DICHLORPHENAMIDE- dichlorphenamide_tablet

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. Dichlorphenamide can cause metabolic acidosis, which can increase the risk of salicylate toxicity with coadministration [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 4) After single-dose administration in healthy subjects in fasted state, dichlorphenamide C max Absorption max Distribution Elimination Metabolism in vitro Drug Interaction Studies In vitro Assessment of Drug Interactions Drug-Metabolizing Enzyme Inhibition in vitro Drug-Metabolizing Enzyme Induction in vitro In vitro Assessment of Transporter-Drug Interactions in vitro Dichlorphenamide is not an inhibitor of OAT3, but is an inhibitor of OAT1 based on in vitro [see Drug Interactions (7. 4) Dichlorphenamide is a substrate for transporters OAT1 and OAT3 based on in vitro [see Drug Interactions (7. 2) In Vivo Drug Interactions Specific Populations Geriatrics.

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

Initiate dosing at 50 mg by mouth once or twice daily ( 2. 1 Titrate up or down dose based on individual response ( 2. 1 The minimum recommended dosage is 50 mg daily, and the maximum recommended dosage is 200 mg daily ( 2. 1 Evaluate response to dichlorphenamide tablets after 2 months of treatment ( 2. 2 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. Primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants are a heterogeneous group of conditions, for which the response to dichlorphenamide tablets may vary. Therefore, prescribers should evaluate the patient's response to dichlorphenamide tablets after 2 months of treatment to decide whether dichlorphenamide tablets should be continued. Baseline and periodic measurements of serum potassium and serum bicarbonate during dichlorphenamide tablets treatment is recommended [see Warnings and Precautions ( 5.

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. gov/medwatch 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 dichlorphenamide tablets, with rates greater than placebo, were paresthesia, cognitive disorder, dysgeusia, and confusional state. The mean dose of dichlorphenamide tablets 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 dichlorphenamide tablets and more commonly than in patients treated with placebo in Study 1. Table 1: Adverse Reactions in Patients Treated with Dichlorphenamide Tablets with Incidence >= 5% and more common than in Patients Treated with Placebo in Study 1 Adverse Reaction Dichlorphenamide Tablets Placebo Nervous system disorders Paresthesia 44 14 Cognitive disorder Cognitive disorder combined cases with the preferred terms of cognitive disorder, disturbance in attention, and mental 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 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.

Dichlorphenamide is contraindicated in the following circumstances: Hypersensitivity to dichlorphenamide or other sulfonamides [see Warnings and Precautions (5. 1) Concomitant use of dichlorphenamide tablets and high dose aspirin [see Warnings and Precautions (5. 2) Drug Interactions (7. 1) Severe pulmonary disease, limiting compensation to metabolic acidosis caused by dichlorphenamide [see Warnings and Precautions (5. 4) Hepatic insufficiency: Dichlorphenamide 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.

Pregnancy: Based on animal data, may cause fetal harm ( 8. 1 Risk Summary The background risk of major birth defects and miscarriage for the indicated population is unknown. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4%, and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions [see Warnings and Precautions (5. 4) Labor or Delivery Data Animal Data 2 Risk Summary The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for dichlorphenamide and any potential adverse effects on the breastfed infant from dichlorphenamide or from the underlying maternal condition. Safety and effectiveness of dichlorphenamide tablets in pediatric patients have not been established. The risk of falls and of metabolic acidosis are greater in elderly patients [see Warnings and Precautions (5.

Aspirin: anorexia, tachypnea, lethargy, and coma have been reported with concomitant use of dichlorphenamide and high-dose aspirin. The concomitant use of dichlorphenamide tablets and high-dose aspirin is contraindicated. Dichlorphenamide tablets should be used with caution in patients receiving lower doses of aspirin ( 4 5. 1 Carbonic anhydrase inhibitors, including dichlorphenamide, can cause metabolic acidosis [see Warnings and Precautions ( 5. 4 ) [see Contraindications (4) Warnings and Precautions (5. 2) In vitro [see Clinical Pharmacology (12. 3) The risk of hypokalemia is greater with coadministration of dichlorphenamide and other drugs that can cause hypokalemia (e. , loop diuretics, thiazide diuretics, laxatives, antifungals, penicillins, and theophylline) [see Warnings and Precautions (5. 3) Coadministration of dichlorphenamide and other drugs that can cause metabolic acidosis may increase the severity of the acidosis [see Warnings and Precautions (5. 4) An in vitro [see Clinical Pharmacology (12.

OVERDOSAGE
Symptoms of overdosage or toxicity may include drowsiness, anorexia, nausea, vomiting, dizziness, ataxia, tremor, and tinnitus. In the event of overdosage, induce emesis or perform gastric lavage. The electrolyte disturbances most likely to be encountered from overdosage are hypokalemia and hyperchloremic metabolic acidosis.
NONCLINICAL TOXICOLOGY
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 dichlorphenamide tablets 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 (increase in attack frequency or severity) was also assessed as an endpoint. In Study 1, the dose of dichlorphenamide tablets was 50 mg b. for treatment-naïve patients. Patients already on dichlorphenamide prior to the study continued on the same dose while on dichlorphenamide tablets during the study. In patients taking acetazolamide prior to the study, the dose of dichlorphenamide tablets 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 dichlorphenamide tablets (n=24) had 2. 2 fewer attacks per week than patients (n=20) treated with placebo (p=0. None of the patients randomized to dichlorphenamide tablets reached the endpoint of withdrawal from the study for acute worsening, vs. five patients randomized to placebo. The mean dose of dichlorphenamide tablets 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 dichlorphenamide tablets (n=12) had 3. 9 fewer attacks per week than patients (n=9) treated with placebo (p=0. two patients randomized to placebo. The mean dose of dichlorphenamide tablets 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 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 The hypokalemic periodic paralysis substudy included patients with a mean age of 38 years; 79% of patients were male. Acute intolerable worsening was observed in 2 patients on dichlorphenamide tablets vs. 11 patients on placebo (p=0. The mean dose of dichlorphenamide tablets at the end of the study was 96 mg/day. Hyperkalemic Periodic Paralysis Substudy of Study 2 The hyperkalemic periodic paralysis substudy included patients with a mean age of 37 years; and 79% of patients were male. Patients treated had 2. 3 fewer attacks per week on dichlorphenamide tablets than on placebo (p=0. The mean dose of dichlorphenamide tablets at the end of the study was 73 mg/day.

Xeris Pharmaceuticals, Inc.

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