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Keveyis(dichlorphenamide)首个获美国批准用于钾周期性麻痹症
KEVEYIS™ is an oral carbonic anhydrase inhibitor indicated for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants (1) DOSAGE AND ADMINISTRATION Initial dose: 50 mg twice daily (2) Titrate dose based on individual response (2) The maximum recommended dose is 200 mg daily (2) DOSAGE FORMS AND STRENGTHS Tablets: 50 mg (3) 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 Hypersensitivity / Anaphylaxis / Idiosyncratic 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 measurement of serum potassium are recommended; if hypokalemia develops or persists, consider reducing the dose or discontinuing KEVEYIS™ (5.3) Metabolic acidosis: baseline and periodic measurement 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) ADVERSE REACTIONS Most common adverse reactions (incidence at least 10% and greater than placebo) include paresthesias, cognitive disorder, dysgeusia, and confusional state (6) To report SUSPECTED ADVERSE REACTIONS, contact Taro at 1-866-923-4914, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG 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 low dose aspirin (4, 5.2, 7.1). USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1) See 17 for PATIENT COUNSELING INFORMATION. Revised: 8/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE KEVEYIS™ is indicated for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants. 2 DOSAGE AND ADMINISTRATION Initiate dosing at 50 mg twice daily. The initial dose may be increased or decreased based on individual response, at weekly intervals (or sooner in case of adverse reaction). The maximum recommended total daily dose is 200 mg. 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. 3 DOSAGE FORMS AND STRENGTHS Round, white tablets, scored on one side, engraved with "TARO" on one side and on the other side "D" above the score and "50" below the score, 50 mg each. 4 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)] Severe pulmonary disease, limiting compensation to metabolic acidosis caused by KEVEYIS™ [see Warnings and Precautions (5.4)] Hepatic insufficiency: KEVEYIS™ may aggravate hepatic encephalopathy. 5 WARNINGS AND PRECAUTIONS 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 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: Hypersensitivity / Anaphylaxis / Idiosyncratic 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)] 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. Table 1: Adverse Reactions in Patients Treated with KEVEYIS™ with Incidence ≥ 5% and more common 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 DRUG INTERACTIONS 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Teratogenic effects (fetal limb reduction defects) were reported following oral administration of dichlorphenamide to pregnant rats during organogenesis at 350 mg/kg, or 17 times the maximum recommended human dose (200 mg/day) on a body surface area (mg/m2) basis. A no-effect dose has not been established. KEVEYIS™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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. 10 OVERDOSAGE Symptoms of overdosage or toxicity may include drowsiness, anorexia, nausea, vomiting, dizziness, paresthesias, ataxia, tremor, and tinnitus. In the event of overdosage, induce emesis or perform gastric lavage. The electrolyte disturbance most likely to be encountered from overdosage is hyperchloremic acidosis. 11 DESCRIPTION KEVEYIS™ (dichlorphenamide) tablets is an oral carbonic anhydrase inhibitor. Dichlorphenamide, a dichlorinated benzenedisulfonamide, is known chemically as 4, 5–dichloro-1,3-benzenedisulfonamide. Its empirical formula is C6H6Cl2N2O4S2 and its structural formula is:
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