VI.2 Elements for a Public Summary

Sodium valproate Risk Management Plan 100 mg/ml 14 February 2018 solution for injection Version 04 (Replaces version 03 of 17 Jan 2018) Safety concern Routine risk minimization measures Additional risk minimization measures (carbapenem agents) minimize the risk: Warnings in Section 4.5 Interaction with other medicinal products and other forms of interaction Carbapenem agents (such as panipenem, meropenem, imipenem): Decreases in serum levels of valproic acid have been reported when it is co-administered with carbapenem agents, resulting in a 60% – 100% decrease in valproic acid levels within two days. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients on valproic acid is difficult to implement and therefore should be avoided. Off-label use in Risk minimisation activities consist of literature patients with manic surveillance for off-label use of the product in episodes in bipolar patients with manic episodes in bipolar disorders and in patients under 18 years of age. Routine disorder pharmacovigilance collection of ADR reports of off- label use in this patient population. VI.2 Elements for a Public Summary VI.2.1 Overview of disease epidemiology Epilepsy Epilepsy is defined as a condition characterized by recurrent (two or more) epileptic seizures (brief episodes of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain), unprovoked by any immediate identified cause. An epileptic seizure is “transient”, demarcated in time, with clear start and finish. Seizure presentation depends on location of onset in the brain, patterns of propagation, maturity of the brain, confounding disease processes, sleep-wake cycle, medications, and a variety of other factors. It can affect sensory, motor, and autonomic function; consciousness; emotional state; memory; cognition; or behaviour. At any given time, it is estimated that 50 million individuals worldwide have a diagnosis of epilepsy. In Europe, age-adjusted prevalence was low, 2.7 per 1000 and 3.3 per 1000, in two studies conducted in Italy, when compared to a prevalence of 7.0 per 1000 in a study conducted in the European region of Turkey. In developed countries, the prevalence of epilepsy increases as age increases. In developing countries, prevalence of epilepsy generally peaks in adolescence and early adulthood. In both developed and 55 Confidential Sodium valproate Risk Management Plan 100 mg/ml 14 February 2018 solution for injection Version 04 (Replaces version 03 of 17 Jan 2018) developing countries, the incidence of epilepsy is high in infancy and early childhood. In developed countries, incidence is several times higher in the elderly than in the adult age groups. VI.2.2 Summary of treatment benefits Sodium valproate is the sodium salt form of valproic acid with anti-epileptic activity. Other available forms include valpromide (the amide of valproic acid) and divalproex sodium (a combination of sodium valproate and valproic acid in a 1:1 molar ratio). Sodium valproate was given to 63 patients with various forms of epilepsy whose attacks were frequent and of whom 40 failed to respond to other treatments. Epileptic seizures stopped completely in 27 patients and 14 showed a reduction of attacks by more than 50%. Myoclonic epilepsies responded well and improvement occurred with tonic-clonic seizures and focal motor fits. Valproate was compared with oxcarbazepine in a study of adults (n=212) with newly diagnosed epilepsy. Sixty patients (56.6%) in the oxcarbazepine group and 57 patients (53.8%) in the valproate group were seizure free during maintenance treatment. Generally, it has good tolerability and breadth of action, however, some side-effects, particularly weight gain, limits its effectiveness in maintenance. VI.2.3 Unknowns relating to treatment benefits None. VI.2.4 Summary of safety concerns Important identified risks: Risk What is known Preventability Severe liver damage including Sodium valproate has been [Invented name] should not hepatic failure described to cause severe, even normally be used for small fatal, liver damage. Patients at a children as therapy of first particular risk of severe liver choice. [Invented name] should damage include patients with a be used with care in small history of liver disease, and children and only if the benefits children under the age of 3 with outweigh the risks. If possible, multiple anticonvulsant therapy, monotherapy should be a genetic metabolic disorder preferred. and severe epilepsy with brain damage and mental retardation. The liver function must be Particular caution should be monitored prior to starting observed when using sodium treatment, then at regular valproate in these patient intervals for the first six months. groups. After the age of 3, the risk is significantly reduced and progressively decreases with age. In most cases, liver damage occurred during the first 6 months of therapy. 56 Confidential Sodium valproate Risk Management Plan 100 mg/ml 14 February 2018 solution for injection Version 04 (Replaces version 03 of 17 Jan 2018) Risk What is known Preventability Suicidal ideation and behaviour Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti- epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data does not exclude the possibility of an increased risk for sodium valproate. 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. Use in female children, women Valproate has a high [Invented name] should not be of childbearing potential and teratogenic potential and risk of used in female children, in pregnant women developmental disorders in female adolescents, in women infants exposed in utero. of childbearing potential and pregnant women unless Both valproate monotherapy alternative treatments are and valproate polytherapy are ineffective or not tolerated. associated with abnormal pregnancy outcomes. Available The benefit and risk should be data suggest that antiepileptic carefully reconsidered at regular polytherapy, including treatment reviews, at puberty valproate, is associated with a and urgently when a woman of greater risk of congenital childbearing potential treated malformations than valproate with [Invented name] plans a monotherapy. pregnancy or if she becomes pregnant. Data have shown that exposure In women planning to become to valproate in utero can have pregnant all efforts should be adverse effects on mental and made to switch to appropriate physical development of the alternative treatment prior to exposed children. The risk conception, if possible. seems to be dose-dependent but a threshold dose below Women of childbearing 57 Confidential Sodium valproate Risk Management Plan 100 mg/ml 14 February 2018 solution for injection Version 04 (Replaces version 03 of 17 Jan 2018) Risk What is known Preventability which no risk exists, cannot be potential must use effective established based on available contraception during treatment data. and be informed of the risks associated with the use of Cases of hemorrhagic [Invented name] during syndrome, hypoglycaemia, and pregnancy. hypothyroidism have been reported in neonates whose The prescriber must ensure that mothers have taken valproate the patient is provided with during pregnancy. comprehensive information on the risks alongside relevant Withdrawal syndrome may materials, such as a patient occur in neonates whose information booklet, to support mothers have taken valproate her understanding of the risks. during the last trimester of their pregnancy. Pancreatitis, anemia, There have been rare reports of Patients experiencing acute thrombocytopenia, leucopenia severe pancreatitis, which can abdominal pains while being be fatal. This is a risk for young treated with valproate must be children, in particular. examined immediately, and if pancreatitis is ascertainable, the Cases of anaemia, [Invented name] therapy must thrombocytopenia, be discontinued. pancytopenia, leukopenia, Bone marrow suppression, including It is recommended monitoring red cell aplasia, agranulocytosis, the blood counts, including anaemia macrocytic, platelet count, bleeding time macrocytosis, eosinophilia and and coagulation tests, before fibrinogen levels decreased initiating treatment and before have occurred with sodium surgical and dental procedures valproate. as well as in cases of spontaneous haematomas or bleeding. Drug-drug interaction Decreases in serum levels of The concomitant use of (carbapenem agents) valproic acid have been valproate/sodium valproate and reported when it is co- drugs containing carbapenems administered with carbapenem is not recommended. agents, resulting in a 60% – 100% decrease in valproic acid levels within two days. Due to the rapid onset and the extent of the decrease, co- administration of carbapenem agents in patients on valproic acid is difficult to implement and therefore should be 58 Confidential Sodium valproate Risk Management Plan 100 mg/ml 14 February 2018 solution for injection Version 04 (Replaces version 03 of 17 Jan 2018) Risk What is known Preventability avoided (see section 4.4). Important potential risks:

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