Levorphanol

INDICATIONS AND USAGE Levorphanol Tartrate Tablets are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see WARNINGS ], reserve Levorphanol Tartrate Tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics): • Have not been tolerated or are not expected to be tolerated, • Have not provided adequate analgesia or are not expected to provide adequate analgesia Levorphanol Tartrate Tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

Mechanism of Action Levorphanol is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of levorphanol is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with levorphanol. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

DOSAGE AND ADMINISTRATION Important Dosage and Administration Instructions Levorphanol Tartrate Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see WARNINGS ]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Levorphanol Tartrate Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see WARNINGS ]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Levorphanol Tartrate Tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see WARNINGS ]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Levorphanol Tartrate Tablets [see WARNINGS, Life-Threatening Respiratory Depression ; PRECAUTIONS, Information for Patients ]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing regulations (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see WARNINGS, Addiction, Abuse, and Misuse ; Life-Threatening Respiratory Depression ; Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants ]. Consider prescribing naloxone when the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. Initial Dosage Use of Levorphanol Tartrate Tablets as the First Opioid Analgesic Initiate treatment with Levorphanol Tartrate Tablets in a dosing range of 1 to 2 mg every 6 to 8 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia, provided the patient is assessed for signs of hypoventilation and excessive sedation. Titrate the dose based upon the individual patient’s response to their initial dose of Levorphanol Tartrate Tablets. If necessary, the dose may be increased to up to 3 mg every 6 to 8 hours, after adequate evaluation of the patient’s response. Higher doses may be appropriate in opioid tolerant patients. Dosage should be adjusted according to the severity of the pain; age, weight and physical status of the patient; the patient’s underlying diseases; use of concomitant medications; and other factors [see CLINICAL PHARMACOLOGY; Individualization of Dosage , WARNINGS AND PRECAUTIONS ]. Conversion from Other Opioids to Levorphanol Tartrate Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations. Theref

ADVERSE REACTIONS In approximately 1400 patients treated with Levorphanol Tartrate Tablets in controlled clinical trials, the type and incidence of side effects were those expected of an opioid analgesic, and no unforeseen or unusual toxicity was reported. Drugs of this type are expected to produce a cluster of typical opioid effects in addition to analgesia, consisting of nausea, vomiting, altered mood and mentation, pruritus, flushing, difficulties in urination, constipation, and biliary spasm. The frequency and intensity of these effects appears to be dose related. Although listed as adverse events these are expected pharmacologic actions of these drugs and should be interpreted as such by the clinician. The following adverse events have been reported with the use of Levorphanol Tartrate Tablets: Body as a Whole: abdominal pain, dry mouth, sweating Cardiovascular System: cardiac arrest, shock, hypotension, arrhythmias including bradycardia and tachycardia, palpitations, extra-systoles Digestive System: nausea, vomiting, dyspepsia, biliary tract spasm Nervous System: coma, suicide attempt, convulsions, depression, dizziness, confusion, lethargy, abnormal dreams, abnormal thinking, nervousness, drug withdrawal, hypokinesia, dyskinesia, hyperkinesia, CNS stimulation, personality disorder, amnesia, insomnia Respiratory System: apnea, cyanosis, hypoventilation Skin & Appendages: pruritus, urticaria, rash, injection site reaction Special Senses: abnormal vision, pupillary disorder, diplopia Urogenital System: kidney failure, urinary retention, difficulty urinating Postmarketing Experience The following adverse reactions have been identified during post approval use of levorphanol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. • Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. • Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Levorphanol Tartrate Tablets. • Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see CLINICAL PHARMACOLOGY ]. • Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see WARNINGS ]. • Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with atleast one predisposing risk factor (e.g., diabetes).

WARNINGS Addiction, Abuse, and Misuse Levorphanol Tartrate Tablets contains levorphanol, a Schedule II controlled substance. As an opioid, Levorphanol Tartrate Tablets exposes users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Levorphanol Tartrate Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Levorphanol Tartrate Tablets, and reassess all patients receiving Levorphanol Tartrate Tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Levorphanol Tartrate Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Levorphanol Tartrate Tablets along with frequent reevaluation for signs of addiction, abuse and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose (see WARNINGS, Life-Threatening Respiratory Depression ; DOSAGE AND ADMINISTRATION, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose ). Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Levorphanol Tartrate Tablets. Strategies to reduce these risks include prescribing the drug in smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug [see PRECAUTIONS; Information for Patients ]. Contact local state professional licensing board or state- controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see OVERDOSAGE ]. Carbon dioxide (CO 2 ) retention from opioid induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Levorphanol Tartrate Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Levorphanol Tartrate Tablets are essential [see DOSAGE AND ADMINISTRATION ]. Overestimating the Levorphanol Tartrate Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of Levorphanol Tartrate Tablets, especially by children, can result in respiratory depression and death due to an overdose of levorphanol. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see PRECAUTIONS, Information for Patients ]. The initial dose of Levorphanol Tartrate Tablets should be reduced by 50% or more when the drug is given to patients with any condition affecting respiratory reserve or in conjunction with other drugs affecting the respiratory center. Subsequent doses should then be individually titrated accordi

CONTRAINDICATIONS Levorphanol Tartrate Tablets are contraindicated in patients with: • Significant respiratory depression [see WARNINGS ] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS ] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS ] • Hypersensitivity to levorphanol or any of the formulation excipients (e.g., anaphylaxis) [see WARNINGS ]

OVERDOSAGE Clinical Presentation Acute overdose with Levorphanol Tartrate Tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia an overdose situations. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patient and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to Levorphanol Tartrate Tablets overdose, administer an opioid antagonist. Because the duration of opioid reversal is expected to be less than the duration of action of levorphanol in Levorphanol Tartrate Tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.