Federal Employee Program 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 5.70.59 Subject: Levorphanol Page: 1 of 8 Last Review Date: March 16, 2018 Levorphanol Description Levorphanol Tartrate Background Levorphanol tartrate is a potent synthetic opioid analgesic for the management of moderate to severe pain where an opioid analgesic is appropriate. Levorphanol is 4 to 8 times as potent as morphine and has a longer half-life, which may have some advantages in the management of chronic pain. Because there is incomplete cross-tolerance among opioids, when converting a patient from morphine to levorphanol, the total daily dose of levorphanol should be approximately 1/15 to 1/12 of the total daily dose of oral morphine that the patient was receiving, and then the dose should be adjusted to the patient s clinical response. To avoid excessive sedation due to drug accumulation, adequate time should be allowed after each dose change (approximately 72 hours) if a patient is to be placed on a fixed-dosing schedule with this drug (1). Regulatory Status FDA-approved indication: Levorphanol Tartrate Tablets are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate (1). Limitations of Use: (1) Because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses, reserve Levorphanol Tartrate tablets for use in patients for whom alternative treatment options [e.g, non-opioid analgesics or opioid combination products]: Have not been tolerated, or are not expected to be tolerated,
Subject: Levorphanol Page: 2 of 8 Have not provided adequate analgesia, or are not expected to provide adequate analgesia The initial dose of levorphanol should be reduced by 50% or more in patients with conditions affecting their respiratory reserve or in patients taking other drugs that might affect their respiratory reserve. Subsequent doses can be titrated per patient response. Respiratory depression caused by levorphanol tartrate can be reversed by naloxone (1). Levorphanol tartrate carries several warnings regarding addiction, abuse, misuse, lifethreatening respiratory depression, accidental ingestion, neonatal opioid withdrawal syndrome, and concomitant use with benzodiazepines or other CNS depressants. (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 (2) 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 (2). 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) (3). Levorphanol is not recommended in pediatric patients below the age of 18 years as the safety and efficacy of the drug in this population has not been established (1). Related policies Abstral, Actiq, Butrans, Duragesic, Extended Release Opioid Drugs, Fentanyl Powder, Fentora, Lazanda, Levorphanol, Meperidine, Methadone, Morphine Drug Class, Nucynta, Onsolis, Opioid Powders, Opioid Step Policy, Oxycodone, Stadol, Suboxone Drug Class, Subsys, Tramadol
Subject: Levorphanol Page: 3 of 8 Policy This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims. Levorphanol may be considered medically necessary in patients that are 18 years of age and older with moderate to severe pain where an opioid analgesic is appropriate and if the conditions below are met. Levorphanol may be considered investigational in below 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 Diagnosis 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 analgesic(s), or opioid combination products 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 or methadone f. NO dual therapy with an anti-anxiety benzodiazepine(s) i. Alprazolam (Xanax) ii. Clonazepam (Klonopin) iii. Diazepam (Valium) iv. Lorazepam (Ativan)
Subject: Levorphanol Page: 4 of 8 v. Oxazepam (Serax) vi. Chlordiazepoxide (Librium) vii. Clorazepate dipotassium (Tranxene) AND ONE of the following: 1. Opioid naïve patient and opioid non-tolerant patient initiation therapy MUST start at 2mg every 6 to 8 hours as needed AND for no less than 7 days before changing to a higher dose OR 1. Opioid tolerant patient patients are considered opioid tolerant if they have been receiving, for one week or longer, at least one of the following: a. 60 mg oral morphine per day b. 25 mcg transdermal fentanyl per hour c. 30 mg oral oxycodone per day d. 8 mg oral hydromorphone per day e. 25 mg oral oxymorphone per day f. Or an equianalgesic dose of another opioid Prior Approval Renewal Requirements Age 18 years of age or older Diagnosis 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 or methadone e. NO dual therapy with an anti-anxiety benzodiazepine(s) i. Alprazolam (Xanax) ii. Clonazepam (Klonopin) iii. Diazepam (Valium)
Subject: Levorphanol Page: 5 of 8 Policy Guidelines Pre - PA Allowance None Prior - Approval Limits iv. Lorazepam (Ativan) v. Oxazepam (Serax) vi. Chlordiazepoxide (Librium) vii. Clorazepate dipotassium (Tranxene) Opioid naïve / opioid non-tolerant Quantity 2 mg 360 tablets per 90 days Duration 6 months Opioid tolerant Quantity 2 mg 540 tablets per 90 days Duration 6 months Prior Approval Renewal Limits Rationale Quantity 2 mg 540 tablets per 90 days Duration 6 months Summary Levorphanol tartrate is an opioid analgesic used for the management of pain severe enough to require opioid analgesic and for which alternative treatments are inadequate. The potential for developing substance abuse and addiction is extreme. Patients should be thoroughly assessed for their risk of developing severe respiratory depression, as well as substance abuse prior to being prescribed levorphanol and should be routinely monitored for signs of misuse, abuse and addiction during therapy. Levorphanol is not recommended in pediatric patients below the age of 18 years as the safety and efficacy of the drug in this population has not been established (1). Prior approval is required to ensure the safe, clinically appropriate and cost effective use of levorphanol while maintaining optimal therapeutic outcomes.
Subject: Levorphanol Page: 6 of 8 References 1. Levorphanol tartrate [package insert]. Solana Beach, CA: Sentynl Therapeutics, Inc.; December 2016. 2. Dowell D, Haegerich T, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain. CDC Guidelines 2016. Accessed on December 1, 2017. 3. FDA Safety Release. FDA Drug Safety Communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. March 22, 2016. Accessed on December 1, 2017. Policy History Date January 2017 March 2017 June 2017 September 2017 March 2018 Action Addition to PA Annual Review Addition of no dual therapy with methadone Annual review Annual editorial review and reference update Addition of prior authorization is not required if the member has paid pharmacy claims for an oncology medication(s) in the past 6 months Keywords This policy was approved by the FEP Pharmacy and Medical Policy Committee on March 16, 2018 and is effective on April 1, 2018.
Subject: Levorphanol Page: 7 of 8 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
Subject: Levorphanol Page: 8 of 8 Other Psychiatric Medicines amoxapine maprotiline nefazodone trazodone buspirone vilazodone mirtazapine lithium No brand name currently marketed No brand name currently marketed No brand name currently marketed Oleptro No brand name currently marketed Viibryd Remeron, Remeron Soltab 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