Although valproic acid capsules have not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of divalproex sodium tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
Although valproic acid capsules have not been evaluated for safety and efficacy in the prophylactic treatment of migraine headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of divalproex sodium tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal haemorrhage.
The following adverse reactions have been identified during post approval use of divalproex sodium tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Dermatologic: Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.
Psychiatric: Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration.
Neurologic: Paradoxical convulsion, parkinsonism
There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation.
There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia levels, elevated valproate levels, or neuroimaging changes. The encephalopathy reversed partially or fully after valproate discontinuation.
Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness.
Hematologic: Relative lymphocytosis, macrocytosis, leukopenia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Endocrine: Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion.
There have been rare reports of Fanconi’s syndrome occurring chiefly in children.
Metabolism and nutrition: Weight gain.
Reproductive: Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss.
Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis.
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.
The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered.
A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.13)].
Cholestyramine, when concurrently administered with valproic acid, led to, on average, a 14% decrease in plasma levels of valproic acid in a study conducted in 6 healthy subjects administered valproic acid and cholestyramine. Delaying the administration of cholestyramine relative to valproic acid administration by 3 hours may lessen the interaction.
Estrogen-Containing Hormonal Contraceptives
Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result in decreased concentration of valproate and potentially increased seizure frequency. Prescribers should monitor serum valproate concentrations and clinical response when adding or discontinuing estrogen containing products.
A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated.
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac — 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
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