Eprolep Cr 200mg. 300mg. 500mg FC tablets

u2022 The treatment of generalised epilepsy, particularly with the following patterns of seizures:

• absence
• myoclonic
• tonic-clonic
• atonic
• mixed

• simple or complex seizures
• secondary generalised seizures
• specific syndromes (West, Lennox-Gastaut).

EPROLEP CR may be taken with food to reduce gastro-intestinal side effects. EPROLEP CR 200, 300 and 500 tablets are intended for oral administration. The tablets should be swallowed whole, if necessary with a little water (but not with aerated mineral water) and not crushed or chewed. EPROLEP CR is a controlled release formulation of EPROLEP CR , which reduces peak concentration and ensures a more even plasma concentration throughout the day. EPROLEP CR may be given once or twice daily. Daily dosage requirements vary according to age and body mass. In patients where adequate control has been achieved, EPROLEP CR formulations are interchangeable with other conventional or prolonged release formulations on an equivalent daily dosage basis.

Adult dose Epilepsy Dosage should start at 600 mg/day, where applicable in divided doses, increasing by 200 mg/day at three day intervals until control is achieved; this is generally within the range of 1 000 to 2 000 mg/day (i.e. 20 u2013 30 mg/kg body mass). If adequate control has not been achieved after two weeks, the dose may be further increased, in stages, to a maximum of 2 500 mg/day, or one other antiepileptic agent may be added at a low dosage. In patients already receiving other therapy, the same pattern should be followed. If increased sedation is observed, dosage of barbiturates or benzodiazepines (e.g. lorazepam) should be reduced as that of EPROLEP CR is increased; dosage of both EPROLEP CR and other agents should be adjusted, during the stabilisation period, to give optimum control at the lowest possible combined dosage level, and it may be found possible to maintain optimum control with EPROLEP CR alone.

Treatment and prevention of mania associated with bipolar disorders The recommended initial dose is 1 000 mg/day. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose, which produces the desired clinical effect. Doses should be adjusted according to individual clinical response. Prophylactic treatment should be established individually with the lowest effective dose.

Elderly patients (65 years and older) Although the pharmacokinetics of EPROLEP CR is modified in the elderly, this is of 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 medicine is increased. This will affect the clinical interpretation of plasma valproic acid levels.

Elderly patients have lowered intrinsic clearances, indicating a reduction of valproate metabolising capacity and a fall in serum albumin. These patients may also be more susceptible to certain adverse reactions, including somnolence. Therefore, these patients should receive a lower daily dosage, and the serum concentrations should be kept in the lower therapeutic range.

Renal insufficiency It may be necessary to decrease the dosage. The dosage should be adjusted according to clinical monitoring, since plasma concentrations may be misleading (see Pharmacokinetics ). Combined therapy When starting EPROLEP CR in patients already on other anticonvulsants, these should be tapered slowly. Initiation of EPROLEP CR therapy should then be gradual, with target dose being reached after about 2 weeks. In certain cases it may be necessary to increase the dose by 5 to 10 mg/kg/day when used in combination with anticonvulsants that induce liver enzyme activity, e.g. phenytoin, phenobarbitone and carbamazepine. Once known enzyme inducers have been withdrawn, or if side effects, such as tremor, are experienced, it may be possible to maintain seizure control on a reduced dose of EPROLEP CR . When barbiturates are being administered concomitantly and particularly if sedation is observed, the dosage of barbiturate should be reduced.

General considerations The concentration of valproate in plasma that appears to be associated with therapeutic effects is approximately 30 - 100 u03bcg/mu2113 . 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 Pharmacokinetics ).

u2022 Hypersensitivity to sodium valproate or any of the ingredients of EPROLEP CR . u2022 Pre-existing liver disease or a family history of severe hepatic dysfunction. u2022 Urea cycle disorders (hyperammonemic encephalopathy) . u2022 Concurrent use with MOAI (see INTERACTIONS ). u2022 Porphyria. u2022 Pregnancy and lactation (see PREGNANCY AND LACTATION ).

Severe liver damage Cases of severe liver damage, resulting in fatalities have been reported. Experience in epilepsy has indicated that patients most at risk, especially in cases of multiple anticonvulsant therapy are infants and young children under the age of 3 with severe disorders, particularly those with brain damage, mental retardation and (or) congenital metabolic or degenerative disease. After the age of 3, the incidence of occurrence is reduced and decrease with age. In most cases, such liver damage occurred during the first 6 months of therapy.

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):

• non-specific symptoms, usually of sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes associated with repeated vomiting and abdominal pain;
• in patients with epilepsy, recurrence of seizures.

Detection Liver function tests should be performed before and then periodically monitored during the first 6 months of therapy. Amongst usual investigations, tests, which reflect protein synthesis, particularly prothrombin rate, are most relevant. An adjustment of dosage may be considered when appropriate and tests should be repeated as necessary. Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors: increased bilirubin level and raised transaminases) requires cessation of EPROLEP CR therapy. As a matter of precaution and in case they are taken concomitantly, salicylates should also be discontinued, since they use the same metabolic pathway.

Pancreatitis Severe pancreatitis, which may result in fatalities, has been reported. Young children are at particular risk. This risk is decreased with increasing age. Severe seizures, neurological impairment or anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. Patients experiencing acute abdominal pain should have a prompt medical evaluation. In case of pancreatitis, EPROLEP CR should be discontinued.

Women of childbearing potential See PREGNANCY AND LACTATION for information on foetal malformations and developmental problems in children exposed to valproate (as in EPROLEP CR ) in utero, EPROLEP CR should not be used in young girls and women of child-bearing potential, or during pregnancy and lactation (see CONTRA-INDICATIONS ). When other treatments are ineffective or not tolerated, see u201c Recommendations to consider in girls reaching puberty and women who can have children u201d under PREGNANCY AND LACTATION .

Suicidal ideation and behaviour Suicidal ideation and behaviour have been reported in patients treated with EPROLEP CR in several indications. Patients should be monitored for signs of suicidal ideation and behaviour, and appropriate treatment should be considered. Patients (and caregivers) should be advised to seek medical advice immediately should signs of suicidal ideation or behaviour emerge.

Special precautions Liver function Liver function tests should be carried out before therapy (see CONTRA-INDICATIONS ), and periodically during the first 6 months especially in patients at risk (see WARNINGS ). More extensive biological investigation (including prothrombin rate) are recommended in those patients; an adjustment of dosage may be considered when appropriate and tests should be repeated as necessary.

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

Renal impairment 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 (see Pharmacokinetics ).

Autoimmune disease Although immune disorders have been infrequently noted during the use of EPROLEP CR , the potential benefit of EPROLEP CR should be weighed against the risk in patients with systemic lupus erythematosus.

Diabetic patients EPROLEP CR is eliminated mainly through the kidney, partly in the form of ketone bodies, and this may give false-positive readings in the urine testing of possible diabetics.

Other disorders When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with valproate. Patients should be warned of the risk of weight gain at the initiation of therapy; and appropriate strategies should be adopted to minimise it (see Side effects ). Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome.

Elderly patients (65 years or older) Elderly patients tend to have increased free, unbound valproate concentrations and lowered intrinsic clearances, indicating a reduction of valproate metabolising capacity and a fall in serum albumin. These patients may also be more susceptible to certain adverse reactions, including somnolence. Therefore, these patients should receive a lower daily dosage, and the serum concentrations should be kept in the lower therapeutic range.

Dental Valproate (contained in EPROLEP CR ) inhibits the secondary phase of platelet aggregation, which may be reflected in prolonged bleeding time and/or frank haemorrhaging. In addition, the leukopenic and thrombocytopenic effects of valproate may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work, whenever possible, should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss and toothpicks.

Surgical Because of the thrombocytopenic effects of valproate, as well as its inhibition of the secondary phase of platelet aggregation and production of abnormal coagulation parameters (e.g., low fibrinogen), monitoring of platelet counts and coagulation tests are recommended in patients prior to scheduled surgery.

Ability to drive or use machines Patients should be warned of the risk of somnolence with EPROLEP CR ; the more so in cases of anticonvulsant polytherapy or association with benzodiazepines (see INTERACTIONS and SIDE EFFECTS ).

There are complex interactions between antiepileptics and toxicity may be enhanced without a corresponding increase in antiepileptic activity. Such interactions are very variable and unpredictable and plasma monitoring is often advisable with combination therapy.

Effects of EPROLEP CR on other medicines Neuroleptics, MAO inhibitors, antidepressants and benzodiazepines EPROLEP CR may potentiate the effect of other psychotropic agents such as neuroleptics, MAO inhibitors, antidepressants and benzodiazepines. Patients should be monitored and the dosage should be adjusted when appropriate.

Phenobarbital EPROLEP CR increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Clinical monitoring is recommended right through the first 15 days of combined treatment. Phenobarbital doses should immediately be reduced if sedation occurs and phenobarbital plasma levels determined when appropriate.

Primidone EPROLEP CR increases primidone plasma levels, thereby aggravating its adverse effects (such as sedation). These symptoms usually cease with long-term treatment. Clinical monitoring is recommended, especially at the beginning of combined therapy, with dosage adjustment when appropriate.

Phenytoin EPROLEP CR decreases phenytoin total plasma concentration. Moreover EPROLEP CR increases phenytoin free form with possible overdosage symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Clinical monitoring is consequently recommended; when phenytoin plasma levels are determined, the free form should be evaluated.

Carbamazepine EPROLEP CR , co-administered with carbamazepine may potentiate the toxic effect of carbamazepine. Clinical monitoring is recommended, especially at the beginning of combined therapy; dosage adjustment should be applied when appropriate.

Lamotrigine EPROLEP CR may reduce lamotrigine metabolism and increase its mean half-life; the lamotrigine dosage should be decreased when appropriate. The risk of rash may possibly be increased by co-administration of lamotrigine with EPROLEP CR.

Zidovudine EPROLEP CR may raise zidovudine plasma concentration, which may result in an increase in zidovudine toxicity.

Effects of other medicines on EPROLEP CR By lowering the seizure threshold, antidepressants and neuroleptics may antagonise the antiepileptic activity of EPROLEP CR and may require EPROLEP CR dosage adjustments. Antiepileptics with enzyme inducing effect (including phenytoin, phenobarbital, carbamazepine) decrease valproate serum concentrations. Dosages should be adjusted according to blood levels where combined therapy is used. Co-administration of felbamate and EPROLEP CR may increase valproate serum concentration. EPROLEP CR dosage should be adjusted where required. Mefloquine increases valproic acid metabolism and has a convulsing effect; therefore epileptic seizures may occur in cases of combined therapy. Chloroquine may also lower the seizure threshold. During concomitant use of EPROLEP CR and highly protein bound agents (aspirin), valproate free serum levels may be increased. Close monitoring of INR should be performed in case of concomitant use of vitamin K dependent factor anticoagulants (e.g. warfarin) because the anticoagulant effect of these agents may be increased due to displacement from plasma protein binding sites by EPROLEP CR. Valproate serum levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin. Carbapenem antibiotics (imipenem/meropenem/ertapenem): Decrease in valproate blood level sometimes associated with convulsions has been observed when panipenem or meropenem were combined. If these antibiotics have to be administered, close monitoring of valproate blood level is recommended. Cholestyramine may decrease the absorption of EPROLEP CR . Rifampicin may decrease the valproic acid blood levels resulting in a lack of therapeutic effect. Therefore, dosage adjustments of EPROLEP CR may be necessary when it is co- administered with rifampicin.

Other interactions EPROLEP CR usually has no enzyme inducing effect; consequently EPROLEP CR does not reduce efficacy of oestrogen- and/or progestogen- containing medicines in women receiving hormonal contraception.

EPROLEP CR should not be used in pregnancy and lactation (see CONTRA- INDICATIONS ). Pregnancy Malformations There have been reports of foetal abnormalities in women receiving valproate during the first trimester. An increased incidence of congenital abnormalities (including facial dysmorphia, neural tube defects hypospadias, malformation of the limbs and multiple malformations) has been demonstrated in offspring born to mothers with epilepsy both untreated and treated, including those treated with sodium valproate (as contained in EPROLEP CR ). Malformations most frequently encountered are cleft lip and cardio-vascular malformations. The incidence of neural tube defects in women taking EPROLEP CR during first trimester has been estimated to be in the region of 1 %.

Developmental problems Developmental problems have been reported in up to 30 to 40 % of pre-school children exposed to valproate (as contained in EPROLEP CR ) in the womb, including delayed walking and talking, memory problems, difficulty with speech and language and lower intellectual ability. Children exposed to valproate in the womb are also at increased risk of autistic spectrum disorder (around 3 times higher than in the general population) and childhood autism (5 times higher than in the general population). There are also limited data suggesting that children exposed to valproate in the womb may be more likely to develop symptoms of attention deficit hyperactivity disorder (ADHD).

Other risks in the neonate Very rare cases of haemorrhagic syndrome have been reported in neonates whose mothers have taken EPROLEP CR 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. However, this syndrome has to be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and other antiepileptic enzyme inducing medicines. 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 the pregnancy. Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy. Hepatic failure, resulting in the death of a newborn and of an infant have been reported following the use of valproate during pregnancy.

Recommendations to consider in girls reaching puberty and women who can have children:

• EPROLEP CR should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.
• Only prescribe valproate medicines (such as EPROLEP CR ) if other treatments are ineffective or not tolerated.
• Inform patients of the risks of taking EPROLEP CR during pregnancy.
• Advise patients taking EPROLEP CR about effective contraception during their treatment.
• Inform patients to urgently consult their doctor in the case of planning a pregnancy, or if pregnancy is suspected.
• Pregnancies should be carefully screened by alpha-foetoprotein measurement and ultrasound and, if indicated, amniocentesis.
• EPROLEP CR treatment must be started and supervised by a doctor experienced in managing epilepsy or bipolar disorder.
• Women and girls who have been prescribed EPROLEP CR should not stop taking their medicines without consulting their doctor as doing so could result in harm to themselves or to an unborn child.
• Inform patients about the need for regular medical checks during treatment.
• Regularly review the need for treatment and re-assess the balance of the benefits and risks for female patients taking valproate and for girls reaching puberty.

Lactation Valproate is distributed into breast milk. Concentrations in breast milk have been reported to be 1 to 10 % of the total maternal serum concentration. See CONTRA-INDICATIONS .

The following side effects have been observed during treatment with EPROLEP CR : Blood and lymphatic system disorders Frequent: Anaemia, thrombocytopenia (see WARNINGS AND SPECIAL PRECAUTIONS u2013 u201c Blood tests u201d). Less frequent: Platelet aggregation inhibition or thrombocytopenia, reversible prolongation of bleeding time, bone marrow depression, red cell hyperplasia and leucopenia, isolated reduction of fibrinogen pancytopenia, agranulocytosis, anaemia macrocytic, macrocytosis.

Immune system disorders Less frequent: Allergic reactions, angioedema.

Endocrine disorders Less frequent: Life-threatening pancreatitis. Plasma amylase should be measured if there is acute abdominal pain, hyperglycaemia , syndrome of inappropriate secretion of ADH (SIADH), hypothyroidism.

Metabolism and nutrition disorders Frequent: Hyponatraemia. Frequency unknown: Hyperammonaemic encephalopathy in patients with urea cycle disorders, hyperglycinaemia.

Psychiatric disorders Frequent: Amnesia, sleep disorders, primarily insomnia, nervousness, somnolence, emotional lability, confusional state, aggression 1 . Less frequent: Behavioural, mood or mental changes, abnormal dreams, agitation, anxiety, confusion, depression, drowsiness, hallucinations, thinking abnormalities, unusual excitement, restlessness, irritability, sedation, 1 Mainly observed in the paediatric population.

Nervous system disorders Frequent: Ataxia, extrapyramidal disorder, stupor, convulsion, memory impairment, trembling of hands and arms, tremor, headache, dizziness. Less frequent: Abnormal gait , encephalopathy, lethargy, reversible parkinsonism, ataxia , catatonic reaction, dysarthria, hypertonia, hypokinesia, paraesthesia, increased reflexes, speech disorder, tardive dyskinesia, twitching, increased alertness.

Eye disorders Frequent: Amblyopia. Less frequent: Nystagmus, spots before eyes, diplopia, conjunctivitis, dry eyes, eye pain.

Ear and labyrinth disorders Frequent: Tinnitus deafness. Less frequent: Otitis media, vertigo, ear disorder or pain.

Cardiac disorders Less frequent: Palpitations, tachycardia.

Vascular disorders Less frequent: Hypotension, hypertension, postural hypotension, vasodilation.

Respiratory, thoracic and mediastinal disorders Frequent: Pharyngitis, flu syndrome. Less frequent: Dyspnoea, pneumonia, bronchitis, epistaxis, increased cough, rhinitis, sinusitis , pleural effusion.

Gastro-intestinal disorders Frequent: Abdominal or stomach cramps, diarrhoea, dyspepsia, nausea and vomiting, indigestion.

Less frequent: Hematemesis, periodontal abscess, anorexia or increase in appetite, constipation, dry mouth, faecal incontinence, flatulence, gastroenteritis, glossitis, stomatitis, taste perversion, minor gastric irritation.

Hepato-biliary disorders Frequency unknown: Hepatic failure resulting in death has occurred in patients taking EPROLEP CR . Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as loss of seizure control, malaise, weakness, lethargy, anorexia, vomiting, jaundice and oedema. Hepatotoxicity, liver dysfunction.

Skin and subcutaneous tissue disorders Frequent: Alopecia, skin rash. Less frequent: Discoid lupus erythematosus, dry skin, ecchymosis, furunculosis, petechia, pruritus, hirsutism, acne, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

Musculoskeletal, connective tissue and bone disorders Frequent: Back pain. Less frequent: Leg cramps, malaise, neck pain, neck rigidity, arthralgia, arthrosis, hypertonia, myalgia, myasthenia , bone mineral density decreased, osteopenia, osteoporosis, fractures in patients on long-term treatment with EPROLEP CR .

Renal and urinary disorders Less frequent: Urinary incontinence, cystitis, dysuria, reversible defects in renal tubular function (Franconiu2019s syndrome) , enuresis.

Reproductive system and breast disorders Frequent: Change in menstrual periods. Less frequent: Vaginal haemorrhage, amenorrhoea, dysmenorrhoea, metrorrhagia, vaginitis, gynaecomastia.

General disorders and administration site disorders Frequent: Infections, asthenia. Less frequent: Peripheral oedema (swelling), fatigue, unusual weight gain or loss, fever, chest pain, chills, oedema, malaise.

Congenital and familial/genetic disorders Frequency unknown: See u201cMalformationsu201d and u201cDevelopmental problems u201d under PREGNANCY AND LACTATION .

Investigations Less frequent: Coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged). ) Frequency unknown: Diagnostic tests Metyrapone test: decreased response to metyrapone. Thyroid function test: decreased T 4 and free T 3 and T 4 concentrations. Urine ketone test: false-positive results. Physiology/laboratory test values Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) and Lactate dehydrogenase (LDH): minor elevations of serum concentrations occur frequently and appear to be dose related; elevations may indicate asymptomatic hepatotoxicity. Amino acid screening: increases in glycine may occur. Bilirubin: serum concentrations may be increased; increase may indicate potentially serious hepatotoxicity.

Symptoms Symptoms of overdose may be serious CNS depression and respiration may be impaired. Full recovery is usual following treatment.

Treatment Treatment of overdose consist primarily of supportive and symptomatic measures. To decrease absorption u2013 The effectiveness of emesis or gastric lavage will depend upon the time elapsed since ingestion. To enhance elimination u2013 Haemodialysis, or tandem haemodialysis and haemoperfusion, may result in significant reductions in valproate serum concentrations. Specific treatment u2013 Maintenance of adequate urinary output must be ensured. Naloxone has been administered to counteract severe CNS depression, but it also theoretically reverses the anticonvulsant effect and should be used with caution. Supportive care u2013 Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.