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 as treatment of corticosteroid-responsive conditions, including but not limited to acute exacerbations of multiple sclerosis in adults, when there is a contraindication to or intolerance of corticosteroids that is not expected to occur with the use of repository corticotropin injection.

Not Medically Necessary: 

Repository corticotropin injection is considered not medically necessary as treatment of corticosteroid-responsive conditions, including but not limited to acute exacerbations of multiple sclerosis in adults, unless there is a contraindication to or intolerance of corticosteroids that is not expected to occur with the use of repository corticotropin injection.

Repository corticotropin injection is considered not medically necessary for all other indications.

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.

Infantile Spasms

In October 2010, 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 is 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.

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.

In a report on the medical treatment of infantile spasms, the American Academy of Neurology and the Child Neurology Society (2004) studied and documented current practices for treatment of infantile spasms in children. In order to determine the current best practice for treatment of infantile spasms, a literature review of 159 articles was performed. Articles analyzed required a clear diagnosis of infantile spasms and an EEG demonstrating hypsarrhythmia. Results included:

• Evidence supports that ACTH is probably effective for the short-term treatment of infantile spasms and in resolution of hypsarrhythmia.
• There is insufficient evidence that oral corticosteroids are effective in the treatment of infantile spasms.
• Vigabatrin is possibly effective for the short-term treatment of infantile spasms.
• There is insufficient evidence to recommend any other treatment of infantile spasms.

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 (2010) states repository corticotropin injection is indicated for the treatment of acute 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 may potentially be an option for an adult experiencing an acute exacerbation of multiple sclerosis when there is a contraindication to or intolerance of corticosteroids. This is expected to be a very small subset of the multiple sclerosis population.

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. 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.

In addition to infantile spasms and multiple sclerosis, the product label (2010) states repository corticotropin injection is indicated for the treatment of rheumatic disorders, collagen diseases, dermatologic diseases, allergic states, ophthalmic diseases, respiratory diseases, and edematous state. 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.

The following are contraindications from the Product Information Label (2010):

• 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, primary adrenocortical insufficiency, adrenocortical hyperfunction, 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. 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.
4. Filippini G, Brusaferri F, Sibley WA, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev. 2000; (4):CD001331.
5. 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.
6. 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.
7. Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev. 2008; (4):CD001770.
8. 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.
9. 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.
10. 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.
11. 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.
12. Miller H, Newell DJ, Ridley A. Multiple sclerosis. Treatment of acute exacerbations with corticotrophin (A.C.T.H.). Lancet. 1961; 2(7212):1120-1122.
13. 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.
14. Riikonen R. Infantile spasms: therapy and outcome. J Child Neurol. 2004; 19(6):401-404.
15. 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.
16. 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.
17. Tsao CY. Current trends in the treatment of infantile spasms. Neuropsychiatr Dis Treat. 2009; 5:289-299.
18. Tsuji T, Okumura A, Ozawa H, et al. Current treatment of West syndrome in Japan. J Child Neurol. 2007; 22(5):560-564.
19. 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 2011^®_.  Bethesda, MD: American Society of Health-System Pharmacists^®_, 2011.
2. Corticotropin (systemic). In: DrugPoints System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Last updated February 14, 2011. Available at: http://www.thomsonhc.com. Accessed on March 1, 2011.
3. H.P. Acthar^® Gel [Product Information], Union City, CA. Questcor Pharmaceuticals, Inc.; October 2010. Available at: http://www.acthar.com/files/Acthar-PI.pdf. Accessed on March 1, 2011.
4. 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 March 1, 2011.

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.