2.1 Dosage Information

Initiate dosing at 50 mg by mouth once or twice daily. The dosage may be increased or decreased based on individual response, at weekly intervals (or sooner in case of adverse reaction). The minimum recommended total daily dosage is 50 mg, and the maximum recommended total daily dosage is 200 mg.

2.2 Monitoring to Assess Effectiveness

Primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants are a heterogeneous group of conditions, for which the response to KEVEYIS may vary. Therefore, prescribers should evaluate the patient's response to KEVEYIS after 2 months of treatment to decide whether KEVEYIS should be continued.

2.3 Monitoring to Assess Safety

Baseline and periodic measurements of serum potassium and serum bicarbonate during KEVEYIS treatment is recommended [see Warnings and Precautions (5.3, 5.4)].

5.1 Hypersensitivity and Other Life-Threatening Reactions

Fatalities associated with the administration of sulfonamides have occurred because of 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 other life-threatening adverse reaction.

5.2 Concomitant Use of Aspirin or Other Salicylates

Carbonic anhydrase inhibitors, including KEVEYIS, can cause metabolic acidosis [see Warnings and Precautions (5.4)] , which can increase the risk of salicylate toxicity. Anorexia, tachypnea, lethargy, and coma have been reported with concomitant use of dichlorphenamide and high-dose aspirin. Therefore, the concomitant use of KEVEYIS and high-dose aspirin is contraindicated. Patients with concomitant use of KEVEYIS and low-dose aspirin should be carefully monitored.

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 excess, renal tubular acidosis type 1 and 2), and in patients receiving other drugs that may cause hypokalemia [see Drug Interactions (7.3)] .

Baseline and periodic measurements of serum potassium during KEVEYIS treatment is recommended.

If hypokalemia develops or persists, consideration should be given to reducing the dose or discontinuing KEVEYIS and correction of potassium levels.

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 acidosis. Concomitant use of KEVEYIS in compensated patients with respiratory acidosis, such as in advanced lung diseases, may lead to respiratory decompensation.

Baseline and periodic measurements 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 [see Drug Interactions (7.4)] .

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

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 during postapproval use of dichlorphenamide and were serious or are not reported in the previous section of labeling [see Clinical Trials Experience (6.1)] : amnesia, cardiac failure, condition aggravated, convulsion, hallucination, nephrolithiasis, pancytopenia, psychotic disorder, renal tubular necrosis, stupor, syncope, tremor.

7.1 Aspirin and Other Salicylates

Carbonic anhydrase inhibitors, including KEVEYIS, can cause metabolic acidosis [see Warnings and Precautions (5.2, 5.4)], which can increase the risk of salicylate toxicity. Anorexia, tachypnea, lethargy, and coma have been reported with concomitant use of dichlorphenamide and high-dose aspirin. Therefore, concomitant use of KEVEYIS and high-dose aspirin is contraindicated. Patients with concomitant use of KEVEYIS and low-dose aspirin should be carefully monitored [see Contraindications (4) and Warnings and Precautions (5.2)].

7.2 Drugs that are Substrates of Organic Anion Transporter1 (OAT1)

In vitro, dichlorphenamide is an inhibitor of OAT1 transporters. The concomitant administration of KEVEYIS may increase the plasma exposures of OAT1 substrates. Use of KEVEYIS with drugs that are sensitive to OAT1 inhibition (e.g., methotrexate, famotidine, oseltamivir) is not recommended [see Clinical Pharmacology (12.3)].

7.3 Drugs that Cause Hypokalemia

The risk of hypokalemia is greater with coadministration of KEVEYIS and other drugs that can cause hypokalemia (e.g., loop diuretics, thiazide diuretics, laxatives, antifungals, penicillins, and theophylline) [see Warnings and Precautions (5.3)] .

7.4 Drugs that Cause Metabolic Acidosis

Coadministration of KEVEYIS and other drugs that can cause metabolic acidosis may increase the severity of the acidosis [see Warnings and Precautions (5.4)].

7.5 Drugs that are Inhibitors of OAT1 or OAT3

An in vitro transporter study indicated that dichlorphenamide is a substrate of human transporters OAT1 and OAT3 [see Clinical Pharmacology (12.3)] . Therefore, signs of dichlorphenamide toxicity should be monitored when administered with OAT1 or OAT3 inhibitors.

8.1 Pregnancy

8.2 Lactation

Risk Summary
There are no data on the presence of dichlorphenamide in human milk, the effects on the breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KEVEYIS and any potential adverse effects on the breastfed infant from KEVEYIS or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of KEVEYIS in pediatric patients have not been established.

8.5 Geriatric Use

The risk of falls and of metabolic acidosis are greater in elderly patients [see Warnings and Precautions (5.4, 5.5)] ​.

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 primary periodic paralysis is unknown.

12.2 Pharmacodynamics

KEVEYIS can cause metabolic acidosis, which can increase the risk of salicylate toxicity with coadministration [see Warnings and Precautions (5.2)]. KEVEYIS-induced metabolic acidosis can also increase in severity with coadministration of other drugs that cause metabolic acidosis [see Warnings and Precautions (5.4)].

12.3 Pharmacokinetics

After single-dose administration in healthy subjects in fasted state, dichlorphenamide C max and AUC increased in a dose-proportional manner within the range of 25 mg to 400 mg (2 times the maximum recommended dose). The steady-state is expected to be achieved within 10 days of twice-daily dosing.

Absorption
The median time to reach maximum concentration (T max) of dichlorphenamide was about 1.5 to 3 hours postdose after both single and multiple dose administrations.

Distribution
The plasma protein binding of dichlorphenamide is approximately 88%.

Elimination
Following a single-dose administration, mean terminal half-life was in the range of 32 to 66 hours.

Metabolism
Dichlorphenamide is not a substrate for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 isoforms when tested in vitro.

Drug Interaction Studies

In vitro Assessment of Drug Interactions

Drug-Metabolizing Enzyme Inhibition
Dichlorphenamide is not an inhibitor for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 enzymes when tested in vitro.

Drug-Metabolizing Enzyme Induction
Dichlorphenamide is not an inducer for CYP1A2, 2B6, or 3A4 enzymes when tested in vitro.

In vitro Assessment of Transporter-Drug Interactions
Dichlorphenamide is neither a substrate nor inhibitor for p-gp, BCRP, OATP1B1, OATP1B3, OAT2, OAT4, OCT1, OCT2, MATE1, or MATE2-K when tested in vitro.

Dichlorphenamide is not an inhibitor of OAT3, but is an inhibitor of OAT1 based on in vitro studies [see Drug Interactions (7.4)].

Dichlorphenamide is a substrate for transporters OAT1 and OAT3 based on in vitro studies [see Drug Interactions (7.2)] .

In Vivo Drug Interactions
The use of dichlorphenamide in combination with high-dose aspirin is contraindicated as it may lead to salicylate toxicity. The mechanism(s) of this interaction is not known.

Specific Populations
Geriatrics
The pharmacokinetics of dichlorphenamide in the elderly has not been determined.

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 (increase in attack frequency or severity) 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 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°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].

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

Hypersensitivity and Other Life-Threatening Reactions
Inform patients that hypersensitivity and immune mediated reactions can occur with KEVEYIS, and could be fatal. Advise patients to discontinue KEVEYIS and notify their healthcare provider immediately if they develop a rash or signs and symptoms of anaphylaxis or other life-threatening reactions [see Warnings and Precautions (5.1)].

Drug Interactions
Instruct patients to notify their healthcare provider of all of the drugs and over-the-counter medications that they take and to not take aspirin or other salicylates without first discussing with their healthcare provider [see Drug Interactions (7.1, 7.2, 7.3, 7.4)].

Metabolic Acidosis
Instruct patients to contact their healthcare provider immediately if they develop possible manifestations of metabolic acidosis (e.g., fast breathing, fatigue/tiredness, loss of appetite, or irregular heart beat or palpitations) [see Warnings and Precautions (5.4)].

Falls
Inform patients that KEVEYIS can increase their risk of falls [see Warnings and Precautions (5.5)].

Cognitive Impairment
Advise patients to notify their healthcare provider if they experience symptoms of cognitive impairment including confusion and memory lapse [see Adverse Reactions (6.1)].

Driving and Operating Machinery
KEVEYIS may cause drowsiness/fatigue in some patients [see Adverse Reactions (6.1)] . Caution patients on the potential for impaired ability to drive and operate machinery.