HYCOTUSS (hydrocodone bitartrate and guaifenesin) Expectorant Syrup contains hydrocodone (dihydrocodeinone) bitartrate, a semi-synthetic centrally-acting opioid antitussive and guaifenesin, an expectorant for oral administration.

Chemically, Hydrocodone Bitartrate is 4, 5α-epoxy-3-methoxy-17-methyl-morphinan-6-one tartrate (1:1) hydrate (2:5) with the following structure:

Chemically, Guaifenesin is 3-(o-methoxyphenoxy)-1, 2-propanediol with the following structure:

Each teaspoonful (5 mL) contains:

Hydrocodone bitartrate, USP......................5 mg
Guaifenesin, USP......................100 mg
Alcohol, USP 1...................... 0% v/v

Inactive Ingredients: FD&C Red No. 40, FD&C Yellow No. 6 (Sunset Yellow), flavoring, glycerin, methylparaben, propylparaben, purified water, sodium saccharin, sorbitol solution, and sucrose.

HYCOTUSS Expectorant Syrup is indicated for the symptomatic relief of irritating nonproductive cough associated with upper and lower respiratory tract congestion.

Usual Adult Dose: One teaspoonful (5 mL) after meals and at bedtime, not less than 4 hours apart (not to exceed 6 teaspoonfuls in a 24 hour period). Treatment should be initiated with one teaspoonful and subsequent doses, up to a maximum single dose of 3 teaspoonfuls, adjusted if required.

Usual Children's Dose:

Over 12 years: Initial dose 1 teaspoonful; maximum single dose, 2 teaspoonfuls.

6 to 12 years: Initial dose 1/2 teaspoonful; maximum single dose, 1 teaspoonful.

HYCOTUSS (hydrocodone bitartrate and guaifenesin) Expectorant Syrup is available as an orange-colored, butterscotch flavored syrup in bottles as follows:

16 fl oz (473 mL)........................NDC 63481-235-16

Store at controlled room temperature between 20° -25° C (68° -77° F). [See USP] Store and dispense in a tight, light-resistant container as described in the U.S.P.

Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, PA 19317. Manufactured by: Pharmaceutical Associates, Inc. Greenville, SC 29605. R02/04. FDA Rev date: n/a

Respiratory System: Hydrocodone produces dose-related respiratory depression by acting directly on brain stem respiratory centers.

Cardiovascular System: Hypertension, postural hypotension and palpitations.

Genitourinary System: Ureteral spasm, spasm of vesical sphincters and urinary retention have been reported with opiates.

Central Nervous System: Sedation, drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, dizziness, psychic dependence, mood changes and blurred vision.

Gastrointestinal System: Nausea and vomiting occur more frequently in ambulatory than in recumbent patients.

Drug Abuse And Dependence

Special care should be exercised in prescribing hydrocodone for emotionally unstable patients and for those with a history of drug misuse. Such patients should be closely supervised when long-term therapy is contemplated.

HYCOTUSS Expectorant Syrup is a Schedule III opioid. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of opioids; therefore, HYCOTUSS Expectorant Syrup should always be prescribed and administered with caution. Physical dependence is the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome.

Patients physically dependent on opioids will develop an abstinence syndrome upon abrupt discontinuation of the opioid or following the administration of a opioid antagonist. The character and severity of the withdrawal symptoms are related to the degree of physical dependence. Manifestations of opioid withdrawal are similar to but milder than that of morphine and include lacrimation, rhinorrhea, yawning, sweating, restlessness, dilated pupils, anorexia, gooseflesh, irritability and tremor. In more severe forms, nausea, vomiting, intestinal spasm and diarrhea, increased heart rate and blood pressure, chills, and pains in bones and muscles of the back and extremities may occur. Peak effects will usually be apparent at 48 to 72 hours.

Treatment of withdrawal is usually managed by providing sufficient quantities of an opioid to suppress severe withdrawal symptoms and then gradually reducing the dose of opioid over a period of several days.

Patients receiving other opioids, analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative hypnotics or other CNS depressants (including alcohol) concomitantly with hydrocodone may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced (see WARNINGS).

Laboratory Interactions: The metabolite of guaifenesin has been found to produce an apparent increase in urinary 5-hydroxyindoleacetic acid, and guaifenesin therefore may interfere with the interpretation of this test for the diagnosis of carcinoid syndrome. Guaifenesin administration should be discontinued 24 hours prior to the collection of urine specimens for the determination of 5-hydroxyindoleacetic acid.

May be habit forming. Hydrocodone can produce drug dependence of the morphine type and therefore has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of HYCOTUSS Expectorant Syrup and it should be prescribed and administered with the same degree of caution appropriate to the use of other opioid drugs (See Drug Abuse And Dependence).

Respiratory Depression: HYCOTUSS Expectorant Syrup produces dose-related respiratory depression by directly acting on the brain stem respiratory centers. If respiratory depression occurs, it may be antagonized by the use of NARCAN® (naloxone hydrochloride) and other supportive measures when indicated.

Head Injury and Increased Intracranial Pressure: The respiratory depressant properties of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a preexisting 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 HYCOTUSS Expectorant Syrup or other opioids may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Before prescribing medication to suppress or modify cough, it is important to ascertain that the underlying cause of cough is identified, that modification of cough does not increase the risk of clinical or physiologic complications, and that appropriate therapy for the primary disease is provided.

Usage in Ambulatory Patients: Hydrocodone, like all opioids, may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery, and patients should be warned accordingly.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity, mutagenicity and reproduction studies have not been conducted with HYCOTUSS Expectorant Syrup.

Usage in Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted with HYCOTUSS Expectorant Syrup. It is also not known whether HYCOTUSS Expectorant Syrup can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. HYCOTUSS Expectorant Syrup should be given to a pregnant woman only if clearly needed.

Nonteratogenic Effects: 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. Chlorpromazine 0.7-1.0 mg/kg q 6 h, phenobarbital 2 mg/kg q 6 h, and paregoric 2-4 drops/kg q 4 h, have been used to treat withdrawal symptoms in infants. The duration of therapy is 4 to 28 days, with the dosages decreased as tolerated.

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from HYCOTUSS Expectorant Syrup, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Signs and Symptoms: Serious overdosage with HYCOTUSS Expectorant Syrup 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.

Treatment: Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The opioid antagonist naloxone hydrochloride is a specific antidote for respiratory depression which may result from overdosage or unusual sensitivity to opioids including hydrocodone. Therefore, an appropriate dose of naloxone

hydrochloride should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. For further information, see full prescribing information for naloxone hydrochloride. An antagonist should not be administered in the absence of clinically significant respiratory depression. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Gastric emptying may be useful in removing unabsorbed drug. Activated charcoal may be of benefit.

HYCOTUSS Expectorant Syrup is contraindicated in patients hypersensitive to hydrocodone or guaifenesin. Patients known to be hypersensitive to other opioids may exhibit cross sensitivity to HYCOTUSS Expectorant Syrup. Hydrocodone is contraindicated in the presence of an intracranial lesion associated with increased intracranial pressure; and whenever ventilatory function is depressed.

Clinical trials have proven hydrocodone bitartrate to be an effective antitussive agent which is pharmacologically 2 to 8 times as potent as codeine. At equi-effective doses, its sedative action is greater than codeine. The precise mechanism of action of hydrocodone and other opiates is not known; however, hydrocodone is believed to act by directly depressing the cough center. In excessive doses, hydrocodone, like other opium derivatives, can depress respiration. The effects of hydrocodone in therapeutic doses on the cardiovascular system is insignificant. The constipation effects of hydrocodone are much weaker than that of morphine and no stronger than that of codeine. Hydrocodone can produce miosis, euphoria, physical and psychological dependence. At therapeutic antitussive doses, it does exert analgesic effects. Following a 10 mg oral dose of hydrocodone administered to five male human subjects, the mean peak concentration was 23.6 ± 5.2 ng/mL. Maximum serum levels were achieved at 1.3 ± 0.3 hours and a half-life was determined to be 3.8 ± 0.3 hours. Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation and 6-keto reduction to the corresponding 6-α- and 6-β-hydroxymetabolites.

The exact mechanism of action is not established, but guaifenesin is believed to act by stimulating receptors in the gastric mucosa that initiate a reflex secretion of respiratory tract fluid, thereby increasing the volume and decreasing the viscosity of bronchial secretions. Studies with guaifenesin indicate that it is rapidly absorbed from the gastrointestinal tract and has a half-life of one hour.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

GUAIFENESIN/HYDROCODONE - ORAL

(gweye-FEN-eh-sin/hi-droh-KOH-doan)

COMMON BRAND NAME(S): Atuss EX, Cotuss-V, Entuss, Vortex

USES: This medication is used for temporary relief of coughs without phlegm that are caused by certain infections of the air passages (e.g., bronchitis, sinusitis, common cold). This product is generally not used for an ongoing cough from smoking or long-term breathing problems (e.g., chronic bronchitis, emphysema), unless directed by your doctor. This product contains two medicines, guaifenesin and hydrocodone. Guaifenesin is called an expectorant. It works by making phlegm in the breathing tubes more fluid. This helps the cough to clear phlegm better. Hydrocodone is a narcotic cough suppressant that works by decreasing the feeling of needing to cough.

Do not use this medication in children younger than 6 years unless specifically directed by the doctor. To decrease the risk for serious side effects, carefully follow all of the doctor's dosage directions. Do not give other cough and cold medication that might contain the same or similar ingredients (see also Drug Interactions section). Ask your doctor or pharmacist about other ways to relieve cough and cold symptoms (e.g., saline nose drops/spray, using a humidifier or infant nasal suction bulb).

HOW TO USE: Take this medication by mouth with or without food, usually every 4-6 hours or as directed by your doctor. For best results, take with a full glass of water. The dosage is based on your age, medical condition, and response to treatment. If you are using the liquid form, measure the dose carefully using a special medication spoon or oral measuring syringe. Do not use a household spoon. Do not take more than the maximum daily dose for your age group unless instructed to do so by your doctor.

Use this medication regularly in order to get the most benefit from it. To help you remember, take it at the same times each day.

This medication may cause dependence, especially if it has been used regularly for an extended time or if it has been used in high doses. In such cases, if you suddenly stop this drug, withdrawal reactions may occur. Such reactions can include runny nose, sweating, restlessness, widened pupils, loss of appetite, goose bumps, irritability, and shakiness. Fast heartbeat and muscle/bone pain may also occur. Report any such reactions to your doctor immediately. When stopping extended, regular treatment with this drug, gradually reducing the dosage as directed will help prevent withdrawal reactions. Consult your doctor or pharmacist for more details.

Though it is very unlikely to occur, this medication can also result in abnormal drug-seeking behavior (addiction/habit forming). Do not increase your dose, take it more frequently or use it for a longer time than prescribed. Properly stop the medication when so directed. This will lessen the chances of becoming addicted.

When used for an extended period, this medication may not work as well and may require different dosing. Talk with your doctor if this medication stops working well.

Inform your doctor if your cough persists or worsens after more than 1 week or if you also have fever, headache, or rash.

SIDE EFFECTS: Nausea, vomiting, constipation, dizziness, sleepiness, loss of appetite, nervousness, dry mouth, or blurred vision may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

To prevent constipation, maintain a diet adequate in fiber and drink plenty of water. If you become constipated while using this drug, consult your pharmacist for help in selecting a laxative (e.g., stimulant-type with stool softener).

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: difficulty staying awake, confusion, slow/shallow breathing, difficult/painful urination, irregular heartbeat, mental/mood changes (e.g., depression, hallucinations).

Tell your doctor immediately if any of these rare but very serious side effects occur: severe stomach/abdominal pain, change in the amount of urine, seizures.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking guaifenesin/hydrocodone, tell your doctor or pharmacist if you are allergic to it; or to sulfites; or to other narcotics (e.g., codeine); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe breathing problems (e.g., severe chronic obstructive pulmonary disease-COPD, advanced emphysema), increased pressure in the brain (intracranial hypertension), certain bowel diseases (e.g., paralytic ileus), intoxication with medications which cause sleepiness or slow/shallow breathing (CNS/respiratory depressants such as alcohol or tranquilizers/sedatives).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: difficulty urinating (e.g., due to enlarged prostate, urethral stricture), personal or family history of regular use/abuse of drugs/alcohol, breathing problems (e.g., asthma, mild chronic obstructive pulmonary disease-COPD, moderate/severe sleep apnea), smoking, cough with large amounts of phlegm, kidney disease, liver disease, heart disease, low blood pressure, gallbladder/biliary tract problems, swollen pancreas (pancreatitis), certain brain problems (e.g., brain tumor, lesions), head injury, seizures, slow/irregular heartbeat, adrenal gland problems (e.g., Addison's disease), mental/mood disorders (e.g., toxic psychosis), a certain spine problem (kyphoscoliosis), recent surgery, underactive thyroid (hypothyroidism), a severe loss of body water (dehydration), severe obesity, stomach pain of unknown cause.

This drug may cause dizziness, drowsiness, or blurred vision; use caution engaging in activities requiring alertness or clear vision such as driving or using machinery. Avoid alcoholic beverages because they may increase the risk of side effects.

To minimize dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Caution is advised when using this drug in the elderly because they may be more sensitive to its side effects (e.g., slow/shallow breathing, drowsiness, dizziness).

Caution is advised when using this drug in children because they may be more sensitive to its side effects (e.g., slow/shallow breathing, drowsiness, dizziness).

This medication should be used only when clearly needed during pregnancy. It is not recommended for use over long periods or in high doses near the expected delivery date because it may harm the unborn baby. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: buprenorphine, butorphanol, nalbuphine, pentazocine, naltrexone.

Avoid taking MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine) within 2 weeks before, during, or after treatment with this medication. In some rare cases a serious, possibly fatal drug interaction may occur.

If you are currently using any of these medications, tell your doctor or pharmacist before starting this product.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: amphetamines (e.g., methylphenidate, mixed amphetamine salts), water pills (diuretics such as furosemide), drugs affecting liver enzymes that remove hydrocodone from your system (e.g., cimetidine, rifamycins including rifampin).

Tell your doctor or pharmacist if you also take drugs that may cause drowsiness, slow your breathing, or lower your blood pressure such as: antihistamines that cause drowsiness (e.g., diphenhydramine), anti-anxiety drugs (e.g., diazepam), anti-seizure drugs (e.g., carbamazepine), medicine for sleep (e.g., sedatives, hypnotics), muscle relaxants, other narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., phenothiazines such as chlorpromazine, tricyclics such as amitriptyline), tranquilizers.

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain drowsiness-causing ingredients. Ask your pharmacist about the safe use of those products.

Guaifenesin is available in both prescription and nonprescription products. Check the labels of all your medications carefully to make sure you are not taking more than one product containing guaifenesin.

This product can affect the results of certain lab tests (e.g., uric acid levels, 5-hydroxyindoleacetic acid levels, vanillylmandelic acid levels). Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: vomiting, slow/shallow breathing, slow heartbeat, inability to wake up, weakness, cold/clammy skin.

NOTES: Do not share this medication with others. It is against the law.

This medication has been prescribed for your current condition only. Do not use it later for another condition unless told to do so by your doctor. A different medication may be necessary in those cases.

Drink plenty of fluids while taking this medication unless your doctor instructs you otherwise. This may help to relieve congestion.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-77 degrees F (15-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.