Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Damage to the liver and/or pancreas
Uncommon cases of severe liver damage and rare cases of damage to the pancreas have been observed. Infants and young children under 3 years of age who suffer from severe epileptic seizures are most often affected.
The risk of liver or pancreatic damage is increased, especially in combination treatment with multiple antiepileptic drugs or in the case of brain damage, mental retardation and/or a congenital metabolic disease including mitochondrial diseases such as carnitine deficiency, urea cycle disorders, POLG mutations (see sections 4.3 and 4.4) or degenerative disease. In these patients, valproic acid should be used with particular caution and as monotherapy.

In the majority of cases, liver damage was observed within the first six months of treatment and in particular between the second and twelfth week. The incidence of disorders decreases considerably in children over 3 years of age and particularly over the age of 10.
These disorders can be fatal. If hepatitis and pancreatitis occur together, the risk of a fatal outcome increases.

Signs of damage to the liver and/or pancreas
Serious or fatal damage to the liver and/or pancreas may be preceded by non-specific symptoms, usually of sudden onset, such as a recurrence or increase in the frequency or severity of epileptic seizures, reduced levels of consciousness with confusion, restlessness, movement disorders, physical malaise and asthenia, loss of appetite, aversion to familiar foods, aversion to valproic acid, nausea, vomiting, upper abdominal symptoms, lethargy, drowsiness and, particularly with liver damage, abnormally frequent haematomas, nosebleeds and oedema, either variably localised or generalised.
Patients, particularly infants and young children, should be monitored closely by a doctor with respect to these signs.

If the aforementioned symptoms are persistent or serious, appropriate laboratory tests should be performed (see section “Measures for the early detection” below) in addition to a thorough examination. However, as the blood test results of patients with a disorder may not necessarily be abnormal, the treating doctor should not rely exclusively on changes in blood test results. Particularly 
at the start of treatment, in isolated cases, liver enzyme values can be temporarily elevated even independent of any impairment of hepatic function. Therefore, medical history and the clinical picture are always of critical importance to the assessment.

In case salicylates are taken concomitantly they should be discontinued as a precautionary measure, since they follow the same metabolic pathway as valproic acid.

Measures for the early detection of damage to the liver and/or pancreas Before treatment starts, a detailed medical history should be taken, covering, in particular, metabolism disorders, hepatopathies, pancreatic disorders and coagulation disorders in the patient and his/her family. Clinical examinations and chemical laboratory tests (e.g. PTT, fibrinogen, coagulation factors, INR, total protein, blood count with platelets, bilirubin, AST, ALT, gamma-GT, lipase, alpha-amylase in the blood, blood sugar) should also be performed.
Four weeks after the start of treatment, follow-up chemical laboratory tests should be performed with measurement of coagulation parameters such as INR and PTT, AST, ALT, bilirubin and amylase.

In children who are clinically normal, a blood count with platelets, AST and ALT, and at every second medical examination, also the clotting parameters should be determined.

In clinically normal patients with pathologically elevated results after 4 weeks, follow-up tests should be performed three times at intervals of no more than 2 weeks, then once a month until the sixth month of treatment.

In adolescents (from the age of about 15) and adults, it is advisable to check the clinical findings and laboratory parameters every month for the first six months and in any case before starting treatment.

After 12 months of treatment with no abnormalities, only 2−3 medical check-ups a year are necessary.

Liver function should be monitored again where necessary if there are changes in concomitant medication (dose increase or new addition) known to have an effect on the liver (see also section 4.5 on the risk of liver damage from salicylates, other anticonvulsants including cannabidiol).

Parents should be instructed to look for possible signs of damage to the liver and/or pancreas (see “Signs of damage to the liver and/or pancreas”) and urged to inform the treating doctor of clinical abnormalities immediately, regardless of this time schedule.

Bleeding and other hematopoietic disorders
Valproate is associated with dose-related thrombocytopenia. In a clinical trial of divalproex sodium as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 × 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Valproate use has also been associated with decreases in other cell lines and myelodysplasia.

Because of reports of cytopenias, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor deficiencies, acquired von Willebrand's disease), measurements of complete blood counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving valproic acid capsules be monitored for blood counts and coagulation parameters prior to planned surgery and during pregnancy. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection.
Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Valproate should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established.

Immediate withdrawal of the treatment should be considered in the event of: an inexplicable disturbance in the patient's general condition, clinical signs of a hepatic or pancreatic disorder or a bleeding tendency, a more than two- to three-fold increase in liver transaminases, even in the absence of clinical signs (consider enzyme induction by any concomitant medication), a slight (one and a half- to two-fold) increase in liver transaminases with a concomitant acute febrile infection, or a severe coagulation disorder.

Pregnancy Prevention Program

Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders (see section 4.6).

Depalept Chrono is contraindicated in the following situations:

Treatment of epilepsy
•     in pregnancy unless there is no suitable alternative treatment (see sections 4.3 and 4.6),
•     in women of childbearing potential, unless the conditions of the pregnancy prevention program are fulfilled (see sections 4.3 and 4.6).

Treatment of bipolar disorder
•     in pregnancy (see sections 4.3 and 4.6).
•     in women of childbearing potential, unless the conditions of the pregnancy prevention program are fulfilled (see sections 4.3 and 4.6).

Conditions of Pregnancy Prevention Program:

The prescriber 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 explain her the risks and the measures needed to minimise the risks.
•     the potential for pregnancy is assessed for all female patients.
•     The prescriber explained the patient the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to valproate in utero.
•     The prescriber explained the patient 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 please refer to subsection "Contraception" of this boxed warning), without interruption during the entire duration of treatment with valproate.
•     The prescriber explained the patient the need for regular (at least annual) review of treatment by a specialist experienced in the management of epilepsy, or bipolar disorders.
•      The prescriber explained the patient the need to consult her physician as soon as she is planning a pregnancy to ensure timely discussion and switching to alternative treatment prior to conception, and before contraception is discontinued.
•      The prescriber explained the patient the need to urgently consult her physician in case of pregnancy.
- The prescriber explained the patient the risks to the unborn child and the patient herself of untreated epilepsy or bipolar disorder.
•      the patient has received the Patient Guide.
•      The prescriber explained the patient the risks and necessary precautions associated with valproate use (according to Physician Checklist).
- Keep a copy of the checklist in the patient's file and give a copy to the patient or her legal guardian
These conditions also concern women who are not sexually active, unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.

Female children
- Valproate should not be prescribed to female children or women of childbearing potential, unless there is no suitable alternative treatment.
•    The prescriber must ensure that parents/caregivers of female children had received an explanation about the need to contact the specialist once the female child using valproate experiences menarche.
•    The prescriber 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 valproate in utero.
•    In patients who experienced menarche, the prescribing specialist must reassess the need for valproate therapy annually and consider alternative treatment options. If valproate is the only suitable treatment, the need for using effective contraception and all other conditions of the pregnancy prevention program should be discussed. Every effort should be made by the specialist to switch the female children to alternative treatment before they reach adulthood.

Pregnancy test
Pregnancy must be excluded before start of treatment with valproate. Treatment with valproate must not be initiated in women of childbearing potential without a negative pregnancy test (plasma pregnancy test) result, confirmed by a health care provider, to rule out unintended use in pregnancy.

Contraception
Women of childbearing potential who are prescribed valproate must use effective contraception, without interruption during the entire duration of treatment with valproate. 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 she has amenorrhea, she must follow all the advice on effective contraception.

Estrogen-containing products
Concomitant use with estrogen-containing products, including estrogen-containing hormonal contraceptives, may potentially result in decreased valproate efficacy (see section 4.5). Prescribers should monitor clinical response (seizure control or mood control) when initiating or discontinuing estrogen-containing products.
On the opposite, valproate does not reduce efficacy of hormonal contraceptives.

Annual treatment reviews by a specialist
The specialist should at least annually review whether valproate is the most suitable treatment for the patient. The specialist should discuss the Physician Checklist, at initiation and during each annual review and ensure that its content was explained to the patient.

Pregnancy planning
For the indication epilepsy, if a woman is planning to become pregnant, a specialist experienced in the management of epilepsy, must reassess valproate 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 section 4.6). If switching is not possible, the woman should receive further counselling regarding the valproate risks for the unborn child to support her informed decision making regarding family planning.

For the indication bipolar disorder, if a woman is planning to become pregnant, a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued and, if needed, switched to an alternative treatment prior to conception, and before contraception is discontinued.


In case of pregnancy
If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to re- evaluate treatment with valproate and consider alternative options. All patients with a valproate exposed pregnancy and their partners should be referred to a Teratology center for evaluation and counselling regarding the exposed pregnancy (see section 4.6).

Pharmacists must ensure that:
•    Reinforce the safety messages including the need for effective contraception. Dispense valproate in the original package with an outer warning. Do not unpack.
•    the patients are advised not to stop valproate medication and to immediately contact a specialist in case of planned or suspected pregnancy.

Educational materials
In order to assist healthcare professionals and patients in avoiding exposure to valproate during pregnancy, a Patient Card, a Patient Guide, a Physician Checklist, and a Guide for prescribers involved in the care of women of childbearing potential using valproate and the details of the Pregnancy Prevention Program will be available to inform healthcare professionals and patients/caregivers on the risks of valproate and the conditions for use. A patient guide and patient card should be provided to all women of childbearing potential using valproate.

Physician Checklist needs to be used by the specialists at time of treatment initiation and during each annual review of valproate treatment by the specialist.


Suicidal ideation and suicidal behaviour
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic drugs has also shown a slightly increased risk of suicidal ideation and suicidal behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for valproic acid.

Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Carbapenem agents
The concomitant use of valproic acid/valproates and carbapenem agents is not recommended (see section 4.5).

Alcohol should be avoided during treatment with valproate.

Urea cycle disorders and risk of hyperammonaemia
An increase in the ammonia serum level (hyperammonaemia) may occur during treatment with products containing valproic acid. Therefore, serum levels of ammonia and valproic acid should be determined in the event of symptoms such as apathy, somnolence, vomiting, hypotension, and an increase in seizure frequency; the dose of the product should be reduced if necessary.

When an urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed before starting valproic acid therapy to avoid the occurrence of hyperammonaemia (see sections 4.3 and 4.4 “Patients at risk of hypocarnitinaemia” and “Liver and/or pancreatic damage”).

Known or suspected mitochondrial disease
Valproate may trigger or worsen clinical signs of underlying mitochondrial diseases caused by mutations of mitochondrial DNA as well as the nuclear encoded POLG gene. In particular, valproate- induced acute liver failure and liver-related deaths have been reported at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor 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).

Patients at risk of hypocarnitinaemia
Valproate administration may trigger occurrence or worsening of hypocarnitinaemia that can result in hyperammonaemia (that may lead to hyperammonemic encephalopathy). Other symptoms such as liver toxicity, hypoketotic hypoglycaemia, myopathy including cardiomyopathy, rhabdomyolysis, Fanconi syndrome have been observed, mainly in patients with risk factors for hypocarnitinaemia or pre-existing hypocarnitinaemia. Patients at increased risk for symptomatic hypocarnitinaemia when treated with valproate include patients with metabolic disorders including mitochondrial disorders related to carnitine (see also section 4.4 “Known or suspected mitochondrial disease” and “Urea cycle disorders and risk of hyperammonaemia”), impairment in carnitine nutritional intake, patients younger than 10 years old, concomitant use of pivalate-conjugated medicines or of other antiepileptics.

Patients should be warned to report immediately any signs of hyperammonaemia such as ataxia, impaired consciousness, vomiting. Carnitine supplementation should be considered when symptoms of hypocarnitinaemia are observed.

Patients with systemic primary carnitine deficiency and corrected for hypocarnitinaemia may only be treated with valproate if the benefits of valproate treatment outweigh the risks in these patients and there is no therapeutic alternative. In these patients, carnitine monitoring should be implemented.

Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the greater risk of rhabdomyolysis when treated with valproic acid. Carnitine supplementation should be considered in these patients.


See also sections 4.5, 4.8 and 4.9.
Aggravated convulsions
As with other antiepileptic drugs, some patients may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately.

Bone marrow damage
Patients with previous bone marrow damage must be strictly monitored.

Immune system reactions
Although immune system disorders have only rarely been observed during treatment with medicinal products containing valproic acid, the latter should not be used in patients with systemic lupus erythematosus until a strict risk-benefit analysis has been carried out.

Renal insufficiency and hypoproteinaemia
In patients with renal insufficiency and hypoproteinaemia, the rise in free valproic acid in serum must be considered and the dose reduced accordingly (see also section 4.2). In patients receiving haemodialysis, it may be necessary to increase the dosage. Valproate is dialysable (see section 4.9).
As monitoring of plasma concentrations alone may be misleading, dosage should be adjusted according to the clinical picture.

Investigations
It should be noted that, as with other anti-epileptics, transaminases can rise temporarily without any clinical symptoms at the start of treatment with valproic acid. In these cases, more extensive laboratory tests (including INR) are recommended. In rare cases, harmless, usually temporary nausea, sometimes with vomiting and loss of appetite, can also occur and regresses spontaneously or after a reduction in the dose.

Coagulation status should be checked before a surgical procedure and in case of injuries or spontaneous bleeding (including blood cell count with platelets, bleeding time and coagulation factors).
If the patient is taking a vitamin K antagonist concomitantly, close monitoring of the INR is recommended.

Patients should be informed about possible weight gain at the start of treatment. Suitable weight control measures should be taken.

Further note:
If undesirable effects that are not dose-dependent are observed, withdrawal of the medicinal product is indicated.

Paediatric population
Monotherapy is recommended in children under the age of 3 years when perscribing Depalept Chrono, but the potential benefit should be weighed against risk of liver damage or pancreatitis in such patients prior to initiation of therapy (see above “Damage to the liver and/or pancreas”, see also section 4.5).

Concomitant treatment with salicylates in children under 12 years of age should be avoided due to the risk of liver damage (see also section 4.5).

One prolonged-release tablet of Depalept Chrono 500 mg contains 47.21 mg sodium per prolonged- release tablet, equivalent to 2.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.



Effects on Driving

4.7   Effects on ability to drive and use machines
At the start of treatment with Depalept Chrono, at higher doses and/or in combination with medicinal products that act on the central nervous system, central nervous effects, e.g. somnolence and/or confusion, can affect reactions to such an extent that the ability to drive a vehicle or use machines is impaired, irrespective of the effect of the underlying disorder being treated. This effect is intensified in combination with alcohol.