SAVELLA, Milnacipran HCl Form

Milnacipran (Savella®) is a selective serotonin and norepinephrine reuptake inhibitor (SNRI).
FDA Approved Indication(s) Savella is indicated for the management of fibromyalgia. Savella is not approved for use in pediatric patients. 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 Savella is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Fibromyalgia (must meet all):

1. Diagnosis of fibromyalgia;
2. Age ≥ 18 years;
3. Member meets one of the following (a or b):
   a. Failure of a 30-day trial of duloxetine at up to maximally indicated doses in the last 180 days; b. Member has contraindication or intolerance to duloxetine, and failure of a 30-day trial of any tricyclic antidepressant (TCA) or cyclobenzaprine at up to maximally indicated doses in the last 180 days, unless clinically significant adverse effects are experienced, member’s age is ≥ 65 years, or all agents are contraindicated;
   4. Dose does not exceed both (a and b): a. 200 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. Depression (off-label) (must meet all):
   5. Diagnosis of depression;

4. Age ≥ 18 years; Page 1 of 7

   CLINICAL POLICY Milnacipran

   3. Failure of a ≥ 4-week trial of one selective serotonin reuptake inhibitor (SSRI) at up to maximally indicated doses unless contraindicated or clinically significant adverse effects are experienced;
   4. Failure of two SNRIs at up to maximally indicated doses, each used for ≥ 4 weeks, unless clinically significant adverse effects are experienced or all are contraindicated;
   5. Failure of a ≥ 4-week trial of another generic antidepressant (e.g., bupropion, TCA, mirtazapine, etc.) at up to maximally indicated doses, unless clinically significant adverse effects are experienced or all are contraindicated;
   6. Dose does not exceed both (a and b): a. 200 mg per day; b. 2 tablets 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):
   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.
      II. Continued Therapy A. All Indications in Section I (must meet all):
   9. 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);
5. Member is responding positively to therapy;

6. If request is for a dose increase, new dose does not exceed both (a and b): a. 200 mg per day; b. 2 tablets per day. Approval duration:
   Page 2 of 7

   CLINICAL POLICY Milnacipran Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less
   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.
      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 FDA: Food and Drug Administration MAOI: monoamine oxidase inhibitor
      SNRI: selective serotonin and norepinephrine reuptake inhibitor SSRI: selective serotonin reuptake inhibitor TCA: tricyclic antidepressant
      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.
      Drug Name Dosing Regimen Dose Limit/ Maximum Dose 150 mg/day 150 mg/day amitriptyline (Elavil®) nortriptyline (Pamelor®) Fibromyalgia: 10 mg to 50 mg PO once daily Depression: 50-100 mg PO daily Depression: 75-100 mg PO either once daily or in divided doses Page 3 of 7

   CLINICAL POLICY Milnacipran Drug Name Dosing Regimen Dose Limit/ Maximum Dose Fibromyalgia: 25 mg to 50 mg PO once daily Fibromyalgia: 10 mg PO every morning and 20 mg at bedtime Depression: 100 mg PO three times daily 450 mg/day 400 mg/day Depression: 150 mg PO twice daily 30 mg/day Depression: 150-450 mg PO once daily 450 mg/day Depression: 20-40 mg PO once daily Depression: 50 mg PO once daily 40 mg/day 400 mg/day cyclobenzaprine (Flexeril®) bupropion (Wellbutrin®) bupropion SR (Wellbutrin SR®) bupropion XL (Wellbutrin XL®) citalopram (Celexa®) desvenlafaxine succinate (Pristiq®, Khedezla®) duloxetine (Cymbalta®)
   escitalopram (Lexapro®) fluoxetine (Prozac®) fluvoxamine (Luvox®) Fibromyalgia: 60 mg PO once daily Depression: 20 mg PO twice daily Depression: 10 mg PO once daily Depression: 20 mg PO once daily Depression (off-label): 50 mg PO once daily mirtazapine (Remeron®) Depression: 15 mg PO once daily paroxetine (Paxil®)
   Depression: 20 mg PO once daily paroxetine SR (Paxil CR®) Depression: 25 mg PO once daily sertraline (Zoloft®) Depression: 50 mg PO once daily venlafaxine( Effexor®) Depression:75 mg PO twice daily Depression: 37.5 mg PO once daily venlafaxine SR (Effexor XR®) doxepin (Sinequan®) imipramine (Tofranil®)
   trazodone (Desyrel®) Depression: 75 mg PO daily Depression: 75 mg PO daily Depression: 150mg PO in divided doses daily 60 mg/day 20 mg/day 80 mg/day 300 mg/day 45 mg/day 50 mg/day 62.5 mg/day 200 mg/day 375 mg/day 225 mg/day 300 mg/day 200 mg/day 400 mg/day 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 use or use within 14 days of discontinuing a monoamine oxidase inhibitor (MAOI) used to treat psychiatric disorders, use of an MAOI within 5 days of discontinuing Savella, initiation of Savella in patients currently treated with linezolid or IV methylene blue due to increased risk of serotonin syndrome. • Boxed warning(s): increased risk of suicidal ideation, thinking, and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder (MDD) and other psychiatric disorders
   Appendix D: General Information
   • Class IIb recommendation in Micromedex for the treatment of depression.
   Page 4 of 7

   CLINICAL POLICY Milnacipran • Use of MAOI with Savella concomitantly is contraindicated due to the risk of serious, sometimes, fatal, drug interactions with serotonergic drugs. These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Allow at least 14 days after stopping an MAOI before starting Savella. Allow at least 5 days after stopping Savella before starting an MAOI. • Savella should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Savella may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. • Serotonin syndrome: Serotonin syndrome has been reported with SNRIs and SSRIs. Concomitant use of serotonergic drugs is not recommended.
   V. Dosage and Administration
   Indication Fibromyalgia Based on efficacy and tolerability, PO dosing may be Dosing Regimen titrated according to the following schedule:
   Day 1: 12.5 mg once
   Days 2-3: 25 mg/day (12.5 mg twice daily)
   Days 4-7: 50 mg/day (25 mg twice daily)
   After Day 7: 100 mg/day (50 mg twice daily) Maximum Dose 200 mg/day (100 mg twice daily) Depression (off-label) Recommended dose is 100 mg/day PO (50 mg twice daily) Initially, 12.5 to 25 mg PO twice daily. Based on individual response, the dose may be titrated to 100 mg PO twice daily 200 mg/day (100 mg twice daily) VI. Product Availability
   Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg VII.