Combunox

COMBUNOX- oxycodone hydrochloride and ibuprofen tablet
Forest Pharmaceuticals, Inc.

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 C18 H21 NO4 HCl and molecular weight is 351.83. Its structural formula is:

Image from Drug Label Content

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 C13 H18 O2 and molecular weight is 206.29. Its structural formula is:

Image from Drug Label Content

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%.

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)

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).

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