DEPAKIN - PACKAGE LEAFLET - LEAFLETS

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Depakin - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Valproic acid (Sodium valproate)

DEPAKIN 50 mg modified release granules
DEPAKIN 100 mg modified release granules
DEPAKIN 250 mg modified release granules
DEPAKIN 500 mg modified release granules
DEPAKIN 750 mg modified release granules
DEPAKIN 1000 mg modified release granules

Depakin package inserts are available for pack sizes:

DEPAKIN 50 mg modified release granules, DEPAKIN 100 mg modified release granules, DEPAKIN 250 mg modified release granules, DEPAKIN 500 mg modified release granules, DEPAKIN 750 mg modified release granules, DEPAKIN 1000 mg modified release granules
DEPAKIN 200 mg gastro-resistant tablets, DEPAKIN 500 mg gastro-resistant tablets, DEPAKIN 200 mg / ml oral solution
DEPAKIN 400 mg / 4 ml powder and solvent for solution for infusion

Why is Depakin 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 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

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 before the start of therapy (see "Contraindications"), 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 hypoproteinemia it is necessary to decrease the dosage. Since monitoring of plasma concentrations can be misleading, the dosage should be adapted according to 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.
Before starting therapy, patients should be warned of the risk of weight gain and appropriate measures must be taken to minimize this risk (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

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 when valproate is administered with carbamazepine, as valproate may potentiate the toxic effect of carbamazepine. Clinical monitoring is recommended especially at the initiation of combination therapy with dosage adjustment when 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 leading to increased toxicity of zidovudine.

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. The plasma rate of valproate should therefore be monitored.

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.

Concomitant food intake does not significantly affect the bioavailability of sodium valproate when administered as modified release Depakin granules.

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.

Experience in epilepsy has indicated that 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, two types of manifestations that may precede jaundice should be considered, especially in patients at risk (see "Onset conditions"):

seizures reappear in epileptic patients
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. Among the usual analyzes, the most relevant are those that reflect protein synthesis, especially prothrombin time. Confirmation of a percentage of prothrombin activity. particularly low, especially if associated with other abnormal biological findings (significant decrease in fibrinogen and coagulation factors; increased levels of bilirubin and transaminases SGOT, SGPT, gamma-GT, lipase, alpha-amylase, glycaemia) requires interruption 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 attacks, 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. and benefits, valproate treatment 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: Dosage

Among the oral pharmaceutical forms, the most appropriate for administration in children under 11 years of age are the oral solution and the granules.

DEPAKIN Modified Release Granules is a pharmaceutical form suitable for everyone, especially children (if they are able to swallow soft food), adults with swallowing difficulties and the elderly.

Based on the amount of the active ingredient, the 50 mg and 100 mg sachets are reserved for children.

DEPAKIN Modified Release Granules is a controlled release formulation of Depakin that reduces peak concentrations and ensures more regular plasma concentrations throughout the day.

Treatment of epilepsy

Daily dosing should be based on age and body weight; however, individual broad sensitivity to valproate should also be taken into consideration.

A definite correlation between daily dose, serum concentration and therapeutic effect has not been established, and the optimal dose should essentially be determined according to clinical response; determination of plasma levels of valproic acid may be considered in addition to clinical monitoring. , when adequate control of attacks is not achieved or when adverse events are suspected.The therapeutic range is generally between 40-100 mg / L (300-700 µmol / L).

The established dose should be divided into 2 daily administrations.

Initiation of therapy with modified-release DEPAKIN granules (oral administration)

In patients not treated with other antiepileptic drugs, the dosage should preferably be increased by successive dose levels, at intervals of 2-3 days, to reach the optimal one in approximately one week.
In patients already being treated with antiepileptic drugs, the substitution with modified-release granules DEPAKIN should be gradual, reaching the optimal dosage in about two weeks, reducing and then stopping the other treatments.
Adding another antiepileptic drug should be done gradually, as needed (see "Interactions").

Oral administration of modified release DEPAKIN granules: practical considerations

Dosage

The initial daily dosage is usually 10-15 mg / kg, then doses are titrated to the optimal dosage (see "Starting therapy with modified-release DEPAKIN granules").

This is generally between 20-30 mg / kg. However, if control of attacks is not achieved with this posology, it is possible to further increase the dose, in an appropriate manner; patients should be closely monitored when receiving daily doses above 50 mg / kg (see "Precautions for use").

In children the usual maintenance dosage is about 30 mg / kg per day.

In adults the usual maintenance dosage is between 20-30 mg / kg per day.

In the elderlyAlthough the pharmacokinetics of modified-release granules DEPAKIN are modified, the clinical significance is limited and the dosage should be determined based on 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.

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.

Children and adolescents:

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

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

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 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 modified-release granules have a more regular plasma profile, with lower fluctuations in the concentrations of valproic acid due to a reduction in blood levels. peaks (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." 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 and correctly stored packaging.

Warning: do not use the medicine after the expiry date shown on the package

Do not store above 25 ° C.

Store in the original package, protect the medicine from moisture or heat sources.

Do not refrigerate or freeze

Keep this medicine out of the reach and sight of children.

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.

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.

Further information on Depakin can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 REVISION DATEOF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXTEMPORARY PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

CLENIL - POWDER FOR INHALATION

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Clenil 100 mcg powder for inhalation

Each delivery contains:

Active ingredient: beclomethasone dipropionate 100 mcg.

Clenil 200 mcg powder for inhalation

Each delivery contains:

Active ingredient: beclomethasone dipropionate 200 mcg.

Clenil 400 mcg powder for inhalation

Each delivery contains:

Active ingredient: beclomethasone dipropionate 400 mcg.

For the complete list of excipients, see section 6.1

03.0 PHARMACEUTICAL FORM

Inhalation powder in Pulvinal inhaler.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Control of the evolution of asthmatic disease and bronchostenosis conditions.

04.2 Posology and method of administration

Adults

One inhalation of Clenil 400mcg Powder twice a day or one inhalation of Clenil 200mcg Powder 3-4 times a day.

In patients requiring higher doses to control asthmatic disease, the dosage can be increased to two inhalations twice daily of Clenil 400 mcg Powder.

Children

One inhalation of Clenil 100mcg Powder 2-4 times a day or one inhalation of Clenil 200mcg Powder twice a day.

To obtain good results, the preparation must be used regularly, even during the asymptomatic phases.

No dosage adjustments are required in elderly patients or patients with hepatic or renal insufficiency.

Clenil Inhalation Powder is for inhalation use only.

Instructions for Use

Please read the following instructions carefully for correct use. If necessary, contact your doctor for more detailed explanations.

Clenil is an inhalation powder based on micronized beclomethasone dipropionate mixed with a "carrier", contained in a multidose inhaler device. The delivery system does not require propellants and does not require coordination between delivery and inhalation

The powder inhaler should be stored in a dry place at room temperature.

Do not remove the protective cap until the moment of use.

TO) Opening

1) Unscrew the protective cap. Before use, check that the mouthpiece is clean. If necessary, clean the mouthpiece with a lint-free paper towel or soft cloth. Before turning the inhaler, hold it upright and tap it gently on a hard surface in order to level the dust in the chamber.

B) Loading

2) Holding the inhaler in a vertical position, press the brown button on the mouthpiece with one hand and with the other rotate the body of the inhaler counterclockwise (half a turn) as far as it will go, with the hole in the mouthpiece positioned exactly on the red dot (dose loading position).

3) While holding the inhaler in a vertical position, rotate the body of the inhaler clockwise (half a turn) until you hear a "click", with the hole positioned exactly on the green dot (dose delivery position).

C) Administration

4) Exhale deeply calmly, not through the inhaler.

5) Place the mouthpiece between your lips, holding the inhaler upright, and inhale through your mouth as quickly and as deeply as possible. Hold your breath for a few seconds.

D) Closure

6) Remove the inhaler from your mouth. Screw the protective cap back on.

General Councils

Always keep the inhaler upright from the dose loading phase until inhalation.

If a dose corresponding to 2 inhalations is to be taken, it is necessary to rotate the inhaler each time as described above in point B before inhaling.

During use, the level of the powder will gradually decrease in the transparent body of the device. When the red rays on the bottom of the inhaler become visible, due to the low level of the powder, the inhaler must be replaced since, from that moment, it will not the correct delivery of the dose is more guaranteed.

After inhaling the dose and before closing the inhaler, check that the hole in the mouthpiece is positioned on the green dot of the body of the inhaler.

The presence of powder in the mouth after inhalation and a slight sensation of sweet taste are a confirmation that the dose has been correctly delivered and the active ingredient has reached the lungs.

The inhaler contains a desiccant capsule which ensures a correct level of humidity inside the dispensing chamber. The cap must always be put back after using the inhaler; moreover, the inhaler must never be placed near sources. heat or humidity. However, if the inhaler is stored uncapped for short periods (eg 24 hours) at room temperature, the effectiveness of the product is not affected.

If, instead of inhaling, you blow into the inhaler, this does not cause any problems: if you do, simply turn the inhaler over and empty the dosing chamber from the powder. You must proceed in the same way if you think you have accidentally loaded two or more more doses in the chamber.

Cleaning instructions

During use, regularly clean the mouthpiece with a lint-free paper tissue or soft cloth.

04.3 Contraindications

Hypersensitivity to cortisones or to any of the excipients.

04.4 Special warnings and appropriate precautions for use

Patients should be instructed on the correct use of the inhaler, and their controlled method of ensuring that the drug reaches the target areas within the lungs. Patients should also be advised that Clenil Powder for Inhalation should be taken regularly at the prescribed doses each day for prolonged periods, even when patients are asymptomatic.

Clenil Inhalation Powder is not effective in ongoing asthma attacks in which a fast-acting inhaled bronchodilator is required. Patients should be advised to have this type of medicine available.

The increase in the use of bronchodilators, particularly short-acting beta2-agonist inhaled bronchodilators, indicates a worsening of the control of the asthmatic disease. action becomes less effective or if you use more inhalations than usual, a medical examination is required.

In this situation, patients should be re-evaluated and the need or possibility of increasing anti-inflammatory therapy (e.g. increasing the dose of inhaled corticosteroids or starting a course with oral corticosteroids) should be considered. Severe exacerbations of asthma must be treated in the conventional way.

Treatment with Clenil Inhalation Powder should not be stopped abruptly.

Significant suppression of adrenal function rarely occurs up to doses of 1500 mcg / day of inhaled beclomethasone dipropionate. Some patients treated with 2000 mcg / day experienced reductions in plasma cortisol levels. In such patients, the risk of developing adrenal suppression should be weighed against therapeutic benefits, and precautions should be taken to provide systemic steroid coverage in prolonged stressful situations (eg, elective surgery). Prolonged suppression of the hypothalamic - pituitary - adrenal axis may have systemic effects with inhaled corticosteroids, particularly when prescribed in high doses for prolonged periods. Such effects are less likely to occur than with oral corticosteroids. Possible effects Systemic disorders include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataracts, glaucoma and, more rarely, a range of psychological or behavioral effects including psychomotor hyperactivity, sleep disturbances, anxiety, depression or aggression (particularly in children). It is therefore important that the dose of inhaled corticosteroids is the lowest possible dose with which effective control of asthma is maintained.

It is recommended to regularly monitor the height of children treated with inhaled corticosteroids. In the case of slowed growth, therapy should be reviewed in order to reduce, if possible, the dose of the inhaled corticosteroid until the minimum effective dose is reached to maintain the control of asthma. In addition, it is recommended to consider whether to refer the patient to a pediatrician who specializes in respiratory diseases.

Particular attention should be paid to transferring patients from continuous systemic, long-term or high-dose steroid therapy to beclomethasone dipropionate therapy, as recovery of suppressed adrenal function may take a considerable period of time. Clenil Powder for inhalation should initially be administered while continuing the systemic treatment; after approximately one week, when the patient is stabilized, systemic steroids can be progressively reduced. The magnitude of the reduction should correspond to the maintenance dose of the systemic steroid. During this tapering of the steroid, adrenal function should be monitored regularly.

Some patients experience general malaise during discontinuation of treatment despite their respiratory function remaining unchanged or even better. Unless there are objective clinical signs of adrenal insufficiency, these patients should be encouraged to continue taking inhaled Clenil Powder and to continue discontinuing the systemic steroid.

These precautions should not be applied to patients on oral steroid therapy for less than 2 weeks. An oral steroid and inhaled Clenil Powder may need to be started simultaneously in a patient with asthma symptoms. Once good asthma control has been achieved (by monitoring peak expiratory flow), the oral steroid can be discontinued. abruptly, again if it has been administered for less than 2 weeks. Treatment with Clenil Powder for inhalation should be continued to maintain control of the asthmatic disease.

Patients who have stopped taking oral corticosteroids and have adrenal dysfunction may need additional systemic steroid treatment during times of stress, for example in the case of a worsening of the "asthma attack," in the case of infections of the chest, concomitant major diseases, surgery, trauma, etc.

Replacing systemic steroid treatment with inhalation therapy may result in allergies (such as allergic rhinitis or eczema) previously controlled by systemic treatment.These allergies should be treated symptomatically with antihistamines and / or local preparations, including local steroids.

As with all inhaled corticosteroids, special care should be taken in patients with active or quiescent pulmonary tuberculosis, viral, bacterial and fungal infections of the eye, mouth and respiratory tract. Bacterial respiratory tract infection may be required. suspension of treatment and specific therapy with antibiotics.

This medicinal product contains approximately 25 mg of lactose monohydrate per dose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Keep this medicine out of the reach and sight of children.

04.5 Interactions with other medicinal products and other forms of interaction

Due to the very low plasma concentration that is achieved following inhaled administration, clinically significant interactions with other drugs are unlikely. However, potential increased systemic exposure to beclomethasone could occur when potent inhibitors of the CYP3A4 enzyme (eg, ketoconazole, itraconazole, nelfinavir, ritonavir) are administered concomitantly.

04.6 Pregnancy and lactation

The safety of use of beclomethasone dipropionate in human pregnancy has not been established. Reproductive toxicology studies in animals have revealed an increased incidence of fetal harm, the importance of which is considered uncertain in humans. Since there is the possibility of suppression of adrenocortical function in neonates after prolonged treatment, the benefit to the mother must be carefully weighed against the risk to the fetus.

It is reasonable to assume that the drug is present in breast milk, but at the inhalation doses used, the possibility of finding significant concentrations in breast milk is low.

Babies born to mothers who received substantial doses of inhaled corticosteroids during pregnancy should be carefully observed for hypoadrenalism.

04.7 Effects on ability to drive and use machines

No effects on the ability to drive and use machines have ever been reported.

04.8 Undesirable effects

No serious undesirable effects have been reported following administration of Clenil Inhalation Powder at the recommended dosage.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as follows: very common (≥1 / 10), common (≥1 / 100 to

ORGANIC SYSTEMIC CLASS ADVERSE EVENT FREQUENCY Infections and infestations Oral candidiasis (mouth and throat) Very common Disorders of the immune system Hypersensitivity reactions with the following manifestations: Skin rash, itchy hives, erythema and bruising Uncommon Edema of the eye, face, lips and throat Very rare Respiratory symptoms (dyspnoea and / or bronchospasm) Very rare Anaphylactic / anaphylactoid reactions Very rare Endocrine pathologies Cushing's syndrome, Cushingoid conformations, adrenal suppression Very rare Psychiatric disorders (see section 4.4 "Special warnings and precautions for use") Psychomotor hyperactivity, sleep disturbances, anxiety, depression, aggression, behavioral disturbances (mainly in children). Not known Eye disorders Cataract, glaucoma Very rare Respiratory, thoracic and mediastinal disorders Hoarseness, throat irritation common Paradoxical bronchospasm, cough Very rare Gastrointestinal disorders Dry mouth Very rare Musculoskeletal and connective tissue disorders Growth retardation (in children and adolescents) Very rare Diagnostic tests Decrease in bone density Very rare

As with other inhalation therapies, paradoxical bronchospasm with immediate increase in wheezing may occur after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with Clenil Powder for inhalation must be discontinued immediately, the patient evaluated and, if necessary, alternative therapy instituted.

Some patients experience candidiasis of the mouth and throat (candida) particularly at higher doses.

It is recommended to rinse the mouth with water immediately after inhalation. Symptomatic candidiasis can be treated with topical antifungal therapy.

Inhaled corticosteroids can have systemic effects, particularly at high doses prescribed for prolonged periods. These include adrenocortical suppression, growth retardation in children and adolescents, decreased bone mineral density leading to osteoporosis, cataracts and glaucoma and simple bruising of the skin, lower respiratory tract infections, including pneumonia, in elderly patients and chronic obstructive pulmonary disease. (COPD).

04.9 Overdose

In the event of an overdose, no emergency interventions are necessary. Restoration of adrenal function is achieved within a few days and can be verified through the determination of cortisolemia.

Treatment with Clenil Inhalation Powder should be continued at the recommended doses for asthma control.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiasthmatic glucocorticoid for inhalation use, ATC code: R03BA01.

Clenil Powder for inhalation contains beclomethasone dipropionate as the active ingredient, a corticosteroid with a strong anti-inflammatory and anti-allergic topical activity on the mucosa of the respiratory tract. In particular, beclomethasone dipropionate exerts a marked antireactive action at the bronchial level, reducing edema and hypersecretion and inhibiting the onset of bronchospasm. Beclomethasone dipropionate administered by inhalation acts exclusively on the structures of the respiratory system and is free from recommended dosages, of systemic effects and inhibitory action on cortico-adrenal function.

05.2 Pharmacokinetic properties

After inhalation of beclomethasone dipropionate, the fraction absorbed directly into the lungs is rapidly metabolised by the liver to beclomethasone-17-monopropionate and subsequently to the inactive metabolite beclomethasone alcohol.

05.3 Preclinical safety data

Acute toxicity

LD50 (rat, by inhalation)> 2.68 mg / kg; (mouse, inhaled route)> 4.93 mg / kg; (mouse, os)> 3000 mg / kg; (rat, os)> 1000 mg / kg.

Repeated dose toxicity (rat, nasal, 4 weeks)

No signs of toxicity up to a dose of 220 mcg / kg / day.

The prolonged administration (1 year) by inhalation, at dosages much higher than those foreseen in therapy, does not cause in the animal signs of suffering in the respiratory tract.