Federal Employee Program 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 5.70.33 Subject: Morphine Drug Class Page: 1 of 13 Last Review Date: September 15, 2016 Morphine Sulfate Hydromorphone Oxymorphone Description Avinza, Kadian, Morphabond, MS Contin (Morphine sulfate extended release), morphine sulfate immediate release, Exalgo (hydromorphone extended release), Dilaudid (hydromorphone), Opana (oxymorphone), Opana ER (oxymorphone extended release) Background Morphine sulfate IR and ER (Avinza, MS Contin, Kadian, Morphabond) and its derivatives hydromorphone (Exalgo, Dilaudid) and oxymorphone (Opana and Opana ER) are Schedule II narcotics prescribed to treat moderate to severe pain (1-7). 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 (3). 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). Regulatory Status FDA-approved indications: Morphine sulfate, hydromorphone and oxymorphone are opioid agonists indicated for the relief of moderate to severe acute and chronic pain where an opioid is appropriate (1-9). Morphine sulfate extended-release (ER), hydromorphone (ER) and oxymorphone (ER) are opioid agonists indicated for the management of severe pain when a continuous, around-theclock opioid analgesic is needed for an extended period of time (1-9).
Subject: Morphine Drug Class Page: 2 of 13 Morphine sulfate IR and ER (Avinza, MS Contin, Kadian, Morphabond) and its derivatives hydromorphone (Exalgo, Dilaudid) and oxymorphone (Opana and Opana ER) have boxed warnings for the following (1-9): 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, 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. Patients should not consume alcohol or any products containing alcohol while taking. Morphine sulfate and oxymorphone are contraindicated in patients with paralytic ileus (1-9). Avoid use of Avinza in patients with other GI obstruction (1). The most common adverse reactions with Avinza include constipation, nausea, and somnolence (1). 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 (10) 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 (10). 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
Subject: Morphine Drug Class Page: 3 of 13 chemical serotonin build up in the brain and cause toxicity (see Appendix 1 for list of drugs) (11). The safety and effectiveness of morphine sulfate in pediatric patients below the age of 18 have not been established (1-9). Related policies Abstral, Actiq, Butrans Patch, Duragesic, Embeda, Fentanyl Powder, Fentora, Hysingla ER, Lazanda, Nucynta, Onsolis, Oxycodone, Subsys, Tramadol, Xartemis ER, Zohydro ER Policy This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims. Morphine sulfate, hydromorphone and oxymorphone may be considered medically necessary in patients that are 18 years of age and older with moderate to severe pain; no dual therapy with other immediate release opioid analgesic(s); alternative treatment options have been ineffective, not tolerated or inadequate for controlling the pain, these include: non-opioid analgesics; 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 an anti-anxiety benzodiazepine(s): alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), lorazepam (Ativan), oxazepam (Serax), chlordiazepoxide (Librium), clorazepate dipotassium (Tranxene). Morphine sulfate (ER), hydromorphone (ER)and oxymorphone (ER) may be considered medically necessary in patient that are 18 years of age and older requiring management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time; no dual therapy with other long acting opioid analgesic(s); alternative treatment options have been ineffective, not tolerated or inadequate for controlling the pain, these include: non-opioid analgesics and immediate release analgesics; 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 an anti-anxiety benzodiazepine(s): alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), lorazepam (Ativan), oxazepam (Serax), chlordiazepoxide (Librium), clorazepate dipotassium (Tranxene). Morphine sulfate and oxymorphone may be considered investigational in patients less than 18 years of age and for all other indications.
Subject: Morphine Drug Class Page: 4 of 13 Prior-Approval Requirements Prior authorization is not required if prescribed by an oncologist Age Diagnoses 18 years of age or older Morphine Sulfate IR, Hydromorphone IR and Oxymorphone IR Patient must have the following: 1. Moderate to severe pain AND ALL of the following: 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 the benefits of pain control (i.e. Care Plan signs of abuse, severity of pain) after 3 months of therapy d. Prescriber agrees to assess patient for serotonin syndrome e. NO dual therapy with opioid addiction treatment f. 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) Morphine Sulfate ER, Hydromorphone ER and Oxymorphone ER Patient must have the following: 1. Pain, severe enough to require daily, around-the clock long term opioid treatment AND ALL of the following:
Subject: Morphine Drug Class Page: 5 of 13 a. NO dual therapy with other long acting opioid analgesic(s) b. Alternative treatment options have been ineffective, not tolerated or inadequate for controlling the pain i. These include: non-opioid analgesics and immediate release analgesics c. Prescriber agrees to assess the benefits of pain control (i.e. Care Plan signs of abuse, severity of pain) after 3 months of therapy d. Prescriber agrees to assess patient for serotonin syndrome e. NO dual therapy with opioid addiction treatment f. 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) Prior Approval Renewal Requirements Age 18 years of age or older Diagnoses Morphine Sulfate IR, Hydromorphone IR and Oxymorphone IR Patient must have the following: 1. Moderate to severe 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 e. NO dual therapy with an anti-anxiety benzodiazepine(s)
Subject: Morphine Drug Class Page: 6 of 13 i. Alprazolam (Xanax) ii. Clonazepam (Klonopin) iii. Diazepam (Valium) iv. Lorazepam (Ativan) v. Oxazepam (Serax) vi. Chlordiazepoxide (Librium) vii. Clorazepate dipotassium (Tranxene) Morphine Sulfate ER, Hydromorphone ER and Oxymorphone ER Patient must have the following: 1. Pain, severe enough to require daily, around-the clock long term opioid treatment AND ALL of the following: a. NO dual therapy with other long acting 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 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 Immediate-release Formulations Morphine sulfate (IR) 360 tablets per 90 days
Subject: Morphine Drug Class Page: 7 of 13 Opana (oxymorphone) IR Dilaudid (hydromorphone) IR Extended-release Formulations Avinza (morphine sulfate ER) Kadian (morphine sulfate ER) MS Contin (morphine sulfate ER) Morphabond Exalgo (hydromorphone ER) Opana (oxymorphone) ER 360 tablets per 90 days Prior - Approval Limits Quantity Immediate-release Formulations Morphine sulfate 15mg (IR) 900 tablets per 90 days OR Morphine sulfate 30mg (IR) 540 tablets per 90 days Maximum daily limit of any combination: 180mg Opana 5mg (Oxymorphone) (IR) 900 tablets per 90 days OR Opana 10mg (Oxymorphone) (IR) 720 tablets per 90 days OR Maximum daily limit of any combination: 80mg Dilaudid 2mg (Hydromorphone) (IR) 900 tablets per 90 days OR Dilaudid 4mg (Hydromorphone) (IR) 900 tablets per 90 days OR Dilaudid 8mg (Hydromorphone) (IR) 810 tablets per 90 days OR Maximum daily limit of any combination: 72mg OR Extended-release Formulations Avinza 30 mg (Morphine sulfate) Avinza 45 mg (Morphine sulfate) 1080 capsules per 90 days OR 1080 capsules per 90 days OR
Subject: Morphine Drug Class Page: 8 of 13 Avinza 60 mg (Morphine sulfate) 1080 capsules per 90 days OR Avinza 75 mg (Morphine sulfate) 1080 capsules per 90 days OR Avinza 90 mg (Morphine sulfate) 1080 capsules per 90 days OR Avinza 120 mg (Morphine sulfate) 1080 capsules per 90 days OR Maximum daily limit of any combination: 1600mg Exalgo 8mg (Hydromorphone) 900 tablets per 90 days OR Exalgo 12mg (Hydromorphone) 900 tablets per 90 days OR Exalgo 16mg (Hydromorphone) 720 tablets per 90 days OR Exalgo 32mg (Hydromorphone) 360 tablets per 90 days OR Maximum daily limit of any combination: 128mg Kadian 10mg (Morphine sulfate) 900 capsules per 90 days OR Kadian 20mg (Morphine sulfate) 900 capsules per 90 days OR Kadian 30mg (Morphine sulfate) 900 capsules per 90 days OR Kadian 40mg (Morphine sulfate) 900 capsules per 90 days OR Kadian 50mg (Morphine sulfate) 900 capsules per 90 days OR Kadian 60mg (Morphine sulfate) 900 capsules per 90 days OR Kadian 80mg (Morphine sulfate) 900 capsules per 90 days OR Kadian 100mg (Morphine sulfate) 900 capsules per 90 days OR Kadian 200mg (Morphine sulfate) 540 capsules per 90 days Maximum daily limit of any combination: 1200mg MS Contin 15mg (Morphine sulfate) 900 tablets per 90 days OR MS Contin 30mg (Morphine sulfate) 900 tablets per 90 days OR MS Contin 60mg (Morphine sulfate) 900 tablets per 90 days OR MS Contin 100mg (Morphine sulfate) 900 tablets per 90 days OR MS Contin 200mg (Morphine sulfate) 540 tablets per 90 days Maximum daily limit of any combination: 1200mg Morphabond 15mg (Morphine sulfate) 900 tablets per 90 days OR Morphabond 30mg (Morphine sulfate) 900 tablets per 90 days OR Morphabond 60mg (Morphine sulfate) 900 tablets per 90 days OR Morphabond 100mg (Morphine sulfate) 900 tablets per 90 days Maximum daily limit of any combination: 1200mg - Opana ER 5mg (Oxymorphone) 900 tablets per 90 days OR Opana ER 7.5mg (Oxymorphone) 900 tablets per 90 days OR
Subject: Morphine Drug Class Page: 9 of 13 Opana ER 10mg (Oxymorphone) 900 tablets per 90 days OR Opana ER 15mg (Oxymorphone) 900 tablets per 90 days OR Opana ER 20mg (Oxymorphone) 900 tablets per 90 days OR Opana ER 30mg (Oxymorphone) 540 tablets per 90 days Opana ER 40mg (Oxymorphone) 450 tablets per 90 days OR Maximum daily limit of any combination: 200mg Duration 6 months Prior Approval Renewal Limits Same as above Rationale Summary Morphine sulfate IR and ER (Avinza, MS Contin, Kadian, Morphabond) and its derivatives hydromorphone (Exalgo, Dilaudid) and oxymorphone (Opana and Opana ER) are Schedule II narcotics prescribed to treat moderate to severe pain (1-7). 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 (1-7). Prior approval is required to ensure the safe, clinically appropriate and cost effective use of morphine sulfate IR/ER, hydromorphone IR/ER and oxymorphone IR/ER while maintaining optimal therapeutic outcomes. References 1. Avinza [package insert]. Bristol, TN: King Pharmaceuticals; April 2014 2. Dilaudid [package insert]. Whippany, NJ: Halo Pharmaceutical, Inc.; June 2013 3. Exalgo [package insert]. Hazelwood, MO: Mallinckrodt Brand Pharmaceuticals, Inc.; April 2014 4. MS Contin [package insert]. Stamford, CT: Purdue Pharma L.P.; April 2014 5. Kadian [package insert]. Morristown, NJ: Actavis Elizabeth LLC; April 2014 6. Opana [package insert]. Malvern, PA: Endo Pharmaceuticals; April 2014 7. Opana ER [package insert]. Chadds Ford, PA: Endo Pharmaceuticals; April 2014
Subject: Morphine Drug Class Page: 10 of 13 8. Morphine sulfate [package insert]. Columbus, OH: Roxane Laboratories, Inc.; January 2012 9. Morphabond [package insert]. Valley Cottage, NY: Inspirion Delivery Technologies LLC; October 2015 10. Dowell D, Haegerich T, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain. CDC Guidelines 2016 11. FDA Safety Release. FDA Drug Safety Communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. March 22, 2016. Policy History Date September 2014 June 2015 November 2015 March2016 September 2016 Action Addition to PA 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 5.02.33 to 5.70.33 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 an antianxiety benzodiazepine(s): 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 Keywords This policy was approved by the FEP Pharmacy and Medical Policy Committee on September 15, 2016 and is effective on October 1, 2016.
Subject: Morphine Drug Class Page: 11 of 13 Deborah M. Smith, MD, MPH
Subject: Morphine Drug Class Page: 12 of 13 Appendex 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
Subject: Morphine Drug Class Page: 13 of 13 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 llthium 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