PROPOXYPHENE NAPSYLATE
AND ACETAMINOPHEN TABLETS, USP

CIV

Rx only

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,1R)-α-[2-(Dimethylamino)-1-methylethyl]-α-phenylphenethyl propionate compound with 2-napthalenesulfonic acid (1:1) monohydrate, which can be represented by the accompanying structural formula:

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 mcmol) of propoxyphene napsylate is required to supply an amount of propoxyphene equivalent to that present in 65 mg (172.9 mcmol) of propoxyphene hydrochloride.

The acetaminophen component is 4'-Hydroxyacetanilide, a white, odorless, crystalline powder possessing a slightly bitter taste, and is represented by the following structural formula:

Propoxyphene napsylate and acetaminophen is supplied in tablet form for oral administration.

Propoxyphene Napsylate and Acetaminophen Tablets, USP 50 mg/325 mg

Each tablet contains:

       Propoxyphene Napsylate ...........................50 mg
       Acetaminophen..........................................325 mg

In addition each tablet contains the following inactive ingredients: carnauba wax, D&C Yellow #10 Aluminum Lake, FD&C Red #40 Aluminum Lake, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide.

Propoxyphene Napsylate and Acetaminophen Tablets, USP 100 mg/650 mg

Each tablet contains:

       Propoxyphene Napsylate ..........................100 mg
       Acetaminophen...........................................650 mg

In addition each tablet contains the following inactive ingredients: carnauba wax, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide. The orange tablets also contain D&C Yellow #10 Aluminum Lake and FD&C Red #40 Aluminum Lake. The pink tablets also contain FD&C Red #40 Aluminum Lake.

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 1/2 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.

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.

Figure 1. Mean plasma concentrations of propopxyphene in 8 human subjects following oral administration of 65 and 130 mg of the hydrochloride salt and 100 mg and 200 mg of the napsylate salt and in 7 given 195 mg of the hydrochloride and 300 mg of the napyslate salt.

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 napsylate is from two-thirds to equal that of codeine.

Propoxyphene napsylate and acetaminophen tablets 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.

Propoxyphene napsylate 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.

In a survey conducted in hospitalized patients, less than 1% of patients taking propoxyphene hydrochloride at recommended doses experienced side effects. The most frequently reported were dizziness, sedation, nausea, and vomiting. Some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include constipation, abdominal pain, skin rashes, lightheadedness, headache, weakness, euphoria, dysphoria, hallucinations, and minor visual disturbances.

Liver dysfunction has been reported in association with both active components of propoxyphene napsylate and acetaminophen tablets. Propoxyphene therapy has been associated with abnormal liver function tests and, more rarely, with instances of reversible jaundice (including cholestatic jaundice). Hepatic necrosis may result from acute overdose of acetaminophen (see OVERDOSAGE). In chronic ethanol abusers, this has been reported rarely with short-term use of acetaminophen doses of 2.5 to 10 g/day. Fatalities have occurred.

Renal papillary necrosis may result from chronic acetaminophen use, particularly when the dosage is greater than recommended and when combined with aspirin. Subacute painful myopathy has occurred following chronic propoxyphene overdosage.

In all cases of suspected overdosage, call your regional Poison Control Center to obtain the most up-to-date information about the treatment of overdose. This recommendation is made because, in general, information regarding the treatment of overdosage may change more rapidly than do package inserts. Initial consideration should be given to the management of the CNS effects of propoxyphene overdosage. Resuscitative measures should be initiated promptly.

This products is given orally. The usual dosage is 100 mg propoxyphene napsylate and 500 mg acetaminophen every 4 hours as needed for pain. The maximum recommended dose of propoxyphene napsylate is 600 mg per day.

Consideration should be given to a reduced total daily dosage in patients with hepatic or renal impairment.

Propoxyphene napsylate and acetaminophen tablets contain 50 mg propoxyphene napsylate and 325 mg acetaminophen. They are supplied as orange film coated, unscored, capsule shaped tablets, debossed "5111" and "V" in containers of 10, 100, 500 and 1000 and unit dose packages of 100's.

Propoxyphene napsylate and acetaminophen tablets contain 100 mg propoxyphene napsylate and 650 mg acetaminophen. They are supplied as orange film coated, unscored, capsule shaped tablets, debossed "5112" and "V", in white film coated, unscored capsule shaped tablets, debossed "5113" and "V" and in pink film coated, unscored capsule shaped tablets, debossed "5114" and "V" in containers of 20, 30, 50, 60, 90, 100, 120, 180, 270, 500 and 1000.