Summary Basis of Decision for Potiga
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Potiga is located below.
Recent Activity for Potiga
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Potiga
Updated:
The following table describes post-authorization activity for Potiga, a product which contains the medicinal ingredient ezogabine. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02394944 - 50 mg ezogabine, tablet, oral
- DIN 02394960 - 100 mg ezogabine, tablet, oral
- DIN 02394979 - 200 mg ezogabine, tablet, oral
- DIN 02394987 - 300 mg ezogabine, tablet, oral
- DIN 02394995 - 400 mg ezogabine, tablet, oral
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| DINs 02394944, 02394960, 02394979, 02394987, 02394995 cancelled | Not applicable | DINs cancelled by sponsor:2013-11-12 | The sponsor requested all DINs for Potiga be cancelled as Potiga will not be made commercially available in Canada at this time. |
| SNDS # 162560 | 2013-02-15 | Submission cancelled by sponsor:2013-11-12 | Submission filed to update the Product Monograph to add new in vivo data on digoxin to the Drug-Drug Interaction section, and to add the results of a haemodialysis study to the Overdose section. The submission was screened but a Health Canada review was not conducted. Due to the emerging safety profile of Potiga, the sponsor has decided to place a hold on new launches while it continues to investigate and actively monitor retinal changes and discolouration events (retinal pigmentation and skin pigmentation/discolouration). The sponsor requested the cancellation of the SNDS, noting the benefit/risk profile of Potiga has changed since Health Canada first authorized the sale of the product. |
| NC # 163343 | 2013-03-19 | Submission cancelled by sponsor:2013-05-03 | Submission filed as a Level II (90 day) safety change to update the Product Monograph to include discolouration events (retinal pigmentation and skin pigmentation/discolouration). Due to this evolving new safety issue for which more data are being gathered, the sponsor was requested by Health Canada to withdraw the submission, and refile to update the Product Monograph prior to product market launch. |
| NC # 161006 | 2012-12-19 | Issued No Objection Letter2013-03-21 | Submission filed as a Level II (90 day) safety change to update the Adverse Reactions section of the Product Monograph (PM) as well as the PM Part III: Consumer Information. The sponsor has also decided to remove the 100 mg strength from the PM. The submission was reviewed and a No Objection Letter was issued. |
| NDS # 134659 | 2011-10-31 | Issued NOC2012-10-18 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Potiga
Date SBD issued: 2012-12-21
The following information relates to the new drug submission for Potiga.
Ezogabine , 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg , tablets, oral
Drug Identification Number (DIN):
- DIN 02394944 - 50 mg tablet
- DIN 02394960 - 100 mg tablet
- DIN 02394979 - 200 mg tablet
- DIN 02394987 - 300 mg tablet
- DIN 02394995 - 400 mg tablet
GlaxoSmithKline Inc.
New Drug Submission Control Number: 134659
On October 18, 2012, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc., for the drug product Potiga.
The market authorization was based on quality (chemistry and manufacturing) non-clinical (pharmacology and toxicology) and clinical (safety and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Potiga is favourable for the treatment of partial onset seizures when taken together with other seizure medicines in adults 18 years and older.
1 What was approved?
Potiga, an antiepileptic agent, was authorized as adjunctive therapy in the management of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy.
Potiga is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Potiga was approved for use under the conditions stated in the Potiga Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Potiga (50 mg, 100 mg, 200 mg, 300 mg, and 400 mg ezogabine) is presented as a tablet. In addition to the medicinal ingredient, all of the strengths include the following non-medicinal ingredients: croscarmellose sodium; hypromellose; magnesium stearate; lecithin (SOY); microcrystalline cellulose; polyvinyl alcohol; talc; titanium dioxide; and xanthan gum. The 50 mg and 400 mg tablets also contain carmine, and FD&C blue number 2/indigo carmine aluminum lake. The 100 mg and 300 mg tablets also contain FD&C blue number 2/indigo carmine aluminum lake, and iron oxide yellow. The 200 mg tablets also contain iron oxide yellow.
For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Potiga Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Potiga approved?
Health Canada considers that the benefit/risk profile of Potiga is favourable as adjunctive therapy in the management of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy.
Epilepsy is a heterogeneous neurological disorder with vastly divergent symptoms, all involving episodic abnormal electrical activity in the brain and numerous seizures. An epileptic seizure can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness. It can manifest as an alteration in mental state, tonic or clonic movements, convulsions, and various other psychic experiences. Epilepsy is usually controlled, but not cured, with medication. More than 30% of patients with epilepsy may require multiple anti-epileptic drugs (AEDs) to achieve adequate seizure control.
In vitro studies suggest that Potiga is a potassium channel opener. It can cause hyperpolarization of neuronal membrane, thereby raising the threshold potential and contributing to the prevention of neuronal hyperexcitability. In three multicentre, randomized, double-blind, placebo-controlled studies, a total of 813 adult patients were treated with Potiga doses 600-1,200 mg/day (placebo: 427 adult patients). Potiga demonstrated efficacy as add-on therapy in patients with partial-onset seizures. This efficacy was comparable to that of other add-on treatments, currently available in Canada.
In addition to the typical adverse events (AEs) associated with anti-epileptic medications (for example; dizziness, somnolence, vision-related AEs), Potiga is associated with two other AEs of interest: urinary-related AEs such as urinary hesitation; retention; dysuria and acute urinary retention; and neuropsychiatric disorders. Despite these AEs, Potiga may be useful as adjunctive therapy in reducing seizure frequency in some patients who are not satisfactorily controlled with their existing AED regimen. The risks associated with the use of Potiga in these patients is managed with a bolded warning statement for: urinary-related AEs; a strong warning statement for neuropsychiatric disorders; proper labelling of all AEs; an effective Risk Management Plan; and a direct communication with health professionals (Dear Health Care Professional Letter) at the time of product launch in Canada. Subsequent DHPLs will be issued as required to include any updated and/or new safety information.
When used under the conditions of use described in the Potiga Product Monograph, the risk-benefit profile of Potiga as adjunctive therapy in the management of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy is favourable at this time.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Potiga?
Submission Milestones: Potiga
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2010-02-23 |
| Submission filed: | 2011-10-31 |
| Screening | |
| Screening Acceptance Letter issued: | 2011-12-23 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2012-07-20 |
| Quality Evaluation complete: | 2012-10-16 |
| Clinical Evaluation complete: | 2012-10-16 |
| Labelling Review complete: | 2012-10-16 |
| Notice of Compliance issued by Director General: | 2012-10-18 |
The Canadian regulatory decision on the non-clinical and clinical review of Potiga was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
In order to effectively communicate the risk of urinary-related events to health professionals, the sponsor will issue a Dear Health Professional Letter (DHPL) at the time of product launch in Canada. Subsequent DHPLs will be issued as required to include any updated and/or new safety information.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been authorized for use in Canada and have been market notified (that is the company has told Health Canada the product is being marketed).
- See the NOC/c-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
In vitro studies suggest that Potiga is a potassium channel opener. It can cause hyperpolarization of neuronal membrane, thereby raising the threshold potential and contributing to the prevention of neuronal hyperexcitability. The anti-epileptic activity of Potiga has been demonstrated in a number of different animal models but its exact mechanism of action in humans is unknown.
The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. Together the clinical and pharmacological data support the use of Potiga at the recommended doses for the recommended indication.
Based on the outcome of pharmacokinetic studies, a reduction in the initial and maintenance doses is recommended in elderly patients, and in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) or moderate to severe hepatic impairment (Child Pugh score ≥7). The maximum recommended daily dose is 750 mg in patients ≥65 years of age, and 600 mg in patients with moderate to severe renal impairment or moderate to severe hepatic impairment.
For further details, please refer to the Potiga Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Potiga in adults as adjunctive therapy in partial-onset seizures was established in two pivotal studies (Studies 301 and 302) and one supportive study (Study 205). All of the studies were multicentre, randomized, double-blind, and placebo-controlled. A total of 1,239 adult patients were treated, 813 were treated with Potiga. All enrolled patients had seizures that were not adequately controlled with 1 to 3 concomitant antiepileptic drugs (AEDs). To participate in the studies, patients were required to have ≥4 partial-onset seizures per 28 days with no seizure-free periods for ≥21 days (Study 301 and 302) or for ≥30 days (Study 205). Patients ranged in age between 14 and 74 years (mean: 37, median: 37), had a mean duration of epilepsy of 22 years and a median baseline seizure frequency ranging from 8 to 12 per 28 days, and were receiving 1-3 established AEDs at the time of randomization (76% of patients were taking 2-3 concomitant AEDs). Overall, 51% of the patients were female.
Following an 8-week baseline phase, patients in all three studies were randomized to receive placebo or daily Potiga doses of 600 mg (Studies 302 and 205), 900 mg (Studies 302 and 205), or 1,200 mg (Studies 301 and 205). All patients were initiated at 300 mg/day (100 mg three times per day) and were up-titrated at weekly increments of 150 mg up to the assigned maintenance dose. Depending on the Potiga dose, the titration phase lasted 4, 6, and 8 weeks in Studies 302, 301, and 205, respectively. Among the patients that were randomized to receive Potiga, 69% completed the double-blind treatment phase (placebo: 83%).
The primary efficacy endpoint was the median percent reduction in the 28-day seizure frequency from baseline to treatment (titration + maintenance). The Responder Rate, defined as the percentage of patients with ≥50% reduction in 28-day seizure frequency from baseline to the maintenance phase, was considered a secondary endpoint.
Potiga demonstrated efficacy as add-on therapy in the three controlled studies and it was both clinically and statistically significantly better than placebo in the dose range of 600 to 1,200 mg/day. The magnitude of efficacy in the controlled studies was similar to that of other currently available AEDs in Canada.
For the primary endpoint, Potiga was statistically significantly better than placebo in the reduction of seizure frequency from baseline to the double-blind treatment phase at daily doses of 600 mg (Study 302), 900 mg (Studies 302 and 205), and 1,200 mg (Studies 301 and 205). In Study 302, the median percent reduction was 28% and 40% for the 600 mg group and the 900 mg group, respectively; compared to the placebo group (16%). In Study 301, the median percent reduction was 44% for the 1,200 mg group compared to the placebo group (18%). In Study 205, the median percent reduction was 23%, 29% and 35% for the 600 mg group, the 900 mg group, and the 1,200 mg group, respectively; compared to the placebo group (13%). Results of the 50% Responder Rates supported the results of the primary efficacy endpoint.
For more information, refer to the Potiga Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
Potiga was administered as adjunctive therapy to 1,365 patients with epilepsy in all of the controlled and uncontrolled clinical studies. Safety data included results from the three placebo-controlled studies (Studies 301, 302, and 205; described in Clinical Efficacy) and from three open-label extension studies.
Adverse events (AEs) in the three placebo-controlled studies included dizziness, somnolence, vertigo, vision-related events (diplopia, blurred vision), urinary-related AEs (hesitation, retention, dysuria), and psychiatric disorders [example (e.g.) psychosis, confusional state, hallucinations). Many of the events were dose-related. Discontinuations due to AEs were also dose-related and included psychotic disorders [e.g. psychosis, visual hallucination; Potiga, ~7%; versus (vs.) placebo, 0%], dizziness (Potiga, 6% vs. placebo, 1%), vertigo (Potiga, 1% vs. placebo, 2%), and vision-related AEs such as diplopia and blurred vision (Potiga, 8% vs. placebo, 0%).
The safety profile of Potiga in the three open-label extension studies was similar to its safety profile in the controlled studies. Adverse events of interest included psychotic disorder, hallucinations, confusional state [at least 30 cases; 9 serious AEs (SAEs), 14 patients discontinued], urinary retention (at least 10 cases; 2 SAEs, 3 patients discontinued), and vision-related AEs (at least 22 cases; 2 SAEs, 4 patients discontinued).
Genitourinary
Potiga can cause urinary-related AEs (e.g. retention, urinary hesitation, and dysuria) in humans. In the placebo-controlled epilepsy studies, Potiga caused urinary retention (Potiga, 0.9%; placebo, 0.5%), urinary hesitation (Potiga, 2.2%; placebo, 0.9%) and dysuria (Potiga, 2.3%; placebo, 0.7%) mostly within the first few weeks following treatment initiation.
Of the 1,365 patients that received Potiga as adjunctive therapy in the controlled and uncontrolled clinical studies, a total of 29 patients experienced urinary retention. Six patients discontinued treatment and the other 23 patients continued either on the same dose or a reduced dose of Potiga. Five of the 29 patients required catheterization, with post-voiding residuals of up to 1,500 mL. Potiga was discontinued in 3 of the patients who required catheterization for urinary retention and all were able to void spontaneously; however, 1 of the 3 patients continued intermittent self-catheterization.
As of March 2012 (cumulative post-marketing exposure: approximately 680 patient-years), there have been 34 spontaneous, post-marketing reports of urinary retention. Review of these cases does not reveal a clear/discernible pattern to predict dose, time-to-onset, sex, age, risk factors, or previous history. Some of these cases were serious and Potiga was discontinued, and some of the patients required bladder catheterization and recovered.
The sponsor has agreed to include a strong, bolded statement in the Warnings and Precautions section of the Potiga Product Monograph to warn prescribers of urinary AEs, and of the need to assess the patient's risk of urinary retention, including medical history and concomitant medication use before initiatingtreatment with Potiga. Prescribers should also instruct patients to seek immediate medical assistance if they experience any symptoms of urinary retention, inability to urinate, and/or pain with urination, as these symptoms may be warning signs for the possible occurrence of acute urinary retention.
Psychiatric Disorders
In the placebo-controlled studies of Potiga, dose-related psychotic symptoms, including visual and auditory hallucinations occurred in 1.4%, 1.5% and 5% of the patients that received Potiga 600, 900, and 1,200 mg/day, respectively (placebo, 0.5%). Nearly half of the patients who discontinued treatment due to hallucinations or psychosis required hospitalization. As of March 2012, there have been 112 reports of psychiatric disorders.
The sponsor has agreed to include a strong statement in the Warnings and Precautions section of the Potiga Product Monograph advising prescribers to inform patients that Potiga can cause psychiatric symptoms such as confusion, disorientation, hallucinations, and other symptoms of psychosis, and that patients should notify their physicians if they experience psychotic symptoms.
Cardiac-related Events
Potiga is associated with QTc interval prolongation. In a placebo and positive-controlled study, the QTc effect of Potiga was assessed in 38 healthy subjects who received Potiga three times a day with daily doses of 750 mg/day to 1,200 mg/day (26 patients received 1,200 mg/day), using the Fridericia correction method. Potiga produced a mean 7.7 ms QT prolongation which occurred within 3 hours of dosing.
In the placebo-controlled studies, 5 cases of syncope (0.6%) were reported in patients that received Potiga (placebo: 1 case or 0.2%). Of the 1,365 patients that received Potiga as adjunctive therapy in the controlled and uncontrolled clinical studies, 12 cases of syncope (~1%) were reported. One patient had a SAE of syncope and discontinued treatment. The sponsor has included sufficient warnings and precautions regarding QT interval prolongation in the Potiga Product Monograph.
Ophthalmological Effects
In the placebo-controlled studies, Potiga treatment was associated with vision-related AEs such as blurred vision (Potiga, 5%; placebo, 2%) and diplopia (Potiga, 7%; placebo, 2%). Approximately 2.7% of the patients treated with Potiga discontinued treatment due to vision-related events, mainly blurred vision (1.1%) and diplopia (1.1%). A warning statement has been added to the Potiga Product Monograph to advise prescribers of the risk of such events during Potiga therapy, and to recommend more frequent assessments for patients with known vision-related issues or for those who are already routinely monitored for ocular conditions.
Dizziness and Somnolence
In the placebo-controlled studies, Potiga treatment was associated with dizziness and somnolence in a dose-related manner. Dizziness was reported by 15%, 23%, and 32% of the patients that were administered Potiga 600, 900, and 1,200 mg/day, respectively; placebo 9%. Somnolence was experienced by 15%, 25%, and 27% of the patients that were administered Potiga 600, 900, and 1,200 mg/day, respectively; placebo 12%. Six percent of the Potiga-treated patients discontinued treatment due to dizziness and 3% discontinued treatment due to somnolence. The Potiga Product Monograph warns prescribers of the risks of dizziness and somnolence, and advises patients to not drive or operate machinery until they have established how Potiga affects them.
For more information, refer to the Potiga Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The maximum dose achieved in the repeat-dose animal studies was limited by the toxicity related to the pharmacology of the active ingredient of Potiga, ezogabine. These effects included ataxia, hypokinesia, and tremors. The no-observed-effect plasma level of the drug achieved in these studies was generally less than that reached at the maximum recommended human therapeutic dose.
In Langendorff-perfused guinea pig hearts, ezogabine at a nominal concentration of 100 µM caused a 17% increase in the QT interval, however, there were no QT interval prolonging effects observed in in vivo non-clinical studies.
Urinary-related AEs associated with the drug were observed in various animal experiments. In mice, rats and dogs, histopathological findings in the urinary bladder included distension (rodent only), thickened urinary bladder wall, proliferation of urinary bladder smooth muscle, and inflammation and focal hemorrhage in the urinary bladder. In rodents, there were also findings of bladder calculi and urothelial hyperplasia. Secondary effects in the kidneys were also observed in rodents such as dilated pelvis, papillary necrosis and tubular degeneration/regeneration/dilation. Reversibility of the effects was observed following a 6-week recovery period.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Potiga Product Monograph. There are no pharmacological/toxicological issues within this submission which preclude authorization of the product as adjunctive therapy for the management of partial-onset seizures in adult patients with epilepsy. Appropriate warnings and precautionary measures are in place in the Potiga Product Monograph to address the identified safety concerns.
For more information, refer to the Potiga Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Potiga has demonstrated that the drug substance (ezogabine) and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. The proposed limits of drug-related impurities are considered adequately qualified from toxicological studies.
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable. The commercial manufacturing process does not differ significantly from the manufacturing process used to manufacture the drug product used in supporting clinical studies, as confirmed through conduct of bioequivalence and comparative in-vitro dissolution studies. Therefore, the commercial drug product formulation is identical to that used in the pivotal clinical studies.
Based on the stability data submitted, the proposed shelf-life is acceptable. The container closure system met all validation test acceptance criteria.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipients used in the drug product formulation are not from animal or human origin.
The design, operations, and controls of the facilities and equipment which are involved in the production of Potiga are considered suitable for the activities and products manufactured. All manufacturing sites are compliant with Good Manufacturing Practices.