Acetaminophen; Propoxyphene Hydrochloride (0081)
[ a-seat-a-min'-oh-fen; proe-pox'-i-feen hye-droe-klor'-ide ]
| Ingredients: |
Acetaminophen; Propoxyphene Hydrochloride |
| Indications: |
Pain, mild to moderate |
| Pregnancy Category: |
C |
| FDA Approved: |
1981- 12- 01 |
| Classes: |
Analgesics, narcotic |
| Brand Names: |
Dacoten
-
Taiwan
;
Depain X
-
Taiwan
;
Dialgirex Ge
-
France
;
DiDolko Ge
-
France
;
Diolago Ge
-
France
;
Dolocin
-
Hong-kong
;
Medonol
-
Hong-kong
;
Propoxacet
-
US
;
Wygesic
-
US; India
;
|
| DEA schedules: |
Schedule IV |
DESCRIPTION
|
| |
Acetaminophen with propoxyphene HCl tablets contain 65 mg propoxyphene HCl and 650 mg acetaminophen. The inactive ingredients
present are cellulose, D&C yellow 10, FD&C blue 1, FD&C yellow 6, hydrogenated vegetable oil, hydroxypropyl methylcellulose,
methylcellulose, polacrilin potassium, polyethylene glycol, and titanium dioxide.
Propoxyphene HCl 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- phenylbenzeneethanol, propanoate (ester), hydrochloride.
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 N- acetyl- p- aminophenol.
|
CLINICAL PHARMACOLOGY
|
| |
Acetaminophen with propoxyphene HCl is a centrally acting narcotic analgesic agent.
Equimolar doses of propoxyphene HCl provide similar plasma concentrations. Following administration of 65, 130, or 195 mg
of propoxyphene HCl, 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 ½ hours. After a 65 mg oral dose of propoxyphene
HCl, peak plasma levels of 0.05 to 0.1 μg/ 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- 12 hours, whereas that
of norpropoxyphene is 30- 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.
Mechanism of Action
|
| |
Propoxyphene is a mild narcotic analgesic structurally related to methadone. The potency of propoxyphene HCl is from two-
thirds to equal that of codeine.
Propoxyphene HCl and acetaminophen 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 alone.
|
|
INDICATIONS AND USAGE
|
| |
Acetaminophen with propoxyphene HCl 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
IN EXCESS.
- TELL YOUR PATIENTS NOT TO EXCEED THE RECOMMENDED DOSE AND TO LIMIT THIER 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.
|
|
PRECAUTIONS
|
| |
General
|
| |
Propoxyphene should be administered with caution to patients with hepatic or renal impairment since higher serum concentrations
or delayed elimination may occur.
|
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.
|
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.
|
Pediatric Use
|
| |
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.
|
A patient Information Sheet is available for this 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.
|
ADVERSE REACTIONS
|
| |
In a survey conducted in hospitalized patients, less than 1% of patients taking propoxyphene HCl 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, light headedness, headache, weakness, euphoria,
dysphoria, and minor visual disturbances.
Liver dysfunction has been reported in association with both active components of propoxyphene and acetaminophen tablets.
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 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.
|
DRUG ABUSE AND 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.
|
|
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 overdosage. 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 (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 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 HCl 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, naloxone should be repeated at 2- 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 HCl 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 hypercapnia 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 adsorb 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- 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- 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- 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- 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 4 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.
|
|
DOSAGE AND ADMINISTRATION
|
| |
This product is given orally. The usual dose is 65 mg propoxyphene HCl and 650 mg acetaminophen every 4 hours as needed for
pain. The maximum recommended dose of propoxyphene HCl is 390 mg per day.
Consideration should be given to a reduced total daily dosage in patients with hepatic or renal impairment.
Store at controlled room temperature, 15- 30°C (59- 86°F).
Dispense in a tight, light- resistant container.
|
ANIMAL PHARMACOLOGY
|
| |
The acute lethal doses of the HCl and napsylate salts of propoxyphene were determined in 4 species. The results shown in TABLE 1 indicate that on a molar basis, the napsylate salt is less toxic than the HCl. This may be due to the relative insolubility
and retarded absorption of propoxyphene napsylate.
| TABLE 1
Acute Oral Toxicity Of Propoxyphene
|
| |
LD50 (mg/ kg) = SE |
|
| |
LD50 (mMole/ kg) |
|
| Species |
Propoxyphene HCl |
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 the 4 dogs given propoxyphene HCl 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.
|
PRODUCT IDENTIFICATION
|
| |
None Available |
PRODUCT LISTING - RATED THERAPEUTICALLY EQUIVALENT
|
| |
| tablet - oral - hydrochloride 650 mg- 65 mg -
|
| 100.0's |
$16.75 |
GENERIC
Major Pharmaceuticals Inc
|
00904217160 |
| 100.0's |
$30.40 |
GENERIC
Watson Pharmaceuticals
|
00591071401 |
| 100.0's |
$30.40 |
GENERIC
Mylan Pharmaceuticals Inc
|
00378013001 |
| 100.0's |
$31.30 |
GENERIC
Sandoz Inc
|
00781137813 |
| 100.0's |
$34.78 |
GENERIC
UDL Laboratories Inc
|
51079074120 |
| 100.0's |
$35.50 |
GENERIC
Major Pharmaceuticals Inc
|
00904217161 |
| 500.0's |
$78.50 |
GENERIC
Major Pharmaceuticals Inc
|
00904217140 |
| 500.0's |
$94.60 |
GENERIC
Qualitest Pharmaceuticals Inc
|
00603546328 |
| 500.0's |
$144.40 |
GENERIC
Watson Pharmaceuticals
|
00591071405 |
| 500.0's |
$144.40 |
GENERIC
Mylan Pharmaceuticals Inc
|
00378013005 |
|
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
|
| |
| tablet - oral - hydrochloride 650 mg- 65 mg -
|
| 10.0's |
$3.80 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027910 |
| 12.0's |
$4.56 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027912 |
| 15.0's |
$5.70 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027915 |
| 20.0's |
$4.30 |
GENERIC
Allscripts Healthcare Solutions
|
54569258800 |
| 20.0's |
$7.59 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027920 |
| 25.0's |
$9.49 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027925 |
| 30.0's |
$6.45 |
GENERIC
Allscripts Healthcare Solutions
|
54569258801 |
| 30.0's |
$8.40 |
GENERIC
Pharma Pac
|
52959016530 |
| 30.0's |
$9.67 |
GENERIC
PD- RX Pharmaceuticals
|
55289032130 |
| 30.0's |
$11.39 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027930 |
| 40.0's |
$15.19 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027940 |
| 50.0's |
$18.98 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027950 |
| 60.0's |
$22.78 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027960 |
| 70.0's |
$26.58 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027970 |
| 80.0's |
$30.37 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027980 |
| 90.0's |
$34.17 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027990 |
| 100.0's |
$22.37 |
GENERIC
Physicians Total Care
|
54868364600 |
| 100.0's |
$37.97 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027900 |
| 100.0's |
$39.99 |
Propoxacet
DispenseXpress Inc
|
68115081500 |
| 120.0's |
$45.56 |
GENERIC
Southwood Pharmaceuticals Inc
|
58016027902 |
|
|