Active ingredients: Valproic acid (Sodium valproate)
DEPAKIN CHRONO 300 mg prolonged-release tablets DEPAKIN CHRONO 500 mg prolonged-release tablets
Why is Depakin Chrono used? What is it for?
In the treatment of generalized epilepsy, in particular in attacks of the type:
- absence
- myoclonic
- tonic
- clonic
- atonic
- mixed
and in partial epilepsy:
- simple or complex
- secondarily generalized
In the treatment of specific syndromes (West, Lennox-Gastaut). In the treatment of manic episodes related to bipolar disorder when lithium is contraindicated or not tolerated. Continuation of therapy after the episode of mania may be considered in patients who have responded to valproate for acute mania.
Contraindications When Depakin Chrono should not be used
- Acute hepatitis
- Chronic hepatitis
- Personal or family history of severe liver disease, especially drug induced
- Hypersensitivity to the active substance or to any of the excipients
- Hepatic porphyria
- Clotting disorders
Precautions for use What you need to know before taking Depakin Chrono
In children aged less than or equal to three years, antiepileptics containing valproic acid are only in exceptional cases the first choice therapy
- Liver function tests should be performed prior to initiation of therapy and repeated periodically during the first 6 months, especially in patients at risk (see "Special warnings").
As with most antiepileptic drugs, increases in liver enzymes may be noted, particularly at the start of therapy; they are transient and isolated, not accompanied by clinical signs. In these patients, more in-depth laboratory investigations are recommended (including time to prothrombin), dosage adjustment may also be considered and tests repeated if necessary.
- In children less than 3 years of age, Depakin should be administered as monotherapy although its potential benefit must be evaluated prior to initiation of treatment, in comparison with the risk of liver damage or pancreatitis in these patients (see "Special warnings" ").
Concomitant use of salicylates should be avoided in children under 3 years of age due to the risk of hepatotoxicity.
- It is recommended that blood tests (complete blood count with platelet count, bleeding time and clotting tests) be performed before the start of therapy or before surgery and in the case of spontaneous hematoma or bleeding (see "Undesirable effects" ).
- In patients with renal insufficiency or hypoproteinaemia, the posology should be decreased. As monitoring of plasma concentrations may give unreliable results, the posology should be adjusted based on clinical monitoring.
- Although immune diseases have been found only exceptionally during the use of valproate, it is worth considering the potential benefit of valproate versus the potential risk in patients with systemic lupus erythematosus.
- As exceptional cases of pancreatitis have been reported, patients with acute abdominal pain should undergo immediate medical examination. In the event of pancreatitis, valproate therapy should be discontinued.
- If an altered urea cycle is suspected, hyperammonaemia should be evaluated prior to treatment, as aggravation is possible with valproate (see "Undesirable Effects"). Therefore, if symptoms such as apathy, drowsiness, vomiting, hypotension and increased frequency of seizures appear, serum levels of ammonia and valproic acid should be determined; if necessary the dose of the medicine should be reduced. If an enzymatic interruption of the urea cycle is suspected, the serum ammonia level should be determined before starting therapy with medicinal products containing valproic acid.
- Patients should be advised of the risk of weight gain at the start of therapy; appropriate measures should be taken to minimize this (see "Undesirable Effects").
- Patients with underlying carnitine palmitoyltransferase (CPT) type II deficiency should be advised of the increased risk of rhabdomyolysis when taking valproate. - The concomitant use of valproic acid / sodium valproate and medicinal products containing carbapenems is not recommended (see Interactions).
- Women of childbearing potential (see "Special warnings")
All women with epilepsy and of childbearing age should be adequately informed about the risks associated with pregnancy.
- Hematology
Blood cell counts, including platelet counts, bleeding time and coagulation tests should be monitored before starting therapy, before surgery or dental surgery, and in case of spontaneous bruising or bleeding (see "Undesirable effects" "). In case of concomitant intake of vitamin K antagonists, close monitoring of INR values is recommended. - Bone marrow damage Patients with previous bone marrow damage should be strictly monitored
Interactions Which drugs or foods can modify the effect of Depakin Chrono
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Effects of valproate on other drugs
- Neuroleptics, anti-MAO, antidepressants and benzodiazepines
Valproate may potentiate the effect of other psychotropic drugs such as neuroleptics, anti-MAO drugs, antidepressants and benzodiazepines; therefore, clinical monitoring and, when necessary, dosage adjustment are recommended.
- Phenobarbital
Since valproate increases plasma phenobarbital concentrations (by inhibition of hepatic catabolism) sedation may occur especially in children. Clinical monitoring is therefore recommended for the first 15 days of combined treatment, with immediate reduction of phenobarbital doses in case of sedation, and possible monitoring of plasma phenobarbital levels.
- Primidone
Valproate increases the plasma levels of primidone with potentiation of its undesirable effects (such as sedation); this interaction ceases with long-term treatment. Clinical monitoring is recommended especially at the initiation of combination therapy with an adjustment of the primidone dosage when necessary.
- Phenytoin
Valproate initially decreases the total plasma concentration of phenytoin but increases its free fraction, with possible symptoms of overdose (valproic acid displaces phenytoin from its protein binding sites and slows down its hepatic catabolism). Clinical monitoring is therefore recommended; in the case of plasma dosage of phenytoin, the free fraction must be taken into consideration Subsequently, following chronic treatment, phenytoin concentrations return to the initial pre-valproate values.
- Carbamazepine
Clinical toxicity has been reported with concomitant administration of valproate and carbamazepine as valproate may potentiate the toxicity of carbamazepine. Clinical monitoring is therefore recommended especially at the start of treatment with the combination of the two drugs, with dosage adjustment if necessary.
- Lamotrigine
Depakin reduces the metabolism of lamotrigine and increases its mean half-life by almost 2-fold. This interaction may lead to increased lamotrigine toxicity, particularly severe skin rashes. Clinical monitoring is therefore recommended and dosage should be decreased when necessary. of lamotrigine.
- Ethosuximide
Valproate can cause increased plasma concentrations of ethosuximide.
- Zidovudine
Valproate may increase the plasma concentration of zidovudine with the consequent increased risk of its toxicity.
- Felbamato
Valproic acid can decrease the mean clearance of felbamate by up to 16%.
Effects of other drugs on valproate
Enzyme-inducing antiepileptics (in particular phenytoin, phenobarbital and carbamazepine) decrease the serum concentrations of valproic acid. In case of combined therapy the dosages should be adjusted according to the blood levels.
On the other hand, the combination of felbamate and valproate decreases the clearance of valproic acid from 22% to 50% and consequently increases the plasma concentration of valproic acid. Monitoring of the plasma levels of valproate is necessary.
Mefloquine increases the metabolism of valproic acid and has a convulsive effect; therefore, seizures may occur in cases of combined therapy.
In case of concomitant use of valproate and substances that bind highly to proteins (acetylsalicylic acid), the free serum levels of valproic acid may increase.
Medicines containing valproic acid should not be administered concomitantly with acetylsalicylic acid to treat fever and pain, particularly in infants and children.
Close monitoring of prothrombin time should be performed in case of concomitant use of vitamin K dependent anticoagulant factors. Serum levels of valproic acid may increase (due to reduced hepatic metabolism) with concomitant use of cimetidine or erythromycin and fluoxetine.
However, there have also been reports of cases in which the serum concentration of valproic acid was lowered following concomitant intake of fluoxetine. A decrease in blood levels of valproic acid has been reported when co-administered with carbapenem-containing medicinal products, resulting in a 60-100% reduction in these blood levels in approximately two days. Due to its rapid onset and marked decrease, concomitant administration of carbapenem-containing medicinal products in patients stabilized with valproic acid is not considered feasible and should therefore be avoided (see Precautions for use).
Rifampicin can decrease the plasma levels of valproic acid leading to the interruption of the therapeutic effect. Therefore, an adjustment of the valproate dosage may be necessary when co-administered with rifampicin.
Other interactions
Concomitant administration of valproate and topiramate has been associated with the onset of encephalopathy and / or hyperammonaemia.
Patients treated with these two drugs should be monitored with particular attention for signs and symptoms of hyperammonaemic encephalopathy. Valproate generally does not have an enzyme inducing effect; consequently it does not reduce the efficacy of estrogen-progestins in the case of hormonal contraception.
In healthy volunteers, valproate displaced diazepam from its binding sites with plasma albumin and inhibited its metabolism. In combination therapy, the concentration of free diazepam may be increased, while the plasma clearance and volume of distribution of the free fraction of diazepam can be reduced (by 25% and 20% respectively). The half-life, however, remains unchanged.
In healthy subjects, concomitant treatment with valproate and lorazepam resulted in a reduction in plasma clearance of lorazepam by more than 40%.
Absence has occurred in patients with a history of absence seizure epilepsy following a combined treatment of valproic acid and clonazepam.
Following concomitant treatment with valproic acid, sertraline and risperidone, catatonia developed in a patient with schizoaffective disorder.
- Quetiapine
Concomitant administration of valproate and quetiapine may increase the risk of neutropenia / leukopenia.
Warnings It is important to know that:
Girls / Adolescents / Women of childbearing age / Pregnancy:
Depakin should not be used in girls, adolescents, women of childbearing potential and pregnant women, unless alternative treatments are ineffective or not tolerated, due to its high teratogenic potential and the risk of developmental disorders in infants exposed to uterus to valproate. The risks and benefits need to be carefully reconsidered during regular treatment re-evaluations, in puberty and as a matter of urgency when a woman of childbearing potential treated with Depakin plans or becomes pregnant.
Women of childbearing potential should use effective contraception during treatment and be informed of the risks associated with the use of Depakin during pregnancy (see "Pregnancy").
The prescriber should ensure that the patient is provided with comprehensive information on the risks as well as relevant materials, such as a patient information booklet, to help her understand the risks.
In particular, the prescriber must ensure that the patient understands:
- The nature and extent of the risks of exposure in pregnancy, in particular the teratogenic risks and risks related to developmental disorders.
- The need to use an effective form of contraception.
- The need for regular treatment review.
- The need to consult your doctor quickly if you think you are becoming pregnant or that there is a possibility of pregnancy.
In women planning to become pregnant, every effort should be made to switch to an appropriate alternative treatment before conception, if possible (see "Pregnancy").
Valproate therapy should only be continued after a re-evaluation of the benefits and risks of valproate treatment for the patient by a physician experienced in the management of epilepsy or bipolar disorder.
A small number of patients being treated with antiepileptic drugs such as valproate have developed thoughts of self-harm or suicide. If, at any time, you have such thoughts, contact your doctor immediately.
Alcohol is not recommended during treatment with valproate. Since valproate is excreted primarily via the kidneys, partly as ketone bodies, the ketone body excretion test may give false positive results in diabetic patients.
HEPATOPATHIES
- Conditions of onset
Exceptionally severe liver damage has been reported and has sometimes been fatal.
The patients most at risk, especially in cases of multiple anticonvulsive therapy, are infants and children under 3 years of age with severe forms of epilepsy, particularly those with brain damage, mental retardation and (or) with congenital metabolic or degenerative disease.
If the Doctor deems it essential to administer the drug to children under three years of age for the treatment of a type of epilepsy responsive to valproate, despite the risk of liver disease, the use of Depakin must be done alone to reduce this risk. After the age of 3, the incidence is significantly reduced and progressively decreases with age.
In most cases, liver damage occurred during the first 6 months of therapy.
- Symptomatology
Clinical symptoms are essential for early diagnosis. In particular, especially in patients at risk (see conditions of onset), two types of manifestations that may precede jaundice should be considered:
- reappearance of seizures
- non-specific symptoms, usually rapid onset, such as asthenia, anorexia, lethargy, somnolence, sometimes associated with repeated vomiting and abdominal pain.
Patients (or their parents if they are children) should be advised to notify their physician immediately if any of the above signs occur. In addition to clinical checks, immediate blood chemistry checks of liver function should be undertaken.
- Detection
Liver function should be checked before the start of therapy and periodically during the first 6 months of therapy. Among the usual analyzes, the most relevant are those that reflect protein synthesis, especially prothrombin time. Confirmation of a percentage of particularly low prothrombin activity, especially if associated with other abnormal biological findings (significant decrease in fibrinogen and coagulation factors; increase in bilirubin levels and increase in transaminases SGOT, SGPT, gamma-GT, lipase, alpha-amylase, glycemia) requires the discontinuation of valproate therapy. As a precaution in case they are taken at the same time, salicylates must also be discontinued, since they are metabolized by the same route.
Four weeks after the start of treatment, laboratory tests for coagulation parameters such as INR and PTT, SGOT, SGPT, bilirubin and amylase should be checked.
In children with no abnormal clinical symptoms, blood counts including thrombocytes, SGOT and SGPT should be checked at each visit.
PANCREATITES
Serious pancreatitis which can be fatal has been reported very rarely. Younger children are particularly at risk. The risk decreases with increasing age. Severe seizures, neurological disorders, or anticonvulsant polypharmacy can be risk factors. Concomitant hepatic failure with pancreatitis increases the risk of fatal outcome. Patients who experience acute abdominal pain should be immediately seen by a physician. In the event of pancreatitis, valproate should be discontinued.
FERTILITY, PREGNANCY AND BREASTFEEDING
Ask your doctor or pharmacist for advice before taking any medicine.
Depakin should not be used in girls, adolescents, women of childbearing potential and pregnant women unless other treatments are ineffective or not tolerated. Women of childbearing potential should use effective contraception during treatment. In women planning to become pregnant, every effort should be made to switch to appropriate alternative treatment before conception, if possible.
Pregnancy
Risk of exposure in pregnancy linked to valproate
Both valproate alone and valproate in polytherapy are associated with abnormal pregnancy outcomes. Available data suggest that antiepileptic polypharmacy including valproate is associated with an increased risk of congenital malformations compared to valproate alone.
Congenital malformations
Data from a meta-analysis (which included registries and cohort studies) showed that 10.73% of children of epileptic women exposed to valproate monotherapy during pregnancy suffer from congenital malformations (95% CI: 8.16 -13.29). There is a greater risk of major malformations than the general population, for which the risk is approximately 2-3%. The risk depends on the dose but a threshold dose below which no risk exists cannot be established.
Available data demonstrate an "increased incidence of major and minor malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniosynostosis, heart, kidney and urogenital defects, limb defects (including aplasia" bilateral radius) and multiple anomalies affecting the various systems of the organism.
Developmental disorders
The data demonstrated that exposure to valproate in utero may have adverse effects on the mental and physical development of exposed children. The risk appears to be dose-dependent but, based on the available data, a threshold dose below the threshold cannot be established. which there is no risk. The precise gestation period at risk for such effects is uncertain and the possibility of risk throughout pregnancy cannot be excluded.
Studies of preschool children exposed in utero to valproate show that up to 30-40% experience early developmental delays, such as delayed speaking and walking, decreased intellectual ability, poor language skills (speaking and understanding) and memory problems.
The intelligence quotient (IQ) measured in school-aged children (6 years) with a history of in utero valproate exposure was on average 7-10 points lower than that of children exposed to other antiepileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent of maternal IQ.
There is limited data on long-term outcomes.
Available data demonstrate that children exposed to valproate in utero are at greater risk for autism spectrum disorders (approximately three times) and childhood autism (approximately five times) than the general study population.
Limited data suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit / hyperactivity disorder (ADHD).
Girls, adolescents and women of childbearing age (see above and "Special warnings")
If a woman wishes to plan a pregnancy
- During pregnancy, maternal tonic-clonic seizures and hypoxic status epilepticus can carry a particular risk of death for the mother and fetus.
- Valproate therapy should be re-evaluated in women planning to become pregnant or pregnant.
- In women planning to become pregnant, every effort should be made to switch to an appropriate alternative treatment before conception, if possible.
Valproate therapy should not be discontinued without a re-evaluation of the benefits and risks of valproate treatment for the patient by a physician experienced in the management of epilepsy or bipolar disorder.If, following a careful evaluation of the risks and benefits, treatment with valproate is continued during pregnancy, it is recommended to:
- Use the lowest effective dose and divide the daily dose of valproate into several small doses to be taken throughout the day. The use of an extended release formulation may be preferable to treatment with other formulations to avoid high peak plasma concentrations. The daily dose should be given in several small doses throughout the day in women who may become pregnant and certainly between days 20 and 40 after conception In addition, plasma concentrations should be monitored regularly, considering the possibility of considerable fluctuations that can occur during pregnancy even with constant dosage.
- Supplementing folic acid before pregnancy could reduce the risk of neural tube defects common to all pregnancies. However, the available evidence does not suggest that it prevents birth defects or malformations due to valproate exposure.
- Establish specialized prenatal monitoring in order to detect the possible onset of neural tube defects or other malformations. Women of childbearing potential should be informed of the risks and benefits of using DEPAKIN during pregnancy.
Risks for the newborn
- Very rarely, there have been reports of haemorrhagic syndrome in newborns whose mothers took valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and / or a reduction in other coagulation factors. Afibrinogenemia has also been reported and could be fatal. However, this syndrome must be distinguished from phenobarbital-induced and enzyme-inducing decrease in vitamin K factors. Consequently, platelet counts, plasma fibrinogen level, coagulation tests, and clotting factors should be examined in neonates.
- Cases of hypoglycaemia have been reported in infants whose mothers took valproate in the third trimester of pregnancy.
- There have been reports of hypothyroidism in newborns whose mothers took valproate during pregnancy.
- Withdrawal syndrome (eg in particular, agitation, irritability, hyper-excitability, nervousness, hyperkinesis, tonicity disturbances, tremor, seizures and eating disorders) may arise in newborns whose mothers have taken valproate in the last trimester of pregnancy.
Valproic acid treatment during pregnancy should not be stopped without consulting your doctor, as well as any abrupt discontinuation of treatment or uncontrolled dosage reduction. This could lead to seizures in the pregnant woman, which could harm the mother and / or the unborn child.
Pregnancy
Valproate is excreted in human milk at a concentration ranging from 1% to 10% of maternal serum levels. Haematological disturbances have been observed in breastfed infants of treated women (see "Undesirable effects").
A decision must be made whether to discontinue breast-feeding or to discontinue / abstain from Depakin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
Amenorrhea, polycystic ovary and increased testosterone levels have been reported in women using valproate (see "Side Effects"). Administration of valproate may also impair fertility in men (see "Undesirable effects"). Clinical cases indicate that fertility dysfunctions are reversible after discontinuation of treatment.
Effects on ability to drive and use machines
In case of concomitant administration with barbiturates or other drugs with central nervous system depressant activity, manifestations of asthenia, drowsiness or confusion may be found in some subjects, which can thus alter the response to the ability to drive a vehicle, use machinery or perform activities connected with the risk of falling or accident, the ability is impaired regardless of the underlying disease.
The same manifestations can be observed after drinking alcoholic beverages. Those subjects who, during the processing, could drive vehicles or attend to operations requiring integrity of the degree of supervision must be warned of this.
Dosage and method of use How to use Depakin Chrono: Dosage
Treatment of epilepsy
Before starting therapy with DEPAKIN CHRONO, keep in mind that:
- in patients not treated with other antiepileptic drugs, the dosage should preferably be increased by successive stages of 2-3 days, to reach the optimal one within about a week;
- in patients already being treated with antiepileptic drugs, the substitution with valproate should be gradual, reaching the optimal posology in about two weeks. The concomitant treatments will be progressively reduced until they are stopped;
- the addition of another antiepileptic agent, where necessary, should be done gradually (see "Interactions").
The daily dosage should be based on age and body weight; however, individual sensitivity to valproate should also be taken into consideration.
The optimal posology must be determined essentially on the basis of the clinical response; determination of plasma levels of valproic acid may be considered as a complement to clinical monitoring when adequate control of attacks is not achieved or when undesirable effects are suspected. Serum concentrations generally believed to be therapeutic are between 40 and 100 mg / l (300-700 µmol / liter) of valproic acid.
Usually the initial daily dosage is 10-15 mg / kg, then the doses must be progressively increased until the optimal dosage is reached, which generally ranges from 20 to 30 mg / kg. However, when adequate control of attacks is not achieved with this posology, doses may be increased further; patients should be closely monitored when treated with daily doses greater than 50 mg / kg (see "Precautions for use").
Particularly:
- in children, the usual dosage is about 30 mg / kg / day;
- in adults, the usual dosage ranges from 20 to 30 mg / kg / day;
- in the elderly, although the pharmacokinetic parameters of valproate are modified, these changes are of limited clinical significance and the posology should be determined according to the clinical response (seizure control).
In patients with renal insufficiency or hypoproteinaemia, the increase of free valproic acid in serum should be considered and, if necessary, the dose should be reduced.
Administration
The use of the prolonged-release formulation - DEPAKIN CHRONO - allows to reduce the administration of the drug to 1 - 2 times a day. Furthermore, the possibility of dividing the tablets allows greater dosage flexibility.
DEPAKIN CHRONO can also be used in children, when they are able to take the tablet form, which can also be divided.
However, among the oral pharmaceutical forms, the most appropriate for administration in children under 11 years of age are the oral solution and the granules.
Episodes of mania related to bipolar disorder
In adults:
The daily dosage must be established and controlled individually by the doctor.
The recommended starting daily dose is 750 mg. In addition, in clinical trials a starting dose of 20 mg valproate / kg body weight also showed an acceptable safety profile. Prolonged-release formulations can be administered once or twice daily. The dose should be be increased as rapidly as possible to achieve the lowest therapeutic dose with which the desired clinical effect is achieved. The daily dose should be adapted to the clinical response to establish the lowest effective dose for the individual patient. The average daily dose usually varies between 1000 and 2000 mg of valproate. Patients receiving a daily dose greater than 45 mg / kg body weight should be closely monitored.
Continuation of treatment in manic episodes related to bipolar disorder should be established on an individual basis at the lowest effective dose.
In children and adolescents:
Children and adolescents under 18 years of age:
Depakin should not be used in children and adolescents under 18 years of age for the treatment of mania.
Girls, adolescents, women of childbearing age and pregnant women
Depakin should be initiated and supervised by a specialist experienced in the management of epilepsy or bipolar disorder. Treatment should only be initiated if other treatments are ineffective or not tolerated (see "Special warnings - Pregnancy") and the benefits and risks should be carefully reconsidered during regular treatment re-evaluations. Preferably, Depakin should be prescribed as monotherapy and at the lowest effective dose, if possible as an extended release formulation to avoid high peak plasma concentrations. The daily dose should be divided into at least two single doses.
Method of administration for both indications
DEPAKIN modified release granules is in tasteless spherical granules and should preferably be administered distributed on soft foods (yoghurt, cooked fruit, fresh cheeses, etc.) or drinks (orange juice, etc.) cold or at room temperature.
DEPAKIN Modified Release Granules should not be administered with lukewarm or hot food or drinks (soups, coffee, tea, etc.).
DEPAKIN Modified Release Granules should not be given into the bottle as it can block the teat.
When taken with liquids, it is recommended to rinse the glass with a small amount of water because some granules may stick to the glass.
If you prefer, the granules can be placed directly in the mouth and swallowed with water or cold drinks or at room temperature.
The preparation must be swallowed immediately and must not be chewed. It should not be stored for later use.
Considering the release process and the nature of the excipients of the formulation, the inert matrix of the granules is not absorbed by the digestive tract and is eliminated with the faeces after the active ingredient is released.
Overdose What to do if you have taken too much Depakin Chrono
In case of ingestion / intake of an excessive dose of Depakin notify your doctor immediately or go to the nearest hospital.
Signs and symptoms
At therapeutic serum levels (50-100 µg / ml), valproic acid has relatively low toxicity. Very rarely, acute valproic acid intoxication at serum levels above 100 µg / ml has occurred in adults and children.
Signs of massive acute overdose generally include coma with muscle hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis, hypotension, cardiovascular disorders, circulatory collapse / shock, and hypernatremia. The presence of sodium in the valproate formulation can lead to hypernatremia when taken in overdose.
In both adults and children, high serum levels cause abnormal neurological disorders, such as an increased tendency to seizures and behavioral changes.
Deaths have occurred following massive overdose, however the prognosis for intoxication is generally favorable.
However, symptoms can be variable and seizures have been reported in the presence of very high plasma levels. Cases of intracranial hypertension linked to cerebral edema have been reported.
Treatment
No specific antidote is known.
Clinical management of overdose should therefore be limited to general measures aimed at eliminating toxins and supporting vital functions.
The measures to be taken at the hospital level must be symptomatic: gastric lavage, which can be useful up to 10-12 hours after ingestion; cardiac and respiratory monitoring. Naloxone has been used successfully in a few isolated cases. overdose, hemodialysis and hemoperfusion have been used successfully.
In case of accidental ingestion / intake of an overdose of DEPAKIN, notify your doctor immediately or go to the nearest hospital.
IF YOU HAVE ANY DOUBTS ABOUT USING DEPAKIN, CONTACT YOUR DOCTOR OR PHARMACIST.
Side Effects What are the side effects of Depakin Chrono
Like all medicines, DEPAKIN can cause side effects, although not everybody gets them.
Very common: ≥ 1/10
Common: ≥ 1/100,
Uncommon: ≥ 1/1000,
Rare: ≥ 1/10000,
Very rare:
- Congenital, familial and genetic disorders
Congenital malformations and developmental disorders (see "Special Warnings - Pregnancy").
- Hepatobiliary disorders
Common: Severe (sometimes fatal) hepatic dysfunction may occur, is dose independent. In children, particularly in combination therapy with other antiepileptics, the risk of liver damage is significantly increased (see "Special warnings").
- Gastrointestinal disorders
Very common: nausea.
Common: Vomiting, gum disease (mainly gingival hyperplasia), stomatitis, upper abdominal pain, diarrhea occur frequently in some patients at the start of treatment, but generally disappear after a few days without stopping treatment.
Uncommon: hypersalivation, pancreatitis, sometimes fatal (see "Special Warnings" and Precautions for use).
- Endocrine pathologies
Uncommon: Inappropriate ADH Secretion Syndrome (SIADH), hyperandrogenism (hirsutism, virilism, acne, male alopecia and / or increased androgen hormones).
Rare: hypothyroidism (see "Special warnings").
- Metabolism and nutrition disorders
Common: Hyponatremia, dose-dependent increase or weight loss, increased appetite and loss of appetite. In a clinical study with 75 children, reduced biotinidase activity was observed during treatment with valproic acid-containing medicines. There were also reports of biotin deficiency.
Rare: hyperammonaemia.
Moderate isolated hyperammonaemia may occur without abnormal liver function tests and this should not cause treatment discontinuation. However, in the course of monotherapy or polytherapy (phenobarbital, carbamazepine, phenytoin, topiramate) there may be an acute syndrome of hyperammonemic encephalopathy, with normal hepatic function and absence of cytolysis. Valproate-induced hyperammonaemic encephalopathy syndrome occurs in acute form and is characterized by loss of consciousness, stupor, muscle weakness (muscle hypotension), motor disturbances (choreoid dyskinesia), severe generalized changes in the EEG, and focal and general neurological signs with increased frequency of seizures. It may appear several days or weeks after the initiation of therapy and regresses with discontinuation of valproate. The encephalopathy is not dose-related, and changes in the EEG are characterized by the appearance of slow waves and increased epileptic discharges.
- Neoplasms benign, malignant and unspecified (including cysts and polyps)
Rare: myelodysplastic syndrome.
- Nervous system disorders
Very common: tremor.
Common: dose-dependent, dose-dependent paraesthesia, extrapyramidal disorders (inability to sit still, stiffness, tremors, slow movements, involuntary movements, muscle contractions). stupor, postural tremor, somnolence, convulsions, insufficient memory, headache, nystagmus, dizziness a few minutes after intravenous administration, which disappear spontaneously within a few minutes.
Uncommon: spasticity, ataxia, particularly at the start of treatment, coma, encephalopathy, lethargy, reversible parkinsonism.
Rare: reversible dementia associated with reversible brain atrophy, cognitive disturbances, confusional states. Stupor and lethargy, sometimes leading to transient coma (encephalopathy), were isolated cases or associated with an increased incidence of seizures during therapy and regressed with treatment discontinuation or dose reduction. These cases have mainly been reported during combination therapy (particularly with phenobarbital or topiramate) or after a sharp increase in valproate doses.
Sedation has been reported.
- Psychiatric disorders
Common: confusional state, hallucinations, aggression *, agitation *, attention disturbance *.
Uncommon: irritability, hyperactivity and confusion, particularly at the start of treatment (occasionally aggression, behavioral disturbances).
Rare: abnormal behavior *, psychomotor hyperactivity *, learning disorders *
* These side effects have mainly been seen in children
- Disorders of the blood and lymphatic system
Common: anemia, thrombocytopenia
Uncommon: neutropenia, leukopenia or pancytopenia, red blood cell hypoplasia. Peripheral edema, bleeding
Rare: bone marrow failure including pure bone marrow aplasia affecting red blood cells.
Agranulocytosis, macrocytic anemia, macrocytosis.
Diagnostic tests
Common: weight gain. Since weight gain is a risk factor for polycystic ovary syndrome it should be carefully monitored (see "Precautions for use").
Rare: decreased coagulation factors (at least one), factor VIII (von Willebrand factor) deficiency, abnormal coagulation tests (such as prolongation of prothrombin time, prolongation of activated partial thromboplastin time, prolongation of thrombin time, prolonged INR ) (see also "Pregnancy").
There have been isolated reports of decreased fibrinogen.
Biotin / biotinidase deficiency.
- Skin and subcutaneous tissue disorders
Common: hypersensitivity, transient and (or) dose-related alopecia.
Uncommon: angioedema, rash, hair changes (such as abnormal hair structure, changes in hair color, abnormal hair growth)
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme. Drug Rush Syndrome with Eosinophilia and Systemic Symptoms (DRESS), allergic reactions.
- Diseases of the reproductive system and breast
Elevated testosterone levels. There have been reports of frequency of polycystic ovary in patients who have had significant weight gain.
Common: dysmenorrhea,
Uncommon: amenorrhea.
Rare: male infertility.
- Vascular pathologies
Common: haemorrhage (see "Precautions for use" and "Special warnings")
Uncommon: vasculitis.
- General disorders and administration site conditions
Uncommon: hypothermia
- Ear and labyrinth disorders
Common: deafness, tinnitus.
- Respiratory, thoracic and mediastinal disorders
Uncommon: pleural effusion
- Renal and urinary disorders
Uncommon: renal failure
Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome, the mechanism of action is not yet clear.
- Disorders of the immune system
Rare: Systemic lupus erythematosus, rhabdomyolysis (see Precautions for use).
- Musculoskeletal and connective tissue disorders
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Depakin. The mechanism by which Depakin affects bone metabolism remains unclear.
As for the undesirable effects related to S.N.C. and the possible teratogenic risk, these could have a "lower incidence than those occurring after administration of Depakin. In fact DEPAKIN CHRONO has a more regular plasma profile, with lower fluctuations in concentrations of valproic acid due to the reduction of peak levels (Cmax ) and with unchanged "cable" levels.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly via the national reporting system at "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". By reporting undesirable effects you can help provide more information on the safety of this medicine
Expiry and Retention
Expiry: see the expiry date printed on the package. The expiry date refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date shown on the package.
Medicines should not be disposed of via wastewater or household waste.
Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Keep this medicine out of the reach and sight of children.
Pharmaceutical form and content
300 mg prolonged-release tablets - 30 divisible tablets
500 mg prolonged-release tablets - 30 divisible tablets
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
DEPAKIN CHRONO PROLONGED RELEASE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
DEPAKIN CHRONO 300 mg prolonged-release tablets
One tablet contains:
Active principle
sodium valproate 199.8 mg;
valproic acid 87.0 mg;
corresponding to 300 mg of sodium valproate.
For the full list of excipients, see section 6.1.
DEPAKIN CHRONO 500 mg prolonged-release tablets
One tablet contains:
Active principle
sodium valproate 333 mg;
valproic acid 145 mg;
corresponding to 500 mg of sodium valproate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Prolonged-release tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
In the treatment of generalized epilepsy, in particular in attacks of the type:
• absence,
• myoclonic,
• tonic-clonic,
• atonic,
• mixed,
and in partial epilepsy:
• simple or complex,
• secondarily generalized,
In the treatment of specific syndromes (West, Lennox-Gastaut).
In the treatment of manic episodes related to bipolar disorder when lithium is contraindicated or not tolerated. Continuation of therapy after the episode of mania may be considered in patients who have responded to valproate for acute mania.
04.2 Posology and method of administration
Treatment of epilepsy
Before starting therapy with DEPAKIN CHRONO, keep in mind that:
• In patients not treated with other antiepileptic drugs, the dosage should preferably be increased by successive stages of 2-3 days, to reach the optimal one within about a week.
• In patients already being treated with antiepileptic drugs, the substitution with valproate should be gradual, reaching the optimal posology in about two weeks. The concomitant treatments will be progressively reduced until they are stopped.
• The addition of another antiepileptic agent, if necessary, should be done gradually (see section 4.5).
The daily dosage should be based on age and body weight; however, individual sensitivity to valproate should also be taken into consideration.
The optimal posology must be determined essentially on the basis of the clinical response; determination of plasma levels of valproic acid may be considered as a complement to clinical monitoring, when adequate control of attacks is not achieved or when undesirable effects are suspected. Serum concentrations generally believed to be therapeutic are between 40 and 100 mg / l (300-700 mcmol / liter) of valproic acid.
Usually the initial daily dosage is 10-15 mg / kg, then the doses must be progressively increased until the optimal dosage is reached, which generally ranges from 20 to 30 mg / kg. However, when adequate control of attacks is not achieved with this posology, doses may be increased further; patients should be closely monitored when treated with daily doses greater than 50 mg / kg (see section 4.4) in particular:
• In children, the usual dosage is about 30 mg / kg / day
• In adults, the usual dosage ranges from 20 to 30 mg / kg / day
• In the elderly, although the pharmacokinetic parameters of valproate are modified, these changes are of limited clinical significance and the posology should be determined according to the clinical response (seizure control).
In patients with renal insufficiency or hypoproteinaemia, the increase of free valproic acid in serum should be considered and, if necessary, the dose should be reduced.
Administration
The use of the prolonged-release formulation - DEPAKIN CHRONO - allows the administration of the drug to be reduced to 1-2 times a day. Furthermore, the possibility of dividing the tablets allows greater dosage flexibility.
DEPAKIN CHRONO can also be used in children, when they are able to take the tablet form, which can also be divided.
However, among the oral pharmaceutical forms, the most appropriate for administration in children under 11 years of age are the oral solution and the granules.
Episodes of mania related to bipolar disorder
In adults:
The daily dosage must be established and controlled individually by the doctor.
The recommended starting daily dose is 750 mg. In addition, a starting dose of 20 mg valproate / kg body weight in clinical studies also showed an acceptable safety profile. Prolonged-release formulations can be administered once or twice daily. The dose should be increased on time. as quickly as possible in order to reach the lowest therapeutic dose with which the desired clinical effect is achieved. The daily dose should be adapted to the clinical response to establish the lowest effective dose for the individual patient.
The average daily dose usually varies between 1000 and 2000 mg of valproate. Patients receiving a daily dose greater than 45 mg / kg body weight should be closely monitored.
Continuation of treatment in manic episodes related to bipolar disorder should be established on an individual basis at the lowest effective dose.
In children and adolescents:
The safety and efficacy of Depakin Chrono in the treatment of manic episodes related to bipolar disorder have not been evaluated in patients below 18 years of age.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients.
• Acute hepatitis.
• Chronic hepatitis.
• Personal or family history of severe liver disease, especially drug induced.
• Hepatic porphyria.
• Clotting disorders
04.4 Special warnings and appropriate precautions for use
Special warnings
In children aged less than or equal to three years, antiepileptics containing valproic acid are only in exceptional cases the first choice therapy
Cases of suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs in their various indications. A meta-analysis of placebo-randomized clinical trials also found a modest increased risk of suicidal ideation and behavior.
The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk with valproate.
Therefore, patients should be monitored for signs of suicidal ideation and behavior and appropriate treatment should be considered if so. Patients (and caregivers) should be advised to notify their physician promptly if signs of suicidal ideation or behavior emerge.
Alcohol is not recommended during treatment with valproate.
Since valproate is excreted primarily via the kidney, partly as ketone bodies, the ketone body excretion test may give false positive results in diabetic patients.
HEPATOPATHIES
• Onset conditions
Exceptionally severe liver damage has been reported and has sometimes been fatal. The patients most at risk, especially in cases of multiple anticonvulsive therapy, are infants and children under 3 years of age with severe forms of epilepsy, in particular those with brain damage, mental retardation and (or) with congenital metabolic or degenerative disease.
If the Doctor deems it essential to administer the drug to children under three years of age for the treatment of a type of epilepsy responsive to valproate, despite the risk of liver disease, the use of Depakin must be done alone to reduce this risk. .
After the age of 3, the incidence is significantly reduced and progressively decreases with age.
In most cases, liver damage occurred during the first 6 months of therapy.
• Symptomatology
Clinical symptoms are essential for early diagnosis. In particular, especially in patients at risk (see conditions of onset), two types of manifestations that may precede jaundice should be considered:
• reappearance of the seizures
• non-specific symptoms, usually rapid onset, such as asthenia, anorexia, lethargy, somnolence, sometimes associated with repeated vomiting and abdominal pain.
Patients (or their parents if they are children) should be advised to notify their physician immediately if any of the above signs occur. In addition to clinical checks, immediate blood chemistry checks of liver function should be undertaken.
• Detection
Liver function should be checked before starting therapy and periodically during the first 6 months of therapy. Among the usual analyzes, the most pertinent are those that reflect protein synthesis, especially prothrombin time. Confirmation of a particularly low percentage of prothrombin activity, especially if associated with other abnormal biological findings (significant decrease in fibrinogen and coagulation factors; increase in bilirubin levels and increase in transaminases, SGOT, SGPT, gamma-GT, lipase, alpha-amylase, glycaemia) requires the interruption of therapy with valproate. As a precaution and in case they are taken at the same time, the salicylates must also be interrupted, since they are metabolized by the same route.
Four weeks after the start of treatment, laboratory tests for coagulation parameters such as INR and PTT, SGOT, SGPT, bilirubin and amylase should be checked.
In children with no abnormal clinical symptoms, blood counts including thrombocytes, SGOT and SGPT should be checked at each visit.
PANCREATITES
Serious pancreatitis which can be fatal has been reported very rarely. Younger children are particularly at risk. The risk decreases with increasing age. Severe seizures, neurological disorders, or anticonvulsant polypharmacy can be risk factors. The presence of hepatic insufficiency concomitant with pancreatitis increases the risk of a fatal outcome. Patients experiencing acute abdominal pain should be immediately seen by a physician. In case of pancreatitis, valproate should be discontinued.
- Women of childbearing potential (see section 4.6)
This medicine should not be used in women of childbearing potential, unless clearly necessary (i.e. in situations where other treatments are ineffective or not tolerated) and only after very careful consideration to determine whether the benefits of using it outweigh the risks of congenital abnormalities of the fetus. This assessment should be done before Depakin is prescribed for the first time, or when a woman of childbearing potential being treated with Depakin plans to become pregnant. Women of childbearing potential must use effective contraception during treatment.
Precautions for use
• Liver function tests should be performed prior to initiation of therapy (see section 4.3), which should be repeated periodically during the first 6 months, especially in patients at risk (see section 4.4).
As with most antiepileptic drugs, increases in liver enzymes may be noted, particularly at the start of therapy; they are transient and isolated, not accompanied by clinical signs. In these patients, more in-depth laboratory investigations are recommended (including time to prothrombin), dosage adjustment may also be considered and tests repeated if necessary.
• In children less than 3 years of age, Depakin should be administered as monotherapy although its potential benefit must be evaluated prior to initiation of treatment, in comparison with the risk of liver damage or pancreatitis in these patients (see section 4.4 ).
Concomitant use of salicylates should be avoided in children under 3 years of age due to the risk of hepatotoxicity.
• It is recommended that blood tests (complete blood count with platelet count, bleeding time and coagulation tests) be performed before the start of therapy or before surgery, and in the case of spontaneous hematoma or bleeding (see section 4.8 ).
• In patients with renal insufficiency or hypoproteinemia it is necessary to decrease the dosage.Since monitoring of plasma concentrations may give unreliable results, the posology should be adjusted based on clinical monitoring (see section 5.2).
• Although immune diseases have been found only exceptionally during the use of valproate, the potential benefit of valproate versus the potential risk in patients with systemic lupus erythematosus should be considered.
• As exceptional cases of pancreatitis have been reported, patients with acute abdominal pain should undergo immediate medical examination. In the event of pancreatitis, valproate therapy should be discontinued.
• If an altered urea cycle is suspected, hyperammonaemia should be evaluated prior to treatment as aggravation is possible with valproate (see section 4.8).
Therefore, if symptoms such as apathy, drowsiness, vomiting, hypotension and increased frequency of seizures appear, serum levels of ammonia and valproic acid should be determined; if necessary the dose of the medicine should be reduced. If an enzymatic interruption of the urea cycle is suspected, the serum ammonia level should be determined before starting therapy with medicinal products containing valproic acid.
• Patients should be warned of the risk of weight gain prior to initiation of therapy and appropriate measures taken to minimize this risk (see section 4.8).
• Patients with underlying carnitine palmitoyltransferase (CPT) type II deficiency should be advised of the increased risk of rhabdomyolysis when taking valproate.
• The concomitant use of valproic acid / sodium valproate and medicinal products containing carbapenems is not recommended (see 4.5).
• Women of childbearing potential (see section 4.6)
All women with epilepsy and of childbearing age should be adequately informed about the risks associated with pregnancy.
Hematology
Blood cell counts, including platelet counts, bleeding time and coagulation tests should be monitored prior to initiation of therapy, prior to surgery or dental surgery, and for spontaneous haematomas or haemorrhages (see section 4.8).
In case of concomitant intake of vitamin K antagonists, close monitoring of INR values is recommended.
Damage to the bone marrow
Patients with previous bone marrow damage should be strictly monitored.
04.5 Interactions with other medicinal products and other forms of interaction
Effects of valproate on other drugs
• Neuroleptics, anti-MAO, antidepressants and benzodiazepines
Valproate may potentiate the effect of other psychotropic drugs such as neuroleptics, anti-MAOs, antidepressants and benzodiazepines; therefore, clinical monitoring and, when necessary, dosage adjustment are recommended.
• Phenobarbital
Since valproate increases plasma phenobarbital concentrations (by inhibition of hepatic catabolism) sedation may occur especially in children. Clinical monitoring is therefore recommended for the first 15 days of combined treatment, with immediate reduction of phenobarbital doses in case of sedation, and possible monitoring of plasma phenobarbital levels.
• Primidone
Valproate increases the plasma levels of primidone with potentiation of its undesirable effects (sedation); this interaction ceases with long-term treatment. Clinical monitoring is recommended especially at the initiation of combination therapy with an adjustment of the primidone dosage when necessary.
• Phenytoin
Initially, valproate decreases the total plasma concentration of phenytoin, increasing however its free fraction, with possible symptoms of overdose (valproic acid displaces phenytoin from its protein binding sites and slows down its hepatic catabolism).
Clinical monitoring is therefore recommended; in the case of a plasma assay of phenytoin, the free fraction must be taken into account in particular.
Subsequently, following chronic treatment, phenytoin concentrations return to the initial pre-valproate values.
• Carbamazepine
Clinical toxicity has been reported with concomitant administration of valproate and carbamazepine as valproate may potentiate the toxicity of carbamazepine. Clinical monitoring is therefore recommended especially at the start of treatment with the combination of the two drugs, with dosage adjustment if necessary.
• Lamotrigine
Depakin reduces the metabolism of lamotrigine and increases its mean half-life by almost 2-fold. This interaction may lead to increased lamotrigine toxicity, particularly severe skin rashes. Clinical monitoring is therefore recommended and, when necessary, should be decreased. the dosage of lamotrigine.
• Ethosuximide
Valproate can cause increased plasma concentrations of ethosuximide.
• Zidovudine
Valproate may increase the plasma concentration of zidovudine with the consequent increased risk of its toxicity.
• Felbamato
Valproic acid can decrease the mean clearance of felbamate by up to 16%.
Effects of other drugs on valproate
Enzyme-inducing antiepileptics (in particular phenytoin, phenobarbital and carbamazepine) decrease the serum concentrations of valproic acid. In the case of combined therapy the dosages should be adjusted according to the blood levels.
On the other hand, the combination of felbamate and valproate decreases the clearance of valproic acid from 22% to 50% and consequently increases the plasma concentration of valproic acid. Monitoring of the plasma levels of valproate is necessary.
Mefloquine increases the metabolism of valproic acid and has a convulsive effect; therefore, seizures may occur in cases of combined therapy.
In case of concomitant use of valproate and substances that bind highly to proteins (acetylsalicylic acid), the free serum levels of valproic acid may increase.
Medicines containing valproic acid should not be administered concomitantly with acetylsalicylic acid to treat fever and pain, particularly in infants and children.
Close monitoring of prothrombin time should be performed in case of concomitant use of vitamin K dependent anticoagulant factors.
Serum levels of valproic acid may increase (due to reduced hepatic metabolism) with concomitant use of cimetidine or erythromycin and fluoxetine. However, there have also been reports of cases in which the serum concentration of valproic acid was lowered following concomitant intake of fluoxetine.
A decrease in blood levels of valproic acid has been reported when co-administered with carbapenem-containing medicinal products, resulting in a 60-100% reduction in these blood levels in approximately two days. Due to the rapid onset and marked decrease, concomitant administration of carbapenem-containing medicinal products in patients stabilized with valproic acid is not considered feasible and should therefore be avoided (see section 4.4).
Rifampicin can decrease the plasma levels of valproic acid leading to the interruption of the therapeutic effect. Therefore, an adjustment of the valproate dosage may be necessary when co-administered with rifampicin.
Other interactions
Concomitant administration of valproate and topiramate has been associated with the onset of encephalopathy and / or hyperammonaemia. Patients treated with these two drugs should be monitored with particular attention for signs and symptoms of hyperammonaemic encephalopathy.
Valproate generally does not have an enzyme inducing effect; consequently it does not reduce the efficacy of estrogen-progestins in the case of hormonal contraception.
In healthy volunteers, valproate displaced diazepam from its binding sites with plasma albumin and inhibited its metabolism. In combination therapy, the concentration of free diazepam may be increased, while the plasma clearance and volume of distribution of the free fraction of diazepam can be reduced (by 25% and 20% respectively). The half-life, however, remains unchanged.
In healthy subjects, concomitant treatment with valproate and lorazepam resulted in a reduction in plasma clearance of lorazepam by more than 40%.
Absence has occurred in patients with a history of absence seizure epilepsy following a combined treatment of valproic acid and clonazepam.
Following concomitant treatment with valproic acid, sertraline and risperidone, catatonia developed in a patient with schizoaffective disorder.
• Quetiapine
Concomitant administration of valproate and quetiapine may increase the risk of neutropenia / leukopenia.
04.6 Pregnancy and lactation
This medicine should not be used during pregnancy and in women of childbearing potential unless strictly necessary (for example in situations where other treatments are ineffective or not tolerated). Women of childbearing potential should use effective contraceptive methods during treatment.
Women of childbearing age
Epilepsy
Women with epilepsy of any type and of childbearing age should be advised of the risk and benefits of using valproate during pregnancy. Because of the potential risks to the fetus, the benefits of using valproate should be weighed against the risks. . When valproate treatment is deemed necessary, precautions should be taken to minimize the potential teratogenic risk (see below "In consideration of the above data ").
Manic episodes in bipolar disorder:
In the event of bipolar disorder, discontinuation of valproate therapy should be considered if pregnancy is planned.
Pregnancy
The experience in the treatment of epileptic mothers allows to describe the risks of using valproate during pregnancy as follows:
Risk associated with epilepsy and antiepileptics
In children of epileptic mothers treated with antiepileptics during pregnancy, the overall rate of malformations is 2-3 times higher than the normal rate (approximately 3%). An increase in the number of children with malformations has been reported with multiple drug therapies. The most frequently encountered malformations are cleft cheeks and cardiovascular malformations.
Developmental delays in children born to epileptic mothers have been reported very rarely. It is not possible to distinguish how much it depends on genetic, social, environmental factors, on whether the mother is epileptic or on antiepileptic treatments.
Despite these potential risks, a decision should not be made about abrupt cessation of antiepileptic therapy which can lead to a significant increase in seizures with serious consequences for both the mother and the fetus.
Risk associated with seizures
During pregnancy, tonic-clonic seizures and status epilepticus with hypoxia in the mother are associated with a particular risk of death for the mother and fetus.
Risk associated with sodium valproate
Valproate is the antiepileptic of choice in patients with certain types of epilepsy such as generalized epilepsy with or without myoclonus or photosensitivity. For partial epilepsy, valproate should only be used in cases resistant to other treatments.
In the animal: teratogenic effects have been demonstrated in mice, rats and rabbits.
In men: the intake of valproate during pregnancy, particularly in the first 3 months, can cause an increased risk of malformations in the unborn child.
Compared to treatment with other antiepileptic drugs, in children born to mothers with epilepsy and treated with valproate the available data suggest an increase in the incidence of minor or major malformations which include neural tube defects, craniofacial defects, limb malformations, cardiovascular malformations and multiple abnormalities involving different body systems (including hypospadias and facial dysmorphia). The use of valproate is associated with neural tube defects with an incidence of 1% to 2%.
Data from a meta-analysis (which included cohort studies and registries) showed an "incidence of congenital malformations of 10.73% (95% CI: 8.16 - 13.29) in children born to epileptic women exposed to valproate monotherapy during pregnancy Available data indicate a dose dependence of this effect.
Some data suggest an "association" between exposure to valproate in utero and the risk of developmental delay, particularly of verbal IQ, in children born to mothers with epilepsy and treated with valproate.
Developmental delay is frequently associated with malformations and / or dysmorphic features. However, it is difficult to establish the causal relationship with possible confounding factors such as low maternal or paternal IQ, other genetic, social, environmental factors and poor control of maternal seizures during pregnancy.
Autism spectrum disorders have been reported in children exposed to valproate in the uterus.
Both valproate monotherapy and valproate polypharmacy are associated with abnormal pregnancy outcomes. Available data suggest that antiepileptic polypharmacy including valproate is associated with a higher risk of abnormal pregnancy outcome than valproate monotherapy.
Valproate during pregnancy should be prescribed as monotherapy at the lowest effective dose, in divided doses and if possible in prolonged-release forms.
The daily dose should be given in several small doses throughout the day in women who may become pregnant and certainly between day 20 and 40 after conception. Furthermore, plasma concentrations should be monitored regularly, considering the possibility of considerable fluctuations that can occur during pregnancy even with constant dosage.
Abnormal pregnancy outcomes tend to be associated with higher daily doses and higher doses for each administration. High plasma peak values and high amounts for each administration have been shown to be associated with neural tube defects. The incidence of neural tube defects increases with increasing dosage, especially above 1000 mg / day.
Dietary supplementation with folic acid before pregnancy may reduce the incidence of neural tube defects in infants of high-risk women. Patients should consider taking 5 mg of folic acid daily when planning pregnancy.
In women who become pregnant, diagnostic investigations during pregnancy such as ultrasound scans or other appropriate techniques should be conducted.
In consideration of the above data
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), and only after very careful consideration to determine whether the benefits deriving from its use outweigh the risks of congenital anomalies in the fetus. This assessment should be done before Depakin is prescribed for the first time, or when a woman of childbearing potential being treated with Depakin plans to become pregnant. Women of childbearing potential must use effective contraception during treatment.
• Women of childbearing potential should be informed of the risks and benefits of using DEPAKIN during pregnancy.
• If a woman plans to become pregnant or is pregnant, DEPAKIN therapy should be re-evaluated for any indication.
• In the indication of bipolar disorders, consideration should be given to discontinuing therapy with DEPAKIN. In epilepsy, valproate therapy should not be discontinued without a benefit / risk reassessment. If, after careful benefit / risk assessment, DEPAKIN treatment is to continue during pregnancy, it is recommended that daily dose monotherapy be used. minimum effective. Administration in different doses throughout the day is preferable. The use of an extended release formulation may be preferable to any other form of treatment.
The use of a folate supplement should begin before pregnancy and at suitable dosages (5 mg / day) that can minimize the risk of neural tube malformations.
• During pregnancy, antiepileptic treatment with valproate should not be discontinued without reassessing the benefit / risk ratio.
• Prenatal specialist monitoring should be instituted to detect the possible presence of anomalies in the closure of the neural tube or of another malformation.
Risk in the newborn
There have been very rare reports of haemorrhagic syndrome in newborns whose mothers took valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and / or decrease in other clotting factors. Cases of afibrinogenemia which can be fatal have also been reported.
However, this syndrome must be distinguished from that linked to the decrease in vitamin K dependent factors induced by phenobarbital and enzyme inducers.
Therefore in neonates the following should be checked: platelet count, plasma fibrinogen level, coagulation test and coagulation factors.
Withdrawal symptoms have been reported in neonates of mothers treated with valproic acid.
Valproic acid treatment during pregnancy should not be stopped without consulting your doctor, as well as any abrupt discontinuation of treatment or uncontrolled dosage reduction.This could lead to seizures in the pregnant woman, which could harm the mother and / or the unborn child.
Cases of hypoglycaemia have been reported in infants whose mothers took valproate during the third trimester of pregnancy.
There have been reports of hypothyroidism in infants whose mothers took valproate during pregnancy.
In infants whose mothers took valproate during the last trimester of pregnancy, drug withdrawal syndrome (such as agitation, irritability, hyperexcitability, nervousness, hyperkinesis, muscle tone disturbances, tremor, seizures and feeding disturbances) may occur.
Feeding time
Valproate is excreted in breast milk. Maternal use of valproate may cause undesirable effects in the infant; therefore, a decision must be made whether to discontinue breastfeeding or treatment with the medicinal product, taking into account the importance of the drug to the mother.
04.7 Effects on ability to drive and use machines
In case of concomitant administration with barbiturates or other drugs with central nervous system depressant activity, manifestations of asthenia, drowsiness or confusion may be found in some subjects, which can thus alter the response to the ability to drive a vehicle, use machinery or perform activities connected with the risk of falling or accident, the ability is impaired regardless of the underlying disease.
The same manifestations can be observed after drinking alcoholic beverages. Those subjects who, during the processing, could drive vehicles or attend to operations requiring integrity of the degree of supervision must be warned of this.
04.8 Undesirable effects
• Congenital, familial and genetic disorders (see section 4.6)
Teratogenic risk (see section 4.6).
- Hepatobiliary disorders
Common: Severe (sometimes fatal) hepatic dysfunction may occur, is dose independent. In children, particularly in combination therapy with other antiepileptics, the risk of liver damage is significantly increased (see section 4.4).
• Gastrointestinal disorders
Very common: nausea.
Common: Vomiting, gum disease (mainly gingival hyperplasia), stomatitis, upper abdominal pain, diarrhea occur frequently in some patients at the start of treatment, but generally disappear after a few days without stopping treatment.
Uncommon: hypersalivation, pancreatitis, sometimes fatal (see section 4.4).
• Endocrine pathologies
Uncommon: Inappropriate ADH Secretion Syndrome (SIADH), hyperandrogenism (hirsutism, virilism, acne, male alopecia and / or increased androgen hormones).
Rare: hypothyroidism (see section 4.6).
• Metabolism and nutrition disorders:
Common: Hyponatremia, dose-dependent gain or weight loss, increased appetite and loss of appetite.
In a clinical study with 75 children, reduced biotinidase activity was observed during treatment with medicinal products containing valproic acid. There have also been reports of biotin deficiency.
Rare: hyperammonaemia.
Moderate isolated hyperammonaemia may occur without abnormal liver function tests and this should not cause treatment discontinuation. However, in the course of monotherapy or polytherapy (phenobarbital, carbamazepine, phenytoin, topiramate) there may be an acute syndrome of hyperammonemic encephalopathy, with normal hepatic function and absence of cytolysis. Valproate-induced hyperammonaemic encephalopathy syndrome occurs in acute form and is characterized by loss of consciousness, stupor, muscle weakness (muscle hypotension), motor disturbances (choreoid dyskinesia), severe generalized changes in the EEG, and focal and general neurological signs with increased frequency of seizures. It may appear several days or weeks after the initiation of therapy and regresses with discontinuation of valproate. The encephalopathy is not dose-related, and changes in the EEG are characterized by the appearance of slow waves and increased epileptic discharges.
• Neoplasms benign, malignant and unspecified (including cysts and polyps)
Rare: myelodysplastic syndrome.
• Nervous system disorders:
Very common: tremor.
Common: Dose-dependent paraesthesia, extrapyramidal disorders (inability to sit still, stiffness, tremors, slow movements, involuntary movements, muscle contractions), stupor, postural tremor, somnolence, convulsions, insufficient memory, headache, nystagmus, dizziness a few minutes after intravenous administration, which disappear spontaneously within a few minutes.
Uncommon: spasticity, ataxia, particularly at the start of treatment, coma, encephalopathy, lethargy, reversible parkinsonism.
Rare: reversible dementia associated with reversible brain atrophy, cognitive disturbances, confusional states.
Stupor and lethargy, which sometimes led to transient coma (encephalopathy); they were isolated cases or associated with an increased incidence of seizures during therapy and regressed with treatment discontinuation or dose reduction. These cases have mainly been reported during combination therapy (particularly with phenobarbital or topiramate) or after a sharp increase in valproate doses.
Sedation has been reported
Psychiatric disorders
Common: confusional state, hallucinations, aggression *, agitation *, attention disturbance *.
Uncommon: irritability, hyperactivity and confusion, particularly at the start of treatment (occasionally aggression, behavioral disturbances).
Rare: abnormal behavior *, psychomotor hyperactivity *, learning disorders *.
* These side effects have mainly been seen in children
• Disorders of the blood and lymphatic system:
Common: anemia, thrombocytopenia,
Uncommon: neutropenia, leukopenia or pancytopenia, red blood cell hypoplasia. Peripheral edema, bleeding
Rare: bone marrow failure including pure bone marrow aplasia affecting red blood cells. Agranulocytosis, macrocytic anemia, macrocytosis.
• Diagnostic tests
Common: weight gain. Since weight gain is a risk factor for polycystic ovary syndrome it should be carefully monitored (see section 4.4).
Rare: decreased coagulation factors (at least one), factor VIII (von Willebrand factor) deficiency, abnormal coagulation tests (such as prolongation of prothrombin time, prolongation of activated partial thromboplastin time, prolongation of thrombin time, prolonged INR ) (see also sections 4.4. and 4.6).
There have been isolated reports of decreased fibrinogen.
Biotin / biotinidase deficiency.
• Skin and subcutaneous tissue disorders
Common: hypersensitivity, transient and (or) dose-related alopecia.
Uncommon: angioedema, rash, hair changes (such as abnormal hair structure, changes in hair color, abnormal hair growth).
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme. Drug Rush Syndrome with Eosinophilia and Systemic Symptoms (DRESS), allergic reactions.
• Reproductive system and breast disorders:
Elevated testosterone levels. There have been reports of frequency of polycystic ovary in patients who have had significant weight gain.
Common: dysmenorrhea,
Uncommon: amenorrhea,
Rare: male infertility.
• Vascular pathologies
Common: haemorrhage (see sections 4.4 and 4.6)
Uncommon: vasculitis.
• General disorders and administration site conditions
Uncommon: hypothermia
• Ear and labyrinth disorders
Common: deafness, tinnitus.
• Respiratory, thoracic and mediastinal disorders
Uncommon: pleural effusion
• Renal and urinary disorders
Uncommon: renal failure
Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome, the mechanism of action is not yet clear.
• Disorders of the immune system
Rare: Systemic lupus erythematosus, rhabdomyolysis (see section 4.4).
- Musculoskeletal and connective tissue disorders
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Depakin. The mechanism by which Depakin affects bone metabolism remains unclear.
As for the undesirable effects related to S.N.C. and the possible teratogenic risk, these could have a "lower incidence than those occurring after administration of Depakin. In fact DEPAKIN CHRONO has a more regular plasma profile, with lower fluctuations in concentrations of valproic acid due to the reduction of peak levels (Cmax ) and with unchanged "cable" levels.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
Signs and symptoms
At therapeutic serum levels (50-100 mcg / ml), valproic acid has relatively low toxicity. Very rarely, acute valproic acid intoxication at serum levels above 100 mcg / ml has occurred in adults and children.
Signs of massive acute overdose generally include coma with muscle hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis, hypotension, cardiovascular disorders, circulatory collapse / shock, and hypernatremia. The presence of sodium in the valproate formulation can lead to hypernatremia when taken in overdose.
In both adults and children, high serum levels cause abnormal neurological disorders, such as an increased tendency to seizures and behavioral changes.
Deaths have occurred following massive overdose, however the prognosis for intoxication is generally favorable.
However, symptoms can be variable and seizures have been reported in the presence of very high plasma levels. Cases of intracranial hypertension linked to cerebral edema have been reported.
Treatment
No specific antidote is known.
Clinical management of overdose should therefore be limited to general measures aimed at eliminating toxins and supporting vital functions.
The measures to be taken at the hospital level must be symptomatic: gastric lavage, which can be useful up to 10-12 hours after ingestion; cardiac and respiratory monitoring. Naloxone has been used successfully in a few isolated cases. overdose, hemodialysis and hemoperfusion have been used successfully.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiepileptic derivatives of fatty acids.
ATC code: N03AG01.
Broad spectrum antiepileptic. Valproate exerts its effect mainly on the central nervous system. Pharmacological studies in animals have shown that it has anticonvulsant properties in various models of experimental epilepsy (generalized and partial seizures). Also in "man it has shown" antiepileptic activity in various types of epilepsy. Its main mechanism of action seems to be linked to a strengthening of the gabaergic pathway.
It has been shown that sodium valproate is able to stimulate the replication of the HIV virus in some studies carried out in vitro; however this effect is modest, inconsistent, not dose related and not reported in patients.
05.2 Pharmacokinetic properties
The bioavailability of sodium valproate is close to 100% after oral or i.v. administration.
The volume of distribution is mainly limited to blood and rapid exchange extracellular fluid. The concentration of valproic acid in the cerebrospinal fluid is close to the free plasma concentration. Valproic acid passes through the placenta. When administered during lactation, valproate is excreted in breast milk at very low concentrations (between 1 and 10% of the total serum concentration).
Steady-state plasma concentration is reached rapidly (3-4 days) after oral administration; with the form i.v. steady-state plasma concentration can be reached in a few minutes and maintained with an i.v.
The protein binding is very high, it is dose dependent and saturable. The valproate molecule can be dialyzed, but only the free form (about 10%) is excreted.
Unlike most other antiepileptics, sodium valproate does not accelerate its own breakdown, nor that of other agents such as estrogen-progestins. This is due to the absence of the enzyme-inducing effect involving cytochrome P 450.
The half-life is about 8 - 20 hours. In children it is generally shorter.
Sodium valproate is primarily excreted in the urine following metabolism by glucurono-conjugation and beta-oxidation.
Features of DEPAKIN CHRONO
Compared to the gastro-resistant form (DEPAKIN), the CHRONO form presents, at equivalent doses:
• disappearance of the absorption latency time after administration;
• prolonged absorption;
• identical bioavailability;
• lower total and maximum free plasma concentrations (Cmax) with a decrease in Cmax of about 25%, but with a relatively stable plateau from 4 to 14 hours after administration: this leveling of peaks allows to obtain more regular concentrations of valproic acid and a more homogeneous nictemeral distribution: after twice daily administration of the same dose, the range of plasma fluctuations is reduced by half.
• more linear correlation between doses and plasma concentrations (total and free).
05.3 Preclinical safety data
Acute toxicity: the oral LD50 in mice is 1700 mg / kg, 1530 mg / kg in rats and 824 mg / kg in the guinea pig, while intraperitoneally in rabbits the LD50 is 1200 mg / kg.
Chronic toxicity: in mice at the dose of 50 mg / kg orally no toxic phenomena were detected after treatment for 325 consecutive days.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
DEPAKIN CHRONO 300 mg prolonged-release tablets
ethylcellulose, hypromellose, colloidal hydrated silica, sodium saccharin, polyacrylate dispersion 30%, macrogol 6000, talc, titanium dioxide.
DEPAKIN CHRONO 500 mg prolonged-release tablets
ethylcellulose, hypromellose, anhydrous colloidal silica, hydrated colloidal silica, sodium saccharin, polyacrylate dispersion 30%, macrogol 6000, talc, titanium dioxide.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions
06.5 Nature of the immediate packaging and contents of the package
Cardboard box containing: blister packs of 30 divisible 300 mg prolonged-release tablets.
Cardboard box containing: blister packs of 30 divisible prolonged-release tablets of 500 mg.
06.6 Instructions for use and handling
No special instructions.
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Sanofi S.p.A. - Viale L. Bodio, 37 / B - Milan
08.0 MARKETING AUTHORIZATION NUMBER
AIC n. 022483109 300 mg prolonged-release tablets 30 divisible tablets
AIC n. 022483111 500 mg prolonged-release tablets 30 divisible tablets
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 3 July 1997 / Renewal: 1 June 2010
10.0 DATE OF REVISION OF THE TEXT
November 2014
