AKYNZEO IV, Fosnetupitant Choride-Palonosetron HCl AKYNZEO, Netupitant-Palonosetron Form

Netupitant/palonosetron (Akynzeo®) and fosnetupitant/palonosetron are fixed combination products of netupitant, a substance P/neurokinin 1 (NK1) receptor antagonist, and palonosetron hydrochloride, a serotonin (5-HT3) receptor antagonist.
FDA Approved Indication(s) Akynzeo capsules are indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Akynzeo for injection and Akynzeo injection are indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. • Limitation(s) of use: Akynzeo for injection and Akynzeo injection have not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy. 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 Akynzeo is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Prevention of Nausea and Vomiting Associated with Cancer Chemotherapy (must meet all):

1. Prescribed for the prevention of chemotherapy-induced nausea/vomiting;
2. Age ≥ 18 years;

3. Member is scheduled to receive moderately to highly emetogenic cancer chemotherapy (see Appendix D);

   4. Member meets one of the following (a or b): a. Both of the following (i and ii): i. Failure of a 5-HT3 receptor antagonist (ondansetron is preferred) at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced;
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   CLINICAL POLICY Netupitant/Palonosetron, Fosnetupitant/Palonosetron ii. Failure of an NK1 antagonist (aprepitant is preferred) at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced; *Prior authorization is required for aprepitant b. Request is for treatment associated with cancer for a State with regulations against step therapy in certain oncology settings (see Appendix E);

   5. Prescribed in combination with dexamethasone;
4. Dose does not exceed one of the following (a or b): a. Akynzeo capsules: netupitant 300 mg/palonosetron 0.5 mg (1 capsule) per chemotherapy cycle; b. Akynzeo for injection/Akynzeo injection: fosnetupitant 235 mg/palonosetron 0.25 mg (1 vial) per chemotherapy cycle. Approval duration: Projected course of chemotherapy B. Other diagnoses/indications (must meet 1 or 2):
   1. 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
   2. 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. Prevention of Nausea and Vomiting Associated with Cancer Chemotherapy (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);
6. Member is responding positively to therapy;

7. Prescribed in combination with dexamethasone; Page 2 of 9

   CLINICAL POLICY Netupitant/Palonosetron, Fosnetupitant/Palonosetron

   4. If request is for a dose increase, new dose does not exceed one of the following (a or b): a. Akynzeo capsules: netupitant 300 mg/palonosetron 0.5 mg (1 capsule) per chemotherapy cycle; b. Akynzeo for injection/Akynzeo injection: fosnetupitant 235 mg/palonosetron 0.25 mg (1 vial) per chemotherapy cycle. Approval duration: Projected course of chemotherapy
      B. Other diagnoses/indications (must meet 1 or 2):
   5. 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
   6. 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 5HT3: serotonin 5-hydroxytryptamine, type 3 FDA: Food and Drug Administration NCCN: National Comprehensive Cancer ASCO: American Society of Clinical Oncology
      Network
      NK1: neurokinin 1
      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.
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   CLINICAL POLICY Netupitant/Palonosetron, Fosnetupitant/Palonosetron Drug Name Dosing Regimen Dose Limit/ Maximum Dose 5-HT3 Serotonin Antagonists Aloxi® (palonosetron) Anzemet® (dolasetron) 0.25 mg IV given 30 min prior to chemotherapy 0.25 mg/day 100 mg PO within 1 hr prior to chemotherapy 100 mg/day
   PO: 2 mg/day PO IV: 10 mcg/kg/day PO: 24 mg/day
   IV: 16 mg/dose (up to 3 doses/day) granisetron (Kytril®) Tablet: 2 mg PO QD given 1 hr prior to chemotherapy, or 1 mg PO BID (one dose given 1 hr prior to chemotherapy and then 12 hours later) ondansetron (Zofran®, Zofran® ODT, Zuplenz®) Injection: 10 mcg/kg IV given within 30 min prior to chemotherapy (on days chemotherapy is given) Prevention of nausea and vomiting associated with moderately emetogenic chemotherapy Age 12 years or older: 8 mg PO given 30 min prior to chemotherapy, then repeat dose 8 hrs after initial dose, then 8 mg PO BID for 1 to 2 days after chemotherapy completion
   Age 4 to 11 years: 4 mg PO given 30 min prior to chemotherapy, then repeat dose 4 and 8 hrs after initial dose, then 8 mg PO TID for 1 to 2 days after chemotherapy completion Prevention of nausea and vomiting associated with highly emetogenic chemotherapy 24 mg PO given 30 min prior to start of single- day chemotherapy NK1 Antagonists aprepitant (Emend®) Emend® (fosaprepitant) Cinvanti® (aprepitant) Capsules: 125 mg PO on day 1 and 80 mg PO on days 2 and 3 Oral suspension: 3 mg/kg PO on Day 1, then 2 mg/kg PO on Days 2 and 3 150 mg IV on day 1 (for single dose chemo regimens) Day 1: 125 mg Days 2 and 3: 80 mg Day 1: 150 mg HEC or MEC (single-dose regimen): 130 mg IV on Day 1 Single-dose: 130 mg/dose MEC (3-day regimen): 100 mg IV on Day 1 3-day regimen: 100 mg/dose Page 4 of 9

   CLINICAL POLICY Netupitant/Palonosetron, Fosnetupitant/Palonosetron Drug Name Dosing Regimen Varubi ™ (rolapitant) 180 mg as a single dose 2 hours prior to the initiation of each chemotherapy, but at no less than 2 week intervals. Dose Limit/ Maximum Dose 180 mg Administer in combination with dexamethasone and a 5-HT3 receptor antagonist 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 None reported Appendix D: American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) Recommendations in Oncology • Minimal emetic risk chemotherapy: No routine prophylaxis is recommended. • Low emetic risk chemotherapy: Recommended options include dexamethasone (recommended by both ASCO and NCCN) or metoclopramide, prochlorperazine, or a 5- HT3 receptor antagonist (recommended by NCCN only). NK1 receptor antagonists are not included in low risk antiemetic recommendations. • Moderate emetic risk chemotherapy: 5-HT3 receptor antagonists and dexamethasone may be used in combination and with or without NK1 receptor antagonists. Olanzapine may also be used in combination with palonosetron and dexamethasone. o Examples of moderate emetic risk chemotherapy: bendamustine, carboplatin AUC < 4, carmustine ≤ 250 mg/m2, clofarabine, cyclophosphamide ≤ 1,500 mg/m2, cytarabine > 200 mg/m2, daunorubicin, doxorubicin < 60 mg/m2, epirubicin ≤ 90 mg/m2, idarubicin, ifosfamide < 2 g/m2 per dose, irinotecan, methotrexate ≥ 250 mg/m2, oxaliplatin • High emetic risk chemotherapy: NK1 receptor antagonists are recommended for use in combination with 5-HT3 receptor antagonists and dexamethasone. Olanzapine may also be used in combination with 5-HT3 receptor antagonists, dexamethasone, and/or NK1 receptor antagonists. o Examples of high emetic risk chemotherapy: carboplatin AUC ≥ 4, carmustine > 250 mg/m2, cisplatin, cyclophosphamide > 1,500 mg/m2, dacarbazine, doxorubicin ≥ 60 mg/m2, epirubicin > 90 mg/m2, fam-trastuzumab deruxtecan-nxki, ifosfamide ≥ 2 mg/m2 per dose, mechlorethamine, sacituzumab govitecan-hziy, streptozocin • Breakthrough emesis: Per NCCN, an agent from a different drug class is recommended to be added to the current antiemetic regimen. Drug classes include atypical antipsychotics (olanzapine), benzodiazepines (lorazepam), cannabinoids (dronabinol, nabilone), phenothiazines (prochlorperazine, promethazine), 5-HT3 receptor antagonists (dolasetron, ondansetron, granisetron), corticosteroids (dexamethasone), or haloperidol, metoclopramide, scopolamine. An NK1 receptor antagonist may be added to the prophylaxis regimen of the next chemotherapy cycle if not previously included. Page 5 of 9

   CLINICAL POLICY Netupitant/Palonosetron, Fosnetupitant/Palonosetron Appendix E: States with Regulations against Redirections in Certain Oncology Settings State Step Therapy Prohibited? Yes Yes FL GA IA LA NV OH PA TN TX Yes Yes Yes Yes Yes Yes Yes Notes For stage 4 metastatic cancer and associated conditions. For stage 4 metastatic cancer. Redirection does not refer to review of medical necessity or clinical appropriateness. For standard of care stage 4 cancer drug use, supported by peer- reviewed, evidence-based literature, and approved by FDA. For stage 4 advanced, metastatic cancer or associated conditions. Exception if “clinically equivalent therapy, contains identical active ingredient(s), and proven to have same efficacy. Stage 3 and stage 4 cancer patients for a prescription drug to treat
   the cancer or any symptom thereof of the covered person Applies to Commercial and HIM requests only For stage 4 metastatic cancer and associated conditions For stage 4 advanced, metastatic cancer For advanced metastatic cancer and associated conditions For stage 4 advanced, metastatic cancer and associated conditions V. Dosage and Administration
   Indication Prevention of chemotherapy- induced nausea and vomiting Dosing Regimen 1 capsule PO given 1 hr prior to chemotherapy on Day 1, in combination with dexamethasone or 1 vial infused IV over 30 minutes starting 30 minutes before chemotherapy on Day 1, in combination with dexamethasone Maximum Dose 1 capsule or 1 vial on Day 1 of chemotherapy cycle VI. Product Availability
   • Capsule: 300 mg netupitant/0.5 mg palonosetron
   • Single dose vial, powder for reconstitution: 235 mg fosnetupitant/0.25 mg palonosetron • Single dose vial, injection solution: 235 mg fosnetupitant/0.25 mg palonosetron per 20 mL o Ready-to-use (with hanger) o To-be-diluted VII.