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Oxymorphone hydrochloride is a white or slightly off-white, odorless powder, which is sparingly soluble in alcohol and ether, but freely soluble in water. The molecular weight of oxymorphone hydrochloride is 337.80. The pK a1 and pK a2 of oxymorphone at 37°C are 8.17 and 9.54, respectively. The octanol/aqueous partition coefficient at 37°C and pH 7.4 is 0.98.
NUMORPHAN Injection is available in two concentrations, 1 mg/mL, 1 mL ampul and 1.5 mg/mL, 10 mL vial of oxymorphone hydrochloride. In addition, each 1 mg/mL ampul contains 8.0 mg/mL sodium chloride. Each 1.5 mg/mL vial contains 8.0 mg/mL sodium chloride, 1.8 mg/mL methylparaben and 0.2 mg/mL propylparaben. pH for both the ampul and vial is adjusted with hydrochloric acid.
Central Nervous System (CNS): Opioid analgesics exert their principal pharmacologic effects on the CNS and the gastrointestinal tract. The principal actions of therapeutic value are analgesia and sedation. The precise mechanism of the analgesic action is unknown. However, specific CNS opiate receptors have been identified and likely play a role in the expression of analgesic effects.
Opioids produce respiratory depression by direct action on brain stem respiratory centers. The mechanism of respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation. Opioids depress the cough reflex by direct action on the cough center in the medulla. Opioids cause miosis. Pinpoint pupils are a common sign of opioid overdose but are not pathognomonic. Marked mydriasis may be seen with worsening hypoxia.
Gastrointestinal Tract and Other Smooth Muscle: Opioids decrease gastric, biliary, and pancreatic secretions. These drugs cause a reduction in motility associated with an increase in 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 is increased to the point of spasm. The end result is constipation. Opioids can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.
Opioids increase smooth muscle tone in the urinary tract and can induce spasms. Urinary urgency and difficulty with urination may result. These effects, in conjunction with the central effect of these drugs on release of vasopressin, may produce oliguria.
Metabolism Oxymorphone undergoes extensive hepatic metabolism in humans. After a 10 mg oral dose, 49% was excreted over a five-day period in the urine. Of this, 82% was excreted in the first 24 hours after administration. The recovered drug-related products contained the oxymorphone (1.9%), the conjugate of oxymorphone (44.1%), the 6(beta)-carbinol produced by 6-keto reduction of oxymorphone (0.3%), and the conjugates of 6(beta)-carbinol (2.6%) and 6(alpha)-carbinol (0.1%).
NUMORPHAN Injection is indicated for the relief of moderate to severe pain. It is also indicated for preoperative medication, for support of anesthesia, for obstetrical analgesia, and for relief of anxiety in patients with dyspnea associated with pulmonary edema secondary to acute left ventricular dysfunction.
NUMORPHAN should not be administered to individuals during an acute asthmatic attack or to patients with severe respiratory depression, upper airway obstruction, or any patient who has or is suspected of having a paralytic ileus. NUMORPHAN should not be used in the treatment of pulmonary edema secondary to a chemical respiratory irritant. Opioid analgesics cause pooling of blood in the extremities by decreasing peripheral vascular resistance. This effect results in decreases in venous return, cardiac work, and pulmonary venous pressure, and blood is shifted from the central to peripheral circulation which would not be beneficial in the treatment of pulmonary edema secondary to a chemical respiratory irritant.
Interactions with Other Central Nervous System Depressants: Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics or other CNS depressants (including alcohol) concomitantly with NUMORPHAN may exhibit an additive CNS depression (See PRECAUTIONS ; Drug Interactions).
Respiratory Depression: NUMORPHAN should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression or coma.
Head Injury and Increased Intracranial Pressure: The possible respiratory depressant effects of potent analgesics and their potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO 2 retention) may be markedly exaggerated in the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure. Furthermore, potent analgesics can produce effects which may obscure the clinical course of patients with head injuries. Therefore, NUMORPHAN should be used in these circumstances only when essential, and then should be administered with extreme caution.
Drug Dependence: NUMORPHAN, as with other opioid drugs, can produce tolerance, psychological dependence, and physical dependence and has the potential for being abused (See DRUG ABUSE AND DEPENDENCE ).
Pregnancy: Safe use in pregnancy has not been established (relative to possible adverse effects on fetal development). As with other analgesics, the use of NUMORPHAN in pregnancy, in nursing mothers, or in women of child-bearing potential requires that the possible benefits of the drug be weighed against the possible hazards to the mother and the child (See PRECAUTIONS ).
Special Risk Patients: NUMORPHAN should be used with caution in elderly and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal or hepatic disease. Caution should also be exercised in patients with hypothyroidism, acute alcoholism, delirium tremens, convulsive disorders, Addison' disease, gallbladder disease or gallstones, prostatic hypertrophy or urethral stricture, recent gastrointestinal or genitourinary tract surgery, inflammatory bowel disease, diarrhea secondary to poisoning until the toxin is eliminated, diarrhea secondary to pseudomembranous colitis, cardiac arrhythmias, increased ocular pressure, and toxic psychosis. Debilitated and elderly patients and those with severe liver disease should receive smaller doses of NUMORPHAN.
Hypotensive Effect: Opioid analgesics may cause severe hypotension in patients whose ability to maintain blood pressure has been compromised by a depleted blood volume or coadministration of drugs such as phenothiazines or general anesthetics. Administer with caution to patients in circulatory shock, since vasodilatation produced by the drug may further reduce cardiac output and blood pressure. Orthostatic hypotension may occur in ambulatory patients.
Patients should be cautioned regarding the following:
Drowsiness, dizziness, or lightheadedness related to the use of this medication may impair mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car, operating machinery, etc.
This medication, like other opioid analgesics, will add to the effect of alcohol and other CNS depressants [such as antihistamines, sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, and monoamine oxidase (MAO) inhibitors]. Alcohol should not be consumed while taking NUMORPHAN.
Withdrawal side effects may be precipitated by suddenly stopping this drug after prolonged use (regular use for several weeks or more). The medication should be gradually reduced before completely discontinuing use.
The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced (See WARNINGS ).
Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established.
Long-term studies have not been performed in animals to evaluate the carcinogenic potential of NUMORPHAN (oxymorphone hydrochloride, USP). Studies to evaluate the mutagenic potential of NUMORPHAN have not been conducted. There have been no studies to evaluate the effect of NUMORPHAN on fertility.
Pregnancy Category C-- NUMORPHAN was reported to produce malformations in offspring of hamsters that received 1,500 times the recommended dose on Day 8 of gestation. There have been no adequate and well-controlled studies of reproductive toxicity in other laboratory animals or in pregnant women. It is not known whether NUMORPHAN can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. As with other opioid analgesics, the use of NUMORPHAN in pregnancy or in women of child-bearing potential requires that the possible benefits of the drug be weighed against the possible hazards to the mother and the child.
Non-teratogenic Effects-- Prolonged use of opioid analgesics during pregnancy may cause fetal-neonatal physical dependence. Neonatal withdrawal may occur. Symptoms usually appear during the first days of life and may include convulsions, irritability, excessive crying, tremors, hyperactive reflexes, fever, vomiting, diarrhea, sneezing, yawning, and increased respiratory rate.
Opioid analgesics in therapeutic doses may prolong labor. Generally, the effect of opioids on the pregnant uterus appears to depend on the time of administration; administration of the drugs during the latent phase of the first stage of labor, or before cervical dilation of 4-5 cm has occurred, may hamper the progress of labor.
Opioid analgesics, including NUMORPHAN, may cause respiratory depression in the newborn. The effect of NUMORPHAN, if any, on the later growth, development, and functional maturation of the child is unknown.
It is not known whether NUMORPHAN is excreted in human milk. Because many drugs, including some opioids, are excreted in human milk, caution should be exercised when NUMORPHAN is administered to a nursing woman.
Central Nervous System: Drowsiness, sedation, lightheadedness, unusual tiredness or weakness, headache, dysphoria, euphoria, miosis, diplopia, blurred vision, nervousness, restlessness, confusion, mental clouding, trouble sleeping, paradoxical CNS stimulation, hallucinations, mental depression.
Gastrointestinal System: Nausea, vomiting, dry mouth, constipation, biliary tract spasm, cramps or pain, loss of appetite, paralytic ileus or toxic megacolon in patients with inflammatory bowel disease.
NUMORPHAN, as with other opioid drugs, can produce tolerance, psychological dependence, and physical dependence and has the potential for being abused. The addiction potential of the drug appears to be about the same as for morphine.
Withdrawal symptoms may occur when opioids are abruptly discontinued after prolonged use. Withdrawal symptoms may be characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, gooseflesh, restless sleep, and mydriasis during the first 24 hours. These symptoms often increase in severity and over the next 72 hours may be accompanied by increasing irritability, anxiety, weakness, twitching, and spasms of muscles; kicking movements; severe backaches; abdominal and leg pains; abdominal and muscle cramps; hot and cold flashes; insomnia; nausea, anorexia, vomiting, intestinal spasm, diarrhea, coryza, and repetitive sneezing; increase in body temperature, blood pressure, respiratory rate and heart rate. Because of excessive loss of fluids through sweating, vomiting and diarrhea, there is usually marked weight loss, dehydration, ketosis, and disturbances in acid-base balance. Cardiovascular collapse can occur. Without treatment most observable symptoms disappear in 5-14 days; however, there appears to be a phase of secondary or chronic abstinence which may last for 2-6 months characterized by decreasing insomnia, irritability, and muscular aches. In addition, the patient may have miosis and a slight lowering of blood pressure, pulse rate, and body temperature; respiratory centers exhibit a decreased response to the stimulatory effects of carbon dioxide.
Signs and Symptons: Serious overdosage with NUMORPHAN is characterized by respiratory depression, (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur.
Treatment Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The opioid antagonist naloxone hydrochloride (NARCAN®) is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to opioids including oxymorphone. Therefore, an appropriate dose of naloxone hydrochloride should be administered (usual initial adult dose 0.4 mg-2 mg) preferably by the intravenous route and simultaneously with efforts at respiratory resuscitation. Since the duration of action of oxymorphone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration.
Naloxone hydrochloride should not be administered in the absence of clinically significant respiratory or cardiovascular depression. In addition, it should be considered that the use of an opioid antagonist in patients physically dependent on opioids may precipitate an acute withdrawal syndrome that cannot be readily suppressed while the action of the antagonist persists. If respiratory depression is associated with muscular rigidity, administration of a neuromuscular blocking agent may be necessary to facilitate assisted or controlled ventilation. Muscular rigidity may also respond to opioid antagonist therapy.
Usual Adult Dosage of NUMORPHAN Injection: Subcutaneous or intramuscular administration: initially 1 mg to 1.5 mg, repeated every 4 to 6 hours as needed. Intravenous: 0.5 mg initially. In nondebilitated patients the dose can be cautiously increased until satisfactory pain relief is obtained. For analgesia during labor 0.5 mg to 1 mg intramuscularly is recommended.
Usual Adult Dosage of NUMORPHAN Rectal Suppositories: One suppository, 5 mg, every 4 to 6 hours. In nondebilitated patients the dose can be cautiously increased until satisfactory pain relief is obtained.
1 mg/mL 1 mL ampuls (paraben/sodium dithionite-free)
(box of 10) NDC 63481-444-10
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].
Protect from light.
Store under refrigeration 2°-8°C (36°-46°F).
NUMORPHAN® is a Registered Trademark of Endo Pharmaceuticals Inc.
NARCAN® is a Registered Trademark of Endo Pharmaceuticals Inc.
Copyright © Endo Pharmaceuticals Inc. 1999
6477-01/Rev. September, 1999