Combunox (oxycodone hcl and ibuprofen) cannot be expected to substitute for corticosteroids or to treat corticosteroid
insufficiency. Abrupt discontinuation of corticosteroids may lead to disease
exacerbation. Patients on prolonged corticosteroid therapy should have their
therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of Combunox (oxycodone hcl and ibuprofen) in reducing fever and inflammation
may diminish the utility of these diagnostic signs in detecting complications
of presumed noninfectious, painful conditions.
Special Risk Patients
As with any opioid analgesic agent, Combunox (oxycodone hcl and ibuprofen) tablets should be used with caution
in elderly or debilitated patients, and those with severe impairment of hepatic,
pulmonary or renal function, hypothyroidism, Addison's disease, acute alcoholism,
convulsive disorders, CNS depression or coma, delirium tremens, kyphoscoliosis
associated with respiratory depression, toxic psychosis, prostatic hypertrophy
or urethral stricture. The usual precautions should be observed and the possibility
of respiratory depression, postural hypotension, and altered mental states should
be kept in mind.
Use in Pancreatic/Biliary Tract Disease
Combunox (oxycodone hcl and ibuprofen) 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 Combunox (oxycodone hcl and ibuprofen) may cause increases in the serum amylase level.
Oxycodone suppresses the cough reflex; as with other opioid containing products,
caution should be exercised when Combunox (oxycodone hcl and ibuprofen) is used postoperatively and in patients
with pulmonary disease.
Borderline elevations of one or more liver tests may occur in up to 15% of
patients taking NSAIDs including ibuprofen as found in Combunox (oxycodone hcl and ibuprofen) . These laboratory
abnormalities may progress, may remain unchanged, or may be transient with continuing
therapy. Notable elevations of ALT or AST (approximately three or more times
the upper limit of normal) have been reported in approximately 1% of patients
in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions,
including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic
failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom
an abnormal liver test has occurred, should be evaluated for evidence of the
development of a more severe hepatic reaction while on therapy with Combunox (oxycodone hcl and ibuprofen) .
If clinical signs and symptoms consistent with liver disease develop, or if
systematic manifestations occur (e.g., eosinophilia, rash, etc.), Combunox (oxycodone hcl and ibuprofen) should
Anemia is sometimes seen in patients receiving NSAIDs, including ibuprofen
as found in Combunox (oxycodone hcl and ibuprofen) . This may be due to fluid retention, occult or gross GI
blood loss, or an incompletely described effect upon erythropoiesis. Patients
on long-term treatment with NSAIDs, including ibuprofen, should have their hemoglobin
or hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding
time in some patients. Unlike aspirin, their effect on platelet function is
quantitatively less, of shorter duration, and reversible. Patients receiving
Combunox (oxycodone hcl and ibuprofen) who may be adversely affected by alterations in platelet function,
such as those with coagulation disorders or patients receiving anticoagulants,
should be carefully monitored. Patients previously treated with NSAIDs and currently
using Combunox (oxycodone hcl and ibuprofen) should have their hemoglobin or hematocrit checked if they exhibit
any signs or symptoms of anemia.
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin
in patients with aspirin-sensitive asthma has been associated with severe bronchospasm,
which can be fatal. Since cross-reactivity between aspirin and other NSAIDs
has been reported in such aspirin-sensitive patients, Combunox (oxycodone hcl and ibuprofen) should not be
administered to patients with this form of aspirin sensitivity and should be
used with caution in patients with pre-existing asthma.
Aseptic meningitis with fever and coma has been observed on rare occasions
in patients on ibuprofen as found in COMBUNOX (oxycodone hcl and ibuprofen) . Although it is probably more
likely to occur in patients with systemic lupus erythematosus and related connective
tissue diseases, it has been reported in patients who do not have an underlying
chronic disease. If signs or symptoms of meningitis develop in a patient on
Combunox (oxycodone hcl and ibuprofen) , the possibility of its being related to ibuprofen should be considered.
Information for Patients
Patients should be informed of the following information before initiating
therapy with an NSAID and periodically during the course of ongoing therapy.
Patients should also be encouraged to read the NSAID Medication Guide that
accompanies each prescription dispensed.
Combunox (oxycodone hcl and ibuprofen) , similar to other opioid-containing analgesics, may impair mental
and/or physical abilities required for the performance of potentially hazardous
tasks such as driving a car or operating machinery; patients should be cautioned
The combination of this product with alcohol and other CNS depressants may
produce an additive CNS depression and should be avoided.
Combunox (oxycodone hcl and ibuprofen) can be abused in a manner similar to other opioid agonists, legal
or illicit. Patients should take the drug only for as long as it is prescribed,
in the amounts prescribed, and no more frequently than prescribed.
Combunox (oxycodone hcl and ibuprofen) , like other NSAIDs, may cause serious CV side effects, such as
MI or stroke, which may result in hospitalization and even death. Although
serious CV events can occur without warning symptoms, patients should be alert
for the signs and symptoms of chest pain, shortness of breath, weakness, slurring
of speech, and should ask for medical advice when observing any indicative
sign or symptoms. Patients should be apprised of the importance of this follow-up
(see WARNINGS; Cardiovascular Effects).
Combunox (oxycodone hcl and ibuprofen) , like other NSAIDs, can cause GI discomfort and, rarely, serious
GI side effects, such as ulcers and bleeding, which may result in hospitalization
and even death. Although serious GI tract ulcerations and bleeding can occur
without warning symptoms, patients should be alert for the signs and symptoms
of ulcerations and bleeding, and should ask for medical advice when observing
any indicative sign or symptoms including epigastric pain, dyspepsia, melena,
and hematemesis. Patients should be apprised of the importance of this follow-up
(see WARNINGS; Gastrointestinal Effects - Risk of Ulceration, Bleeding,
Combunox (oxycodone hcl and ibuprofen) , like other NSAIDs, can cause serious skin side effects such as
exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations
and even death. Although serious skin reactions may occur without warning,
patients should be alert for the signs and symptoms of skin rash and blisters,
fever or other signs of hypersensitivity, and should ask medical advice when
observing any indicative signs or symptoms. Patients should be advised to
stop the drug immediately if they develop any type of rash and contact their
physician as soon as possible.
Patients should promptly report signs or symptoms of unexplained weight
gain or edema to their physicians.
Patients should be informed of the warning signs and symptoms of hepatotoxicity
(e.g., nausea, fatigue, lethargy, pruritius, jaundice, right upper quadrant
tenderness, and “flu-like” symptoms). If these occur, patients
should be instructed to seek immediate medical therapy.
Patients should be informed of the signs and symptoms of an anaphylactoid
reaction (e.g. difficulty breathing, swelling of the face or throat). If
these occur, patients should be instructed to seek immediate emergency help
In late pregnancy, as with other NSAIDs, Combunox (oxycodone hcl and ibuprofen) should be avoided because
it may cause premature closure of the ductus arteriosus.
Because serious GI tract ulcerations and bleeding can occur without warning
symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients
on long-term treatment with NSAIDs should have their CBC and a chemistry profile
checked periodically. If clinical signs and symptoms consistent with liver or
renal disease develop, systemic manifestations occur (e.g. eosinophilia, rash,
etc.) or if abnormal liver tests persist or worsen, Combunox (oxycodone hcl and ibuprofen) should be discontinued.
Carcinogenicity, Mutagenicity and Impairment of Fertility
Studies to evaluate the potential effects of the combination of oxycodone and
ibuprofen on carcinogenicity and mutagenicity have not been conducted.
Oxycodone HCl was not genotoxic in the following assays: Ames bacterial mutuation
assay, chromosomal aberrations in cultured human lymphocytes, and in vivo mouse
micronucleus assay in mice.
There was no evidence of impairment of fertility in either male or female Sprague-Dawley
rats administered oxycodone HCl; ibuprofen up to (1:80 mg/kg/day) which is equivalent
to 0.5-times the maximum recommended human daily dose (MRHD) (20:1600 mg/day)
on a body surface area (mg/m² ) basis.
Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30
Starting at 30 weeks gestation, Combunox (oxycodone hcl and ibuprofen) , and other NSAIDS, should be avoided
by pregnant women as premature closure of the ductus arteriosus in the fetus
may occur. Combunox (oxycodone hcl and ibuprofen) can cause fetal harm when administered to a pregnant woman
starting at 30 weeks gestation. If Combunox (oxycodone hcl and ibuprofen) , and other NSAIDS, are used during
this time period in pregnancy, the patient should be apprised of the potential
hazard to a fetus. There are no adequate and well-controlled studies in pregnant
women. Prior to 30 weeks gestation, Combunox (oxycodone hcl and ibuprofen) should be used during pregnancy
only if the potential benefit justifies the risk to the fetus.
Animal studies to assess the potential effects of the combination of oxycodone
and ibuprofen on embryo-fetal development were conducted in the rat and rabbit
Pregnant rats were treated by oral gavage with combination doses of oxycodone:ibuprofen
mg/kg/day (0.25:20, 0.5:40, 1:80, or 2:160) on days 7-16 of gestation. There
was no evidence for developmental toxicity or teratogenicity at any dose, although maternal toxicity was noted at doses of 0.5:40 and above. The highest dose tested
in the rat (2:160 mg/kg/day) is equivalent to the maximum recommended human
daily dose (20:1600 mg/day) on a body surface area (mg/m²) basis. This
dose was associated with maternal toxicity (death, clinical signs, decreased
Pregnant rabbits were treated by oral gavage with combination doses of oxycodone/ibuprofen
(0.38:30, 0.75:60, 1.5:120 or 3:240 mg/kg/day) on gestation days 7-19. Oxycodone/ibuprofen
treatment was not teratogenic under the conditions of the assay. Maternal toxicity
was noted at doses of 1.5:120 (reduced body weight and food consumption) and
3:240 mg/kg/day (mortality). The NOAEL for maternal toxicity, 0.75:60 mg/kg/day,
is 0.75 fold the proposed maximum daily human dose based upon the body surface
area. Developmental toxicity, as evidenced by delayed ossification and reduced
fetal body weights, was noted at the highest dose, which is approximately 3
times the MRHD on a mg/m² basis, and is likely due to maternal toxicity.
The fetal no adverse effect level (NOAEL) of 1.5:120 mg/kg/day is approximately
1.5 times the MRHD on a mg/m² basis.
In a pre- and postnatal development study conducted in rats, there was increased
mortality of pups born to dams dose with 0.5:40 mg/kg/day oxydocone:ibuprofen
and above which is equivalent to 0.25-times of the MRHD (20:1600 mg/day) on
a body surface area (mg/m²) basis. There was an increase in stillborn F1
pups and decrease in mean pup weight in dams dosed with 1:80 mg/kg/day oxycodone:ibuprofen,
which is 0.5-times the MRHD (20:1600 mg/day) on a body surface area (mg/m²)
Babies born to mothers who have been taking opioids regularly prior to delivery
will be physical dependent. The withdrawal signs include irritability and excessive
crying, tremors, hyperactive reflexes, increased respiratory rate, increased
stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome
does not always correlate with the duration of maternal opioid use or dose.
There is no consensus on the best method of managing withdrawal.
Labor and Delivery
Combunox (oxycodone hcl and ibuprofen) should not be used during the third trimester of pregnancy due to
the potential for ibuprofen to inhibit prostaglandin synthetase which may prolong
pregnancy and inhibit labor. Oxycodone is not recommended for use in women during
and immediately prior to labor and delivery because oral opioids may cause respiratory
depression in the newborn.
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased
pup survival occurred. The effects of Combunox (oxycodone hcl and ibuprofen) on labor and delivery in pregnant
women are unknown.
It is not known whether Combunox (oxycodone hcl and ibuprofen) is excreted in human milk. Oxycodone is excreted
in human milk. Withdrawal symptoms and/or respiratory depression have been observed
in neonates whose mothers were taking narcotic analgesics during pregnancy.
Although adverse effects in the nursing infant have not been documented, withdrawal
can occur in breast-feeding infants when maternal administration of an opioid
analgesic is discontinued. Because many drugs are excreted in human-milk and
because of the potential for serious adverse reactions in nursing infants from
Combunox (oxycodone hcl and ibuprofen) , a decision should be made whether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the mother.
In the placebo-controlled, clinical studies of pain following dental surgery,
109 patients between the ages of 14 and 17 years were administered a single
dose of Combunox (oxycodone hcl and ibuprofen) . No apparent differences were noted in the safety of Combunox (oxycodone hcl and ibuprofen)
in patients below and above 17 years of age. Combunox (oxycodone hcl and ibuprofen) has not been studied in
patients under 14 years of age. Safety and effectiveness in pediatric patients
below the age of 14 have not been established.
Of the total number of subjects in clinical studies of Combunox (oxycodone hcl and ibuprofen) , 89 patients
were 65 and over, while 37 patients were 75 and over. No overall differences
in safety were observed between these subjects and younger subjects, and other
reported clinical experience has not identified differences in responses between
the elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out.
However, because the elderly may be more sensitive to the renal and gastrointestinal
effects of nonsteroidal anti-inflammatory agents as well as possible increased
risk of respiratory depression with opioids, extra caution should be used when
treating the elderly with Combunox (oxycodone hcl and ibuprofen) .