Hydrocodone Bitartrate and Ibuprofen

HYDROCODONE BITARTRATE AND IBUPROFEN- hydrocodone bitartrate and ibuprofen tablet
McKesson Packaging Services a business unit of McKesson Corporation

DESCRIPTION

Hydrocodone bitartrate and ibuprofen tablets are supplied in a fixed combination tablet form for oral administration. Hydrocodone bitartrate and ibuprofen tablets combine the opioid analgesic agent, hydrocodone bitartrate, with the nonsteroidal anti-inflammatory (NSAID) agent, ibuprofen. Hydrocodone bitartrate is a semisynthetic and centrally acting opioid analgesic. Its chemical name is: 4, 5 α-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). Its chemical formula is: C18 H21 NO3 •C4 H6 O6 •21/2 H2 O, and the molecular weight is 494.50. Its structural formula is:

b4355d78-figure-01

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 the molecular weight is: 206.29. Its structural formula is:

b4355d78-figure-02
(click image for full-size original)

silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polydextrose, pregelatinized starch, and titanium dioxide.

CLINICAL PHARMACOLOGY

Hydrocodone component: Hydrocodone is a semisynthetic opioid analgesic and antitussive with multiple actions qualitatively similar to those of codeine. Most of these involve the central nervous system and smooth muscle. The precise mechanism of action of hydrocodone and other opioids is not known, although it is believed to relate to the existence of opiate receptors in the central nervous system. In addition to analgesia, opioids may produce drowsiness, changes in mood, and mental clouding.

Ibuprofen component : Ibuprofen is a non-steroidal anti-inflammatory agent that possesses analgesic and antipyretic activities. Its mode of action, like that of other NSAIDs, is not completely understood, but may be related to 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: After oral dosing with the hydrocodone bitartrate and ibuprofen tablet, a peak hydrocodone plasma level of 27 ng/mL is achieved at 1.7 hours, and a peak ibuprofen plasma level of 30 mcg/mL is achieved at 1.8 hours. The effect of food on the absorption of either component from the hydrocodone Bitartrate and ibuprofen tablets has not been established.

Distribution: Ibuprofen is highly protein bound (99%) like most other non-steroidal anti-inflammatory agents. Although the extent of protein binding of hydrocodone has not been definitely determined, structural similarities to related opioid analgesics suggest that hydrocodone is not extensively protein bound as most agents in the 5-ring morphinan group of semi-synthetic opioids bind plasma protein to a similar degree (range 19% [hydromorphone] to 45% [oxycodone]), hydrocodone is expected to fall within this range.

Metabolism: Hydrocodone exhibits a complex pattern of metabolism, including O-demethylation, N-demethylation, and 6-keto reduction to the corresponding 6-α and 6-β-hydroxy metabolites. Hydromorphone, a potent opioid, is formed from the O-demethylation of hydrocodone and contributes to the total analgesic effect of hydrocodone. The O- and N-demethylation processes are mediated by separate P-450 isoenzymes: CYP2D6 and CYP3A4, respectively.

Ibuprofen is present in this product 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’-(2hydroxy-2-methyl-propyl) phenyl propionic acid and (+)-2-4’-(2carboxypropyl) phenyl propionic acid, both of which circulate in the plasma at low levels relative to the parent.

Elimination: Hydrocodone and its metabolites are eliminated primarily in the kidneys, with a mean plasma half-life of 4.5 hours. Ibuprofen is excreted in the urine, 50% to 60% as metabolites and approximately 15% as unchanged drug and conjugate. The plasma half-life is 2.2 hours.

Special Populations: No significant pharmacokinetic differences based on age or gender have been demonstrated. The pharmacokinetics of hydrocodone and ibuprofen from hydrocodone bitartrate and ibuprofen tablets has not been evaluated in children.

Renal Impairment: The effect of renal insufficiency on the pharmacokinetics of the hydrocodone bitartrate and ibuprofen dosage form has not been determined.

CLINICAL STUDIES

In single-dose studies of post surgical pain (abdominal, gynecological, orthopedic), 940 patients were studied at doses of one or two tablets. Hydrocodone bitartrate and ibuprofen produced greater efficiency than placebo and each of its individual components given at the same dose. No advantage was demonstrated for the two-tablet dose.

INDICATIONS AND USAGE

Hydrocodone bitartrate and ibuprofen tablets are indicated for the short-term (generally less than 10 days) management of acute pain. Hydrocodone Bitartrate and ibuprofen are not indicated for the treatment of such conditions as ostearthritis or rheumatoid arthritis.

CONTRAINDICATIONS

Hydrocodone bitartrate and ibuprofen tablets should not be administered to patients who previously have exhibited hypersensitivity to hydrocodone or ibuprofen. Hydrocodone bitartrate and ibuprofen should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or the NSAIDs. Severe, rarely fatal, anaphylactoid-like reactions to NSAIDs have been reported in such patients (see WARNINGS-Anaphylactoid Reactions, and PRECAUTIONS-Pre-existing Asthma). Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to hydrocodone.

WARNINGS

Abuse and Dependence: Hydrocodone can produce drug dependence of the morphine type and therefore has the potential for being abused. Psychic and physical dependence as well as tolerance may develop upon repeated administration of this drug and it should be prescribed and administered with the same degree of caution as other narcotic drugs (see DRUG ABUSE AND DEPENDENCE).

Respiratory Depression: At high doses or in opioid-sensitive patients, hydrocodone may produce dose-related respiratory depression by acting directly on the brain stem respiratory centers. Hydrocodone also affects the center that controls respiratory rhythm, and may produce irregular and periodic breathing.

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 which 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.

Gastrointestinal (GI) Effects-Risk of GI Ulceration, Bleeding and Perforation: Serious gastrointestinal toxicity, such as inflammation, bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor upper GI problems, such as dypsepsia, are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients, who develop a serious upper GI adverse event of NSAID therapy, is symptomatic. 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. 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, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs have been considered.

Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmaco-epidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status.

Anaphylactoid Reactions: Anaphylactoid reactions may occur in patients without known prior exposure to hydrocodone bitartrate and ibuprofen. Hydrocodone bitartrate and ibuprofen should not be given to patients with the aspirin triad. 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.

Advanced Renal Disease: In cases with advanced kidney disease, treatment with hydrocodone bitartrate and ibuprofen are not recommended. If NSAID therapy, however, must be initiated, close monitoring of the patient’s kidney function is advisable (see PRECAUTIONS-Renal Effects).

Pregnancy: As with other NSAID-containing products, hydrocodone bitartrate and ibuprofen should be avoided in late pregnancy because it may cause premature closure of the ductus arteriosus.

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