PROPOXYPHENE NAPSYLATE AND ACETOMINOPHEN

PROPOXYPHENE NAPSYLATE AND ACETOMINOPHEN- propoxyphene napsylate and acetaminophen tablet, film coated
Andrx Pharmaceuticals, Inc.

CIV

Rx Only

DESCRIPTION

Propoxyphene Napsylate, USP is an odorless, white crystalline solid with a bitter taste. It is very slightly soluble in water and soluble in methanol, ethanol, chloroform, and acetone. Chemically, it is (αS, 1 R)-α-[2-(Dimethylamino)-1-methylethyl]-α-phenylphenethyl propionate compound with 2-naphthalenesulfonic acid (1:1) monohydrate, which can be represented by the accompanying structural formula. Its molecular weight is 565.72.

Image from Drug Label Content

Propoxyphene napsylate differs from propoxyphene hydrochloride in that it allows more stable liquid dosage forms and tablet formulations. Because of differences in molecular weight, a dose of 100 mg (176.8 μmol) of propoxyphene napsylate is required to supply an amount of propoxyphene equivalent to that present in 65 mg (172.9 μmol) of propoxyphene hydrochloride.

Each tablet of propoxyphene napsylate and acetaminophen contains 100 mg (176.8 μmol) propopoxyphene napsylate and 650 mg (4,300 μmol) acetaminophen.

Each tablet also contains colloidal silicon dioxide, croscarmellose sodium, crospovidone, hypromellose 2910 6cP, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polyethylene glycol 8000, and stearic acid. Each white tablet also contains hypromellose 2910 3cP, hypromellose 2910 6cP, hypromellose 2910 50cP, polydextrose, polyethylene glycol 8000, titanium dioxide and triacetin. Each pink tablet also contains FD&C Red #40 Aluminum Lake, FD&C Yellow #6 Aluminum Lake, polyethylene glycol 8000, titanium dioxide and triacetin.

CLINICAL PHARMACOLOGY

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 2.5 hours. After a 100 mg oral dose of propoxyphene napsylate, 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.

Image from Drug Label Content

Figure 1. Mean plasma concentrations of propoxyphene in 8 human subjects following oral administration of 65 and 130 mg of the hydrochloride salt and 100 and 200 mg of the napsylate salt and in 7 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.

Actions

Propoxyphene is a mild narcotic analgesic structurally related to methadone. The potency of propoxyphene napsylate is from two-thirds to equal that of codeine.

Propoxyphene napsylate and acetaminophen tablets, USP provide the analgesic activity of propoxyphene napsylate 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.

INDICATIONS AND USAGE

Propoxyphene napsylate and acetaminophen tablets, 100 mg/650 mg are indicated for the relief of mild to moderate pain, either when pain is present alone or when it is accompanied by fever.

CONTRAINDICATIONS

Hypersensitivity to propoxyphene or acetaminophen

WARNINGS

  • 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.

Drug Dependence:

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.

Usage in Ambulatory Patients:

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.

PRECAUTIONS

General:

Propoxyphene should be administered with caution to patients with hepatic or renal impairment since higher serum concentrations or delayed elimination may occur.

Patient Information

A Patient Information Sheet is available for this product. A separate Patient Information Sheet is available for this drug product.

Drug Interactions:

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.

Usage in Pregnancy:

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 judgment of the physician, the potential benefits outweigh the possible hazards.

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