Levorphanol Tartrate: Package Insert and Label Information (Page 2 of 4)

PRECAUTIONS

Information for patients

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

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Levorphanol Tartrate Tablets without first discussing a tapering plan with the prescriber [see DOSAGE AND ADMINISTRATION].

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), 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.
Mixed Agonist/Antagonist and Partial Opioid Analgesics
The concomitant use of opioid with other opioid analgesics, such as butorphanol, nalbuphine, pentazocine, may reduce the analgesic effect of Levorphanol Tartrate Tablets and precipitate withdrawal symptoms.
Advise patient to avoid concomitant use of these drugs.
Muscle Relaxants
Levorphanol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
If concomitant use is warranted, 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 breast-feeding 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].

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