TRACLEER, Bosentan Form

Bosentan (Tracleer®) is an endothelin receptor antagonist. FDA Approved Indication(s) Tracleer is indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group 1): • In adults to improve exercise ability and to decrease clinical worsening o Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%). • In pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability. 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 bosentan is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Pulmonary Arterial Hypertension (must meet all):

1. Diagnosis of PAH;
   2. Prescribed by or in consultation with a cardiologist or pulmonologist;
   3. Failure of a calcium channel blocker (see Appendix B), unless member meets one of the following (a or b):
      a. Inadequate response or contraindication to acute vasodilator testing; b. Contraindication or clinically significant adverse effects to calcium channel blockers are experienced;
2. If request is for brand Tracleer, member must use generic bosentan, unless contraindicated or clinically significant adverse effects are experienced;

3. Dose does not exceed both of the following (a and b): a. 250 mg per day; b. 2 tablets per day.
   Approval duration:
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   Bosentan Medicaid/HIM – 6 months
   Commercial – 12 months or duration of request, whichever is less B. Other diagnoses/indications (must meet 1 or 2):

4. 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
5. 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. Pulmonary Arterial Hypertension (must meet all):
   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. If request is for brand Tracleer, member must use generic bosentan, unless contraindicated or clinically significant adverse effects are experienced;
6. If request is for a dose increase, new dose does not exceed both of the following (a and b): a. 250 mg per day;
   b. 2 tablets per day. Approval duration:
   Medicaid/HIM – 12 months
   Commercial – 12 months or duration of request, whichever is less B. Other diagnoses/indications (must meet 1 or 2):

7. 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: Page 2 of 8

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   Bosentan 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

8. 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 policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key CTEPH: chronic thromboembolic pulmonary hypertension FC: functional class FDA: Food and Drug Administration
   NYHA: New York Heart Association PA: physical activity PAH: pulmonary arterial hypertension PH: pulmonary hypertension WHO: World Health Organization 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 and may require prior authorization.
   Drug Name Dosing Regimen nifedipine (Adalat® CC, Procardia XL®) 60 mg PO QD; may increase to 120 to 240 mg/day 720 to 960 mg PO QD diltiazem (Dilacor XR®, Dilt-XR®, Cardizem® CD, Cartia XT®, Tiazac®, Taztia XT®, Cardizem® LA, Matzim® LA) amlodipine (Norvasc®) 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. 20 to 30 mg PO QD 960 mg/day 30 mg/day Dose Limit/ Maximum Dose 240 mg/day Appendix C: Contraindications/Boxed Warnings • Contraindication(s): pregnancy; use with cyclosporine; use with glyburide; hypersensitivity Page 3 of 8

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   Bosentan • Boxed warning(s): risk of hepatotoxicity (REMS program); embryo-fetal toxicity (REMS program) Appendix D: Pulmonary Hypertension: WHO Classification • Group 1: PAH
   • Group 2: PH due to left heart disease • Group 3: PH due to lung disease and/or hypoxemia • Group 4: CTEPH
   • Group 5: PH due to unclear multifactorial mechanisms Appendix E: Pulmonary Hypertension: WHO/NYHA Functional Classes (FC) Treatment Approach* Status at Rest PA Limitations FC Heart Failure I Comfortable at rest Tolerance of Physical Activity (PA) No limitation Ordinary PA does not cause undue dyspnea or fatigue, chest pain, or near syncope. Monitoring for progression of PH and treatment of co- existing conditions Advanced treatment of PH with PH- targeted therapy

   • see Appendix F II III IV Comfortable at rest Slight limitation Comfortable at rest Marked limitation Dyspnea or fatigue may be present at rest Inability to carry out any PA without symptoms Ordinary PA causes undue dyspnea or fatigue, chest pain, or near syncope. Less than ordinary PA causes undue dyspnea or fatigue, chest pain, or near syncope. Discomfort is increased by any PA.
     Signs of right heart failure *PH supportive measures may include diuretics, oxygen therapy, anticoagulation, digoxin, exercise, pneumococcal vaccination. Advanced treatment options also include calcium channel blockers. Appendix F: Pulmonary Hypertension: Targeted Therapies Mechanism of Action Drug Subclass Drug Class Drug Brand/Generic Formulations Reduction of pulmonary arterial pressure Prostacyclin pathway agonist Member of the prostanoids Prostacyclin Synthetic prostacyclin analog Epoprostenol Veletri (IV) Flolan (IV) Flolan generic (IV) Treprostinil Orenitram (oral tablet) Remodulin (IV) Page 4 of 8

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   Bosentan Mechanism of Action through vasodilation Drug Class Drug Subclass Drug class of fatty acid derivatives. Endothelin receptor antagonist (ETRA) Nitric oxide- cyclic guanosine monophosphat e enhancer Non-prostanoid prostacyclin receptor (IP receptor) agonist Selective receptor antagonist Nonselective dual action receptor antagonist Phosphodiesterase type 5 (PDE5) inhibitor Guanylate cyclase stimulant (sGC) Brand/Generic Formulations Tyvaso (inhalation) Ventavis (inhalation) Uptravi (oral tablet) Iloprost Selexipag Ambrisentan Letairis (oral Bosentan Macitentan Sildenafil Tadalafil Riociguat tablet) Tracleer (oral tablet) Opsumit (oral tablet) Revatio (IV, oral tablet, oral suspension) Adcirca (oral tablet) Adempas (oral tablet) V. Dosage and Administration
   Indication Dosing Regimen PAH Adults: Initially 62.5 mg PO BID for 4 weeks, then increased to 125 mg PO BID Maximum Dose 250 mg/day Pediatric patients: Patient’s age and weight

   12 years and 40 kg 12 years and < 40 kg ≤ 12 years and ≥ 4 to 8 kg ≤ 12 years and 8 to 16 kg ≤ 12 years and 16 to 24 kg ≤ 12 years and 24 to 40 kg Initial 4 weeks Maintenance 62.5 mg PO BID 62.5 mg PO BID 16 mg PO BID (after 4 weeks) 125 mg PO BID 62.5 mg PO BID 16 mg PO BID 32 mg PO BID 32 mg PO BID 48 mg PO BID 48 mg PO BID 64 mg PO BID 64 mg PO BID Page 5 of 8

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   Bosentan VI. Product Availability
   • Tablets: 62.5 mg, 125 mg • Dispersible tablet for oral suspension: 32 mg VII.