Hydrocodone Bitartrate and Acetaminophen Tablets, USPCIII

hydrocodone bitartrate and acetaminophen (Hydrocodone Bitartrate and Acetaminophentablet 
[Endo Pharmaceuticals Inc.]

DESCRIPTION

Each tablet, for oral administration, contains hydrocodone bitartrate (WARNING: May be habit forming) and acetaminophen in the following strengths:

Hydrocodone bitartrate, USP 7.5 mg
Acetaminophen, USP 500 mg
Hydrocodone bitartrate, USP 7.5 mg
Acetaminophen, USP 650 mg
Hydrocodone bitartrate, USP 10 mg
Acetaminophen, USP 650 mg

Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, crospovidone, microcrystalline cellulose, povidone, pregelatinized starch, and stearic acid.

Hydrocodone bitartrate is an opioid analgesic and antitussive and occurs as fine, white crystals or as a crystalline powder. It is affected by light. The chemical name is 4, 5α -epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). It has the following structural formula:

Image from Drug Label Content

Acetaminophen, 4’-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:

Image from Drug Label Content

CLINICAL PHARMACOLOGY

Hydrocodone is a semisynthetic narcotic 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 opiates is not know, although it is believed to relate to the existence of opiate receptors in the central nervous system. In addition to analgesia, narcotics may produce drowsiness, changes in mood and mental clouding.

The analgesic action of acetaminophen involves peripheral and central influences, but the specific mechanism is as yet undetermined. Antipyretic activity is mediated through hypothalamic heat regulating centers. Acetaminophen inhibits prostaglandin synthetase. Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.

Pharmacokinetics

The behavior of the individual components is described below.

Hydrocodone

Following a 10 mg oral dose of hydrocodone administered to five adult male subjects, the mean peak concentration was 23.6 ± 5.2 ng/mL. Maximum serum levels were achieved at 1.3 ± 0.3 hours and the 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-hydroxymetabilites.

See OVERDOSAGE for toxicity information.

Acetaminophen

Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug.

See OVERDOSAGE for toxicity information.

INDICATIONS AND USAGE

Hydrocodone bitartrate and acetaminophen tablets are indicated for the relief of moderate to moderately severe pain.

CONTRAINDICATIONS

This product should not be administered to patients who have previously exhibited hypersensitivity to hydrocodone or acetaminophen.

WARNINGS

Respiratory Depression

At high doses or in sensitive patients, hydrocodone may produce dose-related respiratory depression by acting directly on the brain stem respiratory center. Hydrocodone also affects the center that controls respiratory rhythm, and may produce irregular and periodic bleeding.

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of narcotics 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, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries.

Acute Abdominal Conditions

The administration of narcotics may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

PRECAUTIONS

General:

Special Risk Patients

As with any narcotic analgesic agent, hydrocodone bitartrate and acetaminophen 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 all narcotics, caution should be exercised when hydrocodone bitartrate and acetaminophen tablets are used postoperatively and in patients with pulmonary disease.

Information for Patients

Hydrocodone and acetaminophen tablets, like all narcotics, 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.

Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this combination product, and should be avoided.

Hydrocodone 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.

Laboratory Tests

In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests.

Drug Interactions

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

The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone.

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

Drug/Laboratory Test Interactions

Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No adequate studies have been conducted in animals to determine whether hydrocodone or acetaminophen have a potential for carcinogenesis, mutagenesis, or impairment of fertility.

Pregnancy

Teratogenic Effects

Pregnancy Category C: Hydrocodone has been shown to be teratogenic in hamsters when given in doses 700 times the human dose. There are no adequate and well-controlled studies in pregnant women. Hydrocodone bitartrate and acetaminophen tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs and 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 to 1 mg/kg q6h, and paregoric 2 to 4 drops/kg q4h, have been used to treat withdrawal symptoms in infants. The duration of therapy is 4 to 28 days, with the dosage decreased as tolerated.

Labor and Delivery

As with all narcotics, administration of this product to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used.

Nursing Mothers

Acetaminophen is excreted in breast milk in small amounts, but the significance of its effects on nursing infants is not known. It is not known whether hydrocodone 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 hydrocodone and acetaminophen, 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

Safety and effectiveness in the pediatric population have not been established.

ADVERSE REACTIONS

The most frequently reported adverse reactions are light-headedness, dizziness, sedation, nausea and vomiting. These effects seem to be more prominent in ambulatory than in non-ambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down.

Other adverse reactions include:

Central Nervous System
Drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, psychic dependence, mood changes.

Gastrointestinal System
The antiemetic phenothiazines are useful in suppressing the nausea and vomiting which may occur (see above); however, some phenothiazine derivatives seem to be antianalgesic and to increase the amount of narcotic required to produce pain relief, while other phenothiazines reduce the amount of narcotic required to produce a given level of analgesia. Prolonged administration of hydrocodone bitartrate and acetaminophen tablets may produce constipation.

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

Respiratory Depression
Hydrocodone bitartrate may produce dose-related respiratory depression by acting directly on brain stem respiratory centers (see OVERDOSAGE). Hydrocodone also affects the center that controls respiratory rhythm, and may produce irregular and periodic breathing. If significant respiratory depression occurs, it may be antagonized by the use of naloxone hydrochloride. Apply other supportive measures when indicated.

Dermatological
Skin rash, pruritus.

The following adverse drug events may be borne in mind as potential effects of acetaminophen: allergic reactions, rash, thrombocytopenia, agranulocytosis.

Potential effects of high dosage are listed in the OVERDOSAGE section.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

Hydrocodone bitartrate and acetaminophen tablets are classified as a Schedule III controlled substance.

Abuse and Dependence

Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of narcotics; therefore, this product should be prescribed and administered with caution. However, psychic dependence is unlikely to develop when hydrocodone bitartrate and acetaminophen tablets are used for a short time for the treatment of pain.

Physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several weeks of continued narcotic use, although some mild degree of physical dependence may develop after a few days of narcotic 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.

OVERDOSAGE

Following an acute overdosage, toxicity may result from hydrocodone or acetaminophen.

Signs and Symptoms

Hydrocodone

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.

Acetaminophen

In acute acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma and thrombocytopenia may also occur.

Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.

In adults, hepatic toxicity has rarely been reported with acute overdoses of less than 10 grams or fatalities with less than 15 grams. Importantly, young pediatric patients seem to be more resistant than adults to the hepatotoxic effects of an acetaminophen overdose. Despite this, the measures outlined below should be initiated in any adult or pediatric patient suspected of having ingested an acetaminophen overdose.

Treatment

A single or multiple overdose with hydrocodone and acetaminophen is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended.

Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Vomiting should be induced mechanically, or with syrup of ipecac, if the patient is alert (adequate pharyngeal and laryngeal reflexes). Oral activated charcoal (1 g/kg) should follow gastric emptying. The first dose should be accompanied by an appropriate cathartic. If repeated doses are used, the cathartic might be included with alternate doses as required. Hypotension is usually hypovolemic and should respond to fluids. Vasopressors and other supportive measures should be employed as indicated. A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and, when necessary, to provide assisted respiration.

Meticulous attention should be given to maintaining adequate pulmonary ventilation. In severe cases of intoxication, peritoneal dialysis, or preferably hemodialysis may be considered. If hypoprothrombinemia occurs due to acetaminophen overdose, vitamin K should be administered intravenously.

Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid overdose. Naloxone hydrochloride 0.4 mg to 2 mg is given parenterally. Since the duration of action of hydrocodone may exceed that of naloxone, the patient should be kept under continuous surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression.

If the dose of acetaminophen may have exceeded 140 mg/kg, acetylcysteine should be administered as early as possible. Serum acetaminophen levels should be obtained, since levels four or more hours following ingestion help predict acetaminophen toxicity. Do not await acetaminophen assay results before initiating treatment. Hepatic enzymes should be obtained initially, and repeated at 24-hour intervals.

Methemoglobinemia over 30% should be treated with methylene blue by slow intravenous administration.

The toxic dose for adults for acetaminophen is 10 grams.

DOSAGE AND ADMINISTRATION

Dosage should be adjusted according to the severity of pain and response of the patient. However, 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 usual adult dosage for the 7.5 mg/500 mg, 7.5 mg/650 mg, and 10 mg/650 mg strengths is one tablet every four to six hours as needed for pain. The total 24 hour dose should not exceed 6 tablets.

HOW SUPPLIED

Hydrocodone Bitartrate (WARNING: May be habit forming) and Acetaminophen Tablets, USP are supplied as follows:

7.5 mg/500 mg
White, oval, convex tablet,
bisected on one side and
debossed with“E725” on
the other side

Bottles of 100
Bottles of 1000

NDC 60951-725-70
NDC 60951-725-90

7.5 mg/650 mg
White, oval, convex tablet,
bisected on one side and
debossed with“E732” on
the other side

Bottles of 100
Bottles of 1000

NDC 60951-732-70
NDC 60951-732-90

10 mg/650 mg
White, capsule shaped,
convex tablet, bisected
on one side and debossed
with “E747” on the other
side

Bottles of 100
Bottles of 1000

NDC 60951-747-70
NDC 60951-747-90

Store at controlled room temperature 15°-30° (59°-86°F).

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Caution: Federal (USA) law prohibits dispensing without prescription.

A Schedule CIII Narcotic. Oral prescription where permitted by state law.

Manufactured for:
Endo Pharmaceuticals Inc.
Chadds Ford, PA 19317

Manufactured by:
DuPont Pharma
Wilmington, DE 19880


Hydrocodone Bitartrate and Acetaminophen (Hydrocodone Bitartrate and Acetaminophen)
PRODUCT INFO
Product Code 60951-725 Dosage Form TABLET
Route Of Administration ORAL DEA Schedule CIII
INGREDIENTS
Name (Active Moiety) Type Strength
Hydrocodone Bitartrate (Hydrocodone) Active 7.5 MILLIGRAM  In 1 TABLET
Acetaminophen (Acetaminophen) Active 500 MILLIGRAM  In 1 TABLET
colloidal silicon dioxide Inactive  
croscarmellose sodium Inactive  
crospovidone Inactive  
microcrystalline cellulose Inactive  
povidone Inactive  
pregelatinized starch Inactive  
stearic acid Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color WHITE (WHITE) Score 2
Shape OVAL (OVAL) Symbol false
Imprint Code E725 Coating false
Size 17mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 60951-725-70 100 TABLET In 1 BOTTLE None
2 60951-725-90 1000 TABLET In 1 BOTTLE None

Hydrocodone Bitartrate and Acetaminophen (Hydrocodone Bitartrate and Acetaminophen)
PRODUCT INFO
Product Code 60951-732 Dosage Form TABLET
Route Of Administration ORAL DEA Schedule CIII
INGREDIENTS
Name (Active Moiety) Type Strength
Hydrocodone Bitartrate (Hydrocodone) Active 7.5 MILLIGRAM  In 1 TABLET
Acetaminophen (Acetaminophen) Active 650 MILLIGRAM  In 1 TABLET
colloidal silicon dioxide Inactive  
croscarmellose sodium Inactive  
crospovidone Inactive  
microcrystalline cellulose Inactive  
povidone Inactive  
pregelatinized starch Inactive  
stearic acid Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color WHITE (WHITE) Score 2
Shape OVAL (OVAL) Symbol false
Imprint Code E732 Coating false
Size 18mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 60951-732-70 100 TABLET In 1 BOTTLE None
2 60951-732-90 1000 TABLET In 1 BOTTLE None

Hydrocodone Bitartrate and Acetaminophen (Hydrocodone Bitartrate and Acetaminophen)
PRODUCT INFO
Product Code 60951-747 Dosage Form TABLET
Route Of Administration ORAL DEA Schedule CIII
INGREDIENTS
Name (Active Moiety) Type Strength
Hydrocodone Bitartrate (Hydrocodone) Active 10 MILLIGRAM  In 1 TABLET
Acetaminophen (Acetaminophen) Active 650 MILLIGRAM  In 1 TABLET
colloidal silicon dioxide Inactive  
croscarmellose sodium Inactive  
crospovidone Inactive  
microcrystalline cellulose Inactive  
povidone Inactive  
pregelatinized starch Inactive  
stearic acid Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color WHITE (WHITE) Score 2
Shape CAPSULE (CAPSULE) Symbol false
Imprint Code E747 Coating false
Size 19mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 60951-747-70 100 TABLET In 1 BOTTLE None
2 60951-747-90 1000 TABLET In 1 BOTTLE None

Revised: 01/2006Endo Pharmaceuticals Inc.