Urinary Dysfunction Stands Out on Retigabine's Safety Profile

BALTIMORE – The safety profile for retigabine is generally consistent with that of other antiepileptic drugs, but data from studies in its evaluation process show that it also carries a novel, small increased risk of urinary voiding dysfunction.

At the annual meeting of the American Epilepsy Society Dr. Neil Brickel of GlaxoSmithKline’s clinical safety and pharmacovigilance group in Middlesex, England, reported on the safety of the novel drug in three phase III, randomized, double-blind, placebo-controlled trials, four phase II studies, and six long-term open-label extension studies, totalling 1,365 patients.

Retigabine is the international nonproprietary name of the drug, but it was approved in the United States in June 2011 under the adopted name ezogabine as an adjunctive therapy in adults with partial-onset seizures. It is a first-in-class potassium channel opener manufactured by GlaxoSmithKline and Valeant Pharmaceuticals International, and sold under the brand name Trobalt in Europe and Potiga in the United States.

In all of the studies that Dr. Brickel analyzed, retigabine was evaluated as a second, add-on agent. As of Oct. 2, 2009, 1,217 of the 1,365 patients had been on treatment at least 1 month, 801 for at least 6 months, and 586 for 1 year or longer.

As expected with any antiepileptic drug (AED), the most frequent adverse events involved the central nervous system. The most common in the three pivotal controlled trials were dizziness (23% of retigabine-treated patients vs. 9% of placebo-treated patients) and somnolence (reported by 22% vs. 12%, respectively). The only CNS adverse events that were not dose related were headache (reported by 15% of the retigabine group vs. 16% of the placebo group) and fatigue (by 15% and 6%, respectively). Other adverse events occurring in more than 10% of subjects were confusional state, tremor, and abnormal coordination. For the most part, patients reported these adverse events early on, during the titration phases of the trials, Dr. Brickel said.

Adverse events led to discontinuation in 437 patients (32%) of the total phase II/III study population. Again, these were primarily CNS and dose related. Discontinuations for any event occurred in 11% of the placebo group. Among those taking retigabine, discontinuations occurred in 17% of those assigned to 600 mg, 25% of those assigned to 900 mg, and 31% of those assigned to 1,200 mg. The most common reason for discontinuation was dizziness.

"Two-thirds of patients were able to continue in the study, even with the fixed titration regimen and at the 1,200-mg dose," Dr. Brickel noted.

Serious adverse events (SAEs) were infrequent, and also typically CNS related. In the three pivotal controlled trials, SAEs occurred in 6% of the placebo group and 9% of the retigabine patients. Six of the patients taking retigabine developed a psychotic disorder (five with 1,200 mg, one with 900 mg), compared with none of the placebo patients. Convulsions occurred in 1.2% of the placebo group and in 1.5% of the retigabine patients, across all doses. This finding was not unexpected, considering the underlying epilepsy, he said.

No other SAE was reported in more than two patients in any group. Deaths occurred in three placebo patients and two patients in the retigabine group. One in each group was a sudden death.

In the three pivotal trials, urinary and renal-related adverse events occurred in 17% of retigabine patients, compared with 13% of the placebo-treated patients. In the entire phase II/III study population, 26% of the 1,365 patients reported a urinary adverse event.

However, events related to urinary voiding dysfunction, which have a plausible biological relation to retigabine’s pharmacology, occurred in less than 4% of retigabine-treated patients in the phase III trials alone and in all phase II and III trial populations combined. Urinary hesitation was the most common of these in the entire phase II and III study group, occurring in 3.1%, followed by urinary retention in 1.9%. Catheterization was required in four patients taking retigabine and in one patient on placebo.

"These all occurred in a smaller number of patients and provide a better guide as to how many patents are potentially at risk. It is also important to note that these events were for the most part ‘mild’ in intensity and the patients were able to continue treatment," Dr. Brickel said in an interview.

Dr. Brickel also said that GSK is "communicating these risks to potential prescribers and encouraging them to advise patients of the symptoms relating to difficulty in passing urine that could range from discomfort on bladder emptying, hesitancy, poor flow through to a complete inability to void (acute urinary retention). GSK is keen to proactively manage this."

The study was funded by GSK and Valeant Pharmaceuticals International, and all of the investigators are employees of either company.

BALTIMORE – The safety profile for retigabine is generally consistent with that of other antiepileptic drugs, but data from studies in its evaluation process show that it also carries a novel, small increased risk of urinary voiding dysfunction.

At the annual meeting of the American Epilepsy Society Dr. Neil Brickel of GlaxoSmithKline’s clinical safety and pharmacovigilance group in Middlesex, England, reported on the safety of the novel drug in three phase III, randomized, double-blind, placebo-controlled trials, four phase II studies, and six long-term open-label extension studies, totalling 1,365 patients.

Retigabine is the international nonproprietary name of the drug, but it was approved in the United States in June 2011 under the adopted name ezogabine as an adjunctive therapy in adults with partial-onset seizures. It is a first-in-class potassium channel opener manufactured by GlaxoSmithKline and Valeant Pharmaceuticals International, and sold under the brand name Trobalt in Europe and Potiga in the United States.

In all of the studies that Dr. Brickel analyzed, retigabine was evaluated as a second, add-on agent. As of Oct. 2, 2009, 1,217 of the 1,365 patients had been on treatment at least 1 month, 801 for at least 6 months, and 586 for 1 year or longer.

As expected with any antiepileptic drug (AED), the most frequent adverse events involved the central nervous system. The most common in the three pivotal controlled trials were dizziness (23% of retigabine-treated patients vs. 9% of placebo-treated patients) and somnolence (reported by 22% vs. 12%, respectively). The only CNS adverse events that were not dose related were headache (reported by 15% of the retigabine group vs. 16% of the placebo group) and fatigue (by 15% and 6%, respectively). Other adverse events occurring in more than 10% of subjects were confusional state, tremor, and abnormal coordination. For the most part, patients reported these adverse events early on, during the titration phases of the trials, Dr. Brickel said.

Adverse events led to discontinuation in 437 patients (32%) of the total phase II/III study population. Again, these were primarily CNS and dose related. Discontinuations for any event occurred in 11% of the placebo group. Among those taking retigabine, discontinuations occurred in 17% of those assigned to 600 mg, 25% of those assigned to 900 mg, and 31% of those assigned to 1,200 mg. The most common reason for discontinuation was dizziness.

"Two-thirds of patients were able to continue in the study, even with the fixed titration regimen and at the 1,200-mg dose," Dr. Brickel noted.

Serious adverse events (SAEs) were infrequent, and also typically CNS related. In the three pivotal controlled trials, SAEs occurred in 6% of the placebo group and 9% of the retigabine patients. Six of the patients taking retigabine developed a psychotic disorder (five with 1,200 mg, one with 900 mg), compared with none of the placebo patients. Convulsions occurred in 1.2% of the placebo group and in 1.5% of the retigabine patients, across all doses. This finding was not unexpected, considering the underlying epilepsy, he said.

No other SAE was reported in more than two patients in any group. Deaths occurred in three placebo patients and two patients in the retigabine group. One in each group was a sudden death.

In the three pivotal trials, urinary and renal-related adverse events occurred in 17% of retigabine patients, compared with 13% of the placebo-treated patients. In the entire phase II/III study population, 26% of the 1,365 patients reported a urinary adverse event.

However, events related to urinary voiding dysfunction, which have a plausible biological relation to retigabine’s pharmacology, occurred in less than 4% of retigabine-treated patients in the phase III trials alone and in all phase II and III trial populations combined. Urinary hesitation was the most common of these in the entire phase II and III study group, occurring in 3.1%, followed by urinary retention in 1.9%. Catheterization was required in four patients taking retigabine and in one patient on placebo.

"These all occurred in a smaller number of patients and provide a better guide as to how many patents are potentially at risk. It is also important to note that these events were for the most part ‘mild’ in intensity and the patients were able to continue treatment," Dr. Brickel said in an interview.

Dr. Brickel also said that GSK is "communicating these risks to potential prescribers and encouraging them to advise patients of the symptoms relating to difficulty in passing urine that could range from discomfort on bladder emptying, hesitancy, poor flow through to a complete inability to void (acute urinary retention). GSK is keen to proactively manage this."

The study was funded by GSK and Valeant Pharmaceuticals International, and all of the investigators are employees of either company.

BALTIMORE – The safety profile for retigabine is generally consistent with that of other antiepileptic drugs, but data from studies in its evaluation process show that it also carries a novel, small increased risk of urinary voiding dysfunction.

At the annual meeting of the American Epilepsy Society Dr. Neil Brickel of GlaxoSmithKline’s clinical safety and pharmacovigilance group in Middlesex, England, reported on the safety of the novel drug in three phase III, randomized, double-blind, placebo-controlled trials, four phase II studies, and six long-term open-label extension studies, totalling 1,365 patients.

Retigabine is the international nonproprietary name of the drug, but it was approved in the United States in June 2011 under the adopted name ezogabine as an adjunctive therapy in adults with partial-onset seizures. It is a first-in-class potassium channel opener manufactured by GlaxoSmithKline and Valeant Pharmaceuticals International, and sold under the brand name Trobalt in Europe and Potiga in the United States.

In all of the studies that Dr. Brickel analyzed, retigabine was evaluated as a second, add-on agent. As of Oct. 2, 2009, 1,217 of the 1,365 patients had been on treatment at least 1 month, 801 for at least 6 months, and 586 for 1 year or longer.

As expected with any antiepileptic drug (AED), the most frequent adverse events involved the central nervous system. The most common in the three pivotal controlled trials were dizziness (23% of retigabine-treated patients vs. 9% of placebo-treated patients) and somnolence (reported by 22% vs. 12%, respectively). The only CNS adverse events that were not dose related were headache (reported by 15% of the retigabine group vs. 16% of the placebo group) and fatigue (by 15% and 6%, respectively). Other adverse events occurring in more than 10% of subjects were confusional state, tremor, and abnormal coordination. For the most part, patients reported these adverse events early on, during the titration phases of the trials, Dr. Brickel said.

Adverse events led to discontinuation in 437 patients (32%) of the total phase II/III study population. Again, these were primarily CNS and dose related. Discontinuations for any event occurred in 11% of the placebo group. Among those taking retigabine, discontinuations occurred in 17% of those assigned to 600 mg, 25% of those assigned to 900 mg, and 31% of those assigned to 1,200 mg. The most common reason for discontinuation was dizziness.

"Two-thirds of patients were able to continue in the study, even with the fixed titration regimen and at the 1,200-mg dose," Dr. Brickel noted.

Serious adverse events (SAEs) were infrequent, and also typically CNS related. In the three pivotal controlled trials, SAEs occurred in 6% of the placebo group and 9% of the retigabine patients. Six of the patients taking retigabine developed a psychotic disorder (five with 1,200 mg, one with 900 mg), compared with none of the placebo patients. Convulsions occurred in 1.2% of the placebo group and in 1.5% of the retigabine patients, across all doses. This finding was not unexpected, considering the underlying epilepsy, he said.

No other SAE was reported in more than two patients in any group. Deaths occurred in three placebo patients and two patients in the retigabine group. One in each group was a sudden death.

In the three pivotal trials, urinary and renal-related adverse events occurred in 17% of retigabine patients, compared with 13% of the placebo-treated patients. In the entire phase II/III study population, 26% of the 1,365 patients reported a urinary adverse event.

However, events related to urinary voiding dysfunction, which have a plausible biological relation to retigabine’s pharmacology, occurred in less than 4% of retigabine-treated patients in the phase III trials alone and in all phase II and III trial populations combined. Urinary hesitation was the most common of these in the entire phase II and III study group, occurring in 3.1%, followed by urinary retention in 1.9%. Catheterization was required in four patients taking retigabine and in one patient on placebo.

"These all occurred in a smaller number of patients and provide a better guide as to how many patents are potentially at risk. It is also important to note that these events were for the most part ‘mild’ in intensity and the patients were able to continue treatment," Dr. Brickel said in an interview.

Dr. Brickel also said that GSK is "communicating these risks to potential prescribers and encouraging them to advise patients of the symptoms relating to difficulty in passing urine that could range from discomfort on bladder emptying, hesitancy, poor flow through to a complete inability to void (acute urinary retention). GSK is keen to proactively manage this."

The study was funded by GSK and Valeant Pharmaceuticals International, and all of the investigators are employees of either company.