valproic acid 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.

Seizures

The dosage should be determined and monitored by a specialist on an individual basis. Determination of the dosage should be primarily based upon clinical features, rather on routine serum concentration monitoring. Determination of serum levels may be helpful in case of toxic symptoms or lack of efficacy (see section 5.2).The aim is to achieve absence of seizures at the lowest possible dose.

Incremental (gradual) dose increases are recommended up to the optimal effective dose. Various dosage strengths and pharmaceutical forms are available to facilitate gradual dose increases and a precise titration of the maintenance dose.

In monotherapy the usual initial dose is 5-10 mg valproic acid/kg body weight, and this should be increased by approximately 5 mg valproic acid/kg body weight every 4-7 days.

In some cases, the full effect is not seen for 4-6 weeks. The daily dose should thus not be increased too rapidly above average amounts.

The usual mean daily dose during long-term treatment is:

-    20 mg valproic acid/kg body weight for adults and elderly patients,

-    25 mg valproic acid/kg body weight for adolescents,

-    30 mg valproic acid/kg body weight for children.

Accordingly, the following daily maintenance doses are recommended as guidelines:

Age	Body weight	Average maintenance dose in mg*/day
Children** 3-6 years 7-14 years	approx. 15-25 kg approx. 25-40 kg	450-600 750-1200
Adolescents from 14 years	approx. 40-60 kg	1000-1500
Adults	from approx. 60 kg	1200-2100
* Data based on mg soc	ium valproate.

** Note:

In children up to 3 years, dosage forms with a lower active substance content (e.g. solution) should preferably be used. For treatment in children > 3 years Valprotek CR 300 mg, which can be divided in equal halves, may be used.

If Valprotek CR is taken in combination with or as substitution therapy for

a previously administered medicinal product, the dose of any other concurrently administered antiepileptic, particularly of phenobarbital, must be immediately reduced. If the previous medicinal product is to be discontinued, this must be tapered off gradually.

As the enzyme-inducing effect of other antiepileptics is reversible, serum valproic acid levels should be monitored approximately 4-6 weeks after the last intake of any such active substance and the daily dose reduced if appropriate.

In patients with renal insufficiency or hypoproteinaemia, the rise in valproic acid free form in the serum must be taken into account and the dose reduced if necessary. The clinical picture, however, is the deciding factor in any dose adjustment, as determining the total serum valproic acid concentration may lead to false conclusions (see section 5.2).

The daily dose is given in 1-2 divided doses.

Manic episodes in bipolar disorder

In 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 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 1000 and 2000 mg valproate. Patients receiving daily doses higher than 45mg/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.

In children and adolescents:

The safety and efficacy of Valprotek CR for the treatment of bipolar disorder have not been evaluated in patients aged less than 18 years.

Method and duration of administration

The prolonged-release tablets should preferably be taken 1 hour before meals (on an empty stomach in the morning). In case of gastrointestinal side-effects due to treatment, the prolonged-release tablets should be taken during or after a meal. They should be swallowed whole or in halves, not chewed, and taken with plenty of fluid (e.g. a glass of water).

The duration of treatment is determined by the treating doctor.

Seizures:

Antiepileptic therapy is always a long-term therapy.

A specialist doctor (neurologist, neuropaediatrician) should decide upon dose titration, the duration of treatment and withdrawal of Valprotek CR on an individual basis. Generally, in the treatment of seizures no dose reduction or withdrawal of the medicine should be attempted until the patient has been free of seizures for at least two to three years. Withdrawal must take the form of a gradual dose reduction over a period of one to two years. Children may be allowed to grow out of the dose per kg body weight instead of making age-related dose adjustments, whereby EEG findings should not deteriorate.

Experience with long-term use of Valprotek CR is limited, particularly in children under 6 years of age.

4.3 Contraindications

-    hypersensitivity to valproic acid or to any of the excipients

-    personal or family history of hepatic disease or severe active hepatic or pancreatic dysfunction

-    hepatic dysfunction with fatal outcome in a sibling during valproic acid treatment

-    porphyria

-    coagulation disorders

-    urea cycle defects (see also section 4.4).

-    Valproate is contraindicated in patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase y (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).

4.4 Special warnings and precautions for use

Warnings

Severe hepatic damage has occurred uncommonly, pancreatic damage has occurred rarely.

These most frequently affect infants and small children below the age of 3 who are susceptible to severe epileptic seizures, particularly when valproic acid is combined with other anticonvulsants or when brain damage, mental retardation or a hereditary metabolic disease is also present. In this group of patients the administration of valproic acid should be carried out with particular care and in the form of a monotherapy.

In the majority of cases liver damage is observed within the first six months of therapy, particularly between the second and twelfth week.

Experience has shown, that above 3 years (above all in patients older than 10) the frequency of liver diseases decreases considerably.

The course of these diseases may be lethal. Simultaneous occurrence of hepatitis and pancreatitis increases the risk of a lethal course.

Suicide/suicidal thoughts or clinical worsening

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 anti-epileptic 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 Valprotek CR.

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.

Signs of hepatic and/or pancreatic damage

Severe or lethal liver and/or pancreatic damage may be preceded by unspecific symptoms such as increase in frequency/severity of seizures, impaired consciousness with confusion, agitation, movement disorders, malaise, asthenia, loss of appetite, aversion to familiar food or valproic acid, nausea, vomiting, abdominal pain, lethargy and, especially in case of hepatic damage, haematomas, epistaxis, and local or generalised oedemas. Patients, especially infants and toddlers should be carefully monitored with respect to these symptoms. If these symptoms are continuing or severe, appropriate laboratory tests (s. below measures for early detection) have to be undertaken besides a thorough clinical examination.

The treating physician should not only rely on laboratory findings, as they are not without normal limits in all cases. Especially after initiation of therapy, liver enzymes may be enhanced independent from an impaired liver function. Therefore, medical history and clinical picture are always crucial for the assessment of laboratory findings.

Measures for early detection of liver and/or pancreatic damage Before the start of treatment: detailed medical history, particularly with respect to metabolic disturbances, hepatopathy, pancreatic affections and coagulopathies, clinical examination and laboratory tests (e.g. PTT, fibrinogen, coagulation factors, INR, total protein, blood count including thrombocytes, bilirubin, SGOT, SGPT, gamma-GT, lipase, alpha-amylase, blood glucose) should be provided.

Four weeks after initiation of treatment, laboratory tests of coagulation parameters like INR and PTT, SGOT, SGPT bilirubin and amylase should be controlled.

In children showing no abnormal clinical symptoms, blood count including thrombocytes, SGOT and SGPT should be controlled at every other clinical visit.

In patients without clinical findings but with pathological laboratory tests after 4 weeks of treatment, follow-up controls should take place three times in maximal twoweekly intervals and in monthly intervals afterwards up to the 6th month of treatment.

In patients > 15 years and adults controls of the clinical and laboratory examination is required before initiation of therapy and monthly during the first 6 month of treatment.

In general, after 12 months of treatment without abnormal findings, 2-3 follow-up examinations per years are considered sufficient.

Parents are to be informed about possible signs of liver and/or pancreatic damage and are to be instructed to inform the attending physician immediately in case of unusual clinical symptoms irrespective of the above schedule.

Immediate withdrawal of therapy should be considered if any of the following symptoms occur:

unexplained impairment of the general condition, clinical signs of hepatic and/or pancreatic damage, coagulation disturbance, more than 2- to 3-fold increase of SGPT or SGPT even without clinical signs (induction of hepatic enzymes by concomitant medication is to be taken into consideration), moderate (1- to 1.5-fold) increase of SGPT or SGOT accompanied by an acute feverish infection, marked impairment of the coagulation parameters, occurrence of dose-independent undesirable effects.

Further precautions

The concomitant use of valproic acid/sodium valproate and carbapenem agents is not recommended (see section 4.5).

Metabolic diseases, in particular hereditary enzymopathies If an enzyme disturbance in the urea cycle is suspected, metabolic investigation should take place before treatment with valproic acid is started on account of the risk of hyperammonaemia as a result of valproic acid (see also section 4.3).

If symptoms such as apathy, somnolence, vomiting, hypotension and an increase in the frequency of seizures occur during treatment with valproic acid, the serum level of ammonia and valproic acid should be determined and dose reduction or withdrawal of Valproinsaure-ratiopharm chrono may be required. Withdrawal should take place while administering an adequate dose of another antiepileptic agent.

It should be noted, that after start of therapy with valproic acid, innocuous nausea may occur, sometimes associated with vomiting and loss of appetite, which is reversible spontaneously or after reduction of dose.

Haematological

Monitoring of the blood count, including platelet count, bleeding time and coagulation tests, is advisable prior to initiation of therapy, before a surgical or dental operation, and in cases of spontaneous haematomas or bleeding (see section 4.8).

In case of concomitant administration of vitamin K antagonists, close monitoring of the INR is recommended.

Bone marrow damage

Patients with previous bone marrow damage must be strictly monitored.

Reactions of the immune system

Valproic acid can, although rarely, induce systemic lupus erythematosus and cause existing systemic lupus erythematosus to flare up. Therefore, in patients with systemic lupus erythematosus, the benefit of Valprotek CR must be weighed against possible risks. The combination of lamotrigine and valproic acid causes an increased risk of (severe) skin reactions, especially in children.

Renal insufficiency and hypoproteinaemia

In patients with renal insufficiency or hypoproteinaemia, the rise in valproic acid unbound to serum proteins must be taken into account and the dose reduced as appropriate.

Weight gain

Patients should be informed about a possible weight-gain and possible measures for weight control. Since it is a risk factor for polycystic ovary syndrome, weight gain should be carefully monitored.

Thyroid hormone

Dependent on its plasma concentration valproate may displace thyroid hormones from plasma protein binding sites and increase their metabolism which may lead to the false presumption diagnosis of hypothyroidism.

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 y (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, opthalmoplegia, 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 (see section 4.3).

4.5. Interaction with other medicinal products and other forms of interaction

If Valprotek CR is combined with other anticonvulsant agents, additive effects on serum concentrations of active substances may occur.

Valproic acid is affected by:

Enzyme-inducing antiepileptics, such as phenobarbital, phenytoin, primidone and carbamazepine, increase elimination of valproic acid and thus reduce its effect.

This should also be considered when ending treatment of such inducers during treatment with valproic acid as the plasma concentrations of valproic acid may rise the first 2 weeks after discontinuing treatment with the inducer.

Felbamate causes a dose-dependent, linear increase of 18% in the serum concentration of valproic acid free form.

Mefloquine increases the breakdown of valproic acid and also has the potential to trigger seizures. Concurrent use may thus cause epileptic seizures.

Decreases in blood levels of valproic acid have been reported when it is coadministered with carbapenem agents resulting in a 60-100 % decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid is not considered to be manageable and therefore should be avoided (see section 4.4).

The serum valproic acid concentration can be increased by concurrent administration of cimetidine, erythromycin and fluoxetine. There have, however, also been reports of cases where the serum valproic acid concentration was lowered following concurrent fluoxetine intake.

Concurrent intake of valproic acid and anticoagulants or acetylsalicylic acid can increase the tendency to haemorrhage. Acetylsalicylic acid also reduces the plasma protein binding of valproic acid.

Medicinal products containing valproic acid should not be administered concurrently with acetylsalicylic acid to treat fever and pain, particularly in infants and toddlers. Regular monitoring of blood coagulation values is thus recommended during concurrent use.

Valproic acid affects:

Increased phenobarbital concentrations due to valproic acid are of particular clinical significance. They can result in profound sedation (particularly in children). In such cases, the phenobarbital or primidone dose should be reduced (primidone is partially metabolised to phenobarbital). Thus close monitoring is particularly recommended during the first 15 days of combination therapy.

In patients already undergoing phenytoin therapy, the additional administration of valproic acid or a dose increase of this product can cause a rise in phenytoin free form (concentration of the non-protein-bound effective fraction), without increasing serum levels of total phenytoin. This can increase the risk of undesirable effects, particularly brain damage (see section 4.8).

In combination therapy with valproic acid and carbamazepine, symptoms have been described which may be due to the potentiation of the toxic effect of carbamazepine by valproic acid. Clinical monitoring is particularly indicated at the beginning of combination therapy and the dose should be adjusted as necessary.

In healthy volunteers, valproate displaced diazepam from its plasma albumin binding sites and inhibited its metabolism. In combination treatment, the concentration of unbound diazepam may be increased and the plasma clearance and the volume of distribution of the free diazepam fraction may be reduced (by 25% and 20%, respectively). The half-life, however, remains unchanged.

In healthy subjects, concurrent treatment with valproate and lorazepam caused a decreased plasma clearance of lorazepam of up to 40%.

In children, serum phenytoin levels may be increased following concurrent administration of clonazepam and valproic acid.

Valproic acid inhibits the metabolism of lamotrigine and a dose adjustment of the latter may thus be necessary. Combination of lamotrigine and valproic acid causes an increased risk of (severe) skin reactions, especially in children. Isolated cases of severe skin reactions have been reported, which occurred within 6 weeks of beginning combination therapy. These subsided partially after withdrawal of the medicinal product or after appropriate treatment.

Valproic acid can increase serum levels of felbamate by approximately 50%.

The metabolism and protein binding of other active substances, such as codeine, are influenced.

In combination with barbiturates, neuroleptics and antidepressants, valproic acid can potentiate the central depressant effect of these medicinal products. Patients receiving such combinations should thus be closely monitored and any appropriate dose adjustments made.

As valproic acid is partially metabolised to ketone bodies, the possibility of a falsepositive reaction to a ketone body elimination test must be considered in diabetic patients with suspected ketoacidosis.

Valproic acid may increase serum zidovudine concentrations, which can lead to increased zidovudine toxicity.

Other interactions:

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either medicinal product alone. This adverse reaction is not due to a pharmacokinetic interaction. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported. In most cases, symptoms and signs abated with discontinuation of either medicinal product.

The effect of oral contraceptives (“the pill”) is not impaired by valproic acid, as the agent has no enzyme-inducing effect.

Potentially hepatotoxic active substances and alcohol can increase the hepatoxicity of valproic acid.

Following concurrent treatment with valproic acid and clonazepam, absence status occurred in patients with a history of absence seizures.

In one female patient with a schizoaffective disorder, catatonia occurred following concurrent treatment with valproic acid, sertraline and risperidone.

4.6 Fertility, pregnancy and lactation

Valproic acid should not be used in female children, in female adolescents, in women of childbearing potential and in pregnant women unless other treatments are ineffective or not tolerated.

Women of childbearing potential have to use effective contraception during treatment. In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible.

Pregnancy Exposure Risk related to valproate

Both valproate monotherapy and valproate polytherapy are 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.

Congenital malformations

Data derived from a meta-analysis (including registries and cohort studies) has shown that 10.73% of children of epileptic women exposed to valproate monotherapy during pregnancy suffer from congenital malformations (95% CI: 8.16 -13.29). This is a greater risk of major malformations than for the general population, for whom the risk is about 2-3%. The risk is dose dependent but a threshold dose below which no risk exists cannot be established.

Available data show an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.

Developmental disorders

Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established based on available data. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.

Studies in preschool children exposed in utero to valproate show that up to 30-40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems.

Intelligence quotient (IQ) measured in school aged children (age 6) with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other antiepileptics.

Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ.

There are limited data on the long term outcomes.

Available data show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population.

Limited data suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit/hyperactivity disorder (ADHD).

Female children, female adolescents and woman of childbearing potential (see above and section 4.4)

If a Woman wants to plan a Pregnancy

•    During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.

•    In women planning to become pregnant or who are pregnant, valproate therapy should be reassessed

•    In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible.

Valproate therapy should not be discontinued without a reassessment of the benefits and risks of the treatment with valproate for the patient by a physician experienced in the management of epilepsy or bipolar disorder.

If based on a careful evaluation of the risks and the benefits valproate treatment is continued during the pregnancy, it is recommended to:

- Use the lowest effective dose and divide the daily dose valproate into several small doses to be taken throughout the day. The use of a prolonged release formulation may be preferable to other treatment formulations in order to avoid high peak plasma concentrations.

-    Folate supplementation before the pregnancy may decrease the risk of neural tube defects common to all pregnancies. However the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.

-    To institute specialized prenatal monitoring in order to detect the possible occurrence of neural tube defects or other malformations.

Risk in the neonate

-    Cases of hemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This hemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to a decrease in other coagulation factors.

Afibrinogenemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. 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 their pregnancy.

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

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

Breastfeeding

Valproate is excreted in human milk with a concentration ranging from 1% to 10% of maternal serum levels. Hematological disorders have been shown in breastfed newborns/infants of treated women (see section 4.8).

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from valproate therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate (see section 4.8). Valproate administration may also impair fertility in men (see section 4.8).

Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.

4.7 Effects on ability to drive and use machines

Especially at the beginning of treatment with Valprotek CR, if higher doses are taken or in combination with centrally acting active substances, central nervous system effects may occur, e.g. drowsiness or confusion, which can so alter responsiveness that the ability to drive a vehicle, operate machinery or perform activities associated with the risk of falling or accident, is impaired regardless of the underlying disease. This effect is more pronounced if there is concurrent alcohol intake.

4.8 Undesirable effects

Very common:	> 1/10
Common:	> 1/100 to < 1/10
Uncommon:	> 1/1000 to < 1/100
Rare:	> 1/10000 to < 1/1000

Very rare:	< 10,000
Not known	cannot be estimated from the available data

Blood and the lymphatic system disorders

Common: Thrombocytopenia or leukopenia. These are often completely reversible if therapy is continued and always upon withdrawal of valproic acid.

Uncommon: Peripheral oedema, bleeding.

Rare:

Reduced fibrinogen; mostly without clinical symptoms and particularly with high doses (sodium valproate has an inhibitory effect on the second phase of platelet aggregation).

Very rare: Impairment of bone marrow function may lead to lymphopenia, neutropenia, pancytopenia or anaemia or agranulocytosis.

Prolonged bleeding time as result of reduced concentration of fibrinogen, disturbed platelet aggregation and/or thrombocytopathy due to factor VIII/Von Willebrand factor deficiency (see section 4.4).

Immune system disorders

Rare: Lupus erythematosus.

Frequency not known:

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

Metabolism and nutrition disorders

Very common: Isolated and moderate hyperammonaemia without any change in hepatic function parameters, which does not necessitate withdrawal of therapy.

In addition, cases of hyperammonaemia have been reported which were accompanied by neurological symptoms. In these cases further examinations are required (see also sections 4.3 and 4.4).

Common: Dose-dependent weight increase or loss, increased appetite or loss of appetite.

Very rare:

Hyponatraemia.

Frequency not known:

Syndrome of inappropriate ADH secretion (SIADH).

In a clinical study with 75 children, reduced biotinidase activity was observed during treatment with medicines containing valproic acid. There have also been reports of biotin deficiency.

Psychiatric disorders

Uncommon: Irritability, hyperactivity and confusion, particularly at the beginning of treatment.

Hallucinations have been observed.

Nervous system disorders

Common: Dose-dependent drowsiness, tremor or paraesthesias.

Fatigue and somnolence, apathy and ataxia have been commonly observed during combined treatment with other antiepileptics.

Uncommon: Headache, spasticity, ataxia, particularly at the beginning of treatment. Encephalopathy has been observed shortly after use of medicines containing valproic acid. The pathogenesis has not been established and the encephalopathy is reversible upon withdrawal of the medicine. In some cases, elevated ammonia levels and, in combination therapy with phenobarbital, a rise in phenobarbital levels has been described.

Also uncommon are cases of stupor sometimes culminating in coma, partially associated with an increased rate of seizures. The symptoms subsided following dose reduction or withdrawal of the medicine. The majority of such cases occurred during combination therapy (particularly with phenobarbital) or following a rapid dose increase.

In rare cases, particularly at high doses or in combination therapy with other antiepileptics, chronic encephalopathy with neurological symptoms and disturbances of higher cortical function have been described. The pathogenesis of such disorders has not been clearly established.

Very rare: Dementia in association with cerebral atrophy, reversible upon withdrawal of the medication.

The occurrence of a reversible Parkinson syndrome has been reported.

In long-term therapy with valproic acid in combination with other antiepileptics, particularly phenytoin, signs of brain damage (encephalopathy) can occur: increased seizures, lack of drive, stupor, muscle weakness (muscular hypotension), motor disturbances (choreoid dyskinesia) and severe generalised changes in the EEG.

Frequency not known: Sedation, extrapyramidal disorders.

Ear and labyrinth disorders

Tinnitus has been observed.

Reversible or irreversible hearing loss has been reported, whereby no causal association with medicines containing valproic acid has been established.

Vascular disorders

Rare: Vasculitis.

Gastrointestinal disorders

Uncommon: Hypersalivation, diarrhoea. Particularly at the beginning of therapy, there have been uncommon reports of gastrointestinal disturbances (nausea, stomach ache), which usually subsided after a few days even if therapy was continued.

Rare: Pancreatic damage, sometimes with fatal outcome (see section 4.4). Hepato-biliary disorders

Uncommon: Dose-independent, severe (sometimes fatal) hepatic dysfunction can occur. In children, particularly in combination therapy with other antiepileptics, the risk of hepatic damage is markedly increased (see section 4.4).

Skin and subcutaneous tissue disorders

Common: Dose-dependent transient hair loss, thinning of the hair.

Rare: erythema multiforme.

Very rare: Severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis or Lyell’s syndrome).

Musculoskeletal and connective tissue disorders

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

Renal and urinary disorders

Rare: Fanconi’s syndrome (metabolic acidosis, phosphaturia, aminoaciduria, glucosuria), which was reversible upon withdrawal of valproic acid.

Enuresis in children has been observed.

Reproductive system and breast disorders

Common: Irregular menstruation.

Rare: Amenorrhoea, dysmenorrhoea, elevated testosterone levels and polycystic ovaries.

Congenital, familial and genetic disorders

Frequency not known:

Congenital malformations and developmental disorders (see section 4.4 and section 4.6).

General disorders and administration site conditions

Very rare: hypothermia, which was reversible upon withdrawal of valproic acid.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Whenever an intoxication is being assessed, the possibility of multiple intoxication must be considered, for example through the intake of several medicinal products with suicidal intent.

At therapeutic serum levels (50-100 pg/ml), valproic acid has relatively low toxicity. Very rarely, acute intoxication with valproic acid at serum levels above 100 pg/ml has occurred in adults and children.

Isolated cases of acute and chronic overdose with fatal outcome have been reported in the scientific literature.

Symptoms of overdose:

Intoxication is characterised by confusion, sedation, sometimes leading to coma, muscle weakness, hyporeflexia and areflexia.

There have been isolated reports of hypotension, miosis, cardiovascular and respiratory disturbances, cerebral oedema, metabolic acidosis and hypernatraemia.

In both adults and children, high serum levels caused abnormal neurological disturbances, such as an increased tendency to seizures and behavioural changes.

Management of overdose:

No specific antidote is known.

Clinical management of overdose should thus be restricted to general measures aimed at toxin elimination and the support of vital functions.

If possible, within 30 minutes of intake, vomiting should be induced, gastric lavage performed or activated charcoal administered. Gastric lavage is useful up to 10-12 hours after the overdose. Intensive care monitoring is necessary.

Haemodialysis and forced diuresis may be effective. Peritoneal dialysis is less effective.

There has been insufficient experience to allow evaluation of the efficacy of haematogenic charcoal perfusion or complete plasma substitution and transfusion. Intensive medical therapy is thus recommended with monitoring of serum concentrations but without any specific detoxification procedures, particularly in children.

Intravenous administration of naloxone to relieve clouding of consciousness has been reported as effective in one case.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptics, fatty acid derivatives

ATC code: N03AG01

Valproic acid is an antiepileptic agent, with no structural similarities to other anticonvulsive active substances. The most probable mode of action of valproic acid is potentiation of GABA-mediated inhibition through a presynaptic effect on GABA metabolism and/or a direct postsynaptic effect on the ion ductules of the neuronal membrane.

5.2 Pharmacokinetic properties

Valproic acid is very poorly soluble in water (1:800), the sodium salt is highly soluble in water (1:0.4).

- Absorption:

Following oral administration, valproic acid and its sodium salt are rapidly and almost completely absorbed in the gastrointestinal tract.

- Serum levels, plasma protein binding, distribution

The time of peak serum concentrations depends upon the galenical formulation:

Valprotek CR 300 mg (prolonged release) tablets

In a single dose study after a high-fat meal the maximum serum concentration was reached approximately 5-12 h after intake of a prolonged-release tablet. After a dose of 300 mg sodium valproate, maximum serum concentrations of 10-29 pg/ml were measured.

There is an almost linear relationship between the dose of prolonged release tablets and the serum concentration.

The mean therapeutic range of the serum concentration is given as 50-100 pg/ml. Undesirable effects, including intoxication, are more likely above 100 pg/ml. Steady-state serum levels are usually reached within 3-5 days (5 times half-life).

In the cerebrospinal fluid, valproic acid concentrations are in accordance with the free-fraction of valproic acid in plasma.

The volume of distribution is age-dependent and is usually 0.13-0.23 l/kg; in younger patients it is 0.13-0.19 l/kg.

Valproic acid is 90-95% plasma-protein bound, mainly to albumin. Protein binding is reduced at higher doses. Plasma protein binding is lower in elderly patients and in patients with renal or hepatic dysfunction. In one study, higher values of the free active substance (8.5 to over 20%) were observed in patients with significantly reduced renal function.

The total valproic acid concentration, consisting of free and protein-bound fractions, may be largely unchanged in the presence of hypoproteinaemia, but may also be reduced due to increased metabolism of the free fraction.

- Metabolism, elimination

Biotransformation involves glucuronidation and P (beta), co (omega) and co-1 (omega-1) oxidation. Approximately 20% of an administered dose is recovered as ester glucuronide in the urine after renal excretion. More than 20 metabolites exist, whereby those resulting from omega oxidation are considered to be hepatotoxic. Less than 5% of the valproic acid dose is recovered in the urine in unchanged form.

The main metabolite is 3-keto-valproic acid, which occurs at 3-60% in the urine. This metabolite has anticonvulsant effects in the mouse but this effect has not been confirmed in humans.

- Plasma clearance, plasma half-life

In one study, plasma clearance was 12.7 ml/min in patients with epilepsy. In healthy volunteers it is 5-10 ml/min and is increased if enzyme-inducing antiepileptics are taken.

In monotherapy, the mean plasma half-life is 12-16 hours and remains constant in long-term therapy.

In combination with other medicinal products (e.g. primidone, phenytoin, phenobarbital and carbamazepine), the half-life is reduced to between 4 and 9 hours, depending on enzyme induction. In new-born infants, infants and toddlers up to 18 months of age, plasma half-lives of between 10 and 67 hours are reported. The longest half-lives have been observed immediately after birth. Above the age of 2 months, half-lives approximate to those of adults.

In patients with hepatic disease the half-life is prolonged. In cases of overdose, halflives of up to 30 hours have been reported.

During pregnancy there is a rise in the volume of distribution in the third trimester and a corresponding increase in hepatic and renal clearance, with a possible fall in the serum concentration at a constant dose.

It must also be taken into account that plasma protein binding can change during pregnancy and the free (therapeutically active) fraction of valproic acid may increase.

- Excretion into the breast milk

Valproic acid crosses the placental barrier and is excreted into the breast milk. At steady state, the concentration in breast milk is up to approximately 10% of the serum concentration.

5.3 Preclinical safety data

During investigations into chronic toxicity, at high doses (250 mg/kg in rats; 90 mg/kg in dogs), testicular atrophy, degeneration of the deferent duct and insufficient spermatogenesis and lung and prostate changes were reported.

Mutagenicity tests on bacteria and on rats and mice were negative.

Long-term studies were performed on rats and mice. At very high doses, an increased incidence of subcutaneous fibrosarcomas was observed in male rats. In animal studies, valproic acid was shown to be teratogenic.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core

Hypromellose 4000 mPas Hypromellose 15000 mPas Acesulfame potassium Silica colloidal hydrate

Tablet coat Sodium laurilsulfate Dibutyl sebacate

Basic butylated methacrylate copolymer Magnesium stearate Titanium dioxide

6.2    Incompatibilities

Not applicable

6.3    Shelf life

3 years

6.4    Special precautions for storage

Store in the original package and keep in a dry place in order to protect from moisture. This medicine is hygroscopic. Prolonged-release tablets should not be removed from their foil until immediately before they are taken. Blister strips should not be cut.

6.5    Nature and contents    of container

Valprotek CR 300 mg (prolonged release) tablets

Blister made from coated double aluminium foil 20, 30, 50, 60, 90, 100, 200, 500 (10x50, hospital pack) prolonged-release tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

ratiopharm GmbH Graf-Arco-Str. 3 89079 Ulm, Germany

8    MARKETING AUTHORISATION NUMBER(S)

PL 15773/0609

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/01/2008

10    DATE OF REVISION OF THE TEXT

29/12/2015