Independent licensees of the Blue Cross and Blue Shield Association Medication Policy Manual Topic: High-Cost Antidepressant Medications: - amitriptyline (Elavil ) - bupropion hydrobromide (Aplenzin ) - bupropion HCL SR (Wellbutrin SR ) - bupropion XL (Forfivo XL, Wellbutrin XL ) - desvenlafaxine (Khedezla, Pristiq ) - escitalopram oxalate (Lexapro ) - levomilnacipran (Fetzima ) - milnacipran-containing medications (generic, Savella ) - sertraline (Zoloft ) - vilazodone (Viibryd ) - venlafaxine HCL ER (Effexor XR ) - vortioxetine (Brintellix, Trintellix ) Policy No: dru352 Date of Origin: May 9, 2014 Committee Approval Date: December 8, 2017 Next Review Date: December 2018 Effective Date: February 1, 2018 IMPORTANT REMINDER This Medication Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medication policy is to provide a guide to coverage. Medication Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Desvenlafaxine-containing medications (Khedezla, Pristiq ), levomilnacipran (Fetzima ), milnacipran-containing medications (generic, Savella ), vilazodone (Viibryd ), vortioxetine (Brintellix, Trintellix ), bupropion hydrobromide (Aplenzin ), and bupropion XL (Forfivo XL ) are oral medications used to treat major depressive disorder (MDD) and other mental health conditions. Many of these medications may also be used to treat other conditions such as neuropathic pain, fibromyalgia, and musculoskeletal pain. This policy also addresses certain high cost antidepressants in which comparable, yet lower cost, generic products are available. dru352.6 Page 1 of 9
Policy/Criteria I. Most contracts require pre-authorization approval of certain high cost antidepressants prior to coverage. High cost antidepressants may be considered medically necessary when criterion A or B below is met. A. Desvenlafaxine, levomilnacipran, milnacipran, vilazodone, vortioxetine, bupropion hydrobromide, and bupropion XL may be considered medically necessary when at least two low-cost generic/preferred medications (examples listed in Appendix 1) have been ineffective, not tolerated, or contraindicated. OR B. Antidepressants included in Table 1 may be considered medically necessary when there is an intolerance or contraindication to an inactive ingredient in all specified alternative(s) listed in Table 1. Table 1. High cost antidepressants with AB-rated alternatives High Cost Drug Effexor XR Elavil Lexapro Wellbutrin SR Wellbutrin XL Zoloft Alternative(s) venlafaxine HCL ER amitriptyline escitalopram oxalate bupropion HCL SR bupropion HCL XL sertraline HCL II. Administration, Quantity Limitations, and Authorization Period A. Regence pharmacy services considers all drugs in this policy to be selfadministered medications. B. Authorization may be reviewed at least annually to confirm that current medical necessity criteria are met and that the medication is effective. Position Statement - Desvenlafaxine, levomilnacipran, and milnacipran are in a class of medications called selective serotonin and norepinephrine reuptake inhibitors (SNRIs). There are low-cost generic treatment options (e.g. venlafaxine) available within the class. - Vortioxetine and vilazodone work by affecting the activity of serotonin in multiple ways, including by inhibiting its reuptake. There are many generically available antidepressants that exhibit their effects by interfering with serotonin activity, and are called selective serotonin reuptake inhibitors (SSRIs) (e.g. fluoxetine, paroxetine, sertraline). dru352.6 Page 2 of 9
- Bupropion hydrobromide and bupropion XL are in a class of medications called aminoketone antidepressants. There are generically available alternatives (e.g., bupropion hydrochloride SR and bupropion hydrochloride XL) available within the class. - High-cost antidepressant medications have not demonstrated superior efficacy, safety, or tolerability relative to generically available treatment options for the same condition. AB-rated generic products are lower cost and considered to be pharmaceutical equivalents of the branded products, with the same clinical effect and safety profile when administered to patients under the conditions specified in the package labelling. Patients who are adherent, yet do not respond to equivalent doses of the generic/otc product(s) are not likely to respond to the branded product. - Appendix 1 includes examples of numerous low-cost generically available treatment options for each diagnosis that desvenlafaxine, levomilnacipran, milnacipran, vilazodone, and vortioxetine are commonly used to treat. Clinical Efficacy - Many antidepressants have been approved for the treatment of mental health conditions other than depression, such as anxiety, obsessive-compulsive and panic disorders, social phobia, bulimia nervosa, and post-traumatic stress disorder (see Appendix 2). [1] Larger doses of each can improve the chances of response, though not in all cases. Additionally, the potential benefits of larger doses need to be weighed against the risk of side effects. For the majority of patients with these conditions, a low-cost generic antidepressant (e.g. SSRI, SNRI, bupropion) provide effective treatment. - SNRIs and other antidepressants such as tricyclic antidepressants (TCAs; e.g. amitriptyline) can be used on-label or off-label to treat some pain conditions including neuropathic pain, fibromyalgia, and musculoskeletal pain. * For the majority of patients with these conditions, low-cost generic SNRIs, TCAs, and other low-cost generic medications such as non-steroidal anti-inflammatory drugs (NSAIDs; e.g. ibuprofen, naproxen) or gabapentin provide effective treatment. MENTAL HEALTH CONDITIONS Depression [2-13] - SSRIs, SNRIs, and other antidepressants (e.g. bupropion, TCAs, mirtazapine) have been shown to improve symptoms of depression relative to placebo. - There is insufficient evidence to establish that any one antidepressant is safer or more effective overall than any other for the treatment of major depressive disorder. Generalized Anxiety Disorder (GAD) [14,15] - Antidepressants such as SSRIs (e.g. citalopram, fluoxetine, paroxetine, sertraline) and SNRIs (e.g. duloxetine, venlafaxine) have demonstrated efficacy in the treatment of GAD. - There is insufficient evidence to establish that any one antidepressant medication is superior in terms of efficacy, safety, or tolerability relative to any other for the treatment of GAD. dru352.6 Page 3 of 9
Posttraumatic Stress Disorder (PTSD) [16] - SSRIs are primary options in the treatment of PTSD. Paroxetine and sertraline have the largest body of evidence for the treatment of PTSD. - There is insufficient evidence to establish the comparative efficacy of antidepressant or any other treatment options for PTSD. Premenstrual Syndrome (PMS)/Premenstrual Dysphoric Disorder (PMDD) [17,18] - SSRIs are commonly used as front-line therapy for premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) because they have demonstrated efficacy in reducing symptoms. - There is insufficient evidence to establish the relative safety, efficacy, and tolerability of treatments for PMS and PMDD. Bulimia Nervosa [19] - Many antidepressants are recognized for their efficacy in treating bulimia nervosa, including fluoxetine, tricyclic antidepressants (imipramine, desipramine and amitriptyline), the monoamine oxidase inhibitor (MAOI) phenelzine (Nardil), and trazodone. - There are no proven differences in efficacy among these various antidepressants in treating bulimia nervosa. PAIN CONDITIONS Neuropathic Pain [20-25] - Antidepressants are effective for a variety neuropathic pain conditions caused by herpes infection or diabetes. These include tricyclic antidepressants (amitriptyline, desipramine) and SNRIs like duloxetine. - Other proven treatment options for neuropathic pain conditions include anticonvulsants (gabapentin, carbamazepine and phenytoin) and tramadol. - None of the SSRIs are recognized as effective in treating neuropathic pain symptoms. - There is insufficient evidence to establish overall differences in safety, efficacy, or tolerability among treatment options for neuropathic pain. Fibromyalgia [26-30] - Medications used for the treatment of fibromyalgia include cyclobenzaprine, duloxetine, gabapentin, and tricyclic antidepressants among others. - Non-medication therapies include aerobic exercise, muscle strengthening, patient education, and cognitive behavioral therapy. - There is insufficient evidence to establish the superiority of any one medication for treating fibromyalgia relative to other options. Chronic Musculoskeletal Pain - Medications used for the treatment of chronic musculoskeletal pain include centrallyacting analgesics such as tramadol or codeine, duloxetine, and non-steroidal antiinflammatory drugs (NSAIDs). - There is insufficient evidence to establish overall differences in safety, efficacy, or tolerability among treatment options for chronic musculoskeletal pain. dru352.6 Page 4 of 9
Safety [1] - All antidepressants carry risk of side effects. In general, the types of common adverse events reported are similar among antidepressants; however, the frequency and severity of adverse events may differ. - Sexual dysfunction is a common side effect among all antidepressants. * The incidence is reported as anywhere from 5% - 70%. The wide range of reported incidence is likely due to differences in how sexual dysfunction was measured. * Bupropion may have less potential for sexual sided effects, but an added risk is for elevating the seizure threshold at higher doses or in patients with history of seizures. - All antidepressants carry the boxed warning for suicidal thoughts in children, adolescents and young adults. - SNRIs are contraindicated for concomitant use with monoamine oxidase inhibitors (MAOIs) due to an increased risk of serotonin syndrome. Some are also contraindicated in patients with narrow-angle glaucoma. dru352.6 Page 5 of 9
Appendix 1: Lower-cost Generic Medication Alternatives Condition Mental Health Conditions including, but not limited to: - major depression - social anxiety disorder - generalized anxiety disorder - panic disorder - bulimia - post-traumatic stress disorder - premenstrual dysphoric disorder Lower-cost Generic Alternatives - citalopram (generic Celexa ) - duloxetine (generic Cymbalta ) - escitalopram (generic Lexapro ) - fluoxetine (generic Prozac ) - fluvoxamine (generic Luvox ) - paroxetine (generic Paxil ) - sertraline (generic Zoloft ) - bupropion SR/XL (generic Wellbutrin SR, Wellbutrin XL 300mg) - mirtazapine (generic Remeron ) - trazodone - venlafaxine (generic Effexor ) - venlafaxine SR tablets Neuropathic Pain - gabapentin (generic Neurontin ) - tricyclic antidepressants (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline) Fibromyalgia - gabapentin (generic Neurontin ) - tricyclic antidepressants (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline) - cyclobenzaprine (generic Flexeril ) Chronic Musculoskeletal Pain - generic prescription non-steroidal antiinflammatories (diclofenac, diflunisal, etodolac, fenoprofen*, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate*, meloxicam, nabumetone, oxaprozin*, piroxicam, sulindac, tolmetin) - generic prescription centrally-acting analgesics, alone or in combination (codeine, hydrocodone, morphine, meperidine, oxycodone, propoxyphene, tramadol) * Most contracts require pre-authorization approval prior to coverage. dru352.6 Page 6 of 9
Appendix 2: FDA-approved indications for selected antidepressants. [1] Indication Selective Serotonin Reuptake Inhibitors (SSRIs) citalopram fluoxetine fluvoxamine paroxetine sertraline Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) Pristiq duloxetine Savella Viibryd Miscellaneous bupropion SR bupropion XL Depression Generalized anxiety disorder mirtazapine Obsessivecompulsive disorder Panic disorder venlafaxine Premenstrual dysphoric disorder Posttraumatic stress disorder Social anxiety disorder Bulimia Nervosa Seasonal Affective Disorder Neuropathic pain Fibromyalgia Musculo-skeletal pain dru352.6 Page 7 of 9
Cross References Lyrica, pregabalin, Medication Policy Manual, Policy No. 122 High cost nonsteroidal anti-inflammatory drugs (NSAIDs), dru447 Codes Number Description N/A References 1. Micromedex Healthcare Series [Internet database]. [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. [cited Updated periodically.]. 2. Magni LR, Purgato M, Gastaldon C, et. al. Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database of Systematic Reviews. 2013;7:CD004185. 3. Cipriani, A, Brambilla, P, Furukawa, T, et al. Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev. 2005(4):CD004185. PMID: 16235353 4. Cipriani, A, Koesters, M, Furukawa, TA, et al. Duloxetine versus other anti-depressive agents for depression. Cochrane Database Syst Rev. 2012;10:CD006533. PMID: 23076926 5. Cipriani, A, La Ferla, T, Furukawa, TA, et al. Sertraline versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2010(4):CD006117. PMID: 20393946 6. Cipriani, A, Purgato, M, Furukawa, TA, et al. Citalopram versus other anti-depressive agents for depression. Cochrane Database Syst Rev. 2012;7:CD006534. PMID: 22786497 7. Omori, IM, Watanabe, N, Nakagawa, A, et al. Fluvoxamine versus other anti-depressive agents for depression. Cochrane Database Syst Rev. 2010(3):CD006114. PMID: 20238342 8. Watanabe, N, Omori, IM, Nakagawa, A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011(12):CD006528. PMID: 22161405 9. Santaguida, PL, MacQueen, G, Keshavarz, H, Levine, M, Beyene, J, Raina, P. Treatment for Depression After Unsatisfactory Response to SSRIs. 2012. PMID: 22696777 10. Arroll, B, Elley, CR, Fishman, T, et al. Antidepressants versus placebo for depression in primary care. Cochrane Database Syst Rev. 2009(3):CD007954. PMID: 19588448 11. Rush, AJ, Trivedi, MH, Wisniewski, SR, et al. Bupropion-SR, sertraline, or venlafaxine-xr after failure of SSRIs for depression. N Engl J Med. 2006;354:1231-42. PMID: 16554525 12. Trivedi, MH, Fava, M, Wisniewski, SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243-52. PMID: 16554526 13. Croft, HA, Pomara, N, Gommoll, C, Chen, D, Nunez, R, Mathews, M. Efficacy and safety of vilazodone in major depressive disorder: a randomized, double-blind, placebo-controlled trial. The Journal of clinical psychiatry. 2014 Nov;75(11):e1291-8. PMID: 25470094 14. Steffens, DC, Krishnan, KR, Helms, MJ. Are SSRIs better than TCAs? Comparison of SSRIs and TCAs: a meta-analysis. Depress Anxiety. 1997;6:10-8. PMID: 9394870 15. National Institute of Mental Health. CGI: Clinical Global Impressions. In: Guy W, Bonato RR, eds. Manual for the ECDEU Assessment Battery.2. Rev ed. Chevy Chase, MD: National Institute of Mental Health; 1970:12-1-12-6. 16. Stein, DJ, Ipser, JC, Seedat, S. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2006(1):CD002795. PMID: 16437445 17. Marjoribanks, J, Brown, J, O'Brien, PM, Wyatt, K. Selective serotonin reuptake inhibitors for premenstrual syndrome. Cochrane Database Syst Rev. 2013;6:CD001396. PMID: 23744611 18. Shah, NR, Jones, JB, Aperi, J, Shemtov, R, Karne, A, Borenstein, J. Selective serotonin reuptake inhibitors for premenstrual syndrome and premenstrual dysphoric disorder: a meta-analysis. Obstet Gynecol. 2008;111:1175-82. PMID: 18448752 dru352.6 Page 8 of 9
19. Bacaltchuk, J, Hay, P. Antidepressants versus placebo for people with bulimia nervosa. Cochrane Database Syst Rev. 2003(4):CD003391. PMID: 14583971 20. Saarto, T, Wiffen, PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007(4):CD005454. PMID: 17943857 21. Brannan, SK, Mallinckrodt, CH, Brown, EB, Wohlreich, MM, Watkin, JG, Schatzberg, AF. Duloxetine 60 mg once-daily in the treatment of painful physical symptoms in patients with major depressive disorder. J Psychiatr Res. 2005;39:43-53. PMID: 15504423 22. Goldstein, DJ, Lu, Y, Detke, MJ, Lee, TC, Iyengar, S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005;116:109-18. PMID: 15927394 23. Rowbotham, MC, Goli, V, Kunz, NR, Lei, D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110:697-706. PMID: 15288411 24. Harati, Y, Gooch, C, Swenson, M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998 Jun;50(6):1842-6. PMID: 9633738 25. Sindrup, SH, Andersen, G, Madsen, C, Smith, T, Brosen, K, Jensen, TS. Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain. 1999;83:85-90. PMID: 10506675 26. Goldenberg, DL, Burckhardt, C, Crofford, L. Management of fibromyalgia syndrome. JAMA. 2004;292:2388-95. PMID: 15547167 27. Arnold, LM, Goldenberg, DL, Stanford, SB, et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 2007 Apr;56(4):1336-44. PMID: 17393438 28. Russell, IJ, Mease, PJ, Smith, TR, et al. Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: Results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial. Pain. 2008;136:432-44. PMID: 18395345 29. Arnold, LM, Rosen, A, Pritchett, YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005;119:5-15. PMID: 16298061 30. Arnold, LM, Lu, Y, Crofford, LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004 Sep;50(9):2974-84. PMID: 15457467 Revision History Revision Date Revision Summary 12/08/2017 No criteria changes with this annual update 09/09/2016 Added Elavil and antidepressants that were previously included in dru420 (Effexor XR, Lexapro, Wellbutrin SR, Wellbutrin XR, Zoloft). Policies reorganized, no true criteria changes. 05/13/2016 Added bupropion hydrobromide (Aplenzin), bupropion XL (Forfivo XL), and generic milnacipran to the policy Updated alternatives in Appendix I 02/12/2016 Delete duloxetine (generic and brand) from the list of High-Cost Antidepressant Medications dru352.6 Page 9 of 9