hydrocodone bitartrate and acetaminophen (hydrocodone bitartrate 7.5 mg / ibuprofen 200 mg) Dailymed

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: C H NO •C H O •21/2 H O, and the molecular weight is 494.50. 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 C H O , and the molecular weight is: 206.29. _{18 21 3 4 6 6 2 13 18 2}

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

Clinical Pharmacology

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. Hydrocodone 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. Ibuprofen component

Pharmacokinetics:

: 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. Absorption

: 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. Distribution

: 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. Metabolism

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.

: 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. Elimination

: 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. Special Populations

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

General Precautions:

As with any opioid analgesic agent, hydrocodone bitartrate and ibuprofen tablets should be used with caution in elderly or debilitated patients, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison’s disease, prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind. Special Risk Patients:

: Hydrocodone suppresses the cough reflex; as with opioids, caution should be exercised when hydrocodone bitartrate and ibuprofen are used postoperatively and in patients with pulmonary disease. Cough Reflex

: The antipyretic and anti-inflammatory activity of ibuprofen may reduce fever and inflammation, thus diminishing their utility as diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions. Effect on Diagnostic Signs

: As with other NSAIDs, ibuprofen has been reported to cause borderline elevations of one or more liver enzymes, this may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Notable (3 times the upper limit of normal) elevations of SGPT (ALT) or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. A patient with symptoms and/or signs suggesting liver dysfunctions, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reactions while on therapy with hydrocodone bitartrate and ibuprofen. Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported with ibuprofen as with other NSAIDs. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), hydrocodone bitartrate and ibuprofen should be discontinued. Hepatic Effects

: Caution should be used when initiating treatment with hydrocodone bitartrate and ibuprofen in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with hydrocodone bitartrate and ibuprofen. Caution is also recommended in patients with pre-existing kidney disease (see WARNINGS-Advanced Renal Disease).   Renal Effects

As with other NSAIDs, long-term administration of ibuprofen has resulted in renal papillary necrosis and other renal pathologic changes. Renal toxicity has also been seen in patients in which 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 nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state.

Ibuprofen metabolites are eliminated primarily by the kidneys. The extent to which the metabolites may accumulate in patients with renal failure has not been studied. Patients with significantly impaired renal function should be more closely monitored.

: Ibuprofen, like other NSAIDs, can inhibit platelet aggregation but the effect is quantitatively less and of shorter duration than that seen with aspirin. Ibuprofen has been shown to prolong bleeding time in normal subjects. Because this prolonged bleeding effect may be exaggerated in patients with underlying hemostatic defects, hydrocodone bitartrate and ibuprofen should be used with caution in persons with intrinsic coagulation defects and those on anticoagulant therapy. Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including ibuprofen. This may be due to fluid retention, GI loss, or an incompletely described effect upon erythropoiesis.

: Fluid retention and edema have been reported in association with ibuprofen; therefore, the drug should be used with caution in patients with a history of cardiac decompensation, hypertension or heart failure. . Fluid Retention and Edema

: 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 may be fatal. Since cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, hydrocodone bitartrate 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. Pre-existing Asthma

: Aseptic meningitis with fever and coma have been observed on rare occasions in patients on ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosous 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 hydrocodone bitartrate and ibuprofen, the possibility of its being related to ibuprofen should be considered Aseptic Meningitis

Information For Patients

Hydrocodone bitartrate and ibuprofen, like 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. Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this combination product, and should be avoided. Hydrocodone bitartrate and ibuprofen may be habitforming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed. Hydrocodone bitartrate and ibuprofen, like other drugs containing ibuprofen, is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, there are more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Patients should be instructed to report any signs and symptoms of gastrointestinal bleeding, blurred vision or other eye symptoms, skin rash, weight-gain, or edema.

Laboratory Tests

A decrease in hemoglobin may occur during hydrocodone bitartrate 7.5 mg and ibuprofen 200 mg tablets therapy, and elevations of liver enzymes may be seen in a small percentage of patients during hydrocodone bitartrate and ibuprofen therapy (see PRECAUTIONS-Hematological Effects and PRECAUTIONS-Hepatic Effects ). In patients with severe hepatic or renal disease, effects of therapy should be monitored with liver and/or renal function tests.

Drug Interactions

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

: The concurrent use of anticholingerics with hydrocodone preparations may produce paralytic ileus. Anticholingerics

: The use of MAO inhibitors of tricyclic antidepressants with hydrocodone bitartrate and ibuprofen may increase the effect of either the antidepressant or hydrocodone. Antidepressants

: Patients receiving other opioids, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with hydrocodone bitartrate and ibuprofen may exhibit an additive CNS depression. When combined therapy is contemplated, the dose of one or both agents should be reduced. CNS Depressants

: 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 prostaglandin synthesis. During concomitant therapy with hydrocodone bitartrate and ibuprofen the patient should be observed closely for signs of renal failure (see PRECAUTIONS-Renal Effects), as well as diuretic efficacy. Furosemide

: Ibuprofen has been shown to elevate plasma lithium concentration and reduce renal lithium clearance. This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when hydrocodone bitartrate and ibuprofen and lithium are administered concurrently, patients should be observed for signs of lithium toxicity. Lithium

: 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 hydrocodone bitartrate and ibuprofen are administered concomitantly with methotrexate. Methotrexate

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

Carcinogenicity, Mutagenicity, and Impairment of Fertility

The carcinogenic and mutagenic potential of hydrocodone bitartrate and ibuprofen has not been investigated. The ability of hydrocodone bitartrate and ibuprofen to impair fertility has not been assessed.

Pregnancy: Pregnancy Category C.

: Hydrocodone bitartrate and ibuprofen, administered to rabbits at 95 mg/kg (5.72 and 1.9 times the maximum clinical dose based on body weight and surface area, respectively), a maternally toxic dose, resulted in an increase in the percentage of litters and fetuses with any major abnormality and an increase in the number of litters and fetuses with one or more nonossified metacarpals (a minor abnormality). Hydrocodone bitartrate and ibuprofen, administered to rats at 166 mg/kg (10.0 and 1.66 times the maximum clinical dose based on body weight and surface area, respectively), a maternally toxic dose, did not result in any reproductive toxicity. There are no adequate and well-controlled studies in pregnant women. Hydrocodone bitartrate and ibuprofen should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Teratogenic Effects

: Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of the ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Babies born to mothers who have been taking opioids regularly prior to delivery will be physically 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 duration of maternal opioid use oral dose. There is no consensus on the best method of managing withdrawal. Nonteratogenic Effects

Labor and Delivery

As with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia and delayed parturition occurred in rats. Administration of hydrocodone bitartrate and ibuprofen are not recommended during labor and delivery.

Nursing Mothers

It is not known whether hydrocodone bitartrate and ibuprofen are excreted in human milk. In limited studies, an assay capable of detecting 1 mcg/mL did not demonstrate ibuprofen in the milk of lactating mothers. However, because of the limited nature of the studies, and the possible adverse effects of prostaglandin inhibiting drugs on neonates, hydrocodone bitartrate and ibuprofen is not recommended for use in nursing mothers.

Pediatric Use

The safety and effectiveness of hydrocodone bitartrate and ibuprofen in pediatric patients below the age of 16 have not been established.

Geriatric Use

In controlled clinical trials there was no difference in tolerability between patients LT 65 years of age and those GE 65, apart from an increased tendency of the elderly to develop constipation. However, because the elderly may be more sensitive to the renal and gastrointestinal effects of nonsteroidal anti-inflammatory agents as well as possible increase risk of respiratory depression with opioids, extra caution and reduced dosages should be used when treating the elderly with

hydrocodone bitartrate and ibuprofen.

Adverse Reactions

Hydrocodone bitartrate and ibuprofen was administered to approximately 300 pain patients in a safety study that employed dosages and a duration of treatment sufficient to encompass the recommended usage (see DOSAGE AND ADMINISTRATION). Adverse event rates generally increased with increasing daily dose. The event rates reported below are from approximately 150 patients who were in a group that received one tablet of hydrocodone bitartrate and ibuprofen an average of three to four times daily. The overall incidence rates of adverse experiences in the trials were fairly similar for this patient group and those who received the comparison treatment, acetaminophen with 600 mg codeine 60 mg.

The following uls adverse events that occurred with an incidence of 1% or greater in clinical trials of hydrocodone bitartrate and ibuprofen, without regard to the causal relationship of the events to the drug. To distinguish different rates of occurrence in clinical studies, the adverse events are uled as follows:

name of adverse event = less than 3%

adverse events marked with an asterisk* = 3% to 9%

adverse event rates over 9% are in parentheses.

: Abdominal pain*, Asthenia*; Fever; Flu syndrome; Headache (27%), Infection*, Pain. Body as a whole

: Palpitations; Vasodilation. Cardiovascular

: Anxiety*; Confusion; Dizziness (14%); Hypertonia; Insomnia*; Nervousness*; Paresthesia; Somnolence (22%); Thinking abnormalities. Central Nervous System

: Anorexia, Constipation (22%); Diarrhea*; Dry Mouth, Dyspepsia (12%); Flatulence, Gastritis; Melena; Mouth ulcers; Nausea (12%), Thirst; Vomiting*. Digestive

: Edema*. Metabolic and Nutritional Disorders

: Dyspnea; Hiccups; Pharyngitis; Rhinitis. Respiratory

: Pruritus*; Sweating*. Skin and Appendages

: Tinnitus. Special Senses

: Urinary frequency. Urogenital

Incidence less than 1%

: Allergic reaction. Body as a Whole

: Arrhythmia; Hypotension; Tachycardia. Cardiovascular

: Agitation; Abnormal dreams; Decreased libido; Depression; Euphoria; Mood changes; Neuralgia; Slurred speech; Tremor, Vertigo. Central Nervous System

: Chalky stool; “Clenching teeth”; Dysphagia; Esophageal spasm; Esophagitis; Gastroenteritis; Glossitis; Liver enzyme elevation. Digestive

: Weight decrease. Metabolic and Nutritional

: Arthralgia; Myalgia. Musculoskeletal

: Asthma; Bronchitis; Hoarseness; Increased cough; Pulmonary congestion; Pneumonia; Shallow breathing; Sinusitis. Respiratory

: Rash; Urticaria. Skin and Appendages

: Altered vision; Bad taste; Dry eyes. Special Senses

: Cystitis, Glyosuria; Impotence, Urinary incontinence; Urinary retention. Urogenital