TYSABRI MS, Natalizumab Form

Natalizumab (Tysabri®) and its biosimilar [(Natalizumab-sztn) Tyruko®] are integrin receptor antagonists.
FDA Approved Indication(s) Tysabri and Tyruko are indicated: • As monotherapy for the treatment of patients with relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults • For inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn’s disease (CD) with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of tumor necrosis factor-α (TNF-α) Limitation(s) of use:
• Tysabri and Tyruko increases the risk of progressive multifocal leukoencephalopathy. When initiating and continuing treatment with Tysabri or Tyruko, physicians should consider whether the expected benefit of Tysabri or Tyrukis sufficient to offset this risk.
In CD, Tysabri and Tyruko should not be used in combination with immunosuppressants or inhibitors of TNF-α.
• Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Tysabri and Tyruko are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Multiple Sclerosis (must meet all):

1. Diagnosis of one of the following (a, b, or c): a. Clinically isolated syndrome, and member is contraindicated to both, or has experienced clinically significant adverse effects to one, of the following at up to maximally indicated doses: an interferon-beta agent (Avonex®, Betaseron®/Extavia®†, Rebif®, or Plegridy®), glatiramer (Copaxone®, Glatopa®); Page 1 of 11

   CLINICAL POLICY Natalizumab b. Relapsing-remitting MS, and one of the following (i or ii): i. Failure of all of the following at up to maximally indicated doses, unless clinically significant adverse effects are experienced or all are contraindicated (1, 2, 3, and 4): 1) Dimethyl fumarate (generic Tecfidera®);
   2) Teriflunomide (generic Aubagio®);
   3) Fingolimod (Gilenya®); 4) An interferon-beta agent (Avonex, Betaseron/Extavia†, Rebif, or Plegridy) or glatiramer (Copaxone, Glatopa); Prior authorization is required for all disease modifying therapies for MS †Betaseron is preferred for the Commercial and HIM lines of business; Extavia is preferred for the Medicaid line of business ii. Member has highly active MS, and failure of Gilenya at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced; c. Secondary progressive MS;

2. Prescribed by or in consultation with a neurologist;
   3. Age ≥ 18 years;
   4. Tysabri and Tyruko are not prescribed concurrently with other disease modifying therapies for MS (see Appendix D);
3. Documentation of both baseline number of relapses per year and expanded disability status scale (EDSS) score;
4. Dose does not exceed 300 mg (1 vial) every 4 weeks. Approval duration:
   Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Crohn’s Disease – FOR MEDICAID ONLY (must meet all): Refer to CP.CPA.194 Biologic DMARDs for Commercial and HIM.PA.SP60 Biologic DMARDs for HIM
   
   1. Diagnosis of CD;
   2. Prescribed by or in consultation with a gastroenterologist;
   3. Age ≥ 18 years;
   4. Member meets one of the following (a or b): a. Failure of a ≥ 3 consecutive month trial of at least ONE immunomodulator (e.g., azathioprine, 6-mercaptopurine [6-MP], methotrexate [MTX]) at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced; b. Medical justification supports inability to use immunomodulators (see Appendix E);

5. Member meets one of the following, unless clinically significant adverse effects are experienced or all are contraindicated (a or b, see Appendix D): a. Failure of one adalimumab product (e.g. Hadlima™, Yusimry™, adalimumab- adaz, adalimumab-adbm, and adalimumab-fkjp are preferred), used for ≥ 3 consecutive months; b. History of failure of two TNF blockers;
   *Prior authorization is required for adalimumab products
   Page 2 of 11

   CLINICAL POLICY Natalizumab

6. Tysabri and Tyruko are not prescribed concurrently with immunosuppressants (e.g., azathioprine, cyclosporine, 6-MP, MTX) or TNF-α inhibitors (note: aminosalicylates may be continued);
7. Dose does not exceed 300 mg (1 vial) every 4 weeks. Approval duration: 6 months C. Other diagnoses/indications (must meet 1 or 2):
8. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
9. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Multiple Sclerosis (must meet all):
10. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
    2. Member meets one of the following (a or b): a. If member has received < 1 year of total treatment: Member is responding positively to therapy; b. If member has received ≥ 1 year of total treatment: Member meets one of the following (i, ii, iii, or iv): i. Member has not had an increase in the number of relapses per year compared to baseline; ii. Member has not had ≥ 2 new MRI-detected lesions; iii. Member has not had an increase in EDSS score from baseline; iv. Medical justification supports that member is responding positively to therapy;

11. Tysabri and Tyruko are not prescribed concurrently with other disease modifying therapies (see Appendix D); Page 3 of 11

    CLINICAL POLICY Natalizumab

12. If request is for a dose increase, new dose does not exceed 300 mg (1 vial) every 4 weeks. Approval duration:
    Medicaid/HIM –
    If member has received < 1 year of total treatment – up to a total of 12 months of treatment If member has received ≥ 1 year of total treatment – 12 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Crohn’s Disease – FOR MEDICAID ONLY (must meet all):
    Refer to CP.CPA.194 Biologic DMARDs for commercial and HIM.PA.SP60 Biologic DMARDs for HIM
    1. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
    2. Member is responding positively to therapy;
    3. Tysabri and Tyruko are not prescribed concurrently immunosuppressants (e.g., azathioprine, cyclosporine, 6-MP, MTX) or TNF-α inhibitors (note: aminosalicylates may be continued);
13. If request is for a dose increase, new dose does not exceed 300 mg (1 vial) every 4 weeks. Approval duration: 12 months C. Other diagnoses/indications (must meet 1 or 2):
14. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

15. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policy – Page 4 of 11

    CLINICAL POLICY Natalizumab CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents; B. Primary progressive MS. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key 6-MP: 6-mercaptopurine CD: Crohn’s disease EDSS: expanded disability status scale
    FDA: Food and Drug Administration GI: gastrointestinal MS: multiple sclerosis MTX: methotrexate TNF-α: tumor necrosis factor-α Appendix B: Therapeutic Alternatives
    This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
    Drug Name Dosing Regimen Dose Limit/ Maximum Dose MS agents Avonex®, Rebif® (interferon beta-1a) Betaseron®, Extavia® (interferon beta-1b) Plegridy® (peginterferon beta-1a) glatiramer acetate (Copaxone®, Glatopa®) teriflunomide (Aubagio®) fingolimod (Gilenya®) dimethyl fumarate (Tecfidera®) CD agents 6-mercaptopurine (Purixan®) azathioprine (Azasan®, Imuran®) corticosteroids methotrexate (Otrexup®, Rasuvo) Pentasa® (mesalamine) tacrolimus (Prograf®)* Avonex: 30 mcg IM Q week Rebif: 22 mcg or 44 mcg SC TIW 250 mcg SC QOD Avonex: 30 mcg/week Rebif: 44 mcg TIW 250 mg QOD 125 mcg SC Q2 weeks 125 mcg/2 weeks 20 mg SC QD or 40 mg SC TIW 7 mg or 14 mg PO QD 0.5 mg PO QD 120 mg PO BID for 7 days, followed by 240 mg PO BID 20 mg/day or 40 mg TIW 14 mg/day 0.5 mg/day 480 mg/day 50 mg PO QD or 1.5 – 2 mg/kg/day PO
    1.5 – 2 mg/kg/day PO 2 mg/kg/day 2.5 mg/kg/day prednisone 40 mg PO QD for 2 weeks or IV 50 – 100 mg Q6H for 1 week Various budesonide (Entocort EC ) 6 – 9 mg PO QD 15 – 25 mg/week IM or SC 30 mg/week 1,000 mg PO QID 0.27 mg/kg/day PO in divided doses or 0.15 – 0.29 mg/kg/day PO 4 g/day N/A Page 5 of 11

    CLINICAL POLICY Natalizumab Drug Name Dosing Regimen Cimzia® (certolizumab) Initial dose: 400 mg SC at 0, 2, and 4 weeks Dose Limit/ Maximum Dose 400 mg every 4 weeks Hadlima (adalimumab- bwwd), Yusimry (adalimumab-aqvh), adalimumab-adaz (Hyrimoz®), adalimumab- fkjp (Hulio®), adalimumab-adbm (Cyltezo®) Avsola™, Renflexis™, Inflectra® (infliximab) Maintenance dose: 400 mg SC every 4 weeks Initial dose:
    160 mg SC on Day 1, then 80 mg SC on Day 15 Maintenance dose: 40 mg SC every other week starting on Day 29 40 mg every other week Initial dose:
    5 mg/kg IV at weeks 0, 2 and 6
    10 mg/kg every 8 weeks Maintenance dose:
    5 mg/kg IV every 8 weeks.
    Some adult patients who initially respond to treatment may benefit from increasing the dose to 10 mg/kg if they later lose their response Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. *Off-label Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Patients who have or have had progressive multifocal leukoencephalopathy o Patients who have had a hypersensitivity reaction to Tysabri or Tyruko • Boxed warning(s): progressive multifocal leukoencephalopathy Appendix D: General Information • Because of the risk of progressive multifocal leukoencephalopathy, Tysabri and Tyruko are only available through a REMS program called the TOUCH® Prescribing Program. • Disease-modifying therapies for MS are: glatiramer acetate (Copaxone®, Glatopa®), interferon beta-1a (Avonex®, Rebif®), interferon beta-1b (Betaseron®, Extavia®), peginterferon beta-1a (Plegridy®), dimethyl fumarate (Tecfidera®), diroximel fumarate (Vumerity®), monomethyl fumarate (Bafiertam™), fingolimod (Gilenya® , Tascenso ODT™), teriflunomide (Aubagio®), alemtuzumab (Lemtrada®), mitoxantrone (Novantrone®), natalizumab (Tysabri®, and biosimilar Tyruko®), ocrelizumab Page 6 of 11

    CLINICAL POLICY Natalizumab (Ocrevus®), cladribine (Mavenclad®), siponimod (Mayzent®), ozanimod (Zeposia®), ponesimod (Ponvory™), ublituximab-xiiy (Briumvi™), and ofatumumab (Kesimpta®). • The American Academy of Neurology 2018 MS guidelines recommend the use of Gilenya, Tysabri, Tyruko, and Lemtrada for patients with highly active MS. Definitions of highly active MS vary and can include measures of relapsing activity and MRI markers of disease activity, such as numbers of gadolinium-enhanced lesions. • Of the disease-modifying therapies for MS that are FDA-labeled for CIS, only the interferon products, glatiramer, and Aubagio have demonstrated any efficacy in decreasing the risk of conversion to MS compared to placebo. This is supported by the American Academy of Neurology 2018 MS guidelines. • Definition of failure of MTX or DMARDs
    o Child-bearing age is not considered a contraindication for use of MTX. Each drug has risks in pregnancy. An educated patient and family planning would allow use of MTX in patients who have no intention of immediate pregnancy. o Social use of alcohol is not considered a contraindication for use of MTX. MTX may only be contraindicated if patients choose to drink over 14 units of alcohol per week. However, excessive alcohol drinking can lead to worsening of the condition, so patients who are serious about clinical response to therapy should refrain from excessive alcohol consumption. • TNF blockers: o Etanercept (Enbrel®), adalimumab (Humira®) and its biosimilars, infliximab (Remicade®) and its biosimilars (Avsola™, Renflexis™, Inflectra®), certolizumab pegol (Cimzia®), and golimumab (Simponi®, Simponi Aria®). Appendix E: Medical Justification • The following may be considered for medical justification supporting inability to use an immunomodulator for Crohn’s disease:
    o Inability to induce short-term symptomatic remission with a 3-month trial of systemic glucocorticoids o High-risk factors for intestinal complications may include: Initial extensive ileal, ileocolonic, or proximal GI involvement Initial extensive perianal/severe rectal disease    Fistulizing disease (e.g., perianal, enterocutaneous, and rectovaginal fistulas)  Deep ulcerations  Penetrating, stricturing or stenosis disease and/or phenotype  Intestinal obstruction or abscess V. Dosage and Administration
    Indication Relapsing MS, CD Dosing Regimen 300 mg IV every 4 weeks
    In CD, discontinue in patients who have not experienced therapeutic benefit by 12 weeks of induction therapy and in patients that cannot discontinue chronic concomitant steroids within six months of starting therapy Maximum Dose 300 mg/4 weeks Page 7 of 11

    CLINICAL POLICY Natalizumab VI. Product Availability
    Single-use vial: 300 mg/15 mL VII.