Rx Drugs Info

propoxyphene hydrochloride & acetaminophen (Propoxyphene Hydrochloride and Acetaminophentablet, film coated 
[Mylan Pharmaceuticals Inc.]

CIV

65 mg/650 mg

Rx only

DESCRIPTION

Propoxyphene hydrochloride, USP is an odorless, white crystalline powder with a bitter taste. It is freely soluble in water. Chemically, it is [S-(R*S*)]-α-[2-(dimethylamino)-1 methylethyl]-α-phenyl-benzene-ethanol, propanoate (ester) hydrochloride, which can be represented by the following structural formula:

Image from Drug Label Content

Acetaminophen, USP is a white, crystalline powder, possessing a slightly bitter taste. It is soluble in boiling water and freely soluble in alcohol. Chemically, it is N-Acetyl-p-aminophenol, which can be represented by the following structural formula:

Image from Drug Label Content

Each tablet for oral administration contains 65 mg of propoxyphene hydrochloride and 650 mg of acetaminophen and the following inactive ingredients: hydroxypropyl cellulose, hypromellose, polyethylene glycol, povidone, pregelatinized starch, sodium starch glycolate, stearic acid, talc, titanium dioxide, and FD&C Yellow #6 aluminum lake.

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 1/2 hours. After a 65 mg oral dose of propoxyphene hydrochloride, peak plasma levels of 0.05 to 0.1 mcg/mL are achieved.

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 (P-R 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 hydrochloride is from two-thirds to equal that of codeine. Propoxyphene hydrochloride and acetaminophen provide the analgesic activity of propoxyphene 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

This 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

Hypersensitivity to propoxyphene or to 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 to 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 nonnarcotic 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 hydrochloride and acetaminophen tablets are a Schedule IV controlled substance.

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.

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.

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

Usage in Nursing Mothers

Low levels of propoxyphene have been detected in human milk. In postpartum studies involving nursing mothers who were given propoxyphene, no adverse effects were noted in infants receiving mother's milk.

Usage in Children

Propoxyphene is not recommended for use in children, because documented clinical experience has been insufficient to establish safety and a suitable dosage regimen in the pediatric age group.

ADVERSE REACTIONS

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 have been 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, and minor visual disturbances.

Liver dysfunction has been reported in association with both active components of propoxyphene hydrochloride and acetaminophen.

Propoxyphene therapy has been associated with abnormal liver function tests and, more rarely, with instances of reversible jaundice.

Hepatic necrosis may result from acute overdoses of acetaminophen (see MANAGEMENT OF 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.

DOSAGE AND ADMINISTRATION

This product is given orally. The usual dose is 65 mg propoxyphene hydrochloride and 650 mg acetaminophen every 4 hours as needed for pain. The maximum recommended dose of propoxyphene hydrochloride is 390 mg per day.

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

MANAGEMENT OF 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.

Symptoms of Propoxyphene Overdosage

The manifestations of acute overdosage with propoxyphene are those of narcotic overdosage. The patient is usually somnolent, but may be stuporous or comatose and convulsing. Respiratory depression is characteristic. The ventilatory rate and/or tidal volume is 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 cardiac performance deteriorates, which ultimately results in pulmonary edema and circulatory collapse, unless the respiratory depression is corrected and adequate ventilation is restored promptly. Cardiac arrhythmias and conduction delay may be present. A combined respiratory-metabolic acidosis occurs, owing to retained CO2 (hypercapnea) 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 Overdosage

Attention should be directed first to establishing a patent airway and to restoring ventilation. Mechanically assisted ventilation, with or without oxygen, may be required, and positive pressure respiration may be desirable if pulmonary edema is present. The narcotic antagonist 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 function is not obtained, naloxone should be repeated at 2 to 3 minute intervals. The duration of action of the antagonist may be brief. If no response is observed after 10 mg of naloxone have been administered, the diagnosis of propoxyphene toxicity should be questioned. Naloxone hydrochloride may also be administered by continuous intravenous infusion.

Treatment of Propoxyphene Overdosage in Children

The usual initial dose of naloxone in children is 0.01 mg/kg body weight given intravenously. If this dose does not result in the desired degree of clinical improvement, a subsequent increased dose of 0.1 mg/kg body weight may be administered. If an IV route of administration is not available, naloxone may be administered IM or subcutaneously in divided doses. If necessary, naloxone can 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 corrected promptly. Acidosis, hypoxia, and generalized CNS depression predispose to the development of cardiac arrhythmias. Ventricular fibrillation or cardiac arrest may occur and necessitate the full complement of cardiopulmonary resuscitation (CPR) measures. Respiratory acidosis rapidly subsides as ventilation is restored and hypercapnea eliminated, but lactic acidosis may require intravenous bicarbonate for prompt correction.

Electrocardiographic monitoring is essential. Prompt correction of hypoxia, acidosis, and electrolyte disturbance (when present) will help prevent these cardiac complications and will increase the effectiveness of agents administered to restore normal cardiac function.

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 absorb a significant amount of ingested propoxyphene. Dialysis is of little value in poisoning due to propoxyphene. Efforts should be made to determine whether other agents, such as alcohol, barbiturates, tranquilizers, or other CNS depressants were also ingested, since these increase CNS depression as well as cause specific toxic effects.

Symptoms of Acetaminophen Overdosage

Shortly after oral ingestion of an overdosage of acetaminophen and for the next 24 hours, anorexia, nausea, vomiting, and abdominal pain have been noted. The patient may then present no symptoms, but evidence of liver dysfunction may be apparent during the next 24 to 48 hours, with elevated serum transaminase and lactic dehydrogenase levels, an increase in serum 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 fulminant hepatic failure. Typically, renal impairment is more apparent 6 to 9 days after ingestion of the overdose.

Treatment of Acetaminophen Overdosage

Acetaminophen in massive overdosage may cause hepatic toxicity in some patients. In all cases of suspected overdose, you may wish to call your regional poison center for assistance in diagnosis and 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. Despite this, the measures outlined below should be initiated in any adult or child suspected of having ingested an acetaminophen overdose.

Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours postingestion. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise.

The stomach should be emptied promptly by lavage or by induction of emesis with syrup of ipecac. Patients' estimates of the quantity of a drug ingested are notoriously unreliable. Therefore, if an acetaminophen overdose is suspected, a serum acetaminophen assay should be obtained as early as possible, but no sooner than four hours following ingestion. Liver function studies should be obtained initially and repeated at 24-hour intervals. The antidote, N-acetylcysteine, should be administered as early as possible, preferably within 16 hours of the overdose ingestion for optimal results, but in any case, within 24 hours. Following recovery, there are no residual, structural or functional hepatic abnormalities.

HOW SUPPLIED

Propoxyphene hydrochloride and Acetaminophen Tablets, USP are available containing 65 mg of propoxyphene hydrochloride, USP and 650 mg of acetaminophen, USP.

The tablets are film-coated orange, capsule-shaped, and debossed with MYLAN 130. They are available as follows:

NDC 0378-0130-01
bottles of 100 tablets

NDC 0378-0130-05
bottles of 500 tablets

STORE AT CONTROLLED ROOM TEMPERATURE 15°–30°C (59°–86°F).

PROTECT FROM LIGHT.

Dispense in a tight, light-resistant container using a child-resistant closure.

ANIMAL TOXICOLOGY

The acute lethal doses of the hydrochloride and napsylate salts of propoxyphene were determined in 4 species. The results shown in Figure 1 indicate that on a molar basis, the napsylate salt is less toxic than the hydrochloride. This may be due to the relative insolubility and retarded absorption of propoxyphene napsylate.

FIGURE 1 - ACUTE ORAL TOXICITY OF PROPOXYPHENE
LD50 (mg/kg) ± SE
LD50 (mmole/kg)
Species Propoxyphene Hydrochloride Propoxyphene Napsylate
Mouse 282 ± 39 915 ± 163
0.75 1.62
Rat 230 ± 44 647 ± 95
0.61 1.14
Rabbit ca 82 >183
0.22 >0.32
Dog ca 100 >183
0.27 >0.32

Some indication of the relative insolubility and retarded absorption of propoxyphene napsylate was obtained by measuring plasma propoxyphene levels in 2 groups of 4 dogs following oral administration of equimolar doses of the 2 salts.

Although none of the animals in this experiment died, 3 of 4 dogs given propoxyphene hydrochloride exhibited convulsive seizures during the time interval corresponding to the peak plasma levels. The 4 animals receiving the napsylate salt were ataxic but not acutely ill.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

REVISED JULY 2003
PXAP:R6AQ


Propoxyphene Hydrochloride & Acetaminophen (Propoxyphene Hydrochloride and Acetaminophen)
PRODUCT INFO
Product Code 0378-0130 Dosage Form TABLET, FILM COATED
Route Of Administration ORAL DEA Schedule CIV
INGREDIENTS
Name (Active Moiety) Type Strength
Propoxyphene Hydrochloride (Propoxyphene) Active 65 MILLIGRAM  In 1 TABLET
Acetaminophen (Acetaminophen) Active 650 MILLIGRAM  In 1 TABLET
hydroxypropyl cellulose Inactive  
hypromellose Inactive  
polyethylene glycol Inactive  
povidone Inactive  
pregelatinized starch Inactive  
sodium starch glycolate Inactive  
stearic acid Inactive  
talc Inactive  
titanium dioxide Inactive  
FD&C Yellow #6 aluminum lake Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color ORANGE Score 1
Shape OVAL (capsule-shaped) Symbol false
Imprint Code MYLAN;130 Coating true
Size 19mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 0378-0130-01 100 TABLET In 1 BOTTLE, PLASTIC None
2 0378-0130-05 500 TABLET In 1 BOTTLE, PLASTIC None

Revised: 01/2008Mylan Pharmaceuticals Inc.

Data are from FDA and U.S. National Library of Medicine.