Pharmacological Class:
Carbonic anhydrase inhibitor.

Active Ingredient(s):
Dichlorphenamide 50mg; scored tabs.

Company
Taro Pharmaceuticals
Indication(s):
Primary hyperkalemic or hypokalemic periodic paralysis and related variants.

Pharmacology:
Dichlorphenamide is a carbonic anhydrase inhibitor. However, the precise mechanism by which dichlorphenamide exerts its therapeutic effects in patients with periodic paralysis is unknown.

Clinical Trials:
The efficacy of Keveyis was eva luated in two clinical studies.

Study 1 was a 9-week, double blind, placebo-controlled multi-center study and consisted of two substudies: a substudy in patients with hypokalemic periodic paralysis (n=44), and a substudy in patients with hyperkalemic periodic paralysis (n=21). The primary efficacy endpoint in both substudies was the average number of self-reported attacks of muscle weakness per week over the final 8 weeks of the trial. Withdrawal from the study for acute severe worsening was also assessed as an endpoint.

In Study 1, the dose of Keveyis was 50mg twice daily for treatment-naïve patients. Patients already on dichlorphenamide prior to the study continued on the same dose while on Keveyis during the study. In patients taking acetazolamide prior to the study, the dose of Keveyis was set at 20% of the acetazolamide dose. Dose reduction for tolerability was permitted. In the hypokalemic periodic paralysis substudy, patients treated with Keveyis (n=24) had 2.2 fewer attacks per week than patients (n=20) treated with placebo (p=0.02). None of the patients randomized to Keveyis reached the endpoint of acute worsening, vs. five patients randomized to placebo. The mean dose of Keveyis at Week 9 was 94mg/day. In the hyperkalemic periodic paralysis substudy during the double-blind treatment period, patients treated with Keveyis (n=12) had 3.9 fewer attacks per week than patients (n=9) treated with placebo (p=0.08). None of the patients randomized to Keveyis reached the endpoint of acute worsening, vs. two patients randomized to placebo. The mean dose of Keveyis at Week 9 was 82mg/day.

Study 2 was a 35-week, double blind, placebo-controlled, multi-center, two-period crossover study and also consisted of two substudies: a substudy in patients with hypokalemic periodic paralysis (n=42), and a substudy in patients with hyperkalemic periodic paralysis (n=31), including patients with Paramyotonia Congenita. The primary endpoint in the hypokalemic periodic paralysis substudy was the incidence of acute intolerable worsening (based on attack frequency or severity) necessitating withdrawal. The primary endpoint in the hyperkalemic periodic paralysis substudy was the average number of self-reported attacks of muscle weakness per week. Dosing was determined similarly to Study 1. In the hypokalemic periodic paralysis substudy, acute intolerable worsening was observed in 2 patients on Keveyis vs. 11 patients on placebo (p=0.02). The mean dose of Keveyis at the end of the study was 96mg/day. In the hyperkalemic periodic paralysis substudy, patients treated had 2.3 fewer attacks per week on Keveyis than on placebo (p=0.006). The mean dose of Keveyis at the end of the study was 73mg/day.

Legal Classification:
Rx

Adults:
Initially 50mg twice daily. Adjust dose based on response, at weekly intervals (or sooner if adverse reactions occur); max 200mg daily. eva luate after 2 months.

Children:
Not established.

Contraindication(s):
Concomitant high-dose aspirin. Severe pulmonary disease. Hepatic insufficiency. Sulfonamides.

Warnings/Precautions:
Discontinue at first sign of skin rash or immune-mediated or idiosyncratic adverse reaction. Adrenocortical insufficiency, hyperchloremic metabolic acidosis, respiratory acidosis: increased risk of hypokalemia. Metabolic acidosis. Monitor serum potassium and bicarbonate at baseline and periodically during treatment; reduce dose or discontinue if hypokalemia or metabolic acidosis develops. Increased risk of falls (esp. elderly, higher doses); consider dose reduction or discontinuation if occurs. Elderly. Pregnancy (Cat.C). Nursing mothers.

Interaction(s)
Caution with concomitant low-dose aspirin. Increased risk of hypokalemia with loop or thiazide diuretics, laxatives, antifungals, penicillin, and theophylline.

Adverse Reaction(s)
Paresthesia, cognitive disorder, dysgeusia, confusion, hypoesthesia, lethargy, dizziness, nausea, fatigue, muscle spasms, rash; hypersensitivity reactions.

How Supplied:
Tabs—100

LAST UPDATED:
10/6/2015