ADCIRCA, Tadalafil (Pulmonary Hypertension) Form

Tadalafil (Adcirca®, Alyq™, Tadliq®) is a phosphodiesterase-5 inhibitor. FDA Approved Indication(s) Adcirca, Alyq, and Tadliq are indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group 1) to improve exercise ability.
Studies establishing effectiveness included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%). 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 tadalafil 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 Adcirca, Alyq, or Tadliq, member must use generic tadalafil, unless contraindicated, clinically significant adverse effects are experienced, or for Tadliq requests member is unable to swallow tablets;

3. Dose does not exceed one of the following (a or b): a. Adcirca, Alyq (i and ii):
   i. 40 mg per day; ii. 2 tablets per day; b. Tadliq (i and ii):
   i. 2 bottles per month;
   ii. 300 mL per month. Page 1 of 8

   CLINICAL POLICY
   Tadalafil 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):

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 Adcirca, Alyq or Tadliq, member must use generic tadalafil, unless contraindicated, clinically significant adverse effects are experienced, or for Tadliq requests member is unable to swallow tablets;

6. If request is for a dose increase, new dose does not exceed one of the following (a or b): a. Adcirca, Alyq (i and ii):
   i. 40 mg per day; ii. 2 tablets per day; b. Tadliq (i and ii):
   i. 2 bottles per month;
   ii. 300 mL per month. Approval duration:
   Medicaid/HIM – 12 months
   Commercial – 12 months or duration of request, whichever is less Page 2 of 8

   CLINICAL POLICY
   Tadalafil 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: 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®) diltiazem (Dilacor XR®, Dilt-XR®, Cardizem® CD, Cartia XT®, Tiazac®, Taztia XT®, Cardizem® LA, Matzim® LA) amlodipine (Norvasc®) 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 20 to 30 mg PO QD 30 mg/day Page 3 of 8

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   Tadalafil 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): concomitant organic nitrates; concomitant guanylate cyclase stimulators; hypersensitivity reactions • Boxed warning(s): none reported 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. 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

   CLINICAL POLICY
   Tadalafil 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 Non-prostanoid prostacyclin receptor (IP receptor) agonist Selective receptor antagonist Nonselective dual action receptor antagonist Phosphodiesterase type 5 (PDE5) inhibitor Endothelin receptor antagonist (ETRA) Nitric oxide- cyclic guanosine monophosphate enhancer Treprostinil Orenitram (oral tablet) Remodulin (IV) Tyvaso (inhalation) Ventavis (inhalation) Uptravi (oral tablet) Iloprost Selexipag Ambrisentan Letairis (oral Bosentan Macitentan Sildenafil Tadalafil tablet) Tracleer (oral tablet) Opsumit (oral tablet) Revatio (IV, oral tablet, oral suspension) Adcirca, Alyq (oral tablet) Tadliq (oral suspension) Adempas (oral tablet) Guanylate cyclase stimulant (sGC) Riociguat V. Dosage and Administration
   Drug Name Adcirca, Alyq Tadliq Dosing Regimen 40 mg PO QD 40 mg (10 mL) PO QD Maximum Dose 40 mg/day 40 mg/day VI. Product Availability
   Drug Name Adcirca, Alyq Tadliq Availability Tablet: 20 mg Oral suspension: 20 mg/5 mL in 150 mL bottle Page 5 of 8

   CLINICAL POLICY
   Tadalafil VII.