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Dichlorphenamide

Class: Carbonic Anhydrase Inhibitors
Chemical Name: 4,5-Dichloro-1,3-benzenedisulfonamide
Molecular Formula: C6H6Cl2N2O4S2
CAS Number: 120-97-8
Brands: Keveyis

Introduction

Carbonic anhydrase inhibitor;1 3 7 8 sulfonamide derivative.1 15

Uses for Dichlorphenamide

Periodic Paralysis

Management of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants.1 3 14 Designated an orphan drug by FDA for such use.2

Decreases the frequency of attacks of muscle weakness or paralysis.1 3 14

Glaucoma

Also has been used to reduce intraocular pressure in patients with glaucoma.8 12 15 16

Although oral carbonic anhydrase inhibitors (i.e., acetazolamide, dichlorphenamide, methazolamide) have been used for many years and are still considered an appropriate treatment option for patients with glaucoma,16 17 18 topical carbonic anhydrase inhibitors generally are preferred over the oral agents because of a more favorable adverse effect profile.17 20

Dichlorphenamide Dosage and Administration

Administration

Oral Administration

Administer orally.1

Dosage

Adults

Periodic Paralysis
Oral

Initially, 50 mg twice daily.1 Adjust dosage at weekly intervals (or sooner if adverse effects occur) based on individual response.1

Because response to dichlorphenamide may vary, assess patient response after 2 months of therapy to determine whether the drug should be continued.1

Glaucoma
Oral

For reduction in intraocular pressure, initial dose of 100–200 mg has been recommended, followed by 100 mg every 12 hours until desired response obtained.8 Usual maintenance dosage is 25–50 mg 1–3 times daily.8

Prescribing Limits

Adults

Periodic Paralysis
Oral

200 mg daily.1

Special Populations

No special population dosage recommendations at this time.1

Cautions for Dichlorphenamide

Contraindications

  • Hypersensitivity to dichlorphenamide or other sulfonamides.1

  • Concomitant use of high-dose aspirin.1 (See Interactions.)

  • Severe pulmonary disease that limits compensation to metabolic acidosis.1

  • Hepatic insufficiency.1 (See Hepatic Impairment under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Sulfonamide Sensitivity Reactions.

Serious, sometimes fatal adverse events (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, other blood dyscrasias) associated with sulfonamide therapy.1 Pulmonary involvement can occur in isolation or as part of a systemic reaction.1

Discontinue at first sign of skin rash or any immune-mediated or idiosyncratic adverse reaction.1

Concomitant Use with Aspirin

Anorexia, tachypnea, lethargy, and coma reported with concomitant use of high-dose aspirin; concomitant use with high-dose aspirin contraindicated.1 Use with caution in patients receiving low-dose aspirin.1 (See Contraindications under Cautions and also see Interactions.)

Hypokalemia

Risk of hypokalemia, particularly in patients with conditions associated with hypokalemia (e.g., adrenocortical insufficiency, hyperchloremic metabolic acidosis, respiratory acidosis) and/or receiving other hypokalemic-inducing drugs.1 (See Interactions.)

Monitor serum potassium concentrations prior to initiating therapy and periodically thereafter; if hypokalemia develops or persists, consider reducing dosage or discontinuing drug.1

Metabolic Acidosis

Risk of hyperchloremic, non-anion gap metabolic acidosis; severity may be increased in patients receiving other drugs that cause metabolic acidosis.1 (See Interactions.)

Monitor serum bicarbonate concentrations prior to initiating therapy and periodically thereafter; if metabolic acidosis develops or persists, consider reducing dosage or discontinuing drug.1

Falls

Increased risk of falls, particularly in geriatric patients and patients receiving higher dosages.1 (See Geriatric Use under Cautions.) Consider reducing dosage or discontinuing drug in patients who experience falls.1

Specific Populations

Pregnancy

Category C.1

No adequate and well-controlled studies in pregnant women; teratogenic effects observed in animals.1

Use during pregnancy only if potential benefits justify potential risks to fetus.1

Lactation

Not known if distributed into human milk.1 Use with caution in nursing women.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Risk of falls and metabolic acidosis appear to be greater in geriatric patients.1

Hepatic Impairment

May aggravate hepatic encephalopathy; contraindicated in patients with hepatic insufficiency.1 (See Contraindications under Cautions.)

Common Adverse Effects

Paresthesia,1 3 14 cognitive disorder,1 3 14 dysgeusia,1 3 14 confusional state,1 headache,1 14 hypoesthesia,1 14 lethargy,1 fatigue,1 14 muscle spasms,1 14 rash,1 3 14 dizziness,1 3 diarrhea,1 3 nausea,1 14 malaise,1 weight loss,1 14 arthralgia,1 muscle twitching,1 dyspnea,1 pharyngolaryngeal pain,1 pruritus.1 3

Interactions for Dichlorphenamide

Drugs Associated with Hypokalemia

Potential additive pharmacologic effects (increased risk of hypokalemia).1 (See Hypokalemia under Cautions.)

Drugs Associated with Metabolic Acidosis

Potential increased risk and severity of metabolic acidosis.1 (See Metabolic Acidosis under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Antifungals

Possible potentiation of hypokalemic effects1

Aspirin

Potential increased risk of salicylate toxicity1

High-dose aspirin: Concomitant use contraindicated1

Low-dose aspirin: Use with caution1

Diuretics (e.g., loop diuretics, thiazides)

Possible potentiation of hypokalemic effects1

Laxatives

Possible potentiation of hypokalemic effects1

Penicillin

Possible potentiation of hypokalemic effects1

Theophylline

Possible potentiation of hypokalemic effects1

Dichlorphenamide Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics following oral administration in patients with periodic paralysis not known.1

Onset

Intraocular pressure decreases within 1 hour; peak effect occurs in 2–4 hours.8

Duration

Reduction in intraocular pressure persists for approximately 6–12 hours.8

Distribution

Extent

Not known whether distributed into human milk.1

Stability

Storage

Oral

Tablets

20–25°C.1

Actions

  • Inhibits carbonic anhydrase.1 3 7 8

  • Precise mechanism of action in periodic paralysis is unknown, but may be related to the drug's ability to reduce potassium concentrations, induce metabolic acidosis, and/or activate calcium-activated potassium channels.1 4 5 7 9 10 12 15

  • Pharmacologic actions are similar to those of other carbonic anhydrase inhibitors.7

Advice to Patients

  • Importance of advising patients to contact their clinician if symptoms of periodic paralysis worsen.1

  • Importance of advising patients that dichlorphenamide can cause drowsiness or fatigue and impair their ability to drive or operate machinery.1

  • Importance of patients informing their clinician if they are allergic to sulfonamides.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., aspirin) and dietary or herbal supplements, as well as any concomitant illnesses (e.g., pulmonary disease, hepatic disease).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Dichlorphenamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

50 mg

Keveyis

Taro

AHFS DI Essentials. © Copyright 2016, Selected Revisions October 18, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Taro Pharma. Keveyis (dichlorphenamide) tablets prescribing information. Hawthorne, NY; 2015 Aug.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2016 Jan 14.

3. Tawil R, McDermott MP, Brown R et al. Randomized trials of dichlorphenamide in the periodic paralyses. Working Group on Periodic Paralysis. Ann Neurol. 2000; 47:46-53. [PubMed 10632100]

4. Lehmann-Horn F, Rudel R, Jurkat-Rott K. Nondystrophic myotonias and periodic paralyses. In: Myology. 5th ed. New York: McGraw-Hill; 2004.

5. Jurkat-Rott K, Lehmann-Horn F. State of the art in hereditary muscle channelopathies. Acta Myol. 2010; 29:343-50. [PubMed 21314017]

6. Lehmann-Horn F, Jurkat-Rott K, Rüdel R et al. Diagnostics and therapy of muscle channelopathies--Guidelines of the Ulm Muscle Centre. Acta Myol. 2008; 27:98-113. [PubMed 19472919]

7. Moxley RT III. Channelopathies. Curr Treat Options Neurol. 2000; 2:31-47. [PubMed 11096735]

8. Taro Pharma. Daranide (dichlorphenamide) tablets prescribing information. Hawthorne, NY; 2012 Feb.

9. Cleland JC, Griggs RC. Treatment of neuromuscular channelopathies: current concepts and future prospects. Neurotherapeutics. 2008; 5:607-12. [PubMed 19019313]

10. Tricarico D, Mele A, Conte Camerino D. Carbonic anhydrase inhibitors ameliorate the symptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels. Neuromuscul Disord. 2006; 16:39-45. [PubMed 16368240]

12. . Dichlorphenamide (Keveyis) for periodic paralysis. Med Lett Drugs Ther. 2016; 58:50. [PubMed 27049510]

13. Sansone V, Meola G, Links TP et al. Treatment for periodic paralysis. Cochrane Database Syst Rev. 2008; :CD005045. [PubMed 18254068]

14. Sansone VA, Burge J, McDermott MP et al. Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis. Neurology. 2016; 86:1408-16. [PubMed 26865514]

15. Greig SL. Dichlorphenamide: A Review in Primary Periodic Paralyses. Drugs. 2016; 76:501-7. [PubMed 26941026]

16. Kanski JJ. Carbonic anhydrase inhibitors and osmotic agents in glaucoma. Carbonic anhydrase inhibitors. Br J Ophthalmol. 1968; 52:642-3. [PubMed 5724852]

17. Costagliola C, dell'Omo R, Romano MR et al. Pharmacotherapy of intraocular pressure - part II. Carbonic anhydrase inhibitors, prostaglandin analogues and prostamides. Expert Opin Pharmacother. 2009; 10:2859-70. [PubMed 19929706]

18. Prum BE, Rosenberg LF, Gedde SJ et al. Primary Open-Angle Glaucoma Preferred Practice Pattern() Guidelines. Ophthalmology. 2016; 123:P41-P111. [PubMed 26581556]

19. Department of Health and Human Services: Food and Drug Administration. Determination that Daranide (dichlorphenamide) tablets, 50 milligrams, were not withdrawn from sale for reasons of safety or effectiveness (Docket No. 2006P-0160). Fed Regist. 2007; 72:43645.

20. Schmidl D, Schmetterer L, Garhöfer G et al. Pharmacotherapy of glaucoma. J Ocul Pharmacol Ther. 2015; 31:63-77. [PubMed 25587905]

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