Valparin XP - instructions for use, dose, side effects, contraindications

Excipients: silicon dioxide colloid 2,4 / 4 mg, hypromellose 105,4 / 176 mg, ethylcellulose (20 cps) 7.2 / 12 mg, silica dioxide hydrate 30/50 mg, sodium saccharinate 6/10 mg;

Film sheath I: hypromellose 3.79 / 5.03 mg, glycerol 1.48 / 1.96 mg, titanium dioxide 0.23 / 0.31 mg;

Film sheath II: hypromellose 1,15 / 1,72 mg, butyl methacrylate dimethylaminoethyl methacrylate and methyl methacrylate copolymer [1: 2: 1] 2.59 / 3.82 mg, methyl methacrylate and ethyl acrylate copolymer [2: 1] 1.42 / 2.12 mg, macrogol -1500 0.87 / 1.28 mg, talc 0.23 / 3.52 mg, titanium dioxide 0.24 / 0.24 mg.

Description:

Tablets 300 mg: white, round, biconvex tablet, film-coated; view of the break: the outer ring of the shell, as well as the core of the tablet is white.

Tablets 500 mg: white, oblong-shaped tablet, film-coated, with a risk on both sides; view of the break: the outer ring of the shell, as well as the core of the tablet is white.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.G.01 Valproic acid

Pharmacodynamics:

Antiepileptic drug, has central miorelaksiruyuschim and sedative effect. It shows antiepileptic activity in various types of epilepsy. The main mechanism of action, apparently, is associated with the influence of valproic acid on the GABA-ergic system: the drug increases the GABA content in the central nervous system (CNS) and activates GABA-ergic transmission.

Therapeutic efficacy begins with a minimum concentration of 40-50 mg / l and can reach 100 mg / l. At a concentration of more than 200 mg / l, a dose reduction is necessary.

Pharmacokinetics:

Bioavailability of the drug is about 100%. It is distributed mainly into the blood and extracellular fluid. Valproic acid penetrates into the cerebrospinal fluid and through the blood-brain barrier.

The half-life is 15-17 hours. Therapeutic effectiveness is manifested when the concentration in the blood plasma is from 40 to 100 mg / l. At levels above 200 mg / l, a dose reduction is necessary. Equilibrium concentration in plasma is achieved after 3-4 days of admission.

Communication with plasma proteins - 90-95% (at a plasma concentration of up to 50 mg / l), at a concentration of 50-100 mg / l, decreases to 80-85%; with uremia, hypoproteinemia and liver cirrhosis, binding to plasma proteins is also reduced.

It is excreted mainly with urine in the form of glucuronide and by beta-oxidation in conjugated form.

Valproic acid is not an inducer of the enzymes of the cytochrome P450 metabolic system. Unlike most other antiepileptic drugs, it does not affect the degree of both its own biotransformation, and the biotransformation of other substances, such as estrogens, progestogens and vitamin K antagonists.

The prolonged form is characterized by a lack of delayed absorption, prolonged absorption, identical bioavailability, a lower (by 25%) but relatively more stable plasma concentration between 4 and 14 hours after administration, a more linear correlation between dose and plasma concentration of the drug.

Indications:

Have of adults as a monotherapy or in combination with other antiepileptic drugs:

- treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, myoclonic, atonic); the Lennox-Gastaut syndrome;

- treatment of partial, epileptic seizures (partial seizures with secondary generalization or without it);

- treatment and prevention of bipolar affective disorders.

Have children as a monotherapy or in combination with other antiepileptic drugs:

- treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, myoclonic, atonic); the Lennox-Gastaut syndrome;

- treatment of partial epileptic seizures (partial seizures with or without secondary generalization).

Contraindications:

- Hypersensitivity to valproic acid or other components of the drug; acute hepatitis; chronic hepatitis; liver disease in history, porphyria; combination with mefloquine; combination with St. John's wort; children under 3 years; It is not recommended to use in combination with lamotrigine.

Carefully:

Oppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia), organic brain diseases, liver and pancreatic history of anamnesis, hypoproteinemia, mental retardation in children, congenital fermentopathies,renal insufficiency.

Pregnancy and lactation:

AT research on animals teratogenic effect is proved.

According to available data in humans valproic acid mainly causes disruption of the development of the neural tube: myelomeningocele, spina bifida (1-2%). Cases of facial dysmorphia and developmental limb development abnormalities (especially limb shortening), as well as developmental defects of the cardiovascular system are described.

The risk of malformations is higher with combined antiepileptic therapy than with monotherapy with valproic acid.

In view of the foregoing, during pregnancy, the use of the drug is only possible if the intended benefit to the mother exceeds the potential risk to the fetus. During pregnancy, antiepileptic treatment with valproic acid should not be interrupted if it is effective. In such cases, monotherapy is recommended; The minimum effective daily dose should be divided into two doses.

In addition to anti-epileptic therapy, folic acid preparations (at a dose of 5 mg / sug) can be added, they minimize the risk of developing neural tube defects.

Valproic acid can cause hemorrhagic syndrome in newborns, which, apparently, is associated with hypofibrinogenemia. There have been cases of development of fetal affinity with lethal outcome.

Valproic acid is excreted in breast milk in concentrations from 1% to 10%. It is recommended to stop breastfeeding while taking the drug.

Dosing and Administration:

Valparin® XP is intended for oral administration.

The daily dose is recommended to be taken in one or two doses, preferably during meals. Use in 1 reception is possible with well-controlled epilepsy. Tablets are taken without crushing or chewing, with a small amount of water.

The initial dose for monotherapy for adults and children weighing more than 25 kg: 5-15 mg / kg / day; then this dose is gradually increased by 5-10 Mg / kg / week. The maximum dose is 30 mg / kg / day (can be increased if it is possible to control the concentration in the plasma to 60 mg / kg / day).

With combined therapy in adults: 10-30 mg / kg / day, followed by a dose increase of 5-10 mg / kg / week.

Children with a body weight of less than 25 kg: the average daily dose for monotherapy - 15-45 mg / kg, the maximum - 50 mg / kg. When combined therapy - 30-100 mg / kg / day.

In elderly patients, the dose should be adjusted according to their clinical condition.

The daily dose is determined depending on the age and body weight of the patient, and also taking into account individual sensitivity to valproic acid.

A good correlation was established between the daily dose, the concentration of the drug in the serum and the therapeutic effect: the dose should be established on the basis of the clinical response. Determining the level of valproic acid in plasma can be considered as an addition to clinical observation, when epilepsy is not controlled, or there is a suspicion of side effects. The concentration range at which the clinical effect is observed is usually 40-100 mg / l (300-700 μmol / l).

When switching from immediate release valproic acid tablets, which provided the necessary control over the disease, a daily dose should be maintained on the form of prolonged action (Valparin® XP):

The substitution of other antiepileptic drugs for Valparin® XP should be carried out gradually, reaching the optimal dose of valproic acid for about 2 weeks.Depending on the patient's condition, the dose of the previous drug is reduced. For patients who do not take other antiepileptic drugs, the dose should be increased after 2-3 days in order to reach the optimal dose within about a week.

If necessary, combinations with other antiepileptic drugs should be administered gradually (see "Interaction with other drugs").

Side effects:

From the central nervous system: ataxia; cases of cognitive impairment with a progressive offensive up to the development of a complete picture of dementia syndrome (reversible within a few weeks or months after discontinuation of the drug); a state of confusion or convulsions; stupor or lethargy, sometimes leading to a transient coma (encephalopathy); reversible parkinsonism; headache, dizziness, slight postural tremor and drowsiness, changes in behavior, mood or mental state (depression, fatigue, hallucinations, aggressiveness, hyperactive state, psychoses, unusual arousal, motor anxiety or irritability), dysarthria.

From the digestive system: often at the beginning of treatment - gastrointestinal disorders (nausea, vomiting, gastralgia, decreased appetite or increased appetite, diarrhea), which usually take place for several days without discontinuing the drug; abnormal liver function; pancreatitis, up to severe lesions with a fatal outcome (in the first 6 months of treatment, more often at 2-12 weeks).

On the part of the organs of hematopoiesis and the system of hemostasis: oppression of bone marrow hematopoiesis (anemia, leukopenia or pancytopenia); thrombocytopenia, decreased fibrinogen and platelet aggregation, leading to the development of hypocoagulation (accompanied by prolonged bleeding time, petechial hemorrhages, bruising, bruising, bleeding, etc.).

From the side of the urinary system: enuresis; cases of reversible Fanconi syndrome (unclear genesis).

From the endocrine system: dysmenorrhea, secondary amenorrhea, breast enlargement, galactorrhea.

Allergic reactions: skin rash, hives, vasculitis; angioedema, photosensitization, cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, multiform erythema.

Laboratory indicators: Isolated and moderate hyperammonemia without changes in liver function tests, especially with polytherapy (drug withdrawal is not required); Possible hyperammonemia associated with neurologic symptoms (further examination is required); may increase the activity of "liver" transaminases; decreased fibrinogen levels or increased bleeding time, usually without clinical manifestations and especially at high doses (valproic acid has an inhibitory effect on the second stage of platelet aggregation); hyponatremia.

Other: teratogenic risk (see "Pregnancy and breastfeeding"); diplopia, nystagmus, flashing of "flies" before the eyes, alopecia; reversible or irreversible hearing loss; peripheral edema; weight gain (since weight gain is a risk factor for polycystic ovary syndrome, careful monitoring of the condition of such patients is recommended); violation of the menstrual cycle, amenorrhea.

Overdose:

Symptoms: coma with muscle hypotension, hyporeflexia, miosis, respiratory depression, metabolic acidosis; cases of intracranial hypertension associated with cerebral edema are described.

Treatment: in the hospital - gastric lavage, if after taking the drug has passed no more than 10-12 hours; monitoring the state of the cardiovascular and respiratory systems and maintaining an effective diuresis. In very severe cases, dialysis is performed. As a rule, the forecast is favorable, however, several cases of a detailed outcome have been described.

Interaction:

Contraindicated combinations

Mefloquine: risk of epileptic seizures in patients with epilepsy due to increased metabolism of valproic acid and convulsant mefloquine.

Saint John's wort: the risk of a decrease in the concentration of valproic acid in the blood plasma.

Unrecommended combinations

Lamotrigine: increased risk of severe skin reactions until the development of toxic epidermal necrolysis. In addition, an increase in the concentration of lamotrigine in plasma (its metabolism in the liver is slowed down by valproic acid). If a combination is necessary, careful clinical and laboratory testing is required.

Combinations, requiring special precautions

Carbamazepine: increase in the concentration of active metabolite carbamazepine in plasma with signs of overdose.In addition, a decrease in the concentration of valproic acid in plasma, associated with increased metabolism of valproic acid in the liver under the influence of carbamazepine. Recommended: clinical observation, determination of plasma concentrations of drugs and, possibly, correction of their dose, especially at the beginning of treatment.

Carbapenems, monobactams: meropenem, panipenem, and, by extrapolation, aztreonam and imipenem: an increased risk of seizures due to a decrease in the concentration of valproic acid in the blood plasma. It is recommended: clinical observation, determination of plasma drug concentrations, valproic acid dose adjustment may be required during treatment with an antibacterial agent and after its withdrawal.

Felbamat: an increase in the concentration of valproic acid in the blood plasma with a risk of overdose. Recommended: clinical and laboratory monitoring and, possibly, a review of the dose of valproic acid during treatment with felbamate and after its cancellation).

Phenobarbital, primidone: increased concentrations of phenobarbital and primidone in plasma with signs of overdose, usually in children.In addition, a decrease in the concentration of valproic acid in plasma, due to the increase in its hepatic metabolism under the influence of phenobarbital or primidone. It is recommended: clinical monitoring during the first 15 days of combined treatment with immediate reduction of the dose of phenobarbital or primidone with the appearance of the first signs of sedation, the determination of concentrations of both anticonvulsants in the blood.

Phenytoin: change in concentration phenytoin in plasma, the risk of a decrease in the concentration of valproic acid, associated with an increase in the metabolism of valproic acid in the liver under the influence of phenytoin. It is recommended: clinical monitoring with determination of concentrations of both antiepileptic drugs in plasma and, if necessary, correction of their doses.

Topiramate: a risk of developing hyperammonemia or encephalopathy. Recommended: clinical and laboratory monitoring during the first month of treatment and in case of symptoms of ammoniasis.

Neuroleptics, monoamine oxidase (MAO) inhibitors, antidepressants, benzodiazepines: Valproic acid potentiates the effect of psychotropic drugs, such as neuroleptics, MAO inhibitors, antidepressants, benzodiazepines. Recommended: clinical monitoring and, if necessary, dose adjustment.

Cimetidine and erythromycin: increases the concentration of valproic acid in blood plasma.

Zidovudine: valproic acid can increase concentration zidovudine in plasma, which leads to an increase in zidovudine toxicity.

Combinations that should be taken into account

Nimodipine (orally and, by extrapolation, parenterally): strengthening of the hypotensive effect of nimodipine due to a decrease in its metabolism under the influence of valproic acid and an increase in the concentration in the blood plasma.

Acetylsalicylic acid: increased effects of valproic acid due to an increase in its concentration in the blood plasma.

With the simultaneous use of anticoagulants with vitamin K antagonists, careful monitoring of the prothrombin index is required.

Other forms of interaction

Valproic acid does not have an enzyme-inducing effect and therefore does not affect the effectiveness of hormonal contraceptives containing combination of estrogen and progesterone.

Special instructions:

Prior to treatment and during the first 6 months of therapy, periodic monitoring of liver function is necessary, especially in patients at risk.

Among the classic tests, the tests reflecting protein synthesis in the liver, and especially the prothrombin index, are most important. With a significant decrease in the concentration of prothrombin, a pronounced decrease in fibrinogen content, clotting factors, increased bilirubin concentration and transaminase activity, treatment with Valparin® XP should be stopped. If the patient receives salicylates concomitantly, they should also be immediately withdrawn, since salicylates and valproic acid have common metabolic pathways.

The risk of developing side effects from the liver is increased when combined anticonvulsant therapy, as well as in children.

Early diagnosis is based primarily on clinical examination. In particular, two factors that may precede jaundice should be taken into account, especially in patients at risk:

- nonspecific general symptoms, usually appearing suddenly, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain;

- relapse of epileptic seizures against the background of antiepileptic therapy.

It is necessary to warn the patient, and if it is a child, then his family, the need to immediately notify the doctor about the occurrence of these symptoms. In addition to clinical examination in such cases, an analysis of liver function should be performed immediately.

In rare cases, severe forms of pancreatitis, sometimes with a fatal outcome. These cases were observed regardless of the patient's age and duration of treatment, although the risk of developing pancreatitis decreased with increasing age of the patients. Lack of liver function in pancreatitis increases the risk of death.

It should be emphasized that in the treatment of both Valparin® XP and other antiepileptic drugs, there may be a small isolated and temporary increase in transaminase activity, especially at the beginning of treatment, in the absence of any clinical symptoms. In this case, a more complete examination (including, in particular, the determination of the prothrombin index) is recommended so that, if necessary, the dose should be reviewed and the analyzes repeated, depending on the changes in the parameters.

Before the beginning of therapy, before surgery, with the appearance of bruising or spontaneous bleeding, a general blood test (including determination of the number of platelets, bleeding time and coagulogram parameters) is necessary.

If you experience symptoms during treatment with "acute" abdomen and gastrointestinal symptoms such as nausea, vomiting and / or anorexia is necessary to determine the activity of amylase in the blood in order to avoid acute pancreatitis. With increased activity of pancreatic enzymes, the drug should be withdrawn, taking alternative therapeutic measures.

In applying Valparina® XP patients with renal failure patients it is recommended to take into account the increased concentration of free form of valproic acid in blood plasma and to reduce the dose.

The appointment of the drug in patients with systemic lupus erythematosus and other diseases of the immune system should be expected to evaluate the therapeutic effect and the possible risks of therapy, because the application of Valparina® XP in extremely rare cases, observed violations of the immune system.

It is not recommended to prescribe the drug to patients with a deficiency of urea enzymes.In such patients, several cases of hyperammonemia accompanied by a stupor and / or coma have been described.

During the treatment, it is not allowed to take drinks containing ethanol.

Patients should be warned about the risk of weight gain at the beginning of treatment and recommend compliance with the diet to minimize such effects.

Effect on the ability to drive transp. cf. and fur:

During the period of treatment, patients should be careful when driving vehicles and other activities that require high concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets of prolonged action, film-coated, 300 mg and 500 mg.

Packaging:

10 tablets per strip of aluminum foil.

By 3, 5 or 10 strips together with instructions for use in cardboard pack.

Storage conditions:

Store in a dry place, at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the time specified on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015033 / 01

Date of registration:12.05.2008 / 09.07.2014

Expiration Date:Unlimited

The owner of the registration certificate:Torrent Pharmaceuticals Co., Ltd.Torrent Pharmaceuticals Co., Ltd. India

Manufacturer: & nbsp

TORRENT PHARMACEUTICALS, Ltd. India

Representation: & nbspTORRENT PHARMACEUTICALS LTD. TORRENT PHARMACEUTICALS LTD. India

Information update date: & nbsp20.01.2017

Illustrated instructions

Instructions

Valparin® XP (Valparine® XR)