Carbamazepine-XR

Carbamazepine-XR is the extended-release carbamazepine available in the United States.

Carbatrol
Tablet

100 milligrams (photo not available)
Bluish-green two-piece capsule, printed with company logo in white ink.

Carbatrol 300mg

200 milligrams
A two-piece capsule with a light gray body and bluish green cap.

Carbatrol 300mg

300 milligrams
A two-piece capsule with a black body and bluish green cap.

Each Carbatrol capsule contains tiny beads of medication. These have three different types of coatings so that they dissolve at different times:

  • 25% of the beads dissolve and release their medication almost immediately
  • 40% dissolve gradually over 8 to 12 hours
  • 35% dissolve only after the medication reaches the small intestine, where it is released slowly
Tegretol XR
Tablet
Tegtretol XR 100mg

100-mg (yellow)

Tegtretol XR 200mg

200-mg (pink)

Tegtretol XR 400mg

400-mg (brown)

How to take and store Carbamazepine-XR?

Carbatrol capsules must not be crushed or chewed. The contents can be sprinkled over food, however, without affecting the extended-release qualities. Advise patients who are unable to swallow capsules to sprinkle the contents over a teaspoonful of applesauce, pudding, ice cream, oatmeal, yogurt, or other similar food and then swallow it immediately without chewing. Drinking a glass of water or another liquid may help with swallowing. Carbatrol also can be given through most feeding tubes.

Carbatrol can be taken either with or without meals. The extent of absorption and elimination half-life are the same, though the rate of absorption is faster when Carbatrol is given with a high-fat meal.

Advise patients to avoid grapefruit juice, which inhibits the hepatic metabolism of Carbatrol.

Store Carbatrol capsules at room temperature (below 77°F) and protect them from light and moisture.

Missed Doses

Because Carbatrol is usually taken only twice daily, patients are less likely to miss doses than if they take many other forms of carbamazepine, which may require tid or qid dosing. Advise patients to take a forgotten dose immediately. If it is almost time for the next dose, they should delay the next dose rather than taking two doses very close together.

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

Mechanisms of actions of Carbamazepine-XR

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-XR

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 of Carbatrol with other medications). The half-life in chronic therapy (that is, after autoinduction is complete) is 10-20 hours in young adults but is shorter in children and longer in the elderly.

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

Efficacy of Carbamazepine-XR

Carbatrol 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 AED may be more effective. Phenytoin or valproate are often used, but many newer AEDs are also available.

Common side effects of Carbamazepine-XR

Dose-related side effects
The most common side effects of carbamazepine are neurotoxic and dose-related. Because the extended-release feature of Carbatrol produces more stable blood levels than Tegretol tablets, Tegretol suspension, or most forms of generic carbamazepine, side effects tend to be less troublesome when Carbatrol is used.

The most common dose-related side effects include:

  • drowsiness
  • diplopia
  • headache
  • ataxia
  • nausea
  • vomiting
  • dizziness

These side effects tend to occur within a week of initiation or dosage increase. 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

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-XR

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, the active ingredient of Carbatrol, are significantly more common in patients who have a particular type of 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 in which HLA-B*1502 is present should have a blood test by their physicians to see if they have the “HLA-B*1502” gene 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 even true for patients who test 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. (http://www.fda.gov/medwatch/getforms.htm.) 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 1000 people taking the placebo (inactive substance) showed suicidality compared to approximately 3.5 out of 1000 people who took an AED.

  • 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-XR on bone health

Carbamazepine use has been associated with osteoporosis and or osteopenia in both men and women taking this drug.  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.

Other Uses of Carbamazepine-XR

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. In fact, a very similar product called "Equetro" is approved for the treatment of acute manic and mixed episodes associated with Bipolar I Disorder. For more information please go to www.equetro.com

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-XR 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 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 to 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-XR 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
  • erythromycin
  • isoniazid
  • verapamil
  • viloxazine
  • fluoxetine
  • fluconazole, ketoconazole, metronidazole, nefazodone

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, even with Carbatrol.

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

  • phenytoin
  • phenobarbital
  • primidone
  • oxcarbazepine
  • felbamate

AED Interaction Sheets:

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

Carbamazepine-XR effects on Children

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

Children metabolize and eliminate carbamazepine faster than adults do. Consequently 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. These differences diminish by the early to mid teens.

Using an extended-release form like Carbatrol or Tegretol-XR may reduce the problems caused by wide swings in blood level. Carbatrol capsules, the contents of which can be sprinkled over a spoonful of food, would appear to be a good choice for children. The smallest capsule is 100 mg, however, which may be too large a dose for very small children, especially as initial treatment.

The initial dosage of carbamazepine for children is generally 5-10 mg/kg, divided into two daily doses. Increases usually go no higher than 35 mg/kg. Very young children tend to require higher dosages relative to weight than older children.

Carbamazepine-XR 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 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 4000 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 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-XR effects on Seniors

Doctors have prescribed carbamazepine to people over 65 for many years with good results. Seniors do have a few special problems, however:

  • Lower doses required, because elderly patients metabolize carbamazepine more slowly than younger adults. A 100-mg Carbatrol capsule once a day may be an appropriate dose for many seniors, especially as initial therapy.
  • More possibilities for drug interactions. Usually seniors can continue to take all their medications, including carbamazepine, if the dosages are changed to compensate for the effects of interactions.
  • Greater susceptibility to side effects. Some common side effects of carbamazepine, such as sleepiness or unsteadiness, may exacerbate pre-existing problems. Because Carbatrol produces more even blood levels than shorter-acting forms of carbamazepine, side effects are likely to be reduced at the same dosage.
  • Greater danger of injury from falls or other accidents resulting from side effects.
  • Need for more frequent monitoring of patients with glaucoma for mild pressure increases.
  • Hyponatremia is much more common in seniors (especially those taking diuretics) than in young people who take carbamazepine. It is usually asymptomatic, but if severe it could be associated with seizures or cardiac arrhythmias. Early symptoms are dizziness, headache, sleepiness, and upset stomach. Fluid restriction may help, but seniors should also be cautioned about dehydration.
  • Confusion or agitation has occasionally been reported in seniors taking carbamazepine. This is probably similar to the effect reported with the use of tricyclic antidepressants, a related group of medications.

Older patients and their family members should be especially encouraged to report any changes in health or behavior promptly.

Carbamazepine-XR Dosing and titration

Many people (especially children) need to take prompt-release carbamazepine in three or four doses a day. Carbatrol, as an extended-release form, is more convenient and may be particularly helpful for patients who have trouble with compliance and for those whose blood levels fluctuate widely throughout the day.

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

In general, 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 600-1200 mg per day.

Seniors should be started at 100 mg/d and may require a lower maintenance dose, reached by small increments.

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.) Carbatrol's use as a sprinkle formulation is convenient, but taking less than the complete contents of the capsule is not recommended.

Carbamazepine-XR 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-XR (carbamazepine-xr) 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."

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