Morphine IR Hydromorphone IR Oxymorphone IR. Morphine IR, Dilaudid IR (hydromorphone), Opana IR (oxymorphone),

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1 Federal Employee Program 1310 G Street, N.W. Washington, D.C Fax Subject: Morphine IR Drug Class Page: 1 of 11 Last Review Date: December 8, 2017 Morphine IR Hydromorphone IR Oxymorphone IR Description Morphine IR, Dilaudid IR (hydromorphone), Opana IR (oxymorphone), Background Morphine sulfate immediate release (IR) and its derivatives hydromorphone immediate release (IR) (Dilaudid) and oxymorphone immediate release (IR) (Opana) are Schedule II narcotics prescribed to treat moderate to severe pain. Morphine produces both its therapeutic and adverse effects by interaction with one or more classes of specific opioid receptors located throughout the body. Morphine acts as a full agonist, binding with and activating opioid receptors at sites in brain and spinal cord. In addition to analgesia, the widely diverse effects of morphine include drowsiness, changes in mood, respiratory depression, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous system (1-3). Regulatory Status FDA-approved indications: Morphine sulfate IR, hydromorphone IR and oxymorphone IR are opioid agonists indicated for the relief of moderate to severe acute and chronic pain where an opioid is appropriate (1-3). Morphine sulfate IR and its derivatives hydromorphone IR (Dilaudid) and oxymorphone IR (Opana) have boxed warnings for the following (1-3): Respiratory depression is the chief hazard of opioid agonists, including morphine sulfate, which if not immediately recognized and treated, may lead to respiratory arrest and death. Risk is increased in patients receiving concurrent CNS depressants (including alcohol), patients with chronic obstructive pulmonary disease, orthostatic hypotension,

2 Subject: Morphine IR Drug Class Page: 2 of 11 increased intracranial pressure, biliary tract diseases, seizure disorders to reduce the risk of respiratory depression, proper dosing, titration, and monitoring are essential. All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prolonged use of opioid agonists during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening. Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Morphine sulfate and oxymorphone are contraindicated in patients with paralytic ileus (1-3). CDC guidelines find that concurrent use of benzodiazepines and opioids might put patients at greater risk for potentially fatal overdose. Three studies of fatal overdose deaths found evidence of concurrent benzodiazepine use in 31% 61% of decedents (4) CDC guidelines finds that given uncertain benefits and substantial risks that opioids should not be considered first-line or routine therapy for chronic pain (i.e., pain continuing or expected to continue longer than 3 months or past the time of normal tissue healing) outside of active cancer, palliative, and end-of-life care (4). The FDA warns that opioids can interact with antidepressants and migraine medicines to cause a serious central nervous system reaction called serotonin syndrome, in which high levels of the chemical serotonin build up in the brain and cause toxicity (see Appendix 1 for list of drugs) (5). The safety and effectiveness of morphine sulfate in pediatric patients below the age of 18 have not been established (1-3). Related policies Abstral, Actiq, Butrans, Duragesic, Extended Release Opioid Drugs, Fentanyl Powder, Fentora, Lazanda, Meperidine, Methadone, Nucynta IR, Onsolis, Oxycodone IR, Subsys, Tramadol Policy This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims.

3 Subject: Morphine IR Drug Class Page: 3 of 11 Morphine sulfate IR, hydromorphone IR and oxymorphone IR may be considered medically necessary in patients that are 18 years of age and older with moderate to severe pain and if the conditions below are met. Morphine sulfate IR, hydromorphone IR, and oxymorphone IR may be considered investigational in patients less than 18 years of age and for all other indications. Prior-Approval Requirements Prior authorization is not required if prescribed by an oncologist and/or the member has paid pharmacy claims for an oncology medication(s) in the past 6 months Age 18 years of age or older Diagnoses Patient must have ONE of the following: 1. Moderate to Severe Acute Pain (short term) a. Prescriber agrees to discontinue therapy after 30 days 2. Moderate to Severe Chronic Pain a. Prescriber agrees to assess the benefits of pain control (i.e. Care Plan signs of abuse, severity of pain) after 3 months of therapy AND ALL of the following for BOTH indications: a. NO dual therapy with other immediate release opioid analgesic(s) b. Alternative treatment options have been ineffective, not tolerated or inadequate for controlling the pain i. These include: non-opioid analgesics c. Prescriber agrees to assess patient for serotonin syndrome d. NO dual therapy with opioid addiction treatment or methadone e. NO dual therapy with an anti-anxiety benzodiazepine(s) i. Alprazolam (Xanax) ii. Clonazepam (Klonopin) iii. Diazepam (Valium) iv. Lorazepam (Ativan) v. Oxazepam (Serax) vi. Chlordiazepoxide (Librium)

4 Subject: Morphine IR Drug Class Page: 4 of 11 vii. Clorazepate dipotassium (Tranxene) Prior Approval Renewal Requirements Age 18 years of age or older Diagnoses Patient must have the following: 1. Moderate to severe Chronic pain AND ALL of the following: a. NO dual therapy with other immediate release opioid analgesic(s) b. Prescriber agrees to assess the benefits of pain control (i.e. Care Plan signs of abuse, severity of pain) after 3 months of therapy c. Prescriber agrees to assess patient for serotonin syndrome d. NO dual therapy with opioid addiction treatment or methadone e. NO dual therapy with an anti-anxiety benzodiazepine(s) i. Alprazolam (Xanax) ii. Clonazepam (Klonopin) iii. Diazepam (Valium) iv. Lorazepam (Ativan) v. Oxazepam (Serax) vi. Chlordiazepoxide (Librium) vii. Clorazepate dipotassium (Tranxene) Policy Guidelines Pre - PA Allowance Quantity Tablets & Suppositories Morphine sulfate tablets Morphine sulfate suppositories Oxymorphone tablets Hydromorphone tablets Hydromorphone suppositories 360 tablets per 90 days OR 360 suppositories per 90 days OR 360 tablets per 90 days OR 360 tablets per 90 days OR 360 suppositories per 90 days

5 Subject: Morphine IR Drug Class Page: 5 of 11 Solution Morphine sulfate oral soln 10 mg/5 ml Morphine sulfate oral soln 20 mg/5 ml Morphine sulfate (conc) oral soln 20 mg/ml (100 mg/5 ml) Hydromorphone liquid 1mg/mL 2700 ml per 90 days OR 2025 ml per 90 days OR 405 ml per 90 days OR 1800 ml per 90 days Prior - Approval Limits Quantity Acute Pain Morphine sulfate tab 15 mg Morphine sulfate tab 30 mg Morphine sulfate supp 5 mg Morphine sulfate supp 10 mg Morphine sulfate supp 15 mg Morphine sulfate supp 20 mg Morphine sulfate supp 30 mg Morphine sulfate oral soln 10 mg/5 ml Morphine sulfate oral soln 20 mg/5 ml Morphine sulfate (conc) oral soln 20 mg/ml (100 mg/5 ml) Quantity Limit for 30 days 1050 ml for 30 days OR 1050 ml for 30 days OR 540 ml for 30 days Oxymorphone tab 5 mg Oxymorphone tab 10 mg Quantity Limit for 30 days 150 tablets for 30 days

6 Subject: Morphine IR Drug Class Page: 6 of 11 Hydromorphone tab 2 mg Hydromorphone tab 4 mg Hydromorphone tab 8 mg Hydromorphone supp 3 mg Hydromorphone liquid 1mg/mL Quantity Limit for 30 days 900 ml for 30 days Duration 1 month Quantity Chronic Pain Morphine sulfate tab 15 mg Morphine sulfate tab 30 mg Morphine sulfate supp 5 mg Morphine sulfate supp 10 mg Morphine sulfate supp 15 mg Morphine sulfate supp 20 mg Morphine sulfate supp 30 mg Morphine sulfate oral soln 10 mg/5 ml Morphine sulfate oral soln 20 mg/5 ml Morphine sulfate (conc) oral soln 20 mg/ml (100 mg/5 ml) 4050 ml per 90 days OR 4050 ml per 90 days OR 810 ml per 90 days Oxymorphone tab 5 mg Oxymorphone tab 10 mg 540 tablets per 90 days

7 Subject: Morphine IR Drug Class Page: 7 of 11 Hydromorphone tab 2 mg Hydromorphone tab 4 mg Hydromorphone tab 8 mg Hydromorphone supp 3 mg Hydromorphone liquid 1mg/mL 450 tablets per 90 days OR 3600 ml per 90 days Duration 6 months Prior Approval Renewal Limits Quantity Chronic Pain Morphine sulfate tab 15 mg Morphine sulfate tab 30 mg Morphine sulfate supp 5 mg Morphine sulfate supp 10 mg Morphine sulfate supp 15 mg Morphine sulfate supp 20 mg Morphine sulfate supp 30 mg Morphine sulfate oral soln 10 mg/5 ml Morphine sulfate oral soln 20 mg/5 ml Morphine sulfate (conc) oral soln 20 mg/ml (100 mg/5 ml) 4050 ml per 90 days OR 4050 ml per 90 days OR 810 ml per 90 days Oxymorphone tab 5 mg Oxymorphone tab 10 mg 540 tablets per 90 days

8 Subject: Morphine IR Drug Class Page: 8 of 11 Hydromorphone tab 2 mg Hydromorphone tab 4 mg Hydromorphone tab 8 mg Hydromorphone supp 3 mg Hydromorphone liquid 1mg/mL 450 tablets per 90 days OR 3600 ml per 90 days Duration 6 months Rationale Summary Morphine sulfate IR and its derivatives hydromorphone (Dilaudid) and oxymorphone (Opana) are Schedule II narcotics prescribed to treat moderate to severe pain. In addition to analgesia, the widely diverse effects of morphine include drowsiness, changes in mood, respiratory depression, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous system. All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use (1-5). Prior approval is required to ensure the safe, clinically appropriate and cost effective use of morphine sulfate IR, hydromorphone IR and oxymorphone IR while maintaining optimal therapeutic outcomes. References 1. Dilaudid [package insert]. Whippany, NJ: Halo Pharmaceutical, Inc.; December Opana [package insert]. Malvern, PA: Endo Pharmaceuticals; December Morphine sulfate [package insert]. Columbus, OH: Roxane Laboratories, Inc.; December Dowell D, Haegerich T, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain. CDC Guidelines FDA Safety Release. FDA Drug Safety Communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. March 22, Policy History Date September 2014 Action Addition to PA

9 Subject: Morphine IR Drug Class Page: 9 of 11 June 2015 November 2015 March2016 September 2016 March 2017 June 2017 June 2017 September 2017 January 2018 Keywords Annual review Addition of Morphabond Annual editorial review and reference update Addition of not used in combination with any other long acting opioids to renewal section Policy code changed from to Annual review Addition of no dual therapy with other immediate release opioid analgesic(s); prescriber agrees to assess the benefits of pain control (i.e. Care Plan signs of abuse, severity of pain) after 3 months of therapy; prescriber agrees to assess patient for serotonin syndrome; no dual therapy with opioid addiction treatment; no dual therapy with any antianxiety benzodiazepines: alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), lorazepam (Ativan), oxazepam (Serax), chlordiazepoxide (Librium), clorazepate dipotassium (Tranxene). Change of the Standard Allowance limits to 360 tabs per 90 days Annual review and reference update Removal of Avinza and addition of Arymo ER Change in Morphabond maximum daily limit from 1200mg to 600mg Annual review Addition of no dual therapy with methadone Annual review Annual editorial review and reference update Removal of Oxycontin and Oxycodone ER and the revision of the quantity limits Addition of the Acute Pain indication and quantity limits This policy was approved by the FEP Pharmacy and Medical Policy Committee on December 8, 2017 and is effective on January 1, 2018.

10 Subject: Morphine IR Drug Class Page: 10 of 11 Appendix 1 - List of Serotonergic Medications Selective Serotonin Reuptake Inhibitors (SSRIs) paroxetine Paxil, Paxil CR, Pexeva, Brisdelle fluvoxamine Luvox, Luvox CR fluoxetine Prozac, Prozac Weekly, Sarafem, Selfemra, Symbyax sertraline Zoloft citalopram Celexa escitalopram Lexapro Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) venlafaxine Effexor XR desvenlafaxine Pristiq, Khedezla duloxetine Cymbalta milnacipran Savella Tricyclic Antidepressants (TCAs) amitriptyline No brand name currently marketed desipramine Norpramin clomipramine Anafranil imipramine Tofranil, Tofranil PM nortriptyline Pamelor, Aventyl protriptyline Vivactil doxepin Zonalon, Silenor trimipramine Surmontil Monoamine Oxidase Inhibitors (MAOIs) isocarboxazid Marplan phenelzine Nardil selegiline Emsam, Eldepryl, Zelapar tranylcypromine Parnate

11 Subject: Morphine IR Drug Class Page: 11 of 11 Other Psychiatric Medicines amoxapine No brand name currently marketed maprotiline No brand name currently marketed nefazodone No brand name currently marketed trazodone Oleptro buspirone No brand name currently marketed vilazodone Viibryd mirtazapine Remeron, Remeron Soltab lithium Lithobid Migraine Medicines almotriptan Axert frovatriptan Frova naratriptan Amerge rizatriptan Maxalt, Maxalt-MLT sumatriptan Imitrex, Imitrex Statdose, Alsuma, Sumavel Dosepro, Zecuity, Treximet zolmitriptan Zomig, Zomig-ZMT Antiemetics ondansetron granisetron dolasetron palonosetron Zofran, Zofran ODT, Zuplenz Kytril, Sancuso Anzemet Aloxi Other Serotonergic Medicines dextromethorphan linezolid cyclobenzaprine methylene blue St. John s wort tryptophan Bromfed-DM, Delsym, Mucinex DM, Nuedexta Zyvox Amrix