DailyMed Label: Dichlorphenamide

DailyMed Label: Dichlorphenamide

2023

DailyMed Prescription

Dichlorphenamide

Dichlorphenamide

Xeris Pharmaceuticals, Inc.

NDC: 72065-002

NDC: 72065-002

Dichlorphenamide tablets contain dichlorphenamide, an oral carbonic anhydrase inhibitor. Dichlorphenamide, a dichlorinated benzenedisulfonamide, is known chemically as 4, 5–dichloro-1,3-benzenedisulfonamide. Its empirical formula is C 6 H 6 Cl 2 N 2 O 4 S 2 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. Dichlorphenamide tablets are supplied as tablets, for oral administration, each containing 50 mg dichlorphenamide. Inactive ingredients are lactose monohydrate, magnesium stearate and pregelatinized starch. Chemical Structure

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 ( 5.3 , 5.4 )] .

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. Tablets: 50 mg ( 3 )

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)  and 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 )

Hypersensitivity and Other Life-Threatening Reactions: discontinue dichlorphenamide tablets 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 dichlorphenamide tablets 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 dichlorphenamide tablets ( 5.4 ) Falls: consider reducing the dose or discontinuing dichlorphenamide tablets in patients who experience falls ( 5.5 ) 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. Dichlorphenamide tablets should be discontinued at the first appearance of skin rash or any sign of immune-mediated or other life-threatening adverse reaction. Carbonic anhydrase inhibitors, including dichlorphenamide, 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 dichlorphenamide tablets and high-dose aspirin is contraindicated. Patients with concomitant use of dichlorphenamide tablets and low-dose aspirin should be carefully monitored. Dichlorphenamide increases potassium excretion and can cause hypokalemia. The risk of hypokalemia is greater when dichlorphenamide 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 dichlorphenamide treatment is recommended. If hypokalemia develops or persists, consideration should be given to reducing the dose or discontinuing dichlorphenamide tablets and correction of potassium levels. Dichlorphenamide can cause hyperchloremic non-anion gap metabolic acidosis. Concomitant use of dichlorphenamide with other drugs that cause metabolic acidosis may increase the severity of acidosis. Concomitant use of dichlorphenamide tablets 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 dichlorphenamide treatment is recommended. If metabolic acidosis develops or persists, consideration should be given to reducing the dose or discontinuing dichlorphenamide tablets  [see Drug Interactions ( 7.4 )]. Dichlorphenamide increases the risk of falls. The risk of falls is greater in the elderly and with higher doses of dichlorphenamide. Consider dose reduction or discontinuation of dichlorphenamide tablets in patients who experience falls while treated with dichlorphenamide.

The following serious adverse reactions are described elsewhere in labeling:

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 , 5.2 , 7.1 ) Carbonic anhydrase inhibitors, including dichlorphenamide, 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 dichlorphenamide tablets and high-dose aspirin is contraindicated. Patients with concomitant use of dichlorphenamide tablets and low-dose aspirin should be carefully monitored [see Contraindications (4) and Warnings and Precautions (5.2) ]. In vitro , dichlorphenamide is an inhibitor of OAT1 transporters. The concomitant administration of dichlorphenamide tablets may increase the plasma exposures of OAT1 substrates. Use of dichlorphenamide tablets with  drugs that are sensitive to OAT1 inhibition (e.g., methotrexate, famotidine, oseltamivir) is not recommended [see Clinical Pharmacology (12.3) ]. The risk of hypokalemia is greater with coadministration of dichlorphenamide and other drugs that can cause hypokalemia (e.g., 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 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.

Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) Risk Summary There are no adequate data on the developmental risk associated with the use of dichlorphenamide in pregnant women. A no-effect dose has not been established. Dichlorphenamide was teratogenic when administered orally to pregnant rats. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. 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 Dichlorphenamide treatment can cause metabolic acidosis [see Warnings and Precautions (5.4) ]. The effect of dichlorphenamide-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state. Newborns of mothers treated with dichlorphenamide should be monitored for metabolic acidosis because of possible occurrence of transient metabolic acidosis following birth. Labor or Delivery Although the effect of dichlorphenamide on labor and delivery in humans has not been established, the development of dichlorphenamide-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor.  Data Animal Data 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/m 2 ) basis. A no-effect dose for adverse effects on embryofetal development has not been established. 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 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 (5.4 , 5.5) ] .

Each 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. Dichlorphenamide tablets are supplied as follows: Bottles of 100......................................NDC 72065-002-01 Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].

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) ]. Dichlorphenamide-induced metabolic acidosis can also increase in severity with coadministration of other drugs that cause metabolic acidosis [see Warnings and Precautions (5.4) ]. 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.

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.

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.i.d. 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=0.02). 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=0.08). None of the patients randomized to dichlorphenamide tablets reached the endpoint of withdrawal from the study for acute worsening, vs. 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=0.02). 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=0.006). The mean dose of dichlorphenamide tablets at the end of the study was 73 mg/day.

NDC 72065-002-01 100 Tablets Tablets 50 mg Keep this and all medications out of the reach of children. Rx only new image