anion transporter1 (oat1) in vitro , dichlorphenamide is an inhibitor of oat1 transporters. the concomitant administration of dichlorphenamide may increase the plasma exposures of oat1 substrates. use of dichlorphenamide 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 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 )]. 7.4 drugs that cause metabolic acidosis coadministration of dichlorphenamide 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.

tic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. pulmonary involvement can occur in isolation or as part of a systemic reaction. dichlorphenamide should be discontinued at the first appearance of skin rash or any sign of immune- mediated or other life-threatening adverse reaction. 5.2 concomitant use of aspirin or other salicylates 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 and high-dose aspirin is contraindicated. patients with concomitant use of dichlorphenamide and low-dose aspirin should be carefully monitored. 5.3 hypokalemia 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 and correction of potassium levels. 5.4 metabolic acidosis 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 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 are recommended. if metabolic acidosis develops or persists, consideration should be given to reducing the dose or discontinuing dichlorphenamide [see drug interactions ( 7.4) ]. 5.5 falls 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 in patients who experience falls while treated with dichlorphenamide.

after 2 months of treatment to decide whether dichlorphenamide tablets should be continued. 2.3 monitoring to assess safety baseline and periodic measurements of serum potassium and sodium bicarbonate during dichlorphenamide treatment is recommended [see warnings and precautions ( 5.3 , 5.4 )] .

lemic or hypokalemic periodic paralysis (study 1), the most common adverse reactions in patients treated with dichlorphenamide, with rates greater than placebo, were paresthesia, cognitive disorder, dysgeusia, and confusional state. the mean dose of dichlorphenamide 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 and more commonly than in patients treated with placebo in study 1. table 1: adverse reactions in patients treated with dichlorphenamide with incidence ≥ 5% and more common than in patients treated with placebo in study 1 adverse reaction dichlorphenamide n = 36 (%) placebo n = 29 (%) paresthesia 44 14 cognitive disorder 1 14 7 dysgeusia 14 0 nervous system disorders 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 muscle spasms 8 0 musculoskeletal and connective tissue disorders arthralgia 6 3 muscle twitching 6 0 respiratory dyspnea 6 0 pharyngolaryngeal pain 6 0 skin rash 8 0 pruritus 6 0 1 cognitive disorder combined cases with the preferred terms of cognitive disorder, disturbance in attention, and mental impairment. 6.2 postmarketing 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.

anion transporter1 (oat1) in vitro , dichlorphenamide is an inhibitor of oat1 transporters. the concomitant administration of dichlorphenamide may increase the plasma exposures of oat1 substrates. use of dichlorphenamide 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 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 )]. 7.4 drugs that cause metabolic acidosis coadministration of dichlorphenamide 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.

nation, 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. 8.2 lactation 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. 8.4 pediatric use safety and effectiveness of dichlorphenamide in pediatric patients have not been established. 8.5 geriatric use the risk of falls and of metabolic acidosis are greater in elderly patients [see warnings and precautions ( 5.4 , 5.5 )].

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.

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.

9, 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.

e 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 (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 reached the endpoint of withdrawal from the study for acute worsening, vs. five patients randomized to placebo. the mean dose of dichlorphenamide 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 (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 reached the endpoint of withdrawal from the study for acute worsening, vs. two patients randomized to placebo. the mean dose of dichlorphenamide 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 vs. 11 patients on placebo (p=0.02). the mean dose of dichlorphenamide 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 than on placebo (p=0.006). the mean dose of dichlorphenamide at the end of the study was 73 mg/day.

abolic acidosis (e.g., fast breathing, fatigue/tiredness, loss of appetite, or irregular heart beat or palpitations) [see warnings and precautions ( 5.4 )]. falls inform patients that dichlorphenamide can increase their risk of falls [see warnings and precautions ( 5.5 )]. cognitive impairment advise patients to notify their healthcare provider if they experience symptoms of cognitive impairment including confusion and memory lapse [see adverse reactions ( 6.1 )]. driving and operating machinery dichlorphenamide may cause drowsiness/fatigue in some patients [see adverse reactions ( 6.1 )]. caution patients on the potential for impaired ability to drive and operate machinery.