PROPOXYPHENE HYDROCHLORIDE AND ACETAMINOPHEN- propoxyphene hydrochloride and acetaminophen tablet
Watson Laboratories, Inc.
Propoxyphene hydrochloride is an odorless white crystalline powder with a bitter taste. It is freely soluble in water. Chemically, it is (2S , 3R)-(+)-4-(Dimethylamino)-3-methyl-1,2-diphenyl-2-butanol propionate (ester) hydrochloride, which can be represented by the following structural formula:
C22 H29 NO2 •HCl Molecular Weight: 375.93
Acetaminophen is a white, crystalline powder, possessing a slightly bitter taste. It is soluble in boiling water and freely soluble in alcohol. Chemically, it is 4’-Hydroxyacetanilide, which can be presented by the following structural formula:
C8 H9 NO2 Molecular Weight: 151.16
Each tablet, for oral administration, contains 65 mg propoxyphene hydrochloride and 650 mg acetaminophen. In addition, each tablet contains the following inactive ingredients: corn starch, crospovidone, D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, hypromellose, magnesium stearate, microcrystalline cellulose, polacrillin potassium, polyethylene glycol, polysorbate 80, povidone, pregelatinized starch, stearic acid, and titanium dioxide.
Propoxyphene is a centrally acting narcotic analgesic agent. Equimolar doses of propoxyphene hydrochloride or napsylate provide similar plasma concentrations. Following administration of 65, 130, or 195 mg of propoxyphene hydrochloride, the bioavailability of propoxyphene is equivalent to that of 100, 200, or 300 mg respectively of propoxyphene napsylate. Peak plasma concentrations of propoxyphene are reached in 2 to 21 /2 hours. After a 65-mg oral dose of propoxyphene hydrochloride, peak plasma levels of 0.05 to 0.1 mcg/mL are achieved. As shown in Figure 1, the napsylate salt tends to be absorbed more slowly than the hydrochloride. At or near therapeutic doses, this absorption difference is small when compared with that among subjects and among doses.
Figure 1. Mean plasma concentrations of propoxyphene in 8 human subjects following oral administration of 65 mg and 130 mg of the hydrochloride salt, and 100 mg and 200 mg of the napsylate; and in 7 subjects given 195 mg of the hydrochloride and 300 mg of the napsylate salt.
Because of this several hundredfold difference in solubility, the absorption rate of very large doses of the napsylate salt is significantly lower than that of equimolar doses of the hydrochloride.
Repeated doses of propoxyphene at 6-hour intervals lead to increasing plasma concentrations, with a plateau after the ninth dose at 48 hours.
Propoxyphene is metabolized in the liver to yield norpropoxyphene. Propoxyphene has a half-life of 6 to 12 hours, whereas that of norpropoxyphene is 30 to 36 hours.
Norpropoxyphene has substantially less central nervous system depressant effect than propoxyphene, but a greater local anesthetic effect, which is similar to that of amitriptyline and antiarrhythmic agents, such as lidocaine and quinidine.
In animal studies in which propoxyphene and norpropoxyphene were continuously infused in large amounts, intracardiac conduction time (PR and QRS intervals) was prolonged. Any intracardiac conduction delay attributable to high concentrations of norpropoxyphene may be of relatively long duration.
Propoxyphene is a mild narcotic analgesic structurally related to methadone. The potency of propoxyphene hydrochloride is from two-thirds to equal that of codeine.
Propoxyphene hydrochloride and acetaminophen provide the analgesic activity of propoxyphene hydrochloride and the antipyretic-analgesic activity of acetaminophen.
The combination of propoxyphene and acetaminophen produces greater analgesia than that produced by either propoxyphene or acetaminophen administered alone.
Propoxyphene Hydrochloride and Acetaminophen Indications and Usage
Propoxyphene hydrochloride and acetaminophen tablets are indicated for the relief of mild-to-moderate pain, either when pain is present alone or when it is accompanied by fever.
Hypersensitivity to propoxyphene or to acetaminophen.
Do not prescribe propoxyphene for patients who are suicidal or addiction-prone.
Prescribe propoxyphene with caution for patients taking tranquilizers or antidepressant drugs and patients who use alcohol in excess.
Tell your patients not to exceed the recommended dose and to limit their intake of alcohol.
Propoxyphene products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a major cause of drug-related deaths. Fatalities within the first hour of overdosage are not uncommon. In a survey of deaths due to overdosage conducted in 1975, in approximately 20% of the fatal cases, death occurred within the first hour (5% occurred within 15 minutes). Propoxyphene should not be taken in doses higher than those recommended by the physician. The judicious prescribing of propoxyphene is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of propoxyphene products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, propoxyphene should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.
Many of the propoxyphene-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts, as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of propoxyphene alone or in combination with other drugs. Patients taking propoxyphene should be warned not to exceed the dosage recommended by the physician.
Propoxyphene, when taken in higher-than-recommended doses over long periods of time, can produce drug dependence characterized by psychic dependence and, less frequently, physical dependence and tolerance. Propoxyphene will only partially suppress the withdrawal syndrome in individuals physically dependent on morphine or other narcotics. The abuse liability of propoxyphene is qualitatively similar to that of codeine although quantitatively less, and propoxyphene should be prescribed with the same degree of caution appropriate to the use of codeine.
Propoxyphene may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly.
Propoxyphene should be administered with caution to patients with hepatic or renal impairment since higher serum concentrations or delayed elimination may occur.
A Patient Information Sheet is available for the product. See text following ANIMAL TOXICOLOGY section below.
The CNS-depressant effect of propoxyphene is additive with that of other CNS depressants, including alcohol.
As is the case with many medicinal agents, propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when propoxyphene was administered to patients on antidepressants, anticonvulsants, or warfarin-like drugs. Severe neurologic signs, including coma, have occurred with concurrent use of carbamazepine.
Safe use in pregnancy has not been established relative to possible adverse effects on fetal development. Instances of withdrawal symptoms in the neonate have been reported following usage during pregnancy. Therefore, propoxyphene should not be used in pregnant women unless, in the judgement of the physician, the potential benefits outweigh the possible hazards.
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