Valproic acid

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Clinical Pharmacology

ATH:

N.03.A.G.01 Valproic acid

Pharmacodynamics:

Antiepileptic drug that has a central muscle relaxant and sedative effect.

It shows antiepileptic activity in various types of epilepsy. The main mechanism of action appears to be related to the effect of valproic acid on the GABAergic system: an increase in the content of gamma-aminobutyric acid (GABA) in the central nervous system and the activation of GABAergic transmission.

Pharmacokinetics:

Absorption.

The bioavailability of sodium valproate and valproic acid when administered orally is close to 100%.

When taking valproic acid, long-acting pills, 500 mg at a dose of 1000 mg / day, the minimum plasma concentration is 44.7 ± 9.8 μg / ml, and the maximum plasma concentration (Cmax) is 81.6 ± 15.8 μg / ml . The time to reach the maximum concentration is 6.58 ± 2.23 hours. The equilibrium concentration is reached within 3-4 days of regular use of the drug.

The average therapeutic range of serum concentrations of valproic acid is 50-100 mg / l. If there is a reasonable need to achieve higher concentrations and blood plasma, the ratio of the expected benefit to the possible risk of unwanted adverse reactions, especially dose-dependent, should be carefully weighed. For example, at concentrations greater than 100 mg / l, an increase in undesirable side reactions is expected, up to the development of intoxication. With a plasma concentration of more than 150 mg / l, a dose reduction of the drug is required.

Distribution

The volume of distribution depends on age and is usually 0.13-0.23 l / kg, in young people it is 0.13-0.19 l / kg.

Communication with plasma proteins (mainly with albumin) is high (90-95%), dose-dependent and saturable. In elderly patients, patients with renal and hepatic insufficiency, communication with plasma proteins is reduced. In severe renal failure, the concentration of the free fraction (therapeutically active) of valproic acid may increase by 8.5–20%.

With hypoproteinemia, the total concentration of valproic acid (free fraction (unbound to plasma proteins) + bound fraction (bound to plasma proteins)) may not change, but may also decrease due to an increase in metabolism of the free fraction (unbound to plasma proteins) valproic acid acid. Valproic acid penetrates into the cerebrospinal fluid and into the brain. The concentration of valproic acid in the cerebrospinal fluid is 10% of the corresponding concentration in serum.

Valproic acid penetrates into breast milk during lactation. In equilibrium, the concentration of valproic acid in breast milk is from 1 to 10% of its concentration in blood serum.

Metabolism

Metabolized in the liver by glucuronidation, as well as beta, omega-, and omega-1 oxidation. Revealed more than 20 metabolites, metabolites after omega-oxidation have a hepatotoxic effect.

Valproic acid does not induce liver microsomal enzymes: unlike most other antiepileptic drugs, valproic acid does not affect the extent of its own metabolism, or the degree of metabolism of other substances, such as estrogens, progestogens and indirect anticoagulants.

Removal

Valproic acid is preferentially excreted by the kidneys after conjugation with glucuronic acid and beta-oxidation. Less than 5% of valproic acid is excreted by the kidneys unchanged.

Plasma clearance of valproic acid in patients with epilepsy is 12.7 ml / min.

The half-life (T1 / 2) is 15-17 hours. When combined with antiepileptic drugs that induce liver microsomal enzymes, plasma clearance of valproic acid increases and T1 / 2 decreases, the degree of their change depends on the degree of induction of liver microsomal enzymes by other antiepileptic drugs.

T1 / 2 in children older than 2 months is close to that in adults.

In patients with liver disease, T1 / 2 valproic acid increases.

In case of overdose, an increase in T1 / 2 up to 30 hours was observed. Only the free fraction of valproic acid in the blood plasma (10%) is subjected to hemodialysis.

Features pharmacokinetics during pregnancy

With an increase in the distribution of valproic acid in the third trimester of pregnancy, its renal and hepatic clearance increases. However, despite taking the drug in a constant dose, a decrease in serum concentrations of valproic acid is possible. During pregnancy, the association of valproic acid with plasma proteins may change, which may lead to an increase in the concentration of the free fraction (therapeutically active) of valproic acid. Compared with the enteric-coated form, the form of prolonged action in equivalent doses is characterized by the following:

- no suction delay after taking;

- prolonged absorption; identical bioavailability;

- less Cmax (reduction of Cmax by about 25%), but with a more stable plateau phase from 4 to 14 hours after ingestion;

- a more linear correlation between the dose and the concentration of valproic acid in the blood plasma.

Indications

In adults: treatment of generalized epileptic seizures: clinical, topical, tonic-clinical, absences, myoclonic, atopic; Lennox-Gasto syndrome (in monotherapy or in combination with other antiepileptic drugs).

Treatment of partial epileptic seizures: partial seizures with secondary generalization or without it (in monotherapy or in combination with other antiepileptic drugs).

Treatment and prevention of bipolar affective disorders.

In children: treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic; Lennox-Gasto syndrome (in monotherapy or in combination with other antiepileptic drugs).

Treatment of partial epileptic seizures: partial seizures with secondary generalization or without it (in monotherapy or in combination with other anti-epidemic drugs).

Composition

1 tablet contains:

active ingredients: sodium valproate 199.80 mg / 333.00 mg, valproic acid 87.00 mg / 145.00 mg (equivalent to sodium valproate 100.20 mg / 167.00 mg);

excipients: hypromellose-2910 57.00 / 95.00 mg, hypromellose-2208 57.00 / 95.00 mg, silicon dioxide, colloidal water, 27.60 / 46.00 mg, acesulfame potassium 3.60 / 6.00 mg ;

sheath: butyl methacrylate copolymer 11.55 / 15.20 mg, magnesium stearate 2.89 / 3.80 mg, titanium dioxide 1.97 / 2.60 mg, dibutyl sebacate 1.75 / 2.30 mg, sodium lauryl sulfate 0.84 / 1.10 mg.

Valproic acid is marketed under different brands and generic names, and comes in different dosage forms:

Brand name	Manufacturer	Country	Dosage form
			pills
Convulex®	Gerot Pharmatsyteka GmbH	Germany	pills
Valparin XR	Torrent	India	pills
Encorate chrono	Sun Pharmaceutical Industries Ltd	India	pills
Depakene Chronosphere	Sanofi-aventis	France	granules
Encorate	Sun Pharmaceutical Industries Ltd	India	pills
Convulex®	Gerot Pharmatsyteka GmbH	Germany	drops
Convulex®	Gerot Pharmatsyteka GmbH	Germany	syrup
Convulex®	Gerot Pharmatsyteka GmbH	Germany	ampoules
Depakene Chrono	Sanofi-aventis	France	pills
Depakene Enteric 300	Sanofi-aventis	France	pills
Depakin	Sanofi-aventis	France	syrup
Depakin	Sanofi-aventis	France	ampoules

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Dosage and Administration

For oral use. during a meal, the dose is set individually. The tablet should be swallowed whole, without breaking, not chewing. You can not change the dose and treatment regimen without consulting a doctor.

Adults: the drug is prescribed in an initial daily dose of 0.3-0.6 g in 2 divided doses. The dose is gradually increased by 0.1-1.15 g / day every 3-4 days until the desired effect is achieved. The maximum daily dose - 2.4 g.

Children weighing less than 40 kg: the drug is prescribed in a daily dose of 20 mg / kg.

Children weighing 40 kg or more: the maximum daily dose is 40 mg / kg body weight. The multiplicity of appointments - 2 times / day.

Cancellation of treatment is done with a gradual decrease in dose, within 1-2 years. In the case of efficacy of therapy, recalculation of the dose depending on the body weight of the child may not be performed, if this does not indicate a deterioration of the ECG.

Adverse reactions

On the part of the digestive system: at the beginning of treatment, transient disorders are possible: anorexia, stomach pain, nausea, vomiting, diarrhea, increased appetite; rarely - constipation, pancreatitis, up to severe lesions with a fatal outcome.

On the part of the central nervous system: lethargy, ataxia, tremor, changes in behavior, mood or mental state (depression, fatigue, hallucinations, aggressiveness, hyperactivity, psychosis, unusual agitation, restlessness or irritability), dizziness, drowsiness, headache, dysarthria, enuresis, stupor, impaired consciousness, coma.

On the part of the senses: diplopia, nystagmus, flashing flies before the eyes

On the part of the liver: a transient increase in liver enzyme activity is observed, which is observed during the first few months of treatment and is often not manifested by any clinical symptoms (about 40%). The risk of developing these side effects depends on the dose of the drug; at lower doses, these effects decrease or disappear. The development of fulminant hepatitis with a fatal outcome is very rarely observed, and it is not always possible to identify previous changes in liver function indicators.

Allergic reactions: possible skin rash, alopecia, urticaria, angioedema, photosensitivity, malignant exudative erythema (Stevens-Johnson syndrome).

On the part of the endocrine system: dysmenorrhea, secondary amenorrhea, breast enlargement, galactorrhea.

On the part of the blood-forming organs: anemia, thrombocytopenia, leukopenia, a decrease in the content of fibrinogen, platelet aggregation and blood clotting, accompanied by prolonged bleeding time, petechial hemorrhages, hemorrhages, hematomas, bleeding.

On the part of metabolism: a decrease or increase in body weight.

Laboratory indicators: hypercreatininemia, hyperbilirubinemia, hyperammonemia.

Other: peripheral edema.

Contraindications

- pronounced dysfunction of the liver and / or pancreas;

- porphyria;

- hemorrhagic diathesis;

- severe thrombocytopenia;

- leukopenia;

- children's age up to 3 years;

- pregnancy;

- lactation period;

- Hypersensitivity to the drug.

Be wary of patients with anamnestic data on liver and pancreas diseases, as well as bone marrow damage; impaired renal function; congenital enzymopathies; mentally retarded children; organic brain damage, gioproteniemia.

Drug interactions

Valproic acid enhances effects, including side, other antiepileptic drugs (phenytoin, lamotrigine), anxiolytic drugs (tranquilizers), MAO inhibitors, thymoleptics, ethanol.

Adding valproate to clonazepam in isolated cases can lead to increased severity of absansnogo status.

With the simultaneous use of valproic acid with barbiturates or irimidone, an increase in their plasma concentration is noted.

Increases T_1/2lamotrigine (inhibits liver enzymes, causes a slowdown in lamotrigine metabolism, resulting in its T_1/2 lengthens up to 70 hours in adults and up to 45-55 hours in children).

Reduces clearance of zidovudine by 38%, while its T_1/2 does not change.

Tricyclic antidepressants, MAO inhibitors, antipsychotics (neuroleptics), drugs that reduce the threshold of seizure activity, reduce the effectiveness of valproic acid.

When combined with salicylates, there is an increase in the effects of valproic acid (displacement from association with plasma proteins).

Enhances the effect of antiplatelet agents (acetylsalicylic acid) and indirect anticoagulants.

When combined with phenytoin, mefloquine, the content of valproic acid in the blood serum decreases (acceleration of metabolism).

Felbamate raises the concentration of valproic acid in plasma by 35-50% (dose adjustment is necessary).

With the simultaneous use of valproic acid with ethanol and other drugs that inhibit the central nervous system (tricyclic antidepressants, MAO inhibitors and antipsychotics), it is possible to increase the inhibition of the central nervous system.

Ethanol and other hepatotoxic drugs increase the likelihood of developing liver damage.

Valproic acid does not induce hepatic enzymes and does not reduce the effectiveness of oral contraceptives.

When combined with phenobarbitate, phenytoin, carbamazepine, mefloquine, the content of valproic acid in blood serum decreases.

When combined with myelotoxic drugs increases the risk of oppression of bone marrow hematopoiesis.

Pregnancy and Lactation

Contraindicated in pregnancy and lactation.

Special instructions

Before treatment and during treatment, it is recommended to monitor the functional state of the liver and pancreas, peripheral blood picture, blood clotting indicators. If a liver or pancreas dysfunction or suspicion of dysfunction, as well as blood clotting abnormalities occur or are suspected, the drug should be canceled.

In combination therapy with other anticonvulsants and drugs, it is desirable to control, especially at the beginning of the treatment, the plasma concentration of another drug, since it may change under the influence of Encoratea.

Patients who receive other antiepileptic drugs, transfer to the reception of valproic acid should be carried out gradually, reaching a clinically effective dose in 2 weeks after which it is possible the gradual abolition of other antiepileptic drugs. In patients not treated with other antiepileptic drugs, a clinically effective dose should be achieved after 1 week.

The risk of developing side effects from the liver is increased during combined anti-convulsant therapy, as well as in children.

The increased risk of bleeding should be considered in patients receiving anticoagulant or thrombolytic therapy.

Against the background of Encorate treatment, a false positive reaction of urine to ketone bodies is possible.

There are reports of changes in the functional state of the thyroid gland in the process of therapy with Encorateh.

Before surgery, a complete blood count is necessary (including platelet counts), bleeding time, and coagulogram values.

If symptoms of acute abdomen occur during treatment, it is recommended to determine the level of amylase in the blood prior to the start of surgery, in order to rule out acute pancreatitis.

During treatment, consideration should be given to the possible distortion of the results of urine tests for diabetes mellitus (due to an increase in keto-products), indicators of thyroid function.

With the development of any acute serious side effects, you should immediately discuss with your doctor the advisability of continuing or stopping treatment.

To reduce the risk of dyspeptic disorders, it is possible to take antispasmodics and coating agents.

Influence on ability to drive motor transport and control mechanisms

When using the drug should refrain from potentially hazardous activities that require increased attention, quick mental and motor responses.

Overdosage

Symptoms: increased severity of side effects - nausea, vomiting, dizziness, diarrhea, impaired respiratory function, muscular hypotonia, hyporeflexia, miosis, coma.

Treatment: gastric lavage, maintaining adequate diuresis, hemodialysis and hemoperfusion, symptomatic therapy.