Depakote

Name: Depakote

Depakote Side Effects

Because one of the risks of this drug is an increase in the chance of liver damage, you should be on the lookout for these symptoms:

  • Nausea
  • Vomiting that does not go away
  • Loss of appetite
  • Pain the in the right side of your stomach
  • Dark urine
  • Swelling of your face, hands, arms, feet, and legs
  • Yellowing of your skin or eyes (jaundice)

Depakote can cause suicidal thoughts or actions. Call your doctor right away if you have any of these symptoms, especially if they are new:

  • Thoughts of suicide or dying
  • Attempts to commit suicide
  • A depression that is new or getting worse
  • Anxiety that is new or getting worse
  • Feeling agitated or restless
  • Panic attacks
  • Trouble sleeping (insomnia)

This drug may cause life-threatening pancreatitis. Get emergency attention if you develop:

  • Nausea
  • Vomiting
  • Abdominal pain, especially pain that radiates to the back or that feels worse after eating
  • Tenderness when pressing on the stomach

Encephalopathy, a severe (sometimes fatal) brain disorder is a rare but possible side effect of this drug, especially in patients with certain metabolic disorders (urea cycle disorders).

Tell your doctor immediately if you develop unexplained weakness, vomiting, or sudden mental/mood changes like confusion.

Nausea is quite common when taking this medication. Between 10 and 20 percent of people who take Depakote report being nauseous at some point.

Common side effects of Depakote include:

  • Diarrhea
  • Dizziness
  • Blurred or double vision
  • Memory impairment
  • Ringing in the ears
  • Shakiness or unsteadiness (tremors)
  • Somnolence (excessive sleepiness)
  • Hair loss
  • Irregular or painful menstrual periods
  • Weight gain

Serious side effects of Depakote include:

  • Chest pain
  • Easy bruising or unexplained bleeding
  • Irregular heartbeat
  • Swelling of hands or deet
  • Nystagmus (involuntary eye movement)
  • Feeling cold or shivering
  • Rapid breathing or loss of consciousness

Seek immediate medical attention if you develop signs of a serious allergic reaction to this medication:

  • Rash
  • Itching
  • Swelling (especially in the face, tongue, or throat)
  • Severe dizziness
  • Trouble breathing

Depakote Interactions

Depakote and Alcohol

Drinking alcohol could increase nervous system side effects of Depakote like drowsiness, dizziness, difficulty concentrating, and impaired judgment.

Avoid alcohol altogether or limit how much you drink while taking this medication.

Depakote and Drug Interactions

The following drugs could interact moderately with Depakote:

  • Carbamazepine (Tegretol)
  • Salicylates (Doans Pills)
  • Topiramate (Topamax and Topamax Sprinkle)
  • Rifampin (Rifadin)
  • Warfarin (Coumadin)
  • Amitriptyline (Elavil)
  • Clomipramine (Anafranil)
  • Nortriptyline (Pamelor)
  • Rufinamide (Banzel)
  • Lorazepam (Ativan)
  • Felbamate (Felbatol)

In addition, certain anticonvulsants, barbiturates, and hydantoins could interact with Depakote.

In some cases, the effect of a barbiturate could increase to toxic levels while the potency of Depakote could decrease, making the medicine ineffective.

You should always tell your healthcare professional about all prescription, non-prescription, over-the-counter, illegal and recreational drugs, herbal remedies, nutritional and dietary supplements, and any other drugs and treatments you are taking.

Depakote Precautions

Serious side effects have been reported with Depakote including:

  • Liver toxicity: Your doctor will want to monitor your liver function tests. Tell your healthcare provider right away if you have some or all of the following symptoms of liver toxicity:
    • yellowish tint to eyes and skih
    • stomach pain and swelling
    • itchiness
    • dark urine color and/or pale stool color
    • bloody or tar-colored stool
    • fatigue
    • nausea and/or loss of appetite
  • 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. The most common birth defects with Depakote 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 can happen. 
    • Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. 
    • Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect. 
    • If you take divalproex during pregnancy for any medical condition, your child is at risk for having a lower IQ. 
    • There may be other medicines to treat your condition that have a lower chance of causing birth defects and decreased IQ in your child. 
    • Women who are pregnant must not take divalproex to prevent migraine headaches. 
    • All women of childbearing age 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 divalproex while you are pregnant. 
    • Pregnancy Registry: If you become pregnant while taking divalproex, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1­888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 
  • Pancreatitis: Tell your healthcare provider right away if you have some or all of the following symptoms of pancreatitis:
    • a swollen and tender abdomen
    • nausea
    • vomiting
    • fever
    • a fast pulse
  • Suicidal behavior or ideation: Tell your healthcare provider right away if you have some or all of the following symptoms of suicidal thoughts or actions:
    • new or worsening feelings of depression
    • suicidal thoughts or behavior
    • any unusual changes in mood or behavior
  • Thrombocytopenia (low platelet counts): Your doctor may want monitor platelet counts and bleeding tests. Tell your healthcare provider right away if you have some or all of the following symptoms thrombocytopenia:
    • bleeding that does not stop
    • bruising
  • Hyperammonemia and hyperammonemic encephalopathy (a condition of brain dysfunction): Tell your healthcare provider right away if you have some or all of the following symptoms of encephalopathy:
    • inexplicable tiredness and fatigue
    • vomiting
    • changes in mental status
  • Hypothermia: A drop in body temperature to 95 degrees Fahrenheit or less (hypothermia) has been reported with Depakote therapy.Tell your healthcare provider right away if you have some or all of the following symptoms of hypothermia:
    • fatigue
    • confusion
    • coma
    • changes heart rate, blood pressure, or breathing
  • Multi-organ hypersensitivity (allergic) reaction: Tell your healthcare provider right away if you have some or all of the following symptoms of an allergic reaction:
    • fever
    • rash
    • decreased urination
    • joint pain
    • weakness or loss of energy
    • Because this reaction may have effects on many organs of the body, not all symptoms are included.
  • Somnolence (drowsiness): This effect is seen especially in the elderly population. The dosage of divalproex should be increased slowly and with regular monitoring for fluid and nutritional intake.

Depakote can cause drowsiness, dizziness, and blurred vision. Do not drive or operate heavy machinery until you know how Depakote affects you.

Do not take Depakote if you:

  • are allergic to Depakote or to any of its ingredients
  • have liver disease or significant liver dysfunction
  • have a known mitochondrial disorder or suspect a mitochondrial disorder in children younger than 2 years old
  • have urea cycle disorders

Depakote Food Interactions

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Depakote, there are no specific foods that you must exclude from your diet when receiving Depakote.

Depakote Usage

Take Depakote exactly as prescribed.

Depakote comes in tablet or sprinkle capsule forms and is taken by mouth 1 to 2 times day.

Depakote tablets should be swallowed whole and should not be crushed or chewed.

Depakote sprinkle capsules may be swallowed whole or may be taken by carefully opening the capsule and sprinkling the entire contents on a small amount of soft food such as applesauce or pudding. The mixture should be swallowed immediately (avoid chewing). Do not store for future use.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Depakote at the same time.

Depakote Dosage

Take Depakote exactly as prescribed by your doctor. Follow the directions on your prescription label carefully. The dosage will vary, depending on the indication and response.

The dose your doctor recommends may be based on the following:

  • the condition being treated
  • other medical conditions you have
  • other medications you are taking
  • how you respond to this medication
  • your weight
  • your age

The recommended starting dose of Depakote for the treatment of mania in bipolar disorder is 750 mg daily. The dose is increased on the basis of response or desired levels in the blood. The maximum recommended dosage is 60 mg/kg/day.

The recommended starting of Depakote for the treatment of complex partial seizures is 10 to 15 mg/kg/day. The dose is increased at 1-week intervals by 5 to 10 mg/kg/day to achieve clinical response. The maximum recommended dosage is 60 mg/kg/day.

The recommended starting dose of Depakote for the treatment of absence seizures is 15 mg/kg/day. The dose is increased at 1-week intervals by 5 to 10 mg/kg/day until seizure control is achieved or side effects are not tolerable. The maximum recommended dosage is 60 mg/kg/day.

The recommended starting dose of Depakote for the prevention of migraine is 250 mg twice daily. The dose may be increased until migraine control is achieved. The maximum recommended dose is 1000 mg/day as needed.

Depakote FDA Warning

Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months.

Fetal Risk

Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure.  Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see Contraindications (4)]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate.

Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

Proper Use of valproic acid

This section provides information on the proper use of a number of products that contain valproic acid. It may not be specific to Depakote. Please read with care.

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine comes with a Medication Guide and patient information insert. Read and follow the instructions in the insert carefully. Ask your doctor if you have any questions.

Swallow the delayed-release capsules and oral capsules whole with a full glass of water. Do not split, crush, or chew it. You may take this medicine with food to decrease stomach upset.

Measure the oral liquid medicine with a marked measuring spoon, oral syringe, or medicine cup.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage forms (capsules, delayed-release capsules, and solution):
    • For seizures:
      • Adults and children 10 years of age or older—Dose is based on body weight and must be determined by your doctor. At first, the usual dose is 10 to 15 milligrams (mg) per kilogram (kg) of body weight per day. Your doctor may gradually increase your dose every week by 5 to 10 mg per kg of body weight if needed. However, the dose is usually not more than 60 mg per kg of body weight per day. If the total dose a day is greater than 250 mg, it is usually divided into smaller doses and taken two or more times during the day.
      • Children younger than 10 years of age—Use and dose must be determined by your doctor.
  • For oral dosage form (delayed-release capsules):
    • For mania:
      • Adults—At first, 750 milligrams (mg) once a day, usually divided in smaller doses. Your doctor may increase your dose as needed.
      • Children—Use and dose must be determined by your doctor.
    • For migraine:
      • Adults—At first, 250 milligrams (mg) two times a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 1000 mg a day.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Depakote

It is very important that your doctor check your progress closely while you are using this medicine to see if it is working properly and to allow for a change in the dose. Blood tests may be needed to check for any unwanted effects.

Using this medicine while you are pregnant (especially during first trimester) can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

It is very important to take folic acid before getting pregnant and during early pregnancy to lower chances of harmful side effects to your unborn baby. Ask your doctor or pharmacist for help if you are not sure how to choose a folic acid product.

Liver problems may occur while you are using this medicine, and some may be serious. Check with your doctor right away if you are having more than one of these symptoms: abdominal or stomach pain or tenderness, clay-colored stools, dark urine, decreased appetite, fever, headache, itching, loss of appetite, nausea and vomiting, skin rash, swelling of the feet or lower legs, unusual tiredness or weakness, or yellow eyes or skin.

Valproic acid may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. If you notice any of these side effects, tell your doctor right away.

Valproic acid may cause serious allergic reactions affecting multiple body organs (eg, liver or kidney). Check with your doctor right away if you have the following symptoms: a fever, dark urine, headache, rash, stomach pain, swollen lymph glands in the neck, armpit, or groin, unusual tiredness, or yellow eyes or skin.

Pancreatitis may occur while you are using this medicine. Tell your doctor right away if you have sudden and severe stomach pain, chills, constipation, nausea, vomiting, fever, or lightheadedness.

Check with your doctor right away if fever, sore throat, rash, ulcers in the mouth, nosebleeds, bleeding gums, swollen glands, or small red or purple spots on the skin occur. These could be symptoms of a serious blood problem.

Check with your doctor right away if you are having unusual drowsiness, dullness, tiredness, weakness or feelings of sluggishness, changes in mental status, low body temperature, or vomiting. These may be symptoms of a serious condition called hyperammonemic encephalopathy.

Valproic acid may cause some people to become dizzy, lightheaded, drowsy, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Do not stop taking this medicine without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping completely. This may help prevent worsening of seizures and reduce the possibility of withdrawal symptoms.

Before you have any medical tests, tell the medical doctor in charge that you are taking this medicine. The results of some tests may be affected by this medicine.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that cause drowsiness). Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies, or colds, sedatives, tranquilizers, or sleeping medicine, prescription pain medicine or narcotics, medicine for seizures (eg, barbiturates), muscle relaxants, or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are taking this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Dosage Forms and Strengths

Depakote tablets (divalproex sodium delayed-release tablets) are supplied as:

125 mg salmon pink-colored tablets

250 mg peach-colored tablets

500 mg lavender-colored tablets

Drug Interactions

Effects of Co-Administered Drugs on Valproate Clearance

Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.

In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.

Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.

The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported.

Drugs for which a potentially important interaction has been observed

Aspirin

A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered.

Carbapenem Antibiotics

A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.13)].

Estrogen-Containing Hormonal Contraceptives

Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result in decreased concentration of valproate and potentially increased seizure frequency. Prescribers should monitor serum valproate concentrations and clinical response when adding or discontinuing estrogen containing products.

Felbamate

A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated.

Rifampin

A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin.

Drugs for which either no interaction or a likely clinically unimportant interaction has been observed

Antacids

A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.

Chlorpromazine

A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.

Haloperidol

A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.

Cimetidine and Ranitidine

Cimetidine and ranitidine do not affect the clearance of valproate.

Effects of Valproate on Other Drugs

Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases.

The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported.

Drugs for which a potentially important valproate interaction has been observed

Amitriptyline/Nortriptyline

Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.

Carbamazepine/carbamazepine-10,11-Epoxide

Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.

Clonazepam

The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures.

Diazepam

Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate.

Ethosuximide

Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.

Lamotrigine

In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.

Phenobarbital

Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.

There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.

Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.

Phenytoin

Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.

In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.

Propofol

The concomitant use of valproate and propofol may lead to increased blood levels of propofol. Reduce the dose of propofol when co-administering with valproate. Monitor patients closely for signs of increased sedation or cardiorespiratory depression.

Rufinamide

Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. Rufinamide concentrations were increased by <16% to 70%, dependent on concentration of valproate (with the larger increases being seen in pediatric patients at high doses or concentrations of valproate). Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose [see Dosage and Administration (2.5)]. Similarly, patients on valproate should begin at a rufinamide dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults).

Tolbutamide

From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.

Warfarin

In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants.

Zidovudine

In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.

Drugs for which either no interaction or a likely clinically unimportant interaction has been observed

Acetaminophen

Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.

Clozapine

In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine.

Lithium

Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium.

Lorazepam

Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.

Olanzapine

No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.

Oral Contraceptive Steroids

Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.

Topiramate

Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.9, 5.11)].

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Depakote side effects

Get emergency medical help if you have any of these signs of an allergic reaction: to Depakote hives; fever, swollen glands, mouth sores, difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if the person taking this medicine has early signs of liver or pancreas problems, such as: loss of appetite, upper stomach pain (that may spread to your back), ongoing nausea or vomiting, dark urine, swelling in the face, or jaundice (yellowing of the skin or eyes).

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, depression, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself.

Call your doctor at once if you have any of these other side effects:

  • confusion, tiredness, cold feeling, vomiting, change in your mental state;

  • easy bruising, unusual bleeding (nose, mouth, or gums), purple or red pinpoint spots under your skin;

  • severe drowsiness;

  • worsening seizures;

  • signs of inflammation in your body - swollen glands, flu symptoms, severe tingling or numbness, muscle weakness, chest pain, new or worsening cough with fever, trouble breathing; or

  • severe skin reaction - fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common Depakote side effects may include:

  • mild nausea or vomiting, mild stomach pain, diarrhea;

  • headache, mild dizziness, weakness, tremors;

  • problems with balance or walking;

  • blurred vision, double vision; or

  • changes in appetite, weight gain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How it works

Experts are not exactly sure how Depakote works although they suspect its activity is related to increased brain concentrations of gamma-aminobutyric acid (GABA) - a neurotransmitter in the brain that calms nervous activity.

(web3)