Document
DailyMed Label: Propoxyphene Napsylate and Acetaminophen
Title
DailyMed Label: PROPOXYPHENE NAPSYLATE AND ACETAMINOPHEN
Date
2010
Document type
DailyMed Prescription
Name
PROPOXYPHENE NAPSYLATE AND ACETAMINOPHEN
Generic name
PROPOXYPHENE NAPSYLATE AND ACETAMINOPHEN
Manufacturer
Apotheca, Inc.
Product information
NDC: 12634-537
Product information
NDC: 12634-537
Description
Propoxyphene napsylate and acetaminophen tablets USP contain
propoxyphene napsylate and acetaminophen.
Propoxyphene napsylate is an odorless, white crystalline powder with a bitter
taste. It is very slightly soluble in water, soluble in methanol, in ethanol, in
chloroform, and in acetone. Chemically it is (α S ,1 R )-α-[2-(dimethylamino)-1-methylethyl]-α-phenylphenethyl
propionate compound with 2-naphthalenesulfonic acid (1:1) monohydrate and can be
represented by the following structural formula:
C 22 H 29 NO 2 •C 10 H 8 O 3 S•H 2 O M.W. 565.74
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.
Acetaminophen, 4'-hydroxyacetanilide, is a non-opiate, non-salicylate
analgesic and antipyretic which occurs as a white, odorless, crystalline powder,
possessing a slightly bitter taste. Chemically, it is acetamide, N -(4-hydroxyphenyl)- and can structurally be represented by
the following:
C 8 H 9 NO 2 M.W. 151.16
Each pink tablet of propoxyphene napsylate and acetaminophen tablets
contains 100 mg propoxyphene napsylate and 650 mg acetaminophen.
Propoxyphene napsylate and acetaminophen tablets, USP 100 mg/650 mg (PINK)
contain the following inactive ingredients:
colloidal silicon dioxide,D and C
red No 27 aluminum lake, D and C yellow No 10 aluminum lake, hydroxypropyl
cellulose, hypromellose, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, povidone, pregelatinized starch, stearic acid, titanium
dioxide, and crospovidone.
image of structural formula
image of formula
Indications
Propoxyphene napsylate and acetaminophen tablets are indicated for the relief of
mild to moderate pain.
Dosage
Proproxyphene napsylate and acetaminophen tablets USP are
intended for the management of mild to moderate pain. The dose should be
individually adjusted according to severity of pain, patient response and
patient size.
Propoxyphene napsylate and acetaminophen tablets USP (100 mg
propoxyphene napsylate and 650 mg acetaminophen)
The usual dosage is one tablet every 4 hours orally as needed for pain. The
maximum dose of propoxyphene napsylate and acetaminophen tablets USP is 6
tablets per day. Do not exceed the maximum daily dose.
Patients receiving propoxyphene and any CYP3A4 inhibitor should be carefully
monitored for an extended period of time and dosage adjustments should be made
if warranted.
Consideration should be given to a reduced total daily dosage in elderly
patients and in patients with hepatic or renal impairment.
For patients who used propoxyphene napsylate and acetaminophen tablets USP on a
regular basis for a period of time, when therapy with propoxyphene napsylate and
acetaminophen tablets USP is no longer needed for the treatment of their pain,
it may be useful to gradually discontinue the propoxyphene napsylate and
acetaminophen tablets USP over time to prevent the development of an opioid
abstinence syndrome (narcotic withdrawal). In general, therapy can be decreased
by 25% to 50% per day with careful monitoring for signs and symptoms of
withdrawal (see DRUG ABUSE AND DEPENDENCE for
description of the signs and symptoms of withdrawal). If the patient develops
these signs or symptoms, the dose should be raised to the previous level and
titrated down more slowly, either by increasing the interval between decreases,
decreasing the amount of change in dose, or both.
Contraindications
Propoxyphene napsylate and acetaminophen tablets are
contraindicated in patients with known hypersensitivity to propoxyphene or
acetaminophen.
Propoxyphene napsylate and acetaminophen tablets are contraindicated in
patients with significant respiratory depression (in unmonitored settings or the
absence of resuscitative equipment) and patients with acute or severe asthma or
hypercarbia.
Propoxyphene napsylate and acetaminophen tablets are contraindicated in any
patient who has or is suspected of having paralytic ileus.
Precautions
Tolerance and Physical Dependence
Tolerance is the need for increasing doses of opioids to maintain
a defined effect such as analgesia (in the absence of disease progression or
other external factors). Physical dependence is manifested by withdrawal
symptoms after abrupt discontinuation of a drug or upon administration of an
antagonist. Physical dependence and tolerance are not unusual during chronic
opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or all
of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration,
chills, myalgia, and mydriasis. Other symptoms also may develop, including:
irritability, anxiety, backache, joint pain, weakness, abdominal cramps,
insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure,
respiratory rate, or heart rate. In general, opioids should not be abruptly
discontinued (see DOSAGE AND ADMINISTRATION , Cessation of Therapy ).
If propoxyphene napsylate and acetaminophen tablets are abruptly discontinued
in a physically dependent patient, an abstinence syndrome may occur (see DRUG ABUSE AND DEPENDENCE ) . If signs and symptoms of
withdrawal occur, patients should be treated by reinstitution of opioid therapy
followed by gradual tapered dose reduction of propoxyphene napsylate and
acetaminophen tablets combined with symptomatic support (see DOSAGE AND ADMINISTRATION , Cessation of
Therapy ).
Propoxyphene napsylate and acetaminophen tablets may cause spasm of the
sphincter of Oddi and should be used with caution in patients with biliary tract
disease, including acute pancreatitis. Opioids like propoxyphene napsylate and
acetaminophen tablets may cause increases in the serum amylase level
Insufficient information exists to make appropriate dosing recommendations
regarding the use of either propoxyphene alone or in combination with
acetaminophen in patients with hepatic or renal impairment as a function of
degree of impairment. Higher plasma concentrations and/or delayed elimination
may occur in case of impaired hepatic function and/or impaired renal function (see CLINICAL
PHARMACOLOGY ). If the drug is used in
these patients, it should be used with caution because of the hepatic metabolism
of propoxyphene and acetaminophen and renal excretion of their metabolites.
Patients should be advised to report pain and adverse experiences occurring
during therapy. Individualization of dosage is essential to make optimal use of
this medication.
Patients should be advised not to adjust the dose of propoxyphene napsylate
and acetaminophen tablets without consulting the prescribing professional.
Patients should be advised that propoxyphene napsylate and acetaminophen
tablets may impair mental and/or physical ability required for the performance
of potentially hazardous tasks (e.g., driving, operating heavy machinery).
Patients should not combine propoxyphene napsylate and acetaminophen tablets
with central nervous system depressants (e.g., sleep aids, tranquilizers) except
by the orders of the prescribing physician, because additive effects may occur.
Patients should be instructed not to consume alcoholic beverages, including
prescription and over-the-counter medications that contain alcohol, while using
propoxyphene napsylate and acetaminophen tablets because of risk of serious
adverse events including death.
Women of childbearing potential who become, or are planning to become,
pregnant should be advised to consult their physician regarding the effects of
analgesics and other drug use during pregnancy on themselves and their unborn
child.
Patients should be advised that propoxyphene napsylate and acetaminophen
tablets are a potential drug of abuse. They should protect it from theft, and it
should never be given to anyone other than the individual for whom it was
prescribed.
Patients should be advised that if they have been receiving treatment with
propoxyphene napsylate and acetaminophen tablets for more than a few weeks and
cessation of therapy is indicated, it may be appropriate to taper the
propoxyphene napsylate and acetaminophen tablet dose, rather than abruptly
discontinue it, due to the risk of precipitating withdrawal symptoms. Their
physician can provide a dose schedule to accomplish a gradual discontinuation of
the medication.
Instruct patients not to consume any other medication that contain
acetaminophen, including acetaminophen-based over-the-counter medications, while
taking propoxyphene napsylate and acetaminophen tablets.
Propoxyphene is metabolized mainly via the human cytochrome P450
3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when
propoxyphene is administered concurrently with agents that affect CYP3A4
activity.
The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors
(such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin,
nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem,
erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil)
leading to enhanced propoxyphene plasma levels. Coadministration with agents
that induce CYP3A4 activity may reduce the efficacy of propoxyphene. Strong
CYP3A4 inducers such as rifampin may lead to enhanced metabolite
(norpropoxyphene) levels.
Propoxyphene is also thought to possess CYP3A4 and CYP2D6 enzyme inhibiting
properties and coadministration with drugs that rely on either of these enzymes
for metabolism may result in increased pharmacologic or adverse effects of that
drug. Severe neurologic signs, including coma, have occurred with concurrent use
of carbamazepine (metabolized by CYP3A4).
Increased risk of bleeding has been observed with warfarin-like agents when
given along with propoxyphene; however, the mechanistic basis of this
interaction is unknown.
CNS Depressants
Patients receiving narcotic analgesics, general anesthetics,
phenothiazines, other tranquilizers, sedative-hypnotics or other CNS depressants
(including alcohol) concomitantly with propoxyphene napsylate and acetaminophen
tablets may exhibit an additive CNS depression. Interactive effects resulting in
respiratory depression, hypotension, profound sedation, or coma may result if
these drugs are taken in combination with the usual dosage of propoxyphene
napsylate and acetaminophen tablets. When such combined therapy is contemplated,
the dose of one or both agents should be reduced.
Mixed Agonist/Antagonist Opioid Analgesics
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine,
butorphanol and buprenorphine) should be administered with caution to patients
who have received or are receiving a course of therapy with a pure opioid
agonist analgesic such as propoxyphene napsylate and acetaminophen tablets. In
this situation, mixed agonist/antagonist analgesics may reduce the analgesic
effect of propoxyphene napsylate and acetaminophen tablets and/or may
precipitate withdrawal symptoms in these patients.
Monoamine Oxidase Inhibitors (MAOIs)
MAOIs have been reported to intensify the effects of at least one
opioid drug causing anxiety, confusion and significant depression of respiration
or coma. The use of propoxyphene napsylate and acetaminophen tablets is not
recommended for patients taking MAOIs or within 14 days of stopping such
treatment.
Alcohol : Hepatotoxicity has occurred
in chronic alcoholics following various dose levels (moderate to excessive) of
acetaminophen.
Anticholinergics : The onset of acetaminophen
effect may be delayed or decreased slightly, but the ultimate pharmacological
effect is not significantly affected by anticholinergics.
Oral Contraceptives : Increase in glucuronidation
resulting in increased plasma clearance and a decreased half-life of
acetaminophen.
Beta Blockers (Propranolol) : Propranolol appears
to inhibit the enzyme systems responsible for the glucuronidation and oxidation
of acetaminophen. Therefore, the pharmacologic effects of acetaminophen may be
increased.
Loop Diuretics : The effects of the loop diuretic
may be decreased because acetaminophen may decrease renal prostaglandin
excretion and decrease plasma renin activity.
Lamotrigine : Serum lamotrigine concentrations
may be reduced, producing a decrease in therapeutic effects.
Probenecid : Probenecid may increase the
therapeutic effectiveness of acetaminophen slightly.
Zidovudine : The pharmacologic effects of
zidovudine may be decreased because of enhanced nonhepatic or renal clearance of
zidovudine.
The mutagenic and carcinogenic potential of propoxyphene and
acetaminophen alone and in combination have not been evaluated.
In animal studies there was no effect of propoxyphene on mating behavior,
fertility, duration of gestation, or parturition when rats were fed propoxyphene
as a component of their daily diet at estimated daily propoxyphene intake up to
8 fold greater than the maximum human equivalent dose (HED) based on body
surface area comparison. At this highest dose, fetal weight and survival on
postnatal day 4 was reduced. Acetaminophen has not been studied in animals for
effects on fertility and the effects on human fertility are unknown.
Risk Summary
Pregnancy category C
There are no adequate and well-controlled studies of propoxyphene
with acetaminophen in pregnant women. While there are limited data in the
published literature, adequate animal reproduction studies have not been
conducted with propoxyphene or acetaminophen. Therefore, it is not known whether
propoxyphene or acetaminophen can affect reproduction or cause fetal harm when
administered to a pregnant woman. Propoxyphene with acetaminophen should be
given to a pregnant woman only if clearly needed.
Clinical Considerations
Acetaminophen, propoxyphene and its major metabolite,
norpropoxyphene, cross the human placenta. Neonates whose mothers have taken
opiates chronically may exhibit respiratory depression or withdrawal
symptoms.
Data
In published animal reproduction studies, no teratogenic effects
occurred in offspring born to pregnant rats or rabbits that received
propoxyphene during organogenesis. Pregnant animals received propoxyphene doses
approximately 10 fold (rats) and 4 fold (rabbits) the maximum recommended human
dose (based on mg/m 2 body surface area comparison).
Propoxyphene, norpropoxyphene (major metabolite), and acetaminophen are excreted
in human milk. Published studies of nursing mothers using propoxyphene detected
no adverse effects in nursing infants. Based on a study of six mother-infant
pairs, an exclusively breastfed infant receives approximately 2% of the maternal
weight-adjusted dose. Norpropoxyphene is renally excreted and renal clearance is
lower in neonates than in adults. Therefore, it is possible that prolonged
maternal propoxyphene use could result in norpropoxyphene accumulation in a
breastfed infant. Watch breastfeeding infants for signs of sedation including
poor feeding, somnolence, or respiratory depression. Caution should be exercised
when propoxyphene napsylate and acetaminophen tablets are administered to a
nursing woman.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of propoxyphene napsylate and acetaminophen did not include
sufficient numbers of subjects aged 65 and over to determine whether they
respond differently from younger subjects. However, postmarketing reports
suggest that patients over the age of 65 may be more susceptible to CNS-related
side effects. Therefore, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy. Decreased total daily dosage should
be considered (see DOSAGE AND ADMINISTRATION ).
Adverse reactions
During clinical trials, the most frequently reported adverse
reactions were dizziness, sedation, nausea, and vomiting. Other adverse
reactions include constipation, abdominal pain, skin rashes, lightheadedness,
headache, weakness, euphoria, dysphoria, hallucinations, and minor visual
disturbances.
How supplied
Propoxyphene napsylate and acetaminophen tablets, USP 100 mg/650 mg (PINK) are
available as film-coated, oblong, pink tablets debossed either "93"-"890" or
"TEVA"-"890". They are supplied as follows:
12634-534-91 Blister Pack UD of 1
12634-537-69 Blister Pack Card of 9
12634-537-55 Blister Pack Card of 15
12634-537-98 Bottle of 8
12634-537-00 Bottle of 10
12634-537-82 Bottle of 12
12634-537-85 Bottle of 15
12634-537-80 Bottle of 20
12634-537-71 Bottle of 30
12634-537-60 Bottle of 60
12634-537-01 Bottle of 100
Clinical pharmacology
Pharmacology
Propoxyphene is a centrally acting opiate analgesic. In vitro studies demonstrated propoxyphene and the
metabolite norpropoxyphene inhibit sodium channels (local anesthetic effect)
with norpropoxyphene being approximately 2 fold more potent than propoxyphene
and propoxyphene approximately 10 fold more potent than lidocaine. Propoxyphene
and norpropoxyphene inhibit the voltage-gated potassium current carried by
cardiac rapidly activating delayed rectifier (hERG) channels with approximately
equal potency. It is unclear if the effects on ion channels occur within
therapeutic dose range.
Acetaminophen is a non-opiate, non-salicylate analgesic and antipyretic. The
site and mechanism for the analgesic effect of acetaminophen has not been
determined. The antipyretic effect of acetaminophen is mediated through activity
in the hypothalamic heat-regulating centers. Acetaminophen inhibits
prostaglandin synthetase. Therapeutic doses of acetaminophen have negligible
effects on the cardiovascular or respiratory systems; however, toxic doses may
cause circulatory failure and rapid, shallow breathing.
Absorption
Peak plasma concentrations of propoxyphene are reached in 2 to
2.5 h. After a 65 mg oral dose of propoxyphene hydrochloride, peak plasma levels
of 0.05 to 0.1 mcg/mL for propoxyphene and 0.1 to 0.2 mcg/mL for norpropoxyphene
(major metabolite) are achieved. Repeated doses of propoxyphene at 6 h intervals
lead to increasing plasma concentrations, with a plateau after the ninth dose at
48 h. Propoxyphene has a half-life of 6 to 12 h, whereas that of norpropoxyphene
is 30 to 36 h.
Acetaminophen is absorbed from the gastrointestinal tract and has a plasma
half-life of 1.25 to 3 h, which may be increased by liver damage and following
overdosage.
Distribution
Propoxyphene is about 80% bound to proteins and has a large
volume of distribution, 16 L/kg.
Acetaminophen is relatively uniformly distributed throughout most body
fluids. Binding of the drug to plasma proteins is variable; only 20% to 50% may
be bound at the concentrations encountered during acute intoxication.
Metabolism
Propoxyphene undergoes extensive first-pass metabolism by
intestinal and hepatic enzymes. The major route of metabolism is cytochrome
CYP3A4 mediated N-demethylation to norpropoxyphene, which is excreted by the
kidneys. Ring hydroxylation and glucuronide formation are minor metabolic
pathways.
Acetaminophen is extensively metabolized in the liver. Less than 5% of
acetaminophen dose is excreted unchanged in the kidney. About 85% of an
acetaminophen dose is metabolized by conjugation, mainly glucuronidation via
UDP-glucuronosyltransferase (mainly UGT1A6) and to a lesser extent sulfation via
sulfotransferase (mainly SLT1A1 and SLT1A3). The glucuronide and sulfate
conjugates are nontoxic and are largely excreted in the urine and bile. About 8
to 10% of an acetaminophen dose is oxidized by cytochrome CYP2E1 to form the
toxic reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is
further metabolized via glutathione (GSH) conjugation, yielding non-toxic thiol
metabolites including cysteine, mercapturate, methylthioacetaminophen, and
methanesulfinylacetaminophen that are excreted in the urine. Acetaminophen is
also oxidized at a low percentage by cytochrome CYP2A6 to form inert catechols
(e.g., methoxyacetaminophen).
Excretion
In 48 h, approximately 20 to 25% of the administered dose of
propoxyphene is excreted via the urine, most of which is free or conjugated
norpropoxyphene. The renal clearance rate of propoxyphene is 2.6 L/min.
Elimination of acetaminophen is principally by liver metabolism (conjugation)
and subsequent renal excretion of metabolites. Approximately 85% of an oral dose
appears in the urine within 24 hours of administration, most as the glucuronide
conjugate, with small amounts of other conjugates and unchanged drug.
Geriatric Patients
After oral administration of propoxyphene in elderly patients (70
to 78 years), much longer half-lives of propoxyphene and norpropoxyphene have
been reported (propropoxyphene 13 to 35 h, norpropoxyphene 22 to 41 h). In
addition, the AUC was an average of 3 fold higher and the C max was an average of 2.5 fold higher in the elderly when
compared to a younger (20 to 28 years) population. Longer dosage intervals may
be considered in the elderly because the metabolism of propoxyphene may be
reduced in this patient population. After multiple oral doses of propoxyphene in
elderly patients (70 to 78 years), the C max of the
metabolite (norpropoxyphene) was increased 5 fold.
Pediatric Patients
Neither propoxyphene alone nor in combination with acetaminophen
has been studied in pediatric patients.
Hepatic Impairment
No formal pharmacokinetic study of either propoxyphene alone or
in combination with acetaminophen has been conducted in patients with mild,
moderate or severe hepatic impairment.
After oral administration of propoxyphene in patients with cirrhosis, plasma
concentrations of propoxyphene were considerably higher and norpropoxyphene
concentrations were much lower than in control patients. This is presumably
because of a decreased first-pass metabolism of orally administered propoxyphene
in these patients. The AUC ratio of norpropoxyphene: propoxyphene was
significantly lower in patients with cirrhosis (0.5 to 0.9) than in controls
(2.5 to 4).
Compared to healthy subjects, acetaminophen had a lower total clearance and
longer half-life in patients with liver disease. Decreased metabolite formation
clearance (8 to 42%) was observed in subjects with liver disease compared to
healthy subjects after both single and multiple-doses (at steady state). In
addition, there is an increase in the amount of acetaminophen excreted unchanged
in the urine (4.7% vs. 2.5%) in patients with liver disease compared to healthy
subjects after repeat doses, suggesting that more acetaminophen was excreted by
renal elimination in the liver disease state.
Renal Impairment
No formal pharmacokinetic study of either propoxyphene alone or
in combination with acetaminophen has been conducted in patients with mild,
moderate or severe renal impairment.
After oral administration of propoxyphene in anephric patients, the AUC and
C max values were an average of 76% and 88% greater,
respectively. Dialysis removes only insignificant amounts (8%) of administered
dose of propoxyphene.
Drug Interactions
The metabolism of propoxyphene may be altered by strong CYP3A4
inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin,
clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant,
diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and
verapamil) leading to enhanced propoxyphene plasma levels. On the other hand,
strong CYP3A4 inducers such as rifampin may lead to enhanced metabolite
(norpropoxyphene) levels.
Propoxyphene is also thought to possess CYP3A4 and CYP2D6 enzyme inhibiting
properties. Coadministration with a drug that is a substrate of CYP3A4 or
CYP2D6, may result in higher plasma concentrations and increased pharmacologic
or adverse effects of that drug.
Clinical studies
The efficacy of propoxyphene in combination with acetaminophen
was studied in seven single-dose, randomized, double-blind, placebo-controlled
trials in patients with mild to severe postpartum pain. One of the studies
demonstrated that both propoxyphene and acetaminophen in the combination
contributed to a greater reduction in pain than acetaminophen and propoxyphene
alone and that propoxyphene was superior to placebo.
There is insufficient information available to assess efficacy of
propoxyphene in combination with acetaminophen in patients with chronic pain.
Package label
NDC 12634-537-00 Propoxyphene Napsylate and Acetaminophen CIV 100mg/650mg Bottle 10 Tablets MFG: Teva Pharmaceuticals Inc. Repackaged and Distributed: Apotheca Inc.
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Apotheca, Inc.