Reprexain

• Centrix Pharmaceutical, Inc.

• Hawthorn Pharmaceuticals, Inc.

• Quinnova Pharmaceuticals, LLC

• Stat Rx Usa Llc

• Watson Pharma, Inc.

Reprexain is part of the drug class:

• Opium alkaloids and derivatives

Ibuprofen can increase your risk of fatal heart attack or stroke, especially if you use it long term or take high doses, or if you have heart disease. Even people without heart disease or risk factors could have a stroke or heart attack while taking this medicine.

Ibuprofen may also cause stomach or intestinal bleeding, which can be fatal. These conditions can occur without warning while you are using this medicine, especially in older adults.

You should not use this medicine if you are allergic to hydrocodone or ibuprofen (Advil, Motrin), or if you have ever had an asthma attack or severe allergic reaction after taking aspirin or an NSAID. Do not use this medicine just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

To make sure this medicine is safe for you, tell your doctor if you have ever had:

• heart disease, high blood pressure, fluid retention, diabetes, or if you smoke;

• stomach ulcers, or bleeding in your stomach or intestines;

• asthma or other breathing problems;

• liver or kidney disease;

• a head injury, brain tumor, or seizures;

• a problem with your gallbladder, pancreas, thyroid, or adrenal gland;

• urination problems;

• drug or alcohol addiction, or mental illness; or

• if you use a sedative like Valium (diazepam, alprazolam, lorazepam, Ativan, Klonopin, Restoril, Tranxene, Versed, Xanax, and others).

Some medicines can interact with hydrocodone and cause a serious condition called serotonin syndrome. Be sure your doctor knows if you also take stimulant medicine, opioid medicine, herbal products, or medicine for depression, mental illness, Parkinson's disease, migraine headaches, serious infections, or prevention of nausea and vomiting. Ask your doctor before making any changes in how or when you take your medications.

If you use hydrocodone while you are pregnant, your baby could become dependent on the drug. This can cause life-threatening withdrawal symptoms in the baby after it is born. Babies born dependent on habit-forming medicine may need medical treatment for several weeks. Tell your doctor if you are pregnant.

This medicine can pass into breast milk and cause drowsiness or breathing problems in a nursing baby. Tell your doctor if you are breast-feeding.

This medication may impair your thinking or reactions. Avoid driving or operating machinery until you know how the medicine will affect you. Dizziness or severe drowsiness can cause falls or other accidents.

Do not drink alcohol. Dangerous side effects or death could occur.

Ask a doctor or pharmacist before using any cold, allergy, or pain medication. Many medicines available over the counter contain aspirin or other medicines similar to ibuprofen. Taking certain products together can cause you to get too much of this type of medication. Check the label to see if a medicine contains aspirin, ibuprofen, ketoprofen, or naproxen.

In the U.S.

• Ibudone
• Reprexain
• Vicoprofen

Available Dosage Forms:

• Tablet

Therapeutic Class: Opioid/NSAID Combination

Pharmacologic Class: NSAID

Chemical Class: Hydrocodone

Hydrocodone and ibuprofen combination is used to relieve acute pain. This medicine should only be used for short periods of time, usually for a total of less than 10 days. This combination is not used for osteoarthritis or rheumatoid arthritis.

Hydrocodone is a narcotic analgesic that acts on the central nervous system to relieve pain. If hydrocodone is used for a long time, it may become habit-forming (causing mental or physical dependence). Physical dependence may lead to withdrawal side effects when you stop taking the medicine. Since hydrocodone and ibuprofen combination is only used for short-term (10 days or less) relief of pain, physical dependence will probably not occur.

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used in this combination to relieve inflammation, swelling, and pain.

This medicine is available only with your doctor's prescription.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Signs of high or low blood pressure like very bad headache or dizziness, passing out, change in eyesight.
• Signs of high potassium levels like a heartbeat that does not feel normal; feeling confused; feeling weak, lightheaded, or dizzy; feeling like passing out; numbness or tingling; or shortness of breath.
• Trouble breathing, slow breathing, or shallow breathing.
• Chest pain or pressure.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Very upset stomach or throwing up.
• Very bad belly pain.
• Any unexplained bruising or bleeding.
• Feeling very tired or weak.
• Change in eyesight, eye pain, or very bad eye irritation.
• Black, tarry, or bloody stools.
• Throwing up blood or throw up that looks like coffee grounds.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Seizures.
• A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.

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 Reprexain™ 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 Reprexain™ 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 Reprexain™ has not been evaluated in children.

Renal Impairment

The effect of renal insufficiency on the pharmacokinetics of the Reprexain™ dosage form has not been determined.

Common side effects of Reprexain include: drowsiness and dyspepsia. See below for a comprehensive list of adverse effects.