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, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy ( see WARNINGS ), reserve opioid analgesics, including Levorphanol Tartrate Tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

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 an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient ( see WARNINGS, Addiction, Abuse, and Misuse ; Life-Threatening Respiratory Depression ; Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants ). Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 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, 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 , PRECAUTIONS ). Conversion from Other Opioids to Levorphanol Tartrate Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulatio…

WARNINGS Addiction, Abuse, and Misuse Levorphanol Tartrate Tablets contain levorphanol, a Schedule II controlled substance. As an opioid, Levorphanol Tartrate Tablets expose 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. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use ( see ADVERSE REACTIONS, Postmarketing Experience ). 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 recommending or prescribing an opioid overdose reversal agent ( see WARNINGS , DOSAGE AND ADMINISTRATION ). 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. 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 overdose reversal agents, 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 Tartrate Tablets. 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 …

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 ).

Drug Interactions Benzodiazepines and Other Central Nervous System (CNS) Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), and other opioids, 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 ). 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 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 concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent ( see WARNINGS , DOSAGE AND ADMINISTRATION ). Examples: Cyclobenzaprine, metaxalone. 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.

Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome ( see WARNINGS ). Available data with Levorphanol Tartrate Tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, oral levorphanol produced malformations and nearly 50% embryo lethality in mice at 10 and 12 times the human daily dose of 12 mg/day, respectively. Paternal exposure to levorphanol prior to mating to an untreated female resulted in reduced litter birth weights, developmental delays, and aberrant behavior in a swim maze at 34 times the human daily dose of 12 mg/day. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly ( see WARNINGS ). Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Levorphanol Tartrate Tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Levorphanol Tartrate Tablets can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Animal Data In a published study, levorphanol has been shown to cause central nervous system malformations consistent with neural tube defects (kinking of the spinal cord, hydromyelia, dilation of the fourth ventricle, and brachyury) in pregnant mice when given a single subcutaneous dose of 25 mg/kg (10 times the human daily dose of 12 mg/day based on a body surface area comparison) on Gestation Day 9. Subcutaneous administration of 30 mg/kg levorphanol to pregnant mice on Gestation Day 9 resulted in approximately 50% mortality of the mouse embryos (12 times the human daily dose of 12 mg/day). In another published study, male mice were injected subcutaneously twice daily with increasing daily doses of levorphanol up to 42 mg/kg/day (34 times the human daily dose of 12 mg based on body surface area) for 5.5 to 8.5 days prior to mating with an untreated female. Paternal exposure to levorphanol resulted in reduced birth weights of the litters, developmental delays in the offspring, and aberrant swim patterns in the progeny when measured at 6.5 to 8.5 weeks of age.

Lactation Risk Summary The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Levorphanol Tartrate Tablets and any potential adverse effects on the breastfed infant from Levorphanol Tartrate Tablets or from the underlying maternal condition. Clinical Considerations Infants exposed to Levorphanol Tartrate Tablets through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. Data Studies of levorphanol concentrations in breast milk have not been performed. However, morphine, which is structurally similar to levorphanol, is excreted in human milk. Because of the potential for serious adverse reactions from levorphanol in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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 of moderate-to-severe…