Active ingredients: Valproic acid (magnesium valproate)
Depamag 200 mg gastro-resistant tablets
Depamag 500 mg gastro-resistant tablets
Depamag 100 mg / ml oral solution
Why is Depamag used? What is it for?
Depamag contains the active ingredient magnesium valproate, a substance with antiepileptic activity.
Depamag is indicated for the treatment of different forms of epilepsy:
- small evil type absence, normally used alone
- grand mal, frequently used in combination with other medicines called barbiturates
- mixed essential epilepsy grand mal / petit mal, used alone, in combination with barbiturates or, in particularly resistant cases, together with other medicines with which the patient had already been treated previously
- different forms of focused epilepsy, which react poorly to classic antiepileptic drugs.
Contraindications When Depamag should not be used
Do not use Depamag
- if you are allergic to magnesium valproate, chemically closely related substances or any of the other ingredients of this medicine (listed in section 6)
- if you have acute or chronic inflammation of the liver (hepatitis)
- if you or someone in your family have or have ever had severe liver disease, particularly caused by the use of medicines
- if you have a blood disorder called porphyria
- if you have ongoing bleeding
- if you are breast-feeding (see section "Pregnancy, breast-feeding and fertility")
- in infants and children under three years of age
- if you have a genetic problem responsible for a mitochondrial disorder (for example, Alpers-Huttenlocher syndrome)
Precautions for use What you need to know before taking Depamag
Talk to your doctor before taking Depamag:
- if you have kidney failure, because the dose of Depamag needs to be reduced
- if you have an autoimmune disease called systemic lupus erythematosus
- if you are aware of the existence of a genetic problem responsible for a mitochondrial disorder in your family.
Exceptionally serious cases of liver problems have been reported with treatment with Depamag and have sometimes been fatal. Infants and children under three years of age are at increased risk of having liver problems (see section "Children and adolescents").
The risk of developing liver problems is greater in the first 6 months of therapy, therefore your doctor will have you have regular liver function checks and based on the results of the tests will decide whether to reduce the dose of Depamag or to stop the therapy.
Tell your doctor immediately if you or the child experience:
- symptoms of liver problems
- reappearance of seizures
- muscle weakness
- lack or reduction of appetite
- predisposition to continuous sleep (lethargy)
- drowsiness
- repeated vomiting
- abdominal pain
- yellowing of the skin, mucous membranes and eyes (jaundice)
- severe abdominal pain because your doctor will do some tests to check if you have "inflammation of the pancreas (pancreatitis)
- self-damaging or suicidal behaviors or thoughts because your doctor will closely monitor you during treatment with Depamag; Tell your caregiver to tell your doctor if you notice any changes in your behavior or the appearance of self-harming or suicidal behaviors or thoughts.
Your doctor may order the following blood tests for you:
- liver function checks. Your doctor will do these tests before the start of treatment with Depamag and periodically during the first six months of treatment because in this period the risk of having liver problems is greater. Based on the results of the tests, the doctor will decide whether to reduce the dose of Depamag or discontinue therapy;
- Complete blood count and coagulation control. Your doctor will have blood tests done before the start of treatment, before surgery and in the case of spontaneous hematomas or bleeding;
- control of ammonia levels (hyperammonaemia). Your doctor will do this examination at the beginning of the treatment only in special cases;
- control of magnesium levels. Your doctor will have this test done periodically during treatment.
- control of valproic acid levels. Your doctor will have this test done during treatment if you have kidney failure and will decide whether to decrease the dose of Depamag.
Children and adolescents
Your doctor will not prescribe Depamag to children and adolescents except in cases where alternative treatments are not effective or tolerated.
If treatment with Depamag is necessary, your doctor will regularly evaluate the risks and benefits of the treatment.
Depamag is contraindicated in infants and children under three years of age (see section "Do not take Depamag").
Exceptionally severe liver damage has been reported with treatment with Depamag and has sometimes been fatal. Infants and children under the age of three, particularly when treated with multiple medicines for seizures, are at increased risk of having liver damage. After the age of three, the risk of liver damage is significantly reduced and progressively decreases with age. See section "Warnings and precautions".
Interactions Which drugs or foods can modify the effect of Depamag
Tell your doctor if you are using, have recently used or might use any other medicines.
Tell your doctor if you are using one or more of the medicines listed below:
- carbapenems (antibiotics to treat bacterial infections)
- erythromycin (antibiotic)
- neuroleptics (psychotropic drugs)
- medicines against depression (anti-MAO, antidepressants)
- medicines for epilepsy:
- phenobarbital
- primidone
- phenytoin
- ethosuximide
- lamotrigine (medicine for epilepsy and bipolar disorders)
- carbamazepine (medicine for epilepsy and manic-depressive psychosis) • mefloquine (medicine for malaria)
- aspirin and other salicylates
- cimetidine (antacid)
- medicines that reduce blood clotting taken by mouth (oral anticoagulants)
If you take the medicines listed above with Depamag your doctor will monitor you and decide whether to change the dose of Depamag or the other medicine.
The concomitant use of Depamag and salicylates (eg aspirin) should be avoided especially in children under three years of age due to the risk of liver problems.
Depamag with alcohol
Co-administration of Depamag and alcohol may cause muscle weakness and drowsiness (see section "Driving and using machines").
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Women of childbearing age
Depamag should not be used by women of childbearing potential unless alternative treatments are not effective or tolerated.
During treatment with Depamag you must use an effective form of contraception to avoid becoming pregnant.
If you think you are pregnant or planning to become pregnant, talk to your doctor to discuss treatment with Depamag and the possibility of switching to an appropriate alternative treatment before conception. Your doctor will also explain the nature and seriousness of the risks of using Depamag during pregnancy.
Pregnancy
Due to its high teratogenic potential (ability to cause abnormalities in the embryo and fetus) and the risk of developmental disturbances in newborns, Depamag should not be used during pregnancy unless alternative treatments are not effective or tolerated. .
If you are pregnant or planning to become pregnant it is important that you contact your doctor who will explain the nature and seriousness of the risks of using Depamag during pregnancy.
Infants from mothers treated with valproate are at risk of developing:
- very rarely hemorrhagic syndrome
- reduced thyroid function (hypothyroidism)
- low blood sugar levels (hypoglycemia) and withdrawal syndrome (for example, agitation, irritability, hyper-excitability, nervousness, excessive movement, tone disturbances, tremor, seizures and eating disorders) in newborns whose mothers have taken valproate in the " last trimester of pregnancy
Feeding time
Valproate is excreted in breast milk. If you are breastfeeding or planning to breastfeed, ask your doctor to discuss with him whether to stop breastfeeding or to stop taking Depamag.
Fertility
Absence of menstruation, polycystic ovary and increased testosterone levels have been reported in women using valproate.
Valproate can impair fertility in men.
Clinical cases indicate that impairments in fertility are reversible after discontinuation of treatment.
Driving and using machines
Co-administration of Depamag with barbiturates, other medicines that depress the central nervous system or alcohol can cause muscle weakness and drowsiness; therefore you should be careful if you have to drive or use machines during treatment.
Dosage and method of use How to use Depamag: Dosage
Always use this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Use in adults
The recommended dose is:
- 4 to 6 tablets of 200 mg per day, or
- 2 to 3 tablets of 500 mg per day, or
- 8 to 12 mL of solution per day (in two to three administrations).
Take the dose prescribed by your doctor in two or three separate doses.
Use in children
The recommended dose is 20 to 30 mg per kg of body weight per day in two or three separate administrations. Give your child Depamag tablets or oral solution with still water.
If you forget to take Depamag
Do not take a double dose to make up for a forgotten dose.
If you stop taking Depamag
Do not stop treatment without first discussing this with your doctor.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken an overdose of Depamag
In case of accidental ingestion of an overdose of Depamag, notify your doctor immediately or go to the nearest hospital.
In case of acute intoxication, the following can occur:
- coma, more or less deep
- reduction of oxygen to the muscles (muscle hypoxia)
- reduced reflexes (hyporeflexia)
- decrease in pupil diameter (miosis)
- decreased respiratory autonomy.
The outcome of these intoxications is generally benign.
Side Effects What are the side effects of Depamag
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Below is the list of side effects that can occur with Depamag.
Frequent cases of:
- reduction in the number of platelets in the blood (thrombocytopenia)
- moderate increase in blood ammonia levels (hyperammonaemia) without abnormal liver function tests which does not require stopping treatment. However during treatment with Depamag alone or together with other medicines (phenobarbital, carbamazepine, phenytoin, topiramate) An acute syndrome in which brain function is impaired (hyperammonaemic encephalopathy), associated with high levels of ammonia in the blood, normal liver function and no breakdown of the liver cell (cytolysis) can occur. This syndrome is characterized by loss of consciousness and neurological signs with increased frequency of epileptic attacks. It may appear after a few days or weeks from the beginning of therapy and regresses with the discontinuation of valproate.
Occasionally cases of:
- inflammation of the pancreas (pancreatitis), sometimes fatal
- Nail and nail bed disorders have been reported commonly.
Isolated cases of:
- confusional or convulsive states and some cases of stupor. These have been isolated cases or associated with an increased incidence of seizures during therapy and regressed with treatment discontinuation or dose decrease. These cases have mainly been reported during therapy with other medicinal products (in particular phenobarbital) or after a sharp increase in valproate doses.
- reduction of fibrinogen in the blood
- lengthening of bleeding time
Rare cases of:
- inflammation of the liver (hepatitis)
- reduction in the number of red blood cells (anemia)
- reduction in the number of white blood cells in the blood (leukopenia)
- reduction in the number of all blood cells (pancytopenia)
- hearing loss, both reversible and irreversible
- weight gain and obesity
Other side effects:
- digestive disorders such as nausea and stomach pain. They occur frequently in some patients at the start of treatment, but generally disappear after a few days without stopping the treatment.
- congenital malformations and developmental disorders in newborns (see section "Pregnancy, lactation and fertility").
- hair loss
- end tremor when trying to hold a certain position (postural tremor)
- inflammation of blood vessels (vasculitis)
- absence of menstruation and irregular menstruation
- skin irritation
- irritability (occasionally aggression, hyperactivity and behavioral disturbances)
- red blood cell abnormalities
- severe skin reactions which can be fatal (Stevens-Johnson syndrome and toxic epidermal necrolysis)
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. You can also report side effects directly via the national reporting system at www.agenziafarmaco.it/it/responsabili.By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
This medicine does not require any special storage conditions.
Do not use this medicine after the expiry date which is stated on the package after EXP. The expiry date refers to the last day of that month.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What Depamag contains
Depamag 200 mg gastro-resistant tablets
- The active ingredient is magnesium valproate. Each gastro-resistant tablet contains 200 mg of magnesium valproate.
- The other ingredients are hydroxypropylcellulose, sodium carboxymethylcellulose, precipitated silica, talc, magnesium stearate, microcrystalline cellulose, cellulose acetophthalate, diethyl phthalate, dimethicone 350, hydroxypropylmethylcellulose, polyethylene glycol 6000.
Depamag 500 mg gastro-resistant tablets
- The active ingredient is magnesium valproate. Each gastro-resistant tablet contains 500 mg of magnesium valproate.
- The other ingredients are hydroxypropylcellulose, sodium carboxymethylcellulose, precipitated silica, talc, magnesium stearate, microcrystalline cellulose, cellulose acetophthalate, diethyl phthalate, dimethicone 350, hydroxypropylmethylcellulose, polyethylene glycol 6000.
Depamag 100 mg / ml oral solution
- The active ingredient is magnesium valproate. 100 ml of solution contain 10 g of magnesium valproate.
- The other component is purified water.
What Depamag looks like and contents of the pack
Depamag 200 mg gastro-resistant tablets
- Each pack contains 40 gastro-resistant tablets of 200 mg.
Depamag 500 mg gastro-resistant tablets
- Each pack contains 40 500 mg gastro-resistant tablets.
Depamag 100 mg / ml oral solution
- Each pack contains 1 bottle of 100 mL of oral solution.
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
DEPAMAG
▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Depamag 200 mg gastro-resistant tablet contains 200 mg of magnesium valproate.
Each Depamag 500 mg gastro-resistant tablet contains 500 mg of magnesium valproate.
100 ml of Depamag 100 mg / ml oral solution contains 10 g of magnesium valproate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Gastro-resistant tablets.
Oral solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
- small evil such as absence, where it is normally used alone;
- grand mal, where it is used more frequently in association with barbiturates;
• mixed essential epilepsy grand mal / petit mal, where it can be used both alone and in combination with barbiturates, and, in particularly rebellious cases resistant to therapy, it can be associated with other medications with which the patient had already been treated previously;
• different forms of focused epilepsy, which react poorly to classic antiepileptic drugs.
04.2 Posology and method of administration
Adults
4-6 tablets of 200 mg; 2-3 tablets of 500 mg; 8-12 ml of solution per day (in two-three administrations).
Pediatric population
20-30 mg per kg of weight per day in two to three administrations.
Girls, adolescents, women of childbearing age and pregnant women
DEPAMAG should be initiated and supervised by a specialist experienced in the management of epilepsy. Treatment should only be initiated if other treatments are ineffective or not tolerated (see sections 4.4 and 4.6) and the benefits and risks should be carefully reconsidered during regular re-evaluations of the Treatment Preferably, DEPAMAG 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.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1;
Acute hepatitis;
Chronic hepatitis;
Personal or family history of severe liver disease, especially drug-induced; Hypersensitivity to components or other closely related substances from a chemical point of view;
Porphyria;
Bleeding in progress;
Feeding time;
Generally contraindicated in infants and children under three years of age.
Valproate is contraindicated in patients with mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase y (POLG), for example Alpers-Huttenlocher syndrome, as well as in children under the age of two with suspected disorder. associated with POLG (see section 4.4).
04.4 Special warnings and appropriate precautions for use
Girls / Adolescents / Women of childbearing age / Pregnancy
DEPAMAG 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 should be carefully reconsidered during regular treatment re-evaluations, in puberty and as a matter of urgency when a woman of childbearing potential treated with DEPAMAG 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 DEPAMAG during pregnancy (see section 4.6).
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 may become pregnant or there is a possibility of pregnancy.
In women planning to become pregnant, every effort should be made to switch to an appropriate alternative treatment prior to conception, if possible (see section 4.6).
Valproate therapy should only be continued after a re-evaluation of the patient's benefits and risks of valproate treatment by a physician experienced in the management of epilepsy.
Liver diseases
Exceptionally severe hepatic damage has been reported which has sometimes been fatal. The patients most at risk, especially in the case of multiple anticonvulsive therapy, are infants and children under three years of age with severe forms of epilepsy, particularly those with brain damage, mental retardation and / or with congenital metabolic or degenerative disease. After the age of three, the incidence is significantly reduced and progressively decreases with age.
In most cases, liver damage occurred during the first six months of therapy.
Clinical symptoms are essential for early diagnosis. In particular, especially in patients at risk, two types of manifestations that may precede jaundice should be considered: reappearance of epileptic attacks; non-specific symptoms, generally of rapid onset, such as asthenia, anorexia, lethargy, somnolence, sometimes associated with repeated vomiting and abdominal pain.
Patients (or their parents, if these are children) should be advised to notify their physician immediately if any of the above signs occur. In addition to clinical monitoring, immediate blood chemistry monitoring of liver function should be undertaken.
Liver function should be checked periodically during the first six 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) requires interruption of valproate therapy. precaution and if they are taken at the same time, the salicylates must also be interrupted, since they are metabolized by the same route.
Liver function tests should be performed prior to initiation of therapy (see section 4.3) which should be repeated periodically during the first six months, especially in patients at risk.
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.
Prescribing monotherapy is recommended for children under three years of age, but the potential benefit should be weighed prior to initiation of therapy against the high risk of liver injury in these patients. Concomitant use of salicylates should be avoided in children under three 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 prior to initiation of therapy or prior to surgery and in the case of spontaneous hematoma or bleeding (see section 4.8).
In patients with renal insufficiency it is necessary to take into account the increase in serum levels of free valproic acid and to decrease the dosage accordingly.
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, it is recommended that amylasemia is measured in patients with acute abdominal pain.
If an abnormal urea cycle is suspected, hyperammonaemia should be evaluated prior to treatment, as aggravation is possible with valproate.
During therapeutic treatment, magnesaemia should be checked periodically.
Cases of suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs in their various indications. A meta-analysis of randomized clinical trials versus placebo also highlighted the presence of a modest increase in the risk of suicidal ideation and behavior.
The mechanism of this risk has not been established and the available data do not exclude the possibility of increased risk with DEPAMAG.
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 instructed to notify their treating physician if signs of suicidal ideation or behavior emerge.
The concomitant use of valproic acid / sodium valproate and carbapenems is not recommended (see section 4.5).
Patients with known or suspected mitochondrial disease
Valproate may trigger or worsen the clinical signs of concomitant mitochondrial diseases caused by mutations in the mitochondrial DNA as well as the nuclear gene encoded by POLG. In particular, in patients with inherited neurometabolic syndromes caused by mutations in the gene for the mitochondrial enzyme polymerase y (POLG), for example the Alpers-Huttenlocher syndrome, acute liver failure and deaths from liver disease induced by valproate have been reported more frequently. .
POLG-associated disorders should be suspected in patients with a family history or symptoms suggestive of such a disorder, including but not limited to unexplained encephalopathy, refractory (focal, myoclonic) epilepsy, status epilepticus at presentation, developmental delays, regression psychomotor, sensory-motor axonal neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders (see section 4.3).
04.5 Interactions with other medicinal products and other forms of interaction
Effects of valproate on other drugs:
• Neuroleptics, anti-MAO and antidepressants
Valproate may potentiate the effect of other psychotropic drugs such as neuroleptics, anti-MAOs and antidepressants; 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 fifteen days of combined treatment, with immediate reduction of phenobarbital doses in case of sedation and possible control 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 initiation of combination therapy, with primidone dosage adjustment as needed.
• 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 phenytoin assay, the free fraction must be taken into account in particular.
Subsequently, following chronic treatment, phenytoin concentrations return to the initial pre-valproate values.
• Lamotrigine
Valproate can reduce the metabolism of lamotrigine, therefore when necessary it is advisable to reduce the dosage of the latter.
• Ethosuximide
Valproate can cause increased plasma concentrations of ethosuximide.
• Carbapenems
Reductions of between 60% and 100% in blood levels of valproic acid have been reported in the two days following the co-administration of carbapenems. Due to the magnitude and rapidity of these reductions, co-administration of carbapenems in patients on stable treatment with valproic acid cannot be considered suitable and should therefore be avoided (see section 4.4).
• Effects of other drugs on valproate
Antiepileptics with enzyme inducing effect (in particular phenytoin, phenobarbital and carbamazepine) decrease the serum concentrations of valproate. In the case of combined therapy the dosages should be adjusted according to the blood levels.
Mefloquine increases the metabolism of valproic acid and, moreover, 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 (aspirin), the free serum levels of valproate may increase.
Serum levels of valproate may increase (due to reduced hepatic metabolism) with concomitant use of cimetidine or erythromycin.
• Other interactions
Valproate generally does not have an enzyme inducing effect; consequently it does not reduce the efficacy of estrogen-progestins in case of hormonal contraception. In case of concomitant use of oral anticoagulant drugs, careful monitoring of the prothrombin time should be carried out.
04.6 Pregnancy and breastfeeding
DEPAMAG 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
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 derived 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 in 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 these effects is uncertain and the possibility of risk throughout pregnancy cannot be excluded.
Studies of preschool-aged 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 an increased risk of autism spectrum disorders (approximately three times) and childhood autism (approximately five times) compared to 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 potential (see above and section 4.4).
If a woman wishes to plan a pregnancy
- During pregnancy, maternal tonic-clonic seizures and status epilepticus with hypoxia can carry a particular risk of death for the mother and fetus.
• In women planning to become pregnant or pregnant, valproate therapy should be re-evaluated.
• 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 patient's benefits and risks of valproate treatment by a physician experienced in the management of epilepsy. 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.
• Folic acid supplementation 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 to detect the possible onset of neural tube defects or other malformations.
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.
• There have been reports of hypoglycaemia in newborns 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 infants whose mothers have taken valproate in the last trimester of pregnancy.
Feeding time
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 section 4.8).
A decision must be made whether to discontinue breast-feeding or to discontinue / abstain from DEPAMAG 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 section 4.8). Administration of valproate may also impair fertility in men (see section 4.8). Clinical cases indicate that fertility dysfunctions are reversible after discontinuation of treatment.
04.7 Effects on ability to drive and use machines
In case of simultaneous administration with barbiturates or other drugs with depressive activity of the central nervous system, manifestations of asthenia and drowsiness may be found in some subjects.
The same manifestations can be observed after drinking alcoholic beverages.
Of this, these subjects must be warned that during the treatment they could drive vehicles or attend to operations requiring integrity of the degree of supervision.
04.8 Undesirable effects
Congenital malformations and developmental disorders (see section 4.4 and section 4.6).
Rare cases of hepatitis (see section 4.4).
Confusional or convulsive states: some cases of stupor have been described during therapy with valproic acid; they were isolated cases or associated with an increased incidence of seizures during therapy and regressed with treatment interruption or with Dosage decreases These cases have been reported mainly during combination therapy (particularly with phenobarbital) or after a sharp increase in valproate doses.
Digestive disorders (nausea, gastralgia) occur frequently in some patients at the start of treatment, but generally disappear after a few days without stopping the treatment.
Transient and / or dose-dependent undesirable effects have often been reported: hair loss, fine postural tremor.
There have been isolated reports of decreased fibrinogen or prolonged bleeding time, generally without associated clinical signs and particularly with high doses (valproate has an inhibitory effect on the second phase of platelet aggregation).
Frequent occurrence of: thrombocytopenia, rare cases of anemia, leukopenia or pancytopenia.
Cases of pancreatitis, sometimes fatal, have occasionally been reported.
The appearance of vasculitis has been reported.
Moderate isolated hyperammonaemia may frequently occur without abnormal liver function tests and should not be a cause for discontinuation of treatment.
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, 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.
Metabolism and Nutrition Disorders: Obesity has been reported rarely; Amenorrhea and irregular menstruation have also been reported.
Hearing loss, both reversible and irreversible, has rarely been reported; however, a cause-and-effect relationship has not been established.
Rash, irritability (occasionally aggression, hyperactivity and behavioral disturbances), red blood cell hypoplasia, decreased fibrinogen.
Skin and subcutaneous tissue disorders: Disorders of the nail and nail bed have been reported commonly. Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported.
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 www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
The clinical picture of maximum acute intoxication generally involves a more or less deep coma with muscle hypoxia, hyporreflexia, miosis, decreased respiratory autonomy. The measures to be taken in the hospital are: gastric lavage, establishment of an osmotic diuresis, monitoring of functions cardiorespiratory.
In very severe cases, dialysis or blood transfusion may be performed.
The use of naloxone may be attempted. The prognosis of such intoxications is generally benign.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Medicinal drug category: Antiepileptics, derivatives of fatty acids.
ATC code: N03AG01.
Depamag is an antiepileptic drug structurally characterized by two molecules of valproic acid salified with a magnesium atom.
Salification with this ion enhances the already known antiepileptic activity of valproic acid due to the ability of magnesium to modulate synaptic activity in some particular conditions, such as the comitial one.
The magnesium ion, in addition to representing an important balancing factor of the intra-extracellular electrolyte balance, both directly and indirectly through the activity of some ATPases, performs a "specific inhibition action of the glutaminergic receptors, which so heavily enter the epileptogenic mechanisms, this action can occur as long as the cell membrane is in the condition of hyperpolarization, such as that induced by valproic acid.
Depamag therefore appears to be an antiepileptic drug in which the anticomitial activities of valproic acid are enhanced and complemented with those possessed by the magnesium ion, with which the valproic acid itself is salified.
05.2 Pharmacokinetic properties
Distribution
After oral administration, valproic acid passes very quickly into the circulation and is equally rapidly distributed in the various organs and tissues, including the CNS, where it is present already after the first 5 minutes. The most affected organs are in the order: liver, muscle tissue, kidney, testis, brain, eye and thyroid, where tissue concentrations peak within 30-60 minutes, then gradually decrease to almost total disappearance at the 24th hour.
Autoradiographic studies on the mouse show that in the CNS valproic acid is concentrated more in the white matter than in the cortex, localizing mainly in the areas where the GABA-transaminase activity is greater (caudate nucleus, putamen, n. Accumbens, substantia nigra, red nucleus , reticular formation).
In man, using oral doses of 500 mg, the bioavailability of Depamag was comparable to that of sodium valproate. The oral administration of 500 mg of Depamag, in tablet form, resulted in a maximum blood concentration (Cmax) equal to 61.67 mcg / ml after 2.50 h (Tmax), the half-life (T1 / 2) is 7.20 h.
In the blood, valproic acid is extensively bound to plasma proteins (approximately 90%).
The extent of the link is comparable between the different animal species examined (mice, rats, dogs) and humans. In man the bond is about 90% (of which 60% with albumin), but it undergoes considerable variations in relation to individual and dietary factors, being influenced by the circulating level of fatty acids: these, increasing after meals, they tend to displace it from the binding sites, with a consequent increase in the amount of "free" valproate and in the plasma clearance of the compound.
In pregnant animals (rat, monkey), valproic acid crosses the placental barrier, reaching plasma concentrations comparable to maternal ones in the fetus and extensively distributed in all tissues.
Biotransformation
Metabolism occurs, in all animal species, very rapidly by beta oxidation, with the formation of hydrophilic metabolites (including mainly 5-hydroxy-2-propylvalerate and 2-propylglutarate) which are excreted as such or glucuronated, partly by route biliary and, to a greater extent, with the urine, while only minimal quantities of valproic acid are eliminated in an unaltered form.
Comparative studies show in humans a metabolic behavior quite similar to that found in the various animal species examined.
05.3 Preclinical safety data
Acute toxicity
Orally.
The LD50 determined in mice and rats was found to be 932 mg / kg and 885 mg / kg, respectively.
Intraperitoneally.
The LD50 determined in mice and rats was found to be 592 mg / kg and 537 mg / kg, respectively.
Repeated dose toxicity
It has been studied orally up to doses of 300 mg / kg in the growing rat (subacute toxicity) and 200 mg / kg in the rat and minipig (chronic toxicity) administered for 30 and 180 days, respectively. A modest and transient sedation it was found in the two hours following treatment with doses equal to or greater than 200 mg / kg, but was interpreted as a pharmacological activity of Depamag and not as a manifestation of CNS toxicity.
Fetal toxicity and examination of reproductive function
In embryotoxicity studies (in rats and rabbits) and in peri- and postnatal fertility studies (in rats) the 25 mg / kg dose of Depamag does not affect reproductive function and does not exert any embryotoxic or teratogenic effects. At higher doses (75-200 mg / kg) the drug determines the onset of dose-dependent negative effects, even if of slight entity, and more precisely a modest increase in the incidence of uterine resorptions and fetal malformations.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Gastro-resistant tablets of 200 mg and 500 mg
Hydroxypropylcellulose, sodium carboxymethylcellulose, precipitated silica, talc, magnesium stearate, microcrystalline cellulose, acetophthalate cellulose, diethyl phthalate, dimethicone 350, hydroxypropylmethylcellulose, polyethylene glycol 6000.
10% oral solution
Purified water F.U.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
Both the tablets and the oral solution are valid for 2 years.
06.4 Special precautions for storage
No particular precautions for storage.
06.5 Nature of the immediate packaging and contents of the package
The tablets are contained in PVC / PVDC - Aluminum PVDC blisters
Box of 40 gastro-resistant tablets of 200 mg
Box of 40 gastro-resistant tablets of 500 mg
The solution is contained in a yellow glass bottle.
100 ml of 10% solution
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A.
Viale Shakespeare, 47 - 00144 Rome
Dealership for sale
BIOFUTURA PHARMA S.p.A.
Via Pontina km 30,400 - 00071 Pomezia (Rome)
08.0 MARKETING AUTHORIZATION NUMBER
Gastro-resistant tablets of 200 mg A.I.C. n. 027107010
500 mg gastro-resistant tablets A.I.C. n. 027107022
10% oral solution A.I.C. n. 027107034
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: June 1989
Date of most recent renewal: June 2010
10.0 DATE OF REVISION OF THE TEXT
January 2017
