Levo-Dromoran

IV Incompatibilities

Additive: aminophylline, ammonium chloride, amobarbital, chlorothiazide, heparin, pentobarbital, phenobarbital, phenytoin, sodium bicarbonate, thiopental

IV Administration

IV: inject 3 mg over 4-5 min

Storage

Store at room temp

Protect from freezing

Pharmacodynamics

Levo-Dromoran (levorphanol) is a potent synthetic opioid similar to morphine in its actions. Like other mu-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 when administered at equianalgesic doses.

Levorphanol produces a degree of respiratory depression similar to that produced by morphine at equianalgesic doses, and like many mu-opioid drugs, levorphanol produces euphoria or has a positive effect on mood in many individuals. Two mg of intramuscular levorphanol tartrate depresses respiration to a degree approximately equivalent to that produced by 10 to 15 mg of intramuscular morphine in man. The hemodynamic changes after intravenous administration of levorphanol have not been studied in man but are expected to clinically resemble those seen after morphine.

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 concentrations of levorphanol decline in a triexponential manner with a terminal half-life of approximately 11 to 16 hours and a clearance of 0.78 to 1.1 L/kg/hr. Based on terminal half-life, steady-state plasma concentrations should be achieved by the third day of dosing. Levorphanol is rapidly distributed ( < 1 hr) and redistributed (1 to 2 hours) following IV administration and has a steady-state volume of distribution of 10 to 13 L/kg. In vitro studies of protein binding indicate that levorphanol is only 40% bound to plasma proteins.

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

Levorphanol is well absorbed after PO administration with peak plasma concentrations occurring approximately 1 hour after dosing. The bioavailability of levorphanol 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 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, 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.

Clinical Trials

Clinical trials have been reported in the medical literature that investigated the use of Levo-Dromoran (levorphanol) 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 Levo-Dromoran (levorphanol) has been shown to be an effective analgesic of the mu-opioid type and similar to morphine, meperidine or fentanyl. A single 2 mg intramuscular dose of Levo-Dromoran (levorphanol) was studied as a routine preoperative medication in 100 patients as part of a blinded 1500 patient trial of a number of synthetic opioids and was found to provide sedation similar to that observed with 100 mg meperidine or 10 mg of methadone.

Levo-Dromoran (levorphanol) 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 indicates that the relative potency is approximately 4 to 8 times that of morphine, depending on the specific circumstances of use. In postoperative patients, intramuscular levorphanol was determined to be about 8 times as potent as intramuscular morphine, whereas in cancer patients with chronic pain, it was found to be only about 4 times as potent.

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. This is especially important during recovery from anesthesia because of the residual CNS-depressant effects of anesthetic agents and the adverse effects of surgery on respiratory reserve. In consequence, the dose of Levo-Dromoran (levorphanol) should be reduced under circumstances likely to increase the patient's sensitivity to the adverse effects of opioids. As there is substantial redistribution involved in the kinetics of levorphanol, the duration of effect of a single dose may vary and physicians must judge the need for a repeat dose based on the clinical response of the patient. Clinicians are advised to remember that while the long terminal half-life of levorphanol may reduce the need for postoperative analgesics, the administration of an excessive dose preoperatively may cause a delay in the return of spontaneous respirations or prolonged hypoventilation in the postoperative period. In addition, accumulation of the drug following excessive dosage postoperatively may prolong or result in hypoventilation.

Levo-Dromoran (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. Levo-Dromoran (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 Levo-Dromoran (levorphanol) , the total daily dose of oral Levo-Dromoran (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 steadystate before a subsequent dose adjustment to avoid excessive sedation due to drug accumulation.

You should not use levorphanol if you are allergic to it.

Do not use levorphanol if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

You should not use levorphanol unless you are already being treated with a similar opioid medicine and your body is tolerant to it. Opioid medicines include fentanyl (Actiq, Duragesic), hydromorphone (Dilaudid, Palladone), methadone (Methadose, Dolophine), morphine (Kadian, MS Contin, Oramorph), oxycodone (Oxycontin), oxymorphone (Opana), and many others. Talk with your doctor if you are not sure you are opioid-tolerant.

To make sure you can safely take levorphanol, tell your doctor if you have any of these other conditions:

• asthma, COPD, sleep apnea, or other breathing disorder;
• liver or kidney disease;
• heart disease;
• low blood pressure;
• a history of head injury or brain tumor;
• a thyroid disorder;
• gallbladder disease;
• enlarged prostate or urination problems;
• an adrenal gland tumor or disorder (such as Addison's disease);
• mental illness;
• a history of alcoholism or drug addiction; or
• if you recently drank large amounts of alcohol.

Levorphanol may be habit forming and should be used only by the person for whom it was prescribed. Never share levorphanol with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it.

FDA pregnancy category C. It is not known whether levorphanol will harm an unborn baby. Levorphanol may cause addiction or withdrawal symptoms in a newborn if the mother takes the medication during pregnancy. Tell your doctor if you are pregnant or plan to become pregnant while using levorphanol.

It is not known whether levorphanol passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using levorphanol.

Do not give this medication to anyone under 18 years old without medical advice.

Serious side effects may be more likely in older adults taking levorphanol.

Levorphanol is an opioid pain medication. An opioid is sometimes called a narcotic.

Levorphanol is used to treat moderate to severe pain.

Levorphanol may also be used for purposes not listed in this medication guide.

Since levorphanol is used for pain, you are not likely to miss a dose. Skip any missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. A levorphanol overdose can be fatal, especially in a child or other person using the medicine without a prescription. Overdose symptoms may include slow breathing and heart rate, severe drowsiness, muscle weakness, cold and clammy skin, pinpoint pupils, and fainting.

Taking levorphanol with other drugs that make you sleepy or slow your breathing can cause dangerous side effects or death. Ask your doctor before taking a sleeping pill, narcotic pain medicine, prescription cough medicine, a muscle relaxer, or medicine for anxiety, depression, or seizures.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• an MAO inhibitor--isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, tranylcypromine, and others.

This list is not complete. Other drugs may interact with levorphanol, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Administration

Administer orally.b

Dosage

Available as levorphanol tartrate; dosage expressed in terms of the salt.b

Give the smallest effective dose as infrequently as possible to minimize the development of tolerance and physical dependence.a

Individualize dosage according to clinical status of the patient, desired therapeutic effect, degree of existing opiate tolerance, and age and weight; assess dosage at periodic intervals.b

Reduce dosage in poor-risk patients, in geriatric patients, in patients receiving other CNS depressants.a b

Reduce initial dose ≥50% in patients with compromised respiratory function and in those receiving other drugs that depress respiration.b (See Specific Drugs under Interactions.)

Reduce initial dose in patients with hypothyroidism, Addison’s disease, toxic psychosis, prostatic hypertrophy, urethral strictures, acute alcoholism, or delirium tremens.b

In patients who are tolerant to opiate agonists and who require high dosages (e.g., patients with severe chronic pain associated with cancer), individualize dosage of highly potent preparations based on response and tolerance.b

Avoid abrupt withdrawal from relatively high dosages (e.g., in chronic pain patients) since precipitation of severe abstinence syndrome is likely.b

Assess patients for signs of hypoventilation or excessive sedation during therapy.b

Adults

Usually, initiate with 2 mg every 6–8 hours as needed.b May increase to 3 mg every 6–8 hours.b Adjust according to response and tolerance.b

Initial dosages >6–12 mg in 24 hours not recommended in non-opiate-tolerant patients; lower dosages may be appropriate.b

If a patient is placed on an “around-the-clock” dosing regimen, allow at least 72 hours to elapse between dosage adjustments; this is needed to avoid excessive sedation.b (See Half-life under Pharmacokinetics.)

The manufacturer states that the initial total daily dose of oral levorphanol should be 1/15 to 1/12 of the total daily dose of oral morphine; adjust subsequent dosage based on clinical response.b

Prescribing Limits

Adults

Maximum initial daily dose in non-opiate-tolerant patients: 6–12 mg in 24 hours.b

Special Populations

Hepatic Impairment

Reduce initial dose in patients with severe hepatic impairment.b

Renal Impairment

Reduce initial dose in patients with severe renal impairment.b

Geriatric Patients

Reduce initial dose by ≥50% in debilitated geriatric patients.b

Respiratory Impairment

Reduce initial dose by ≥50% in patients with any condition affecting respiratory reserve.b Titrate subsequent doses according to patient’s response.b

Pharmacodynamics

Levo-Dromoran is a potent synthetic opioid similar to morphine in its actions. Like other mu-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 when administered at equianalgesic doses.

Levorphanol produces a degree of respiratory depression similar to that produced by morphine at equianalgesic doses, and like many mu-opioid drugs, levorphanol produces euphoria or has a positive effect on mood in many individuals. Two mg of intramuscular levorphanol tartrate depresses respiration to a degree approximately equivalent to that produced by 10 to 15 mg of intramuscular morphine in man. The hemodynamic changes after intravenous administration of levorphanol have not been studied in man but are expected to clinically resemble those seen after morphine.

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 concentrations of levorphanol decline in a triexponential manner with a terminal half-life of approximately 11 to 16 hours and a clearance of 0.78 to 1.1 L/kg/hr. Based on terminal half-life, steady-state plasma concentrations should be achieved by the third day of dosing. Levorphanol is rapidly distributed (<1 hr) and redistributed (1 to 2 hours) following IV administration and has a steady-state volume of distribution of 10 to 13 L/kg. In vitro studies of protein binding indicate that levorphanol is only 40% bound to plasma proteins.

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

Levorphanol is well absorbed after PO administration with peak plasma concentrations occurring approximately 1 hour after dosing. The bioavailability of levorphanol 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 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, 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.

Warning: May be Habit Forming

Levo-Dromoran is a Schedule II Controlled Substance. All drugs of this class (mu-opioids of the morphine type) are habit forming and should be stored, prescribed, used and disposed of accordingly. Psychological/physical dependence and tolerance may develop upon repeated administration of Levo-Dromoran.

Discontinuation of Levo-Dromoran 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 usually expected in postoperative patients who used the drug for less than a week or in patients who are gradually tapered off the drug after longer use.

Ampuls: 1 mL, 2 mg/mL levorphanol tartrate – boxes of 10 (NDC 0187-3072-10).

Multiple-Dose Vials: 10 mL, 2 mg/mL levorphanol tartrate – boxes of 1 (NDC 0187-3074-20).

Scored Oral Tablets: 2 mg round, white, flat beveled edge tablets in bottles of 100 (NDC 0187-3251-10); with LEVO engraved on one side and 3251 and full bisect scored on the other side.

Storage: Tablets should be stored at 25°C (77°F); excursions permitted to 15°C- 30°C (59°F - 86°F).

Dispense in tight containers as defined in USP/NF.

Parenteral dosage forms should be stored at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F).

DEA Order Form Required.

Manufactured for:
Valeant Pharmaceuticals International
Costa Mesa, CA 92626

Valeant Pharmaceuticals International
3300 Hyland Ave., Costa Mesa, CA 92626 U.S.A.
714-545-0100

3325197EX03

Rev. April 2004

Applies to levorphanol: compounding powder, injectable solution, oral tablet

General

The adverse effects of levorphanol (the active ingredient contained in Levo-Dromoran) are generally similar to the adverse effects observed with other narcotic analgesics.[Ref]

Nervous system

Opioids may result in psychotic symptoms in some patients.[Ref]

Nervous system side effects include mental and respiratory depression, stupor, delirium, somnolence, and dysphoria.[Ref]

Other

Other side effects including withdrawal symptoms after either abrupt cessation or fast tapering of narcotic analgesics may occur and include agitation, restlessness, anxiety, insomnia, tremor, abdominal cramps, blurred vision, vomiting and sweating.[Ref]

Cardiovascular

Cardiovascular adverse effects include hypotension and arrhythmias rarely.[Ref]

Gastrointestinal

Gastrointestinal side effects including nausea, vomiting, and constipation are relatively common effects of narcotic analgesics.[Ref]

Genitourinary

Genitourinary side effects including urinary retention has been reported for other narcotic analgesics.[Ref]

Dermatologic

Dermatologic side effects including rashes have been reported rarely. Narcotic induced rashes may be related to direct stimulation of histamine release.[Ref]

Some side effects of Levo-Dromoran may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.