CombunoxTM (Oxycodone HCl and Ibuprofen) Tablets

FOREST LABORATORIES CII Rx only

Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events,
myocardial infarction, and stroke, which can be fatal. This risk may increase with
duration of use. Patients with cardiovascular disease or risk factors for cardiovascular
disease may be at greater risk (See WARNINGS).
• Combunox™ is contraindicated for the treatment of peri-operative pain in the setting
of coronary artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including
bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.
These events can occur at any time during use and without warning symptoms.
Elderly patients are at greater risk for serious gastrointestinal events (See
WARNINGS).

DESCRIPTION

Each combination Combunox™ tablet contains:

Oxycodone HCl, USP 5 mg
Ibuprofen, USP 400 mg

Combunox is supplied in a fixed combination tablet form for oral administration and
combines the opioid analgesic agent, oxycodone HCl, with the nonsteroidal anti-inflammatory
(NSAID) agent, ibuprofen.

Oxycodone HCl is a centrally acting semisynthetic opioid analgesic. Its chemical name is
4,5α-Epoxy-14-hydroxy-3-methoxy-methylmorphinan-6-one hydrochloride. Its chemical
formula is C18H21NO4 HCl and molecular weight is 351.83. Its structural formula is:

Ibuprofen is a nonsteroidal anti-inflammatory drug with analgesic and antipyretic properties.

Its chemical name is (±)-2-(p-isobutylphenyl) propionic acid. Its chemical formula is
C13H18O2 and molecular weight is 206.29. Its structural formula is:

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Inactive ingredients in Combunox tablets include: sodium starch glycolate, microcrystalline
cellulose, colloidal silicon dioxide, stearic acid, calcium stearate, carboxymethylcellulose,
povidone, Opadry® II White, Y-22 7719 coloring agent. Opadry® II White, Y-22 7719
coloring agent consists of titanium dioxide, polydextrose, hypromellose, triacetin and
polyethylene glycol 8000.

CLINICAL PHARMACOLOGY

Oxycodone HCl component:

Oxycodone HCl is a semisynthetic opioid analgesic with multiple actions which involve the
central nervous system and smooth muscle. The mechanism of action of oxycodone is not
known but is thought to be related to its binding to opiate receptors in the central nervous
system. In addition to analgesia, opioids may produce sedation and respiratory depression.

Ibuprofen component:
Ibuprofen is a nonsteroidal anti-inflammatory agent that possesses analgesic and antipyretic
activities. Its mode of action, similar to other NSAIDs, is not completely understood, but is
thought to be related to its inhibition of cyclooxygenase activity and prostaglandin synthesis.
Ibuprofen is a peripherally acting analgesic. Ibuprofen does not have any known effects on
opiate receptors.

Pharmacokinetics

Absorption:
Oxycodone is rapidly absorbed after single dose administration of Combunox. Maximum
concentrations (Cmax) of oxycodone, ranging from 9.8 ng/mL to 11.7 ng/mL, are obtained
within 1.3 hr to 2.1 hr after administration of Combunox. Repeated administration of
Combunox every 6 hours results in approximately 50-65% increase in Cmax. In the presence
of food, the bioavailability of oxycodone is slightly (25%) increased.

Ibuprofen is rapidly absorbed after oral administration of Combunox. Cmax values range from
18.5 mcg/mL to 34.3 mcg/mL and are reached 1.6 hr to 3.1 hr after oral administration of
Combunox. Repeated administration of Combunox every 6 hours does not result in any
accumulation of ibuprofen. The bioavailability of ibuprofen is not altered in the presence of
food.

Distribution:
Oxycodone binding to protein in serum is approximately 45%.

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Ibuprofen is extensively bound to plasma proteins (99%).

Metabolism:
Oxycodone is metabolized in the liver by means of N-demethylation and O-demethylation, 6­
ketoreduction and glucuronidation. The major circulating metabolite is noroxycodone, which
possesses weak analgesic activity.

Oxymorphone, the end product of O-demethylation, has analgesic activity but is present in the
plasma at low concentrations. Metabolism of oxycodone to oxymorphone occurs via
CYP2D6.

Ibuprofen is present as a racemate and following absorption, it undergoes interconversion in

the plasma from the R-isomer to the S-isomer.
Both the R- and S- isomers are metabolized to two primary metabolites: (+)-2-4'-(2-hydroxy­
2-methyl-propyl) phenyl propionic acid and (+)-2-4'-(2-carboxypropyl) phenyl propionic acid,
both of which circulate in the plasma at low levels relative to the parent.

Elimination:
Oxycodone is eliminated from the systemic circulation with half life (T1/2) values ranging
from 3.1 hr to 3.7 hr after single dose administration of Combunox. Urinary excretion of
unchanged oxycodone amounts to approximately 4% of the administered oxycodone dose.

Ibuprofen is eliminated from the systemic circulation with half life (T1/2) values ranging from
1.8 hr to 2.6 hr after single dose administration of Combunox. Urinary excretion of
unchanged ibuprofen is minimal (less than 0.2% of administered ibuprofen dose).

Special Populations:

Gender: There are no gender effects on the pharmacokinetics of oxycodone or ibuprofen after
administration of Combunox.

Age: The effects of age on the pharmacokinetics of oxycodone and ibuprofen after
administration of Combunox have not been evaluated.

When either drug was administered alone, the pharmacokinetics of oxycodone and ibuprofen
were similar in elderly subjects, compared to young healthy subjects.

Pediatrics: The pharmacokinetics of oxycodone and ibuprofen after administration of

Combunox have not been evaluated in a pediatric population.

Renal Impairment: The effects of renal impairment on the pharmacokinetics of oxycodone

and ibuprofen after administration of Combunox have not been evaluated.

Hepatic Impairment: The effects of hepatic impairment on the pharmacokinetics of

oxycodone and ibuprofen after administration of Combunox have not been evaluated. (See
PRECAUTIONS; Hepatic Effects)

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CLINICAL STUDIES

Combunox was investigated in three clinical studies. Two studies involving a total of 949
patients following dental surgery (removal of ipsilateral molars) and a third study of 456
patients following abdominal/pelvic surgery were conducted. In the three studies patients
were administered a single dose of the Combunox, ibuprofen alone, oxycodone HCl alone or
placebo for acute, moderate to severe pain.

In these single dose studies, Combunox produced greater efficacy than placebo and each of
Combunox’s individual components as measured by the magnitude of pain relief and the
reduction in pain intensity through six hours. No multiple dose efficacy studies have been
performed with Combunox.

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of Combunox and other treatment options
before deciding to use Combunox. Use the lowest effective dose for the shortest duration
consistent with individual patient treatment goals (see WARNINGS).

Combunox tablet is indicated for the short term (no more than 7 days) management of acute,
moderate to severe pain.

CONTRAINDICATIONS

Combunox should not be administered to patients who have previously exhibited

hypersensitivity to oxycodone HCl, ibuprofen, or any of Combunox’s components.

Combunox should not be administered in any situation where opioids are contraindicated.
This includes patients with significant respiratory depression (in unmonitored settings or the
absence of resuscitative equipment) and patients with acute or severe bronchial asthma or
hypercarbia. Patients known to be hypersensitive to other opioids may exhibit cross-
sensitivity to oxycodone. Combunox is contraindicated in any patient who has or is suspected
of having paralytic ileus.

Combunox should not be given to patients who have experienced asthma, urticaria, or
allergic-type reactions after taking aspirin or other NSAIDs. Severe anaphylactoid reactions to
NSAIDs, some of which were fatal, have been reported in such patients (see WARNINGS;
Anaphylactoid Reactions, and PRECAUTIONS; Pre-existing Asthma).

Combunox is contraindicated for the treatment of peri-operative pain in the setting of

coronary artery bypass graft (CABG) surgery (see WARNINGS).

WARNINGS

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Cardiovascular Effects
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years
duration have shown an increased risk of serious cardiovascular (CV) thrombotic events,
myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and
nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV
disease may be at greater risk. To minimize the potential risk for an adverse CV event in
patients treated with an NSAID, the lowest effective dose should be used for the shortest
duration possible. Physicians and patients should remain alert for the development of such
events, even in the absence of previous CV symptoms. Patients should be informed about the
signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of
serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and
an NSAID does increase the risk of serious GI events (see WARNINGS; Gastrointestinal
Effects - Risk of Ulceration, Bleeding, and Perforation).

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in
the first 10-14 days following CABG surgery found an increased incidence of myocardial
infarction and stroke (see CONTRAINDICATIONS).

Hypertension
NSAIDs, including Combunox, can lead to onset of new hypertension or worsening of pre­
existing hypertension, either of which may contribute to the increased incidence of CV events.
Patients taking thiazides or loop diuretics may have impaired response to these therapies when
taking NSAIDs. NSAIDs, including Combunox, should be used with caution in patients with
hypertension. Blood pressure (BP) should be monitored closely during the initiation of
NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. Combunox
should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including Combunox, can cause serious gastrointestinal (GI) adverse events
including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine,
or large intestine, which can be fatal. These serious adverse events can occur at any time,
with or without warning symptoms, in patients treated with NSAIDs. Only one in five
patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic.
Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1%
of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These
trends continue with longer duration of use, increasing the likelihood of developing a serious
GI event at some time during the course of therapy. However, even short-term therapy is not
without risk.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer
disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease

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and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk
for developing a GI bleed compared to patients with neither of these risk factors. Other
factors that increase risk for GI bleeding in patients treated with NSAIDs include concomitant
use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use
of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI
events are in elderly or debilitated patients and therefore, special care should be taken in
treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the
lowest effective dose should be used for the shortest possible duration. Patients and
physicians should remain alert for signs and symptoms of GI ulceration and bleeding during
NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI
adverse event is suspected. This should include discontinuation of the NSAID until a serious
GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve
NSAIDs should be considered.

Misuse Abuse and Diversion of Opioids

Combunox contains oxycodone, which is an opioid agonist, and a Schedule II controlled
substance. Opioid agonists have the potential for being abused and are sought by abusers and
people with addiction disorders, and are subject to diversion.

Combunox can be abused in a manner similar to other opioid agonists, legal or illicit. This
should be considered when prescribing or dispensing Combunox in situations where the
physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion
(see DRUG ABUSE AND DEPENDENCE).

Respiratory Depression
Oxycodone may produce dose-related respiratory depression by acting directly on the brain
stem respiratory centers. Oxycodone HCl also affects the center that controls respiratory
rhythm, and may produce irregular and periodic breathing. Respiratory depression occurs
most frequently in elderly or debilitated patients, usually following large initial doses in non-
tolerant patients, or when opioids are given in conjunction with other agents that depress
respiration. Combunox should be used with extreme caution in patients with significant
chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially
decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In
such patients, even usual therapeutic doses of Combunox may decrease respiratory drive to
the point of apnea.

Hypotensive Effect
Combunox, like all opioid analgesics, may cause severe hypotension in an individual whose
ability to maintain blood pressure has been compromised by a depleted blood volume, or after
concurrent administration with drugs such as phenothiazines or other agents which
compromise vasomotor tone. Combunox may produce orthostatic hypotension in ambulatory
patients. Combunox, like all opioid analgesics, should be administered with caution to
patients in circulatory shock, since vasodilatation produced by the drug may further reduce
cardiac output and blood pressure.

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Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid
pressure may be markedly exaggerated in the presence of head injury, intracranial lesions or a
pre-existing increase in intracranial pressure. Furthermore, opioids produce adverse reactions
that may obscure the clinical course of patients with head injuries.

Acute Abdominal Conditions

The administration of opioids may obscure the diagnosis or clinical course of patients with
acute abdominal conditions.

Anaphylactoid Reactions
Anaphylactoid reactions may occur in patients without known prior exposure to Combunox.
Combunox should not be given to patients with the aspirin triad or a history of angioedema.
The triad typically occurs in asthmatic patients who experience rhinitis with or without nasal
polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other
NSAIDs. Fatal reactions to NSAIDs have been reported in such patients (see
CONTRAINDICATIONS and PRECAUTIONS; Pre-existing Asthma). Emergency help
should be sought when anaphylactoid reaction occurs.

Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal
injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a
compensatory role in the maintenance of renal perfusion. In these patients, administration of
a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin
formation and, secondarily, in renal blood flow, which may precipitate overt renal
decompensation. Patients at greatest risk of this reaction are those with impaired renal
function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the
elderly. Discontinuation of NSAID therapy is usually followed by recovery to the
pretreatment state.

Advanced Renal Disease

In patients with advanced kidney disease, treatment with Combunox is not recommended. No
information is available from controlled clinical studies regarding the use of Combunox in
patients with advanced renal disease However, if Combunox therapy must be initiated, due to
the NSAID component, close monitoring of the patient’s kidney function is advisable (see
WARNINGS; Renal Effects).

Skin Reactions
NSAIDs, including Combunox, can cause serious skin adverse events such as exfoliative
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which
can be fatal. These serious events may occur without warning. Patients should be informed
about the signs and symptoms of serious skin manifestations and use of the drug should be
discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy

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Starting at 30 weeks gestation, Combunox, and other NSAIDs, should be avoided by pregnant
women as premature closure of the ductus arteriosus may occur.

Interactions with Alcohol and Drugs of Abuse

Oxycodone may be expected to have additive effects when used in conjunction with alcohol,
other opioids, or illicit drugs that cause central nervous system depression.

PRECAUTIONS

General
Combunox 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 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 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 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 may
cause increases in the serum amylase level.

Cough Reflex
Oxycodone suppresses the cough reflex; as with other opioid containing products, caution
should be exercised when Combunox is used postoperatively and in patients with pulmonary
disease.

Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking
NSAIDs including ibuprofen as found in Combunox. 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.

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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. If clinical signs and symptoms consistent
with liver disease develop, or if systematic manifestations occur (e.g., eosinophilia, rash, etc.),
Combunox should be discontinued.

Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including ibuprofen as found in
Combunox. 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 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 should have their hemoglobin or hematocrit checked if they
exhibit any signs or symptoms of anemia.

Pre-existing Asthma
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 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
Aseptic meningitis with fever and coma has been observed on rare occasions in patients on
ibuprofen as found in COMBUNOX. 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, the possibility of its being related to ibuprofen should be
considered.

Information for Patients

1. 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.
2. Combunox, 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 accordingly.

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 3. The combination of this product with alcohol and other CNS depressants may produce
an additive CNS depression and should be avoided.
4. Combunox 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.
5. Combunox, 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).
6. Combunox, 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, and Perforation).
7. Combunox, 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.
8. Patients should promptly report signs or symptoms of unexplained weight gain or
edema to their physicians.
9. 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.
10. 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 (see WARNINGS).
11. In late pregnancy, as with other NSAIDs, Combunox should be avoided because it
may cause premature closure of the ductus arteriosus.

Laboratory Tests
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 should be discontinued.

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Drug Interactions
Oxycodone is metabolized in part to oxymorphone via the cytochrome P450 isoenzyme
CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain
cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of
clinical significance with this agent. However, clinicians should be aware of this possible
interaction.

Anticholinergics: The concurrent use of anticholinergics with oxycodone preparations may

produce paralytic ileus.

CNS Depressants: Patients receiving narcotic analgesics, general anesthetics, phenothiazines,

other tranquilizers, sedative-hypnotics or other CNS depressants (including alcohol)
concomitantly with oxycodone 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 oxycodone. 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 oxycodone. In this situation, mixed agonist/antagonist analgesics
may reduce the analgesic effect of oxycodone 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 oxycodone is not recommended for patients taking MAOIs or within 14
days of stopping such treatment.

Neuromuscular Blocking Agents: Oxycodone, as well as other opioid analgesics, may

enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an
increased degree of respiratory depression.

ACE-Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of
ACE-inhibitors. This interaction should be given consideration in patients taking Combunox
concomitantly with ACE-inhibitors.

Aspirin: When Combunox is administered with aspirin, its protein binding is reduced,
although the clearance of free Combunox is not altered. The clinical significance of this
interaction is not known; however as with other products containing NSAIDs, concomitant
administration of Combunox and aspirin is not generally recommended because of the
potential of increased adverse effects.

Diuretics: Ibuprofen has been shown to reduce the natriuretic effect of furosemide and
thiazides in some patients. This response has been attributed to inhibition of renal

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prostaglandin synthesis. During concomitant therapy with Combunox the patient should be
observed closely for signs of renal failure (see WARNINGS; Renal Effects), as well as
diuretic efficacy.

Lithium: Ibuprofen has been shown to produce an elevation of plasma lithium levels and a
reduction in renal lithium clearance. The mean minimum lithium concentration increased
15% and the renal clearance was decreased by approximately 20%. These effects have been
attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when
Combunox and lithium are administered concurrently, subjects should be observed carefully
for signs of lithium toxicity.

Methotrexate: Ibuprofen, as well as other NSAIDs, has been reported to competitively inhibit
methotrexate accumulation in rabbit kidney slices. This may indicate that ibuprofen could
enhance the toxicity of methotrexate. Caution should be used when Combunox is
administered concomitantly with methotrexate.

Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users
of both drugs together have a greater risk of serious GI bleeding than users of either drug
alone.

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

Teratogenic Effects

Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation

Starting at 30 weeks gestation, Combunox, and other NSAIDS, should be avoided by

pregnant women as premature closure of the ductus arteriosus in the fetus may occur.
Combunox can cause fetal harm when administered to a pregnant woman starting at 30 weeks
gestation. If Combunox, 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 should be
used during pregnancy only if the potential benefit justifies the risk to the fetus.

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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 model.

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 BW).

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) basis.

Non-teratogenic effects
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 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.

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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 on labor and delivery in pregnant women are unknown.

Nursing Mothers
It is not known whether Combunox 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, 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.

Pediatric Use
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. No
apparent differences were noted in the safety of Combunox in patients below and above 17
years of age. Combunox 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.

Geriatric Use
Of the total number of subjects in clinical studies of Combunox, 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.

ADVERSE REACTIONS

Listed below are the adverse event incidence rates from single dose analgesia trials in which a
total of 2437 patients received either Combunox, ibuprofen (400 mg), oxycodone HCl (5 mg),
or placebo. Adverse event information is also provided from an additional 334 patients who
were exposed to Combunox in a multiple dose analgesia trial, without placebo or active
component comparison arms, given up to four times daily for up to 7 days.

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Adverse Events Which Occurred at a Frequency of ≥ 1% and at a Higher Incidence
than in the Placebo Group in Single Dose Studies

5/400 mg 400 mg 5 mg Placebo

(n=923) Ibuprofen Oxycodone HCl (n=315)
(n=913) (n = 286)
Digestive
Nausea 81 (8.8%) 44 (4.8%) 46 (16.1%) 21 (6.7%)
Vomiting 49 (5.3%) 16 (1.8%) 30 (10.5%) 10 (3.2%)
Flatulence 9 (1.0%) 7 (0.8%) 3 (1.0%) 0
Nervous System
Somnolence 67 (7.3%) 38 (4.2%) 12 (4.2%) 7 (2.2%)
Dizziness 47 (5.1%) 21 (2.3%) 17 (5.9%) 8 (2.5%)
Skin and Appendages
Sweat 15 (1.6%) 7 (0.8%) 4 (1.4%) 1 (0.3%)

Adverse events that were reported by at least 1% of patients taking Combunox but were
observed at a greater incidence in the placebo treated patients were fever, headache and
pruritus.

Adverse events that occurred in less than 1% and in at least two Combunox treated patients in
Single Dose studies not listed above include the following: Body as Whole: abdominal
pain, asthenia, chest pain, enlarged abdomen. Cardiovascular System: hypotension,
syncope, tachycardia, vasodilation. Digestive System: constipation, dry mouth, dyspepsia,
eructation, ileus. Hemic and Lymphatic System: anemia. Metabolic and Nutritional
Disorders: edema. Nervous System: euphoria, insomnia, nervousness. Respiratory
System: hypoxia, lung disorder, pharyngitis. Urogenital System: urinary retention.

Adverse events that occurred in the Multiple Dose study in at least 2% of patients treated
with Combunox include the following: Body as Whole: asthenia (3.3%), fever (3.0%),
headache (10.2%). Cardiovascular System: vasodilation (3.0%). Digestive System:
constipation (4.5%), diarrhea (2.1%), dyspepsia (2.1%), nausea (25.4%), vomiting (4.5%).
Nervous System: dizziness (19.2%), somnolence (17.4%).

Adverse events that occurred in less than 2% of and at least two Combunox treated patients in
the Multiple Dose study not listed previously include the following: Body as Whole: back
pain, chills, infection. Cardiovascular System: thrombophlebitis. Hemic and Lymphatic
System: ecchymosis. Metabolic and Nutritional Disorders: hypokalemia.
Musculoskeletal System: arthritis. Nervous System: abnormal thinking, anxiety,
hyperkinesia, hypertonia. Skin and Appendages: rash. Special Senses: amblyopia, taste
perversion. Urogenital System: urinary frequency.

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DRUG ABUSE AND DEPENDENCE

Combunox contains oxycodone, which is a mu-opioid agonist with an abuse liability similar
to other opioid agonists and is a Schedule II controlled substance. Combunox, and other
opioids used in analgesia, can be abused and are subject to criminal diversion.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and

environmental factors influencing its development and manifestations. It is characterized by
behaviors that include one or more of the following: impaired control over drug use,
compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease
utilizing a multidisciplinary approach, but relapse is common.

“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics
include emergency calls or visits near the end of office hours, refusal to undergo appropriate
examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions
and reluctance to provide prior medical records or contact information for other treating
physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug
abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance.
Physical dependence usually assumes clinically significant dimensions only after several
weeks of continued opioid use, although a mild degree of physical dependence may develop
after a few days of opioid therapy. Tolerance, in which increasingly large doses are required
in order to produce the same degree of analgesia, is manifested initially by a shortened
duration of analgesic effect, and subsequently by decreases in the intensity of analgesia. The
rate of development of tolerance varies among patients. Physicians should be aware that
abuse of opioids can occur in the absence of true addiction and is characterized by misuse for
non-medical purposes, often in combination with other psychoactive substances. Combunox,
like other opioids, may be diverted for non-medical use. Record-keeping of prescribing
information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of

therapy, and proper dispensing and storage are appropriate measures that help to limit abuse
of opioid drugs.

OVERDOSAGE

Following an acute overdosage, toxicity may result from oxycodone and/or ibuprofen.

Signs and Symptoms

Acute overdosage with oxycodone may be manifested by respiratory depression, somnolence
progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted
pupils, bradycardia, or hypotension. In severe cases death may occur.

The toxicity of ibuprofen overdose is dependent on the amount of drug ingested and the time
elapsed since ingestion, although individual response may vary, necessitating individual

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evaluation of each case. Although uncommon, serious toxicity and death have been reported
in the medical literature with ibuprofen overdosage. The most frequently reported symptoms
of ibuprofen overdose include abdominal pain, nausea, vomiting, lethargy, and drowsiness.
Other central nervous system symptoms include headache, tinnitus, CNS depression, and
seizures. Cardiovascular toxicity, including hypotension, bradycardia, tachycardia, and atrial
fibrillation, have also been reported.

Treatment
In the treatment of opioid overdosage, primary attention should be given to the re­
establishment of a patent airway and institution of assisted or controlled ventilation.
Supportive measures (including oxygen and vasopressors) should be employed in the
management of circulatory shock and pulmonary edema accompanying overdose, as
indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. The
narcotic antagonist naloxone hydrochloride is a specific antidote against respiratory
depression, which may result from overdosage or unusual sensitivity to narcotics including
oxycodone. An appropriate dose of naloxone hydrochloride should be administered
intravenously with simultaneous efforts at respiratory resuscitation. Since the duration of
action of oxycodone may exceed that of the naloxone, the patient should be kept under
continuous surveillance and repeated doses of the antagonist should be administered as
needed to maintain adequate respiration. Management of hypotension, acidosis and
gastrointestinal bleeding may be necessary. In cases of acute overdose, the stomach should be
emptied through ipecac-induced emesis or gastric lavage. Orally administered activated
charcoal may help in reducing the absorption and reabsorption of ibuprofen. Emesis is most
effective if initiated within 30 minutes of ingestion. Induced emesis is not recommended in
patients with impaired consciousness or overdoses greater than 400 mg/kg of the ibuprofen
component in children because of the risk for convulsions and the potential for aspiration of
gastric contents.

DOSAGE AND ADMINISTRATION

Carefully consider the potential benefits and risks of Combunox and other treatment options
before deciding to use Combunox. Use the lowest effective dose for the shortest duration
consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with Combunox, the dose and frequency should
be adjusted to suit an individual patient's needs.”

For the management of acute moderate to severe pain, the recommended dose of Combunox
is one tablet given orally.

Dosage should not exceed 4 tablets in a 24-hour period and should not exceed 7 days.

HOW SUPPLIED

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Combunox are capsule shaped, white to off-white, film-coated tablets with “F” bisect “P” on
one side and “5400” on the other side.

Bottles of 100-NDC #0456-5200-01

Storage:
Store at 25ºC (77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF).

A Schedule CII Narcotic

Forest Pharmaceuticals, Inc.

Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045 USA

Rev XX/2010
(c) 2010 Forest Laboratories, Inc.

Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to
death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any
time during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health

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NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from
medical conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other
NSAID medicine
• for pain right before or after heart bypass surgery

Tell your healthcare provider:

• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact
with each other and cause serious side effects. Keep a list of your medicines to show to
your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late
in their pregnancy.
• if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Serious side effects include: Other side effects include:

• heart attack • stomach pain
• stroke • constipation
• high blood pressure • diarrhea
• heart failure from body swelling (fluid retention) • gas
• kidney problems including kidney failure • heartburn
• bleeding and ulcers in the stomach and intestine • nausea
• low red blood cells (anemia) • vomiting
• life-threatening skin reactions • dizziness
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma

Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing • slurred speech
• chest pain • swelling of the face or throat

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 • weakness in one part or side of your body
Stop your NSAID medicine and call your healthcare provider right away if you have any
of the following symptoms:
• nausea • there is blood in your bowel
• more tired or weaker than usual movement or it is black and sticky
• itching like tar
• your skin or eyes look yellow • unusual weight gain
• stomach pain • skin rash or blisters with fever
• flu-like symptoms • swelling of the arms and legs, hands
• vomit blood and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin
can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the
stomach and intestines.

• Some of these NSAID medicines are sold in lower doses without a prescription
(over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs
for more than 10 days.

NSAID medicines that need a prescription

Generic Name Tradename

Celecoxib Celebrex
Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal Dolobid
Etodolac Lodine, Lodine XL
Fenoprofen Nalfon, Nalfon 200
Flurbirofen Ansaid
Ibuprofen Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen Oruvail
Ketorolac Toradol
Mefenamic Acid Ponstel
Meloxicam Mobic
Nabumetone Relafen
Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac
(copackaged with lansoprazole)
Oxaprozin Daypro
Piroxicam Feldene
Sulindac Clinoril
Tolmetin Tolectin, Tolectin DS, Tolectin 600

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* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is
usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term
continuous use may increase the risk of heart attack or stroke.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Forest Pharmaceuticals, Inc.

Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045 USA
Rev 02/07
(c) 2010 Forest Laboratories, Inc.

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