Levorphanol Tartrate

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.

DOSAGE AND ADMINISTRATION Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see WARNINGS ]. Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see WARNINGS ]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Levorphanol Tartrate Tablets and adjust the dosage accordingly [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, provided the patient is assessed for signs of hypoventilation and excessive sedation. 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 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. Therefore, a conservative approach is advised when determining the total daily dosage of Levorphanol Tartrate Tablets. It is safer to underestimate a patient's 24-hour Levorphanol Tartrate Tablets dosage than to overestimate the 24-hour Levorphanol Tartrate Tablets dosage and manage an adverse reaction due to overdose. The dosage of levorphanol in patients with cancer or with other conditions for which chronic opioid therapy is indicated must be individualized. Levorphanol is 4 to 8 times as potent as morphine and has a longer half-life. Because there is incomplete cross-tolerance among opioids, when converting a patient from morphine to levorphanol, the total daily dose of levorphanol should begin at approximately 1/15 to 1/12 of the total daily dose of oral morphine that such patients had previously required and then the dose should be adjusted to the patient's clinical response. If a patient is to be placed on fixed-schedule dosing (round-the-clock) with this drug, care should be taken to allow adequate time after each dose change (approximately 72 hours) for the patient to reach a new steady-state before a subsequent dose adjustm …

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 ]

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 at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see WARNINGS ] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: • approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview based measures …

Drug Interactions Benzodiazepines and Other Central Nervous System (CNS) Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, such as benzodiazepines, and other sedative hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), and other opioids, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see WARNINGS , DOSAGE AND ADMINISTRATION ]. Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome. [see PRECAUTIONS; Information for Patients/Caregivers ]. If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue levorphanol tartrate tablets if serotonin syndrome is suspected. Mixed Agonist/Antagonist and Partial Opioid Analgesics The concomitant use of opioid with other opioid analgesics, such as butorphanol, nalbuphine, pentazocine, may reduce the analgesic effect of levorphanol tartrate tablets and precipitate withdrawal symptoms. Advise patient to avoid concomitant use of these drugs. Muscle Relaxants (examples: cyclobenzaprine, metaxalone) Levorphanol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. If concomitant use is warranted, because respiratory depression may be greater than otherwise expected, decrease the dosage of levorphanol tartrate tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with the concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see WARNINGS, DOSAGE AND ADMINISTRATION ]. Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. If concomitant use is warranted, evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. If concomitant use is warranted, evaluate patients for signs of urinary retention or reduced gastric motility when levorphanol tartrate tablets are used concomitantly with anticholinergic drugs.

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.

DESCRIPTION Levorphanol tartrate tablets USP, contain levorphanol, an opioid agonist with a molecular formula of C 17 H 23 NO • C 4 H 6 O 6 • 2H 2 O and molecular weight 443.5. Each milligram of levorphanol tartrate is equivalent to 0.58 mg levorphanol base. Levorphanol's chemical name is levo-3-hydroxy-N-methylmorphinan. The USP nomenclature is 17- methylmorphinan 3-ol tartrate (1:1) (Salt) dihydrate. The material has 3 asymmetric carbon atoms. The chemical structure is: Levorphanol tartrate, USP is a white crystalline powder, soluble in water and ether, but insoluble in chloroform. Levorphanol tartrate tablets, USP, for oral administration, are available in two strengths: 2 mg tablet: white to off-white, flat face beveled edge tablet, bisect scored on one side and debossed with “762” on other side. 3 mg tablet: white to off-white, oval tablet, debossed with “058” on one side. In addition, each tablet contains microcrystalline cellulose, anhydrous lactose, pregelatinized starch, and magnesium stearate. structure

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 in overdose situations [see CLINICAL PHARMACOLOGY ] . Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent 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. For clinically significant respiratory or circulatory depression secondary to morphine overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. 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 overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product's prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the opioid overdose reversal agent 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 reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.

HOW SUPPLIED Levorphanol Tartrate Tablets, USP Dosage Strength Tablet Color Tablet Shape Tablet Debossing Tablet Scored NDC Number Pack Size 2 mg White to off-white Flat face beveled edge Bisect scored on one side and debossed with “762” on other side Yes 57664-762-88 Bottles of 100 3 mg White to off-white Oval Debossed with “058” on one side No 57664-058-88 Bottles of 100 Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure. Store levorphanol tartrate tablets securely and dispose of properly [see PRECAUTIONS, Information for Patients/Caregivers ]. Manufactured by: Ohm Laboratories Inc. New Brunswick, NJ Distributed by: Sun Pharmaceutical Industries, Inc., Cranbury, NJ 08512 Iss. 01/2026 5269277