Levorphanol Tartrate Tablet
FDA Label NDC 0406-2224

Addiction, Abuse, and Misuse
Levorphanol Tartrate Tablets expose patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing Levorphanol Tartrate Tablets, and monitor all patients regularly for the development of these behaviors and conditions (see WARNINGS).

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse,
the Food and Drug Administration (FDA) has required a REMS for these products (see WARNINGS).
Under the requirements of the REMS, drug companies with approved opioid analgesic products
must make REMS-compliant education programs available to healthcare providers. Healthcare
providers are strongly encouraged to

• Complete a REMS-compliant education program,
• counsel patients and/or their caregivers, with every prescription, on safe use, serious risks,
  storage, and disposal of these products,
• emphasize to patients and their caregivers the importance of reading the Medication Guide every
  time it is provided by their pharmacist, and
• consider other tools to improve patient, household, and community safety.

Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of Levorphanol Tartrate Tablets. Monitor for respiratory depression, especially during initiation of Levorphanol Tartrate Tablets or following a dose increase (see WARNINGS).

Accidental Ingestion
Accidental ingestion of Levorphanol Tartrate Tablets, especially by children, can result in a fatal overdose of Levorphanol Tartrate Tablets (see WARNINGS).

Neonatal Opioid Withdrawal Syndrome
Prolonged use of Levorphanol Tartrate Tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see WARNINGS).

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (see WARNINGS).

• Reserve concomitant prescribing of Levorphanol Tartrate Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

Levorphanol Tartrate Tablets contain levorphanol, an opioid agonist with a molecular formula of

C₁₇H₂₃NO • C₄H₆O₆ • 2H₂O 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:

Chemical Structure (Levorphanol Tartrate Tablets 1)

Levorphanol tartrate is a white crystalline powder, soluble in water and ether, but insoluble in chloroform.

Levorphanol Tartrate Tablets, for oral administration, is available in one strength, distinguishable by the shape, size and debossing on the tablet surface:

2 mg tablet: white to off white, round, flat faced tablet, debossed logo “M” inside square on one side and a score on the opposite side of the tablet.

In addition, each tablet contains lactose anhydrous, pregelatinized corn starch, and magnesium stearate.

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.

The principal therapeutic action of levorphanol is analgesia.

Levorphanol produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide retention and electrical stimulation.

Levorphanol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Levorphanol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Levorphanol produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans (see ADVERSE REACTIONS). They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date (see ADVERSE REACTIONS).

Opioids have been shown to have a variety of effects on components of the immune system. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of levorphanol for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance (see DOSAGE AND ADMINISTRATION).

There is a relationship between increasing levorphanol plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions (see DOSAGE AND ADMINISTRATION).

The pharmacokinetics of levorphanol have been studied in a limited number of cancer patients following intravenous (IV), intramuscular (IM) and oral (PO) administration. Following IV administration plasma concentrations of levorphanol decline in a triexponential manner with a terminal half-life of 11 to 16 hours and a clearance of 0.78 to 1.1 L/kg/hr. Based on terminal half-life, steady-state plasma concentrations should be achieved by the third day of dosing.

Levorphanol is rapidly distributed (<1 hr) and redistributed (1 to 2 hours) following IV administration and has a steady-state volume of distribution of 10 to 13 L/kg. In vitro studies of protein binding indicate that levorphanol is only 40% bound to plasma proteins.

No pharmacokinetic studies of the absorption of IM levorphanol are available, but clinical data suggests that absorption is rapid with onset of effects within 15 to 30 minutes of administration.

Levorphanol is well absorbed after PO administration with peak plasma concentrations occurring approximately 1 hour after dosing. The bioavailability of Levorphanol Tartrate Tablets compared to IM or IV administration is not known.

Plasma concentrations of levorphanol following chronic administration in patients with cancer increased with the dose, but the analgesic effect was dependent on the degree of opioid tolerance of the patient. Expected steady-state plasma concentrations for a 6-hour dosing interval can reach 2 to 5 times those following a single dose, depending on the patient's individual clearance of the drug. Very high plasma concentrations of levorphanol can be reached in patients on chronic therapy due to the long half-life of the drug. One study in 11 patients using the drug for control of cancer pain reported plasma concentrations from 5 to 10 ng/mL after a single 2 mg dose and up to 50 to 100 ng/mL after repeated oral doses of 20 to 50 mg/day.

Animal studies suggest that levorphanol is extensively metabolized in the liver and is eliminated as the glucuronide metabolite. This renally excreted inactive glucuronide metabolite accumulates with chronic dosing in plasma at concentrations that reach fivefold that of the parent compound.

The effects of age, sex, hepatic and renal disease on the pharmacokinetics of levorphanol are not known. As with all drugs of this class, patients at the extremes of age are expected to be more susceptible to adverse effects because of a greater pharmacodynamic sensitivity and probable increased variability in pharmacokinetics due to age or disease.

Clinical trials have been reported in the medical literature that investigated the use of Levorphanol Tartrate Tablets as a preoperative medication, as a postoperative analgesic, and in the management of chronic pain due primarily to malignancy. In each of these clinical settings Levorphanol Tartrate Tablets have been shown to be an effective analgesic of the mu-opioid type and similar to morphine, meperidine, or fentanyl.

Levorphanol Tartrate Tablets have been studied in chronic cancer patients. Dosages were individualized to each patient's level of opioid tolerance. In one study, starting doses of 2 mg twice a day often had to be advanced by 50% or more within a few weeks of starting therapy. A study of Levorphanol Tartrate Tablets indicates that the relative potency is approximately 4 to 8 times that of morphine, depending on the specific circumstances of use. In postoperative patients, intramuscular levorphanol was determined to be about 8 times as potent as intramuscular morphine, whereas in cancer patients with chronic pain, it was found to be only about 4 times as potent.

Accepted medical practice dictates that the dose of any opioid analgesic be appropriate to the degree of pain to be relieved, the clinical setting, the physical condition of the patient, and the kind and dose of concurrent medication.

Levorphanol has a long half-life similar to methadone or other slowly excreted opioids, rather than quickly excreted agents such as morphine or meperidine. Slowly excreted drugs may have some advantages in the management of chronic pain. Unfortunately, the duration of pain relief after a single dose of a slowly excreted opioid cannot always be predicted from pharmacokinetic principles, and the inter-dose interval may have to be adjusted to suit the patient's individual pharmacodynamic response.

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 oral 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 adjustment to avoid excessive sedation due to drug accumulation.

Levorphanol Tartrate Tablets are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses (see WARNINGS), 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,
• Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

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).

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.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Levorphanol Tartrate Tablets, and monitor 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 intensive monitoring for signs of addiction, abuse and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. 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 the 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.

Inform patients that the use of Levorphanol Tartrate Tablets even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death (see WARNINGS). Instruct patients not to share Levorphanol Tartrate Tablets with others and to take steps to protect Levorphanol Tartrate Tablets from theft or misuse.

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

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 (CO₂) 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. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Levorphanol Tartrate Tablets.

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 Levorphanol Tartrate Tablets, especially by children, can result in respiratory depression and death due to an overdose of Levorphanol Tartrate Tablets.

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 according to the patient's response.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper (see DOSAGE AND ADMINISTRATION).

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Levorphanol Tartrate Tablets or when the dosage is increased, and that it can occur even at recommended dosages (see WARNINGS). Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Prolonged use of Levorphanol Tartrate Tablets during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see PRECAUTIONS, Information for Patients, Pregnancy).

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Levorphanol Tartrate Tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see PRECAUTIONS, Drug Interactions).

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Levorphanol Tartrate Tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see PRECAUTIONS, Information for Patients, Drug Interactions).

The use of Levorphanol Tartrate Tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms (see WARNINGS).

The use of Levorphanol Tartrate Tablets in acute myocardial infarction or in cardiac patients with myocardial dysfunction or coronary insufficiency should be limited because the effects of Levorphanol Tartrate Tablets on the work of the heart are unknown.

Levorphanol Tartrate Tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) (see PRECAUTIONS, Drug Interactions). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Levorphanol Tartrate Tablets. In patients with circulatory shock Levorphanol Tartrate Tablets may cause vasodilatation that can further reduce cardiac output and blood pressure. Avoid the use of Levorphanol Tartrate Tablets with circulatory shock.

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Levorphanol Tartrate Tablets may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Levorphanol Tartrate Tablets.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Levorphanol Tartrate Tablets in patients with impaired consciousness or coma.

Levorphanol Tartrate Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The levorphanol in Levorphanol Tartrate Tablets may cause spasm of the sphincter of Oddi. Levorphanol Tartrate Tablets have been shown to cause moderate to marked rises in pressure in the common bile duct when given in analgesic doses. It is not recommended for use in biliary surgery. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

The levorphanol in Levorphanol Tartrate Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Levorphanol Tartrate Tablets therapy.

Do not abruptly discontinue Levorphanol in a patient physically dependent on opioids. When discontinuing Levorphanol in a physically dependent patient, gradually taper the dosage. Rapid tapering of Levorphanol in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain (see DOSAGE AND ADMINISTRATION and DRUG ABUSE AND DEPENDENCE).

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Levorphanol. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms (see DRUG INTERACTIONS).

Levorphanol Tartrate Tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Levorphanol Tartrate Tablets and know how they will react to the medication (see PRECAUTIONS, Information for Patients/Caregivers).

Levorphanol Tartrate Tablets should be administered with caution to patients with extensive liver disease who may be vulnerable to excessive sedation due to increased pharmacodynamic sensitivity or impaired metabolism of the drug.

Storage and Disposal
Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Levorphanol Tartrate Tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home (see WARNINGS and DRUG ABUSE AND DEPENDENCE). Inform patients that leaving Levorphanol Tartrate Tablets unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Levorphanol Tartrate Tablets should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death (see WARNINGS).

Inform patients and caregivers that potentially fatal additive effects may occur if Levorphanol Tartrate Tablets are used with benzodiazepine or other CNS depressants, including alcohol, and not to use these drugs concomitantly unless supervised by a healthcare provider (see WARNINGS and PRECAUTIONS, Drug Interactions).

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop.

Instruct patients to inform their physician or healthcare provider if they are taking, or plan to take serotonergic medications (see PRECAUTIONS, Drug Interactions).

Inform patients that Levorphanol Tartrate Tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) (see WARNINGS).

Inform patients that anaphylaxis has been reported with ingredients contained in Levorphanol Tartrate Tablets. Advise patients how to recognize such a reaction, and if they develop signs of allergy such as a rash or difficulty breathing to stop taking Levorphanol Tartrate Tablets and seek medical attention (see CONTRAINDICATIONS and ADVERSE REACTIONS).

Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to see immediate medical care if they notice these signs (see PRECAUTIONS, Nursing Mothers).

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible (see ADVERSE REACTIONS).

Inform patients that Levorphanol Tartrate Tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication (see PRECAUTIONS).

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (see ADVERSE REACTIONS).

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 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. Follow patients closely for signs of respiratory depression and sedation (see WARNINGS).

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, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Levorphanol Tartrate Tablets if serotonin syndrome is suspected.

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.

Levorphanol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

If concomitant use is warranted, monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Levorphanol Tartrate Tablets and/or the muscle relaxant as necessary.

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. If concomitant use is warranted, monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

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, monitor patients for signs of urinary retention or reduced gastric motility when Levorphanol Tartrate Tablets are used concomitantly with anticholinergic drugs.

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.

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.

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.

Levorphanol Tartrate Tablets are not recommended in children under the age of 18 years as the safety and efficacy of the drug in this population has not been established.

Elderly patients (aged 65 years or older) may have increased sensitivity to levorphanol. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. The initial dose of Levorphanol Tartrate Tablets should be reduced by 50% or more in the infirm elderly patient.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid- tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Levorphanol Tartrate Tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression (see WARNINGS).

This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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

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 chronic use of opioids (see CLINICAL PHARMACOLOGY).

Levorphanol Tartrate Tablets contain levorphanol, a Schedule II controlled substance.

Levorphanol Tartrate Tablets contain levorphanol, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone and tapentadol. Levorphanol can be abused and is subject to misuse, addiction, and criminal diversion (see WARNINGS).

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional nontherapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Levorphanol Tartrate Tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Levorphanol Tartrate Tablets are for oral use only. Abuse of Levorphanol Tartrate Tablets poses a risk of overdose and death. The risk is increased with concurrent abuse of Levorphanol Tartrate Tablets with alcohol and other central nervous system depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Do not abruptly discontinue Levorphanol Tartrate Tablets in a patient physically dependent on opioids. Rapid tapering of Levorphanol Tartrate Tablets in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing Levorphanol Tartrate Tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Levorphanol Tartrate Tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper (see DOSAGE AND ADMINISTRATION and WARNINGS).

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs (see PRECAUTIONS, Pregnancy).

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, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia an overdose situations.

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 techniques.

The opioid antagonists, naloxone or nalmefene, 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. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to Levorphanol Tartrate Tablets overdose.

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.

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).

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 CLINICAL PHARMACOLOGY, Individualization of Dosage, WARNINGS and PRECAUTIONS).

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 adjustment to avoid excessive sedation due to drug accumulation.

Note: As with all controlled substances, abuse by healthcare personnel is possible and the drug should be handled accordingly.

Elderly patients (aged 65 years or older) may have increased sensitivity to levorphanol. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. The initial dose of Levorphanol Tartrate Tablets should be reduced by 50% or more in the infirm elderly patient (see PRECAUTIONS).

Individually titrate the dose of Levorphanol Tartrate Tablets that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Levorphanol Tartrate Tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse (see WARNINGS). Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

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 adjustment to avoid excessive sedation due to drug accumulation.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing Levorphanol Tartrate Tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Levorphanol has a long half-life. The duration of pain relief after a single dose cannot always be predicted from pharmacokinetic principles, and the inter-dose interval may have to be adjusted to suit the patient's individual pharmacodynamic response.

Do not abruptly discontinue Levorphanol Tartrate Tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Levorphanol Tartrate Tablets, there are a variety of factors that should be considered, including the dose of Levorphanol Tartrate Tablets the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Levorphanol Tartrate Tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic (see WARNINGS, Withdrawal and DRUG ABUSE AND DEPENDENCE).

Levorphanol Tartrate Tablets USP

Bottles of 100 tablets.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Store Levorphanol Tartrate Tablets securely and dispose of properly (see PRECAUTIONS, Information for Patients).

Dispense in a tight, light-resistant container as defined in the USP.

Manufactured by:
SpecGx LLC
Webster Groves, MO 63119 USA

Mallinckrodt, the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company.

© 2019 Mallinckrodt.

Rev 11/2019

Mallinckrodt™
Pharmaceuticals

An electronic copy of this medication guide can be obtained from www.mallinckrodt.com/Medguide/MG20L04.pdf or by calling 1-800-778-7898 for alternate delivery options.

NDC 0406-2224-01

100 Tablets

Levorphanol Tartrate
Tablets USP

CII

2 mg

Rx only

PHARMACIST: Dispense the Medication Guide
provided separately to each patient.

Mallinckrodt™

L00L09
Rev 09/2018

Package Display Panel (2 mg Label)