Patients vary in their response to the various available epilepsy therapies, often requiring clinicians to weigh the risks of untreated disease with those for potential drug toxicities. Pharmacists should consider these constraints when consulting with epilepsy patients about their therapy, according to experts in the field of epilepsy.
For example, pharmacists should respect—but not fear—the agent felbamate because, although it has some associated toxicity, it is an excellent drug for refractory epilepsy in patients over the age of 4 years, especially those with refractory Lennox-Gastaut syndrome (LGS), according to pediatric neurologist Mary L. Zupanc, MD.
Calling felbamate “one of the best drugs we have available” for intractable epilepsy, Dr. Zupanc told Pharmacy Practice News that “doctors are increasingly using it, and pharmacists need to become familiar with this drug.”
Some pharmacists have cautioned patients against taking felbamate, based on fears stemming from reports of aplastic anemia and liver toxicity after the drug received FDA approval in 1993. But these warnings to patients are misguided, said Dr. Zupanc, the director of the Comprehensive Epilepsy Program and the chief of the Division of Child Neurology at the Children’s Hospital of Orange County, in Orange, Calif. Dr. Zupanc said she was part of the investigational team for the drug and has used it extensively since 1987, before it was FDA-approved.
The risks associated with felbamate must be weighed against the risks of inadequately controlled epilepsy, Dr. Zupanc stressed. Those risks include sudden unexplained death in epilepsy, progressive cognitive and motor decline and loss of independence, as well as depression, anxiety and suicide.
Timothy E. Welty, PharmD, FCCP, BCPS, a professor and the chair of the Department of Clinical Sciences at the College of Pharmacy and Health Science of Drake University, in Des Moines, Iowa, agreed that pharmacists should be more circumspect in their criticism of a given antiepileptic drug (AED) because it might be appropriate for a particular patient despite its side-effect profile. Suggesting “a bit of caution,” he said, “Making broad statements about the appropriateness or safety of certain [epilepsy] drugs may not be needed. That’s especially true with a drug like felbamate, which requires a patient’s consent to be signed,” said Dr. Welty, whose practice is in neurology with a focus on epilepsy.
Dr. Welty said he has seen similar overreaching in community pharmacy databases for such medications as lamotrigine, which can cause an allergic rash. “Clearly there’s an increased risk for serious dermatologic reactions in children who take lamotrigine versus adults, but nowhere is it strictly contraindicated,” he said.
Pharmacists should “try to understand that in treating patients with epilepsy drugs … especially when the patient is treated in an epilepsy center, a good amount of effort has been given to weighing the various options.”
Concern about felbamate initially arose when 34 cases of aplastic anemia, 14 of them fatal, and 18 cases of liver toxicity, nine fatal, were reported among the 110,000 patients who were prescribed felbamate in the first year after its release. Virtually all cases occurred within six months of starting treatment; 68% were women, none were children under the age of 13 years, and all were on polytherapy.
As a result of those incidents, felbamate almost was removed from the market. But it has stayed on-label for children over the age of 4 years who have LGS and for patients with medically refractory epilepsy for whom the benefits of the drug outweigh the risks, due, in part, to advocacy efforts by the Child Neurology Society and parents who have seen the drug effectively control their children’s illness, she said.
The estimated risk for aplastic anemia in patients taking felbamate is 27 to 209 per million, compared with two to six per million in the general population, she reported (Pediatr Neurol 2010;46:396-403). Major risk factors include female gender, postpubertal status, history of cytopenia or autoimmune disorder and a positive antinuclear antibody titer. Of the 18 reported cases of liver toxicity, nine were adults and nine were children, 78% were females, and most patients were on polytherapy. The risk for liver toxicity with felbamate is estimated at between 1:6097 and 1:15,625, she said.
Weekly or biweekly monitoring for side effects—including monitoring of complete blood count with differential, reticulocyte count and aspartate aminotransferase/alanine aminotransferase ratio—is recommended during the first three to six months of treatment.
Properly monitored, felbamate plays an important role in helping many young patients who are severely disabled due to their epilepsy, particularly those with LGS, said Dr. Zupanc. “Felbamate wakes these kids up,” she said, noting that before felbamate came on the market, many of her patients with LGS were nonverbal and wheelchair-bound. After taking felbamate, she added, “a significant proportion of these patients became more alert and started verbalizing. Some of them even started walking.”
No Ideal Agent; Clinicians
Must Choose the Best Option
Dr. Zupanc reviewed the role of several other AEDs that clinicians have in their armamentarium. Some of them are not ideal, but in certain patients, they are the most viable option.
For example, valproate is FDA-approved for both partial and generalized seizures, but it is relatively contraindicated in women of reproductive age. In adolescent girls, the drug may increase the risk for polycystic ovarian syndrome (POS) and anovulatory cycles. (The risk for POS is approximately 56% in women with generalized epilepsy with exposure to valproate within the previous three years.) An international study indicated that babies born to women who had been taking valproate had a 10-point lower IQ than children in a control population.
Despite these collective risks, Dr. Zupanc noted that for some women with epilepsy, valproate “is the only medication that controls their seizures, and so it is not a strict prohibition, it is just something that most clinicians are aware of. They will try to use other medications first.”
Lamotrigine carries a black box warning for an allergic rash, but if it is titrated up slowly, the risk for an allergic rash is no greater than that for other AEDs, noted Dr. Zupanc. The risk for rash increases in the pediatric population, when the drug is coadministered with valproate or if it is titrated too rapidly. “If you add valproate to lamotrigine, you must cut the lamotrigine dose by over 50% because valproate inhibits the metabolism of lamotrigine,” she said (Epilepsy Curr 2004;4:206-207). Most rashes occur within two to eight weeks of starting treatment. Lamotrigine also can lead to anxiety, obsessive-compulsive behavior, tics and sleep disturbance, said Dr. Zupanc. “The good news is that it does not affect cognitive function,” she added.
Levetiracetam is used as adjunctive therapy for myoclonic seizures, generalized tonic-clonic seizures and partial-onset seizures. “Parents like it because there are no drug interactions, it does not cause an allergic rash and it does not affect the bone marrow or liver,” Dr. Zupanc said. The most significant side effect is behavior disinhibition, which can be problematic in irritable patients or those with autism.
Topiramate, which is indicated for use in children aged 2 years and older for adjunctive therapy in the treatment of partial seizures or generalized tonic-clonic seizures, can cause cognitive impairment and word-finding difficulties. “I’d use it with caution in someone who has a normal IQ,” she said. Thus in toddlers learning to speak or normal teenagers, topiramate probably is not the medication of choice; however, for a nonverbal, cognitively impaired child, it may be an appropriate option.
Zonisamide, indicated for the control of partial seizures, is similar to topiramate, but “probably has less cognitive side effects,” said Dr. Zupanc. But she noted that both drugs “can cause oligohydrosis, and in southern California that can be a real problem.” Both drugs also can cause decreased appetite and weight loss.
Dr. Zupanc stressed that surgery for epilepsy should not be viewed as a last resort. If an AED is not effective in controlling seizures, the chance of a second drug working is only 10%, and if an AED is not well tolerated due to side effects, the chance of another AED working is 40%. Patients should be evaluated at a tertiary care center for epilepsy surgery if two or three AEDs have failed, she said. Specifically, she noted, “If I have a baby who has a lesion and they’re failing their first antiepileptic medicine, I’ll be working them up for epilepsy surgery right away because the catastrophic effects of epilepsy on the developing brain are real, and the time to intervene with epilepsy surgery is when a patient is young. The developing brain is much more vulnerable to the catastrophic effects of epilepsy, and the brain has the greatest plasticity … when [patients are] young, so the time to intervene is right away.”
Pharmacists can play a key role by regularly asking epilepsy patients whether they are having side effects from their medications and whether they are continuing to have seizures, said Dr. Welty. “If the answer to either question is yes, the patient should get to an epilepsy center if they’re not already there,” he said.
In some types of epilepsy, the data show that approximately 70% of patients who continue to have seizures on medications will become seizure-free with surgery, Dr. Welty noted. The current standard is to consider surgery after two or three medications have failed, but national data show that the time from a diagnosis of epilepsy to the recognition that the illness is refractory and that surgery may be warranted averages about 10 years for adults. “It’s taking too long, and pharmacists can play a very important role in identifying patients who would benefit from getting to an epilepsy center” where treatment options such as surgery or clinical trials are available, he said.
The Ketogenic Diet: Challenging but Effective
The ketogenic diet, a high-fat, low-carbohydrate diet that forces the body to burn fats rather than carbohydrates, inducing a state of ketosis, can be an effective treatment for epilepsy, but “the problem is that you have to weigh and measure every piece of food that comes across your mouth,” said Dr. Zupanc. The classic ketogenic diet consists of a 4:1 ratio by weight of fat to carbohydrate and proteins, so it requires highly motivated and organized families, she noted. In such patients, the diet can be very successful, said Beth Zupec-Kania, RD, a consultant dietician with The Charlie Foundation, an organization established to raise awareness of the diet. According to a Blue Cross Blue Shield meta-analysis, 50% of patients who trial the diet experience a 50% or greater improvement in seizure control and 15% become seizure-free (Lefevre FV. Chicago: Blue Cross Blue Shield Association; 1998).
Pharmacists can play an important role in supporting families whose children are on the ketogenic diet because medications are a key source of carbohydrates. Pharmacists can review medications for patients, recommend low-carbohydrate alternatives and determine if certain medications can be crushed or dissolved without affecting the integrity of the active ingredients, she said. They can inform parents of the carbohydrate content of medications, so that carbohydrates in the diet can be adjusted accordingly, and they can compound carbohydrate-free medications and determine whether a compounded medication will lose its potency with time.
Additionally, pharmacists can help establish protocols for dealing with patients on ketogenic diets who are admitted to their institutions. For example, Ms. Zupec-Kania noted that some hospitals have protocols in place that require patients on the ketogenic diet to be identified at admission and define protocols for “NPO [nothing-by-mouth] status-ketogenic diet therapy,” with further instructions to obtain glucose every four hours and address as needed. Additional protocols delineating the use of supplements and medications provided by the family can be helpful as well. “We can prevent problems by having these protocols in place,” she said.
Ms. Zupec-Kania has developed a comprehensive database for licensed health care professionals listing the carbohydrate content of various foods, vitamin and mineral supplements and brand-name prescription medications called the KetoCalculator (www.ketocalculator.com). The nutrient content based on data from the USDA, food manufacturers, baby formula makers and pharmaceutical companies is reviewed and updated annually on the website. Ms. Zupec-Kania also has created a second database of over-the-counter products that can be downloaded from The Charlie Foundation’s website.
Based in part on presentations during the 2012 summer meeting of the American Society of Health-System Pharmacists.
Dr. Zupanc is a consultant for Lunbeck and Questor. Ms. Zupec-Kania is the author of the KetoCalculator and a consultant for The Charlie Foundation. Dr. Welty is an investigator for the Equigen study of
generic antiepileptic drug substitution funded by the FDA, the American Epilepsy Society and the Epilepsy Foundation.