Professional Information — Vicoprofen

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.

Dosage and Administration

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).

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

For the short-term (generally less than 10 days) management of acute pain, the recommended dose of VICOPROFEN is one tablet every 4 to 6 hours, as necessary. Dosage should not exceed 5 tablets in a 24-hour period. It should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related.

The lowest effective dose or the longest dosing interval should be sought for each patient (see WARNINGS), especially in the elderly. After observing the initial response to therapy with VICOPROFEN, the dose and frequency of dosing should be adjusted to suit the individual patient's need, without exceeding the total daily dose recommended.

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 ).

Adverse Reactions

VICOPROFEN 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 VICOPROFEN 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 600 mg with codeine 60 mg.

The following lists adverse events that occurred with an incidence of 1% or greater in clinical trials of VICOPROFEN, 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 listed 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.

Body as a Whole

Abdominal pain*; Asthenia*; Fever; Flu syndrome; Headache (27%); Infection*; Pain.

Cardiovascular

Palpitations; Vasodilation.

Central Nervous System

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

Digestive

Anorexia; Constipation (22%); Diarrhea*; Dry mouth*; Dyspepsia (12%); Flatulence*; Gastritis; Melena; Mouth ulcers; Nausea (21%); Thirst; Vomiting*.

Metabolic and Nutritional Disorders

Edema*.

Respiratory

Dyspnea; Hiccups; Pharyngitis; Rhinitis.

Skin and Appendages

Pruritus*; Sweating*.

Special Senses

Tinnitus.

Urogenital

Urinary frequency.

Incidence less than 1%

Body as a Whole

Allergic reaction.

Cardiovascular

Arrhythmia; Hypotension; Tachycardia.

Central Nervous System

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

Digestive

Chalky stool; "Clenching teeth"; Dysphagia; Esophageal spasm; Esophagitis; Gastroenteritis; Glossitis; Liver enzyme elevation.

Metabolic and Nutritional

Weight decrease.

Musculoskeletal

Arthralgia; Myalgia.

Respiratory

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

Skin and Appendages

Rash; Urticaria.

Special Senses

Altered vision; Bad taste; Dry eyes.

Urogenital

Cystitis; Glycosuria; Impotence; Urinary incontinence; Urinary retention.

Drug Interactions

ACE-inhibitors

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

Anticholinergics

The concurrent use of anticholinergics with hydrocodone preparations may produce paralytic ileus.

Antidepressants

The use of Monoamine Oxidase Inhibitors (MAOIs) or tricyclic antidepressants with VICOPROFEN may increase the effect of either the antidepressant or hydrocodone.

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 hydrocodone is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Aspirin

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

CNS Depressants

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

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 prostaglandin synthesis. During concomitant therapy with VICOPROFEN 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 elevate plasma lithium concentration and reduce renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when VICOPROFEN and lithium are administered concurrently, patients should be observed 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 VICOPROFEN is administered concomitantly with methotrexate.

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 hydrocodone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of hydrocodone and/or may precipitate withdrawal symptoms in these patients.

Neuromuscular Blocking Agents

Hydrocodone, as well as other opioid analgesics, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Warfarin

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.

Drug Abuse and Dependence

Misuse Abuse and Diversion of Opioids

VICOPROFEN contains hydrocodone, an opioid agonist, and is a Schedule III controlled substance. VICOPROFEN, 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. VICOPROFEN, 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 hydrocodone and/or ibuprofen.

Signs and Symptoms

Hydrocodone Component

Serious overdose with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis) extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur.

Ibuprofen Component

Symptoms include gastrointestinal irritation with erosion and hemorrhage or perforation, kidney damage, liver damage, heart damage, hemolytic anemia, agranulocytosis, thrombocytopenia, aplastic anemia, and meningitis. Other symptoms may include headache, dizziness, tinnitus, confusion, blurred vision, mental disturbances, skin rash, stomatitis, edema, reduced retinal sensitivity, corneal deposits, and hyperkalemia.

Treatment

Primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid overdose or unusual sensitivity to opioids, including hydrocodone. Therefore, an appropriate dose of naloxone hydrochloride should be administered intravenously with simultaneous efforts at respiratory resuscitation. Since the duration of action of hydrocodone 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. Supportive measures should be employed as indicated. Gastric emptying may be useful in removing unabsorbed drug. In cases where consciousness is impaired it may be inadvisable to perform gastric lavage. If gastric lavage is performed, little drug will likely be recovered if more than an hour has elapsed since ingestion. Ibuprofen is acidic and is excreted in the urine; therefore, it may be beneficial to administer alkali and induce diuresis. In addition to supportive measures the use of oral activated charcoal may help to reduce the absorption and reabsorption of ibuprofen. Dialysis is not likely to be effective for removal of ibuprofen because it is very highly bound to plasma proteins.

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 α-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). Its chemical formula is: C₁₈H₂₁NO₃ •C₄H₆O₆ •2½H₂O, 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: C₁₃H₁₈O₂, 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, propylene glycol 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 anti-inflammatory 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 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 VICOPROFEN has not been evaluated 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.

How Supplied / Storage and Handling

VICOPROFEN tablets are available as:
White film-coated round convex tablets, engraved with "VP" over Abbott "A" logo on one side and plain on the other side.

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container.

A Schedule CS-III Controlled Substance.

© Abbott

Manufactured by Halo Pharmaceutical Inc.
Whippany, NJ 07981 U.S.A.
for Abbott Laboratories
North Chicago, IL 60064 U.S.A.

Rev. 10/2009

Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, Oklahoma   74146

Patient Counseling Information

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.

1. VICOPROFEN® (hydrocodone bitartrate 7.5 mg and ibuprofen 200 mg), 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.
2. Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this combination product, and should be avoided.
3. VICOPROFEN can be abused in a manner similar to other opioid agonists, legal or illicit. VICOPROFEN may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.
4. VICOPROFEN, like other NSAID-containing products, 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).
5. VICOPROFEN, like other NSAID-containing products, can cause GI discomfort and 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).
6. VICOPROFEN, like other NSAID-containing products, 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 such as itching, and should ask for 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 physicians as soon as possible.
7. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
8. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
9. Patients should be informed of the signs 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).
10. In late pregnancy, as with other NSAIDs, VICOPROFEN should be avoided because it may cause premature closure of the ductus arteriosus.
11. Patients should be instructed to report any signs of blurred vision or other eye symptoms.