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HEPATOTOXICITY: General Population: Hepatic failure resulting in fatalities has occurred in patients receiving Valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see PRECAUTIONS].
Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of Valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndrome caused by DNA mutation of the mitochondrial DNA polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Valproate is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorders [see CONTRAINDICATIONS]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Valproate should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Valproate for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see PRECAUTIONS].
FETAL RISK: Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, Valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis in migraine [see CONTRAINDICATIONS]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when Valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using Valproate [see PRECAUTIONS].
A Medication Guide describing the risks of Valproate is available for patients [see PATIENT INFORMATION under PRECAUTIONS].
PANCREATITIS: Cases of life-threatening pancreatitis have been reported in both children and adults receiving Valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Valproate should ordinary be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see PRECAUTIONS].
Female children/Female adolescents/Women of childbearing potential/Pregnancy: Divalproex sodium has a high teratogenic potential and children exposed in utero to Divalproex sodium have a high risk for congenital malformations and neuro developmental disorders [see USE IN PREGNANCY & LACTATION]. Divalproex sodium is contraindicated in the following situations: Treatment of epilepsy: In pregnancy unless there is no suitable alternative treatment [see PRECAUTIONS and USE IN PREGNANCY & LACTATION].
In women of childbearing potential, unless the measures for prevention of pregnancy as mentioned as follows and in CONTRAINDICATIONS and USE IN PREGNANCY & LACTATION are met.
The treating physician must ensure that: Individual circumstances should be evaluated in each case, involving the patient in the discussion, to guarantee her engagement, discuss therapeutic options and ensure her understanding of the risks and the measures needed to minimise the risks.
The potential for pregnancy is assessed for all female patients.
The patient has understood and acknowledged the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to Divalproex Sodium.
The patient understands the need to undergo pregnancy testing prior to initiation of treatment and during treatment, as needed.
The patient is counselled regarding contraception, and that the patient is capable of complying with the need to use effective contraception (for further details refer to contraception as follows), without interruption during the entire duration of treatment with Divalproex Sodium.
The patient understands the need for regular (at least annual) review of treatment by the treating physician, preferably by a specialist experienced in the management of epilepsy.
The patient understands the need to consult her physician as soon as she is planning pregnancy to ensure timely discussion and switching to alternative treatment options prior to conception, and before contraception is discontinued.
The patient understands the hazards and necessary precautions associated with Divalproex sodium use and the need to urgently consult her physician in case of pregnancy.
The patient has received the patient guide.
These conditions also concern women who are not currently sexually active unless the treating physician considers that there are compelling reasons to indicate that there is no risk of pregnancy.
Female children: The treating physician must ensure that parents/caregivers of female children understand the need to contact the specialist once the female child using Divalproex sodium experiences menarche.
The treating physician must ensure that parents/caregivers of female children who have experienced menarche are provided with comprehensive information about the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to Divalproex sodium in utero.
In patients who experienced menarche, the prescribing specialist must reassess the need for Divalproex sodium therapy annually and consider alternative treatment options. If Divalproex sodium is the only suitable treatment, the need for using effective contraception and all other measures as described in CONTRAINDICATIONS, PRECAUTIONS, and USE IN PREGNANCY & LACTATION should be discussed. Every effort should be made by the specialist to switch the female children to alternative treatment before they reach childbearing potential.
Pregnancy must be excluded before start of treatment with Divalproex sodium.
Contraception: Women of childbearing potential who are prescribed Divalproex sodium must use effective contraception, without interruption during the entire duration of treatment with Divalproex sodium. These patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. At least one effective method of contraception (preferably a user independent form such as an intra-uterine device or implant) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case, when choosing the contraception method involving the patient in the discussion, to guarantee her engagement and compliance with the chosen measures. Even if patient has amenorrhea the patient must follow all the advice on effective contraception.
Annual treatment reviews preferably by a specialist: The treating physician should at least annually review whether Divalproex sodium is the most suitable treatment for the patient. The treating physician should ensure the patient has understood and acknowledged the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to Divalproex sodium in utero.
Pregnancy planning: For the indication epilepsy, if a woman is planning to become pregnant, a specialist experienced in the management of epilepsy, must reassess Divalproex sodium therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued [see USE IN PREGNANCY & LACTATION]. If switching is not possible, the woman should receive further counselling regarding the Divalproex sodium risks for the unborn child to support her informed decision making regarding family planning.
In case of pregnancy: In case of pregnancy, the patient should immediately contact a specialist/ physician to re-evaluate treatment and consider alternative options.
Pharmacist must ensure that: The patients are advised not to stop Divalproex sodium medication and to immediately contact a specialist in case of planned or suspected pregnancy.
WARNING FOR WOMEN AND GIRLS: This medicine can seriously harm an unborn baby. Always use effective contraception during treatment. If the patient is thinking about becoming pregnant, or become pregnant, talk to a doctor straight away. Do not stop taking this medicine unless a doctor tells.
