Opioid analgesics should be used with caution when combined with CNS depressant drugs, and should
be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory
depression, altered mental state, and postural hypotension.
ENDODAN tablets should be given with caution to patients with CNS depression, elderly or debilitated
patients, patients with severe impairment of hepatic, pulmonary, or renal function, hypothyroidism,
Addison's disease, prostatic hypertrophy, urethral stricture, acute alcoholism, delirium tremens,
kyphoscoliosis with respiratory depression, myxedema, and toxic psychosis.
ENDODAN tablets may obscure the diagnosis or clinical course in patients with acute abdominal
conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids
may induce or aggravate seizures in some clinical settings.
Following administration of ENDODAN tablets, anaphylactic reactions have been reported in patients
with a known hypersensitivity to codeine, a compound with a structure similar to morphine and
oxycodone. The frequency of this possible cross-sensitivity is unknown.
Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine,
hyperkalemia, proteinuria, and prolonged bleeding time.
Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet
function (prolongation of bleeding time). Salicylates should be used with caution in the presence of
peptic ulcer or coagulation abnormalities.
Aspirin can cause fetal harm when administered to a pregnant woman. Salicylates readily cross the
placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus, resulting
in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects.
Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms.
Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence
of intracranial hemorrhage in premature infants, stillbirths and neonatal death. The use of aspirin during
pregnancy especially in the third trimester should be avoided. If ENDODAN tablets are used during
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of
the potential hazard to the fetus.
Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute).
Avoid aspirin in patients with severe hepatic insufficiency.
Interactions With Other CNS Depressants
Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers,
centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol)
concomitantly with ENDODAN tablets may exhibit an additive CNS depression. When such combined
therapy is contemplated, the dose of one or both agents should be reduced.
Interactions With Mixed Agonist/Antagonist Opioid Analgesics
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered
with caution to a patient who has received or is receiving a course of therapy with a pure opioid
agonist analgesic such as oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce
the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these patients.
Ambulatory Surgery And Postoperative Use
Oxycodone and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a
common postoperative complication, especially after intra-abdominal surgery with use of opioid
analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients
receiving opioids. Standard supportive therapy should be implemented.
Use In Pancreatic/Biliary Tract Disease
Oxycodone 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 oxycodone may cause increases in the
serum amylase level.
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,
respiratory rate, or heart rate.
In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION:
Cessation Of Therapy).
Although oxycodone may cross-react with some drug urine tests, no available studies were found
which determined the duration of detectability of oxycodone in urine drug screens. However, based on
pharmacokinetic data, the approximate duration of detectability for a single dose of oxycodone is
roughly estimated to be one to two days following drug exposure.
Urine testing for opiates may be performed to determine illicit drug use and for medical reasons such as
evaluation of patients with altered states of consciousness or monitoring efficacy of drug rehabilitation
efforts. The preliminary identification of opiates in urine involves the use of an immunoassay screening
and thin-layer chromatography (TLC). Gas chromatography/mass spectrometry (GC/MS) may be utilized
as a third-stage identification step in the medical investigational sequence for opiate testing after
immunoassay and TLC. The identities of 6-keto opiates (e.g., oxycodone) can further be differentiated
by the analysis of their methoxime-trimethylsilyl (MO-TMS) derivative.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Animal studies to evaluate the carcinogenic potential of oxycodone and aspirin have not been
The combination of oxycodone and aspirin has not been evaluated for mutagenicity. Oxycodone alone
was negative in a bacterial reverse mutation assay (Ames), an in vitro chromosome aberration assay with
human lymphocytes without metabolic activation and an in vivo mouse micronucleus assay. Oxycodone
was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation
and in the mouse lymphoma assay with or without metabolic activation. Aspirin induced chromosome
aberrations in cultured human fibroblasts.
Animal studies to evaluate the effects of oxycodone on fertility have not been performed. Aspirin has
been shown to inhibit ovulation in rats.
Pregnancy Category B
Reproduction studies in rats and rabbits demonstrated that oral administration of oxycodone was not
teratogenic or embryo-fetal toxic.
Pregnancy Category D (see PRECAUTIONS)
Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction
of ductus arteriosus resulting in pulmonary hypertension and increased fetal mortality and, possibly
other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and
neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low
birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal
death. Use during pregnancy, especially in the third trimester, should be avoided.
Safe use of ENDODAN (Oxycodone and Aspirin Tablets, USP) in pregnancy has not been established
relative to possible adverse effects on fetal development. Therefore, ENDODAN tablets should not be
used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the
Opioids can cross the placental barrier and have the potential to cause neonatal respiratory depression.
Opioid use during pregnancy may result in a physically drug-dependent fetus. After birth, the neonate
may suffer severe withdrawal symptoms. Aspirin may produce anemia, ante- or postpartum hemorrhage,
prolonged gestation and labor, and oligohydramnios.
Labor And Delivery
ENDODAN tablets are not recommended for use in women during and immediately prior to labor and
delivery due to its potential effects on respiratory function in the newborn. Aspirin should be avoided
one week prior to and during labor and delivery because it can result in excessive blood loss at
delivery. Prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported.
Ordinarily, nursing should not be undertaken while a patient is receiving ENDODAN tablets because of
the possibility of sedation and/or respiratory depression in the infant. Oxycodone is excreted in breast
milk in low concentrations, and there have been rare reports of somnolence and lethargy in babies of
nursing mothers taking an oxycodone/acetaminophen product. Salicylic acid has also been detected in
breast milk. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk
may be a potential risk. Furthermore, the risk of Reye Syndrome caused by salicylate in breast milk is
unknown. Because of the potential for serious adverse reactions in nursing infants, a decision should be
made whether to discontinue nursing or to discontinue the drug, taking into account the potential benefits
to the woman and the possible hazards to the nursing infant.
ENDODAN tablets should not be administered to pediatric patients. Reye Syndrome is a rare but
serious disease which can follow flu or chicken pox in children and teenagers. While the cause of
Reye Syndrome is unknown, some reports claim aspirin (or salicylates) may increase the risk of
developing this disease.
Special precaution should be given when determining the dosing amount and frequency of ENDODAN
tablets for geriatric patients, since clearance of oxycodone may be slightly reduced in this patient
population when compared to younger patients.
In a pharmacokinetic study of oxycodone in patients with end-stage liver disease, oxycodone plasma
clearance decreased and the elimination half-life increased. Care should be exercised when oxycodone
is used in patients with hepatic impairment.
In a study of patients with end stage renal impairment, mean elimination half-life was prolonged in
uremic patients due to increased volume of distribution and reduced clearance. Oxycodone should be
used with caution in patients with renal impairment.