Orfiril Injection

/ Megapharm

The dosage should be determined according to age and weight and monitored individually by the physician on the basis of concentration determinations. Close monitoring of plasma levels and – if necessary – dosage adjustments have to be performed during the change-over to a parenteral therapy, during the parenteral therapy and during the switch back to oral therapy, in particular in such patients receiving higher doses of valproate or in patients receiving medicinal products potentially influencing the metabolism of valproate. Therapeutic efficacy is usually reached at plasma levels between 50 and 100 mg/L (340-700 µmol/L). The mean :daily dosages during maintenance treatment are as follows:
Children: 30 mg sodium valproate/kg body weight
Adolescents: 25 mg sodium valproate/kg body weight
Adults: 20 mg sodium valproate/kg body weight Higher maintenance doses for children and adolescents arise from higher valproate clearence values in these patients.
Starting of treatment and continuation of maintenance treatment in patients on valproate
Children and adults: (.To a new patient, initially a 5-10 mg/kg bolus dose as a slow intravenous (i.v injection over 3-5 minutes of sodium valproate is recommended. The dosage should be elevated by 5 mg/kg every 4 – 7 days to the recommended maintenance dose for each age group, or until a satisfactory clinical response is achieved. The total daily dose should be divided in three to four single administrations. To a patient previously on the medicinal product, an equivalent of the usual oral single dose mg) as a slow intravenous (i.v.) injection over 3-5 minutes or as a short infusion is) recommended; if necessary, the administration is continued as repeated injections every 6 hours, or as a slow intravenous infusion at 0.6-1 mg/kg/h until the patient can take the medicine orally. For children, a maintenance dose of 30 mg/kg/day of ,sodium valproate is recommended, but if adequate seizure control is not achieved the dose can be elevated to 40 mg/kg/day. In such cases, plasma valproic acid levels should be monitored frequently. It should be noted that in infants younger than 2 months, the elimination half-life of valproic acid might be up to 60 h. This should be taken in consideration when increasing the dosage to maintenance .treatment. The maximal dose recommended for adults is 2400 mg/day In patients with renal failure, the rise in free valproic acid in the plasma must be taken into consideration and the dose reduced accordingly.

General seizure in form of absence, myoclonic/tonic-clonic seizure, partial, secondary general seizure.

Sodium valproate must not be used in patients with:
– Hypersensitivity to sodium valproate or to any of the excipients.
– Previous or present liver disease and/or severe current dysfunction of the liver or pancreas.
– Liver disease in family history.
– A history of a sibling having died from liver dysfunction during sodium valproate  treatment.
– Porphyria.
– In patients with blood coagulation disorders or thrombocytopenia.
For full details see prescribing information.

Sodium valproate must be used only with special care (relative contraindication):
In infants and children in whom concomitant treatment with several antiepileptics is necessary.
In patients with bone marrow damage.
In children and adolescents with multiple handicaps and severe forms of epilepsy.
In patients with metabolic diseases, particularly with hereditary enzyme deficiency diseases.
In patients with systemic lupus erythematodes.
In patients with insufficient renal function and hypoproteinaemia In rare cases, severe liver or pancreatic damage with a fatal outcome has been observed in children and adolescents particularly in combination therapy with other antiepileptics. Those most frequently affected are infants and children below the age of 3 years suffering from severe epileptic seizures, particularly in the presence of brain damage, mental retardation and/or a hereditary metabolic disease. Sodium valproate should be administered with special care and as monotherapy in this patient group. Experience has shown that above this age (particularly after the age of 10 years) the frequency of liver diseases declines substantially. In the majority of cases, liver damage was observed within the first 6 months of treatment, particularly between weeks 2 and 12, and mostly associated with concomitant use of other antiepileptics. Severe or fatal liver damage may be preceded by non-specific symptoms such as an increase in the frequency of seizures, physical malaise, loss of appetite, averseness for usual food or valproate, epigastric pain, nausea, vomiting, localised or generalised oedema of various types, haematoma/epistaxis, fatigue, jaundice and lethargy. The occurrence of these symptoms should be closely monitored. Sodium valproate treatment must be discontinued immediately if severe liver dysfunction or pancreatic damage is suspected. Tripling of the serum aspartate aminotranferase (AST) and alanine aminotransferase (ALT) values, moderate (1.5-2-fold) increase of ALT or AST accompanied by an acute infection with fever, abnormally prolonged prothrombin time (particularly in the presence of other changes in laboratory parameters, such as fibrinogen and clotting factors (mainly factor VIII) or elevated bilirubin or liver enzymes), elevation of alkaline phosphatase and bilirubin values and changes in protein values can be considered to be criteria for discontinuation. In infants, sodium valproate is the first-line active substance only in exceptional cases; it should be used only with great caution and after careful consideration of the risk-benefit ratio and, if possible, as monotherapy.
Children: Before the onset of treatment, then once monthly for 6 months, and after this twice at 3-month intervals. In addition, it is recommended that the parents/guardians have telephone contact to the attending physician regularly between the laboratory controls to ensure early detection of toxic or other clinical symptoms.
For full details see prescribing information.

The undesireable effects that can result from use of Orfiril® injection include all of those associated with oral forms of valproate. With parenteral administration also burning sensation at the injection site might occur. The most commonly reported undesirable effects for sodium valproate are gastrointestinal disturbances, occuring in approximately 20% of the patients. Cases of severe (and even fatal) liver damage have been observed particularly in children treated with high doses or in combination with other antiepileptics. The undesireable effects have been classified in order of frequency by the mentioned convention: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), including isolated reports.
Blood and the lymphatic system disorders:  Common: Thrombocytopenia, leucopenia.
Metabolism and nutrition disorders:  Common: Hyperammonemia, increased or decreased weight, increased or reduced appetite.
Psychiatric disorders: Rare: Irritability, hallucinations, confusion.
Nervous system disorders:  Common: Drowsiness, tremor, paraesthesias, sleepiness. Uncommon: Transient coma, in some cases associated with increased seizure frequency. Rare: Headache, hyperactivity, spasticity, ataxia, stupor,hypersalivation.
For full details see prescribing information.

If sodium valproate is combined with other antiepileptics, it should be noted that reciprocal effects on plasma concentrations are possible: enzyme-inducing antiepileptics such as phenobarbitone, phenytoin and carbamazepine increase valproic acid excretion and therefore reduce its effect. Concomitant use with inducing medicinal products can increase the risk of liver toxicity and hyperammonaemia. Felbamate increases dose-dependently the plasma concentration of free valproic acid linearly about 18 %. Mefloquine increases the breakdown of valproic acid and also has potentially spasmogenic effects. Concomitant administration can therefore lead to epileptic seizures.
The serum concentration of valproic acid can be elevated by the concomitant administration of cimetidine, fluoxetine and erythromycin. However, cases of decreased valproic acid serum levels with coadministration of fluoxetine have been reported as well. Antimicrobial drugs belonging to the carbapenem group can decrease the serum concentration of sodium valproate. Concomitant use of sodium valproate and anticoagulants (warfarin) or acetylsalicylic acid may increase the tendency to bleeding. Acetylsalicylic acid also reduces the plasma-protein binding of valproic acid. Regular monitoring of blood coagulation is therefore recommended. Sodium valproate and acetylsalicylic acid should not be administered concomitantly in fever and pain, particularly in babies and infants. It is possible that potentially hepatotoxic medicinal products, including alcohol, may exacerbate liver toxicity. In combination therapy with lithium, the concentrations of both active substances in plasma should be monitored regularly. The valproate-induced rise in phenobarbitone concentration, which may manifest
as severe sedation, is of special clinical importance. If this occurs, the dose of phenobarbitone or primidone must be reduced (primidone is partly metabolised to phenobarbitone). Therefore, careful clinical monitoring is recommended throughout the first 24 hours of treatment of status epilepticus and during the first 15 days of combination therapy in electic antiepileptic treatment. Valproic acid may cause a transient considerable increase of free (unbound) phenytoin levels but as a result of concomitant use, total phenytoin levels decrease. This has, however, usually no clinical significance since the amount of free phenytoin remains sufficient. Valproic acid can increase carbamazepine-10,11-epoxide levels to a toxic region despite carbamazepine level within the therapeutic range. In concomitant use, nimodipine level may increase significantly because of metabolic inhibition. Valproic acid inhibits the metabolism of lamotrigine. Therefore, the dosage of lamotrigine must be reduced in concomitant use. The risk of skin reactions appears to be increased if drugs containing valproic acid
are combined with lamotrigine. Sodium valproate increases the concentration of ethosuximide in plasma, with risk for undesirable effects. When the two medicinal products are combined, control of plasma levels of ethosuximide is recommended. Valproic acid may increase the plasma concentration of zidovudine, with the increased risk of toxic reactions.
For full details see prescribing information.

Pregnancy: Risk related to epilepsy and antiepileptic drugs in general.The risk of birth defect is increased by factor 2 – 3 in the offspring of mothers treated with an antiepileptic. Most frequently reported are cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic drug therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is important that monotherapy is practised whenever possible. Specialist advice should be given to women who are likely to become pregnant or who are of childbearing potential and the need for antiepileptic treatment should be reviewed when a woman is planning to become pregnant. No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures which could have serious consequences for both mother and child. Developmental delay in children of mothers with epilepsy has been observed rarely. It is not possible to differentiate if the developmental delay is caused by genetic, social factors, maternal epilepsy or the antiepileptic therapy.
Risk linked to valproate: Congenital abnormalities including neural tube defects (spina bifida, meningomyelocele) and other midline defects like hypospadias in male children, skeletal deformities (facial dysmorphia – also in conjugation with mental retardation, limb malformations) and cardiac deformities have been reported in offspring born to mothers with epilepsy who have been treated with valproate. Bilateral aplasia of the radius would appear to be a rare but specific effect of pharmaceuticals containing valproate. A foetal antiepileptic syndrome has been described. Some data have suggested an association between in-utero valproate exposure and the risk of developmental delay (frequently associated with craniofacial abnormalities), particularly of verbal IQ. In the case of women of a childbearing age, attention should be drawn to the necessity of planning and monitoring a pregnancy even before the start of treatment. Prenatal diagnostic measures for the early detection of damage (ultrasound and alpha-fetoprotein determination) are recommended. A combination with other antiepileptics increases the risk of deformities. Therefore valproic acid should be administered in the form of a monotherapy whenever this is possible. Folic acid supplementation, prior to pregnancy may reduce the incidence of neural tube defects in infants born to women at high risk. Women should consider taking 5 mg folic acid /day when she plans to become pregnant. Orfiril treatment should not be interrupted during pregnancy without the agreement of the doctor, as a sudden discontinuation of the therapy or uncontrolled reduction in the dose may lead to epileptic seizures in expecting mothers which may prove harmful to her and/or the unborn child. Abnormal pregnancy outcomes tend to be associated with higher total daily dosage and size of an individual dose. There is evidence that high plasma peak levels and the size of an individual dose are associated with neural tube defects. The incidence of neural tube defects rises with increasing dosage, particularly above 1000 mg/day. Valproic acid passes through the placenta and reaches higher concentrations in the foetal plasma than in the maternal plasma. If Orfiril® is indispensable, it should be administered in the lowest seizure-controlling dose during pregnancy, particularly in the first trimester. As deformities are very probably caused by peak concentrations in the plasma, the daily dose should be distributed over several small doses throughout the day if the patient intends to bear the child, particularly between the 20th and 40th day of pregnancy. In addition, there should also be regular monitoring of the plasma concentration, as the plasma concentrations may evidently be subject to considerable fluctuations during the course of the pregnancy even if the dosage remains. Withdrawal symptoms in neonates whose mothers were treated with valproic acid have been reported. There are reported cases of disturbances to blood coagulation (haemorrhagic syndrome) in neonates whose mothers were treated with valproate during pregnancy. This syndrome is attributed to hypofibrinogenaemia. There have also been reports of fatalities due to the total absence of fibrin. The hypofibrinogenaemia may occur together with a reduction in coagulation factors. However, this syndrome must be distinguished from a drop in vitamin K-dependent coagulation factors caused by enzyme inducers such as phenobarbitone. For this reason the blood platelets, fibrinogen level and coagulation factors in the newborn should be examined and coagulation tests carried out.
Lactation: Valproic acid passes into the mother’s milk. However, the quantities are small and are not generally associated with any risk to the child, so that weaning is not necessary as a rule.

Whenever intoxication is evaluated, the possibility of multiple intoxication as a result of the possible ingestion of several medicinal products, for example in suicide attempts, should be considered. At a reference range (340-700 μmol/l), valproic acid has relatively low toxicity. Individual, rare cases of acute and chronic over-dosage with a fatal outcome have been reported in the literature.
Symptoms of overdose:  The symptoms of intoxication are characterised by confusion, sedation or even coma, myasthenia and hypo- or areflexia. Hypotension, myosis, cardiovascular and respiratory disorders, cerebral oedema, metabolic acidosis, hypocalcaemia and hypernatraemia have also been observed in individual cases. In adults and children, high plasma levels provoke abnormal neurological reactions and behavioural changes.
Management of overdose: No specific antidote is known. Treatment must therefore be limited to general measures to remove the active substance from the body and to support vital functions. In case of oral intoxication, vomiting should be induced or a gastric lavage administered and activated charcoal given if possible within 30 minutes after ingestion. In this case, intensive medical supervision is necessary. Haemodialysis or forced diuresis may be useful. Peritoneal dialysis has little effect. There is insufficient experience on the efficacy of haematogenic charcoal perfusion or complete plasma replacement and blood transfusion. For this reason, particularly in children, intensive in-patient treatment is recommended, with no special detoxification techniques but with monitoring of the plasma concentration.