Carbamazepine

Carbamazepine (CAR-buh-MAZ-uh-peen) is the generic name of a widely used antiepileptic drug (AED). Brand names for carbamazepine in the United States include Tegretol and Carbatrol. In other countries, brand names include Carbagen SR, Mazepine, Tegrital, Teril, and Timonil.

Epitol
Tegretol
Tablet
Tegretol 200mg

200-mg (capsule-shaped, pink)
One side says "Tegretol" and the other side says "27" on each half. These should be swallowed whole, not chewed.

Tegretol Chewable 100mg

100-mg Chewable tablets (round, white with red speckles)
One side says "Tegretol" and the other side says "52" on each half. These tablets are flavored and can be either swallowed whole or chewed.

Liquid Solution

100 mg per 5 mL (yellow-orange, citrus-vanilla flavored liquid). 

Indications

Carbamazepine is indicated for use as an anticonvulsant in people of all ages. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:

  • Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types.
  • Generalized tonic-clonic seizures (grand mal).
  • Mixed seizure patterns that include the above, or other partial or generalized seizures.

Forms

Various companies make and sell carbamazepine under different names, including Epitol and Atretol. It is generally available in three forms:

  • 200-mg tablets: to be swallowed whole, not chewed
  • 100-mg chewable tablets: to be either swallowed whole or chewed
  • Suspension (100 mg/5 mL)

Dosing

See package insert.

How to take and store Carbamazepine?

Most doctors recommend taking carbamazepine with food to avoid an upset stomach, but it can also be taken on an empty stomach. Consistency is important, to avoid variations in absorption.

Remind patients using the suspension to shake the bottle just before measuring. Advise them not to mix carbamazepine suspension with any other liquid or take it at the same time as another liquid medication. (A precipitate may be produced when carbamazepine suspension is mixed with some other liquids.)

Store all types of carbamazepine at controlled room temperature (below 86°F, 30°C). Protect the suspension from light.

Missed doses of carbamazepine are common because many people need to take it three or four times per day. Advise patients to take a forgotten dose immediately unless it is almost time for the next dose. In that case, they should either skip the forgotten dose (rather than taking a double dose) or make it up with the next 2 or 3 doses.

Patients who often forget doses may benefit from using a special pillbox or watch with an alarm. Switching to a twice-a-day extended-release form (in the U.S., Tegretol-XR or Carbatrol) may also be helpful.

Missed Doses

Missed doses of carbamazepine are common because many people need to take it three or four times per day. Advise patients to take a forgotten dose immediately unless it is almost time for the next dose. In that case, they should either skip the forgotten dose (rather than taking a double dose) or make it up with the next 2 or 3 doses.

Patients who often forget doses may benefit from using a special pillbox or watch with an alarm. Switching to a twice-a-day extended-release form (in the U.S., Tegretol-XR or Carbatrol) may also be helpful.

Mechanisms of actions of Carbamazepine

Carbamazepine blocks frequency-, use- and voltage-dependent neuronal sodium channels and therefore limits repetitive firing of action potentials.

It also affects calcium channels, GABA receptors, and adenosine receptors and increases concentrations of serotonin and other neurotransmitters. Whether these effects contribute to its anticonvulsant activity is not clear.

Clinical Pharmacology of Carbamazepine

Carbamazepine is metabolized and eliminated by the liver. It is metabolized by the hepatic P450 system (in particular, the 3A4 isoenzyme). Carbamazepine is ~70-80% protein-bound.

Carbamazepine induces its own metabolism (autoinduction) within the first month of treatment and also accelerates the metabolism of other hepatically metabolized drugs (see Interactions with other medications). The half-life in chronic therapy (that is, after autoinduction is complete) is 10-20 hours.

The main metabolite of carbamazepine is carbamazepine-10,11-epoxide. This metabolite is active and also is associated with neurotoxicity.

Efficacy of Carbamazepine

Carbamazepine is effective against partial seizures, secondarily generalized seizures, and tonic-clonic seizures. It is not effective against other generalized seizure types, such as absence seizures or myoclonic seizures.

Effective serum concentrations generally range from 4-12 mg/L, though lower or higher concentrations may be necessary in some individual patients. Serum concentrations should be checked after approximately one month of treatment, when autoinduction may occur.

A VA Cooperative study in adults with partial and generalized tonic-clonic seizures (Mattson et al. 1985) showed that carbamazepine was as effective as phenytoin and better tolerated than phenobarbital or primidone. Another VA study (Mattson et al. 1992) showed that carbamazepine was as effective as valproate for secondarily generalized seizures and more effective for partial seizures.

If carbamazepine alone does not stop all seizures, a combination of carbamazepine and another anti-epileptic drug (AED) may be more effective. Phenytoin or valproate are often used, but many newer AEDs are also available.

Common side effects of Carbamazepine

Dose-related side effects: The most common side effects are neurotoxic and dose-related. They include:

  • Drowsiness
  • Diplopia
  • Headache
  • Ataxia
  • Nausea
  • Vomiting
  • Dizziness

These side effects tend to occur within a week of initiation or dosage increase. In chronic therapy, they typically are noticeable 3-4 hours after a dose (associated with peak serum concentrations).

They can be lessened by:

  • Reducing the total daily dosage
  • Splitting the total daily dosage into more frequent doses
  • Shifting more of the total daily dosage to bedtime, especially for patients with nocturnal or early-morning seizures
  • Switching to an extended-release form of carbamazepine, like Tegretol-XR or Carbatrol

Other systemic side effects include:

  • Abdominal pain
  • Constipation
  • Diarrhea
  • Loss of appetite

Hyponatremia is generally asymptomatic, though fluid retention, confusion, and increased seizures may signal symptomatic hyponatremia. In such cases, fluid restriction may be helpful. If symptomatic hyponatremia persists, discontinuation is warranted. Elderly patients and others with heart disease appear to be at particular risk for hyponatremia. Serum sodium should be checked before treatment and within the first month of treatment.

Adverse effects on cognition, memory, or mood generally are not commonly associated with carbamazepine.

To avoid possible bone loss associated with long-term use, patients should be advised to meet recommended requirements for vitamin D and calcium, expose their skin to sunlight in moderation, and engage in antigravity exercises.

Idiosyncratic reactions: Idiosyncratic reactions include a morbilliform rash in approximately 5-10% of patients. More serious rashes, such as Stevens-Johnson syndrome, photosensitivity, exfoliative dermatitis, and erythema multiforme, occur rarely.

Serious Side effects of Carbamazepine

Potentially life-threatening reactions to carbamazepine involve aplastic anemia, toxic hepatitis, pancreatitis and skin reactions, specifically Stevens Johnson syndrome and toxic epidermal necrolysis.

About 1 in 30,000 people who take carbamazepine will develop serious blood disorders. Baseline blood and platelet counts should be obtained and repeated early in the course of therapy. Generally, discontinuation of carbamazepine is not necessary unless blood counts are significantly reduced or leukopenia persists. (Up to 10% of patients have a leukopenia that reverses within 1-2 weeks.) Patients should be told to report easy bruising, fever, or infections.

Renal and hepatic function tests also can be performed before treatment and repeated later if clinically indicated. Patients should be advised to report possible symptoms of hepatitis, including:

  • Yellow eyes or skin
  • Loss of appetite
  • Upset stomach with vomiting
  • Black or pale bowel movements

On December 12, 2007, the Food and Drug Administration informed healthcare professionals that dangerous or even fatal skin reactions (Stevens Johnson syndrome and toxic epidermal necrolysis), that can be caused by carbamazepine therapy, are significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B*1502. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. Patients with ancestry from areas in which HLA-B*1502 is present should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine. If these individuals test positive, carbamazepine should not be started unless the expected benefit clearly outweighs the increased risk of serious skin reactions. Patients who have been taking carbamazepine for more than a few months without developing skin reactions are at low risk of these events ever developing from carbamazepine. This is true for patients of any ethnicity or genotype, including patients positive for HLA-B*1502. (source: http://www.fda.gov/medwatch/safety/2007/safety07.htm#carbamazepine)

If you believe that you have experienced a serious side effect from a medication, you or your physician can bring it to the attention of the FDA, through their MedWatch program, by completing an adverse event report form (http://www.fda.gov/medwatch/getforms.htm). MedWatch is the FDA's program for reporting serious reactions and problems with medical products, such as drugs and medical devices. To learn more about the Medwatch program go to: http://www.fda.gov/medwatch/report/consumer/consumer.htm

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 1,000 people taking the placebo (inactive substance) showed suicidality compared to approximately 3.5 out of 1,000 people who took an anti-epileptic drug (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.

Impact of Carbamazepine on bone health

Carbamazepine use has been associated with osteoporosis or osteopenia in both men and women taking this drug. It is essential if you are taking this medication that you take supplemental calcium of 1,000 milligrams per day. Talk to your doctor about bone health. He or she may decide to check vitamin D levels and perform other tests to check for the impact of this drug on your bones.

Other Uses of Carbamazepine

Carbamazepine is a first-line treatment and FDA-approved for trigeminal neuralgia. It also is used to treat glossopharyngeal neuralgia and painful peripheral neuropathy (particularly due to diabetes).

The use of carbamazepine in the management of patients with acute mania is supported by a number of studies, which have found it similar in effectiveness to lithium.

The literature also supports the use of carbamazepine for long-term prophylaxis of bipolar disorder, particularly for rapid cyclers.

It is sometimes used for other psychiatric disorders and diabetes insipidus, but few studies have been performed to confirm its effectiveness for those conditions.

Carbamazepine Contraindications

Carbamazepine may exacerbate absence and myoclonic seizures. Therefore, if complex partial seizures are diagnosed on the basis of the history and the episodes increase after carbamazepine is started, one possibility is that the patient actually has absence seizures. EEG (electroencephalogram) testing should be undertaken to classify the seizure type.

Rashes that may be very serious are more likely to occur in persons with a particular gene called “HLA-B*1502”. This gene occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. Patients with ancestry from these areas should have a blood test by their physician to see if they have the “HLA-B*1502” gene before starting treatment.

Carbamazepine should not be taken by anyone who:*

  • is allergic to carbamazepine or any ingredients of the tablets or suspension
  • is allergic to tricyclic compounds such as amitriptyline, trimipramine, or imipramine
  • has liver disease
  • has a history of acute intermittent porphyria
  • has a history of hyponatremia
  • has a serious blood disorder
  • has a history of bone marrow depression
  • has taken an MAO inhibitor within the past 14 days or will take one within the next 14 days
  • has certain kinds of heart rhythm disturbances (AV block)

*Information adapted from www.HealthyOntario.com, accessed Aug. 12, 2003.

Carbamazepine Interactions with other medications

Effects of carbamazepine on other drugs: Because carbamazepine accelerates hepatic metabolism, it will increase the clearance of:

  • Oral contraceptives
  • Valproate
  • Phenytoin
  • Phenobarbital
  • Primidone
  • Clonazepam
  • Topiramate
  • Ethosuximide
  • Corticosteroids
  • Warfarin
  • Antipsychotics
  • Cyclosporine

Effects of other drugs on carbamazepine: Drugs that will increase the serum concentration of carbamazepine by inhibiting its hepatic metabolism include:

  • Valproate
  • Cimetidine
  • Dextropropoxyphene
  • Diltiazem
  • Drythromycin
  • Isoniazid
  • Verapamil
  • Viloxazine
  • Fluconazole, ketoconazole, metronidazole, nefazodone
  • Fluoxetine

Grapefruit juice has a similar effect.

Taking carbamazepine simultaneously with lamotrigine may increase the likelihood of neurotoxic side effects. Staggering the doses of carbamazepine and lamotrigine by 1 to 2 hours may lessen this effect.

On the other hand, drugs that accelerate hepatic metabolism will lower serum concentrations of carbamazepine. These include:

  • Phenytoin
  • Oxcarbazepine
  • Phenobarbital
  • Primidone
  • Felbamate

AED Interaction Sheets: Seizure drugs are often affected by drug-drug interactions. Print these informative sheets for practical help.

Interaction sheet for carbamazepine (Tegretol, Tegretol XR, Carbatrol)

Carbamazepine effects on Children

Carbamazepine is useful in treating many kinds of seizures that occur in children. But other types can be exacerbated (see Contraindications), so a correct diagnosis is critical.

Because children metabolize and eliminate carbamazepine faster than adults do, they require higher doses, relative to their weight. Their blood levels may fluctuate widely, so they often are more affected by dose-related side effects and may need to take smaller, more frequent doses. Using an extended-release form like Tegretol-XR or Carbatrol may reduce this problem. These differences diminish by the early to mid teens.

The initial dosage for children is generally 5-10 mg/kg, divided into two daily doses. Increases usually go no higher than 35 mg/kg, divided into 3 or 4 doses if an extended-release form is not used. Very young children and infants tend to require higher dosages relative to weight than older children.

Carbamazepine and Pregnancy

Carbamazepine is listed in Pregnancy Category D. A warning appears in the package insert.

Patients who require carbamazepine monotherapy to control their seizures can be advised that up to 90% of women who use it during pregnancy have normal, healthy babies. Approximately 0.5% of fetuses exposed to carbamazepine during weeks 4-6 have spina bifida, so Level II ultrasound at 16 weeks gestation is recommended, as is amniocentesis in selected cases. Minor craniofacial defects, fingernail hypoplasia, and developmental delay may occur somewhat more frequently.

The risk of defects is higher for women who take several medicines and for women with a family history of birth defects.

Women who are capable of becoming pregnant should be advised to take at least 400 mcg (0.4 mg) of folic acid (folate) daily to help prevent neural tube defects. Women at high risk, such as those with a history of a neural tube defect in a previous pregnancy, should take 4,000 mcg (4 mg) daily, beginning before they become pregnant.

Check the levels of carbamazepine in the woman's blood at intervals during pregnancy, since changes in her body may affect them. Dosage adjustments may be needed to prevent seizures or side effects.

During the last month of pregnancy, the woman should take 10 mg per day of vitamin K to prevent a bleeding disorder that affects some babies born to mothers who are taking anticonvulsants.

No studies have been performed to demonstrate the effect of specific anti-epileptic drugs (AEDs) during labor and delivery. Possible causes of seizures include:

  • Failure or inability to take medication
  • Sleep deprivation
  • Hyperventilation
  • Stress
  • Pain

If the mother is taking carbamazepine, a breast-fed newborn will get about 2-5 mg per day in the breast milk. The effect of such a dose has not been evaluated but is unlikely to be harmful for a healthy, full-term baby.

Carbamazepine Dosing and titration

Rashes that may be more serious are more likely to occur in persons with a particular gene called “HLA-B*1502.” This gene occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. Patients with ancestry from these areas should have a blood test to see if they have the “HLA-B*1502” gene before starting treatment. Further Information for Healthcare Professionals Related to this Topic: http://www.fda.gov/cder/drug/InfoSheets/HCP/carbamazepineHCP.htm

Carbamazepine should be started at 100-200 mg per day and titrated by increments of 100-200 mg every week or two as clinically needed. The average maintenance dose as monotherapy for adults is 600-1,200 mg per day. In children over 6, the usual maintenance dose is 15-30 mg/kg per day. The dosage may need to be increased within a month of initiation due to autoinduction. (See Clinical pharmacology.)

Many people (especially children) need to take carbamazepine in three or four doses a day. The extended-release forms, Tegretol-XR or Carbatrol, are often preferable for patients who have trouble with compliance and for those whose blood levels fluctuate widely throughout the day.

Algorithm for Dosing Carbamazepine

Carbamazepine effects on Seniors

See package insert.

Carbamazepine Package insert

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 Tegretol (carbamazepine) is found at:

Some of the information may differ in other countries.

Learn how to read a package insert here.

Carbamazepine References for Professionals

Abstracts of articles relevant to this topic are available through PubMed, a service of the National Library of Medicine.

Mattson, RH, Cramer, JA, et al. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondarily generalized tonic clonic seizures. N Engl J Med 313:145-151, 1985. PMID: 3925335.

Carbamazepine was more effective than primidone (Mysoline) or phenobarbital in controlling partial seizures. Overall, carbamazepine and phenytoin (Dilantin) are the first choices for a single medication to treat adults with newly diagnosed partial seizures, generalized tonic-clonic seizures, or both.

Mattson, RH, Cramer, JA, et al. A comparison of valproate with carbamazepine for the treatment of partial seizures and secondarily generalized tonic-clonic seizures in adults. N Engl J Med, 327:765-771, 1992. PMID: 1298221.

Carbamazepine and valproate (Depakote) are equally effective for treating generalized tonic-clonic seizures in adults. Although other studies show that valproate is effective for newly diagnosed partial seizures, in this study carbamazepine provided better control of complex partial seizures. The side effects of these two medications are different.

Snead OC III, Hosey LC. Exacerbation of seizures in children by carbamazepine. N Engl J Med 1985;313:916-21.

A call for caution when using carbamazepine in children with mixed seizure disorders.

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