Introduction to Potiga
One of the exciting new developments in 2011 is the introduction of new antiepileptic drugs for their use in epilepsy. As drugs are approved for use in the United States, epilepsy.com will cover these new agents in order to best guide you, your physician, and other healthcare professionals on the best way to use these new medications. One of the new medications that has recently been approved and will soon be available for use is Ezogabine (Potiga).
Potiga is a trade name for a new drug known as Ezogabine. This drug is important because it prevents seizures in a new way different from currently existing antiseizure medications. Its mechanism of action appears to be enhancement of potassium currents mediated by a particular family of ion channels known as KCNQ. By activating these specific channels on nerve cells, Ezogabine is thought to stabilize these nerve cells and reduce brain excitability. It may also have an impact on another neurotransmitter, known as GABA, which is known to cause the nerve cells to calm in some manner. There are several other seizure drugs that work via increasing GABA in the cell; however, Potiga will be the first drug to prevent seizures by the potassium channel mechanism.
Pharmacology, Pharmacodynamics, Pharmacokinetics
Co-administration of Ezogabine or Potiga with medications that are inhibitors or inducers of the cytochrome P450 system do not impact the pharmacokinetics of this medication. This is important because this will dictate whether the drug has interactions. This drug is eliminated via the kidney by actively being secreted into the urine. The half life for Ezogabine is seven to eleven hours and the clearance of Ezogabine following IV dosing is approximately .4 to .6 liters per hour per kilogram.
Interactions with Other Antiepileptic Drugs
Interactions with Other Medications
With regards to oral contraceptives, there were no significant alterations of the pharmacokinetics of either estrogen or progesterone. With regards to alcohol, the coadministration of ethanol over 20 minutes and 200 mg. of Ezogabine results in an increase in Ezogabine concentration and it may actually lead to increased side effects related to the medications.
All patients enrolled in these studies were adults, had partial onset seizures with or without secondary generalization and were not adequately controlled with up to three concurrent antiseizure drugs or vagus nerve stimulation. More than 75% of patients were taking two or more other seizure drugs. Patients experienced a minimum of four partial onset seizures every month with no seizure-free period exceeding three to four weeks, with the mean duration of epilepsy of 22 years.
Across the three studies the median baseline seizure frequency ranged from eight to twelve seizures per month. Patients were randomized to total daily maintenance doses of either 600 mg. per day, 900 mg. per day, or 1200 mg. per day, each administered in three equally divided doses. During the titration phase of all three studies treatment was initiated at 300 mg. per day in a dose of 100 mg. three times daily and increased in increments of 150 mg. per day to a target dose. Potiga was then compared to placebo at these various rates.
Potiga reduced seizure frequency at 600 mg., 900 mg., and 1200 mg. per day. The reduction in seizure frequency was 27% for 600 mg. of Potiga; 25% for 900 mg.; and up to 24% seizure reduction for 1200 mg. per day. These were all found to be statistically significant for all of these doses compared to a placebo.
With regards to urinary retention, Potiga did cause urinary retention in clinical trials and was reported within the first six months of treatment, but was also observed at later times. It was seen in approximately 2% of patients treated in the open label and placebo controlled epilepsy databases. Of these 29 patients who reported problems, 14 required catheterization. Following discontinuation of Potiga all four patients who required catheterization were able to void spontaneously; however, one of the four required a continuous intermittent self-catheterization afterwards. A condition known as hydronephrosis occurred in two patients, one of whom had associated renal functional impairment. Therefore, because of the increased risk of urinary retention on Potiga, urologic symptoms need to be carefully monitored, particularly for patients with benign prostatic hypertrophy, patients who are unable to communicate clinical symptoms, or patients who use other medications that can affect voiding, such as anticholinergics. In these patients a comprehensive evaluation of urological symptoms prior to and during treatment with Potiga may be appropriate.
Confusional states, psychotic symptoms and hallucinations were reported more frequently as side effects in patients treated with Potiga than in those on placebo. Discontinuations resulting from these reactions were more common in the drug related group. The psychiatric symptoms in the mass majority of patients resolved within seven days of stopping the drug. Rapid titration at greater than the recommended doses appears to increase the risk of these side effects.
Potiga does seem to increase the chances for dizziness and somnolence. In placebo-controlled trials in patients with epilepsy, dizziness is reported in 23% of patients treated with Potiga, but yet only 9% in people treated with a placebo. Somnolence was reported in 22% with Potiga and 12% with placebo. Most of these side effects were considered mild to moderate in intensity.
With regards to QT interval effect, a study of cardiac conduction showed that Potiga does produce a mean 7.7 millisecond prolongation in healthy volunteers, titrated to 400 mg. three times a day. The QT prolonging effect occurred within three hours, so QT intervals should be monitored with Potiga prescribed with medicines known to increase QT interval and in patients with known prolonged QT intervals, such as congestive heart failure, ventricular hypertrophy, hyperchloremia or hypomagnesemia.
As with all seizure drugs it is important to always be wary of issues of depression and or suicidal thoughts associated with seizure medication. This is also the case for Potiga. Because of this it is important that one always be very cautious when prescribing this drug to see if there is any change in mood or behavior. Any change in these behaviors or vocalizing a sense that something is happening with regards to self harm would lead us to discontinue the medication.
As with all seizure drugs when Potiga is stopped it should be withdrawn gradually in order to minimize the potential of increased seizure frequency. Potiga needs to be reduced over a period of at least three weeks in order to safely eliminate the medication.
With regards to pediatric patients or children, the safety and effectiveness of Potiga in patients under 18 years of age have not been established. Further studies are clearly needed in order to understand its impact on children.
As opposed to older adults, there are an insufficient number of older patients enrolled in these trials to determine its safety and efficacy. One needs to adjust the dose of medications in patients if 65 years and older. Elderly men with symptomatic benign prostatic hypertrophy could be at increased risk for urinary retention. Patients with renal impairment and hepatic impairment should have dose adjustments made in order to account for these issues.
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