5.1 Hypersensitivity / Anaphylaxis / Idiosyncratic Reactions

Fatalities associated with the administration of sulfonamides have occurred due to adverse reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias. Pulmonary involvement can occur in isolation or as part of a systemic reaction.

KEVEYIS™ should be discontinued at the first appearance of skin rash or any sign of immune-mediated or idiosyncratic adverse reaction.

5.2 Concomitant Use of Aspirin

Anorexia, tachypnea, lethargy, and coma have been reported with concomitant use of dichlorphenamide and high-dose aspirin. The concomitant use of KEVEYIS™ and high dose aspirin is contraindicated. KEVEYIS™ should be used with caution in patients receiving low dose aspirin.

5.3 Hypokalemia

KEVEYIS™ increases potassium excretion and can cause hypokalemia. The risk of hypokalemia is greater when KEVEYIS™ is used in patients with conditions associated with hypokalemia (e.g., adrenocortical insufficiency, hyperchloremic metabolic acidosis, or respiratory acidosis), and in patients receiving other drugs that may cause hypokalemia (e.g., loop diuretics, thiazide diuretics, laxatives, antifungals, penicillin, and theophylline).

Baseline and periodic measurement of serum potassium during KEVEYIS™ treatment are recommended.

If hypokalemia develops or persists, consideration should be given to reducing the dose or discontinuing KEVEYIS™.

5.4 Metabolic Acidosis

KEVEYIS™ can cause hyperchloremic non-anion gap metabolic acidosis. Concomitant use of KEVEYIS™ with other drugs that cause metabolic acidosis may increase the severity of metabolic acidosis.

Baseline and periodic measurement of serum bicarbonate during KEVEYIS™ treatment are recommended.

If metabolic acidosis develops or persists, consideration should be given to reducing the dose or discontinuing KEVEYIS™.

5.5 Falls

KEVEYIS™ increases the risk of falls. The risk of falls is greater in the elderly and with higher doses of KEVEYIS™. Consider dose reduction or discontinuation of KEVEYIS™ in patients who experience falls while treated with KEVEYIS™.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a 9-week randomized controlled trial in adults with hyperkalemic or hypokalemic periodic paralysis (Study 1), the most common adverse reactions in patients treated with KEVEYIS™, with rates greater than placebo, were paresthesia, cognitive disorder, dysgeusia, and confusional state. The mean dose of KEVEYIS™ was 94 mg/day in patients with hypokalemic periodic paralysis and 82 mg/day in patients with hyperkalemic periodic paralysis.

Table 1 lists the incidence of adverse reactions that occurred in ≥ 5% of patients treated with KEVEYIS™ and more commonly than in patients treated with placebo in Study 1.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of dichlorphenamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following are adverse reactions which have been reported for dichlorphenamide that were serious adverse events or are not reported in the previous section of labeling [see Clinical Trials Experience (6.1)]: amnesia, cardiac failure, condition aggravated, convulsion, fetal death, hallucination, nephrolithiasis, pancytopenia, psychotic disorder, renal tubular necrosis, stupor, syncope, tremor.

7.1 Aspirin and Salicylates

KEVEYIS™ may cause an elevation in salicylate levels in patients receiving aspirin. Anorexia, tachypnea, lethargy, and coma have been reported with concomitant use of dichlorphenamide and high-dose aspirin.

Concomitant use of KEVEYIS™ and high dose aspirin is contraindicated. KEVEYIS™ should be used with caution in patients receiving low dose aspirin. [see Contraindications (4) and Warnings and Precautions (5.2)]

8.1 Pregnancy

8.3 Nursing Mothers

It is not known whether dichlorphenamide is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when dichlorphenamide is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

The risk of falls and of metabolic acidosis are greater in elderly patients.

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

The pharmacokinetic properties of dichlorphenamide after oral absorption are not known.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Study 1

Study 1 was a 9-week, double blind, placebo-controlled multi-center study. Study 1 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 50 mg b.i.d. 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.

Study 2

Study 2 was a 35-week, double blind, placebo-controlled, multi-center, two-period crossover study. Study 2 also consisted of two substudies: a substudy in 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.

Store at 20° to 25° C (68° to 77° F) [See USP Controlled Room Temperature].

Worsening of Symptoms

Advise patients to notify their physician if they experience worsening of symptoms of periodic paralysis.

Driving and Operating Machinery

KEVEYIS™ may cause drowsiness/fatigue in some patients. Caution patients on the potential for impaired ability to drive and operate machinery.