Clinical UM Guideline
|Subject:||Repository Corticotropin Injection (H.P. Acthar® Gel)|
|Guideline #:||CG-DRUG-24||Current Effective Date:||10/06/2015|
|Status:||Reviewed||Last Review Date:||08/06/2015|
This document addresses the use of repository corticotropin injection (H.P. Acthar® Gel, Questcor®, Union City, CA), 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.
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. 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.
|J0800||Injection, corticotropin, up to 40 units|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2015]|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2015]|
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:
In 2014, 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 2 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.
The product label (2012) 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 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 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 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.
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 (2012) 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 under very specific circumstances.
Bomback and colleagues (2011) evaluated the use of repository corticotropin injection in 21 individuals with nephrotic syndrome. Overall, 11 of 21 individuals (52%) achieved a complete or partial remission, with 4 (19%) in complete remission. Follow-up time ranged from 6 to 14 months. Limitations of the study include a very small size, retrospective analysis of data and a short term follow-up.
Recently, there have been several small studies and a case report published evaluating repository corticotropin for various conditions, including systemic lupus erythematosus (Fiechtner, 2014); nephrotic syndrome (Hladunewich, 2014); and membranous glomerulopathy (Watson, 2014). All the authors concluded that repository corticotropin may be an effective therapy for their respective conditions; however, limitations included a small number of participants.
The following are contraindications from the Product Information Label (2012):
Hypsarrhythmia: Chaotic abnormal brain wave patterns.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
Adrenocorticotropic Hormone (ACTH)
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.
|Reviewed||08/06/2015||Medical Policy & Technology Assessment Committee (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.|