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Methotrexate Injectable Step Therapy Program Summary

Policy Number: PH-1014

This program applies to Blue Partner, Commercial, NetResults A Series, SourceRx and Health Insurance Marketplace formularies.      

POLICY REVIEW CYCLE

Effective Date

Date of Origin 

04-01-2024            

07-01-2015

FDA APPROVED INDICATIONS AND DOSAGE

Agent(s)

FDA Indication(s)

Notes

Ref#

Otrexup®

(methotrexate)

Subcutaneous injection 

Management of selected adults with severe, active rheumatoid arthritis (RA) (ACR criteria), or children with polyarticular juvenile idiopathic arthritis (pJIA), who have had an insufficient therapeutic response to, or are intolerant of, an inadequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).

Indicated in adults for the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation.

Limitation of Use: not indicated for the treatment of neoplastic diseases.

1

Rasuvo®

(methotrexate)

Subcutaneous injection 

Management of selected adults with severe, active rheumatoid arthritis (RA) (ACR criteria), or children with polyarticular juvenile idiopathic arthritis (pJIA), who have had an insufficient therapeutic response to, or are intolerant of, an inadequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).

Indicated in adults for the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation.

Limitation of Use: not indicated for the treatment of neoplastic diseases.  

2

RediTrex®

methotrexate)

Subcutaneous injection  

Management of selected adults with severe, active rheumatoid arthritis (RA) (ACR criteria), or children with polyarticular juvenile idiopathic arthritis (pJIA), who have had an insufficient therapeutic response to, or are intolerant of, an inadequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).

Indicated in adults for the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation.

Limitation of Use: not indicated for the treatment of neoplastic diseases. 

7

See package insert for FDA prescribing information:  https://dailymed.nlm.nih.gov/dailymed/index.cfm

CLINICAL RATIONALE

 Methotrexate

Methotrexate (MTX) is commonly used for the treatment of patients with rheumatoid arthritis (RA), polyarticular juvenile idiopathic arthritis (pJIA), psoriasis, and other forms of autoimmune disease.(3) Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate.(1,2,7)

MTX can be given by oral or parenteral [i.e., intravenous (IV), intramuscular (IM), subcutaneous (SC)] route of administration (ROA). The existence of different ROAs of MTX has led to the conduction of pharmacokinetic studies designed to compare and highlight any significant differences in the drug’s therapeutic impact. Oral MTX has been a mainstay in the field of rheumatology and dermatology for decades, due to its efficacy, easy intake, and low cost. However, some patients may require higher doses of oral MTX within the therapeutic range that can be poorly tolerated. There is considerable interpatient variability of clinical and safety outcomes with low-dose MTX, which can be due to differences in patients’ individual pharmacogenomic profile. Several studies support better bioavailability, higher efficacy, better tolerability (e.g., lower frequency of gastrointestinal toxicities), and better compliance of parenteral MTX as compared to oral MTX.(3-5) This does not mean that all patients should be treated with parenteral MTX; rather suggests that patients with an inadequate response and/or intolerance to oral MTX may benefit from parenteral MTX.

The pharmacokinetics of MTX at various dosages in oral, intramuscular (IM), and subcutaneous (SC) formulations were studied in patients with RA. The authors showed that mean bioavailability was significantly lower with oral MTX than with parenteral MTX, and that there was no significant difference between the IM and SC ROAs. Overall, SC MTX is characterized by higher bioavailability, greater clinical efficacy, and a better tolerability profile than oral MTX, thus suggesting that the choice of the ROA route of administration is a fundamental parameter for optimizing treatment.(4) In a separate study comparing IM and SC injections, values for the observed peak concentration, the time to the observed peak concentration, and the area under the time versus concentration curve for IM injections were not significantly different from these values for SC injections. These results suggest that IM and SC are interchangeable ROAs.(5) In recent years, the use of SC injections gained in importance with the development of prefilled syringes containing MTX. Compared to injection by nursing staff, self-injection can increase patients’ treatment adherence and reduce costs for society and patients by decreasing frequency of healthcare professionals’ visits and transport. However, reduced manual dexterity, dependence on others, injection site reactions, and injection pain can impair compliance to MTX injections in patients with RA. Manual injections require grip and dexterity. This could be difficult in case of functional limitations due to joint pain and impaired mobility commonly encountered in RA patients. Prefilled auto-injector (AI) technology is a valuable response to such limitations. AIs automatically insert the needle and deliver a controlled and fixed dose of drug. Minimizing the pain at injection site, they are easy to learn and use and RA patients express a high level of satisfaction.(6)   

Safety

Otrexup, Rasuvo, and RediTrex have a boxed warning for the following:(1,2,7)

  • Serious toxic reactions and death have been reported with the use of methotrexate. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities.
  • Methotrexate has been reported to cause fetal death and/or congenital anomalies and is contraindicated in pregnancy.
  • Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some NSAIDs.
  • Hepatotoxicity, fibrosis, and cirrhosis may occur after prolonged use.
  • Methotrexate may cause interstitial pneumonitis at any time during therapy and has been reported at low doses. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
  • Diarrhea, ulcerative stomatitis, hemorrhagic enteritis, and death from intestinal perforation may occur.
  • Severe, occasionally fatal, skin reactions have been reported.
  • Potentially fatal opportunistic infections may occur.

Otrexup, Rasuvo, and RediTrex have the following contraindications:(1,2,7)

  • Pregnancy
  • Alcoholism or liver disease
  • Immunodeficiency syndromes
  • Preexisting blood dyscrasias
  • Hypersensitivity to methotrexate

REFERENCES

Number

Reference

1

Otrexup prescribing information. Antares Pharma, Inc. December 2019.

2

Rasuvo prescribing information. Medac Pharma Inc. March 2020.

3

Vena, G. A., Cassano, N., & Iannone, F. (2018). Update on subcutaneous methotrexate for inflammatory arthritis and psoriasis. Therapeutics and Clinical Risk Management, 14, 105–116. https://doi.org/10.2147/tcrm.s154745  

4

Bianchi, G., Caporali, R., Todoerti, M., & Mattana, P. (2016). Methotrexate and rheumatoid arthritis: Current evidence regarding subcutaneous versus oral routes of administration. Advances in Therapy, 33(3), 369–378. https://doi.org/10.1007/s12325-016-0295-8 

5

Brooks, P. J., Spruill, W. J., Parish, R. C., & Birchmore, D. A. (1990). Pharmacokinetics of Methotrexate Administered by Intramuscular and Subcutaneous Injections in Patients with Rheumatoid Arthritis. Arthritis & Rheumatology, 33(1), 91–94. https://doi.org/10.1002/art.1780330112 

6

Saraux A, Hudry C, Zinovieva E, et al. Use of Auto-Injector for Methotrexate Subcutaneous Self-Injections: High Satisfaction Level and Good Compliance in SELF-I Study, a Randomized, Open-Label, Parallel Group Study. Rheumatol Ther. 2019;6(1):47-60. Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC6393262/.

7

RediTrex prescribing information. Cumberland Pharmaceuticals Inc. March 2023. 

POLICY AGENT SUMMARY STEP THERAPY

Target Brand Agent Name(s)

Target Generic Agent Name(s)

Strength

Targeted MSC

Available MSC

Final Age Limit

Preferred Status

Otrexup

methotrexate soln pf auto-injector

20 MG/0.4ML

M ; N ; O

N

Otrexup

Methotrexate Soln PF Auto-Injector 10 MG/0.4ML

10 MG/0.4ML

M ; N ; O

N

Otrexup

Methotrexate Soln PF Auto-Injector 12.5 MG/0.4ML

12.5 MG/0.4ML

M ; N ; O

N

Otrexup

Methotrexate Soln PF Auto-Injector 15 MG/0.4ML

15 MG/0.4ML

M ; N ; O

N

Otrexup

Methotrexate Soln PF Auto-Injector 17.5 MG/0.4ML

17.5 MG/0.4ML

M ; N ; O

N

Otrexup

Methotrexate Soln PF Auto-Injector 22.5 MG/0.4ML

22.5 MG/0.4ML

M ; N ; O

N

Otrexup

Methotrexate Soln PF Auto-Injector 25 MG/0.4ML

25 MG/0.4ML

M ; N ; O

N

Rasuvo

methotrexate soln pf auto-injector

20 MG/0.4ML

M ; N ; O

N

Rasuvo

Methotrexate Soln PF Auto-Injector 10 MG/0.2ML

10 MG/0.2ML

M ; N ; O

N

Rasuvo

Methotrexate Soln PF Auto-Injector 12.5 MG/0.25ML

12.5 MG/0.25ML

M ; N ; O

N

Rasuvo

Methotrexate Soln PF Auto-Injector 15 MG/0.3ML

15 MG/0.3ML

M ; N ; O

N

Rasuvo

Methotrexate Soln PF Auto-Injector 17.5 MG/0.35ML

17.5 MG/0.35ML

M ; N ; O

N

Rasuvo

Methotrexate Soln PF Auto-Injector 22.5 MG/0.45ML

22.5 MG/0.45ML

M ; N ; O

N

Rasuvo

Methotrexate Soln PF Auto-Injector 25 MG/0.5ML

25 MG/0.5ML

M ; N ; O

N

Rasuvo

Methotrexate Soln PF Auto-Injector 30 MG/0.6ML

30 MG/0.6ML

M ; N ; O

N

Rasuvo

Methotrexate Soln PF Auto-Injector 7.5 MG/0.15ML

7.5 MG/0.15ML

M ; N ; O

N

Reditrex

methotrexate soln prefilled syringe

10 MG/0.4ML ; 12.5 MG/0.5ML ; 15 MG/0.6ML ; 17.5 MG/0.7ML ; 20 MG/0.8ML ; 22.5 MG/0.9ML ; 25 MG/ML ; 7.5 MG/0.3ML

M ; N ; O

N

CLIENT SUMMARY – STEP THERAPY

Target Brand Agent Name(s)

Target Generic Agent Name(s)

Strength

Client Formulary

Otrexup

methotrexate soln pf auto-injector

20 MG/0.4ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Otrexup

Methotrexate Soln PF Auto-Injector 10 MG/0.4ML

10 MG/0.4ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Otrexup

Methotrexate Soln PF Auto-Injector 12.5 MG/0.4ML

12.5 MG/0.4ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Otrexup

Methotrexate Soln PF Auto-Injector 15 MG/0.4ML

15 MG/0.4ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Otrexup

Methotrexate Soln PF Auto-Injector 17.5 MG/0.4ML

17.5 MG/0.4ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Otrexup

Methotrexate Soln PF Auto-Injector 22.5 MG/0.4ML

22.5 MG/0.4ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Otrexup

Methotrexate Soln PF Auto-Injector 25 MG/0.4ML

25 MG/0.4ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Rasuvo

methotrexate soln pf auto-injector

20 MG/0.4ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Rasuvo

Methotrexate Soln PF Auto-Injector 10 MG/0.2ML

10 MG/0.2ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Rasuvo

Methotrexate Soln PF Auto-Injector 12.5 MG/0.25ML

12.5 MG/0.25ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Rasuvo

Methotrexate Soln PF Auto-Injector 15 MG/0.3ML

15 MG/0.3ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Rasuvo

Methotrexate Soln PF Auto-Injector 17.5 MG/0.35ML

17.5 MG/0.35ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Rasuvo

Methotrexate Soln PF Auto-Injector 22.5 MG/0.45ML

22.5 MG/0.45ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Rasuvo

Methotrexate Soln PF Auto-Injector 25 MG/0.5ML

25 MG/0.5ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Rasuvo

Methotrexate Soln PF Auto-Injector 30 MG/0.6ML

30 MG/0.6ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Rasuvo

Methotrexate Soln PF Auto-Injector 7.5 MG/0.15ML

7.5 MG/0.15ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Reditrex

methotrexate soln prefilled syringe

10 MG/0.4ML ; 12.5 MG/0.5ML ; 15 MG/0.6ML ; 17.5 MG/0.7ML ; 20 MG/0.8ML ; 22.5 MG/0.9ML ; 25 MG/ML ; 7.5 MG/0.3ML

Blue Partner ; Commercial ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

STEP THERAPY CLINICAL CRITERIA FOR APPROVAL

Module

Clinical Criteria for Approval

ST (preferred agents)

TARGET AGENT(S)

Preferred Agent(s)

Otrexup (methotrexate auto-injector)
RediTrex (methotrexate prefilled syringe)

Non-preferred Agent(s)

  Rasuvo (methotrexate auto-injector)

 

Otrexup, RediTrex will be approved when ONE of the following is met:

  1. The requested agent is eligible for continuation of therapy AND ONE of the following:

Agents Eligible for Continuation of Therapy

Otrexup
Reditrex
  1. Information has been provided that indicates the patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days OR
  2. The prescriber states the patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days AND is at risk if therapy is changed OR
  3. The patient's medication history includes use of a generic methotrexate injectable agent within the past 365 days OR
  4. The patient has an intolerance or hypersensitivity to a generic methotrexate injectable agent OR
  5. The patient has an FDA labeled contraindication to ALL generic methotrexate injectable agents OR
  6. There is information that the patient has a physical or a mental disability that would prevent the patient from using ALL generic methotrexate injectable agents

Length of Approval: 12 months

 

Rasuvo will be approved when ONE of the following is met:

  1. The patient's medication history includes use of a generic methotrexate injectable agent, Otrexup, AND RediTrex within the past 365 days OR
  2. The patient has an intolerance or hypersensitivity to a generic methotrexate injectable agent, Otrexup, AND Reditrex OR
  3. The patient has an FDA labeled contraindication to ALL generic methotrexate injectable agents, Otrexup, AND RediTrex OR
  4. There is information that the patient has a physical or a mental disability that would prevent the patient from using ALL generic methotrexate injectable agents, Otrexup, AND RediTrex

Length of Approval: 12 months

*Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.

Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.

ALBP _  Commercial _ CS _ Methotrexate_Injectable_ST _ProgSum_ 04-01-2024  _© Copyright Prime Therapeutics LLC. January 2024 All Rights Reserved