Repository corticotropin injection (H.P. Acthar^® Gel, Questcor^®_, Union City, CA) is a highly purified sterile preparation of the adrenocorticotropic hormone (ACTH) in 16% gelatin to provide a prolonged release after intramuscular or subcutaneous injection. ACTH stimulates the adrenal cortex to secrete cortisol, corticosterone, aldosterone, and a number of weakly androgenic substances. This document addresses the use of repository corticotropin injection (H.P. Acthar Gel).

Medically Necessary:

Repository corticotropin injection is considered medically necessary as monotherapy for the treatment of infantile spasms (West syndrome) in infants and children less than two years of age.

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. There is no contraindication to or intolerance of corticosteroids; AND
3. There is clear documentation that a corticosteroid can't be used and that a repository corticotropin injection can be used effectively.

Not Medically Necessary:

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

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  A draft of future ICD-10 Coding (effective10/01/2014) related to this document, as it might look today, is included below for your reference.  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.

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 two 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 spasms 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 two years of age (median age of six months) with clinical spasms were randomized to receive either a two 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 two 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 four 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.

Hancock and colleagues (2008), in a Cochrane review, 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:

• The strongest evidence suggests that hormonal treatment (prednisone, tetrocosactide [synthetic ACTH (cosyntropin)] and ACTH) leads to resolution of spasms faster and in more infants that does vigabatrin.
• Responses without subsequent relapse may be no different; that is, the percent of cases that remain seizure-free may be similar when recurrence of seizures is considered.
• There is a suggestion that prednisolone or tetrocosactide (cosyntropin) might improve the long-term developmental outcomes compared to vigabatrin in infants not found to have an underlying cause of their infantile spasms.
• Vigabatrin may be the treatment of choice in infantile spasms related to tuberous sclerosis.
• The authors also noted that naturally occurring ACTH is not available in the U.K.

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."

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:

• Low-dose ACTH should be considered for treatment of infantile spasms.
• ACTH or vigabatrin (VGB) may be useful for short-term treatment of infantile spasms, with ACTH considered preferentially over VGB.
• Hormonal therapy (ACTH or prednisolone) may be considered for use in preference to VGB in infants with cryptogenic infantile spasms, to possibly improve developmental outcome.
• A shorter lag time to treatment of infantile spasms with either hormonal therapy or VGB may be considered to improve long-term cognitive outcomes.

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.

The product label (2011) 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, sub-cutaneous), 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 mainly consists 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 five weeks of treatment (odds ratio 0.37, 95% confidence interval 0.24 to 0.57) with some but non significant 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 five-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 five-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 addition to infantile spasms and multiple sclerosis, the product label (2011) states repository corticotropin injection may be used for the treatment of rheumatic disorders, collagen diseases, dermatologic diseases, allergic states, ophthalmic diseases, respiratory diseases, and edematous state (to induce a diuresis or remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus). The published evidence in support of these conditions is sparse; however, repository corticotropin injection may potentially be a treatment option for an individual with one of these corticosteroid responsive conditions who has contraindications to or intolerance of the use of corticosteroids.

Bomback and colleagues (2011) evaluated the use of repository corticotropin injection in 21 individuals with the kidney disease, nephrotic syndrome. Overall, 11 of 21 individuals (52%) achieved a complete or partial remission, with four (19%) in complete remission. Follow-up time ranged from six to 14 months. Limitations of this study included a very small size, retrospective analysis of data and a short term follow-up.

The following are contraindications from the Product Information Label (2011):

• Administration of live or live attenuated vaccines is contraindicated in individuals receiving immunosuppressive doses of repository corticotropin injection.
• Intravenous administration of this drug is contraindicated.
• Repository corticotropin injection is contraindicated in individuals with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, or sensitivity to proteins of porcine origin.
• Repository corticotropin injection is contraindicated in children under two years of age with suspected congenital infections.
• Treatment is contraindicated when conditions are accompanied by primary adrenocortical insufficiency or adrenocortical hyperfunction.

Hypsarrhythmia: Chaotic abnormal brain wave patterns.

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. 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.
3. 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.
4. 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.
5. Filippini G, Brusaferri F, Sibley WA, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev. 2000; (4):CD001331.
6. 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.
7. 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.
8. Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev. 2008; (4):CD001770.
9. 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.
10. 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.
11. 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.
12. 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.
13. Miller H, Newell DJ, Ridley A. Multiple sclerosis. Treatment of acute exacerbations with corticotrophin (A.C.T.H.). Lancet. 1961; 2(7212):1120-1122.
14. 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.
15. Pellock JM, Hrachovy R, Shinner S, et al. Infantile spasms: A U.S. consensus report. Epilepsia 2010; 5: 2175-2189.
16. Riikonen R. Infantile spasms: therapy and outcome. J Child Neurol. 2004; 19(6):401-404.
17. 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.
18. 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.
19. 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.
20. Tsao CY. Current trends in the treatment of infantile spasms. Neuropsychiatr Dis Treat. 2009; 5:289-299.
21. Tsuji T, Okumura A, Ozawa H, et al. Current treatment of West syndrome in Japan. J Child Neurol. 2007; 22(5):560-564.
22. Verrotti A, Manco R, Coppola GG, et al. Update of the medical treatment of West syndrome. Minerva Pediatr. 2007; 59(3):249-253.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2012^®_. Bethesda, MD: American Society of Health-System Pharmacists^®_, 2012.
2. Corticotropin (systemic). In: DrugPoints System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Last updated  December 12, 2012. Available at: http://www.thomsonhc.com. Accessed on October 9, 2012.
3. 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.
4. H.P. Acthar^® Gel [Product Information], Union City, CA. Questcor Pharmaceuticals, Inc.; June 2011. Available at: http://www.acthar.com/files/Acthar-PI.pdf. Accessed on October 9, 2012.
5. Mackay MT, Weiss SK, Adams-Webber T, et al. American Academy of Neurology; Child Neurology Society. Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society. Neurology. 2004; 62(10):1668-1681. Available at: http://www.neurology.org/cgi/reprint/62/10/1668.pdf. Accessed on October 9, 2012.

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.