Epilepsan ECC

Valproic acid

Monotherapy & adjunctive therapy in patients w/ complex partial seizures that occur either in isolation or in association w/ other types of seizures. Sole & adjunctive therapy of simple & complex absence seizures, & adjunctively in patients w/ multiple seizure types including absence seizures.

Monotherapy & conversion to monotherapy Initially 10-15 mg/kg/day, may be increased by 5-10 mg/kg/wk. Adjunctive Therapy 10-15 mg/kg/day, may be increased by 5-10 mg/kg/wk. Dose >250 mg/day should be given in divided doses. Simple & complex absence seizures Initially 15 mg/kg/day, increasing at 1 wk intervals by 5-10 mg/kg/day until seizures are controlled or side effects preclude further increases. Max: 60 mg/kg/day. Dose >250 mg/day should be given in divided doses.

May be taken with or without food: Swallow whole, do not chew. May be taken w/ food to reduce GI irritation.

Hypersensitivity. Mitochondrial disorders caused by mitochondrial DNA polymerase γ mutations (POLG; eg, Alpers-Huttenlocher syndrome) & childn <2 yr who are suspected of having a POLG- related disorder; urea cycle disorders; porphyria. Not to be administered to patients w/ hepatic disease or significant hepatic dysfunction. Treatment of epilepsy in pregnancy; women of childbearing potential.

Patients on multiple anticonvulsants, those w/ congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, & w/ organic brain disease. Loss of seizure control may occur in patients w/ epilepsy. Monitor closely for appearance of serious or fatal hepatotoxicity. Perform LFTs prior to therapy & at frequent intervals thereafter, especially during the 1st 6 mth. Discontinue immediately in the presence of significant hepatic dysfunction, suspected or apparent. Patients w/ known or suspected mitochondrial disease. Closely monitor for the development of acute liver injury w/ regular clinical assessments & LFT monitoring in patients w/ a family history or suggestive symptoms of a POLG-related disorder during treatment. Life-threatening pancreatitis in both childn & adults. Discontinue if pancreatitis is diagnosed; multi-organ hypersensitivity reactions is suspected. Increased risk of suicidal thoughts or behavior. Concomitant use of INN & carbapenem agents is not recommended. Always use effective contraception during treatment. Hyperammonemia, hypothermia, reversible & irreversible cerebral & cerebellar atrophy, DRESS. Consider measuring ammonia level in patients who develop unexplained lethargy & vomiting or changes in mental status, hyperammonemic encephalopathy. Discontinue if ammonia is increased; asymptomatic elevations persists. Consider evaluation for urea cycle disorders (UCD) in patients w/ history of unexplained encephalopathy or coma, encephalopathy associated w/ protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; cyclical vomiting & lethargy, episodic extreme irritability, ataxia, low BUN, protein avoidance; family history of UCD or unexplained infant deaths (particularly males); other signs or symptoms of UCD. Increased risk of hyperammonemia w/ or w/o encephalopathy in patients w/ inborn errors of metabolism or reduced hepatic mitochondrial activity. Concomitant administration of topiramate & valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons. Consider to stop giving valproate in patients who develop hypothermia. Routinely monitor the motor & cognitive functions of patients; discontinue in the presence of suspected or apparent signs of brain atrophy. Thrombocytopenia, inhibition of the secondary phase of platelet aggregation, & abnormal coagulation parameters (eg, low fibrinogen); perform platelet counts, & coagulation tests before initiating therapy & at periodic intervals. Monitor for platelet count & coagulation parameters prior to planned surgery. Periodic plasma conc determinations of valproate & concomitant drugs are recommended during the early course of therapy. False interpretation of urine ketone test. Altered thyroid function tests. Evidence of hemorrhage, bruising or hemostasis/coagulation disorder is an indication for dosage reduction or w/drawal of therapy. Valproate stimulates the replication of HIV & CMV viruses under certain conditions. Greater risk of rhabdomyolysis in patients w/ an underlying carnitine palmitoyltransferase (CPT) type II deficiency. Medication residue in the stool, in patients w/ anatomic (including ileostomy or colostomy) or functional GI disorders w/ shortened GI transit times. Consider dose reductions or discontinuation of valproate in patients w/ decreased food or fluid intake & w/ excessive somnolence. Congenital malformations. Monitoring of signs & symptoms of ototoxicity is recommended. Amenorrhoea, polycystic ovaries & increased testosterone levels in women. May impair fertility in men. History of hepatic disease. Advise patients not to engage in hazardous activities eg, driving an automobile or operating dangerous machinery. Advise female patients of childbearing age the risks of certain types of birth defects & developmental risk associated w/ therapy during pregnancy. Reassessed or discontinue therapy in women planning to become pregnant or who are pregnant. Abnormal pregnancy outcomes. Consider alternative treatment options if a woman becomes pregnant during therapy. Hemorrhagic & w/drawal syndrome, afibrinogenemia, hypoglycaemia, hypothyroidism in neonates whose mothers have taken Divalproex Na during pregnancy. Lactation. Increased risk of developing fatal hepatotoxicity in childn <2 yr. Cerebral atrophy w/ various forms of neurological problems including developmental delays & psychomotor impairment; increased risk of autistic spectrum disorder, childhood autism, & developing ADHD in childn who were exposed in-utero to valproate products. Treatment of acute mania in individuals <18 yr. Prophylaxis of migraines in individuals <16 yr. Elderly >65 yr. Somnolence in the elderly.

Increased appetite, pancreatitis; petechia; increased SGOT, SGPT; confusion, incoordination; increased cough, pneumonia, epistaxis; deafness; rash, pruritus; otitis media; amenorrhea. Epilepsy: Complex partial seizure (CPS): Back pain, chest pain, malaise; tachycardia, HTN, palpitation; flatulence, hematemesis, eructation, periodontal abscess; myalgia, twitching, arthralgia, leg cramps, myasthenia; anxiety, abnormal gait, paresthesia, hypertonia, abnormal dreams, personality disorder; sinusitis; dry skin; taste perversion, abnormal vision; urinary incontinence, vaginitis, dysmenorrhea, urinary frequency. Other patient populations: Nausea, vomiting, indigestion, diarrhea, abdominal cramps, constipation & gingival disorder (mainly gingival hyperplasia), anorexia w/ some wt loss; sedation, tremor, hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, hypesthesia, vertigo, memory impairment, cognitive disorder, & extrapyramidal disorders including parkinsonism, encephalopathy in the absence of elevated ammonia levels, reversible & irreversible cerebral & cerebellar atrophy; congenital malformations & developmental disorders; transient hair loss, hair disorders (eg, abnormal hair texture & growth, hair colour changes), photosensitivity, erythema multiforme, SJS, serious skin reactions, nail & nail bed disorders; emotional upset, depression, psychosis, aggression, psychomotor hyperactivity, hostility, agitation, attention disturbance, abnormal behavior, learning disorders, & behavioral deterioration; weakness, decreased bone mass; thrombocytopenia, altered bleeding time, bruising, hematoma formation, & hemorrhage, relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic w/ or w/o folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, & acute intermittent porphyria; minor LDH elevations, potentially serious hepatotoxicity; irregular menses, breast enlargement, galactorrhea, parotid gland swelling, hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia, &/or increased androgen), hypothyroidism; hyperammonemia, hyponatremia, inappropriate ADH secretion, hyperglycinemia (elevated plasma glycine conc), insulin resistance & dyslipidemia; enuresis, renal failure, tubulointerstitial nephritis & UTI; male infertility including azoospermia, abnormal semen analysis & spermatozoa morphology, decrease sperm count & spermatozoa motility, aspermia; ear pain; myelodysplastic syndrome; pleura effusion; allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, rhabdomyolysis, biotin/biotinidase deficiency, bone pain, bradycardia, cutaneous vasculitis, fever, & hypothermia.

Increased valproate clearance w/ ritonavir. Phenytoin, carbamazepine & phenobarb (or primidone) can double the clearance of valproate. Concomitant use w/ aspirin, amitriptyline/nortriptyline. Reports of serious skin reactions eg, SJS & TEN w/ lamotrigine. Reduction in serum conc & loss of seizure control w/ carbapenem antibiotics (eg, ertapenem, imipenem, meropenem). Decreased valproate conc & potentially increased seizure frequency w/ estrogen containing hormonal contraceptives. Dosage adjustment may be necessary w/ felbamate, rifampicin. Decreased valproate plasma level w/ PIs (eg, lopinavir, ritonavir), cholestyramine. Increased valproate plasma levels w/ chlorpromazine. Decreased carbamazepine (CBZ) & increased carbamazepine-10,11-epoxide (CBZ-E) serum levels by co-administration of valproate to epileptic patients. Concomitant use w/ clonazepam may induce absence status in patients w/ a history of absence type seizures. Valproate displaces diazepam & phenytoin from its plasma albumin binding sites & inhibits its metabolism. Metabolism of ethosuximide, phenobarb, primidone is inhibited by valproate. Increased blood level of propofol. Serum levels may be increased w/ phenytoin or phenobarb. May increase nimodipine plasma conc. Increased unbound fraction of tolbutamide, warfarin. Hyperammonemia w/ & w/o encephalopathy w/ topiramate or acetazolamide. Hypothermia w/ topiramate. Decreased clearance of zidovudine. May increase the risk of neutropenia/leucopenia w/ quetiapine. Decreased plasma clearance of lorazepam. May decrease plasma conc of olanzapine. May increase plasma level of rufinamide.

Anticonvulsants

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

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