DESCRIPTION

DESCRIPTIONPropoxyphene napsylate USP is an odorless, white crystalline powder with a bitter taste. It is very slightly soluble in water and solublein methanol, ethanol, chloroform, and acetone. Chemically, it is (aS,1R)-a-[2-(Dimethylamino)-1-methylethyl]-a-phenylphenethylpropionate compound with 2-naphthalenesulfonic acid (1:1) monohydrate, which can be represented by the accompanying structuralformula: Propoxyphene napsylate differs from propoxyphene hydrochloride in that it allows more stable liquid dosage forms and tabletformulations. Because of differences in molecular weight, a dose of 100 mg (176.8 mmol) of propoxyphene napsylate is required tosupply an amount of propoxyphene equivalent to that present in 65 mg (172.9 mmol) of propoxyphene hydrochloride.The acetaminophen component is 4#-Hydroxyacetanilide, a white, odorless, crystalline powder possessing a slightly bitter taste, and isrepresented by the following structural formula: Each tablet of Propoxyphene Napsylate and Acetaminophen Tablets USP, for oral administration, contains 100 mg (176.8 mmol)propoxyphene napsylate and 650 mg (4,300 mmol) acetaminophen.Each pink tablet also contains crospovidone, D & C Red No. 27 Aluminum Lake, FD & C Yellow No. 6 Aluminum Lake,hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone,pregelatinized starch, silicon dioxide, stearic acid, titanium dioxide, and triacetin.Each white tablet also contains crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose,polydextrose, polyethylene glycol, povidone, pregelatinized starch, silicon dioxide, stearic acid, titanium dioxide, and triacetin.

CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGYPropoxyphene is a centrally acting narcotic analgesic agent. Equimolar doses of propoxyphene hydrochloride or napsylate providesimilar plasma concentrations. Following administration of 65, 130, or 195 mg of propoxyphene hydrochloride, the bioavailabilityof propoxyphene is equivalent to that of 100, 200, or 300 mg respectively of propoxyphene napsylate. Peak plasma concentrations ofpropoxyphene 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 0.1mcg/mL are achieved. As shown in Figure 1, the napsylate salt tends to be absorbed more slowly than the hydrochloride. At or neartherapeutic 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 and 130 mg of thehydrochloride salt and 100 and 200 mg of the napsylate salt and in 7 given 195 mg of the hydrochloride and 300 mg of the napsylatesalt. page 2 of 8 Because of this several hundredfold difference in solubility, the absorption rate of very large doses of the napsylate salt is significantlylower 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 48hours.Propoxyphene is metabolized in the liver to yield norpropoxyphene. Propoxyphene has a half-life of 6 to 12 hours, whereas that ofnorpropoxyphene is 30 to 36 hours.Norpropoxyphene has substantially less central-nervous-system-depressant effect than propoxyphene but a greater local anestheticeffect, 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, intracardiacconduction time (PR and QRS intervals) was prolonged. Any intracardiac conduction delay attributable to high concentrations ofnorpropoxyphene may be of relatively long duration.ActionsPropoxyphene is a mild narcotic analgesic structurally related to methadone. The potency of propoxyphene napsylate is from twothirds 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 oracetaminophen administered alone.INDICATIONS AND USAGEThis product is indicated for the relief of mild to moderate pain, either when pain is present alone or when it is accompanied by fever.

CONTRAINDICATIONS

CONTRAINDICATIONSHypersensitivity to propoxyphene or acetaminophen. page 3 of 8

WARNINGS

WARNINGS 225Do not prescribe propoxyphene for patients who are suicidal or addiction-prone.225Prescribe propoxyphene with caution for patients taking tranquilizers or antidepressant drugs and patients who use alcoholin excess.225Tell 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 amajor cause of drug-related deaths. Fatalities within the first hour of

OVERDOSAGE

overdosage are not uncommon. In a survey of deaths dueto overdosage conducted in 1975, in approximately 20% of the fatal cases, death occurred within the first hour (5% occurredwithin 15 minutes). Propoxyphene should not be taken in doses higher than those recommended by the physician. Thejudicious 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 ofpropoxyphene products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its addeddepressant effects, propoxyphene should be prescribed with caution for those patients whose medical condition requires theconcomitant 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 orsuicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deathshave occurred as a consequence of the accidental ingestion of excessive quantities of propoxyphene alone or in combinationwith other drugs. Patients taking propoxyphene should be warned not to exceed the dosage recommended by the physician.USAGE IN AMBULATORY PATIENTSPropoxyphene may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such asdriving a car or operating machinery. The patient should be cautioned accordingly.

PRECAUTIONS

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

INFORMATION FOR PATIENTS

Information for PatientsSee accompanying Patient Information Sheet.

DRUG INTERACTIONS

Drug InteractionsThe 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. Shouldthis occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Suchoccurrences have been reported when propoxyphene was administered to patients on antidepressants, anticonvulsants, or warfarin-likedrugs. Severe neurologic signs, including coma, have occurred with concurrent use of carbamazepine.

PREGNANCY

PregnancySafe use in pregnancy has not been established relative to possible adverse effects on fetal development. Instances of withdrawalsymptoms in the neonate have been reported following usage during pregnancy. Therefore, propoxyphene should not be used inpregnant women unless, in the judgment of the physician, the potential benefits outweigh the possible hazards.

NURSING MOTHERS

Nursing MothersLow levels of propoxyphene have been detected in human milk. In postpartum studies involving nursing mothers who were givenpropoxyphene, no adverse effects were noted in infants receiving mother222s milk.

PEDIATRIC USE

Pediatric UseSafety and effectiveness in pediatric patients have not been established.

GERIATRIC USE

Geriatric UseThe rate of propoxyphene metabolism may be reduced in some patients. Increased dosing interval should be considered. page 4 of 8

ADVERSE REACTIONS

ADVERSE REACTIONSIn a survey conducted in hospitalized patients, less than 1% of patients taking propoxyphene hydrochloride at recommended dosesexperienced side effects. The most frequently reported were dizziness, sedation, nausea, and vomiting. Some of these adversereactions 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 acetaminophentablets. Propoxyphene therapy has been associated with abnormal liver function tests and, more rarely, with instances of reversiblejaundice (including cholestatic jaundice). Hepatic necrosis may result from acute overdose of acetaminophen (see OVERDOSAGE).In chronic ethanol

ABUSE

abusers, this has been reported rarely with short-term use of acetaminophen dosages of 2.5 to 10 g/day. Fatalitieshave occurred.Renal papillary necrosis may result from chronic acetaminophen use, particularly when the dosage is greater than recommended andwhen combined with aspirin.Subacute painful myopathy has occurred following chronic propoxyphene overdosage.

DRUG ABUSE AND DEPENDENCE

DRUG ABUSE AND

DEPENDENCE

DEPENDENCEPropoxyphene, when taken in higher-than-recommended doses over long periods of time, can produce drug dependence characterizedby psychic dependence and, less frequently, physical dependence and tolerance. Propoxyphene will only partially suppress thewithdrawal syndrome in individuals physically dependent on morphine or other narcotics. The abuse liability of propoxyphene isqualitatively similar to that of codeine although quantitatively less, and propoxyphene should be prescribed with the same degree ofcaution appropriate to the use of codeine.OVERDOSAGEIn all cases of suspected overdosage, call your regional Poison Control Center to obtain the most up-to-date information about thetreatment of overdose. This recommendation is made because, in general, information regarding the treatment of overdosage maychange more rapidly than do package inserts.Initial consideration should be given to the management of the CNS effects of propoxyphene overdosage. Resuscitative measuresshould be initiated promptly.Symptoms of Propoxyphene OverdosageThe manifestations of acute overdosage with propoxyphene are those of narcotic overdosage. The patient is usually somnolent butmay be stuporous or comatose and convulsing. Respiratory depression is characteristic. The ventilatory rate and/or tidal volumeis decreased, which results in cyanosis and hypoxia. Pupils, initially pinpoint, may become dilated as hypoxia increases. Cheyne-Stokes respiration and apnea may occur. Blood pressure and heart rate are usually normal initially, but blood pressure falls and cardiacperformance deteriorates, which ultimately results in pulmonary edema and circulatory collapse, unless the respiratory depressionis corrected and adequate ventilation is restored promptly. Cardiac arrhythmias and conduction delay may be present. A combinedrespiratory-metabolic acidosis occurs owing to retained CO2 (hypercapnia) and to lactic acid formed during anaerobic glycolysis.Acidosis may be severe if large amounts of salicylates have also been ingested. Death may occur.Treatment of Propoxyphene OverdosageAttention should be directed first to establishing a patent airway and to restoring ventilation. Mechanically assisted ventilation, withor without oxygen, may be required, and positive pressure respiration may be desirable if pulmonary edema is present. The narcoticantagonist naloxone will markedly reduce the degree of respiratory depression, and 0.4 to 2 mg should be administered promptly,preferably intravenously. If the desired degree of counteraction with improvement in respiratory functions is not obtained, naloxoneshould be repeated at 2- to 3-minute intervals. The duration of action of the antagonist may be brief. If no response is observed after10 mg of naloxone have been administered, the diagnosis of propoxyphene toxicity should be questioned. Naloxone may also beadministered by continuous intravenous infusion.Treatment of Propoxyphene Overdosage in Pediatric PatientsThe usual initial dose of naloxone in pediatric patients is 0.01 mg/kg body weight given intravenously. If this dose does not resultin the desired degree of clinical improvement, a subsequent increased dose of 0.1 mg/kg body weight may be administered. If an IVroute of administration is not available, naloxone may be administered IM or subcutaneously in divided doses. If necessary, naloxonecan be diluted with Sterile Water for Injection.Blood gases, pH, and electrolytes should be monitored in order that acidosis and any electrolyte disturbance present may be correctedpromptly. Acidosis, hypoxia, and generalized CNS depression predispose to the development of cardiac arrhythmias. Ventricularfibrillation or cardiac arrest may occur and necessitate the full complement of cardiopulmonary resuscitation (CPR) measures.Respiratory acidosis rapidly subsides as ventilation is restored and hypercapnia eliminated, but lactic acidosis may require intravenousbicarbonate for prompt correction.Electrocardiographic monitoring is essential. Prompt correction of hypoxia, acidosis, and electrolyte disturbance (when present) willhelp prevent these cardiac complications and will increase the effectiveness of agents administered to restore normal cardiac function. page 5 of 8 In addition to the use of a narcotic antagonist, the patient may require careful titration with an anticonvulsant to control convulsions.Analeptic drugs (for example, caffeine or amphetamine) should not be used because of their tendency to precipitate convulsions.General supportive measures, in addition to oxygen, include, when necessary, intravenous fluids, vasopressor-inotropic compounds,and, when infection is likely, anti-infective agents. Gastric lavage may be useful, and activated charcoal can adsorb a significantamount of ingested propoxyphene. Dialysis is of little value in poisoning due to propoxyphene. Efforts should be made to determinewhether other agents, such as alcohol, barbiturates, tranquilizers, or other CNS depressants, were also ingested, since these increaseCNS depression as well as cause specific toxic effects.Symptoms of Acetaminophen OverdosageShortly after oral ingestion or an overdose of acetaminophen and for the next 24 hours, anorexia, nausea, vomiting, diaphoresis,general malaise, and abdominal pain have been noted. The patient may then present no symptoms, but evidence of liver dysfunctionmay become apparent up to 72 hours after ingestion, with elevated serum transaminase and lactic dehydrogenase levels, an increase inserum bilirubin concentrations, and a prolonged prothrombin time. Death from hepatic failure may result 3 to 7 days after overdosage.Acute renal failure may accompany the hepatic dysfunction and has been noted in patients who do not exhibit signs of fulminanthepatic failure. Typically, renal impairment is more apparent 6 to 9 days after ingestion of the overdose.Treatment of Acetaminophen OverdosageAcetaminophen in massive overdosage may cause hepatic toxicity in some patients. In all cases of suspected overdose, immediatelycall your regional poison center or the Rocky Mountain Poison Center222s toll-free number (800-525-6115) for assistance in diagnosisand for directions in the use of N-acetylcysteine as an antidote.In adults, hepatic toxicity has rarely been reported with acute overdoses of less than 10 g and fatalities with less than 15 g.Importantly, young children seem to be more resistant than adults to the hepatotoxic effect of an acetaminophen overdose. Despitethis, the measures outlined below should be initiated in any adult or pediatric patients suspected of having ingested an acetaminophenoverdose.Because clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours postingestion, liver functionstudies should be obtained initially and repeated at 24-hour intervals.Consider emptying the stomach promptly by lavage or by induction of emesis with syrup of ipecac. Patients222 estimates of the quantityof a drug ingested are notoriously unreliable. Therefore, if an acetaminophen overdose is suspected, a serum acetaminophen assayshould be obtained as early as possible, but no sooner than 4 hours following ingestion. The antidote, N-acetylcysteine, should beadministered as early as possible, and within 16 hours of the overdose ingestion for optimal results. Following recovery, there are noresidual, structural, or functional hepatic abnormalities.DOSAGE AND ADMINISTRATIONThis product is given orally. The usual dosage is 100 mg propoxyphene napsylate and 650 mg acetaminophen every 4 hours as neededfor 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.

HOW SUPPLIED

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

DRUG: Propoxyphene Napsylate and Acetaminophen

GENERIC: Propoxyphene Napsylate and Acetaminophen

DOSAGE: TABLET

ADMINSTRATION: ORAL

NDC: 49349-159-02

STRENGTH:100.650 mg

COLOR: pink

SHAPE: OVAL

SCORE: No score

SIZE: 19 mm

IMPRINT: 30

QTY: 30