Reprexain

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of REPREXAIN™ and other treatment options before deciding to use REPREXAIN™. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
REPREXAIN™ tablets are indicated for the short-term (generally less than 10 days) management of acute pain. REPREXAIN™ 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 REPREXAIN™ (hydrocodone bitartrate and ibuprofen tablets) and other treatment options before deciding to use REPREXAIN™. 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 REPREXAIN™, 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 REPREXAIN™ 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 REPREXAIN™, the dose and frequency of dosing should be adjusted to suit the individual patient’s need, without exceeding the total daily dose recommended.

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.

Information for Patients

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 REPREXAIN™ Medication Guide that accompanies each prescription dispensed.
1. REPREXAIN™ (hydrocodone bitartrate and ibuprofen tablets), 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. REPREXAIN™ (hydrocodone bitartrate and ibuprofen tablets) can be abused in a manner similar to other opioid agonists, legal or illicit. REPREXAIN™ 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. REPREXAIN™, 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. REPREXAIN™, 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. REPREXAIN™, 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, REPREXAIN™ 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.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, REPREXAIN™ should be discontinued.

Drug InteractionsACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking REPREXAIN™ 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 REPREXAIN™ 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 REPREXAIN™ is administered with aspirin, the protein binding of aspirin is reduced, although the clearance of free REPREXAIN™ is not altered. The clinical significance of this interaction is not known; however, as with other NSAID-containing products, concomitant administration of REPREXAIN™ 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 REPREXAIN™ 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 REPREXAIN™  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 REPREXAIN™ 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 REPREXAIN™ 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.
Carcinogenesis, Mutangenicity, and Impairment of Fertility

 
The carcinogenic and mutagenic potential of REPREXAIN™ has not been investigated. The ability of REPREXAIN™ to impair fertility has not been assessed.

Pregnancy

Pregnancy Category C.
Teratogenic Effects: Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities.

REPREXAIN™, 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). REPREXAIN™, 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. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. REPREXAIN™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic 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 the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.

Labor and Delivery

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 REPREXAIN™ is not recommended during labor and delivery. The effects of REPREXAIN™ on labor and delivery in pregnant women are unknown.

Nursing Mothers

It is not known whether hydrocodone is 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 because of the potential for serious adverse reactions in nursing infants from REPREXAIN™, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of REPREXAIN™ 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 less than 65 years of age and those more than or equal to 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 increased risk of respiratory depression with opioids, extra caution and reduced dosages should be used when treating the elderly with REPREXAIN™  (hydrocodone bitartrate and ibuprofen tablets).

DESCRIPTIONEach REPREXAIN™ (hydrocodone bitartrate and ibuprofen tablets) contains either:  Hydrocodone Bitartrate, USP 2.5 mg and ibuprofen, USP 200 mg, Hydrocodone Bitartrate, USP 5 mg and ibuprofen, USP    200 mg or Hydrocodone Bitartrate, USP 10 mg and ibuprofen, USP 200 mg.
REPREXAIN™ is supplied in a fixed combination tablet form for oral administration.
REPREXAIN™ 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 a-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). Its chemical formula is: C₁₈H ₂₁NO₃•C₄H₆O₆•2½H₂O, and the molecular weight is 494.50. Its structural formula is:

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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:


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[image: MM3]    Label Image

[image: MM4]     REPREXAIN 10-200 MG LABEL

HOW SUPPLIED

REPREXAIN™ (hydrocodone bitartrate and ibuprofen tablets) are available as:
2.5 mg/200 mg: white capsule shaped, film coated tablets, debossed “IP 116” on obverse and plain on reverse.   
Bottles of 100: NDC 63717-900-01
Sample boxes of 10 tablets: NDC 63717-900-99
5 mg/200 mg: white, oval shaped, film coated tablets, debossed “IP 146” on obverse and plain on reverse.  
Bottles of 100: NDC 63717-901-01
Sample boxes of 10 tablets: NDC 63717-901-99
10 mg/200 mg: yellow, round shaped, film coated tablets, debossed “IP 117” on obverse and plain on reverse.  
Bottles of 100: NDC 63717-902-01
Sample boxes of 10 tablets: NDC 63717-902-99

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.

Manufactured For:
Hawthorn Pharmaceuticals, Inc.
Madison, MS 39110

Rev. 12/08 HI251

NDC 63717-900-01

Reprexain™ CIII

(hydrocodone bitartrate and ibuprofen tablet)

2.5 mg/200 mg

Rx only

100 Tablets

Hawthorn Pharmaceuticals, Inc.

Each tablet contains:

Hydrocodone bitartrate USP, 2.5 mg

Ibuprofen USP, 200 mg

Usual Dosage: See package insert.

Dispense in light resistant container as defined in the USP.

Store at 25^oC (77^oF); excursions permitted to controlled room temperature 15^o-30^oC

(59^o-86^oF).

Mfd. for: Hawthorn Pharmaceuticals, Inc.

Madison, Ms 39110

HI200 11/05