Divalproex Sodium (Page 5 of 18)

5.4 Use in Women of Childbearing Potential

Because of the risk to the fetus of decreased IQ, neurodevelopmental disorders, and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headaches [see Contraindications (4)] . Women should use effective contraception while using valproate.

Women of childbearing potential should be counseled regularly regarding the relative risks and benefits of valproate use during pregnancy. This is especially important for women planning a pregnancy and for girls at the onset of puberty; alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)] .

To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate.Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate.

5.5 Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use.The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience.Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, divalproex sodium extended-release tablets should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning] .

5.6 Urea Cycle Disorders

Divalproex sodium extended-release tablets are contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of divalproex sodium extended-release tablets therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].

5.7 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including divalproex sodium extended-release tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication

Placebo Patients with Events Per 1,000 Patients

Drug Patients with Events Per 1,000 Patients

Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients

Risk Difference: Additional Drug Patients with Events Per 1,000 Patients

Epilepsy

1.0

3.4

3.5

2.4

Psychiatric

5.7

8.5

1.5

2.9

Other

1.0

1.8

1.9

0.9

Total

2.4

4.3

1.8

1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing divalproex sodium extended-release tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

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