Valproate sodium

500 mg/5mL

 (100 mg/mL)

Injectable solution only for I.v. Infusion (over 60 min)

Therapeutic indications

The treatment of epileptic patients who normally be maintained on oral sodium valproate, and for whom oral therapy is temporarily not possible.

Posology and method of administration

Valproate sodium should be administered as a 60 minute infusion (but not more the 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary it should be diluted with the at least 50 ml of a compatible diluted any unused portion of the vial contents should be discarded. 

Valproate sodium intravenous may be given by infusion using a separate intravenous line in

 Dextrose (5%) injection, USP

 Sodium chloride (0.9%) injection, USP

Lactated ringer^’s injection, USP

Dosage

Each vial of Valproate sodium intravenous is for single dose injection only. Any unused portion should be discarded.

Valproate sodium intravenous should not be administered via the same IV line as other IV additives. The intravenous solution is suitable for infusion by PVC, polyethylene or glass containers.

Patients already satisfactory treated with oral sodium valproate may be continued at their current dosage using continuous or repeated infusion. Other patients may be given a slow intravenous injection over 3-5 minutes, usually 400-800 mg depending on body weight (up to 10 mg/kg) followed by continues or repeated infusion up to a maximum of 2500 mg/day. Patients generally tolerated the rapid infusion well; however, the incidence of adverse event may be higher than with the standard infusion rate. The efficacy of faster infusion rates vs. the standard rate has not been determined. Use of the standard infusion rate is recommended unless the faster infusion rate is deemed medically necessary.

Use with children

Daily requirement for children is usually in the range 20-30 mg/kg/day and method of administration is as above. Where adequate control is not achieved within this range, the dose may be increased up to 40 mg/kg/day but only in patients in whom plasma valproic acid levels can be monitored. Above 40 mg/kg/day clinical chemistry and hematological parameters should be monitored.

Use in the elderly

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

In patients with renal insufficiency

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

In patients with hepatic insufficiency

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

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

Combined Therapy

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

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.

Contraindications

-Active liver disease

-In pregnancy unless there is no suitable alternative treatment

-Patients with known urea cycle disorders

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

-Hypersensitivity to Valproate sodium

-Porphyria

- Valproate is contraindicated in patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome and in children under two years of age who are suspected of having a POLG-related disorder

Special warnings

Liver dysfunction: Valproate sodium and its analogs are hepatotoxic and are contraindicated in patients with hepatic disease or significant hepatic dysfunction. Use with extreme caution in patients with a prior history of hepatic disease. Hepatotoxicity, including hepatic failure, has been fatal and may more commonly occur in the first 6 months of treatment. Because carnitine deficiency may promote hepatotoxicity, valproate should be avoided in patients with inborn errors of carnitine metabolism. Liver function tests (LFTs) should be performed before therapy and at frequent intervals for patients at risk, especially during the first 6 months of therapy. Clinicians should not completely rely on serum biochemistry since these LFTs may not always be abnormal, but should also consider the results of a detailed medical history and physical examination. In some instances, hepatotoxicity progressed even after the drug was discontinued. Patients with organic brain syndrome, congenital metabolic disorders, severe seizures or a severe seizure disorder accompanied by mental retardation, on multiple anticonvulsants, and pediatric patients less than 2 years of age may be at highest risk for hepatotoxicity. Valproate sodium also should be dosed carefully in patients with hypo albumin because protein binding is reduced, which can increase the likelihood for drug-induced toxicity.

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

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:

• Non-specific symptoms, usually of sudden onset, such as asthenia, malaise, anorexia, lethargy, edema 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 should be instructed to report immediately any such sings to physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.

Liver function should be measured before therapy and then periodically monitored during the first 6 months of therapy, especially in those who seem most at risk, and those with a prior history of liver disease.

Amongst usual investigations, test 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 decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminase) requires cessation of Sodium valproate 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 anti-epileptic 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 whit increasing age. Severe seizures and sever neurological important whit combination anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, Sodium valproate should be discontinued.

Women of childbearing potential: This medicine should not be used in women of childbearing potential unless clearly necessary.

Suicidal ideation and behavior: Suicidal ideation and behavior have been reported in patients treated with anti-epileptic agents in several indications.

Precautions

Hematological tests: Blood 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.

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

Hyperammonemia:When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk ofhyperammonemiawith 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 minimize it.

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

Interaction with other medicinal products and other forms of interaction

Alcohol: Alcohol intake is not recommended during treatment with valproate

Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines: Sodium valproate may potentiate the effect of other psychotropics, therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.

Lithium: Sodium valproate has no effect on serum lithium levels.

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

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

Phenytoin: Sodium valproate decreases phenytoin total plasma concentration. Moreover Sodium valproate increases phenytoin free form with possible overdose symptoms. Therefore clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.

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

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

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

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

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

Zidovudine: Sodium valproate may raise zidovudine plasma concentration leading to increased zidovudine toxicity.

Nimodipine: In patients concomitantly treated with sodium valproate and nimodipine the exposure to

nimodipine can be increased by 50%. The nimodipine dose should therefore be

decreased in case of hypotension

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

Effects of other drugs on Sodium valproate

-Anti-epileptics with enzyme inducing effect including phenytoin, phenobarbital, carbamazepine decrease valproic acid plasma concentrations. On the other hand, combination of felbamate and Sodium valproate decreases valproic acid clearance by 22% to 50% and consequently increase the valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.

-Mefloquine and chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore epileptic seizure my occur in cases of combined therapy. Accordingly, the dosage of Sodium valproate may need adjustment.

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

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

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

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

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

- Protease inhibitors such as lopinavir and ritonavir decrease valproate plasma level when co-administered

- Cholestyramine may lead to a decrease in plasma level of valproate when co-administered.

Other Interactions

-Caution is advised when using Sodium valproate in combination with newer anti-epileptics whose pharmacodynamics may not be well established.

-Concomitant administration of Sodium valproate and topiramate has been associated with encephalopathy and/or hyperammonemia. In patients taking these two drugs, careful monitoring of signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.

-Sodium valproate usually has no enzyme-inducing effect; as a consequence, Sodium valproate dose not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception, including the oral contraceptive pill.

Fertility, pregnancy and lactation

Women of childbearing potential should not be started on Sodium valproate without specialist neurological advice.

The following recommendations should be taken into consideration:

This medicine should not be used during pregnancy and in women of childbearing potential unless clearly necessary (i.e. in situations where other treatments are ineffective or not tolerated). This assessment is to be made before Sodium valproate is prescribed for the first time, or when a woman of childbearing potential treated with Sodium valproate plans a pregnancy. Woman of childbearing potential must use effective contraception during treatment. Woman of childbearing potential should be informed of the risks and benefits of the use of Sodium valproate during pregnancy.

If a woman plans a pregnancy or becomes pregnant, Sodium valproate therapy should be reassessed whatever the indication:

-In epilepsy, valproate therapy should not be discontinued without reassessment of the benefit risk, if further to a careful evaluation of the risks and benefits, Sodium valproate treatment is to be continued during pregnancy it is recommended to use Sodium valproate in divided doses over the day at the lowest effective dose, as abnormal pregnancy outcome tends to be associated with higher total daily dosage and with the size of an individual dose. The incidence of neural tube defects rises with increasing dosage, particularly above 1000mg daily.

-In addition, if appropriate, folate supplementation should be started before pregnancy at a relevant dosage (5mg daily) as it may minimize the risk of neural tube defects.

-Specialized prenatal monitoring should be instituted in order to detect the possible occurrence of neural tube defects or other malformations.

The available evidence suggests that anticonvulsant monotherapy is preferred.

Pregnancies should be carefully screened by ultrasound, and other techniques if appropriate.

Risk in the neonate:

Very rare cases of hemorrhagic syndrome have been reported in neonates whose mothers have taken Sodium valproate during pregnancy. This hemorrhagic syndrome is related to hypofibrinogenemia; afibrinogenemia has also been reported and may be fatal. These are possibly associated with a decreased of coagulation factors. However, this syndrome has to be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and other anti-epileptic enzyme inducing drugs. Therefore, plant count, fibrinogen plasma level, coagulation test and coagulation factors should be investigated neonates.

Cases of hypoglycemia have been reported in neonates, whose mothers have taken valproate during the third trimester of the pregnancy.

Lactation

Excretion of Sodium valproate in breast milk is low, with a concentration between 1% to 10% of total maternal serum levels. Although there appears to be no contra-indication to breastfeeding, physicians are advised that in any individual case, consideration should be given to the safety profile of Sodium valproate, specifically hematological disorder.

Effects on ability to drive and use machines

Use of intravenous formulation restricted to patients unable to take oral therapy. However, note use of Sodium valproate may provide seizure control such the patient may again be eligible to hold a driving license.

Patients should be warned of the risk of transient drowsiness, especially in case of anticonvulsant polytherapy or association with benzodiazepines.

Undesirable effects

Congenital and familial/genetic disorders: See section fertility, pregnancy and lactation.

Hepato-biliary disorders: See Special warnings.

Gastrointestinal disorders (nausea, gastralgia, diarrhea) frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking Sodium valproate with or after food or by using Enteric Coated Sodium valproate.

Very rare cases of pancreatitis, sometimes lethal, have been reported (see Special warnings).

Nervous system disorders: Sedation has been reported occasionally, usually when in combination with other anticonvulsant. 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 come have very rarely 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.

Very rare cases of extrapyramidal symptoms which may not be reversible including reversible Parkinsonism, or reversible dementia associated with reversible cerebral atrophy have been reported. Dose-related ataxia and fine postural tremor have occasionally been reported.

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

Psychiatric disorder: Confusion has been reported.

Metabolic disorders: Cases of isolated and moderate hyperammonemiawithout change in liver function test may occur frequently, 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 Sodium valproate should be discontinued. Very rare cases of hyponatremia have been reported.

Syndrome of inappropriate secretion of ADH (SIDAH)

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

Dizziness: When using Sodium valproate intravenously, dizziness may occur a few minutes after injection.

Blood and lymphatic system disorders:

Frequent occurrence of thrombocytopenia, rare cases of anemia, leucopenia or pancytopenia. The blood picture returned to normal when the drug was discontinued.

-Bone marrow failure, including pure red cell aplasia.

-Agranulocytosis.

-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 (Sodium valproate has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations.

Skin and subcutaneous tissue disorders:

Rash rarely occurs with Sodium valproate in very rare cases toxic epidermal, necrolysis, Stevens-Johnson syndrome and erythema multiform have been reported.

Transient hair loss, which may sometimes be dose-related, has often been reported. Regrowth normally begins within six months, although the hair may become curlier than previously. Hirsutism and acne have been very rarely reported.

Reproductive system and breast disorders:

Amenorrhea and dysmenorrhoea have been reported. Very rarely gynecomastia has occurred. Male infertility.

Vascular disorders:

The occurrence of vasculitishas occasionally been reported.

Ear disorders:

Hearing loss, either reversible or irreversible has been reported rarely; however a cause and effect relationship has not been established.

Renal and urinary disorders:

There have been isolated reports of a reversible Falcone’s syndrome associated with Sodium valproate therapy, but the mode of action is as yet unclear.

Very rare cases of enuresis have been reported.

Immune system disorders:

Angioedema, Drug Rash with Eosinophilia, System Symptoms (DRESS) syndrome, and allergic reactions (ranging from rash to hypersensitivity reactions) have been reported.

General disorders and administration site conditions:

Very rare cases of non-severe peripheral edema have been reported.

Increase in weight may also occur. Weight gain being a risk factor for polycystic ovary syndrome, it should be carefully monitored. When using Sodium valproate intravenously, nausea or dizziness may occur a few minutes after injection; they disappear spontaneously within a few minutes.

Musculoskeletal and connective tissue disorders:

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients a long-term therapy with Sodium valproate.

Overdose

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 10 to 20 times maximum therapeutic levels, usually include CNS depression or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis. A favorable outcome is usual; however, some deaths have occurred following massive overdose.

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 edema have been reported.

Hospital management of overdose should be symptomatic, including cardio-respiratory monitoring. Gastric lavage may be useful up to 10 to 12 hours following ingestion.

Hemodialysis and hemoperfusion have been used successfully.

Naloxone has been successfully used in a few isolated cases, sometimes in associated with activated charcoal given orally.

In case of massive overdose, hemodialysis and hemoperfusion have been used successfully.

Pharmacokinetic properties

The half-life of Valproate sodium is usually reported to be within the range 8-20 hours. It is usually shorter in children.

In patients with severe renal insufficiency it may be necessary to alter dosage in accordance with free plasma valproic acid levels.

The reported effective therapeutic range for plasma valproic acid levels is 40-100mg/liter (278-694 micromole/liter). This reported range may depend on time of sampling and presence of co-medication. The percentage of free (unbound) drug is usually between 6% and 15% of the total plasma levels. An increased incidence of adverse effects may occur with plasma levels above the effective therapeutic range.

The pharmacological (or therapeutic) effects of Valproate sodium may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.

Incompatibilities

Valproate sodium Intravenous should not be administered via the same line as other IV additives.

How Supplied

Valproate sodium 500 mg/mL, solution is a clear colorless and sterile solution. It is supplied in single use    5 mL vials, available in box of 5 vials.

Storage

Keep in original package and store below 30^˚C and protect from light and freezing.

References

FDA Lable

PDR 2020

EMC 2020

Marketing Authorization Holder:DarouDarmanArang