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Levorphanol

Generic Name: Levorphanol tartrate
Dosage Form: tablet

Revised: December 2016

RX ONLY

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Addiction, Abuse, and Misuse

Levorphanol Tartrate Tablets exposes 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].

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.

DESCRIPTION

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-Nmethylmorphinan. 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 is a white crystalline powder, soluble in water and ether, but insoluble in chloroform.

Each tablet, for oral administration, contains 2 mg Levorphanol tartrate. In addition, each tablet contains anhydrous lactose, corn starch, and magnesium stearate.

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

Effects on the Central Nervous System

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.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

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.

Effects on the Cardiovascular System

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.

Effects on the Endocrine System

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].

Effects on the Immune System

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.

Concentration–Efficacy Relationships

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].

Concentration–Adverse Reaction Relationships

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].

Pharmacokinetics

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 to16 hours and a clearance of 0.78 to 1.1 L/kg/hr. Based on terminal halflife, 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

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 has been shown to be an effective analgesic of the mu-opioid type and similar to morphine, meperidine, or fentanyl.

Levorphanol Tartrate Tablets has 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 only to be about 4 times as potent.

Individualization of Dosage

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.

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, 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

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]

WARNINGS

Addiction, Abuse, and Misuse

Levorphanol Tartrate Tablets contains Levorphanol, a Schedule II controlled substance. As an opioid, Levorphanol Tartrate Tablets exposes users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Levorphanol Tartrate Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.

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

Life Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see OVERDOSAGE]. Carbon dioxide (CO2) retention from opioidinduced 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 2472 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.

Neonatal Opioid Withdrawal Syndrome

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].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

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., nonbenzodiazepine 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].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patient

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.

Patients with Chronic Pulmonary Disease: Patients treated with Levorphanol Tartrate Tablets with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Levorphanol [see WARNINGS].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see WARNINGS].

Monitor such patients closely, particularly when initiating and titrating Levorphanol Tartrate Tablets and when Levorphanol Tartrate Tablets are given concomitantly with other drugs that depress respiration [see WARNINGS]. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency

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.

Cardiovascular Effects

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.

Severe Hypotension

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.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

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.

Risks of Use in Patients with Gastrointestinal Conditions

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 has 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.

Increased Risk of Seizures in Patients with Seizure Disorders

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.

Withdrawal

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 Tartrate Tablets. In these patients, mixed agonist/antagonist and partial analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

When discontinuing Levorphanol Tartrate Tablets, gradually taper the dosage [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue Levorphanol Tartrate Tablets [see DRUG ABUSE AND DEPENDENCE].

Risks of Driving and Operating Machinery

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].

Use in Liver Disease

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

PRECAUTIONS

Information for patients

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

Addiction, Abuse, and Misuse

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.

Life-Threatening Respiratory Depression

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.

Most cases of serious or fatal adverse events involving Levorphanol Tartrate Tablets reported to the manufacturer or the FDA have involved either the administration of large initial doses of the drug or too frequent doses of the drug to non-opioid tolerant patients, or the simultaneous administration of Levorphanol Tartrate Tablets with other drugs affecting respiration [see

INDIVIDUALIZATION OF DOSAGE and WARNINGS]. The initial dose of Levorphanol Tartrate Tablets should be reduced by approximately 50% or more when it is given to patients along with another drug affecting respiration.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see WARNINGS]. Instruct patients to take steps to store Levorphanol Tartrate Tablets securely and to dispose of unused Levorphanol Tartrate Tablets by flushing down the toilet.

Interactions with Benzodiazepine and Other CNS Depressants

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, PRECAUTIONS; Drug Interactions].

Serotonin Syndrome

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].

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].

Hypotension

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].

Anaphylaxis

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, ADVERSE REACTIONS].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that 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 [see WARNINGS, PRECAUTIONS; Pregnancy]

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that Levorphanol Tartrate Tablets can cause fetal harm and to inform the prescriber of a known or suspected pregnancy [see WARNINGS, PRECAUTIONS; Pregnancy].

Lactation

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].

Infertility

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].

Driving or Operating Heavy Machinery

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].

Constipation

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

Disposal of Unused Levorphanol

Advise patients to flush unused Levorphanol Tartrate Tablets down the toilet.

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 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].

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), 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.

Mixed Agonist/Antagonist and Partial Opioid Analgesics

The concomitant use of opioid with other opioid t 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, 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.

Diuretics

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.

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of Levorphanol have not been conducted.

Mutagenesis

Animal studies to evaluate the mutagenic potential of Levorphanol have not been conducted.

Impairment of Fertility

Animal studies to determine the effect of Levorphanol on fertility have not been conducted

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS].

Pregnancy

Risk Summary

Prolonged use of opioid analgesics 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 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics 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 antagonist, such as naloxone, 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.

Pediatric Use

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.

Geriatric Use

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

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 chronic use of opioids [see Clinical Pharmacology].

DRUG ABUSE AND DEPENDENCE

Controlled Substance

Levorphanol Tartrate Tablets contains Levorphanol, a Schedule II controlled substance.

Abuse

Levorphanol Tartrate Tablets contains 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 health care 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. Health care 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.

Risks Specific to Abuse of Levorphanol Tartrate Tablets

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.

Dependence

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 results 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.

Levorphanol Tartrate Table should not be abruptly discontinued in a physically-dependent patient [see DOSAGE AND ADMINISTRATION]. If Levorphanol Tartrate Tablets are abruptly discontinued in a physically- dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: 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.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see PRECAUTIONS; Pregnancy].

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

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patient and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life- support 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.

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 24-72 hours of initiating therapy and following dosage increases with Levorphanol Tartrate Tablets and adjust the dosage accordingly [see WARNINGS].

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 adjustment to avoid excessive sedation due to drug accumulation.

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

Geriatric Patients

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].

Titration and Maintenance of Therapy

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.

Discontinuation of Levorphanol Tartrate Tablets

When a patient who has been taking Levorphanol Tartrate Tablets regularly and may be physically dependent no longer requires therapy with Levorphanol Tartrate Tablets taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Levorphanol Tartrate Tablets in a physically-dependent patient [see WARNINGS, DRUG ABUSE AND DEPENDENCE].

HOW SUPPLIED

Levorphanol Tartrate Tablets USP, 2 mg White, scored tablets (Identified 54 410).

NDC: 42358-102-10 Bottles of 100 tablets.

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

Dispense in an amber airtight container as defined in the USP.

Manufactured for:

Sentynl Therapeutics, Inc.
Solana Beach, CA 92075

Revised December 2016            LV20161201.1

Medication Guide
Levorphanol Tartrate (lee vor' fa nol tar' trate) Tablets, CII
Levorphanol Tartrate Tablets are:
  • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain, severe enough to require an opioid pain medicine when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
  • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
Important information about Levorphanol Tartrate Tablets:
  • Get emergency help right away if you take too much Levorphanol Tartrate Tablets (overdose). When you first start taking Levorphanol Tartrate Tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
  • Taking Levorphanol Tartrate Tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma and death. Never give anyone else your Levorphanol Tartrate Tablets. They could die from taking it. Store Levorphanol Tartrate Tablets away from children and in a safe place to prevent stealing or abuse. Selling or giving away Levorphanol Tartrate Tablets is against the law.
Do not take Levorphanol Tartrate Tablets if you have:
severe asthma trouble breathing, or other lung problems
a bowel blockage or have narrowing of the stomach or intestines.
previously had an allergic reaction to Levorphanol
Before taking Levorphanol Tartrate Tablets, tell your healthcare provider if you have a history of:
  • head injury, seizures
  • problems urinating
  • liver, kidney, thyroid problems
  • pancreas or gallbladder problems
  • abuse of street or prescription drugs, alcohol addiction, or mental health problems.
Tell your healthcare provider if you are:
  • pregnant or planning to become pregnant. Prolonged use of Levorphanol Tartrate Tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
  • breastfeeding. Levorphanol Tartrate Tablets passes into breast milk and may harm your baby.
  • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Levorphanol Tartrate Tablets with certain other medicines can cause serious side effects that could lead to death.
When taking Levorphanol Tartrate Tablets:
  • Do not change your dose. Take Levorphanol Tartrate Tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
  • Take your prescribed dose every 6 to 8 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.
  • Call your healthcare provider if the dose you are taking does not control your pain.
  • If you have been taking Levorphanol Tartrate Tablets regularly, do not stop taking without talking to your healthcare provider.
  • After you stop taking Levorphanol Tartrate Tablets, flush all unused tablets down the toilet.
While taking Levorphanol Tartrate Tablets DO NOT:
  • Drive or operate heavy machinery, until you know how Levorphanol Tartrate Tablets affects you. Levorphanol Tartrate Tablets can make you sleepy, dizzy, or lightheaded.
  • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Levorphanol Tartrate Tablets may cause you to overdose and die.The possible side effects of Levorphanol Tartrate Tablets:
  • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.
Get emergency medical help if you have:
  • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.
These are not all the possible side effects of Levorphanol Tartrate Tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov

Distributed by: Sentynl Therapeutics, Inc. 420 Stevens Ave Suite 200 Solana Beach, CA 92075, or call 1-888-227-8725

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: 12/2016

Package/Label Display Panel

NDC: 42358-102-10 Bottles of 100 tablets

Sentynl Therapeutics, Inc.

Rx only

Levorphanol TARTRATE 
Levorphanol tartrate tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:42358-102
Route of Administration ORAL DEA Schedule CII    
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Levorphanol tartrate (Levorphanol) Levorphanol tartrate 2 mg
Inactive Ingredients
Ingredient Name Strength
anhydrous lactose  
Starch, corn  
Magnesium Stearate  
Product Characteristics
Color white (white) Score 2 pieces
Shape ROUND (ROUND) Size 6mm
Flavor Imprint Code 54;410
Contains         
Packaging
# Item Code Package Description
1 NDC:42358-102-10 100 TABLET in 1 BOTTLE, PLASTIC
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA074278 05/28/2015
Labeler - Sentynl Therapeutics, Inc. (078313706)
Establishment
Name Address ID/FEI Operations
Boehringer Ingelheim Roxane Inc 833490464 MANUFACTURE(42358-102)
Revised: 12/2016
 
Sentynl Therapeutics, Inc.
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