Carbonic Anhydrase Inhibitor

Keveyis

Approved 22 Jul 1958OralTablet

Indications

KEVEYIS is indicated for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants. KEVEYIS is an oral carbonic anhydrase inhibitor indicated for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants ( 1 )

Contraindications

KEVEYIS is contraindicated in the following circumstances: Hypersensitivity to dichlorphenamide or other sulfonamides [see Warnings and Precautions (5.1) ] Concomitant use of KEVEYIS and high dose aspirin [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] Severe pulmonary disease, limiting compensation to metabolic acidosis caused by KEVEYIS [see Warnings and Precautions (5.4) ] Hepatic insufficiency: KEVEYIS may aggravate hepatic encephalopathy.

Hepatic insufficiency ( 4 ) Severe pulmonary obstruction ( 4 ) Hypersensitivity to dichlorphenamide or other sulfonamides ( 4 ) Concomitant use with high dose aspirin ( 4 )

Warnings and precautions

Hypersensitivity and Other Life-Threatening Reactions: discontinue KEVEYIS at the first appearance of skin rash or any sign of immune-mediated or idiosyncratic adverse reaction ( 5.1 ) Hypokalemia: baseline and periodic measurements of serum potassium are recommended; if hypokalemia develops or persists, consider reducing the dose or discontinuing KEVEYIS and correcting potassium levels ( 5.3 ) Metabolic acidosis: baseline and periodic measurements of serum bicarbonate are recommended; if metabolic acidosis develops or persists, consider reducing the dose or discontinuing KEVEYIS ( 5.4 ) Falls: consider reducing the dose or discontinuing KEVEYIS in patients who experience falls ( 5.5 )

5.1Hypersensitivity 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

At a glance

Brand name: Keveyis
Active substance: dichlorphenamide
Pharmacologic class: Carbonic Anhydrase Inhibitor
Route: Oral
Dosage form: Tablet
Applicant: Xeris
Status: Prescription
FDA approval: 22 Jul 1958
Application: NDA011366-002

Indications

Contraindications

Hepatic insufficiency ( 4 ) Severe pulmonary obstruction ( 4 ) Hypersensitivity to dichlorphenamide or other sulfonamides ( 4 ) Concomitant use with high dose aspirin ( 4 )

Warnings and precautions

5.1Hypersensitivity and Other Life-Threatening Reactions

5.2

Interactions

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 lower doses of aspirin ( 4 , 5.2 , 7.1 )

7.1Aspirin 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.

Adverse reactions

The following serious adverse reactions are described elsewhere in labeling: Hypersensitivity and Other Life-Threatening Reactions [see Warnings and Precautions (5.1) ] Hypokalemia [see Warnings and Precautions (5.3) ] Metabolic Acidosis [see Warnings and Precautions (5.4) ] Falls [see Warnings and Precautions (5.5) ] Most common adverse reactions (incidence at least 10% and greater than placebo) include paresthesias, cognitive disorder, dysgeusia, and confusional state ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xeris Pharmaceuticals, Inc. at 1-855-324-8912, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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. Table 1: Adverse Reactions in Patients Treated with KEVEYIS with Incidence ≥ 5% and more common than in Patients Treated with Placebo in Study 1 Adverse Reaction KEVEYIS N = 36 (%) Placebo N = 29 (%) Nervous system disorders Paresthesia 44 14 Cognitive disorder Cognitive disorder combined cases with the preferred terms of cognitive disorder, disturbance in attention, and mental impairment. 14 7 Dysgeusia 14 0 Confusional state 11 0 Headache 8 7 Hypoesthesia 8 0 Lethargy 8 0 Dizziness 6 0 Gastrointestinal disorders Diarrhea 6 3 Nausea 6 0 General disorders and administration site conditions Fatigue 8 0 Malaise 6 0 Investigations Weight decreased 6 0 Musculoskeletal and connective tissue disorders Muscle spasms 8 0 Arthralgia 6 3 Muscle twitching 6 0 Respiratory Dyspnea 6 0 Pharyngolaryngeal pain 6 0 Skin Rash 8 0 Pruritus 6 0

6.2Postmarketing 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.

Keveyis

Indications

Contraindications

Warnings and precautions

5.1Hypersensitivity and Other Life-Threatening Reactions

5.2

At a glance

Two medicines in one question?

Keveyis

Indications

Contraindications

Warnings and precautions

5.1Hypersensitivity and Other Life-Threatening Reactions

5.2

At a glance

Two medicines in one question?

5.3Hypokalemia

5.4Metabolic Acidosis

5.5Falls

Interactions

7.1Aspirin and Other Salicylates

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Official product information