Valproate adverse effects

A double-blind, crossover comparison of oxcarbazepine and car-bamazepine in 42 epileptic patients found that when carbamazepine was replaced by oxcarbazepine, the serum levels of valproate rose by 32%, and the serum levels of phenytoin rose by 23%. In patients taking both valproate and phenytoin together, oxcarbazepine caused a rise in the serum levels of 21% and 25% respectively. The study extended over 12 weeks to establish steady-state levels. Another study in 4 young epileptic patients (aged 13 to 17) found that the level to dose ratio of free valproate rose when switched from concurrent carbamazepine to oxcarbazepine, with an increase in valproate adverse effects, which resolved when the valproate dose was decreased. ... 

When valproate protein binding is altered, the risk for severe dose-related adverse effects is much less compared to phenytoin. Michaelis-Menten metabolism is not a factor with valproate, so hepatic enzymes are able to efficiently metabolize the additional unbound portion. 

One chronic adverse effect that is of concern is osteoporosis.32,33 Carbamazepine, phenytoin, phenobarbital, oxcarbazepine, and valproate have all been shown to decrease bone mineral density, even after only 6 months of treatment. Data on the relationship between other AEDs and osteoporosis are not currently available. Multiple studies have shown the risk of osteoporosis due to chronic AED use to be similar to the risk with chronic use of corticosteroids. Patients taking carbamazepine, phenytoin, phenobarbital, or valproate for longer than 6 months should take supplemental calcium and vitamin D. Additionally routine monitoring for osteoporosis should be performed every 2 years, and patients should be instructed on ways to protect themselves from fractures. 

BC, a 22-year-old woman, was diagnosed 2 years ago with juvenile myoclonic epilepsy. She has been treated with valproate 1500 mg/day. Since starting valproate she has gained 45 pounds (20.5 kg), continues to have occasional myoclonic jerks, had a generalized tonic-clonic seizure 3 months ago, and is sexually active. Additionally, she complains of easily falling asleep during the day. Due to adverse effects, poor seizure control, and the risk of birth defects with valproate, the decision is made to switch to a different antiepileptic drug. 

Monitor for acute and chronic adverse effects of AEDs. Acute adverse effects are best detected by a thorough neurologic examination at clinic visits. Instruct patients to report sedation, ataxia, rash, or other problems immediately. Monitor for chronic adverse effects including a loss of bone mineral density, which should be measured every 2 years in patients taking phenytoin, phenobarbital, carbamazepine, and valproate. 

Lamotrigine is not approved for the acute treatment of depression, and the dose must be started low and slowly titrated up to decrease adverse effects if used for maintenance therapy of bipolar I disorder. A drug interaction and a severe dermatologic rash may occur when lamotrigine is combined with valproate (i.e., lamotrigine doses must be halved from standard dosing titration). 

Use standard therapeutic serum concentration ranges if clinically indicated if partial response or breakthrough episode, adjust dose to achieve higher serum concentrations without causing intolerable adverse effects valproate is preferred over lithium for mixed episodes and rapid cycling lithium and/or lamotrigine is preferred over valproate for bipolar depression. 

ADVERSE EFFECTS OF LITHIUM, VALPROATE, AND OTHER ANTICONVULSANTS... 

At least three drugs are effective against absence seizures. Two are nonsedating and therefore preferred ethosuximide and valproate. Clonazepam is also highly effective but has disadvantages of dose-related adverse effects and development of tolerance. Lamotrigine and topiramate may also be useful. 

Carbamazepine has been considered to be a reasonable alternative to lithium when the latter is less than optimally efficacious. The mode of action of carbamazepine is unclear, and oxcarbazepine is not effective. Carbamazepine may be used to treat acute mania and also for prophylactic therapy. Adverse effects (discussed in Chapter 24) are generally no greater and sometimes less than those associated with lithium. Carbamazepine may be used alone or, in refractory patients, in combination with lithium or, rarely, valproate. 

Hyperammonemia and carnitine deficiency are adverse effects of valproate, although carnitine deficiency can also be caused by other anticonvulsants (132). 

Valproate also causes urinary loss of carnitine (SEDA-12, 209), most probably by a different mechanism than pivalic acid (44). However, the combination can rapidly cause serious adverse effects (45). 

Consider the difference in response to drugs between older and younger people. Treatment should reflect biological age (rather than chronological). Pharmacokinetics, pharmacodynamics, tolerability, adverse reactions, economy and patient choice will all influence therapy chosen. Most commonly, car-bamazepine or sodium valproate are chosen for older people as their effects in older people are well documented. Both show a favourable balance of safety, efficacy and economy. Phenytoin is less preferable because of drug interactions, adverse effects and potential for toxicity (zero order kinetics). 

A 26-year-old woman with bipolar I disorder took lithium and valproate, and sometimes additional risperidone and lamotrigine. Both risperidone and lamo-trigine produced dermatological adverse effects. Her serum lithium concentration was 0.82 mmol/1. Topiramate 75 mg/day was added. A week later, she continued to show a mixed state with mostly manic features and a raised lithium concentration of 1.24 mmol/1. The lithium concentration continued to increase over the next 4 days to 1.97 mmol/1 even though the lithium dosage was reduced from 900 to 750 mg/day. Lithium was withdrawn and the lithium concentration fell. Lithium was then restarted at half the admission dose to achieve a blood concentration of 0.67 mmol/1. Subsequent increases in the dose of topiramate resulted in further increases in the lithium concentration. 

Although mania has been associated with olanzapine (SEDA-24, 68 SEDA-25, 68 SEDA-26, 62), it has also been used in the treatment of acute mania. In a 12-week, double-blind, double-dummy, randomized trial, 120 patients with bipolar disorder type I hospitalized for an acute manic episode were randomly assigned to either sodium valproate (n = 63) or olanzapine (n = 57) and were followed in hospital for up to 21 days (60). Valproate and olanzapine had similar short-term effects on clinical or health-related quality of life outcomes in bipolar disorder adverse effects that occurred in a higher percentage of olanzapine-treated than valproate-treated patients included somnolence (47% versus 29%), weight gain (25% versus 10%), rhinitis (14% versus 3%), edema (14% versus 0%), and slurred speech (7% versus 0%) no adverse events occurred significantly more often with valproate. 

Patients with bipolar disorders may benefit from risperidone. This has been observed in an open trial of ten patients with rapid cycling bipolar disorder who were refractory to lithium carbonate, carbamazepine, and valproate eight improved after 6 months of treatment. One patient dropped out through non-adherence to therapy and one because of adverse effects (agitation, anxiety, insomnia, and headache) (5). There was a similar beneficial effect in eight adults with moderate to profound mental retardation (6). Risperidone was associated with a significant reduction in aggression and self-injurious behavior, whereas adverse effects were primarily those of sedation and restlessness. 

In a 6-week open study of risperidone (mean dosage 4.7 mg/day) in combination with mood-stabilizing treatments (usually lithium, carbamazepine, or valproate) for the treatment of schizoaffective disorder in 102 patients, 95 of whom completed the trial, at week 4 most patients had improved symptom severity and 9.3% were completely symptom-free (35). There were no statistically significant differences between baseline and week 4 in the severity of extrapyramidal symptoms, as measured by the UKU Side-Effect Rating Scale subscale for neurological adverse effects other adverse effects included depressive symptoms (n = 13), exacerbation of mania ( n = 5), drowsiness (n = 3), and impotence (n = 2). 

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