Divalproex Sodium: Package Insert and Label Information (Page 8 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

Valproate was administered orally to rats and mice at doses of 80 mg/kg/day and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m 2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate.

Mutagenesis

Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate; this association was not observed in another study conducted in adults.

Impairment of Fertility

In chronic toxicity studies in juvenile and adult rats and dogs, administration of valproate resulted in testicular atrophy and reduced spermatogenesis at oral doses of 400 mg/kg/day or greater in rats (approximately equal to or greater than the maximum recommended human dose (MRHD) on a mg/m 2 basis) and 150 mg/kg/day or greater in dogs (approximately equal to or greater than the MRHD on a mg/m 2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m 2 basis) for 60 days.

14 CLINICAL STUDIES

14.1 Mania

The effectiveness of divalproex sodium extended-release for the treatment of acute mania is based in part on studies establishing the effectiveness of divalproex sodium delayed-release tablets for this indication. Divalproex sodium extended-release’s effectiveness was confirmed in one randomized, double-blind, placebo-controlled, parallel group, 3-week, multicenter study. The study was designed to evaluate the safety and efficacy of divalproex sodium extended-release in the treatment of bipolar I disorder, manic or mixed type, in adults. Adult male and female patients who had a current DSM-IV TR primary diagnosis of bipolar I disorder, manic or mixed type, and who were hospitalized for acute mania, were enrolled into this study. Divalproex sodium extended-release was initiated at a dose of 25 mg/kg/day given once daily, increased by 500 mg/day on Day 3, then adjusted to achieve plasma valproate concentrations in the range of 85 mcg/mL to 125 mcg/mL. Mean daily divalproex sodium extended-release doses for observed cases were 2,362 mg (range: 500 to 4,000), 2,874 mg (range: 1,500 to 4,500), 2,993 mg (range: 1,500 to 4,500), 3,181 mg (range: 1,500 to 5,000) and 3,353 mg (range: 1,500 to 5,500) at Days 1, 5, 10, 15 and 21, respectively. Mean valproate concentrations were 96.5 mcg/mL, 102.1 mcg/mL, 98.5 mcg/mL, 89.5 mcg/mL at Days 5, 10, 15, and 21, respectively. Patients were assessed on the Mania Rating Scale (MRS; score ranges from 0 to 52).

Divalproex sodium extended-release was significantly more effective than placebo in reduction of the MRS total score.

14.2 Epilepsy

The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials.

In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the “therapeutic range” were randomized to receive, in addition to their original antiepilepsy drug (AED), either divalproex sodium delayed-release or placebo. Randomized patients were to be followed for a total of 16 weeks. The following table presents the findings.

Table 9. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks

Add-on Treatment

Number of Patients

Baseline Incidence

Experimental Incidence

Divalproex Sodium Delayed-release

75

16.0

8.9*

Placebo

69

14.5

11.5

* Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level.

Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.

Figure 1:

Figure 1
(click image for full-size original)

The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to divalproex sodium delayed-release monotherapy, the mean total valproate concentrations during monotherapy were 71 mcg/mL and 123 mcg/mL in the low dose and high dose groups, respectively.

The following table presents the findings for all patients randomized who had at least one post-randomization assessment.

Table 10. Monotherapy Study Median Incidence of CPS per 8-Weeks

Treatment

Number of Patients

Baseline Incidence

Randomized Phase Incidence

High dose Valproate

131

13.2

10.7*

Low dose Valproate

134

14.2

13.8

* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.

Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate.

Figure 2:

Figure 2
(click image for full-size original)

Information on pediatric studies is presented in section 8.

14.3 Migraine

The results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial demonstrated the effectiveness of divalproex sodium extended-release in the prophylactic treatment of migraine headache. This trial recruited patients with a history of migraine headaches with or without aura occurring on average twice or more a month for the preceding three months. Patients with cluster or chronic daily headaches were excluded. Women of childbearing potential were allowed in the trial if they were deemed to be practicing an effective method of contraception.

Patients who experienced ≥ 2 migraine headaches in the 4-week baseline period were randomized in a 1:1 ratio to divalproex sodium extended-release or placebo and treated for 12 weeks. Patients initiated treatment on 500 mg once daily for one week, and were then increased to 1,000 mg once daily with an option to permanently decrease the dose back to 500 mg once daily during the second week of treatment if intolerance occurred. Ninety-eight of 114 divalproex sodium extended-release-treated patients (86%) and 100 of 110 placebo-treated patients (91%) treated at least two weeks maintained the 1,000 mg once daily dose for the duration of their treatment periods. Treatment outcome was assessed on the basis of reduction in 4-week migraine headache rate in the treatment period compared to the baseline period.

Patients (50 male, 187 female) ranging in age from 16 to 69 were treated with divalproex sodium extended-release (N=122) or placebo (N=115). Four patients were below the age of 18 and 3 were above the age of 65. Two hundred and two patients (101 in each treatment group) completed the treatment period. The mean reduction in 4-week migraine headache rate was 1.2 from a baseline mean of 4.4 in the divalproex sodium extended-release group, versus 0.6 from a baseline mean of 4.2 in the placebo group. The treatment difference was statistically significant (see Figure 3).

Figure 3: Mean Reduction In 4-Week Migraine Headache Rates

Figure 3
(click image for full-size original)

15 REFERENCES

  1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3):244-252.

16 HOW SUPPLIED/STORAGE AND HANDLING

Divalproex sodium extended-release tablets USP, 250 mg are available as white to off-white, round, coated tablets with imprinting “AN 755” on one side and plain on the other side. Each divalproex sodium extended-release tablet, USP contains divalproex sodium, USP equivalent to 250 mg of valproic acid in the following package sizes:

NDC 50268-259-15 (10 tablets per card, 5 cards per carton).

Divalproex sodium extended-release tablets USP, 500 mg are available as white to off-white, capsule shaped, coated tablets with imprinting “AN 757” on one side and plain on the other side. Each divalproex sodium extended-release tablet, USP contains divalproex sodium, USP equivalent to 500 mg of valproic acid in the following packaging sizes:

NDC 50268-260-13 (10 tablets per card, 3 cards per carton).

Dispensed in Unit Dose Package. For Institutional Use Only.

Recommended Storage:

Store tablets at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Hepatotoxicity

Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)] .

Pancreatitis

Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.5)] .

Birth Defects and Decreased IQ

Inform pregnant women and women of childbearing potential (including girls beginning the onset of puberty) that use of valproate during pregnancy increases the risk of birth defects, decreased IQ, and neurodevelopmental disorders in children who were exposed in utero. Advise women to use effective contraception while taking valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headache [see Contraindications (4)] . Advise patients to read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions ( 5.2, 5.3, 5.4) and Use in Specific Populations (8.1)] .

Pregnancy Registry

Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant.

Encourage women who are taking divalproex sodium extended-release to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 or visit the website, http://www.aedpregnancyregistry.org/ [see Use in Specific Populations (8.1)] .

Suicidal Thinking and Behavior

Counsel patients, their caregivers, and families that AEDs, including divalproex sodium extended-release, may increase the risk of suicidal thoughts and behavior and to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers [see Warnings and Precautions (5.7)] .

Hyperammonemia

Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and to notify the prescriber if any of these symptoms occur [see Warnings and Precautions (5.9, 5.10)] .

CNS Depression

Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.

Multiorgan Hypersensitivity Reactions

Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.12)] .

Medication Residue in the Stool

Instruct patients to notify their healthcare provider if they notice a medication residue in the stool [see Warnings and Precautions (5.18)] .


Manufactured for:
AvKARE
Pulaski, TN 38478
Mfg. Rev. 03-2022-11
AV 09/22 (W) AvPAK

MEDICATION GUIDE

Divalproex ( dye val’ proe ex ) Sodium Extended-Release Tablets, USP

Read this Medication Guide before you start taking divalproex sodium extended-release tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about divalproex sodium extended-release tablets?

Do not stop taking divalproex sodium extended-release tablets without first talking to your healthcare provider.

Stopping divalproex sodium extended-release tablets suddenly can cause serious problems.

Divalproex sodium extended-release tablets can cause serious side effects, including:

  1. Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment.

    Call your healthcare provider right away if you get any of the following symptoms:

    • nausea or vomiting that does not go away
    • loss of appetite
    • pain on the right side of your stomach (abdomen)
    • dark urine
    • swelling of your face
    • yellowing of your skin or the whites of your eyes

    In some cases, liver damage may continue despite stopping the drug.

  2. Divalproex sodium extended-release tablets may harm your unborn baby.
    • If you take divalproex sodium extended-release tablets during pregnancy for any medical condition, your baby is at risk for serious birth defects that affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects that affect the structures of the heart, head, arms, legs, and the opening where the urine comes out (urethra) on the bottom of the penis can also happen. Decreased hearing or hearing loss can also happen.
    • Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
    • Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect.
    • If you take divalproex sodium extended-release tablets during pregnancy for any medical condition, your child is at risk for having lower IQ and may be at risk for developing autism or attention deficit/hyperactivity disorder.
    • There may be other medicines to treat your condition that have a lower chance of causing birth defects, decreased IQ, or other disorders in your child.
    • Women who are pregnant must not take divalproex sodium extended-release tablets to prevent migraine headaches.
    • All women of childbearing age (including girls from the start of puberty) should talk to their healthcare provider about using other possible treatments instead of divalproex sodium extended-release tablets. If the decision is made to use divalproex sodium extended-release tablets, you should use effective birth control (contraception).
    • Tell your healthcare provider right away if you become pregnant while taking divalproex sodium extended-release tablets. You and your healthcare provider should decide if you will continue to take divalproex sodium extended-release tablets while you are pregnant.
    • Pregnancy Registry: If you become pregnant while taking divalproex sodium extended-release tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling toll-free 1-888-233-2334 or by visiting the website, http://www.aedpregnancyregistry.org/. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
  3. Inflammation of your pancreas that can cause death.

    Call your healthcare provider right away if you have any of these symptoms:

    • severe stomach pain that you may also feel in your back
    • nausea or vomiting that does not go away
  4. Like other antiepileptic drugs, divalproex sodium extended-release tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

  • thoughts about suicide or dying
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling agitated or restless
  • panic attacks
  • trouble sleeping (insomnia)
  • new or worse irritability
  • acting aggressive, being angry, or violent
  • acting on dangerous impulses
  • an extreme increase in activity and talking (mania)
  • other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

  • Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop divalproex sodium extended-release tablets without first talking to a healthcare provider.

Stopping divalproex sodium extended-release tablets suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

What are divalproex sodium extended-release tablets?

Divalproex Sodium Extended-release Tablets are prescription medicines used:

  • to treat manic episodes associated with bipolar disorder
  • alone or with other medicines to treat:
  • complex partial seizures in adults and children 10 years of age and older
  • simple and complex absence seizures, with or without other seizure types
  • to prevent migraine headaches

Who should not take divalproex sodium extended-release tablets?

Do not take divalproex sodium extended-release tablets if you:

  • have liver problems
  • have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g., Alpers-Huttenlocher syndrome)
  • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in divalproex sodium extended-release tablets. See the end of this leaflet for a complete list of ingredients in divalproex sodium extended-release tablets.
  • have a genetic problem called urea cycle disorder
  • are taking it to prevent migraine headaches and are either pregnant or may become pregnant because you are not using effective birth control (contraception)

What should I tell my healthcare provider before taking divalproex sodium extended-release tablets?

Before you take divalproex sodium extended-release tablets, tell your healthcare provider if you:

  • have a genetic liver problem caused by a mitochondrial disorder (e.g., Alpers-Huttenlocher syndrome)
  • drink alcohol
  • are pregnant or breastfeeding. Divalproex sodium can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take divalproex sodium extended-release tablets.
  • have or have had depression, mood problems, or suicidal thoughts or behavior
  • have any other medical conditions

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time.

Taking divalproex sodium extended-release tablets with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine.

How should I take divalproex sodium extended-release tablets?

  • Take divalproex sodium extended-release tablets exactly as your healthcare provider tells you. Your healthcare provider will tell you how much divalproex sodium extended-release tablets to take and when to take it.
  • Your healthcare provider may change your dose.
  • Do not change your dose of divalproex sodium extended-release tablets without talking to your healthcare provider.
  • Do not stop taking divalproex sodium extended-release tablets without first talking to your healthcare provider. Stopping divalproex sodium extended-release tablets suddenly can cause serious problems.
  • Swallow divalproex sodium extended-release tablets whole. Do not crush or chew divalproex sodium extended-release tablets. Tell your healthcare provider if you cannot swallow divalproex sodium extended-release tablets whole. You may need a different medicine.
  • If you take too much divalproex sodium extended-release tablets, call your healthcare provider or local Poison Control Center right away.

What should I avoid while taking divalproex sodium extended-release tablets?

  • Divalproex sodium extended-release tablets can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking divalproex sodium extended-release tablets, until you talk with your doctor. Taking divalproex sodium extended-release tablets with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
  • Do not drive a car or operate dangerous machinery until you know how divalproex sodium extended-release tablets affect you. Divalproex sodium extended-release tablets can slow your thinking and motor skills.

What are the possible side effects of divalproex sodium extended-release tablets?

  • See “What is the most important information I should know about divalproex sodium extended-release tablets?”

Divalproex sodium extended-release tablets can cause serious side effects including:

  • Bleeding problems: red or purple spots on your skin, bruising, pain and swelling into your joints due to bleeding or bleeding from your mouth or nose.
  • High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
  • Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling tired, confusion, coma.
  • Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing.
  • Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of divalproex sodium extended-release tablets.

Call your healthcare provider right away, if you have any of the symptoms listed above.

The common side effects of divalproex sodium extended-release tablets include:

  • nausea
  • headache
  • sleepiness
  • vomiting
  • weakness
  • tremor
  • dizziness
  • stomach pain
  • blurry vision
  • double vision
  • diarrhea
  • increased appetite
  • weight gain
  • hair loss
  • loss of appetite
  • problems with walking or coordination

These are not all of the possible side effects of divalproex sodium extended-release tablets. For more information, ask your healthcare provider or pharmacist.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store divalproex sodium extended-release tablets?

  • Store divalproex sodium extended-release tablets at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).

Keep divalproex sodium extended-release tablets and all medicines out of the reach of children.

General information about the safe and effective use of divalproex sodium extended-release tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use divalproex sodium extended-release tablets for a condition for which it was not prescribed. Do not give divalproex sodium extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about divalproex sodium extended-release tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about divalproex sodium extended-release tablets that is written for health professionals.

For more information, go to www.avkare.com or call 1-855-361-3993. What are the ingredients in divalproex sodium extended-release tablets?

Active Ingredient: divalproex sodium, USP.

Inactive Ingredients:

  • ammonium hydroxide, ethyl acrylate and methyl methacrylate co-polymer dispersion, hypromellose, iron oxide, isopropyl alcohol, lactose monohydrate, macrogol, magnesium stearate, microcrystalline cellulose, n-butyl alcohol, polyvinyl alcohol, propylene glycol, shellac, silicon dioxide, talc, and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for: AvKARE Pulaski, TN 38478 Mfg. Rev. 03-2022-11 AV 09/22 (W) AvPAK

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