POTIGA caused urinary retention in clinical trials. Urinary retention was generally reported within the first 6 months of treatment, but was also observed later. Urinary retention was reported as an adverse event in 29 of 1,365 (approximately 2%) patients treated with POTIGA in the open-label and placebo-controlled epilepsy database [see Clinical Studies]. Of these 29 patients, 5 (17%) required catheterization, with post-voiding residuals of up to 1,500 mL. POTIGA was discontinued in 4 patients who required catheterization. Following discontinuation, these 4 patients were able to void spontaneously; however, 1 of the 4 patients continued intermittent self-catheterization. A fifth patient continued treatment with POTIGA and was able to void spontaneously after catheter removal. Hydronephrosis occurred in 2 patients, one of whom had associated renal function impairment that resolved upon discontinuation of POTIGA. Hydronephrosis was not reported in placebo patients.
In the placebo-controlled epilepsy trials, “urinary retention,” “urinary hesitation,” and “dysuria” were reported in 0.9%, 2.2%, and 2.3% of patients on POTIGA, respectively, and in 0.5%, 0.9%, and 0.7% of patients on placebo, respectively.
Because of the increased risk of urinary retention on POTIGA, urologic symptoms should be carefully monitored. Closer monitoring is recommended for patients who have other risk factors for urinary retention (e.g., benign prostatic hyperplasia [BPH]), patients who are unable to communicate clinical symptoms (e.g., cognitively impaired patients), or patients who use concomitant medications that may affect voiding (e.g., anticholinergics). In these patients, a comprehensive evaluation of urologic symptoms prior to and during treatment with POTIGA may be appropriate.
Confusional state, psychotic symptoms, and hallucinations were reported more frequently as adverse reactions in patients treated with POTIGA than in those treated with placebo in placebo-controlled epilepsy trials (see Table 2). Discontinuations resulting from these reactions were more common in the drug-treated group (see Table 2). These effects were dose-related and generally appeared within the first 8 weeks of treatment. Half of the patients in the controlled trials who discontinued POTIGA due to hallucinations or psychosis required hospitalization. Approximately two-thirds of patients with psychosis in controlled trials had no prior psychiatric history. The psychiatric symptoms in the vast majority of patients in both controlled and open- label trials resolved within 7 days of discontinuation of POTIGA. Rapid titration at greater than the recommended doses appeared to increase the risk of psychosis and hallucinations.
Table 2: Major Neuro-Psychiatric Symptoms in Placebo-Controlled
|Adverse Reaction||Number (%) With Adverse Reaction||Number (%) Discontinuing|
(n = 813)
(n = 427)
(n = 427)
|Confusional state||75 (9%)||11 (3%)||32 (4%)||4 ( < 1%)|
|Psychosis||9 (1%)||0||6 ( < 1%)||0|
|Hallucinationsa||14 (2%)||2 ( < 1%)||6 ( < 1%)||0|
|a Hallucinations includes visual, auditory, and mixed hallucinations.|
Dizziness and Somnolence
POTIGA causes dose-related increases in dizziness and somnolence [see ADVERSE REACTIONS]. In placebo-controlled trials in patients with epilepsy, dizziness was reported in 23% of patients treated with POTIGA and 9% of patients treated with placebo. Somnolence was reported in 22% of patients treated with POTIGA and 12% of patients treated with placebo. In these trials 6% of patients on POTIGA and 1.2% on placebo discontinued treatment because of dizziness; 3% of patients on POTIGA and < 1.0% on placebo discontinued because of somnolence.
Most of these adverse reactions were mild to moderate in intensity and occurred during the titration phase. For those patients continued on POTIGA, dizziness and somnolence appeared to diminish with continued use.
QT Interval Effect
A study of cardiac conduction showed that POTIGA produced a mean 7.7-msec QT prolongation in healthy volunteers titrated to 400 mg 3 times daily. The QT-prolonging effect occurred within 3 hours. The QT interval should be monitored when POTIGA is prescribed with medicines known to increase QT interval and in patients with known prolonged QT interval, congestive heart failure, ventricular hypertrophy, hypokalemia, or hypomagnesemia [see CLINICAL PHARMACOLOGY].
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including POTIGA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive-therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24% among 16,029 placebo- treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 3 shows absolute and relative risk by indication for all evaluated AEDs.
Table 3: Risk of Suicidal Thoughts or Behaviors by
Indication for Antiepileptic Drugs in the Pooled Analysis
|Indication||Placebo Patients With Events per 1,000 Patients||Drug Patients With Events per 1,000 Patients||Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients||Risk Difference: Additional Drug Patients With Events per 1,000 Patients|
The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for epilepsy and psychiatric indications.
Anyone considering prescribing POTIGA or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
As with all AEDs, when POTIGA is discontinued, it should be withdrawn gradually when possible to minimize the potential of increased seizure frequency [see DOSAGE AND ADMINISTRATION]. The dosage of POTIGA should be reduced over a period of at least 3 weeks, unless safety concerns require abrupt withdrawal.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Patients should be informed that POTIGA can cause urinary retention (including urinary hesitation and dysuria). If patients experience any symptoms of urinary retention, inability to urinate, and/or pain with urination, they should be instructed to seek immediate medical assistance [see WARNINGS AND PRECAUTIONS]. For patients who cannot reliably report symptoms of urinary retention (for example, patients with cognitive impairment), urologic consultation may be helpful.
Patients should be informed that POTIGA can cause psychiatric symptoms such as confusional state, disorientation, hallucinations, and other symptoms of psychosis. Patients and their caregivers should be instructed to notify their physicians if they experience psychotic symptoms [see WARNINGS AND PRECAUTIONS].
Central Nervous System Effects
Patients should be informed that POTIGA may cause dizziness, somnolence, memory impairment, abnormal coordination/balance, disturbance in attention, and ophthalmological effects such as diplopia or blurred vision. Patients taking POTIGA should be advised not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with POTIGA [see WARNINGS AND PRECAUTIONS].
Suicidal Thinking and Behavior
Patients, their caregivers, and families should be informed that AEDs, including POTIGA, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about selfharm. Behaviors of concern should be reported immediately to healthcare providers [see WARNINGS AND PRECAUTIONS].
Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant.
Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry collects information about the safety of AEDs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a one-year neonatal mouse study of ezogabine (2 single-dose oral administrations of up to 96 mg/kg on postnatal days 8 and 15), a dose-related increase in the frequency of lung neoplasms (bronchioalveolar carcinoma and/or adenoma) was observed in treated males. No evidence of carcinogenicity was observed in rats following oral administration of ezogabine (oral gavage doses of up to 50 mg/kg/day) for 2 years. Plasma exposure (AUC) to ezogabine at the highest doses tested was less than that in humans at the maximum recommended human dose (MRHD) of 1,200 mg per day.
Highly purified ezogabine was negative in the in vitro Ames assay, the in vitro Chinese hamster ovary (CHO) Hprt gene mutation assay, and the in vivo mouse micronucleus assay. Ezogabine was positive in the in vitro chromosomal aberration assay in human lymphocytes. The major circulating metabolite of ezogabine, NAMR, was negative in the in vitro Ames assay, but positive in the in vitro chromosomal aberration assay in CHO cells.
Impairment of Fertility
Ezogabine had no effect on fertility, general reproductive performance, or early embryonic development when administered to male and female rats at doses of up to 46.4 mg/kg/day (associated with a plasma ezogabine exposure [AUC] less than that in humans at the MRHD) prior to and during mating, and continuing in females through gestation day 7.
Use In Specific Populations
Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. POTIGA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In animal studies, doses associated with maternal plasma exposures (AUC) to ezogabine and its major circulating metabolite, NAMR, similar to or below those expected in humans at the maximum recommended human dose (MRHD) of 1,200 mg per day produced developmental toxicity when administered to pregnant rats and rabbits. The maximum doses evaluated were limited by maternal toxicity (acute neurotoxicity).
Treatment of pregnant rats with ezogabine (oral doses of up to 46 mg/kg/day) throughout organogenesis increased the incidences of fetal skeletal variations. The no-effect dose for embryo-fetal toxicity in rats (21 mg/kg/day) was associated with maternal plasma exposures (AUC) to ezogabine and NAMR less than those in humans at the MRHD. Treatment of pregnant rabbits with ezogabine (oral doses of up to 60 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal skeletal variations. The no-effect dose for embryo-fetal toxicity in rabbits (12 mg/kg/day) was associated with maternal plasma exposures to ezogabine and NAMR less than those in humans at the MRHD.
Administration of ezogabine (oral doses of up to 61.9 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased pre- and postnatal mortality, decreased body weight gain, and delayed reflex development in the offspring. The no-effect dose for pre- and postnatal developmental effects in rats (17.8 mg/kg/day) was associated with maternal plasma exposures to ezogabine and NAMR less than those in humans at the MRHD.
Pregnancy Registry: To provide information regarding the effects of in utero exposure to POTIGA, physicians are advised to recommend that pregnant patients taking POTIGA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website www.aedpregnancyregistry.org.
Labor and Delivery
The effects of POTIGA on labor and delivery in humans are unknown.
It is not known whether ezogabine is excreted in human milk. However, ezogabine and/or its metabolites are present in the milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants from POTIGA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of POTIGA in patients under 18 years of age have not been established.
In juvenile animal studies, increased sensitivity to acute neurotoxicity and urinary bladder toxicity was observed in young rats compared to adults. In studies in which rats were dosed starting on postnatal day 7, ezogabine-related mortality, clinical signs of neurotoxicity, and renal and urinary tract toxicities were observed at doses > 2 mg/kg/day. The no-effect level was associated with plasma ezogabine exposures (AUC) less than those expected in human adults at the MRHD of 1,200 mg per day. In studies in which dosing began on postnatal day 28, acute central nervous system effects, but no apparent renal or urinary tract effects, were observed at doses of up to 30 mg/kg/day. These doses were associated with plasma ezogabine exposures less than those achieved clinically at the MRHD.
There were insufficient numbers of elderly patients enrolled in partial-onset seizure controlled trials (n = 8 patients on ezogabine) to determine the safety and efficacy of POTIGA in this population. Dosage adjustment is recommended in patients aged 65 years and older [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
POTIGA may cause urinary retention. Elderly men with symptomatic BPH may be at increased risk for urinary retention.
Patients With Renal Impairment
Dosage adjustment is recommended for patients with creatinine clearance < 50 mL/min or patients with end-stage renal disease (ESRD) receiving dialysis treatments [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Patients With Hepatic Impairment
No dosage adjustment is required for patients with mild hepatic impairment.
Last reviewed on RxList: 7/12/2012
This monograph has been modified to include the generic and brand name in many instances.
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