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09-J2000-47

Original Effective Date: 01/15/16

Reviewed: 12/14/16

Revised: 01/15/17

Subject: Dichlorphenamide (Keveyis)

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           

Dosage/ Administration

Position Statement

Billing/Coding

Reimbursement

Program Exceptions

Definitions

 

 

 

 

 

 

Related Guidelines

Other

References

Updates

 

Previous Version

           

DESCRIPTION:

The primary periodic paralyses (PP) are rare muscle diseases (estimated population prevalence of one per 100,000) affecting males and females of all ages, characterized by episodes of flaccid paresis affecting one or more limbs. They result from genetic disorders of ion channels. Hypokalemic periodic paralysis (HypoPP) is caused in 80% of cases by point mutations in the voltage-gated calcium channel gene on chromosome 1 or due to a gain-of function on the voltage-gated sodium channel on chromosome 17. Hyperkalemic periodic paralysis (HyperPP) is caused by point mutations in the voltage-gated sodium channel on chromosome 17.

Diagnostic criteria for primary periodic paralyses have been proposed by an expert committee at the 87th European Neuromuscular Centre (ENMC) International Workshop in 2000 (Table 1; Table 2). It should be noted that these were unpublished and only available for review as reported in a 2008 Cochrane review.

Serum potassium abnormalities in PP and the response to potassium administration provided a rationale for the utilization of drugs capable of affecting serum potassium levels, such as the carbonic anhydrase inhibitors. Acetazolamide is the most commonly used of the carbonic anhydrase inhibitors based on the results of non-randomized, single-blind trials in HypoPP. Dichlorphenamide (or DCP) is an alternative carbonic anhydrase inhibitor with similar but milder side effects compared with acetazolamide. In general, studies have aimed to show a reduction in the frequency and severity of the attacks using these drugs. Gastrointestinal disturbances (anorexia, nausea and vomiting), drowsiness, paraesthesias, and electrolyte imbalance are the most common long term side effects of carbonic anhydrase inhibitors. Alternative treatments in HyperPP have included reduction of potassium levels either by reducing intake or the use of diuretics such as hydrochlorothiazide.

Dichlorphenamide (Keveyis), an oral carbonic anhydrase inhibitor, was approved by the U.S. Food and Drug Administration (FDA) in July 2015 for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants.

The safety and efficacy of dichlorphenamide was evaluated in a 9-week, double blind, placebo-controlled multi-center study in patients with HypoPP (n=44) or HyperPP (n=21). The primary efficacy endpoint 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. The dose of DCP was 50 mg twice daily for treatment-naïve patients. Patients already on DCP prior to the study continued on the same dose during the study. In patients taking acetazolamide prior to the study, the dose of DCP was set at 20% of the acetazolamide dose. Dose reduction for tolerability was permitted.

In HypoPP, patients treated with DCP (n=24) had 2.2 fewer attacks per week than patients (n=20) treated with placebo (p=0.02). The mean dose of DCP at Week 9 was 94 mg/day. In HyperPP, patients treated with DCP (n=12) had 3.9 fewer attacks per week than patients (n=9) treated with placebo (p=0.08). The mean dose of DCP at Week 9 was 82 mg/day.

A Cochrane review of the treatment of PP was published in 2008. Authors systematically reviewed randomized and quasi-randomized trials in participants with primary PP, in which any form of treatment, including physical therapy and alternative therapies, was compared to placebo or another treatment. Three studies met inclusion criteria. In one study DCP vs placebo was tested in two groups of participants: 42 with HypoPP and 31 with HyperPP, based on clinical criteria. Thirty-four of 42 participants with HypoPP completed both treatment phases. For the 34 participants having attack rate data for both treatment phases, the mean improvement in attack rate (P = 0.02) and severity-weighted attack rate (P = 0.01) on DCP relative to placebo were statistically significant. Fifteen preferred DCP, three placebo and six their baseline medication. Twenty-four of 31 participants with HyperPP completed both treatment phases: for the 16 participants who had attack rate data for both treatment phases, the mean improvement in attack rate (P = 0.006) and in severity-weighted attack rate (P = 0.02) on DCP relative to placebo were significant. Fifteen preferred DCP, one placebo and five their baseline medication. Acetazolamide proved to improve muscle strength in eight participants with HypoPP in one other study and pinacidil, a potassium channel opener, also improved muscle strength in 2/4 participants with HypoPP in a third study.

POSITION STATEMENT:

Comparative Effectiveness

The Food and Drug Administration has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, or emergency facility is not considered medically necessary.

Initiation of dichlorphenamide (Keveyis) meets the definition of medical necessity when ALL of the following criteria are met:

1. Member is diagnosed with one of the following:

a. Primary hyperkalemic periodic paralysis and related variants as evidenced by genetic testing – laboratory documentation must be provided

b. Primary hypokalemic periodic paralysis and related variants as evidenced by genetic testing – laboratory documentation must be provided

2. Member did not achieve treatment goals (i.e., treatment failure), had persistent intolerable adverse effects, or has a contraindication to treatment with acetazolamide (Diamox)

3. Member does not have hepatic insufficiency

4. Member does not have severe pulmonary obstruction

5. Dichlorphenamide is prescribed by a board certified neurologist

6. Dose does not exceed 200 mg daily – dosage will be achieved using the fewest number of tablets per day

Approval duration: 3 months

Continuation of dichlorphenamide (Keveyis) meets the definition of medical necessity for members meeting the following criteria:

1. Authorization/reauthorization has been previously approved by Florida Blue in the past two years OR the member has previously met all indication-specific initiation criteria

2. Member demonstrates a reduction in the number of attacks of muscle weakness from baseline (i.e., prior to initiation of dichlorphenamide)

3. Dose does not exceed 200 mg daily – dosage will be achieved using the fewest number of tablets per day

Approval duration: 6 months

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved

Dose Adjustments

Drug Availability

PRECAUTIONS:

Boxed Warning

Contraindications

Precautions/Warnings

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

J8499

Prescription drug, oral, non-chemotherapeutic, Not Otherwise Specified

ICD-10 Diagnoses Codes That Support Medical Necessity (Effective 10/01/15)

G72.3

Periodic paralysis

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Part D: BCBSF has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

Medicare Advantage: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline revised date.

DEFINITIONS:

None

RELATED GUIDELINES:

None

OTHER:

Table 1. Diagnostic criteria for primary hypokalemic periodic paralysis

1. Two or more attacks of muscle weakness with documented serum K < 3.5 mEq/L.

2. One attack of muscle weakness in the proband and one attack of weakness in one relative with documented serum K < 3.5 mEq/L in at least one attack.

3. Three of six clinical or laboratory features outlined below:

a. Onset in the 1st or 2nd decade.

b. Attack duration (muscle weakness involving one or more limbs) > 2 hours.

c. Positive triggers (high CHO rich meal, rest after exercise, stress).

d. Improvement with potassium intake.

e. Positive family history or genetically confirmed skeletal calcium or sodium channel mutation.

f. Positive McManis short exercise test.

4. Exclusion of other causes of hypokalaemia (renal, adrenal, thyroid dysfunction; renal tubular acidosis; diuretic and laxative abuse).

Table 2. Diagnostic criteria for primary hyperkalemic periodic paralysis

1. Two or more attacks of muscle weakness with documented serum K > 4.5 mEq/L.

2. One attack of muscle weakness in the proband and one attack of weakness in one relative with documented serum K > 4.5 mEq/L in at least one attack.

3. Three of six clinical or laboratory features outlined below:

a. Onset < 3rd decade.

b. Attack duration (muscle weakness involving one or more limbs) < 2 hours.

c. Positive triggers (exercise, stress).

d. Myotonia.

e. Positive family history or genetically confirmed skeletal sodium channel mutation.

f. Positive McManis short exercise test.

4. Exclusion of other causes of hyperkalaemia (renal, adrenal, thyroid dysfunction; potassium-sparing diuretics use).

REFERENCES:

  1. AHFS Drug Information. Bethesda (MD): American Society of Health-System Pharmacists, Inc; 2015 [cited 2015-11-23]. In: STAT!Ref Online Electronic Medical Library [Internet]. Available from: http://online.statref.com/.
  2. Bendahhou S, Cummins TR, Griggs RC, Fu YH, Ptacek LJ. Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis. Annals of Neurology 2001;50(3):417-20.
  3. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2016 [cited 2016-11-23]. Available from: http://www.clinicalpharmacology.com/.
  4. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; 2000 Feb 29 - [cited 2016-11-23]. Available from: http://clinicaltrials.gov/.
  5. Dalakas MC, Engel WK. Treatment of 'permanent' muscle weakness in familial hypokalemic periodic paralysis. Muscle & Nerve 1983;6(3):182-6.
  6. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2016-11-23]. Available from: http://www.thomsonhc.com/.
  7. Griggs RC, Engel WK, Resnick JS. Acetazolamide treatment of hypokalemic periodic paralysis. Prevention of attacks and improvement of persistent weakness. Annals of Internal Medicine 1970;73(1):39-48.
  8. Links TP, Smit AJ, Molenaar WM, Zwarts MJ, Oosterhuis HJ. Familial hypokalemic periodic paralysis. Clinical, diagnostic and therapeutic aspects. Journal of the Neurological Sciences 1994;122(1):33-43.
  9. Links TP, Zwarts MJ, Oosterhuis HJ. Improvement of muscle strength in familial hypokalemic periodic paralysis with acetazolamide. Journal of Neurology, Neurosurgery and Psychiatry 1988;51(9):1142-5.
  10. McManis PG, Lambert EH, Daube JR. The exercise test in periodic paralysis. Muscle & Nerve 1986;9(8):704-10.
  11. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2016 [cited 2016-11-23]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.
  12. Ptacek LJ, Tawil R, Griggs RC, Meola G, McManis P, Barohn RJ, et al. Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita and hyperkalemic periodic paralysis. Neurology 1994;44(8):1500-3.
  13. Resnick JS, Engel WK, Griggs RC, Stam AC. Acetazolamide prophylaxis in hypokalemic periodic paralysis. New England Journal of Medicine 1968;278(11):582-6.
  14. Ricker K, Bohlen R, Rohkamm R. Different effectiveness of tocainide and hydrochlorothiazide in paramyotonia congenita with hyperkalemic episodic paralysis. Neurology 1983;33(12):1615-18.
  15. Sansone V, Meola G, Links T, Panzeri M, Rose MR. Treatment for periodic paralysis. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD005045.
  16. Taro. Keveyis (dichlorphenamide) tablet. 2016 [cited 2016-11-23]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4e274191-b1fc-43df-af35-beb5bbacc16c/.
  17. Tawil R, McDermott MP, Brown R Jr, Shapiro BC, Ptacek LJ, McManis PG, et al. Randomized trials of dichlorphenamide in the periodic paralysis. Working Group on Periodic Paralyses. Annals of Neurology 2000;47(1):46-53.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 12/14/16.

GUIDELINE UPDATE INFORMATION:

01/15/16

New Medical Coverage Guideline.

01/15/17

Review and revision to guideline; updated position statement, references.

Date Printed: October 17, 2017: 04:11 PM