Volume 7, Issue 7 July 2011
Carbamazepine (CBZ) is one of the most commonly prescribed drugs worldwide for the treatment of neurologic disorders. Carbamazepine is considered an effective compound for the treatment of partial and secondary generalized seizures in children and adults with an acceptable side effect profile. Given the popularity of this particular medication, epilepsy.com will discuss carbamazepine and its use in this month’s column focusing on antiepileptic drugs (AEDs). Carbamazepine has been on the world market since the mid 1960s. It is available in a variety of formulations including tablets, solutions, oral suspension, chewable tablets, and extended release tablets. The peak concentration or the highest blood level after taking an immediate release form of the medication occurs approximately three to four hours later. However, the extended release form has increased this value by up to 12 hours. One of the positive aspects of carbamazepine is the fact that it is fat soluble. Compounds that are fat soluble cross the barrier between the blood and the brain rather easily, and therefore it is able to access the neurons in the cortex of the brain quickly which is where seizures are generated.
Carbamazepine exerts its effect by blocking L-type calcium channels, as well as voltage dependent sodium channels of neurons. This helps to prevent seizures by decreasing excitability. Carbamazepine is metabolized through the liver. Similar to phenytoin, discussed last month, carbamazepine also is processed through the cytochrome P450 system. Carbamazepine, however, is different from phenytoin in that it causes a process in its metabolism called autoinduction, which means, that after taking the pill for a short period of time, it actually increases its own metabolism, leading to a shorter half life in the body and lowering its level. Typically, this process can take two to six weeks to occur after starting the medication. Clinically, this translates to the fact that over time, the toxic feeling one may develop after starting carbamazepine will likely ease once autoinduction begins.
Because carbamazepine is processed through the liver it has a number of drug interactions. Noteworthy medications that interact with carbamazepine include grapefruit juice, hormones and antibiotics. It is often noted that carbamazepine can reduce the effectiveness of oral contraceptives. It can also interact with a number of other medications. For a comprehensive list of the potential drug interactions of carbamazepine and other medications it is important to speak to your doctor or refer to the Physicians’ Desk Reference (PDR), the FDA web site or epilepsy.com for more information.
Carbamazepine’s popularity is primarily due to the fact that it has been proven to be an effective drug. It is considered to be a first line treatment choice for patients with focal onset seizures. In comparison to drugs such as phenytoin, there is no difference in how effective carbamazepine or phenytoin is with regards to control of seizures. No differences in effectiveness have been reported in trials that compare carbamazepine and phenobarbital in children. In one study in the mid 1980’s carbamazepine appeared to be more effective than valproic acid for the treatment of patients with partial seizures, including the number of seizures, and the time to first seizure. Other studies have not revealed a significant differences between carbamazepine and valproic acid in adults or children.
The first Veterans Administration (VA) study was performed comparing carbamazepine versus phenobarbital, phenytoin, and primidone in monotherapy. Carbamazepine was found to be as useful as phenobarbital, phenytoin and primidone in controlling secondary generalized atonic clonic seizures. However, carbamazepine was more effective than phenobarbital for the treatment of partial seizures whether simple or complex. No differences were found between carbamazepine and phenytoin. Other studies have not demonstrated the difference between carbamazepine, phenobarbital, phenytoin or valproic acid.
A more recent VA study compared 593 older aged patients ( 65 years or older) with newly diagnosed seizures comparing gabapentin, lamotrigine and carbamazepine and concluded, although the three medications are fairly similar in terms of their helpfulness, patients who take lamotrigine or gabapentin did better than those taking carbamazepine. The authors concluded that carbamazepine should not be first choice in patients who are older than the age of 65 years.
Carbamazepine has been tested against all new AEDs as monotherapy. The majority of these studies have shown no difference in efficacy between carbamazepine and lamotrigine in adults, adolescents, and children; oxcarbazepine or topiramate in children and adults as well. However, carbamazepine has been found to be more effective than vigabatrin and gabapentin. A newer study compared carbamazepine and levetiracetam but did not show differences in the effectiveness between these medications. In sum, carbamazepine is considered a top AED choice for partial seizures and is a drug standard. It usefulness is limited by tolerability of its side effects.
Carbamazepine side effects tend to be mild, temporary, and related to dose. The most common side effects are nausea, gastrointestinal discomfort, headache, dizziness, vertigo, blurred vision, and imbalance. There can also be other disturbances, particularly with thought processing, including restlessness, agitation, and anxiety. Reported neuropsychological adverse effects have included a feeling as though one is “drugged”. In rare instances, movement conditions involving ticks and conditions known as dystonia have been reported, but typically the serum level of the medication is reportedly high.
One of the more concerning adverse effects related to carbamazepine is rash. Rash has been reported in up to 10% of patients. In some cases it causes a rather serious reaction, otherwise known as the anticonvulsant hypersensitivity syndrome. This syndrome is typically characterized by a combination of fever, rash, and another internal organ involvement. This can be seen two to eight weeks after starting the medication and the reaction typically starts with a low fever, and a rash occurs subsequently, often with lymph node swelling. This reaction is something that must be reported to one’s physician or healthcare professional immediately.
Other prominent complications include a fall in white blood cell count within the first three months of treatment in up to 10 to 20% of patients taking the drug. A persistent drop in white blood cell count is seen in almost 2% of patients and completely reverses on stopping the medication. Low platelets has also been reported and there is even a rare risk for a condition known as aplastic anemia in which much of the blood cells within the bone marrow are seriously impacted. The risk for aplastic anemia in the general population is about 2 to 2.5 per million patients; however, in individuals taking carbamazepine the level is 5.1 patients per one million. This reaction occurs when one begins to take carbamazepine and not later. The only treatment for this rare side effect is a bone marrow transplant.
One of the more problematic side effects of carbamazepine is something known as low sodium or hyponatremia. The risk for hyponatremia is related to the dose of carbamazepine and the age of the patient. This side effect does not occur in children. Other side effects include the fact that thyroid function tests can be abnormal. Carbamazepine does tend to increase the metabolism of thyroid hormones, so hypothyroid patients may require higher dose of thyroid supplementation.
Similar to phenytoin and other antiepileptic drugs, carbamazepine does have teratogenic effects or an impact on children of women who are taking the medication. Carbamazepine exposure has been associated with neural tube defects and major congenital malformations if taken during the first trimester of pregnancy. When taking carbamazepine with other seizure medications it also elevates teratogenic risk. The mechanism for this effect is believed to be related to folate. Thus, all women of child bearing years taking carbamazepine should be on daily supplemental folic acid. Women taking carbamazepine should have prenatal diagnostic ultrasound to detect any congenital malformations. However, on a positive note, breastfeeding is considered safe for women taking carbamazepine.
Weight gain is a side effect associated with carbamazepine but does not tend to be pronounced. Liver enzymes may be elevated as well in taking carbamazepine. There has been some report of changes in heart rhythms. Similar to phenytoin, carbamazepine use can lead to osteoporosis and it is essential that people taking carbamazepine supplement with a minimum of 1000 mg. of calcium in order to prevent osteoporosis.
Carbamazepine is one of the agents of choice for the treatment of localization related epilepsies, primarily for partial seizures and generalized tonic clonic seizures. Doses are adjusted individually. Carbamazepine levels are available and can be monitored. The usual range is between 4 to 12 mg. per liter. Similar to phenytoin, having a carbamazepine level that falls between a “normal” range that does not necessarily mean that you will be guaranteed seizure freedom. The drug is typically taken two to three times a day unless you have an extended release form, where you might take it one to two times a day. Toxicity can be avoided by taking carbamazepine up to three times a day in order to minimize the peak dose effect of the medication. Older adults may not require higher doses as younger individuals.
Carbamazepine should not be used in patients with a known hypersensitivity to any tricyclic antidepressant. Carbamazepine can worsen certain epilepsies by aggravating preexisting seizures or leading to new seizure types. In particular, carbamazepine can worsen absence and myoclonic seizures and therefore it is likely that one needs to avoid this medication in individuals who have those seizure types.
Recently, severe allergic reactions associated with rash caused by carbamazepine have been found to be highly associated in patients with a particular human leukocyte antigen (HLA) allele. HLA-B 1502 occurs exclusively in patients with Asian ancestry. A recent FDA alert recommended that patients with ancestry of an at risk population be screened for this prior to starting carbamazepine and that positive patients should be excluded from taking this medication.
THINGS THAT YOU SHOULD KNOW ABOUT CARBAMAZEPINE
Carbamazepine is probably most useful as one of the first choice medications for individuals who present with partial seizures but needs to be avoided in individuals with generalized epilepsy, as the drug could worsen that condition. There are a number of adverse effects, including the feeling of being drugged, tiredness, imbalance, bone health, the impact on children of women who are exposed to the drug in the first trimester, rash, diminished white blood cell count and low sodium.
How can the Epilepsy Therapy Project help?
The Epilepsy Therapy Project is involved in helping to fund research into new treatments for epilepsy that can be brought to the patient as soon as it is safely feasible to do so. The Epilepsy Therapy Project helps by promoting the discovery of newer alternatives to carbamazepine. It can also, through the use of My Seizure Diary on Epilepsy.com, help patients track how well they are doing with regards to seizure control potential drug interactions, and side effects ultimately leading to an improved quality of life.
Hallway Conversations, a series of audio podcasts in which Dr. Joseph Sirven, Editor-in-Chief of epilepsy.com, has the pleasure of having a brief conversation with thought leaders and newsmakers in the field of epilepsy on a range of seizure related topics. The series is intended as a second opinion to help clinicians understand the latest research as explained by the investigator or perhaps focus on a clinical issue with the help of a leading epilepsy authority on the topic. The purpose is to frame the latest epilepsy news in the right context so as to better manage patients with seizures and improve quality of life. We hope that you find the series informative and helpful and that you join us in listening on a regular basis.
Listen to the latest podcasts in the Hallway Conversations series from:
July 26, 2011, 9:00am EDT
Scott Mintzer, MD
Associate Professor of Neurology
Director, Epilepsy Monitoring Unit and Epilepsy Surgery Program
Jefferson Comprehensive Epilepsy Center
Thomas Jefferson University
Topic: Antiepileptic drug selection and effectiveness
June 3, 2011
Jacqueline French, MD
President Epilepsy Study Consortium
Epilepsy Therapy Project,
Board of Directors; Chair, Scientific Advisory Board
Professor of Neurology NYU School of Medicine
Topic: Highlights from the AED XI Pipeline Conference
May 18, 2011
Avani Modi, Ph.D.
Assistant Professor in Pediatrics
Division of Behavioral Medicine and Clinical Psychology
Center for Treatment Adherence and Self Management
Cincinnati Children's Hospital Medical Center
Topic: Taking Your Medications: Following Doctors Orders and Seizures
Interested In Participating?
If you are interested in participating in a Hallway Conversation interview, please contact ETP at: firstname.lastname@example.org
AED XI CONFERENCE PRESENTATIONS ARE NOW ONLINE:
For those of you who want to know more about the Epilepsy Pipeline and could not attend the recent AED XI Conference in Miami, we can now bring the conference to you. We are proud to offer the slides and audio presentations of the conference lectures on epilepsy.com.
For a more summarized view of the proceedings, listen to the recent Hallway Conversation with Dr. Jackie French discussing the Conference with epilepsy.com editor, Dr. Joseph Sirven. Follow the link in the Hallway Conversations section below.
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The New Therapy - Commercialization Grants Program is a unique partnership between two leading epilepsy non-profit organizations, the Epilepsy Therapy Project and the Epilepsy Foundation. The mission of the New Therapy - Commercialization Grants Program is to drive the development of new therapies for epilepsy, accelerating the advancement of research from the laboratory to the patient. Funding is provided to academic and commercial groups worldwide.
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