Special Warning : אזהרת שימוש

4.4.    Special warnings and precautions for use
Suicidal ideation and behavior have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs has also shown a small increased risk of suicidal ideation and behavior. The mechanism of this risk is not known, and the available data do not exclude the possibility of an increased risk for sodium valproate.
Therefore, patients should be monitored for signs of suicidal ideation and behaviors and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behavior emerge.
Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally only be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms.
NICE has advised that generic switching of valproate preparations is not normally recommended due to the clinical implications of possible variations in plasma concentrations.
The concomitant use of sodium valproate and carbapenem is not recommended (see section 4.5).
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 (see section 4.8).
Hepatic dysfunction
Conditions of occurrence
Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported. Experience in epilepsy has indicated that patients most at risk, especially in cases of multiple anticonvulsants therapy, are infants and in particular young children under the age of 3 and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic disorders including mitochondrial disorders such as carnitine deficiency, urea cycle disorders, POLG mutations (see sections 4.3 and 4.4) or degenerative disease associated with mental retardation. After the age of 3, the incidence of occurrence is significantly reduced and progressively decreases with age. The concomitant use of salicylates should be avoided in children under 3 years of age due to the risk liver toxicity (see also section 4.5).
Additionally, salicylates should not be used in children under 16 years of age (see aspirin/salicylate product information on Reye's syndrome).
Monotherapy is recommended in children under the age of 3 years when prescribing Orifiril injection, but the potential benefit of Orifiril injection should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy (see also section 4.4 Severe liver damage and also section 4.5).
In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2 – 12 weeks.
Suggestive signs
Clinical symptoms are essential for early diagnosis. In particular the following conditions, which may precede jaundice, should be taken into consideration, especially in patients at risk (see above: Conditions of occurrence):
- non-specific symptoms, usually of sudden onset, such as asthenia, malaise, anorexia, lethargy, oedema and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain.
- in patients with epilepsy, recurrence of seizures
These are an indication for immediate withdrawal of the drug.
Patients (or their carers) should be instructed to report immediately any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.
Detection
Liver function should be measured before and then periodically monitored during the first 6 months of therapy, especially in those who seem at risk, and those with a prior history of liver disease. Upon changes in concomitant medicinal products (dose increase or additions) that are known to impact the liver, liver monitoring should be restarted as appropriate (see section 4.5).
Amongst usual investigations, tests which reflect protein synthesis, particularly prothrombin rate, are most relevant. Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decreases in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) require cessation of Orfiril injection therapy.
As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.
As with most antiepileptic drugs, increased liver enzymes are common, particularly at the beginning of therapy; they are also transient.
More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary.
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 Patients with 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 taking valproate. Carnitine supplementation should be considered in these patients. See also section 4.5, 4.8 and 4.9.

Pancreatitis
Pancreatitis, which may be severe and result in fatalities, has been very rarely reported. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase).
Young children are at particular risk; this risk decreases with increasing age. Severe seizures and severe neurological impairment with combination anticonvulsant therapy may be risk factors.
Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, Orfiril injection should be discontinued.
Haematological
Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding. (see section 4.8).
Renal insufficiency
In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (see sections 4.2 and 5.2).
Systemic lupus erythematosus
Although immune disorders have only rarely been noted during the use of sodium valproate, the potential benefit of Orfiril injection should be weighed against its potential risk in patients with systemic lupus erythematosus (see section 4.8).
Urea cycle disorders Hyperammonaemia
When urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of risk of hyperammonaemia with sodium valproate.Weight gain
Sodium valproate very commonly causes weight gain, which may be marked and progressive.
Patients should be warned of the risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimize it (see section 4.8).
Diabetic Patients
Sodium valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies: this may give false positive in the urine testing of possible diabetics.
Patients with 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 the 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 but not limited to 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).
Alcohol
Alcohol intake is not recommended during treatment with valproate.
Excipient with known effect
This medicinal product contains 41.6 mg sodium per 3 mL ampoule, equivalent to 2 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This medicinal product contains 138.8 mg sodium per 10 mL ampoule, equivalent to 7 % 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
Use of Orfiril injection may provide seizure control such that the patient may be eligible to hold a driving license.
At the start of treatment with sodium valproate, at higher dosages or with a combination of other centrally acting drugs, reaction time may be altered to an extent that affects the ability to drive or to operate machinery, irrespective of the effect on the primary disease being treated. Patients should be warned of the risk of transient drowsiness. This is especially the case when taken during anticonvulsant polytherapy, concomitant use of benzodiazepines or in combination with alcohol.