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VICOPROFEN(hydrocodone bitartrate and ibuprofen tablets)
DESCRIPTION
Each VICOPROFEN tablet contains:
Hydrocodone Bitartrate, USP 7.5 mg
Ibuprofen, USP 200 mg
VICOPROFEN is supplied in a fixed combination tablet form for oral administration. VICOPROFEN combines 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 ⟨-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). Its chemical formula is: C18H21N03•C4H606•2½H20, and the molecular weight is 494.50. Its structural formula is:
Ibuprofen is a nonsteroidal anti-inflammatory agent [non-selective COX inhibitor] with analgesic and antipyretic properties. Its chemical name is: (±)-2-(p-isobutylphenyl) propionic acid. Its chemical formula is: C13H1802, and the molecular weight is: 206.29. Its structural formula is:
Inactive ingredients in VICOPROFEN tablets include: colloidal silicon dioxide, corn starch, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, 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 VICOPROFEN 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 VICOPROFEN tablet has not been established.
Distribution
Ibuprofen is highly protein-bound (99%) like most other non-steroidal antiinflammatory agents. Although the extent of protein binding of hydrocodone in human plasma 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 0-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 0- 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 VICOPROFEN has not been eva luated in children.
Renal Impairment
The effect of renal insufficiency on the pharmacokinetics of the VICOPROFEN 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. VICOPROFEN produced greater efficacy 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
Carefully consider the potential benefits and risks of VICOPROFEN and other treatment options before deciding to use VICOPROFEN. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). VICOPROFEN tablets are indicated for the short-term (generally less than 10 days) management of acute pain. VICOPROFEN is not indicated for the treatment of such conditions as osteoarthritis or rheumatoid arthritis.
CONTRAINDICATIONS
VICOPROFEN is contraindicated in patients with known hypersensitivity to hydrocodone or ibuprofen. Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to hydrocodone.
VICOPROFEN should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS - Anaphylactoid Reactions, and PRECAUTIONS -Preexisting Asthma).
VICOPROFEN is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
WARNINGS
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 Gl events (see Gl WARNINGS).
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
NSAID-containing products, including VICOPROFEN, can lead to onset of new hypertension or worsening of preexisting 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. NSAID-containing products, including VICOPROFEN, 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. VICOPROFEN should be used with caution in patients with fluid retention or heart failure.
Misuse Abuse and Diversion of Opioids
VICOPROFEN contains hydrocodone an opioid agonist, and is a Schedule III 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.
VICOPROFEN can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing VICOPROFEN 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
At high doses or in opioid-sensitive patients, hydrocodone may produce doserelated 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
NSAIDs, including VICOPROFEN, can cause serious gastrointestinal (Gl) 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 develops a serious upper Gl adverse event on NSAID therapy, is symptomatic. Upper Gl 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 Gl 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 and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a Gl bleed compared to patients with neither of these risk factors. Other factors that increase the risk for Gl 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 Gl 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 Gl 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 Gl ulceration and bleeding during NSAID therapy and promptly initiate additional eva luation and treatment if a serious Gl adverse event is suspected. This should include discontinuation of the NSAID until a serious Gl adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.
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
No information is available from controlled clinical studies regarding the use of VICOPROFEN in patients with advanced renal disease. Therefore, treatment with VICOPROFEN is not recommended in patients with advanced renal disease. If VICOPROFEN therapy must be initiated, close monitoring of the patient’s renal function is advisable.
Anaphylactoid Reactions
As with other NSAID-containing products, anaphylactoid reactions may occur in patients without known prior exposure to VICOPROFEN. VICOPROFEN should not be given to patients with the aspirin triad. This symptom complex 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 in cases where an anaphylactoid reaction occurs.
Skin Reactions
Products containing NSAIDs, including VICOPROFEN, 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
As with other NSAID-containing products, VICOPROFEN should be avoided in late pregnancy because it may cause premature closure of the ductus arteriosus.
PRECAUTIONS
General Precautions
VICOPROFEN 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 VICOPROFEN 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, VICOPROFEN 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.
Cough Reflex
Hydrocodone suppresses the cough reflex; as with opioids, caution should be exercised when VICOPROFEN is used postoperatively and in patients with pulmonary disease.
Effect on Diagnostic Signs
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.
Hepatic Effects
Borderline elevations of one or more liver enzymes may occur in up to 15% of patients taking NSAIDs including ibuprofen as found in VICOPROFEN. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Notable elevations of SGPT (ALT) or SGOT (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 eva luated for evidence of the development of more severe hepatic reactions while on VICOPROFEN therapy. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), VICOPROFEN should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs including ibuprofen as found in VICOPROFEN. This may be due to fluid retention, occult or gross Gl blood loss, or an incompletely described effect |
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