Rx only.

DESCRIPTION

Levorphanol tartrate dihydrate is a potent narcotic analgesic with a molecular formula of C 17 H 23 NO · C 4 H 6 O 6 · 2H 2 O and molecular weight 443.5. Each mg of levorphanol tartrate dihydrate is equivalent to 0.58 mg levorphanol base. Levorphanol's chemical name is levo-3-hydroxy-N-methylmorphinan with the following structural formula, and has 3 asymmetric carbon atoms and the possibility of cis-trans isomerism:

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

Each tablet, for oral administration, contains 2 mg levorphanol tartrate dihydrate. In addition, each tablet contains anhydrous lactose, corn starch, stearic acid, magnesium stearate and talc.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Levorphanol is a potent synthetic opioid similar to morphine in its actions. Like other µ-agonist opioids it is believed to act at receptors in the periventricular and periaqueductal gray matter in both the brain and spinal cord to alter the transmission and perception of pain. Onset of analgesia and peak analgesic effect following administration of levorphanol are similar to morphine and other drugs of this class when administered at equianalgesic doses.

Levorphanol produces a degree of respiratory depression similar to that produced by morphine at equianalgesic doses, and like many µ-opioid drugs, levorphanol produces euphoria or has a positive effect on mood in many individuals.

As with other opioids, the blood levels required for analgesia are determined by the opioid tolerance of the patient, and are likely to rise with chronic use. The rate of development of tolerance is highly variable, and is determined by the dose, dosing interval, age, use of concomitant drugs and physical status of the patient. While blood levels of opioid drugs may be helpful in assessing individual cases, dosage is usually adjusted by careful clinical observation of the patient.

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 levels of levorphanol decline in a triexponential manner with a terminal half-life of 11-16 hours and a clearance of 0.75-1.0 L/kg/hr. Based on terminal half-life, steady-state plasma levels should be achieved by the second day of dosing. Levorphanol undergoes rapid (<1 hr) distribution and redistribution phases following IV administration and has a steady-state volume of distribution of from 10-13 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 data from preoperative studies of a 2 mg IM dose in 1500 patients suggests that absorption is rapid with onset of effects within 15-30 minutes of administration.

Levorphanol is well absorbed after PO administration with peak blood levels occurring 1 hour after dosing. The extent of first-pass metabolism of levorphanol is not well defined, but is likely to lie within the range of 30-70% based on a comparison of blood levels after oral and parenteral administration. The relative bioavailability of levorphanol tablets compared to IM or IV administration is not known.

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

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 five-fold that of the parent compound.

The effects of age, gender, 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.

Effect on Respiration

Two mg of intravenous levorphanol tartrate depresses respiration to a degree approximately equivalent to that produced by 10-15 mg of intravenous morphine in man. Initial doses of levorphanol above 3 mg have been associated with serious respiratory depression in patients not tolerant to the effects of opioids and are not recommended. As with all drugs of this class, the initial dose of levorphanol 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' response. Respiratory depression produced by levorphanol tartrate can be reversed by naloxone, a specific antagonist.

Cardiovascular Effects

The hemodynamic changes after the intravenous administration of levorphanol have not been studied in man, but clinically resemble those seen after morphine.

Clinical Trials

Clinical trials have been reported in the medical literature that investigated the use of levorphanol as a preoperative medication, as the narcotic component of nitrous-narcotic anesthesia, as a postoperative analgesic, and in the management of chronic pain due to malignancy. In each of these clinical settings levorphanol has been shown to be an effective analgesic of the µ-opioid type, and similar to morphine, meperidine, oxycodone, or fentanyl.

A single 2 mg dose of levorphanol tartrate was studied as a routine preoperative premedicant in a blinded 1500 patient trial of a number of synthetic opiates, and was found to provide sedation similar to that observed with 100 mg meperidine or 10 mg of methadone. Levorphanol was also tested in doses of 1.5-2 mg in three intra-operative trials in a total of 300 patients against morphine, meperidine and fentanyl, and the clinical course of anesthesia was found to be equivalent to that produced by other drugs of this class as evaluated by sequential analysis of the analgesic records.

Levorphanol has been studied in oral, IM and IV dosage forms in three trials in chronic cancer patients. As is usual in such trials the dosages were individualized to each patient' level of opioid tolerance, with starting doses of 2 mg twice a day having to be advanced by 50% or more within a few weeks of starting therapy. Studies of levorphanol both in animals and man indicate that the relative potency of levorphanol is approximately 4-8 times that of morphine, depending on the specific circumstances of use.

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' individual pharmacodynamic response.

Levorphanol is 4-8 times more potent than morphine, has a longer half-life, is better absorbed, and may be less subject to first-pass metabolism. When converting a patient to levorphanol, the total daily dose of levorphanol should begin at 1/12 of the total daily dose of oral morphine that such patients would be expected to require and then adjusted on subsequent days to the patient' 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 (36-48 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 where an opioid analgesic is appropriate.

CONTRAINDICATIONS

Levorphanol tartrate tablets are contraindicated in patients allergic to levorphanol.

WARNINGS

Respiratory Depression

Levorphanol, like morphine, may be expected to produce serious or potentially fatal respiratory depression if given in excessive dosage, too frequently, or if given in full dosage to compromised or vulnerable patients. This is because the doses required to produce analgesia in the general clinical population may cause serious respiratory depression in vulnerable patients. Safe usage of this potent narcotic requires that the dosage and dosage interval be individualized to each patient based on the severity of the pain, weight, age, diagnosis and physical status of the patient, and the kind and dose of concurrently administered medication.

PRECAUTIONS

Head Injury and Increased Intracranial Pressure

Levorphanol tartrate must be used with extreme caution and only if the benefits of use outweigh the potential risks in patients with head injury. This is because levorphanol, like other potent analgesics, may elevate cerebrospinal fluid pressure and can produce effects (e.g. miosis) that obscure the clinical course.

Cardiovascular Effects

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

Pre-Existing Pulmonary Disease

Because levorphanol tartrate causes respiratory depression, it should be administered with caution to patients with impaired respiratory reserve or respiratory depression from some other cause (e.g., from other medication, uremia, or severe infection, bronchial asthma, obstructive respiratory conditions, or intra-pulmonary shunting).

Use in Liver Disease

The drug 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. Laboratory tests have not indicated that levorphanol tartrate otherwise affects preexisting hepatic impairment.

Biliary Surgery

The safety of levorphanol in biliary surgery has not been studied and its use is not recommended.

Use in Alcoholism or Drug Dependence

Levorphanol has an abuse potential as great as morphine, and the prescription of this drug in such patients must always balance the prospective benefits against the risk of abuse and dependence. The use of levorphanol in patients with a history of alcohol or other drug dependence, either active or in remission, has not been specifically studied.

Drug Interactions

Concomitant use with other CNS agents--The dose of levorphanol should be reduced by about 50% or more when administered concomitantly with phenothiazines, droperidol, hydroxyzine, and other tranquilizers that potentiate the action of opioids. Concurrent use of levorphanol tartrate with all central nervous system depressants (e.g., alcohol, barbiturates, tranquilizers, and antihistamines) may result in additive central nervous system depressant effects. Although no interaction between MAO inhibitors and levorphanol has been observed, it is not recommended for use with MAO inhibitors.

Most cases of serious or fatal adverse events involving levorphanol reported to the manufacturer or the FDA have involved either the administration of large initial doses of the drug to non-opioid tolerant patients, or the simultaneous administration of levorphanol with other drugs affecting respiration (see WARNINGS ). The initial dose of levorphanol should be reduced by approximately 50% or more when it is given to patients along with another drug affecting respiration.

Use in Ambulatory Patients

Levorphanol has been used in both inpatient and outpatient settings, but both physicians and patients must be aware of the risk of orthostatic hypotension, dizziness and syncope in ambulatory patients.

As with other opioids the use of levorphanol may impair mental and/or physical abilities required for the performance of potentially hazardous tasks or for the exercise of normal good judgement and patients and staff should be advised accordingly.

Concurrent use of levorphanol with central nervous system depressants (e.g., alcohol, barbiturates, tranquilizers, and antihistamines) may result in additive central nervous system depressant effects.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No information about the effects of levorphanol on carcinogenesis, mutagenesis, or fertility is available.

Pregnancy

Pregnancy Category C.

The use of levorphanol in pregnancy is not recommended as no information about the effects of the drug on animal or human reproduction is available.

Labor and Delivery

The safety of levorphanol in labor and delivery is unknown and its use is not recommended.

Nursing Mothers

Levorphanol is not recommended for use in nursing mothers as it is not known if levorphanol is secreted in pharmacologically active amounts in human milk.

Pediatric Use

Levorphanol is 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

The initial dose of the drug should be reduced by 50% or more in the infirm elderly patient, even though there have been no reports of unexpected adverse events in older populations. All drugs of this class may be associated with a profound or prolonged effect in elderly patients for both pharmacokinetic and pharmacodynamic reasons and caution is indicated.

ADVERSE REACTIONS

In 4365 patients treated with levorphanol 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, dyskinesia, difficulties in urination, and biliary spasm. The frequency and intensity of these effects appears to be dose related and proportional to the relative potency of each opioid. Although listed as adverse events these are expected pharmacologic actions of these drugs and should be interpreted as such by the clinician.

The incidence of adverse effects with levorphanol is based on data obtained from patients treated in controlled clinical trials and the uncontrolled clinical use of the drug. The adverse effects are listed below by frequency of occurrence within the body system affected and reflect the actual frequencies of each adverse effect in patients who received levorphanol. There has been no attempt to correct for a placebo effect or to subtract the frequencies reported by placebo-treated patients.

The following adverse events have been associated with the use of levorphanol and have been attributed to its use:

Body as a Whole:   abdominal pain**, dry mouth**.

Cardiovascular System:   hypotension***, dysrhythmia** (bradycardia).

Digestive System:   nausea****, vomiting***.

Nervous System:   dizziness****, confusion***, lethargy***, abnormal dreams**, abnormal thinking**, nervousness**, drug withdrawal*, hypokinesia*, dyskinesia*.

Respiratory System:   hypoventilation****.

Skin & Appendages:   Pruritus****, urticaria***, rash**, injection site reaction*.

Special Senses:   abnormal vision**.

Urogenital System:   difficulty urinating**.

(****) >10%

(***) 3-9%

(**) 1-3%

(*) <1%

DRUG ABUSE AND DEPENDENCE

(Schedule II Controlled Substance)

All drugs of this class (pure µ-opioids of the morphine type) are habit forming and should be stored, prescribed, used, and disposed of accordingly.

Discontinuation of levorphanol after chronic use has been reported to result in withdrawal syndromes, and some reports of overuse and self reported addiction have been received. Neither withdrawal nor withdrawal symptoms are expected in postoperative patients who used the drug for less than a week or in patients who are tapered off the drug over 1-2 weeks after longer use.

OVERDOSAGE

Most reports of overdosage known to the manufacturer and to the FDA involve three clinical situations. These are: 1) the use of larger than recommended doses, 2) administration of the drug to children or small adults without any reduction in dosage, and 3) the use of the drug in ordinary dosage in patients compromised by concurrent illness.

As with all oral narcotics, overdose can occur due to accidental or intentional misuse of this product, especially in infants and children who may gain access to the drug in the home. Based on its pharmacology, levorphanol overdosage would be expected to produce signs of respiratory depression, cardiovascular failure (especially in predisposed patients), and/or central nervous system depression.

Treatment

The specific treatment of suspected levorphanol tartrate overdosage is immediate establishment of an adequate airway and ventilation, followed (if necessary) by intravenous naloxone. The respiratory and cardiac status of the patient should be continuously monitored and appropriate supportive measures instituted, such as oxygen, intravenous fluids, and/or vasopressors if required. Physicians are reminded that the duration of levorphanol action far exceeds the duration of action of naloxone, and repeated dosing with naloxone may be required.

DOSAGE AND ADMINISTRATION

Oral

The usual recommended starting dose for oral administration is 2 mg. This may be repeated in 3-6 hours as needed, provided the patient is assessed for signs of hypoventilation and excessive sedation. The effective daily dosage range, depending on the severity of the pain, is 8-16 mg in 24 hours in the non-tolerant patient. Total daily doses of more than 16 mg are generally not recommended as starting doses in non-opioid tolerant patients.

Use in Chronic Pain

The dosage of levorphanol tartrate in cancer patients or in other conditions where chronic opioid therapy is indicated must be individualized (see CLINICAL PHARMACOLOGY , Individualization of Dosage ). Since levorphanol is 4-8 times as potent as morphine and less subject to first pass metabolism, the daily dose of levorphanol should be estimated at about 1/12 the daily oral morphine dose, but may require prompt individualization of dosage owing to intra-individual differences in clearance and opioid tolerance.

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

HOW SUPPLIED

Levorphanol Tartrate Tablets USP, 2 mg

White, scored tablets (Identified 54 410).

NDC 0054-4494-25: Bottles of 100 tablets.

Store at Controlled Room Temperature 15°-30°C (59°-86°F).

DEA Order Form Required

4055209                Revised April 2000

                                  040 © RLI, 2000

Roxane

Laboratories, Inc.

Columbus, Ohio 43216



Copyright© 2002 Medical Economics