REMODULIN, Treprostinil Sodium TYVASO, Treprostinil ORENITRAM, Treprostinil Diolamine Form

Treprostinil (Orenitram®, Remodulin®, Tyvaso®, Tyvaso DPI™) is a prostacyclin analog. FDA Approved Indication(s) Orenitram, Remodulin, Tyvaso and Tyvaso DPI are indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group 1) to improve exercise ability.
• Orenitram is also indicated to delay disease progression.
• Remodulin is also indicated to reduce the rate of clinical deterioration in patients with PAH requiring transition from epoprostenol (Flolan®, Veletri®). The risks and benefits of each drug should be carefully considered prior to transition. • Tyvaso and Tyvaso DPI are indicated for the treatment of pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. o The study with Tyvaso establishing effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%), and WHO Group 3 connective tissue disease (22%) For PAH, studies establishing effectiveness included predominately patients with New York Heart Association (NYHA) Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH, PAH associated with congenital systemic-to-pulmonary shunts, or PAH associated with connective tissue diseases. Nearly all controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor) with study duration of 12 weeks.
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 treprostinil 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; Page 1 of 11

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   Treprostinil

2. 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;
3. If request is for brand Remodulin, member must use generic treprostinil, unless contraindicated or clinically significant adverse effects are experienced;
4. Request meets one of the following (a, b, c, or d):
   a. Orenitram: If member requires titration, provider must submit a titration plan; b. Remodulin: Provider must submit treatment plan detailing pump rate, dose, quantity (in mL), and frequency of cassette change; c. Tyvaso: Dose does not exceed 12 breaths per treatment session (72 mcg of treprostinil) four times daily to be used with the Tyvaso Inhalation System (a second back-up system device is recommended);
   d. Tyvaso DPI: Dose does not exceed 64 mcg per treatment session (1 cartridge) four times daily to be used with the Tyvaso DPI inhaler (256 mcg [4 cartridges] per day).
   Approval duration:
   Medicaid/HIM – 6 months
   Commercial – 12 months or duration of request, whichever is less B. Pulmonary Hypertension Associated with Interstitial Lung Disease (must meet all):
5. Diagnosis of PH-ILD;
   2. Member has WHO Group 3 pulmonary hypertension;
   3. Request is for Tyvaso or Tyvaso DPI;
   4. Prescribed by or in consultation with a cardiologist or pulmonologist;
   5. Age ≥ 18 years;
   6. Member has had right heart catheterization which confirmed all of the following (a, b, and c): a. Pulmonary vascular resistance (PVR) > 3 Wood Units (WU); b. Pulmonary capillary wedge pressure (PCWP) of < 15 mmHg; c. Mean pulmonary arterial pressure (mPAP) of ≥ 25 mmHg;
6. If member’s pulmonary hypertension is due to connective tissue disease, member’s baseline forced vital capacity (FVC) is < 70%;

7. Dose does not exceed either one of the following (a or b): a. Tyvaso: 12 breaths per treatment session (72 mcg of treprostinil) four times daily to be used with the Tyvaso Inhalation System (a second back-up system device is recommended);
   b. Tyvaso DPI: 64 mcg per treatment session (1 cartridge) four times daily to be used with the Tyvaso DPI inhaler (256 mcg [4 cartridges] per day). Approval duration:
   Medicaid/HIM – 6 months
   Commercial – 12 months or duration of request, whichever is less Page 2 of 11

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   Treprostinil 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. 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 Remodulin, member must use generic treprostinil, unless contraindicated or clinically significant adverse effects are experienced;
10. Request meets one of the following (a, b, c, or d):
    a. Orenitram: If member requires titration, provider must submit a titration plan; b. Remodulin: Provider must submit treatment plan detailing pump rate, dose, quantity (in mL) and frequency of cassette change; c. Tyvaso: If request is for a dose increase, new dose does not exceed 12 breaths per treatment session (72 mcg of treprostinil) four times daily to be used with the Tyvaso Inhalation System (a second back-up system device is recommended);
    d. Tyvaso DPI: If request is for a dose increase, new dose does not exceed 64 mcg per treatment session (1 cartridge) four times daily to be used with the Tyvaso DPI inhaler (256 mcg [4 cartridges] per day). Approval duration:
    Medicaid/HIM – 12 months
    Commercial – 12 months or duration of request, whichever is less B. Pulmonary Hypertension Associated with Interstitial Lung Disease (must meet all):

11. Member meets one of the following (a or b): Page 3 of 11

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    Treprostinil 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);

12. Request is for Tyvaso or Tyvaso DPI;
    3. Member is responding positively to therapy;
    4. If request is for a dose increase, new dose does not exceed either one of the following (a or b):
       a. Tyvaso: 12 breaths per treatment session (72 mcg of treprostinil) four times daily to be used with the Tyvaso Inhalation System (a second back-up system device is recommended);
       b. Tyvaso DPI: 64 mcg per treatment session (1 cartridge) four times daily to be used with the Tyvaso DPI inhaler (256 mcg [4 cartridges] per day). Approval duration:
       Medicaid/HIM – 12 months
       Commercial – 12 months or duration of request, whichever is less C. Other diagnoses/indications (must meet 1 or 2):
13. 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

14. 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
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    Treprostinil FVC: forced vital capacity mPAP: mean pulmonary arterial pressure NYHA: New York Heart Association PA: physical ability PAH: pulmonary arterial hypertension PCWP: pulmonary capillary wedge pressure PH: pulmonary hypertension PVR: pulmonary vascular resistance WHO: World Health Organization WU: Wood Units 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®) Dose Limit/ Maximum Dose 240 mg/day 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 Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Orenitram: Severe hepatic impairment (Child Pugh Class C) • Boxed warnings(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 FC Heart Failure PA Limitations Tolerance of Physical Activity (PA) No limitation Ordinary PA does not cause undue dyspnea or fatigue, chest pain, or near syncope. I Comfortable at rest Monitoring for progression of PH and treatment of co- existing conditions Page 5 of 11

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    Treprostinil Treatment Approach FC Status at Rest II III IV Advanced treatment of PH with PH- targeted therapy – see Appendix F* Tolerance of Physical Activity (PA) Slight limitation Comfortable at rest Comfortable at rest Marked limitation Dyspnea or fatigue may be present at rest Inability to carry out any PA without symptoms PA Limitations Heart Failure 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 through vasodilation Prostacyclin pathway agonist Prostacyclin 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 Endothelin receptor antagonist (ETRA) Nitric oxide- cyclic guanosine Phosphodiesterase type 5 (PDE5) inhibitor Epoprostenol Veletri (IV) Flolan (IV) Flolan generic (IV) Treprostinil Orenitram (oral tablet) Remodulin (IV) Tyvaso, Tyvaso DPI (inhalation) Ventavis (inhalation) Uptravi (oral tablet) Iloprost Selexipag Ambrisentan Letairis (oral Bosentan Macitentan Sildenafil tablet) Tracleer (oral tablet) Opsumit (oral tablet) Revatio (IV, oral tablet, oral suspension) Page 6 of 11

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    Treprostinil Mechanism of Action Drug Class Drug Subclass Drug monophosphate enhancer Tadalafil Riociguat Guanylate cyclase stimulant (sGC) V. Dosage and Administration
    Drug Name Treprostinil (Orenitram) Treprostinil (Remodulin) Treprostinil (Tyvaso) Treprostinil (Tyvaso DPI) Dosing Regimen 0.25 mg PO BID or 0.125 mg PO TID; can be increased every 3-4 days as tolerated
    1.25 ng/kg/min SC or IV; can be increased weekly based on clinical response
    4 treatment sessions per day with 3 breaths (18 mcg) per treatment session, titrated up to 12 breaths (72 mcg) per treatment session 4 treatment sessions per day approximately 4 hours apart, during waking hours. Initial dosage: one 16 mcg cartridge per treatment sessions. Dosage should be increased by an additional 16 mcg per treatment session at approximately 1- to 2-week intervals, if tolerated. Titrate to a target maintenance dose of 48 mcg to 64 mcg per treatment, 4 times daily Brand/Generic Formulations Adcirca (oral tablet) Adempas (oral tablet) Maximum Dose Based on tolerability Based on weight and tolerability 72 mcg per treatment session (288 mcg/day) 64 mcg per treatment session (256 mcg/day) VI. Product Availability
    Drug Treprostinil (Orenitram) Treprostinil (Remodulin) Treprostinil (Tyvaso) Treprostinil
    (Tyvaso DPI) Availability
    Extended-release tablets: 0.125 mg, 0.25 mg, 1 mg, 2.5 mg, 5 mg 20 mL vials: 20 mg, 50 mg, 100 mg, 200 mg Solution for inhalation (ampule): 1.74 mg/2.9 mL Inhalation powder: single-dose plastic cartridges containing 16, 32, 48, or 64 mcg of treprostinil as a dry powder formulation
    VII.