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Med Trileptal: Another Choice for Partial Onset Epilepsy

| Filed under Antiepileptics

Brand Name: Trileptal
Active Ingredient: oxcarbazepine
Indication: Treatment of partial epileptic seizures as monotherapy in adults or adjunctive therapy in adults and children as young as age 4
Company Name: Novartis Pharmaceuticals Corporation
Availability: Approved by FDA January 10, 2000

Trileptal: Introduction

More than 2 million people in the US have some form of epilepsy. Seventy percent of them are adults. Although contemporary treatment approaches can provide full or partial control of seizures in about 85% of patients, some 15% of patients do not achieve this control, and many patients are virtually resistant to available drug therapies. Some patients with partial onset seizures – those that originate in one hemisphere of the brain, often without loss of consciousness – resort to surgery to remove the affected area of the brain, ideally without affecting personality or function.

Novartis Pharmaceuticals Corporation recently received FDA approval to market Trileptal (oxcarbazepine), a new drug for both adults and children with partial seizures. The recommended daily doses range from 1200 mg/day as adjunctive therapy and 2400 mg/day as monotherapy in adults (given as two daily doses), and 30-46 mg/kg/day as adjunctive therapy for children ages 4-16.

Trileptal: How It Works

The activity of Trileptal is primarily exerted through its metabolite, monohydroxy metabolite (MHD). The precise mechanism by which Trileptal and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the brain.

Trileptal: Clinical Study Results

The efficacy of Trileptal in adults and children was established in six multicenter randomized double-blind controlled trials. Four of these studies demonstrated Trileptal’s effectiveness as monotherapy. One trial was conducted in 102 adult patients with refractory partial seizures who had been withdrawn from other antiepileptic drugs (AEDs) and received either placebo or Trileptal. Trileptal was given as 1500 mg/day on day 1 and 2400 mg/day thereafter for an additional 9 days. During the 10-day study period, patients who took Trileptal experienced significantly fewer partial seizures than those on placebo.

Similar results in favor of Trileptal were observed in a study of 67 untreated patients with newly diagnosed and recent-onset partial seizures who began treatment with either placebo or 300 mg Trileptal twice daily. Trileptal was titrated to 1200 mg/day (600 mg twice daily) in 6 days, followed by maintenance treatment for 84 days.

A third study substituted Trileptal monotherapy 2400 mg/day for carbamazepine in 143 patients whose seizures were inadequately controlled by carbamazepine at a stable dose of 800 to 1600 mg/day. The Trileptal dose was maintained for 56 days. Patients who were able to tolerate 2400 mg/day of Trileptal during carbamazepine withdrawal were randomized to receive either 300 mg/day or stay on the 2400 mg/day dose. After an observation period of 126 days, patients who received 2400 mg/day of Trileptal experienced significantly fewer seizures than those on the 300 mg/day dose.

Similar results in favor of the 2400 mg/day dose of Trileptal were observed in a fourth monotherapy trial conducted in 87 patients whose seizures were inadequately controlled on 1 or 2 AEDs. Patients were randomized to receive either 2400 mg/day or 300 mg/day Trileptal while eliminating their standard AED regimen over a 6-week period. Seizure frequency was evaluated over an additional 84 days.

Two studies assessed the efficacy of Trileptal as adjunctive therapy for partial seizures in 692 adults and 264 children (3-17 years of age). In both trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients were randomized to receive either placebo or a specific dose of Trileptal in addition to their other AEDs. Adults were followed for 24 weeks while children were observed for 14 weeks. The adults received fixed Trileptal doses of 600, 1200, or 2400 mg/day, while the children received 30-46 mg/kg/day. Trileptal significantly reduced seizure frequency at all doses tested. In the group of adults receiving 2400 mg/day Trileptal, however, more than 65% of the adults discontinued treatment because of adverse events.

Trileptal: What the Patient Should Know

Trileptal may render hormonal contraceptives less effective, so other non-hormonal forms of contraception are recommended in women taking Trileptal (particularly since Trileptal may have the potential to result in birth defects). Caution should be exercised if alcohol is consumed by patients who are taking Trileptal, since an additive sedative effect may result. Trileptal may also result in dizziness or drowsiness, so patients should avoid driving or operating machinery until they have adequately gauged the effects of Trileptal on their ability to perform these tasks.

The most common adverse reactions reported with Trileptal include dizziness, drowsiness, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, and abnormal gait. Hyponatremia may develop during Trileptal use. Patients with a known sensitivity to carbamazepine should be aware that 25-30% of them may experience hypersensitivity to Trileptal, and if so, should immediately discontinue using Trileptal. Patients should inform their physicians of other medications they may be taking, since Trileptal may interact with certain drugs (such as felodipine and verapamil).

Drug Keppra: Adjunctive Therapy for Epilepsy

| Filed under Antiepileptics

Brand Name: Keppra
Active Ingredient: levetiracetam
Indication: Adjunctive therapy for patients with partial onset epileptic seizures
Company Name: UCB Pharma, Inc
Availability: Approved for marketing in the US on December 1, 1999

Keppra: Introduction

More than 2 million people in the US have some form of epilepsy. Seventy percent of them are adults. Although contemporary treatment approaches can provide full or partial control of seizures in about 85% of patients, some 15% of patients do not achieve this control, and many patients are virtually resistant to available drug therapies. Some patients with partial onset seizures – those that originate in one hemisphere of the brain, often without loss of consciousness – resort to surgery to remove the affected area of the brain, ideally without affecting personality or function.

Now a new drug manufactured by UCB Pharma, Inc. – Keppra (levetiracetam) – may help patients with partial onset epileptic seizures when administered with other antiepileptic drugs (AEDs). Keppra’s approval within ten months of NDA submission to the FDA makes it the fastest AED approval to date. Keppra has several features that make it a valuable antiseizure medication: Clinicians can initiate treatment with an effective 500 mg daily dose, rather than begin with a subtherapeutic dose and titrate upward. Moreover, Keppra displays a favorable safety profile and does not interact with concomitantly administered AEDs or other drugs (such as oral contraceptives, digoxin, warfarin, and probenecid).

Keppra is approved for use in adults and is available in 250 mg, 500 mg, and 750 mg tablets for oral administration with or without food.

Keppra: How It Works

The exact mechanism by which Keppra exerts its antiepileptic effect is not known and does not appear to derive from any interaction with mechanisms known to be involved in inhibitory and excitatory neurotransmission. In vitro studies show that a stereoselective binding site for Keppra exists exclusively in the synaptic plasma membranes of the central nervous system, but not in peripheral tissues. Both in vitro and in vivo recordings of epileptiform activity from the hippocampus show that Keppra inhibits burst firing without affecting normal neuronal excitability. This finding suggests that Keppra may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.

Keppra: Clinical Study Results

The efficacy of Keppra was demonstrated in three multicenter, randomized, double-blind, placebo-controlled studies in 904 patients with refractory partial onset seizures with or without secondary generalization. At the time of the study, patients were taking a stable dose of 1 to 2 AEDs and were required to have experienced at least four partial onset seizures during each 4-week period during the 12-week baseline period.

Each of the three studies consisted of the 12-week baseline period followed by an 18-week treatment period. The treatment period included a 6-week titration period followed by a 12-week fixed-dose evaluation period, during which concomitant AED regimens were continued. The primary measure of effectiveness was the percent reduction in weekly partial seizure frequency relative to placebo during the entire 18-week treatment period. Responder rate (the incidence of patients with a seizure reduction of 50% or more) was measured as a secondary outcome.

Study 1 was conducted at 41 sites in the US and compared Keppra 1000 mg/day (97 patients), Keppra 3000 mg/day (101 patients), and placebo (95 patients) given in equally divided doses twice daily. The reduction in weekly seizure frequency was 26.1% in the Keppra 1000 mg group and 30.1% in the Keppra 3000 mg group, a significant reduction compared to placebo. Responder rates were 7.4% for placebo, 37.1% for patients who received 1000 mg Keppra, and 39.6% for the 3000 mg Keppra group – a significant difference.

Study 2 was conducted at 62 centers in Europe and compared Keppra 1000 mg/day (106 patients), Keppra 2000 mg/day (105 patients), and placebo (111 patients) given in equally divided doses twice daily. The reduction in weekly seizure frequency was 17.1% in the Keppra 1000 mg group and 21.4% in the Keppra 2000 mg group, a significant reduction compared to placebo. Responder rates were 6.3% for placebo, 20.8% for patients who received 1000 mg Keppra, and 35.2% for the 3000 mg Keppra group – a significant difference between Keppra and placebo and between the two doses of Keppra.

Study 3 was conducted at 47 centers in Europe and compared Keppra 3000 mg/day (180 patients) and placebo (104 patients). The patients who received Keppra experienced a 23.0% reduction in weekly seizure frequency and achieved a 39.4% responder rate (compared to 14.4% in the placebo group).

Keppra: What the Patient Should Know

Adverse effects associated with Keppra include somnolence and fatigue, dizziness, coordination difficulties (ataxia, abnormal gait, or incoordination), and asthenia. Keppra may also be associated with behavioral symptoms, such as agitation, hostility, anxiety, and depression. These effects occurred primarily during the first four weeks of treatment. Because of associated dizziness and somnolence, patients should be advised to avoid driving or operating heavy machinery until they have gauged the effect of Keppra on their performance. Keppra is also substantially excreted by the kidney, so caution should be taken in administering the proper dose to patients with moderate to severe renal impairment and patients undergoing hemodialysis.

Drug Zonegran for Epilepsy

| Filed under Antiepileptics

Brand Name: Zonegran
Active Ingredient: zonisamide
Indication: Adjunctive therapy in the treatment of partial seizures in adults with epilepsy
Company Name: Elan Corporation, plc
Availability: Approved by FDA on March 28, 2000; Zonegran has been marketed under the trade name Excegran since 1989 in Japan

Zonegran: Introduction

Another new antiseizure medication has entered to drug arena, the latest in a spate of new drugs for partial onset epilepsy (see previous articles on Keppra and Trileptal). On March 28, 2000, the FDA approved Zonegran (zonisamide) to be used in addition to other drugs in the treatment of partial seizures in adults with epilepsy. Zonegran has been marketed under the trade name Excegran since 1989 in Japan. Zonegran is manufactured by Elan Corporation, plc, a biotechnology company headquartered in Ireland.

Zonegran: Clinical Study Results

The effectiveness of Zonegran was established in three 3-month clinical trials involving 499 patients (209 women and 290 men) with a history of at last four partial onset seizures per month in spite of receiving one or two antiepilepsy drugs. Zonegran or a placebo was added to each patient’s existing therapy.

All three studies showed that patients who took Zonegran experienced a significantly greater reduction in partial seizures – between 27% and 40%, versus 1%-9% for placebo. Moreover, the percentage of patients who responded to Zonegran was greater than that for placebo – generally about twice as much. The response to Zonegran was significantly greater than that for placebo for all dose levels studied (100 mg/day, 200 mg/day, and 400-600 mg/day).

Zonegran: What You Should Know

Zonegran has been associated with side effects similar to those of other antiepileptic drugs. The most commonly observed side effects are drowsiness, weight loss, dizziness, headache, nausea and vomiting, agitation/irritability, fatigue, and difficulty concentrating. Patients should not drive a car or operate other complex machinery until they have gauged their experiences on Zonegran and determined how it affects their performance.

Patients should contact their physician immediately if they develop a skin rash or if their seizures worsen; if they develop signs or symptoms such as sudden back or abdominal pain or blood in the urine (which may indicate kidney stones); or if they develop a fever, sore throat, mouth sores, or easy bruising.

Since Zonegran may cause birth defects, patients should use contraceptives while taking the drug, and notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should also notify their physicians if they intend to breastfeed an infant while taking Zonegran. Because Zonegran is a sulfonamide, patients who are allergic to sulfa drugs should not take Zonegran.

Many Patients Conceal Seizures from Their Doctors

| Filed under Neurology

More than 16 percent of patients with epilepsy conceal seizures from their doctors, according to a recent study. Previous research has reported that many people with epilepsy hide it to avoid social stigma and loss of employment or driving privileges.

Researchers, from the University of East Anglia in Norwich, England, and at King’s Fund in London, distributed two identical questionnaires to 111 adult patients who’d had epilepsy for an average of 21.5 years. The first questionnaire was completed with the general practitioner at an office visit, and the second was completed anonymously by the same patients about two weeks later. The researchers compared the two questionnaires for each patient.

Forty-two patients (38 percent) told their doctors that they’d had a seizure within the past year. Sixty patients (54 percent) admitted this on the anonymous questionnaire. The researchers suggest that an important reason for not telling the doctor is to keep driving privileges. In England, patients must be seizure-free for 12 months to drive. Six of the 42 patients who told their doctors about seizures still had a driver’s license, compared to 24 of the 60 who admitted anonymously to having seizures.

Another reason for concealing seizures may be to maintain employment. About 47 percent of the patients who told their doctors about seizures were unemployed, compared to 17 percent of those who concealed their seizures.

Patients who’d had seizures in the past year, whether or not they’d told their doctors, were also significantly more likely to be anxious or depressed or to feel stigmatized, than those whose epilepsy was controlled.

Writing in the January 8, 2000, issue of the British Medical Journal, the researchers conclude that while concealing seizures may prevent these patients from getting the best care, many consider that price worthwhile if it allows them to keep driving and working.

The researchers also point out that the doctor’s role in determining whether patients with epilepsy can drive or participate in other activities hampers their ability to provide appropriate care for those patients. They suggest that driving regulations for people with epilepsy be changed. They noted that in Wisconsin, which has a low accident rate, epileptics only need to be seizure-free for three months to drive.

The authors also call on general practitioners to explain to their patients that they must report their seizures if they want to receive optimal care.

Temporal lobectomy for refractory epilepsy

| Filed under Neurology

A conservative estimate is that more than 100,000 people with epilepsy in the United States alone have uncontrolled seizures and could benefit from surgery. Most of them have seizures that arise from a problem in a temporal lobe of the brain, and the most common operation to treat refractory epilepsy is anterior temporal lobectomy. This is a procedure with a proven record of efficacy, eliminating or greatly reducing the prevalence of seizures in trial after trial. A group of researchers at the University of Pennsylvania and Dartmouth University decided to delve deeper into the impact of this procedure on the lives of patients in the first five years after lobectomy.

The test subjects were 89 volunteers, ranging from 10 years old to 60, all suffering persistent seizures at least once a month for at least one straight year. All had elected to have surgery after at least three different antiepileptic drugs (AEDs) and one attempt at combination therapy failed to improve their condition. Neurologists had confirmed in each case that their seizures probably arose from a single temporal lobe and could therefore be addressed by its excision; all those patients whose seizures originated in more than one site, or in a site other than the temporal lobe, were excluded from surgery because of the obvious undesirability of removing large or valuable pieces of brain tissue. Surgery does not immediately cancel the need for medication; patients were initially advised to continue taking their AEDs at moderate doses for two years after study, and this was later extended to five years.

The results of surgery

The most basic yardstick for measuring the value of any surgery aimed at reducing seizures is obviously the impact on seizure frequency. This was documented at two weeks, two months, six months, and again at one year after surgery. Follow-up continued every year in those patients who were seizure-free to see how long they stayed that way. Patients were grouped into four categories according to the degree of improvement. Class One patients were seizure-free after surgery, or currently seizure-free for at least one year (exceptions were made for isolated seizures associated with withdrawal of medication). Class Two patients were those who still had occasional seizures, but no more than three in a year – a significant improvement in a group that had previously averaged at least eight seizures per month. Class Three patients had more than three seizures in a year, but still registered a post-surgery reduction of over 80% in seizure frequency. Finally, Class Four patients included all patients whose seizures had become less frequent, but by less than 80%, and those who had registered very little improvement or none at all.

By any standards, the surgery was very effective. After five years, 62 patients (70%) were in Class One, a further eight (9%) were in Class Two, and 10 more (11%) were in Class Three. Thus, 90% of patients had achieved significant relief from their seizures, and most of them were effectively cured. Only five patients (6%) had fallen into Class Four, while four (4%) had died of various causes, none of them related to surgery. More than half of all patients never had another seizure following surgery. (This does not include those seizures that sometimes follow immediately after the operation, which are caused by the trauma to the brain inherent in surgery, and do not reflect any permanent epileptic condition.)

Lobectomy does not impair intelligence

One common misconception about lobectomies (arising, no doubt, from the connotations of the similar word lobotomy) is that it can reduce intelligence. IQ tests administered to patients before and one year after surgery showed no change in verbal scores and a noticeable improvement in the performance score, especially among those who had left (as opposed to right) temporal lobectomies. Both left and right-side patients (especially left) raised their average overall IQs. Thirty-minute visual memory and facial memory were also improved. Most importantly, the patients showed greatly reduced scores on standard tests of depression and anxiety; they were happier and more relaxed.

These changes could not be expressed more clearly than in the improvements that those patients who became seizure-free achieved in their own lives over the five years following surgery. Before the operation, only 34% of all patients were working full-time and 24% were unemployed. Five years later, 63% were working full-time and only 11% were unemployed. Full-time employment rose even higher in the majority who became seizure-free, and unemployment in Class One patients dropped to 3% – below the national average. The psychological, social and material benefits of having a paying job, which can hardly be overestimated, are among the biggest dividends of successful treatment of seizures.

Rarely does a medical procedure offer such a clear and long-term improvement to the well-being of patients as temporal lobectomy. In the face of such encouraging findings, the researchers recommend that patients with epilepsy focused in the temporal lobe be encouraged to consider surgery as soon as the failure of drug treatment becomes apparent. Much unnecessary suffering and marginalization could be avoided and thousands of people rescued from the trap of epilepsy if this procedure were applied in more cases.

New Treatment May Benefit Epilepsy Patients

| Filed under Neurology

Research has come a long way in providing effective treatment for people with epilepsy, but for some, it just is not enough. Despite adequate and therapeutic doses of medication, many still continue to experience several seizures a month. But according to researchers from the University of Michigan, a drug called oxcarbazepine may provide relief to those who continue to have a type of seizure known as a partial seizure, even if they have already been through the gamut of other medications.

In their study, researchers found that oxcarbazepine, sold under the brand name of Trileptal, was safe and effective for this population. They followed 87 patients, some as young as 12 years old, who had partial seizures that remained uncontrolled despite the fact that they were on medication. The study participants were first tapered off of their regular drug regimens, and then they were divided into two treatment groups. One group received a low dose of 300mg/day and the other group a much higher dose of 2,400 mg/day of oxcarbazepine. (The drug’s manufacturer currently recommends a daily dose of 1200 mg/day.)

The results, says study author Ahmad Beydoun, M.D., associate professor of neurology and director of the Comprehensive Epilepsy Center at the University of Michigan, are encouraging and he believes that the patients responded well to this drug. In the group receiving 2400 mg/day, 12 percent remained free of seizures and almost half had a 50 percent reduction in the number of seizures they were experiencing. The results were less encouraging for those on the lower dose — none of the patients became seizure free.

Epilepsy is a neurological disorder and affects more than 2.3 million American adults and children. It is characterized by seizures, which occur when specific brain cells release high amounts of electrical energy and in turn, trigger a sudden loss of control over movement, thought or awareness.

There are many types of seizures, and experts have divided them loosely into generalized and partial seizures. The most common type is the partial seizure, which occurs when the disturbance takes place in just one area of the brain, and affects whatever physical or mental activity that particular region controls. The generalized seizure happens when a massive burst of electrical energy occurs throughout the brain at one time, causing unconsciousness, convulsions and other severe effects.

“In epilepsy drug therapy, tolerability and efficacy are often closely related,” says Beydoun. “One of the challenges in treating this disorder is the side effects associated with the standard antiepileptic drugs.” Many patients cannot control their seizures because they are unable to tolerate high enough doses of their medication. For the most part, oxcarbazepine was well tolerated by the people in the study, and the majority of them were able to reach the highest recommended dose, which may partially explain why it worked so well for them.

Some epilepsy drugs are given in combination with other drugs, while some are used alone in what is called monotherapy. This study examined the efficacy of oxcarbazepine as a monotherapy, and it has been approved by the FDA to be used alone. However, Carmel Armon, MD, a professor of medicine at Loma Linda University in California and a Fellow with the American Academy of Neurology, is not yet ready to switch his patients over to oxycarbazepine. He believes that a closer look is needed at this drug, particularly if it is going to be used as monotherapy.

The four-month trial period, he points out, was not long enough to test the long-term efficacy of oxcarbazepine. “Even though it’s very gratifying that 12 percent had a chance to go seizure free on this medicine, the study design is not such that it would tell us how long that benefit would be sustained,” he says. Often a patient may do well initially on a new drug, but then after a few months, the same problems emerge. A much longer period of time is needed to truly test the efficacy of a drug, Armon believes.

Sometimes, just a change in a medication regimen can temporarily reduce the number of seizures, Armon points out, and so the reduction in seizures seen in the study could be partially attributed to that. “It’s frequently seen that when you make a change, a small percentage of your patients will be seizure free and then relapse, ” says Armon, who specializes in treating patients with epilepsy. “And in fact, many of my patients will give me a story that every change I’ve made seems to be a change for the better, and then they broke through.”

Armon believes while the study did demonstrate some effectiveness as a monotherapy in treating partial seizures, the results were just not that striking. Only a small percentage of the patients became seizure free, and since the study followed them for just four months, it is unknown how long the effect will last.

“Based on this knowledge,” says Armon, “They may better off working with the drugs that they are currently taking, and using oxcarbazepine as an add-on or addition to their current medication regimen.”