Clinical UM Guideline

 

Subject: Repository Corticotropin Injection (H.P. Acthar® Gel)
Guideline #:  CG-DRUG-24 Publish Date:    08/29/2018
Status: Reviewed Last Review Date:    07/26/2018

Description

This document addresses the use of repository corticotropin injection (H.P. Acthar Gel, Mallinckrodt ARD Inc., Hazelwood, MO), a highly purified sterile preparation of the adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal cortex to secrete cortisol, corticosterone, aldosterone, and a number of weakly androgenic substances.

Clinical Indications

Medically Necessary:

  1. Repository corticotropin injection is considered medically necessary as monotherapy for the treatment of infantile spasms (West syndrome) in infants and children less than 2 years of age.
  2. Repository corticotropin injection is considered medically necessary when all of the following criteria are met:
    1. The individual is an adult with a corticosteroid-responsive condition, including but not limited to acute exacerbations of multiple sclerosis; and
    2. The individual has no contraindications to or is not limited by contraindication to or intolerance of glucocorticoid effects; and
    3. There is clear documentation of why all other well-established routes for corticosteroid therapy (for example, oral prednisone and intravenous methylprednisolone) cannot be used.

Not Medically Necessary:

Repository corticotropin injection is considered not medically necessary when the above criteria are not met and for all other indications.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J0800

Injection, corticotropin, up to 40 units [H.P. Acthar]

 

 

ICD-10 Diagnosis

 

 

All diagnoses

Discussion/General Information

Infantile Spasms

In October 2010, repository corticotropin (H.P. Acthar Gel) was approved by the United States Food and Drug Administration (FDA) as monotherapy for the treatment of infantile spasms in infants and children under 2 years of age. Prior to this approval, repository corticotropin injection had been used as an off-label treatment in thousands of infants since its introduction in 1952. Infantile spasms are a very rare and potentially life-threatening form of epilepsy that typically begins in the first year of life. It is characterized by a peculiar type of seizure and electroencephalogram (EEG) findings of hypsarrhythmia and mental retardation, although not all three components are required. Often the term infantile spasm is used synonymously with West syndrome. Infantile spasms are characterized by an initial contraction phase followed by a more sustained tonic phase.

The current FDA approved product label describes a study by Baram and colleagues (1996) supporting the effectiveness of repository corticotropin injection for infantile spasms. In a single blinded clinical trial, infants under 2 years of age (median age of 6 months) with clinical spasms were randomized to receive either a 2-week course of treatment with repository corticotropin (intramuscular injection twice daily) or prednisone (by mouth twice daily). The primary outcome was a comparison of the number of infants in each group who were treatment responders (defined as having complete suppression of both clinical spasms and hypsarrhythmia on a full sleep cycle video electroencephalogram [EEG] performed 2 weeks following initiation of treatment, rated by an investigator blinded to the treatment). Of 15 infants randomized to repository corticotropin injection, 13 (86.7%) responded as compared to 4 of 14 subjects (28.6%) given prednisone.

In a retrospective, multi-center study, Ito and colleagues (2002) reviewed the medical records of 138 infants or children (age at onset of spasms, 1.5 to 60 months; mean age 7.8 months) given low dose synthetic ACTH for the treatment of cryptogenic or symptomatic West syndrome between 1989 and 1998. The authors concluded that at the end of ACTH therapy, excellent effect on seizures was noted in 106 of 138 (76%) subjects, good effect in 23 (17%), and poor effect in 9 (7%).

According to Riikonen (2004), ACTH should be the first choice for treatment of infantile spasms because it is a safe drug when used at the minimal effective dose and duration. The side effects of ACTH are well known, treatable, and reversible (Riikonen, 2004).

Verrotti and colleagues (2007) report that in the United States, the majority of child neurologists use ACTH as the drug of choice for the treatment of infantile spasms. There are variations in the dosage and treatment duration reported. The literature also suggests that ACTH is more effective than oral corticosteroids in causing the cessation of seizures.

Cohen-Sadan and colleagues (2009) reported on a long-term follow-up of children with West syndrome treated with ACTH or vigabatrin. The medical records of 28 normal MRI West syndrome cases were reviewed for seizure development and cognitive outcome in relation to treatment type and timing. The authors concluded that for West syndrome:

ACTH and vigabatrin appear to be equally effective in the short term if treatment is administered within one month of symptom onset. On long-term follow-up, early ACTH treatment appeared to yield a better outcome than early vigabatrin or late ACTH treatment in terms of both cognition and seizure development.

Pellock and colleagues (2010), in an industry-sponsored Infantile Spasms Working Group, published a consensus report on diagnosis and treatment of infantile spasms. Regarding treatment, the report concluded: “At this time, ACTH and VGB (vigabatrin) are the only drugs with proven efficacy to suppress clinical spasms and abolish the hyparrhythmic EEG in a randomized clinical trial setting (Mackay, 2004) and thus remain first-line treatment.”

Hussain and colleagues (2014) evaluated the short-term response of infantile spasms to very high dose prednisolone administered before high dose ACTH. A total of 27 children with infantile spasms confirmed by video EEG received high dose oral prednisolone (maximum of 60 mg/day) for 2 weeks. Responders were tapered over 2 weeks and non-responders were immediately transitioned to high dose intramuscular ACTH. Response was determined by repeat video EEG. The majority of the participants, 63% (17/27) responded completely to prednisolone. A total of 40% (4/10) of prednisolone non-responders demonstrated a complete response following the additional 2-week course of ACTH. Of 27 subjects with a median follow-up of 13.5 months, 12% (2/17) of prednisolone responders and 50% (2/4) of ACTH responders experienced a relapse between 2 and 9 months after initial response. The authors reported study limitations consisting of a small study population, lack of a control group, lack of standardized and blinded developmental assessments and limited follow-up time.

The American Academy of Neurology and the Practice Committee of the Child Neurology Society (2012) analyzed pre-2002 and more recent evidence on infantile spasms, and subsequently revised their corresponding practice parameters. Recommendations include the following:

A Cochrane review (Hancock, 2013) compared the effects of single drugs used to treat infantile spasms in terms of long-term psychomotor development, spasm control, subsequent epilepsy, and adverse effects. Eleven randomized controlled trials (n=514) were included and eight different drugs were tested. Overall methodology of the studies appeared to be poor. No study assessed long-term psychomotor development or onset of other seizure types. The authors concluded:

We found no single treatment to be proven to be more efficacious in treating infantile spasms than any of the others (other than vigabatrin in the treatment of infantile spasms in tuberous sclerosis in one underpowered study). Few studies considered psychomotor development or subsequent seizure rates as outcomes and none had long-term follow-up. Further trials with larger numbers of participants, and longer follow-up are required.

Other conclusions of the Cochrane review include:

Wanigasinghe and colleagues (2014) published a randomized controlled trial that blindly assigned children with previously untreated West syndrome to treatment with 40 to 60 IU synthetic ACTH every other day or 40 to 60 mg/day of oral prednisolone. The primary outcome was change in a hypsarrhythmia severity scale (possible score range, 0-16). A total of 92 children (age 2 months-2 years) were randomized, and follow-up data were available on 80 (82%) of them. Mean improvement in the hypsarrhythmia score was 7.95 in the prednisolone arm and 6.00 in the ACTH arm. The difference between the two groups was significantly different (p<0.01), favoring treatment with prednisolone. Both forms of therapy were well tolerated; however, irritability, frequent crying, weight gain, increased appetite, and abdominal distension were more common, but not statistically significant with prednisolone. This study suggests that prednisolone may at least as effective as synthetic ACTH for treatment of infantile spams. Multiple limitations of the study were noted including a dropout rate of over 20%, lack of intention-to-treat analysis, short-term follow-up only, and use of intermediate outcomes.

Multiple Sclerosis

The product label (2015) states repository corticotropin injection is indicated for the treatment of exacerbations of multiple sclerosis in adults. Acute exacerbations of multiple sclerosis or relapses are typically steroid responsive and as such are treated with corticosteroids such as methylprednisolone (MP). The term “acute exacerbation” in multiple sclerosis is synonymous with “relapse” or “attack”. Repository corticotropin injection augments circulating steroids via adrenal gland stimulation and therefore produces the same types of effects and side effects which occur when steroids are used. Unlike steroids, repository corticotropin acts indirectly since the adrenal glands are activated. Exogenous corticosteroids act directly, are available in multiple formulations and delivery methods (oral, intravenous, intramuscular, subcutaneous), and are widely accepted as the appropriate therapy for steroid responsive conditions. Accordingly, there is no clinical basis for selecting a repository corticotropin when an individual is able to receive exogenous corticosteroids.

Available peer reviewed literature describing the use of repository corticotropin injection for the treatment of multiple sclerosis relapses or exacerbations consists mainly of old studies which are not of high quality (Miller, 1961; Rose, 1970; Thompson, 1989). In addition, Abbruzzese (1983) indicated there was equal efficacy for IV MP and ACTH for the treatment of multiple sclerosis. In a systematic review, Filippini and colleagues (2000) attempted to determine the safety and efficacy of corticosteroids (MP) or ACTH in reducing the short- and long-term morbidity from multiple sclerosis. The authors noted that overall, MP or ACTH showed a protective effect against the disease getting worse or stable within the first 5 weeks of treatment (odds ratio 0.37, 95% confidence interval, 0.24 to 0.57) with some but nonsignificant greater effect for MP and intravenous administration. More recently, Sismarian and colleagues (2011) in a prospective, randomized, open-label pilot trial examined the safety and efficacy of a 5-day self-administered ACTH dosing protocol for multiple sclerosis exacerbations, and also compared intramuscular and subcutaneous routes of administration. Of the 20 subjects enrolled, 19 completed the study and results suggested that a 5-day course of “patient-administered” ACTH gel therapy may relieve symptoms of acute exacerbations of multiple sclerosis when administered either as intramuscular or subcutaneous injections. The authors concluded that larger, placebo-controlled studies are needed to determine the optimal dose of ACTH gel, duration of treatment, and route of administration, as well as its role compared with steroid therapy.

In 2016, Murray and colleagues reported on a small case series of 6 individuals with multiple sclerosis and a history of neuropsychiatric side effects after treatment with intravenous MP. All 6 individuals were subsequently treated with repository corticotropin injection for MS exacerbations and each appeared to tolerate treatment without mood changes and showed improvement in MS symptoms. Limitations included the inherent observational nature of a cases series and the very small number of individuals involved.

Other Uses

Repository corticotropin injection has been used as an aid in the diagnosis of adrenocortical insufficiency; however, this indication was removed from the product label in October 2010. There is a lack of peer reviewed published literature to support this use.

In addition to infantile spasms and multiple sclerosis, the product label (2015) states repository corticotropin injection may be used for treatment of the following disorders and diseases: rheumatic; collagen; dermatologic; allergic states; ophthalmic; respiratory; and edematous state. The published evidence in support of these conditions is limited; however, repository corticotropin injection may potentially be a treatment option for an individual with one of these corticosteroid responsive conditions under very specific circumstances.

A systematic review and meta-analysis of 36 clinical trials by Chen (2013) evaluated immunosuppression for treatment of the most common form of primary nephrotic syndrome in adults, membranous nephropathy. Of all the studies, two (n=62 subjects) evaluated adrenocorticotropic hormone (versus no treatment or corticosteroids and alkylating agents). Adrenocorticotropic hormone significantly decreased proteinuria at the end of 22 months of follow-up. However, multiple study limitations were present including small sample sizes and a high risk of bias. The authors concluded: “More methodologically sound and sufficiently powered studies with adequate follow-up are still urgently needed for clinical decision making, especially for adrenocorticotropic hormone and rituximab.”

There have been additional small studies and case series published evaluating repository corticotropin for a variety of conditions, including rheumatoid arthritis (Gillis, 2017; Fischer, 2018), myositis (Aggarwal, 2018), chronic pulmonary sarcoidosis (Baughman, 2017), systemic lupus erythematosus (Fiechtner, 2014); nephrotic syndrome (Bomback, 2011; Hladunewich, 2014; Madan, 2016); and membranous glomerulopathy (Watson, 2014). All authors concluded that repository corticotropin may be an effective therapy for their respective conditions. However, limitations included small numbers of participants.

The following are contraindications included in the Product Information Label (2015):

Definitions

Hypsarrhythmia: Chaotic abnormal brain wave patterns.

References

Peer Reviewed Publications:

  1. Abbruzzese G, Gandolfo C, Loeb C. "Bolus" methylprednisolone versus ACTH in the treatment of multiple sclerosis. Ital J Neurol Sci. 1983; 4(2):169-172.
  2. Aggarwal R, Marder G, Koontz DC, et al. Efficacy and safety of adrenocorticotropic hormone gel in refractory dermatomyositis and polymyositis. Ann Rheum Dis. 2017; 77(5):720-727.
  3. Baram TZ, Mitchell WG, Tournay A, et al. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study. Pediatrics. 1996; 97(3):375-379.
  4. Baughman RP, Sweiss N, Keijsers R, et al. Repository corticotropin for chronic pulmonary sarcoidosis. Lung. 2017; 195(3):313-322.
  5. Bomback AS, Tumlin JA, Baranski J, et al. Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel. Drug Des Devel Ther. 2011; 5:147-153.
  6. Chen Y, Schieppati A, Cai G, et al. Immunosuppression for membranous nephropathy: a systematic review and meta-analysis of 36 clinical trials. Clin J Am Soc Nephrol. 2013; 8(5):787-796.
  7. Cohen-Sadan S, Kramer U, Ben-Zeev B, et al. Multicenter long-term follow-up of children with idiopathic West syndrome: ACTH versus vigabatrin. Eur J Neurol. 2009; 16(4):482-487.
  8. Fiechtner J, Montroy T. Treatment of moderately to severely active systemic lupus erythematosus with adrenocorticotropic hormone: a single-site, open-label trial. Lupus. 2014; 23(9):905-912.
  9. Fischer PA, Rapoport RJ. Repository corticotropin injection in patients with rheumatoid arthritis resistant to biologic therapies. Open Access Rheumatol. 2018; 10:13-19.
  10. Gillis T, Crane M, Hinkle C, Wei N. Repository corticotropin injection as adjunctive therapy in patients with rheumatoid arthritis who have failed previous therapies with at least three different modes of action. Open Access Rheumatol. 2017; 9:131-138.
  11. Hamano S, Tanaka M, Mochizuki M, et al. Long-term follow-up study of West syndrome: differences of outcome among symptomatic etiologies. J Pediatr. 2003; 143(2):231-235.
  12. Hamano S, Yamashita S, Tanaka M, et al. Therapeutic efficacy and adverse effects of adrenocorticotropic hormone therapy in west syndrome: differences in dosage of adrenocorticotropic hormone, onset of age, and cause. J Pediatr. 2006; 148(4):485-488.
  13. Hattori A, Ando N, Hamaguchi K, et al. Short-duration ACTH therapy for cryptogenic West syndrome with better outcome. Pediatr Neurol. 2006; 35(6):415-418.
  14. Hladunewich MA, Cattran D, Beck LH, et al. A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P Acthar(R) Gel) in nephrotic syndrome due to idiopathic membranous nephropathy. Nephrol Dial Transplant. 2014; 29(8):1570-1577.
  15. Hussain SA, Shinnar S, Kwong G, et al. Treatment of infantile spasms with very high dose prednisolone before high dose adrenocorticotropic hormone. Epilepsia. 2014; 55(1):103-107.
  16. Ito M, Aiba H, Hashimoto K, et al. Low-dose ACTH therapy for West syndrome: initial effects and long-term outcome. Neurology. 2002; 58(1):110-114.
  17. Kivity S, Lerman P, Ariel R, et al. Long-term cognitive outcomes of a cohort of children with cryptogenic infantile spasms treated with high-dose adrenocorticotropic hormone. Epilepsia. 2004; 45(3):255-262.
  18. Kondo Y, Okumura A, Watanabe K, et al. Comparison of two low dose ACTH therapies for West syndrome: their efficacy and side effect. Brain Dev. 2005; 27(5):326-330.
  19. Madan A, Mijovic-Das S, Stankovic A, et al. Acthar gel in the treatment of nephrotic syndrome: a multicenter retrospective case series. BMC Nephrol. 2016; 17:37.
  20. Miller H, Newell DJ, Ridley A. Multiple sclerosis. Treatment of acute exacerbations with corticotrophin (A.C.T.H.). Lancet. 1961; 2(7212):1120-1122.
  21. Murray S, Woo A. Clinical experience with repository corticotropin injection in patients with multiple sclerosis experiencing mood changes with intravenous methylprednisolone: a case series. Ther Adv Neurol Disord. 2016; 9(3):189-197.
  22. Oguni H, Yanagaki S, Hayashi K, et al. Extremely low-dose ACTH step-up protocol for West syndrome: maximum therapeutic effect with minimal side effects. Brain Dev. 2006; 28(1):8-13.
  23. Pellock JM, Hrachovy R, Shinner S, et al. Infantile spasms: a U.S. consensus report. Epilepsia. 2010; 51(10): 2175-2189.
  24. Riikonen R. Infantile spasms: therapy and outcome. J Child Neurol. 2004; 19(6):401-404.
  25. Rose AS, Kuzma JW, Kurtzke JF, et al. Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo--final report. Neurology. 1970; 20(5):1-59.
  26. Simsarian JP, Saunders C, Smith DM. Five-day regimen of intramuscular or subcutaneous self-administered adrenocorticotropic hormone gel for acute exacerbations of multiple sclerosis: a prospective, randomized, open-label pilot trial. Drug Des Devel Ther. 2011; 5:381-389.
  27. Thompson AJ, Kennard C, Swash M, et al. Relative efficacy of intravenous methylprednisolone and ACTH in the treatment of acute relapse in MS. Neurology. 1989; 39(7):969-971.
  28. Tsao CY. Current trends in the treatment of infantile spasms. Neuropsychiatr Dis Treat. 2009; 5:289-299.
  29. Tsuji T, Okumura A, Ozawa H, et al. Current treatment of West syndrome in Japan. J Child Neurol. 2007; 22(5):560-564.
  30. Verrotti A, Manco R, Coppola GG, et al. Update of the medical treatment of West syndrome. Minerva Pediatr. 2007; 59(3):249-253.
  31. Wanigasinghe J, Arambepola C, Sri Ranganathan S, et al. The efficacy of moderate-to-high dose oral prednisolone versus low-to-moderate dose intramuscular corticotropin for improvement of hypsarrhythmia in West syndrome: a randomized, single-blind, parallel clinical trial. Pediatr Neurol. 2014; 51(1):24-30.
  32. Watson MJ. Membranous glomerulopathy and treatment with Acthar®: a case study. Int J Nephrol Renovasc Dis. 2013; 6:229-232.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Corticotropin Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised Jan. 1, 2013. Accessed on June 12, 2018.
  2. Corticotropin (systemic). In: DrugPoints System [Electronic Version]. Truven Health Analytics. Greenwood Village, Colo. Last updated February 19, 2018. Available at: http://www.micromedexsolutions.com. Accessed on June 18, 2018.
  3. Filippini G, Brusaferri F, Sibley WA, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev. 2000;(4):CD001331.
  4. Go CY, Mackay MT, Weiss SK, et al; Child Neurology Society; American Academy of Neurology. Evidence-based guideline update: medical treatment of infantile spasms. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2012; 78(24):1974-1980.
  5. Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev. 2013; (6):CD001770.
  6. H.P. Acthar® Gel [Product Information], Hazelwood, MO. Mallinckrodt ARD Inc.; April 2018. Available at: http://www.acthar.com/pdf/Acthar-PI.pdf. Accessed on June 18, 2018.
Index

Acthar
Adrenocorticotropic Hormone (ACTH)
Corticotropin
H.P. Acthar Gel
Repository Corticotropin Injection

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed

07/26/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. The document header wording updated from “Current Effective Date” to “Publish Date.” Discussion and References sections updated.

Reviewed

08/03/2017

MPTAC review. Description, Discussion and References sections updated.

Revised

08/04/2016

MPTAC review. Formatting updated in clinical indication section. Minor numerical edit made to medically necessary statement for the treatment of infantile spasms. Discussion and Reference sections updated. Removed ICD-9 codes from Coding section.

Reviewed

08/06/2015

MPTAC review. Discussion and Reference sections updated.

Revised

08/14/2014

MPTAC review. Clarified medically necessary statement for an adult with a corticosteroid-responsive condition. Description, Discussion and Reference sections updated.

Reviewed

11/14/2013

MPTAC review. Discussion and Reference sections updated.

Revised

11/08/2012

MPTAC review. Clarification of medically necessary and not medically necessary statements. Discussion and Reference sections updated.

Reviewed

05/10/2012

MPTAC review. Discussion and Reference sections updated.

Revised

05/19/2011

MPTAC review. Removed medically necessary statement for diagnostic testing of adrenocortical function. Updated medically necessary statements for infantile spasms and corticosteroid-responsive conditions. Added a not medically necessary statement for corticosteroid responsive conditions. Coding, Discussion, References, Definitions, and Index sections updated.

Reviewed

02/17/2011

MPTAC review. Discussion, Coding and References updated.

 

10/01/2010

Updated Coding section with 10/01/2010 ICD-9 changes.

Reviewed

02/25/2010

MPTAC review. Discussion and references updated. Dosage section removed.

Revised

05/21/2009

MPTAC review. Medically necessary statement clarified for conditions that are responsive to corticosteroid therapy. Discussion and reference links updated. Place of service section deleted.

Reviewed

02/26/2009

MPTAC review. Discussion and references updated.

 

10/01/2008

Updated Coding section with 10/01/2008 ICD-9 changes.

New

02/21/2008

MPTAC review. Initial guideline development.