Valproic acid

Known mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG) such as Alpers-Huttenlocher syndrome; known urea cycle disorders, porphyria, personal or family history of severe hepatic dysfunction. Hepatic impairment. Children <2 years of age who are clinically suspected of having a POLG-related disorder. Pregnancy and women of childbearing potential who are not using effective contraception (when used for prophylaxis of migraine).

Patient with SLE, carnitine palmitoyltransferase (CPT) type II deficiency; risk factors for hepatotoxicity (e.g. children <3 years of age, those on multiple anticonvulsant agents, those with severe seizure disorders, organic brain disease, congenital metabolic or degenerative disease associated with mental retardation). Patients undergoing surgery. Use valproic acid in patients >2 years who are clinically suspected of having hereditary mitochondrial disease only after other anticonvulsant agents have failed. Medication residue in the stool may occur rarely in patients taking oral valproate semisodium. Refer to specific product guidelines when switching between different brands or formulations. Avoid abrupt withdrawal. Not recommended for the treatment of dementia-associated agitation or aggression, and post-traumatic seizure prophylaxis in patients with acute head trauma. Children and elderly. When used for epilepsy and bipolar disorder, valproic acid must not be used in pregnant women, those planning to become pregnant, and women of childbearing potential unless other agents failed to provide adequate symptom control or are otherwise unacceptable. Lactation. Patient Counselling This drug may cause transient drowsiness, if affected, do not drive or operate machinery. Women of childbearing potential must use highly effective birth control methods without interruption during therapy. Monitoring Parameters Pregnancy test may be considered in women of childbearing potential to rule out pregnancy before initiating treatment. Perform POLG mutation testing in accordance with the current clinical practice for the diagnosis of such disorders. Monitor serum valproate levels as clinically indicated; LFTs (at baseline and frequently thereafter, particularly during the 1st 6 months of therapy), CBC with platelets (at baseline and periodically), prothrombin time/partial thromboplastin time (prior to therapy initiation and especially before surgery), and serum ammonia (with mental status changes). Check for mental alertness; evidence of haemorrhage, bruising, or a disorder of haemostasis/coagulation; menstrual history to assess for polycystic ovary syndrome (at 3-6 monthly intervals for the 1st year, and annually thereafter). Closely assess for signs and symptoms of hepatotoxicity (particularly in patients >2 years who are suspected of having a hereditary mitochondrial disease), pancreatitis, suicidal ideation, behavioural changes, depression, decline in motor and cognitive function, and DRESS.

Significant: Suicidal ideation and behaviour, CNS effects (e.g. dizziness, drowsiness, nervousness, insomnia, tremor, delirium, hallucinations, parkinsonism, cognitive dysfunction); thrombocytopenia (dose-related), acquired von Willebrand disease type I, haemorrhage, haemorrhagic stroke; hyperammonaemia (may be present despite normal LFTs), hypothermia; delayed hypersensitivity reactions (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome [SJS]); porphyria, increased liver enzymes, weight gain; reversible worsening of convulsion frequency and severity, new-onset of other types of convulsions; rhabdomyolysis (specifically in patients with CPT type II deficiency); major congenital malformation, particularly neural tube defects (e.g. spina bifida). Blood and lymphatic system disorders: Aanaemia, pancytopenia, leucopenia. Ear and labyrinth disorders: Tinnitus, deafness (reversible or irreversible). Endocrine disorders: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH), hyperandrogenism (e.g. hirsutism, acne). Eye disorders: Nystagmus. Rarely, diplopia. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, gingival hyperplasia, stomatitis, gastralgia, dyspepsia, abdominal pain, flatulence. General disorders and administration site conditions: Asthenia, peripheral oedema. IV: Inj site reactions (e.g. pain, inflammation). Investigations: Decreased bone mineral density. Immune system disorders: Hypersensitivity. Metabolism and nutrition disorders: Hyponatraemia, anorexia. Musculoskeletal and connective tissue disorders: Osteopenia, osteoporosis, fractures (prolonged use). Nervous system disorders: Headache, extrapyramidal disorder, encephalopathy, memory impairment. Psychiatric disorders: Aggression, agitation, attention disturbance, confusional state, stupor. Renal and urinary disorders: Urinary incontinence. Reproductive system and breast disorders: Dysmenorrhoea, amenorrhoea. Very rarely, gynaecomastia. Respiratory, thoracic and mediastinal disorders: Pharyngitis, rhinitis, bronchitis, dyspnoea. Skin and subcutaneous tissue disorders: Transient or dose-related alopecia, nail and nail bed disorders, ecchymosis.
Potentially Fatal: Serious hepatotoxicity, including hepatic failure; hyperammonemic encephalopathy, pancreatitis or haemorrhagic pancreatitis that progresses rapidly from initial symptoms; drug reaction with eosinophilia and systemic symptoms (DRESS).

Increased risk of liver toxicity with salicylates. May enhance the effects of other psychotropic agents (e.g. antipsychotics, MAO inhibitors, antidepressants, benzodiazepines). Increased plasma concentrations of phenobarbital and primidone leading to sedation. May decrease the plasma concentrations of phenytoin and olanzapine. May potentiate the toxic effects of carbamazepine. May reduce the metabolism and increase the half-life of lamotrigine resulting in an increased risk of SJS and toxic epidermal necrolysis. May decrease the plasma protein binding and increase the anticoagulant effects of warfarin and other coumarin anticoagulants. Increased valproic acid plasma concentration with felbamate, aspirin, cimetidine, erythromycin, and chlorpromazine. Increased valproic acid metabolism causing a lower seizure threshold with mefloquine and chloroquine. Increased risk of hyperammonaemia (with or without encephalopathy) with topiramate and acetazolamide. Valproic acid plasma concentrations may be decreased with enzyme-inducing antiepileptics (e.g. phenytoin, phenobarbital, carbamazepine), carbapenem antibiotics (e.g. meropenem, imipenem), protease inhibitors (e.g. ritonavir, lopinavir), colestyramine, rifampicin, and metamizole. Estrogen-containing hormonal contraceptives may increase valproate clearance which may result in decreased valproate serum concentration and potentially reduced valproate efficacy. May increase the plasma levels of rufinamide, nimodipine, propofol, and zidovudine. May increase the risk of neutropenia/leucopenia with quetiapine.

Anticonvulsants / Antimigraine Preparations / Antipsychotics

N03AG01 - valproic acid ; Belongs to the class of fatty acid derivatives antiepileptic.