|
依佐加滨片Potiga(ezogabine,retigabine，瑞替加滨)(十一)
VERDOSAGE
10.1 Signs, Symptoms, and Laboratory Findings
There is limited experience of overdose with POTIGA. Total daily doses of POTIGA over 2,500 mg were reported during clinical trials. In addition to adverse reactions seen at therapeutic doses, symptoms reported with POTIGA overdose included agitation, aggressive behavior, and irritability. There were no reported sequelae.
In an abuse potential study, cardiac arrhythmia (asystole or ventricular tachycardia) occurred in 2 volunteers within 3 hours of receiving a single 900-mg dose of POTIGA. The arrhythmias spontaneously resolved and both volunteers recovered without sequelae.
10.2 Management of Overdose
There is no specific antidote for overdose with POTIGA. In the event of overdose, standard medical practice for the management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rhythm and vital sign measurement is recommended. A certified poison control center should be contacted for updated information on the management of overdose with POTIGA.
11 DESCRIPTION
The chemical name of ezogabine is N-[2-amino-4-(4-fluorobenzylamino)-phenyl] carbamic acid ethyl ester, and it has the following structure:
The empirical formula is C16H18FN3O2, representing a molecular weight of 303.3. Ezogabine is a white to slightly colored, odorless, tasteless, crystalline powder. At room temperature, ezogabine is practically insoluble in aqueous media at pH values above 4, while the solubility is higher in polar organic solvents. At gastric pH, ezogabine is sparingly soluble in water (about 16 g/L). The pKa is approximately 3.7 (basic).
POTIGA is supplied for oral administration as 50-mg, 200-mg, 300-mg, and 400-mg film-coated immediate-release tablets. Each tablet contains the labeled amount of ezogabine and the following inactive ingredients: carmine (50-mg and 400-mg tablets), croscarmellose sodium, FD&C Blue No. 2 (50-mg, 300-mg, and 400-mg tablets), hypromellose, iron oxide yellow (200‑mg and 300-mg tablets), lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc, titanium dioxide, and xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism by which ezogabine exerts its therapeutic effects has not been fully elucidated. In vitro studies indicate that ezogabine enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating KCNQ channels, ezogabine is thought to stabilize the resting membrane potential and reduce brain excitability. In vitro studies suggest that ezogabine may also exert therapeutic effects through augmentation of GABA-mediated currents.
12.2 Pharmacodynamics
The QTc prolongation risk of POTIGA was eva luated in healthy subjects. In a randomized, double-blind, active- and placebo-controlled parallel-group study, 120 healthy subjects (40 in each group) were administered POTIGA titrated up to the final dose of 400 mg 3 times daily, placebo, and placebo and moxifloxacin (on day 22). After 22 days of dosing, the maximum mean (upper 1-sided, 95% CI) increase of baseline- and placebo-adjusted QTc interval based on Fridericia correction method (QTcF) was 7.7 msec (11.9 msec) and was observed at 3 hours after dosing in subjects who achieved 1,200 mg per day. No effects on heart rate, PR, or QRS intervals were noted.
Patients who are prescribed POTIGA with medicines known to increase QT |
|
