ADEMPAS, Riociguat Form

Riociguat (Adempas®) is a soluble guanylate cyclase stimulator. FDA Approved Indication(s) Adempas is indicated for the treatment of: • Adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (World Health Organization [WHO] Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class • Adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class, and to delay clinical worsening; o Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominately patients with WHO functional class II-III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%) 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 Adempas is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Pulmonary Hypertension (must meet all):

1. Diagnosis of PAH or CTEPH;

   2. Prescribed by or in consultation with a cardiologist or pulmonologist;
   3. Member meets one of the following:
      a. For PAH: Failure of a calcium channel blocker (see Appendix B), unless member meets one of the following (i or ii):
      i. ii. Contraindication or clinically significant adverse effects to calcium channel Inadequate response or contraindication to acute vasodilator testing; blockers are experienced; b. For CTEPH: Disease is inoperable or persistent (i.e., suboptimal surgical outcome); Page 1 of 8

   CLINICAL POLICY
   Riociguat

2. Dose does not exceed both of the following (a and b) (members who smoke may require higher doses): a. 7.5 mg per day;
   b. 3 tablets per day. Approval duration:
   Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less B. Other diagnoses/indications (must meet 1 or 2):
3. 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
4. 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 Hypertension (must meet all):

5. 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 a dose increase, new dose does not exceed both of the following (a and b) (members who smoke may require higher doses):
      a. 7.5 mg per day; b. 3 tablets per day. Approval duration:
      Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less Page 2 of 8

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   Riociguat B. Other diagnoses/indications (must meet 1 or 2):

6. 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

7. 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 60 mg PO QD; may increase to 120 to 240 mg/day 720 to 960 mg PO QD Dose Limit/ Maximum Dose 240 mg/day 960 mg/day nifedipine (Adalat® CC, Procardia XL®) diltiazem (Dilacor XR®, Dilt-XR®, Cardizem® CD, Cartia XT®, Tiazac®, Taztia XT®, Cardizem® LA, Matzim® LA) amlodipine (Norvasc®) 20 to 30 mg PO QD 30 mg/day Page 3 of 8

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   Riociguat 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. Appendix C: Contraindications/Boxed Warnings • Contraindication(s): pregnancy, nitrates and nitric oxide donors, phosphodiesterase inhibitors, pulmonary hypertension associated with idiopathic interstitial pneumonitis • Boxed warning(s): 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 FC Heart Failure I Comfortable at rest PA Limitations 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. Drug Class Appendix F: Pulmonary Hypertension: Targeted Therapies Mechanism of Action Reduction of Prostacyclin* pathway agonist Drug Subclass Prostacyclin Drug Brand/Generic Formulations Epoprostenol Veletri (IV) Flolan (IV) Page 4 of 8

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   Riociguat Mechanism of Action pulmonary arterial pressure through vasodilation Drug Class Drug Subclass Drug Brand/Generic Formulations Flolan generic (IV) *Member of the prostanoid class of fatty acid derivatives. Synthetic prostacyclin analog Endothelin receptor antagonist (ETRA) Nitric oxide- cyclic guanosine monophosphate 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) Treprostinil Orenitram (oral tablet) Remodulin (IV) 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 PAH
   CTEPH Dosing Regimen 1 mg PO TID, increased by 0.5 mg every 2 weeks as tolerated to 2.5 mg TID Maximum Dose 7.5 mg/day VI. Product Availability
   Tablets: 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg VII.