Divalproex er

Divalproex er DEFAULT

Extended-release divalproex in bipolar and other psychiatric disorders: A comprehensive review

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Sours: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2656326/

Divalproex Sodium, Oral Tablet

Highlights for divalproex sodium

  1. Divalproex sodium oral tablet is available as brand-name drugs and as generic drugs. Brand names: Depakote, Depakote ER.
  2. Divalproex sodium comes in three forms: oral delayed-release tablets, oral extended-release tablets, and oral delayed-release sprinkle capsules.
  3. Divalproex sodium oral tablet is used to treat certain types of seizures, to treat manic episodes of bipolar disorder, and to prevent migraine headaches.

Important warnings

  • This drug has black box warnings. These are the most serious warnings from the Food and Drug Administration (FDA). Black box warnings alert doctors and patients about drug effects that may be dangerous.
  • Liver damage warning: This drug can cause serious liver damage that can be fatal, especially in children younger than 2 years old and anyone with certain hereditary neurometabolic syndromes. Your risk of serious liver damage may be higher during your first 6 months of treatment with this drug. In some cases, liver damage may continue even after you stop taking the drug. Your doctor will monitor you closely for symptoms and will check your liver function before and during treatment with this drug.
  • Birth defects warning: This drug may cause serious harm to your pregnancy. If you take this drug during pregnancy, your baby is at risk for serious birth defects. These include birth defects that affect the brain, spinal cord, heart, head, arms, legs, and the opening where urine comes out. These defects can happen in the first month of pregnancy, before you know you’re pregnant. This drug may also cause decreased IQ and thinking, learning, and emotional disorders in your baby.
  • Pancreatitis warning: This drug can cause pancreatitis (severe inflammation in your pancreas). This condition can be fatal. This can happen shortly after you start treatment or several years after you have used the drug.

Other warnings

  • Suicidal thoughts warning: Divalproex sodium may cause suicidal thoughts or actions in a small number of people, about 1 in 500. Your risk may be higher if you already have a mood disorder, such as depression or anxiety. Call your doctor right away if you have any of these symptoms, especially if they are new or worse, or if they worry you:
    • thoughts about suicide or dying
    • attempts to commit suicide
    • new or worsened depression
    • new or worsened anxiety
    • feeling agitated or restless
    • panic attacks
    • trouble sleeping
    • new or worsened irritability
    • acting aggressive or violent or being angry
    • acting on dangerous impulses
    • an extreme increase in activity and talking (mania)
    • other unusual changes in behavior or mood
  • Allergic reaction: This drug can cause a severe allergic reaction (hypersensitivity). Call your doctor if you have the following symptoms. If your symptoms are severe or life-threatening, call 911 or your local emergency services or go to the nearest emergency room. These symptoms can include:
    • fever
    • trouble swallowing or breathing
    • swelling of your throat, tongue, eyes, or lips
    • hives or skin rash
    • sores in your mouth
    • blistering and peeling of your skin
    • swelling of your lymph nodes
WHEN TO CALL THE DOCTOR

Call your doctor if you take this drug and have any sudden changes in mood, behaviors, thoughts, or feelings that may lead to suicidal thoughts or actions.

What is divalproex sodium?

Divalproex sodium is a prescription drug. It comes in three forms: oral delayed-release tablets, oral extended-release tablets, and oral sprinkle capsules.

Divalproex sodium oral tablet is available as the brand-name drugs Depakote (delayed release) and Depakote ER (extended release). It’s also available in generic forms. Generic drugs usually cost less than the brand-name version. In some cases, they may not be available in every strength or form as the brand-name drug.

Divalproex sodium may be used as part of a combination therapy. That means you may need to take it with other drugs.

Why it’s used

Divalproex sodium oral tablet is used alone or with other medications to:

  • Treat seizures. These include:
    • complex partial seizures that occur by themselves or in association with other types of seizures.
    • simple and complex absence seizures.
    • multiple seizure types that include absence seizures.
  • Treat the manic phase of bipolar disorder. A manic episode is a period of time where your mood is extremely strong. This may include an elevated or an irritated mood.
  • Prevent migraine headaches. There is no evidence that it works to treat a migraine headache when you already have one.

How it works

Divalproex sodium oral tablet belongs to a class of drugs called anti-epileptics. A class of drugs is a group of medications that work in a similar way. These drugs are often used to treat similar conditions.

This drug works by increasing brain concentrations of a certain chemical, GABA, which reduces the excitability of your nervous system. This helps to treat seizures and manic episodes and prevent migraine headaches.

Divalproex sodium side effects

Divalproex sodium oral tablet can cause drowsiness and dizziness. Don’t drive a vehicle, use machinery, or do other activities that require alertness until you know how this drug affects you.

This drug can also cause other side effects.

More common side effects

The more common side effects that can occur with divalproex sodium include:

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

If these effects are mild, they may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk to your doctor or pharmacist.

Serious side effects

Call your doctor right away if you have serious side effects. Call 911 or your local emergency services or go to the nearest emergency room if your symptoms feel life-threatening or if you think you’re having a medical emergency. Serious side effects and their symptoms can include the following:

  • Bleeding problems. Symptoms can include:
    • red or purple spots on your skin
    • bruising more easily than normal
    • bleeding from your mouth or nose
  • High ammonia levels in your blood. Symptoms can include:
    • feeling tired
    • vomiting
    • confusion
  • Low body temperature (hypothermia). Symptoms can include:
    • drop in your body temperature to less than 95°F (35°C)
    • tiredness
    • confusion
    • coma
    • slow, shallow breathing
    • weak pulse
    • slurred speech
  • Allergic (hypersensitivity) reactions, including multi-organ hypersensitivity reactions. Symptoms can include:
    • 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
    • swollen lymph nodes
    • pain and swelling around major organs, such as the liver, kidneys, heart, or muscles
  • Drowsiness or sleepiness, especially in seniors
  • Liver damage. Symptoms can include:
    • weakness
    • facial swelling
    • lack of appetite
    • vomiting
  • Pancreatitis. Symptoms can include:
    • nausea
    • vomiting
    • severe abdominal pain
    • loss of appetite

Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs affect each person differently, we cannot guarantee that this information includes all possible side effects. This information is not a substitute for medical advice. Always discuss possible side effects with a healthcare provider who knows your medical history.

Divalproex sodium may interact with other medications

Divalproex sodium oral tablet can interact with other medications, vitamins, or herbs you may be taking. An interaction is when a substance changes the way a drug works. This can be harmful or prevent the drug from working well.

To help avoid interactions, your doctor should manage all of your medications carefully. Be sure to tell your doctor about all medications, vitamins, or herbs you’re taking. To find out how this drug might interact with something else you’re taking, talk to your doctor or pharmacist.

Examples of drugs that can cause interactions with divalproex sodium are listed below.

Anesthetic drug

Taking propofol with divalproex sodium can increase the levels of propofol in your body. If you need to take these drugs together, your doctor will likely decrease your dosage of propofol.

Antiseizure drug

Taking felbamate with divalproex sodium may increase the level of divalproex sodium in your body and increase your risk of side effects. If you take felbamate with divalproex sodium, your doctor may adjust your dosage of divalproex sodium.

Antiseizure and migraine prevention drug

Taking topiramate with divalproex sodium may increase your risk of high ammonia levels in your blood, or low body temperature (hypothermia). If you’re taking these drugs together, your doctor should monitor your blood ammonia levels and temperature.

Aspirin

Taking aspirin with divalproex sodium may increase the level of divalproex sodium in your body and increase your risk of side effects. If you take aspirin with divalproex sodium, your doctor may adjust your dosage of divalproex sodium.

Blood thinner drug

Taking warfarin with divalproex sodium may increase the levels of warfarin in your body. Your doctor may monitor your INR more often if you need to take divalproex sodium together with warfarin.

Carbapenem antibiotics

Taking these drugs with divalproex sodium may decrease the level of divalproex sodium in your body. This means that it may not work as well to treat your condition. If you have to take a carbapenem antibiotic while taking divalproex sodium, your doctor will monitor your blood levels closely. Examples of these antibiotics include:

  • ertapenem
  • imipenem
  • meropenem

HIV drug

Taking zidovudine with divalproex sodium may increase the levels of zidovudine in your body. Your doctor may monitor you more closely for side effects.

Hormonal birth control that contains estrogen

Taking some birth control medications with divalproex sodium can lower the amount of divalproex sodium in your body, making it less effective. If you need to use hormonal contraception, such as the pill, your doctor will likely monitor the amount of divalproex sodium in your body.

Mood disorder and seizure drugs

Taking certain mood disorder and seizure drugs with divalproex sodium may increase the levels of these drugs in your body. Your doctor may adjust your dosage of these medications or monitor you more closely for side effects. Examples of these drugs include:

  • amitriptyline/nortriptyline
  • diazepam
  • ethosuximide
  • lamotrigine
  • phenobarbital
  • phenytoin
  • primidone
  • rufinamide

Taking other mood disorder and seizure drugs with divalproex sodium may decrease the level of divalproex sodium in your body. This means that it may not work as well to treat your condition. Your doctor may adjust your dosage of divalproex sodium. Examples of these drugs include:

  • carbamazepine
  • phenobarbital
  • phenytoin
  • primidone

Tuberculosis drug

Taking rifampin with divalproex sodium may decrease the level of divalproex sodium in your body. This means that it may not work as well to treat your condition. If you take these drugs together, your doctor may adjust your dosage of divalproex sodium.

Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs interact differently in each person, we cannot guarantee that this information includes all possible interactions. This information is not a substitute for medical advice. Always speak with your healthcare provider about possible interactions with all prescription drugs, vitamins, herbs and supplements, and over-the-counter drugs that you are taking.

Divalproex sodium warnings

This drug comes with several warnings.

Allergy warning

This drug can cause a severe allergic reaction (hypersensitivity). Symptoms may include:

  • fever
  • trouble swallowing or breathing
  • swelling of your throat, tongue, eyes, or lips
  • hives or skin rash
  • sores in your mouth
  • blistering and peeling of your skin
  • swelling of your lymph nodes

If you develop these symptoms, call 911 or your local emergency services or go to the nearest emergency room.

Don’t take this drug again if you’ve ever had an allergic reaction to it. Taking it again could be fatal (cause death).

Alcohol interaction warning

Divalproex sodium can cause drowsiness and dizziness. Don’t drink alcohol while taking this drug because it can increase your risks of slowed reflexes, poor judgment, and sleepiness.

Warnings for people with certain health conditions

For people with liver disease: If you have a history of liver disease, you may have a higher risk of liver failure within the first six months of treatment with this drug. Your doctor will monitor you for signs of liver damage.

For people with mitochondrial disease: If you have Alpers-Huttenlocher syndrome or have a family history of this metabolic disorder, you may have a higher risk of liver failure when taking divalproex sodium.

For people with urea cycle disorders: If you have a urea cycle disorder, you shouldn’t take this drug. It may raise your risk of hyperammonemia (high ammonia levels in your blood). This condition can be fatal.

Warnings for other groups

For pregnant women: This drug may cause serious harm to your pregnancy. If you take this drug during pregnancy, your baby is at risk for serious birth defects. These include birth defects that affect the brain, spinal cord, heart, head, arms, legs, and the opening where urine comes out. These defects can happen in the first month of pregnancy, before you know you’re pregnant. This drug may also cause decreased IQ and thinking, learning, and emotional disorders in your baby.

According to published case reports, fatal liver failure has also been observed in the children of women who used this drug while pregnant.

If you become pregnant while taking this drug, talk to your doctor about registering with the North American Antiepileptic Drug Pregnancy Registry. The purpose of this registry is to collect information about the safety of drugs used to treat seizures during pregnancy.

If you become pregnant while taking this drug, call your doctor right away. Do not stop taking the medication unless directed to by your doctor.

  • For treatment of seizures and manic episodes of bipolar disorder in pregnant women: Studies show a risk of adverse effects to the fetus when the mother takes divalproex sodium. The benefits of taking the drug during pregnancy may outweigh the potential risks in certain cases.

Tell your doctor if you’re pregnant. Divalproex sodium should only be used during pregnancy by women with seizures or manic episodes whose symptoms cannot be controlled by other medications.

  • For prevention of migraine headaches in pregnant women: Divalproex sodium should never be used during pregnancy for women with migraine headaches.

For women who are breastfeeding: This drug passes through breast milk and may cause side effects in a breastfeeding child. Talk with your doctor about the risks and benefits of breastfeeding while taking divalproex.

For nonpregnant women of childbearing age: If you’re planning to become pregnant and you have epilepsy or bipolar disorder, you should not use this drug unless your symptoms cannot be controlled by other medications.

If you have migraine headaches, you should not use this drug unless your symptoms cannot be controlled by other medications and you’re also using effective contraception.

Talk with your doctor to determine what’s best for you.

For seniors: Your body processes divalproex sodium more slowly. You may also experience more of a sedative effect from this medication. Extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if this happens.

Your doctor will monitor how much you eat and drink and check you for signs of dehydration, drowsiness, dizziness, and other side effects. They may stop giving you this drug if you aren’t eating or drinking enough or if you have extreme sleepiness.

For children: Children younger than 2 years old have an increased risk of liver damage while taking this drug, especially if they also take other drugs to treat seizures.

How to take divalproex sodium

All possible dosages and forms may not be included here. Your dose, form, and how often you take it will depend on:

  • your age
  • the condition being treated
  • how severe your condition is
  • other medical conditions you have
  • how your body reacts to the drug

Drug forms and strengths

Generic: Divalproex sodium

  • Form: delayed-release oral tablet
  • Strengths: 125 mg, 250 mg, 500 mg
  • Form: extended-release oral tablet
  • Strengths: 250 mg, 500 mg

Brand: Depakote

  • Form: delayed-release oral tablet
  • Strengths: 125 mg, 250 mg, 500 mg

Brand: Depakote ER

  • Form: extended-release oral tablet
  • Strengths: 250 mg, 500 mg

Dosage for seizures

Adult dosage (ages 18 to 64 years)

  • Complex partial seizures:
    • Typical initial dosage: 10–15 mg/kg taken by mouth once per day if you’re taking extended-release tablets. For delayed-release tablets, the dosage is two to three times per day.
    • Typical dosage increases: Your doctor will likely increase your dosage at 1-week intervals by 5–10 mg/kg per day.
    • Maximum dosage: 60 mg/kg per day.
  • Absence seizures:
    • Typical initial dosage: 15 mg/kg taken by mouth once per day if you’re taking extended-release tablets. For delayed-release tablets, the dosage is two to three times per day.
    • Typical dosage increases: Your doctor will likely increase your dosage at 1-week intervals by 5–10 mg/kg per day.
    • Maximum dosage: 60 mg/kg per day.

Child dosage (ages 10 to 17 years)

  • Complex partial seizures:
    • Typical initial dosage: 10–15 mg/kg taken by mouth once per day if your child is taking extended-release tablets. For delayed-release tablets, the dosage is two to three times per day.
    • Typical dosage increases: Your doctor will likely increase your child’s dosage at 1-week intervals by 5–10 mg/kg per day.
    • Maximum dosage: 60 mg/kg per day.
  • Absence seizures:
    • Typical initial dosage: 15 mg/kg taken by mouth once per day if your child is taking extended-release tablets. For delayed-release tablets, the dosage is two to three times per day.
    • Typical dosage increases: Your doctor will likely increase your child’s dosage at 1-week intervals by 5–10 mg/kg per day.
    • Maximum dosage: 60 mg/kg per day.

Child dosage (ages 0 to 9 years)

This medication hasn’t been studied in children younger than 10 years old. It shouldn’t be used in children in this age range.

Senior dosage (ages 65 years and older)

Your body may process this drug more slowly and you may have more of a sedative effect. Your doctor may start you on a lowered dosage and increase it slowly so that too much of this drug doesn’t build up in your body. Too much of the drug in your body can cause dangerous effects.

In general, your doctor will keep you at the lowest effective dosage that you’re able to tolerate without side effects.

Dosage for bipolar disorder mania

Adult dosage (ages 18 to 64 years)

  • Typical initial dosage: For delayed-release tablets, it’s 375 mg taken by mouth twice per day, or 250 mg three times per day. For extended-release tablets, it’s 25 mg/kg taken by mouth once per day.
  • Typical dosage increases: Your doctor will likely increase your dosage as quickly as possible until the drug is effective or until a desired blood level is reached.
  • Maximum dosage: 60 mg/kg per day.

Child dosage (ages 0 to 17 years)

This medication did not show effectiveness in children for mania. It shouldn’t be used in people with mania who are younger than 18 years.

Senior dosage (ages 65 years and older)

Your body may process this drug more slowly and you may have more of a sedative effect. Your doctor may start you on a lowered dosage and increase it slowly so that too much of this drug doesn’t build up in your body. Too much of the drug in your body can cause dangerous effects.

In general, your doctor will keep you at the lowest effective dosage that you’re able to tolerate without side effects.

Dosage warning

There is no evidence that divalproex is effective for long-term use in mania (longer than three weeks). If your doctor would like you to take this drug for a longer period of time, they will check if you still need the drug regularly.

Dosage for migraine prevention

Adult dosage (ages 18 to 64 years)

  • Typical initial dosage: For delayed-release tablets, it’s 250 mg taken twice per day. For extended-release tablets, it’s 500 mg taken once per day.
  • Typical dosage increases: Your doctor will likely increase your dosage as needed.
  • Maximum dosage: 1,000 mg per day.

Child dosage (ages 0 to 17 years)

This medication did not show effectiveness in children for migraine prevention. It shouldn’t be used in people with migraine headaches who are younger than 18 years.

Senior dosage (ages 65 years and older)

Your body may process this drug more slowly and you may have more of a sedative effect. Your doctor may start you on a lowered dosage and increase it slowly so that too much of this drug doesn’t build up in your body. Too much of the drug in your body can cause dangerous effects.

In general, your doctor will keep you at the lowest effective dosage that you’re able to tolerate without side effects.

Special dosage considerations

For people with liver disease: If you have liver disease, you may not be able to process this drug as well as you should. You should avoid taking divalproex sodium if you have severe liver problems.

Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs affect each person differently, we cannot guarantee that this list includes all possible dosages. This information is not a substitute for medical advice. Always speak with your doctor or pharmacist about dosages that are right for you.

Take as directed

Divalproex sodium oral tablet is used for long-term drug treatment. For manic episodes of bipolar disorder, your doctor will decide whether this is a short-term or long-term drug treatment.

This drug comes with serious risks if you don’t take it as prescribed.

If you don’t take it at all or miss doses: If you don’t take this drug regularly, you miss doses, or you stop taking it suddenly, there can be serious risks. The condition that you’re trying to treat may not get better. You may also experience more side effects from this drug if you take it on and off.

If you stop taking it suddenly: If you’re taking this drug to treat seizures, stopping it suddenly can cause a seizure that won’t stop (status epilepticus).

If you take too much: Taking too much of this drug can cause dangerous effects, such as:

  • extreme fatigue
  • irregular heart rate and rhythm
  • high levels of salt in your blood
  • deep coma
  • death

If you think you’ve taken too much of this drug, call your doctor or local poison control center. If your symptoms are severe, call 911 or your local emergency services or go to the nearest emergency room right away.

What to do if you miss a dose: If you forget to take your dose of this drug, take it as soon as you remember. If it’s just a few hours until the time for your next dose, wait and take only one dose at that time.

Never try to catch up by taking two doses at once. This could cause dangerous side effects.

How to tell if the drug is working:For treatment of seizures: You should have fewer seizures.

For treatment of manic episodes of bipolar disorder: You should see a decrease in symptoms caused by the manic phase of bipolar disorder. Your mood should be well-controlled.

For prevention of migraine headaches: You should have fewer migraine headaches.

Important considerations for taking divalproex sodium

Keep these considerations in mind if your doctor prescribes divalproex sodium for you.

General

  • If this drug upsets your stomach, take it with food.
  • Don’t crush or chew the tablets.

Storage

  • Store delayed release tablets below 86°F (30°C).
  • Store extended-release tablets at a temperature between 59°F and 86°F (15°C and 30°C).
  • Don’t store this medication in moist or damp areas, such as bathrooms.

Refills

A prescription for this medication is refillable. You should not need a new prescription for this medication to be refilled. Your doctor will write the number of refills authorized on your prescription.

Travel

When traveling with your medication:

  • Always carry your medication with you. When flying, never put it into a checked bag. Keep it in your carry-on bag.
  • Don’t worry about airport X-ray machines. They can’t harm your medication.
  • You may need to show airport staff the pharmacy label for your medication. Always carry the original prescription-labeled container with you.
  • Don’t put this medication in your car’s glove compartment or leave it in the car. Be sure to avoid doing this when the weather is very hot or very cold.

Clinical monitoring

Before starting and during treatment with this drug, your doctor may check your:

  • drug plasma levels (your doctor may test the levels of the drug in your body if you’re having side effects or to decide if you need a dosage adjustment)
  • liver function
  • body temperature
  • ammonia level

Your doctor may also monitor you for signs of pancreatitis or suicidal thoughts or actions.

Are there any alternatives?

There are other drugs available to treat your condition. Some may be better suited for you than others. Talk to your doctor about other drug options that may work for you.

Disclaimer: Healthline has made every effort to make certain that all information is factually correct, comprehensive, and up-to-date. However, this article should not be used as a substitute for the knowledge and expertise of a licensed healthcare professional. You should always consult your doctor or other healthcare professional before taking any medication. The drug information contained herein is subject to change and is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. The absence of warnings or other information for a given drug does not indicate that the drug or drug combination is safe, effective, or appropriate for all patients or all specific uses.

Sours: https://www.healthline.com/health/drugs/divalproex-sodium-oral-tablet
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Divalproex Sodium-ER

Depakote (DEH-pah-kote) is a brand name used in the United States for a type of medicine called divalproex (di-VAL-pro-eks) sodium.

Depakote ER is a different form of the same medicine. The "ER" stands for "extended-release," which means that the time it takes the pills to dissolve and release the medicine is longer. Most people need to take regular Depakote two, three, or even four times a day because the pills release all their medicine within a few hours. It's hard to remember to take pills that often. Depakote ER is designed so that the pills can be taken only once a day. So it's a lot easier to remember and more convenient.

Another advantage of Depakote ER is that the amount of medicine in the blood stays more even than when regular Depakote is used. Having an even level of medicine in the blood may reduce side effects from very high levels and seizures from very low levels.

When you read about Depakote or Depakote ER, you will also see the word valproate (val-PRO-ate). This is the name of the medicine in Depakote ER after it has changed into the form that actually works in the body. A few other seizure medicines also are changed into valproate, so they work in the same way as Depakote and Depakote ER. The other valproate medicines in the United States are Depakene, Depacon (given by injection), and valproic acid.

Depakote ER became available in the United States in 2000. It is not available in Canada, the UK, or Australia. There is no generic (non–brand name) form of Depakote ER.

Depakote ER 250mg

250-mg
White ovaloid tablets with Abbott logo and "HF".

Depakote ER 500mg

500-mg
Gray ovaloid tablets with Abbott logo and "HC".

Used to treat

Focal Aware or Simple Partial Seizure

Forms

In the United States, Depakote ER is sold by Abbott Laboratories. The name or appearance may be different in various countries but usually the dose (measured in milligrams, abbreviated "mg") will be the same. These descriptions apply to the U.S. versions:

Dosing

Please see package insert.

Depakote ER tablets should be swallowed whole, not chewed or crushed. Most doctors recommend taking them with food to avoid an upset stomach, but they also can be taken without food. Because food affects the way medicine is used by the body, try to be consistent day in and day out. A person who usually takes Depakote with meals should do that all the time.

As the doctor increases the amount of Depakote ER, you may be given a different kind of pills than the ones you've been using. You may start out using 250-mg tablets and then switch to 500-mg tablets. If this happens, be careful to use the correct number. Don't automatically continue to use the same number of pills as before.

Store Depakote ER at room temperature and keep the pills away from light and dampness. Don't keep them in the bathroom if it's damp there. And of course keep them where children can't get at them.

In general, tell patients that if they forget a dose, they should take it as soon as they remember. If it is almost time for the next dose, they should delay that dose instead of taking two doses close together. Since Depakote ER is generally taken once every 24 hours, they should allow an interval of about 12 hours before taking the second dose, and then resume a 24-hour schedule the next day.

Patients who often forget doses may benefit from using a special pillbox or watch with an alarm.

Brain cells need to work (fire) at a certain rate to function normally. During a seizure, brain cells are forced to work much more rapidly than normal. Depakote ER helps prevent brain cells from working as fast as a seizure requires them to. In this way, seizures can be stopped when they are just beginning.

We don't completely understand how Depakote ER works. Doctors think that it may work in several ways at once. That could be why it works for so many different kinds of seizures.

After medicine is swallowed, it must be absorbed into the blood so it can move throughout the body. The process of absorbing, digesting, and excreting a medicine or food is called metabolism. The way the body metabolizes a particular medicine affects how often it must be taken. It also determines whether it will interact with other medicines or be affected by conditions such as liver disease.

Depakote ER tablets use special coatings to release the medicine over a longer time than regular Depakote. After the outside film coating dissolves in the stomach, the outer layer of the tablet's contents begins to absorb fluid. It forms a layer of gel that releases the medicine slowly.

The highest level of medicine in the blood is reached in 7 to 14 hours after Depakote ER is taken. The highest levels are not as high as with regular Depakote, and the lowest levels are not as low. This difference may reduce side effects at the highest levels and improve seizure control when the levels are lowest.

If the same amount is taken, the body absorbs only about 89% as much medication from Depakote ER as from regular Depakote. This means that most people who change from regular Depakote to Depakote ER need to take a slightly higher amount each day to have the same effect.

Like many other medicines, Depakote ER is broken down (digested) in the liver. People with liver disease should not take it. Anyone who also takes other medicines that are digested in the liver need to be careful. How well each medicine works and how quickly it leaves the body may be changed.

This is why the doctor needs to know about everything that a person takes—not just prescription medicines but even things like vitamins, herbs, and aspirin! These things can affect how much Depakote ER the doctor prescribes.

Doctors have studied large numbers of people to find out how well Depakote ER and the other medicines that contain valproate control seizures. (There is hardly any difference in the way the different valproate medicines work.) They have reported that these medicines are very good at completely controlling absence seizures in many people who take them. In another group, over 80% of people with new tonic-clonic seizures and related types didn't have any seizures during the period when they were given this kind of medicine.

These promising results are not always matched in everyday life. Sometimes people don't take all their medicine on time. Not everyone's seizures can be controlled at a dose that can be taken without side effects. Because of individual differences, there is no "best" amount for everyone. Adjustments are often needed to reduce seizures or side effects.

In studies of seizure medicines, some people do better with medicines like Depakote ER and others do better with something else. It's difficult to forecast the results for any given person. Differences in side effects may be important in deciding which medicine is best for each person.

If seizures continue, the doctor probably will change the amount of Depakote ER prescribed. If that doesn't work, the next step may be either to prescribe a different seizure medicine by itself or to prescribe a combination of Depakote ER and another seizure medicine. Many are available. No single combination is best for everyone. Depakote ER is often used as an "add-on" medicine for people who continue to have certain kinds of seizures while taking other seizure medicines.

Most people who take Depakote ER don't have too much trouble with side effects. That's one of the reasons it's used so much. The most common complaints (usually not too severe) are:

  • tiredness (sometimes with slower thinking)
  • dizziness
  • upset stomach
  • vomiting
  • tremor (shaking of the hands or other parts of the body)
  • hair loss
  • weight gain
  • changes in behavior (depression in adults, irritability in children)

If you notice any of these problems, call the doctor. Sometimes the doctor can help by changing the amount of Depakote ER prescribed. No one should stop taking Depakote ER or change the amount they take without their doctor's guidance.

Stomach upset from Depakote ER may be less of a problem if the pills are taken on a full stomach. Stomach upset is more likely when another seizure medicine with similar side effects (for example, Tegretol) is also being used.

Tremor (shaking of the hands or other body parts) tends to be worse when the level of Depakote ER in the blood is highest, 7 to 14 hours after the pills are taken. Anxiety or caffeine also may make it worse. Tremor may be less of a problem with Depakote ER than with regular Depakote, since the highest level of medicine in the blood usually is not quite as high.

Weight gain affects 30% to 50% of people who take Depakote ER. It is more common in adult women but can affect anyone. The average gain for adults is 15 pounds. Exercise and a reduced-calorie diet can be very helpful. It's uncertain whether weight gain is greater when higher doses of Depakote ER are taken.

Hair loss occurs in 5% to 10% of people who take Depakote ER. The hair almost always grows back after the Depakote ER is stopped, but it often has a different texture. (For example, it may grow in curly instead of straight.)

People who have just started taking Depakote ER (or who have just started taking a larger amount) should be careful during activities that might be dangerous, until they know whether they are having any side effects.

Allergic reactions

Allergic reactions such as rashes are less common with Depakote ER than with most other seizure medicines. Even so, you should report any rash to the doctor or nurse right away, especially if treatment has just begun. It's rare for the rash to be serious, but don't ignore it. It's often necessary to switch to a different seizure medicine.

A very small number of people who take Depakote ER develop life-threatening disorders. See Serious side effects.

Long-term side effects

Some people who have taken Depakote ER or other valproate medicines (such as Depakote) for many years have experienced bone loss and a few other disorders. Taking both calcium and vitamin D may help to prevent this kind of problem. Many doctors recommend a bone density test to identify which people need treatment for bone loss.

The risk of liver failure is much lower in children between 2 and 10. The risk is very low in older children and adults, perhaps 1 in 50,000. There is no evidence that long-term use of Depakote ER will cause gradual damage to the liver.

Another rare reaction to Depakote ER is a disorder of the pancreas. Occasionally it is so severe that bleeding and death can occur. Both children and adults can be affected, even after several years of taking Depakote ER or another valproate medicine. Report pain in the abdomen, upset stomach, vomiting, or loss of appetite to the doctor right away.

Problems with blood clotting are more likely in people who take large amounts of Depakote ER. Sometimes the blood returns to normal without stopping the medicine. The doctor probably will order some blood tests before prescribing Depakote ER, and will repeat them some time later and before any elective surgery.

A complete list of all reactions to Depakote ER can be found in the package insert, but it is important to remember that only a tiny number of people have any of these serious problems.

On July 10, 2008, an advisory panel was convened by the Food and Drug Administration (FDA) to review data that the FDA had previously collected from drug studies showing an association between many of the antiepileptic drugs (AEDs) and suicidal ideation and behavior, which together are called suicidality. According to the FDA’s Alert, among the patients with epilepsy in these drug studies, 1 out of 1000 people taking the placebo (inactive substance) showed suicidality compared to approximately 3.5 out of 1000 people who took an AED. The FDA advisory panel voted to accept the FDA's data at its meeting on July 10.

  • Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions;
    • Do not make any changes to the medication regimen without first talking with the responsible healthcare professional;
    • Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
  • Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:
    • Talking or thinking about wanting to hurt yourself or end your life
    • Withdrawing from friends and family
    • Becoming depressed or having your depression get worse
    • Becoming preoccupied with death and dying
    • Giving away prized possessions

We again urge patients and families to contact their doctor before stopping an epilepsy medication because this may possibly lead to seizures and worsening of mood.

At this time there is no evidence to support this medication causes bone health problems.   However, it might.  It is essential that if you taking this medication, that one take supplemental calcium of 1000 milligrams per day.  Talk to your doctor about bone health.  He/She may decide to check Vitamin D levels and other tests to check for the impact of this drug on your bones.

Often doctors find that medicines are useful for more than one purpose. Besides controlling seizures, Depakote ER has been approved by the Food and Drug Administration (FDA) for the prevention of migraine headaches. (In fact, it was used for this purpose before it was approved for epilepsy.) It does not appear to relieve headaches while they're occurring. Depakote ER is also FDA-approved for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features.

People with liver disease should not take Depakote ER. Neither should anyone who has shown an allergy to Depakote or another valproate medicine in the past. Make sure the doctor knows about any liver problems, so a different medicine can be prescribed instead.

Sometimes one kind of medicine changes the way another kind of medicine works in the body. This is true not only for prescription medicines, but also for medicines you just pick up off the shelf at the store. For instance, aspirin (ASA) may increase the side effects from taking Depakote ER.

If someone who is taking Depakote ER—especially a child—also starts to take the seizure medicine called Lamictal, the chances of a very dangerous rash will be increased. Adding the Lamictal slowly reduces this danger.

Taking both Depakote ER and another seizure medicine, Klonopin, sometimes causes absence seizures to be much longer.

Any time a doctor suggests a new prescription, be sure to talk about what other medicines you are already using. If two kinds of medicine affect each other, the doctor may want to prescribe something else or change the amount to be taken.

How does Depakote ER affect other medicines?

Depakote ER affects the way the body handles many other seizure medicines. Some of these are:

  • Felbatol (felbamate)
  • Lamictal (lamotrigine)
  • Mysoline (primidone)
  • phenobarbital

Depakote ER can be effective against many types of seizures common in children:

  • absence seizures (this is one of the most effective medicines for these brief staring spells)
  • myoclonic seizures
  • tonic-clonic seizures, such as those in Lennox-Gastaut syndrome.
  • seizures triggered by flashing lights

Valproate medicines are also effective for infantile spasms (West syndrome), but the tablet form of Depakote ER makes it unsuitable for that purpose.

Children under 2 or 3 years of age who take valproate in any form have a much higher risk of liver failure than adults or older children. (The risk of liver failure is very low for children over 10, perhaps 1 in 50,000.) The tablet form of Depakote ER means that it's unlikely to be prescribed for very young children anyway, so this is seldom a concern. Liver damage usually occurs within the first 6 months of treatment. The first signs of it are vomiting, loss of appetite, sluggishness, and perhaps loss of seizure control, yellow skin and eyes, or swelling.

Higher-than-usual levels of the hormone testosterone have been found in many girls who take Depakote ER when they're older than about age 10. No symptoms are apparent, but the doctor may want to watch for later problems, perhaps related to weight gain.

A few children who take Depakote ER seem to become more irritable but this is seldom a serious problem.

To reduce side effects, the doctor probably will prescribe a low dose of Depakote ER to start and increase it slowly. Children usually start with a dose of 5 to 10 milligrams (mg) for each kilogram (kg, about 2.2 pounds) of their body weight per day. Since the smallest Depakote ER tablet is 250 milligrams (and it cannot be divided), smaller children may need to begin by using regular Depakote or another valproate medicine. They can switch to Depakote ER when they reach a higher dosage.

Most children do best at about 15 to 60 mg/kg per day. Children taking a combination of Depakote and another seizure medicine usually need the higher doses because of interactions between the medicines.

In the United States, the Food and Drug Administration (FDA) assigns each medication to a Pregnancy Category according to whether it has been proven to be harmful in pregnancy. Depakote ER is listed in Pregnancy Category D. This means that there is a risk to the baby, but the benefits may outweigh the risk for some women.

In fact, a large majority of women who use Depakote ER during pregnancy have normal, healthy babies. Certain types of defects are increased (especially if Depakote ER is taken during the first 3 months of pregnancy) but they are still relatively uncommon. The risk of defects is higher for women who take more than one seizure medicine. Women with a family history of birth defects also have a higher risk.

The babies of women taking valproic acid have a greater than usual number of minor craniofacial abnormalities, organ malformations, limb deficiencies, or developmental delay. The risk of defects is higher for women who take more than one AED and for women with a family history of birth defects.  Moreover the NEAD study showed that children born to women who took Valproic acid, had lower IQ scores than children born to women with epilepsy who tool other seizure medications.

Women with epilepsy who are pregnant or thinking about becoming pregnant should talk to their doctor about their seizure medicines. Taking more than one seizure medicine may increase the risk of birth defects, so doctors sometimes gradually reduce the number or amount of seizure medicines taken by women planning for pregnancy. This is not done routinely, however, because it increases the risk of seizures. Some kinds of seizures can injure the baby, so do not stop using seizure medicines or reduce the amount without the doctor’s OK.

All women who are capable of becoming pregnant should take at least 400 mcg (0.4 mg) of the vitamin called folic acid every day because it helps to prevent one type of birth defect. (The most well-known of these is spina bifida, in which the spinal cord is not completely enclosed.) These defects are more common in the babies of women who take Depakote ER during the first 4 to 6 weeks of pregnancy. If the doctor thinks a woman is at especially high risk, a much larger dose of folic acid—4000 mcg (4 mg) per day—may be recommended. There's no proof that the folic acid will prevent the defects, however, so the doctor may recommend a check-up later in pregnancy.

About 20% to 35% of women have seizures more often during pregnancy because of changes in hormones or changes in how their seizure medicine is handled by the body. It is helpful for the doctor to check the levels of medicine in the blood regularly during pregnancy so that the dosage can be adjusted if necessary.

Breast-feeding by mothers taking Depakote ER should be safe for healthy, full-term newborns. The amount of medicine the baby gets through the milk is much less than the amount that doctors safely give to babies who take Depakote for seizures.

Doctors have prescribed Depakote ER and other valproate medicines to people over 65 for many years with good results. These seniors do have a few special problems, however.

Most seniors take more medicines than younger people, so there’s a greater risk that the medicines may affect each other. Usually seniors can continue to take all the medicines they need, including Depakote ER, without trouble if the doctor changes the amount of some of them to make up for the way they affect each other.

Seniors also tend to be more sensitive than younger adults to medicines and their side effects. For instance, many seniors have a problem with sleepiness, depression, weight gain, or shaking of the hands even before they start taking Depakote ER. These are common side effects of this medicine, so these problems may become worse and cause real trouble. Because the level of medicine in the blood is more steady with Depakote ER than with other valproate medicines, however, side effects like tremor may be less of a problem when Depakote ER is used.

Seniors also face more danger from some side effects because they are more likely to be seriously hurt if they fall or have another kind of accident.

To reduce side effects, the doctor probably will prescribe a very low dose of medicine to start and then be cautious about any increases. The smallest tablet of Depakote ER, 250 mg, may be too large for some seniors to start with. They may begin by taking regular Depakote or another valproate medicine instead. They can change to Depakote ER later, when they're ready for a higher dose.

It’s especially important for seniors to keep the doctor informed about any changes that they notice.

The best amount is the amount that completely controls seizures without causing troublesome side effects. It depends on many factors, which are different for every individual. Follow the doctor's directions. Call if you have any questions.

No one should stop taking Depakote ER or change the amount they take without talking to the doctor first. Stopping any seizure medicine all at once can cause a problem that may be life-threatening.

Don’t use more than the doctor prescribes. If one or two extra tablets are taken by accident, call the doctor for advice. For a larger overdose, call a poison control center or emergency room right away unless you have other specific directions from your doctor.

To avoid unwanted side effects, the doctor will prescribe a low dose to start and increase it gradually until the seizures are controlled, unless side effects get too bad first. People who change to Depakote ER after taking regular Depakote or another valproate medicine will need to take a little more Depakote ER to achieve the same effect.

In the United States, companies that manufacture medicines are required to publish certain kinds of information about each product. This document is commonly known as a “package insert” because it is usually included with each package of the medicine.

You can also read these documents (also called "prescribing information") online. The U.S. package insert for Depakote capsules is found at:

http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=7042   

The U.S. package insert for Depakote-ER tablets is found at:

Some of the information may differ in other countries.

To learn how to read and understand a package insert, see "How to read a package insert."

Sours: https://www.epilepsy.com/medications/divalproex-sodium-er
Psychopharmacology - Divalproex Sodium

divalproex ER 250 mg tablet,extended release 24 hr

1019Medication name

Generic name:
Divalproex sodium extended-release - oral

Pronunciation
(dye-VAL-pro-ex)

Brand name(s)
Depakote ER

Warning

Rarely, this medication has caused serious (sometimes fatal) liver problems, usually within the first 6 months of starting treatment. Laboratory tests should be performed before you start treatment and periodically during treatment, especially within the first 6 months, to monitor this side effect.

The risk of serious liver problems is increased in children younger than 2 years, especially if they have an inherited metabolic disorder, severe seizure disorder with mental retardation, organic brain disease, or if they take more than one seizure medication. Talk with the doctor about the risks and benefits of using this medication in children younger than 2 years.

Due to an increased risk for liver problems, people with certain inherited metabolic disorders (such as Alpers-Huttenlocher syndrome) should not use this medication. Children younger than 2 years who might have these disorders should not use this medication. Children older than 2 years who might have these disorders should be closely monitored during treatment with divalproex sodium. Talk to your doctor for details.

This medication has rarely caused severe (sometimes fatal) disease of the pancreas (pancreatitis). This may occur at any time during treatment and can quickly worsen.

Tell your doctor right away if you develop symptoms of liver problems or pancreatitis such as unusual tiredness, weakness, swelling of the face, stomach/abdominal pain, loss of appetite, dark urine, yellowing eyes/skin, or persistent nausea/vomiting.

Taking this medication during pregnancy can cause birth defects, may lower your child's IQ, and may increase the risk of your child having certain brain/mental disorders (such as autism, attention deficit/hyperactivity disorder). Women of childbearing age should discuss the risks and benefits of this medication, other treatment options, and use of reliable forms of birth control with their doctor. If you are planning pregnancy, become pregnant, or think you may be pregnant, immediately talk to your doctor. If you are taking divalproex sodium only to prevent migraine headaches, this medication must not be used during pregnancy. If you are taking divalproex sodium to treat seizures or mental/mood problems (such as bipolar disorder), do not stop taking this medication unless directed by your doctor. Untreated seizures and mental/mood problems (such as bipolar disorder) are serious conditions that can harm both a pregnant woman and her unborn baby.

Uses

This medication is used to treat seizure disorders, mental/mood conditions (such as manic phase of bipolar disorder), and to prevent migraine headaches. It works by restoring the balance of certain natural substances (neurotransmitters) in the brain.

How to use

Read the Medication Guide and, if available, the Patient Information Leaflet provided by your pharmacist before you start taking divalproex sodium and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth once daily or as directed by your doctor. You may take it with food if stomach upset occurs. Do not crush or chew extended-release tablets. Doing so can release all of the drug at once, increasing the risk of side effects. Also, do not split the tablets unless they have a score line and your doctor or pharmacist tells you to do so. Swallow the whole or split tablet without crushing or chewing.

The dosage is based on your age, weight, medical condition, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products). Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time each day to keep the amount of medication in your blood constant.

If this medication is used for seizures, do not stop taking it without consulting your doctor. Your condition may become worse if the drug is suddenly stopped. Your dose may need to be gradually decreased.

Divalproex sodium does not relieve acute migraine headaches. Take other medications as directed by your doctor for acute attacks.

Inform your doctor if your condition does not improve.

Side effects

See also Warning section.

Diarrhea, dizziness, drowsiness, hair loss, blurred/double vision, change in menstrual periods, ringing in the ears, shakiness (tremor), unsteadiness, weight changes may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A small number of people who take anticonvulsants for any condition (such as seizure, bipolar disorder, pain) may experience depression, suicidal thoughts/attempts, or other mental/mood problems. Tell your doctor right away if you or your family/caregiver notice any unusual/sudden changes in your mood, thoughts, or behavior including signs of depression, suicidal thoughts/attempts, thoughts about harming yourself.

Severe (sometimes fatal) brain disorder (encephalopathy) has rarely occurred, particularly in patients with certain metabolic disorders (urea cycle disorders). Tell your doctor right away if you develop unexplained weakness, vomiting, or sudden mental/mood changes (such as confusion).

Get medical help right away if you have any very serious side effects, including:

  • chest pain
  • easy bruising/unexplained bleeding
  • fast/slow/irregular heartbeat
  • swelling of hands/feet
  • uncontrolled eye movement (nystagmus)
  • feeling cold/shivering
  • rapid breathing
  • loss of consciousness

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including:

  • fever
  • swollen lymph nodes
  • rash
  • itching/swelling (especially of the face/tongue/throat)
  • severe dizziness
  • trouble breathing

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Precautions

See also Warning section.

Before taking divalproex sodium, tell your doctor or pharmacist if you are allergic to it; or to valproic acid or valproate sodium; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of:

  • liver disease
  • pancreatitis
  • certain metabolic disorders (such as urea cycle disorders, Alpers-Huttenlocher syndrome)
  • alcohol abuse
  • bleeding problems
  • brain disease (dementia)
  • kidney disease
  • dehydration
  • poor nutrition

To lower the chance of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

This drug may make you dizzy or drowsy or blur your vision. Alcohol or marijuana (cannabis) can make you more dizzy or drowsy. Do not drive, use machinery, or do anything that needs alertness or clear vision until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).

Children younger than 6 years may be at greater risk for liver problems and pancreatitis.

Older adults may be more sensitive to the side effects of this drug, especially drowsiness, dizziness, unsteadiness, or tremor. Drowsiness, dizziness, unsteadiness can increase the risk of falling.

This medication is not recommended for use during pregnancy. It may harm an unborn baby. See also Warning section.

This medication passes into breast milk. While there have been no reports of harm to nursing infants, consult your doctor before breast-feeding.

Drug interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include:

  • certain antidepressants (e.g., amitriptyline, nortriptyline, phenelzine)
  • certain antibiotics (carbapenems such as imipenem)
  • irinotecan
  • mefloquine
  • orlistat
  • other medications for seizure (e.g., ethosuximide, lamotrigine, phenytoin, rufinamide, topiramate)
  • rifampin
  • vorinostat
  • warfarin
  • zidovudine

Low-dose aspirin, as prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention (usually 81-162 milligrams a day), should be continued. Consult your doctor or pharmacist if you are using aspirin for any reason.

Tell your doctor or pharmacist if you are taking other products that cause drowsiness including alcohol, marijuana (cannabis), antihistamines (such as cetirizine, diphenhydramine), drugs for sleep or anxiety (such as alprazolam, zolpidem), muscle relaxants (such as carisoprodol, cyclobenzaprine), and opioid pain relievers (such as codeine, hydrocodone).

Check the labels on all your medicines (such as allergy or cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.

This drug may affect certain lab tests (e.g., urine ketones). Make sure laboratory personnel and your doctors know you use this medication.

Overdose

If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: excessive drowsiness, coma, irregular/slow heartbeat.

Notes

Do not share this medication with others.

Laboratory and/or medical tests (such as drug levels, liver function tests, complete blood counts, clotting tests) should be performed before you start treatment, periodically to monitor your progress, or to check for side effects. Consult your doctor for more details.

Missed dose

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

Storage

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Important note

HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

Information last revised September 2021.

Copyright(c) 2021 First Databank, Inc.

Selected from NATIONAL DRUG DATA FILE (NDDF) data included with permission and copyrighted by First Databank, Inc., 2019. This copyrighted material has been downloaded from a licensed data provider.

The above information is intended to supplement, not substitute for, the expertise and judgment of your health care professional. You should consult your health care professional before taking any drug, changing your diet, or commencing or discontinuing any course of treatment.

Sours: https://healthy.kaiserpermanente.org/health-wellness/drug-encyclopedia/drug.divalproex-er-250-mg-tablet-extended-release-24-hr.446881

Er divalproex

Divalproex Sodium 500 mg Extended Release Tablets Under Non-Fasting Conditions

Brief Summary:

This study was designed to compare the relative bioavailability (rate and extent of absorption) of Divalproex Sodium ER Tablets 500 mg with that of Depakote® ER Tablets 500 mg following a single, oral dose (1 x 500 mg extended release tablet) administered to healthy, adult subjects under non-fasting conditions.


HealthyDrug: Divalproex SodiumDrug: Depakote®Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment :24 participants
Allocation:Randomized
Intervention Model:Crossover Assignment
Masking: None (Open Label)
Official Title:A Relative Bioavailability Study of 500 mg Divalproex Sodium Extended Release Tablets Under Non-Fasting Conditions
Study Start Date :October 2006
Actual Primary Completion Date :October 2006
Actual Study Completion Date :October 2006

Sours: https://clinicaltrials.gov/ct2/show/NCT00974012
Valproate/Divalproex: Metabolism, Kinetics, and Warnings

Divalproex ER Combined with Olanzapine or Risperidone for Treatment of Acute Exacerbations of Schizophrenia

Abstract

The objective of this study was to evaluate the efficacy and safety of divalproex sodium extended release (divalproex ER) vs placebo in combination with olanzapine or risperidone for the treatment of acute exacerbations of schizophrenia. In this 12-week, randomized, double-blind, parallel-group, multi-center trial, a total of 402 patients were randomized and treated; 103 received olanzapine/placebo, 99 received olanzapine/divalproex ER, 101 received risperidone/placebo, and 99 received risperidone/divalproex ER. Divalproex ER was initiated on day 1 at 20 mg/kg per day q AM and was titrated to clinical effect on days 3, 7, and 10, not to exceed a maximum dosage of 35 mg/kg per day. Olanzapine and risperidone were initiated at 5 and 2 mg/day q PM, respectively, increased to 10 and 4 mg/day on day 3, and increased to fixed target doses of 15 and 6 mg/day on day 6. No significant treatment difference was demonstrated between the combination therapy and antipsychotic monotherapy groups on the primary efficacy variable of the mean change from baseline to day 14 last observation carried forward on the Positive and Negative Syndrome Scale (PANSS) total score, although antipsychotic monotherapy did demonstrate superiority to combination therapy on the PANSS Negative subscale at several time points. Combination therapy also failed to show an advantage over antipsychotic monotherapy at day 84 on the PANSS total score. Most adverse events observed in the study were mild to moderate in severity, and the overall number of adverse events did not differ significantly between the combination therapy groups and their corresponding antipsychotic monotherapy group.

INTRODUCTION

Schizophrenia is a severe, debilitating, and chronic mental disorder characterized by positive (hallucinations, delusions) and negative (withdrawal, apathy, anhedonia) symptoms. The conventional antipsychotic drugs used to treat schizophrenia are believed to produce their effects through blockade of the dopamine type 2-receptor and are effective in treating positive symptoms but are associated with extrapyramidal side effects (EPS). The second generation antipsychotic drugs (such as risperidone and olanzapine) cause fewer EPS, and have shown promise in reducing the negative symptoms of schizophrenia, possibly due to their inhibition of serotonin type-2 receptor activity (Möller, 2003). In spite of these advances, the treatment of schizophrenia remains suboptimal; the disorder usually follows a chronic relapsing course, and the side effects of current therapies are of concern (Meltzer, 1999).

Although the monoamines (especially dopamine) have been the major focus of research in the pathophysiology of schizophrenia for many years, evidence also indicates abnormalities in other neurotransmitter systems, including the GABAergic system (Benes, 2000; Lewis et al, 2005). Studies have demonstrated a loss of inhibitory GABAergic neurons in the brains of schizophrenic patients. These findings produced speculation that drugs that enhance GABAergic activity may provide benefit in the treatment of schizophrenia (Benes, 2000; Berle and Spigset, 2005; Lewis et al, 2005).

Divalproex sodium (divalproex hereafter) has putative GABA agonism via multiple mechanisms (reviewed by Wassef et al, 2003) and potentiates antipsychotic-induced dopamine release in the prefrontal cortex of rats (Melzer et al, 2001). A number of small, open-label studies support the clinical benefit of divalproex in combination with conventional antipsychotic medications for the treatment of psychotic symptoms (Gunderewa et al, 1980; Moringo et al, 1989; Wassef et al, 1989, 2000; Chong et al, 1998). Recently, a large, double-blind, multi-center trial demonstrated improvement in psychotic symptoms for divalproex vs placebo when given in combination with olanzapine or risperidone for the treatment of acute exacerbations of schizophrenia. Improvement with divalproex was seen as early as day 3 and continued to day 21 (Casey et al, 2003).

The objective of this study was to evaluate the effects of divalproex sodium extended release (divalproex ER hereafter) in combination with olanzapine or risperidone vs antipsychotic monotherapy with olanzapine or risperidone for the treatment of schizophrenia over a 12-week period.

METHODS

Patients

Hospitalized patients between the ages of 18 and 65 years with an acute exacerbation of schizophrenia were enrolled. Patients with a current DSM-IV-TR diagnosis of schizophrenia, as confirmed by a Structured Clinical Interview for DSM-IV-TR (SCID; First et al, 2002) were selected for inclusion on the basis of having (1) a Positive and Negative Syndrome Scale (PANSS; Kay et al, 1987) total score ⩾70 (based on a 1–7-point scale for each measure), (2) a score totaling ⩾8 on any two of the four items from the psychosis cluster of the Brief Psychiatric Rating Scale-derived (BPRSd), and (3) a total score ⩾6 on either hostility and uncooperativeness or excitement and tension items from the BPRSd. For inclusion, a patient must have had, in the investigator's opinion, a positive response to treatment with antipsychotics within the previous 2 years.

Patients were excluded from the study if they had a current diagnosis of schizoaffective disorder, drug-induced psychosis, manic episode, or major depressive episode, as were those who had serious violent, homicidal, or suicidal ideation, or had more than three psychiatric hospitalizations in the previous 6 months or more than 8 weeks of psychiatric hospitalization in the previous 12 months.

Study Design

The study was a randomized, double-blind, parallel-group, multi-center trial, consisting of a 1- to 5-day screening/washout period and a 12-week double-blind treatment period. The protocol was approved by the institutional review board of each participating study site. Written informed consent was obtained from each patient or the patient's authorized representative before enrollment in the study.

Patients were randomized to one of four treatment groups: (1) olanzapine/placebo, (2) risperidone/placebo, (3) olanzapine/divalproex ER, or (4) risperidone/divalproex ER. Divalproex ER was initiated on day 1 at 20 mg/kg per day q AM and was titrated to clinical effect on days 3, 7, and 10, not to exceed a maximum dosage of 35 mg/kg per day. Olanzapine and risperidone were initiated at 5 and 2 mg/day q PM respectively, increased to 10 and 4 mg/day on day 3, and increased to fixed target doses of 15 and 6 mg/day on day 6. Once these doses were achieved, they were continued for the remainder of the study.

Lorazepam, propranolol hydrochloride, and benztropine mesylate could be used as adjunctive medications, but were not to be used prophylactically. Lorazepam (up to 6 mg/day during screening, up to 4 mg/day on days 1–7 of the treatment period, and up to 2 mg/day from day 8 until hospital discharge) could be prescribed for severe agitation and for control of insomnia, but not within 8 h before efficacy ratings. Propranolol hydrochloride (according to the investigator's discretion) could be prescribed for severe or intolerable akathisia. Benztropine mesylate (up to 4 mg/day throughout the study) could be prescribed for severe or intolerable akathisia, EPS, or dystonia.

The double-blind treatment period consisted of a 14-day acute phase followed by a 10-week stabilization phase. Patients were required to remain hospitalized for a minimum of 14 days during the Acute Phase of the study and could be discharged (per investigator discretion) anytime after day 14. Once discharged, patients were seen as outpatients for the remainder of the study and were required to return to the study site for regularly scheduled assessments.

Clinical Evaluations

The psychiatric status of patients was evaluated using the PANSS total and subscales, and the Clinician's Global Impression (CGI) Severity and Improvement scales (Guy, 1976). The evaluations were conducted on days 1 (baseline), 3, 5, 7, 10, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, and 84. The PANSS was scored based on the previous 48 h symptoms. The BPRSd was administered as a secondary efficacy measure.

All raters received extensive training on rating the PANSS and other key scales, including initial training sessions in which raters were required to rate scales and score within 1.5 standard deviations of the mean of all raters. At approximately midstudy, raters attended refresher training sessions, during which rater scores demonstrated good reliability. Only individuals who successfully completed a rater-training program were permitted to administer and score the rating scales. If at all possible, the same rater performed all ratings for a given subject throughout the study.

Safety Assessment

Safety assessments included a physical examination, vital sign monitoring, body weight measurement, adverse event collection, and laboratory tests. EPS side effects were evaluated during the double-blind treatment period using the Simpson–Angus Scale (SAS; Simpson and Angus, 1970), the Barnes Akathisia Scale (BAS; Barnes, 1989), and the Abnormal Involuntary Movement Scale (AIMS; Guy, 1976).

Statistical Analysis

All statistical tests were two tailed with a significance level of 0.05. The primary treatment comparison for demographic and baseline characteristics and for efficacy endpoints was combination therapy vs antipsychotic monotherapy. The combination therapy group consisted of patients from the olanzapine/divalproex ER and risperidone/divalproex ER groups, and the monotherapy group consisted of patients from the olanzapine/placebo and risperidone/placebo treatment groups. Comparability of treatment groups was assessed by a one-way analysis of variance (ANOVA) for age and weight and by a Wilcoxon rank sum test for age at first diagnosis of schizophrenia. Treatment group differences for lifetime number of hospitalizations and number of suicide attempts (collected as 0, 1–5, 6–10, 11–15, 16–20, and >20) were assessed with the Cochran–Mantel–Haenszel test. Fisher's exact test was used to assess treatment differences in gender and race and in reason for discontinuation of study drug.

All efficacy analyses were performed on the intent-to-treat (ITT) dataset, defined as all randomized patients who received study medication and who were rated on the PANSS total at baseline and at least once while receiving treatment. The primary efficacy variable was the change from baseline to the day 14 evaluation using the last observation carried forward (LOCF) for the PANSS total score. The day 14 evaluation point was chosen because it was thought that the 2-week acute stabilization period would be the most clinically relevant, and that this period would also be the most controlled environment in which to test for efficacy given the potential for variations in compliance and environmental factors after discharge. In addition, the day 14 evaluation point was also within the time period in which apparent efficacy was demonstrated in the previous Casey et al (2003) study, thus allowing possible comparison of efficacy between the two studies. Treatment group differences for the primary efficacy variable were assessed by a two-way ANOVA with factors for treatment group and study center. Based on the results of Casey et al (2003), the planned sample size of 200 subjects each in the antipsychotic monotherapy and combination therapy groups had 80% power to detect a treatment difference of 5.1 with a pooled standard deviation of 18.2 (standardized effect size=0.28) and a Type I error rate of 0.05 for a two-tailed test.

Supportive efficacy endpoints included change from baseline to each scheduled visit (using LOCF) for the PANSS total, positive, and negative scores, the BPRS total score derived from the PANSS, and CGI severity and improvement scores. All secondary endpoints except the CGI Improvement score were assessed as described for the primary efficacy endpoint. For the CGI Improvement score, the primary treatment comparison was assessed by Cochran–Mantel–Haenszel with study centers as strata.

All randomized patients who received at least one dose of study medication were evaluated for safety. The primary treatment comparison for safety data was each individual combination therapy group vs its corresponding antipsychotic monotherapy group (ie olanzapine/divalproex ER vs olanzapine/placebo and risperidone/divalproex ER vs risperidone/placebo). Adverse events were coded using the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) Version V dictionary. Treatment-emergent adverse events were those events that began or worsened in severity on or after the first day of dosing. Treatment differences in the percentage of patients reporting each treatment-emergent adverse event were assessed by Fisher's exact test. Treatment group differences in laboratory data were analyzed by a one-way ANOVA with treatment as the main effect. The primary analysis was the change from baseline (last determination obtained on or before day 1 of dosing) to the final evaluation for each variable.

RESULTS

A total of 402 patients were randomized for treatment: 103 received olanzapine/placebo, 99 received olanzapine/divalproex ER, 101 received risperidone/placebo, and 99 received risperidone/divalproex ER. 251 patients (62%) discontinued study drug. Reasons for premature discontinuations were adverse event (12% monotherapy, 16% combination therapy), withdrew consent (21% monotherapy, 17% combination therapy), lost to follow-up (5% monotherapy, 7% combination therapy), noncompliance (7% monotherapy, 9% combination therapy), ineffectiveness (19% monotherapy, 14% combination therapy), and other (12% monotherapy, 8% combination therapy); subjects may have reported more than one reason for premature discontinuations, but were counted only once in the total. No significant treatment differences were noted for overall discontinuation rate or discontinuation rate by specific reason. Overall, the majority of subjects who prematurely discontinued did so during the first 4 weeks of treatment (37%; 147/402). A total of 43, 46, 32, and 30 patients in the olanzapine/placebo, olanzapine/divalproex ER, risperidone/placebo, and risperidone/divalproex ER groups, respectively, completed the study.

Baseline demographic and clinical characteristics are listed in Table 1. The treatment groups did not differ in demographics, schizophrenia subtype, age at first diagnosis, or number of suicide attempts. Most patients (86%) had a diagnosis of paranoid schizophrenia, with more than six lifetime hospitalizations (55%), and at least one suicide attempt (51%). The mean baseline PANSS total score was 99.1 for the antipsychotic monotherapy group and 98.3 for the combination therapy group.

Full size table

Efficacy Results

Efficacy results are summarized in Figure 1 and Table 2. The primary efficacy variable, mean change from baseline to day 14 LOCF in PANSS total score, did not demonstrate a significant treatment difference between the combination therapy group and the monotherapy group (p=0.307). Similarly, there was no treatment difference on the PANSS total at day 84 (p=0.229). No statistically significant differences were found between treatment groups on the PANSS positive subscale at day 14 (p=0.473) or day 84 (p=0.623), or the PANSS general psychopathology subscale at day 14 (p=0.603) or day 84 (p=0.355). Results of the PANSS negative subscale demonstrated a numerical advantage of antipsychotic monotherapy over combination therapy (p=0.085) at day 14, and showed a significant treatment difference favoring antipsychotic monotherapy vs combination therapy on days 3, 5, 7, 10, 42, 49, 63, 77, and 84.

Change from baseline for the PANSS total LOCF. There were no significant differences between DVPX ER/antipsychotic combination therapy and antipsychotic monotherapy at any time point.

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Full size table

Change from baseline on the BPRSd was not significantly different for combination therapy vs antipsychotic monotherapy at day 14 (p=0.457) or at day 84 (p=0.364). The CGI severity and improvement scores also failed to show a statistically significant difference between antipsychotic monotherapy and combination therapy at days 14 or 84.

The use of adjunctive rescue medications (ie lorazepam, propranolol hydrochloride, and benztropine mesylate) during the study, including dosage (mg/day), number of days used, and percentage of patients using rescue medications, was similar between the antipsychotic monotherapy and combination therapy groups. Lorazepam was used by 65% of patients on antipsychotic monotherapy for an average of 6.2 days, and by 59% of patients on combination therapy for an average of 6.4 days. The mean daily lorazepam dose was 1.5 mg in both groups. Only 16% of patients used either propranolol hydrochloride or benztropine mesylate.

Safety Results

The mean modal daily divalproex ER dose was 2828 mg in the olanzapine/divalproex ER group and 2712 mg in the risperidone/divalproex ER group. From weeks 2 through 12, the mean daily dose of olanzapine was 15 mg/day, and the mean daily dose of risperidone was 6 mg/day. According to pill counts, 82% of subjects were compliant at least 70% of the time. Valproate serum levels for observed cases are presented in Figure 2 and suggest a meaningful drop off in compliance following the inpatient phase of the study. The overall incidence of treatment-emergent adverse events was 83% in the olanzapine/placebo group, 88% in the olanzapine/divalproex ER group, 79% in the risperidone/placebo group, and 84% in the risperidone/divalproex ER group, with no significant differences between a specific combination therapy group and its corresponding antipsychotic monotherapy group. Most of the adverse events observed during the study were mild or moderate in severity. The incidence of constipation was significantly higher for risperidone compared to risperidone/divalproex ER (8 vs 1%; p=0.035). Conversely, the incidence of somnolence (45 vs 19%; p<0.001), weight gain (22 vs 10%; p=0.021), and urinary incontinence (5 vs 0%; p=0.028) was significantly higher for risperidone/divalproex ER vs risperidone monotherapy. The incidence of dry mouth was significantly higher in the olanzapine group compared to the olanzapine/divalproex ER group (13 vs 4%; p=0.041), but the incidence of back pain was significantly higher in the olanzapine/divalproex ER group compared to the olanzapine monotherapy group (5 vs 0%; p=0.027). One patient in the risperidone/divalproex ER group died on day 24 due to an accidental opioid overdose, which was considered not related to study drug by the investigator.

Serum trough valproate levels (μg/ml) mean and SE by Study Day for observed cases. The drop in serum levels on day 14 (after the inpatient phase) suggests decreased compliance in the outpatient phase of the study.

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Laboratory assessments showed a significant decrease from baseline in platelet counts in each combination therapy group when compared to its respective monotherapy group. The mean serum level of LDL cholesterol was statistically significantly decreased from baseline in the antipsychotic combination therapy group vs the antipsychotic monotherapy group (p=0.004). A similar decrease in LDL cholesterol level was seen when risperidone/divalproex ER was compared with risperidone monotherapy (p=0.036) and when olanzapine/divalproex ER was compared with olanzapine monotherapy (p=0.056). Table 3 presents the safety parameters by drug groups.

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DISCUSSION

In this study, the addition of divalproex ER to olanzapine or risperidone did not enhance efficacy at either the primary endpoint of 14 days or in the extended 12-week treatment period. These results contrast somewhat with other reports of adjunctive or combination therapy using valproate in psychotic populations (eg Wassef et al, 1989, 2000) and with the findings from a similarly designed study of divalproex combination therapy with risperidone or olanzapine (Casey et al, 2003), in which improvement with divalproex was demonstrated as early as day 3 and which continued to day 21, but which failed to reach its primary efficacy endpoint of PANSS change score from baseline to week 4. In this study, mean negative symptom scores on the PANSS Negative subscales improved from baseline in both groups, but more so in the monotherapy group. However, statistically significant treatment differences in negative symptoms favoring antipsychotic monotherapy vs combination therapy were not seen in the earlier Casey et al (2003) study. It is possible that the effects of combination therapy on negative symptoms in this study were partially masked by sedative effects. For example, in this study, the incidence of somnolence was higher for the risperidone/divalproex ER vs risperidone monotherapy group (45 vs 19%; p<0.001).

Overall, the basis for the different outcomes in these two similar studies is unclear. A comparison between the Casey et al (2003) study and this study suggests similar patient characteristics at enrollment. The duration of this study was 12 weeks, compared to 4 weeks for the previous study, and the primary endpoint in this study was 14 days, compared to the 28-day primary endpoint in Casey et al (2003). Although the primary efficacy measure was the same in both studies, different supportive efficacy measures were used in this study. Another difference was that the Casey et al (2003) study utilized divalproex BID whereas this study utilized divalproex ER administered QD. To account for differences in bioavailability between formulations, this study used a more rapid titration schedule than Casey et al (2003). By day 14, dosing was comparable in the two studies, as were serum valproate concentrations (in μg/ml, OLZ+DVPX, mean (SD): 91.2 (33.04) (this study) vs 97.2 (28.47) (Casey et al, 2003); RISP+DVPX, mean (SD): 105.5 (27.26) (this study) vs 102.5 (24.15) (Casey et al, 2003); all DVPX, mean (SD): 97.9 (31.20) (this study) vs 99.7 (26.53) (Casey et al, 2003)).

Another difference between the two studies is the serum valproate levels of subjects in the later time points of the studies. Final day mean trough levels of valproate at day 28 in the Casey et al (2003) study were 98.2 and 100.2 μg/ml in combination with risperidone and olanzapine, respectively, compared to levels in the 65–80 μg/ml range at the later time points in this study. The decrease in serum valproate levels over time in this study may be due to a reduction in compliance during the outpatient portion of the study. As the therapeutic range for adjunctive divalproex in the treatment of schizophrenic symptoms is not well delineated, it is unclear if the serum valproate levels achieved after day 14 in this study should be adequate to treat the symptoms of schizophrenia; however, in a previously reported 4-week open-label study (Citrome et al, 2004), thirty schizophrenic subjects were converted from divalproex DR to ER, and the 12-h post-dose trough plasma levels were 80.1±20.4 and 73.1±24.2 μg/ml (mean±SD), respectively. In this previously reported study, psychopathology as measured on the total BPRS improved slightly (p=0.0322), indicating that plasma levels of valproate in the vicinity of 73.1 μg/ml may have some therapeutic effect in schizophrenia. This suggests that the serum valproate levels achieved in the later stages of this study could be clinically relevant in the treatment of schizophrenia.

In addition, another key distinction between the two studies that is likely related to the differences in serum valproate levels discussed above is that in the Casey et al (2003) study, the subjects spent the study duration in an inpatient setting, whereas in this study, subjects could be discharged after 14 days of treatment. The length of time in the hospital very likely correlates with improved compliance, in contrast to an unsupervised outpatient setting. In Figure 1, the early reduction in psychotic symptoms in this study parallels the time course and degree of improvement that has been seen in several second-generation antipsychotic trials done primarily with inpatients (Casey et al, 2003). However, from days 14–84 there was virtually no change in response to 10 more weeks of treatment. This is highly unusual for antipsychotic trials in schizophrenia (Sherwood et al, 2006). Furthermore, the drop-off in serum valproate levels seen after day 14 (Figure 2) is consistent with decreased compliance as subjects left the inpatient setting. Additionally, the percent of patients completing this study was lower than usual for antipsychotic trials, and was likely influenced by the lengthy period of time that many patients spent as outpatients, during which many extraneous variables may have influenced their participation and/or compliance in the study.

An examination of the efficacy results from the current trial and the similarly designed Casey et al (2003) study suggests that the combination therapies led to similar improvements through day 14 (the primary endpoint in this study). Figure 3 illustrates the change from baseline on PANSS total at day 14 for antipsychotic monotherapy and combination therapy for both studies. The striking difference between the studies is the change from baseline for the antipsychotic monotherapy groups. In fact, the difference in change scores for antipsychotic monotherapy across studies is larger than the within-study change scores between the antipsychotic monotherapy and combination therapy groups that led to a statistically significant result in Casey et al (2003). Likewise, the responder rates (20% improvement) across studies show that the most profound difference from one study to the next was in the antipsychotic monotherapy group. The combination therapy responder rates at day 14 were similar between the Casey et al (2003) study and this study (66 and 65%, respectively); however, the rate of responders in the antipsychotic monotherapy group was 53% in Casey et al (2003)vs 71% in this study. Taken together, these data suggest the possibility of a greater placebo response in this study, which may have diminished the apparent efficacy of the combination treatment when compared against the monotherapy treatment.

Across-study comparison of efficacy at day 14. The combination therapy groups across the two studies (this study and Casey et al, 2003) had identical PANSS total changes at day 14, however, the monotherapy group showed greater improvement in this study.

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This study did not raise new safety concerns; the addition of divalproex ER to olanzapine or risperidone was associated with known adverse events such as somnolence, weight gain, and decreased platelet count. Consistent with a number of other previous studies across a variety of illnesses (Swann et al, 2001; Jafari et al, 2002; Beydoun et al, 2002; Bowden et al, 2006), divalproex ER lowered serum total and LDL cholesterol. This study extended previous findings showing that divalproex mitigates the increase in total cholesterol associated with olanzapine and risperidone (Jafari et al, 2003), an effect that remained robust through 12 weeks of combination therapy. Although not statistically significant, it is noteworthy that divalproex ER appeared to lower serum HDL cholesterol in the combination treatment group compared to the antipsychotic monotherapy group.

In conclusion, the lack of a significant efficacy benefit from adding divalproex ER to risperidone or olanzapine in this study contrasts with previous reports of efficacy for valproate combination therapy. Considering the potential for increased safety risks associated with combination treatment and the conflicting data regarding its efficacy, the use of antipsychotic/divalproex ER combination treatment for the treatment of schizophrenia is not strongly supported. Indeed, further studies are required to clarify the conflicting efficacy results reported to date and to better define the risk/benefit ratio of adding divalproex ER to olanzapine or risperidone in the treatment of acute schizophrenia.

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Acknowledgements

This study was supported by Abbott Laboratories, Abbott Park, IL. We thank Sharon Stec of Abbott Laboratories who served capably as clinical project manager for this study. We also thank the members of the Depakote ER Combination Treatment Study Group, as follows, for their enrollment of patients and participation in this study: Jose J Alvarez, MD, Comprehensive NeuroScience Inc., Melbourne, FL; Mohammed Bari, MD, Synergy Clinical Research, Chula Vista, CA; Louise M Beckett MD, IPS Research Company, Oklahoma City, OK; Jeffrey A Borenstein, MD, Holliswood Hospital, Holliswood, NY; Guy E Brannon, MD, Brentwood Research Institute, Shreveport, LA; David W Brown, MD, Community Clinical Research Inc., Austin, TX; Jesse M Carr, MD California Clinical Trials Medical Group Inc., Glendale, CA; Lori L Davis, MD, Tuscaloosa VA Medical Center, Tuscaloosa, AL; David Feifel, MD, PhD, UCSD Medical Center, San Diego, CA; David H Flaherty, DO, Segal Institute for Clinical Research, North Miami, FL; Donald J Garcia, Jr, MD, Future Search Trials, Austin, TX; Lev Gertsik, MD, Cedars Sinai Medical Center, Los Angeles, CA; Steven Glass, MD, CNS Research Institute, PC, Clementon, NJ; Armen Goenjian, MD, Collaborative NeuroScience Network Inc., Garden Grove, CA; Clifford Goldman, MD, ClinSearch Inc., Kenilworth, NJ; Ram Gopalan, MD, Comprehensive Neuroscience of Northern Virginia, Falls Church, VA; Richard R Jaffe, MD, Belmont Center for Comprehensive Treatment, Philadelphia, PA; John Kasckow, MD, PhD, University of Cincinnati Medical Center, Cincinnati, OH; Richard D Knapp, DO, CORE Research Inc., Winter Park, FL; Mary Ann Knesevich, MD, University Hills Clinical Research, Irving, TX; Joseph Kwentus, MD, University of Mississippi Medical Center, Jackson, MS; Mark N Lerman, MD, Comprehensive NeuroScience Inc., Hoffman Estates, IL; Robert E Litman, MD, Centers for Behavioral Health, LLC, Rockville, MD; H Edward Logue, MD, Birmingham Psychiatry Pharmaceutical Studies Inc., Birmingham, AL; Joseph P McEvoy, MD, Duke University Medical Center, Butner, NC; Alexander L Miller, MD, University of Texas Health Science Center at San Antonio, San Antonio, TX; Michael G Plopper, MD, Sharp Mesa Vista Hospital, San Diego, CA; Raj Rajani, MD, Behavioral and Medical Research, LLC, Anaheim, CA; Robert A Riesenberg, MD, Atlanta Center for Medical Research, Atlanta, GA; Murray H Rosenthal, DO, HealthQuest Clinical Trials, San Diego, CA; David Sack, MD, Comprehensive NeuroScience Inc., Cerritos, CA; Scott D Segal, MD, Segal Institute for Clinical Research, North Miami, FL; Rajiv P Sharma, MD, The Psychiatric Institute University of Illinois at Chicago Medical Center, Chicago, IL; Anantha Shekhar, MD, PhD, Indiana University, Indianapolis, IN.

Author information

Author notes
  1. David G Daniel

    Present address: 9Current address: United BioSource Corporation, McLean, VA, USA,

Affiliations

  1. Oregon Health and Science University, Portland, OR, USA

    Daniel E Casey

  2. George Washington University, Washington, DC, USA

    David G Daniel

  3. Bioniche Development, Falls Church, VA, USA

    David G Daniel

  4. University of Texas Southwestern Medical Center, Dallas, TX, USA

    Carol Tamminga

  5. The Zucker Hillside Hospital, Glen Oaks, NY, USA

    John M Kane

  6. California Neuropsychopharmacology Clinical Research Institute, San Diego, CA, USA

    Tram Tran-Johnson

  7. Abbott Laboratories, Abbott Park, IL, USA

    Patricia Wozniak, Walid Abi-Saab, Jeff Baker, Laura Redden, Nicholas Greco & Mario Saltarelli

  8. Advanced Clinical Research Services, Bannockburn, IL, USA

    Patricia Wozniak

Corresponding author

Correspondence to Daniel E Casey.

Additional information

Disclosures

Daniel Casey has received consultant fees from Abbott Laboratories, Bristol-Myers Squibb, Dainippon Sumitomo Pharmaceuticals, Janssen Pharmaceuticals, NuPathe Inc., Pfizer Inc., Solvay Pharmaceuticals and Wyeth Pharmaceuticals. He has been on Speakers Bureaus for Abbott Laboratories, Bristol-Meyers Squibb, Janssen Pharmaceuticals and Pfizer. Dr Casey receives financial support from Danicas Foundation. John Kane has served as a consultant for Abbott Laboratories, Astra-Zeneca, Bristol-Meyers Squibb, Janssen, Eli Lilly and Company, Pfizer Inc., Wyeth Pharmaceuticals and on Speakers Bureaus for Bristol-Meyers Squibb, Janssen, and Astra-Zeneca. Carol Tamminga has been a paid consultant for Acadia Pharmaceuticals, Intra-cellular Therapies, Orexigen, Alexza Pharmaceuticals, and Lunbeck Inc. She is on the Advisory Boards for Acadia Pharmaceutical and Intracellular Therapies. David Daniel is employed by United Biosource Corporation. Walid Abi-Saab and Patricia Wozniak are former employees of Abbott Laboratories. Laura Redden, Mario Saltarelli, Jeff Baker and Nicholas Greco are current employees of and owners of equity in Abbott Laboratories. Tram Tran-Johnson was an investigator in this study and reports no other financial conflicts.

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Casey, D., Daniel, D., Tamminga, C. et al. Divalproex ER Combined with Olanzapine or Risperidone for Treatment of Acute Exacerbations of Schizophrenia. Neuropsychopharmacol34, 1330–1338 (2009). https://doi.org/10.1038/npp.2008.209

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Keywords

  • divalproex sodium ER
  • schizophrenia
  • atypical antipsychotic
  • psychosis
  • risperidone
  • olanzapine

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    Middle East Current Psychiatry (2020)

  • The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

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    •  & Alessandro Guidotti

    Neuropsychopharmacology (2013)

Sours: https://www.nature.com/articles/npp2008209

Now discussing:

WHAT IS DEPAKOTE USED FOR?1-3

DEPAKOTE comes in different dosage forms. DEPAKOTE® (divalproex sodium) delayed-release tablets, for oral use, and DEPAKOTE® ER (divalproex sodium) extended-release tablets, for oral use, are prescription medications 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

DEPAKOTE® Sprinkle Capsules (divalproex sodium delayed release capsules), for oral use, is a prescription medicine used 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

IMPORTANT SAFETY INFORMATION1-3

The most important information about DEPAKOTE is:

Do not stop taking DEPAKOTE without first talking to your healthcare provider. Stopping DEPAKOTE suddenly can cause serious problems.

DEPAKOTE can cause serious side effects, including:

  • 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. In some cases, liver damage may continue despite stopping the drug. 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, or yellowing of your skin or the whites of your eyes.
  • DEPAKOTE may harm your unborn baby. If you take DEPAKOTE 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. 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 DEPAKOTE during pregnancy for any medical condition, your child is at risk for having a 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 DEPAKOTE 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 DEPAKOTE. If the decision is made to use DEPAKOTE, you should use effective birth control (contraception). Tell your healthcare provider right away if you become pregnant while taking DEPAKOTE. You and your healthcare provider should decide if you will continue to take DEPAKOTE while you are pregnant. Pregnancy Registry: If you become pregnant while taking DEPAKOTE, 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, www.aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
  • 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.
  • Like other antiepileptic drugs, DEPAKOTE 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 take DEPAKOTE 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 DEPAKOTE
  • 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)

Before taking DEPAKOTE, 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 since DEPAKOTE can pass into breast milk. Ask your healthcare provider about the best way to feed your baby.
  • have or have had depression, mood problems, or suicidal thoughts or behavior
  • have any other medical condition

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, herbal supplements.

Taking DEPAKOTE with certain other medicines, even for a short period of time, can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

DEPAKOTE can cause other 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 95º 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 DEPAKOTE.

Common side effects of DEPAKOTE include:

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

Please see the full Prescribing Information, including Medication Guide, for additional information about DEPAKOTE. Talk to your healthcare provider if you have questions.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you are having difficulty paying for your medicine, AbbVie may be able to help. Visit Abbvie.com/myAbbVieAssist to learn more.

Sours: https://www.depakote.com/prescribing-information


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