纽约州霍桑市（商业新闻）--2015年8月10日--塔罗制药工业有限公司（纽约证券交易所：塔罗）今天宣布，美国食品和药物管理局（FDA）已批准凯维（二氯苯甲酰胺）50毫克片剂治疗原发性高钾和低钾性周期性麻痹，导致肌肉无力或瘫痪的一组罕见的遗传性疾病[1]。Keveyis是FDA批准的治疗原发性周期性麻痹的第一种药物，据估计在美国约有5000人患有该病（2）。

Taro首席执行官Kal Sundaram说：“Keveyis的批准证明了工业界、科研人员、患者权益倡导者和FDA共同努力确定并将原发性周期性麻痹的治疗方法推向市场的重要性。”“Taro为它对这个社区的承诺感到骄傲，这个社区多年来一直在等待一个新的、有效的治疗方案。我们感谢食品和药物管理局继续合作，使这一重要的一天成为现实。”

Taro预计Keveyis将在2015年第三季度提供给患者。该公司已经创建了keys2care计划，该计划将提供一套患者支持服务，以确保被诊断为周期性瘫痪的患者能够尽快接受keveyis的治疗。作为这项计划的一部分，该公司正与专业药房Digitalt Pharmacy，Inc.合作，为开处方药的患者及其护理人员提供访问和支持。

罗切斯特大学医学中心神经学系首席研究员兼教授罗伯特·格里格斯（Robert Griggs）医学博士说：“由于周期性麻痹非常罕见，患者在数年后才得到准确诊断并不罕见。”“对于那些经常出现虚弱症状的患者来说，Keveyis的批准既是一项重要且急需的治疗进展，也是一个提高对疾病认识和理解的机会，这对这些人来说是一个长期的挑战。”

关于周期性麻痹

周期性瘫痪是一组罕见的遗传性疾病，会导致肌肉无力或瘫痪。周期性瘫痪的类型根据标准来区分，包括潜在的基因突变和发作时血钾的变化。低钾和高钾是两种常见的周期性麻痹[1]。

指示

Keveyis用于治疗原发性高钾性周期性麻痹、原发性低钾性周期性麻痹及相关变异。

重要安全信息

在临床研究中，keveyis最常见的副作用是灼热或刺痛感、思维和注意力困难、味觉变化和困惑。这些并不是所有你可能会遇到的副作用。如果你有任何困扰你的症状或者没有消失，就和你的医生谈谈。

Keveyis并不适合所有人。如果你不带Keveyis

正在服用大剂量阿司匹林

对磺胺类药物过敏

有肝、肾或某些肺病

怀孕、计划怀孕或哺乳

18岁以下

服用keveyis可能导致体内钾（一种电解质）含量下降，从而导致心脏问题。如果你需要吃含钾量高的食物，请咨询你的医生。

你的身体可能会产生过多的酸，或者在服用凯维时无法从体液中清除足够的酸。你的医生将定期进行检查，以检查是否有积酸迹象，并可能减少你的剂量或停止你的治疗与凯维。

Keveyis也可能增加跌倒的风险，特别是在老年患者和服用高剂量Keveyis的患者中。在驾驶、操作机器或进行任何其他危险活动时要小心，因为这种药物可能会导致困倦。

如果你的周期性麻痹症状恶化，告诉你的医生。

纽约州霍桑市（商业新闻）--2015年8月10日--塔罗制药工业有限公司（纽约证券交易所：塔罗）今天宣布，美国食品和药物管理局（FDA）已批准凯维（二氯苯甲酰胺）50毫克片剂治疗原发性高钾和低钾性周期性麻痹，导致肌肉无力或瘫痪的一组罕见的遗传性疾病[1]。Keveyis是FDA批准的治疗原发性周期性麻痹的第一种药物，据估计在美国约有5000人患有该病（2）。

Taro首席执行官Kal Sundaram说：“Keveyis的批准证明了工业界、科研人员、患者权益倡导者和FDA共同努力确定并将原发性周期性麻痹的治疗方法推向市场的重要性。”“Taro为它对这个社区的承诺感到骄傲，这个社区多年来一直在等待一个新的、有效的治疗方案。我们感谢食品和药物管理局继续合作，使这一重要的一天成为现实。”

Taro预计Keveyis将在2015年第三季度提供给患者。该公司已经创建了keys2care计划，该计划将提供一套患者支持服务，以确保被诊断为周期性瘫痪的患者能够尽快接受keveyis的治疗。作为这项计划的一部分，该公司正与专业药房Digitalt Pharmacy，Inc.合作，为开处方药的患者及其护理人员提供访问和支持。

罗切斯特大学医学中心神经学系首席研究员兼教授罗伯特·格里格斯（Robert Griggs）医学博士说：“由于周期性麻痹非常罕见，患者在数年后才得到准确诊断并不罕见。”“对于那些经常出现虚弱症状的患者来说，Keveyis的批准既是一项重要且急需的治疗进展，也是一个提高对疾病认识和理解的机会，这对这些人来说是一个长期的挑战。”

关于周期性麻痹

周期性瘫痪是一组罕见的遗传性疾病，会导致肌肉无力或瘫痪。周期性瘫痪的类型根据标准来区分，包括潜在的基因突变和发作时血钾的变化。低钾和高钾是两种常见的周期性麻痹[1]。

指示

Keveyis用于治疗原发性高钾性周期性麻痹、原发性低钾性周期性麻痹及相关变异。

重要安全信息

在临床研究中，keveyis最常见的副作用是灼热或刺痛感、思维和注意力困难、味觉变化和困惑。这些并不是所有你可能会遇到的副作用。如果你有任何困扰你的症状或者没有消失，就和你的医生谈谈。

Keveyis并不适合所有人。如果你不带Keveyis

正在服用大剂量阿司匹林

对磺胺类药物过敏

有肝、肾或某些肺病

怀孕、计划怀孕或哺乳

18岁以下

服用keveyis可能导致体内钾（一种电解质）含量下降，从而导致心脏问题。如果你需要吃含钾量高的食物，请咨询你的医生。

你的身体可能会产生过多的酸，或者在服用凯维时无法从体液中清除足够的酸。你的医生将定期进行检查，以检查是否有积酸迹象，并可能减少你的剂量或停止你的治疗与凯维。

Keveyis也可能增加跌倒的风险，特别是在老年患者和服用高剂量Keveyis的患者中。在驾驶、操作机器或进行任何其他危险活动时要小心，因为这种药物可能会导致困倦。

如果你的周期性麻痹症状恶化，告诉你的医生。

Keveyis (dichlorphenamide) Tablets

Date of Approval: August 7, 2015
Company: Taro Pharmaceutical Industries Ltd.
Treatment for: Primary Hyperkalemic and Hypokalemic Periodic Paralysis

Keveyis (dichlorphenamide) is an oral carbonic anhydrase inhibitor indicated for the treatment of primary hyperkalemic and hypokalemic periodic paralysis.

Keveyis

Generic Name: dichlorphenamide
Dosage Form: tablet

Medically reviewed by Drugs.com. Last updated on Oct 1, 2018.

Indications and Usage for Keveyis

Keveyis is indicated for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants.

Keveyis 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.

Dosage Forms and Strengths

Round, white tablets, scored on one side, engraved with "D" above the score and "50" below the score, the other side is plain, 50 mg each.

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.

Warnings and Precautions

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.

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.

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.

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.

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.

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)]

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.

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.

Drug Interactions

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)]

USE IN SPECIFIC POPULATIONS

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.

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

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

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.

Keveyis 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:

Dichlorphenamide USP is a white or practically white, crystalline compound with a molecular weight of 305.16. It is very slightly soluble in water but soluble in dilute solutions of sodium carbonate and sodium hydroxide. Dilute alkaline solutions of dichlorphenamide are stable at room temperature.

Keveyis (dichlorphenamide) tablets is supplied as tablets, for oral administration, each containing 50 mg dichlorphenamide. Inactive ingredients are lactose monohydrate, magnesium stearate and pregelatinized maize starch.

Keveyis - Clinical Pharmacology

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.

Pharmacokinetics

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Studies to assess the carcinogenic potential of dichlorphenamide have not been conducted.

Mutagenesis

Studies to assess the genotoxicity of dichlorphenamide have not been conducted.

Impairment of Fertility

Studies to assess the effects of dichlorphenamide on fertility have not been conducted.

Clinical Studies

The efficacy of Keveyis was evaluated in two clinical studies, Study 1 and Study 2.

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.

Hypokalemic Periodic Paralysis Substudy of Study 1

In the hypokalemic periodic paralysis substudy, median age of patients was 45 years and 73% of patients were male. 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 94 mg/day.

Hyperkalemic Periodic Paralysis Substudy of Study 1

In the Hyperkalemic Periodic Paralysis substudy, median age of patients was 43 years and 43% of patients were male. 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 82 mg/day.

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.

Hypokalemic Periodic Paralysis Substudy of Study 2

In the hypokalemic periodic paralysis substudy, mean age of patients was 38 years and 79% of patients were male. 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 96 mg/day.

Hyperkalemic Periodic Paralysis Substudy of Study 2

In the hyperkalemic periodic paralysis substudy, mean age of patients was 37 years and 79% of patients were male. 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 73 mg/day.

How Supplied/Storage and Handling

Each Keveyis (dichlorphenamide) tablet, 50 mg is round, white, scored on one side, engraved with "D" above the score and "50" below the score. The other side is plain.

Keveyis (dichlorphenamide) tablets are supplied as follows:

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

Patient Counseling Information

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.

Mfd. by: Taro Pharmaceutical Industries Ltd., Haifa Bay, Israel 2624761
Dist. by: Strongbridge US Inc., Trevose, PA 19053

Keveyis® is a licensed trademark of Strongbridge Biopharma plc.

STRONGBRIDGE BIOPHARMA™ is a trademark of Strongbridge Biopharma plc. Strongbridge Biopharma plc is the parent company of Strongbridge US Inc.

Revised: January 2017
21061-0117-0

PRINCIPAL DISPLAY PANEL - 50 mg Tablet Bottle Label

NDC 71090-001-01
100 Tablets

Keveyis®
(dichlorphenamide)
Tablets 50 mg

Keep this and all medications out
of the reach of children.
Rx only

Strongbridge US Inc.