HYDROCODONE BITARTRATE AND ACETAMINOPHEN  - hydrocodone bitartrate and acetaminophen tablet 
HYDROCODONE BITARTRATE AND ACETAMINOPHEN  - hydrocodone bitartrate and acetaminophen tablet 
Apotheca Inc.

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HYDROCODONE BITARTRATE AND ACETAMINOPHEN TABLET USP 7.5MG/500MG 7.5MG/650MG 7.5MG/750MG CSIII

DESCRIPTION




image of structural formula

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 of formula



Hydrocodone bitartrate and acetaminophen tablets, USP for oral administration are available in the following strengths





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 known, 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 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, Ndemethylation and 6-keto reduction to the corresponding 6-a- and 6-b-hydroxy-metabolites. 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

CONTRAINDICATIONS

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

Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to hydrocodone

WARNINGS

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 breathing.

Head Injury and Increased Intracranial Pressure

Acute Abdominal Conditions

Misuse, Abuse, and Diversion of Opioids

Hydrocodone bitartrate and acetaminophen tablets contain hydrocodone, an opioid agonist, and is a Schedule III controlled substance. Opioid agonists have the potential for being abused and are sought by abusers and people with addiction disorders, and are subject to diversion.

Hydrocodone bitartrate and acetaminophen tablets can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing hydrocodone bitartrate and acetaminophen tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion (see DRUG ABUSE AND DEPENDENCE).

PRECAUTIONS

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, like all narcotics, may impair the 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

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.

Drug and Laboratory Test Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

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 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

Nursing Mothers

Pediatric Use

Geriatric Use

Clinical studies of hydrocodone bitartrate and acetaminophen tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hydrocodone and the major metabolites of acetaminophen are known to be substantially excreted by the kidney. Thus the risk of toxic reactions may be greater in patients with impaired renal function due to the accumulation of the parent compound and/or metabolites in the plasma. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hydrocodone may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of hydrocodone bitartrate and acetaminophen tablets and observed closely.

ADVERSE REACTIONS

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

Other adverse reactions include:

Central Nervous System:

Gastrointestinal System

Genitourinary System

Respiratory Depression

OVERDOSAGE

Special Senses

Dermatological

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

Hydrocodone bitartrate and acetaminophen tablets contain hydrocodone, an opioid agonist, and is a Schedule III controlled substance. Hydrocodone bitartrate and acetaminophen, 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. Hydrocodone bitartrate and acetaminophen, 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

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 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

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 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. 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 g

DOSAGE AND ADMINISTRATION

Dosage should be adjusted according to the severity of the 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 Hydrocodone Bitartrate and Acetaminophen Tablets USP is:

7.5 mg/500 mg The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 6 tablets.
7.5 mg/650 mg
The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 6 tablets.
7.5 mg/750 mg
The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 5 tablets.

HOW SUPPLIED


7.5mg/500mg









7.5mg/650mg




7.5mg/750mg












Storage

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

Store at 20 - 25°C (68 - 77°F). (See USP for Controlled Room Temperature).

PACKAGE LABEL AND PRINCIPAL DISPLAY PANEL, Additional Labels Upon Request


NDC 12634-783-71 30 Tablets
Each Tablet Contains


Usual Adult Dosage


Keep this and all medication Out Of The Reach Of Children.
Manufactured By:



Repackaged and Distributed by:


image of label


HYDROCODONE BITARTRATE AND ACETAMINOPHEN 
hydrocodone bitartrate and acetaminophen   tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 12634-783 (0591-0385)
Route of Administration ORAL DEA Schedule CIII    
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
HYDROCODONE BITARTRATE (HYDROCODONE) HYDROCODONE BITARTRATE 7.5 mg
ACETAMINOPHEN (ACETAMINOPHEN) ACETAMINOPHEN 500 mg
Inactive Ingredients
Ingredient Name Strength
CROSCARMELLOSE SODIUM  
CROSPOVIDONE  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POVIDONE  
STEARIC ACID  
Product Characteristics
Color white (WHITE) Score 2 pieces
Shape CAPSULE (Capsule-shape) Size 18mm
Flavor Imprint Code Watson;385
Contains     
Packaging
# NDC Package Description Multilevel Packaging
1 12634-783-91 1 TABLET In 1 BLISTER PACK None
2 12634-783-55 15 TABLET In 1 BLISTER PACK None
3 12634-783-96 6 TABLET In 1 BOTTLE None
4 12634-783-00 10 TABLET In 1 BOTTLE None
5 12634-783-85 15 TABLET In 1 BOTTLE None
6 12634-783-80 20 TABLET In 1 BOTTLE None
7 12634-783-71 30 TABLET In 1 BOTTLE None
8 12634-783-01 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA081080 05/02/2006

HYDROCODONE BITARTRATE AND ACETAMINOPHEN 
hydrocodone bitartrate and acetaminophen   tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 12634-166 (0591-0502)
Route of Administration ORAL DEA Schedule CIII    
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
HYDROCODONE BITARTRATE (HYDROCODONE) HYDROCODONE BITARTRATE 7.5 mg
ACETAMINOPHEN (ACETAMINOPHEN) ACETAMINOPHEN 650 mg
Inactive Ingredients
Ingredient Name Strength
CROSCARMELLOSE SODIUM  
CROSPOVIDONE  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POVIDONE  
STEARIC ACID  
Product Characteristics
Color pink (pink tablets) Score 2 pieces
Shape CAPSULE (Capsule-shape) Size 18mm
Flavor Imprint Code watson;502
Contains     
Packaging
# NDC Package Description Multilevel Packaging
1 12634-166-00 10 TABLET In 1 BOTTLE None
2 12634-166-91 1 TABLET In 1 BLISTER PACK None
3 12634-166-61 10 TABLET In 1 BLISTER PACK None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA040094 09/24/2009

HYDROCODONE BITARTRATE AND ACETAMINOPHEN 
hydrocodone bitartrate and acetaminophen   tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 12634-849 (0591-0387)
Route of Administration ORAL DEA Schedule CIII    
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
HYDROCODONE BITARTRATE (HYDROCODONE) HYDROCODONE BITARTRATE 7.5 mg
ACETAMINOPHEN (ACETAMINOPHEN) ACETAMINOPHEN 750 mg
Inactive Ingredients
Ingredient Name Strength
CROSCARMELLOSE SODIUM  
CROSPOVIDONE  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POVIDONE  
STEARIC ACID  
Product Characteristics
Color white (white) Score 2 pieces
Shape CAPSULE (oblong) Size 19mm
Flavor Imprint Code Watson;387
Contains     
Packaging
# NDC Package Description Multilevel Packaging
1 12634-849-91 1 TABLET In 1 BLISTER PACK None
2 12634-849-61 10 TABLET In 1 BLISTER PACK None
3 12634-849-55 15 TABLET In 1 BLISTER PACK None
4 12634-849-00 10 TABLET In 1 BOTTLE None
5 12634-849-82 12 TABLET In 1 BOTTLE None
6 12634-849-85 15 TABLET In 1 BOTTLE None
7 12634-849-80 20 TABLET In 1 BOTTLE None
8 12634-849-79 25 TABLET In 1 BOTTLE None
9 12634-849-71 30 TABLET In 1 BOTTLE None
10 12634-849-01 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA081083 04/23/2007

Labeler - Apotheca Inc. (051457844)
Establishment
Name Address ID/FEI Operations
Apotheca Inc 051457844 repack, relabel
Establishment
Name Address ID/FEI Operations
Amneal Pharmaceuticals 831227801 manufacture
Establishment
Name Address ID/FEI Operations
Watson Laboratories 840054118 manufacture
Revised: 02/2010 Apotheca Inc.