Hydrocodone Bitartrate Acetaminophen ®
Tablets, USP
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
DRUG ABUSE AND DEPENDENCE
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
Hydrocodone Bitartrate and Acetaminophen Tablets for oral administration are available in a
variety of strengths as described below:
Strength (WARNING:)May be Habit Forming Acetaminophen 2.5 mg/500 mg 2.5 mg 500 mg
5 mg/500 mg 5 mg 500 mg
7.5 mg/500 mg 7.5 mg 500 mg
7.5 mg/750 mg 7.5 mg 750 mg
Hydrocodone bitartrate is an opioid analgesic and antitussive which occurs as fine, white crystals or as a crystalline powder. It is affected by light. The chemical name is 4,5 alpha-epoxy-3-methoxy-
17-methyl-morphinan-6-one tartrate (1:1) hydrate (2:5). Its structure is as follows:
Acetaminophen, 4′-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic which occurs as a white, odorless, crystaline powder possessing a slightly bitter taste. Its structure is as follows:
Inactive ingredients include croscarmellose sodium, microcrystalline cellulose, anhydrous lactose, magnesium sterate, pregelatinized starch, povidone, crospovidone and stearic acid.
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.
Radioimmunoassay techniques have recently been developed for the analysis of hydrocodone in human plasma. After a 10 mg oral dose of hydrocodone bitartrate, a mean peak serum drug level of 23.6 ng/ml and an elimination half-life of 3.8 hours were found.
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 have negligible effects on the cardiovascular or respiratory systems: however, toxic doses may cause circulatory failure and rapid, shallow breathing. Acetaminophen is rapidly and almost completely absorbed from the gastrointestinal tract, producing maximum serum concentrations within 30 minutes to one hour. The plasma half-life in adults and children ranges from 0.90 hours to 3.25 hours with an average of approximately 2 hours. The drug distributes uniformly in most body fluids and is approximately 25 % protein bound. Acetaminophen is conjugated in the liver, with less than 3% of the dose excreted unchanged in 24 hours. The primary metabolic pathway is conjugation to sulfate and glucuronide by-products. A minor oxidative pathway forms cysteine and mercapturic acid. These compounds are subsequently excreted by the kidneys into the urine.
For the relief of moderate to moderately severe pain.
Hypersensitivity to acetaminophen or hydrocodone.
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 breathing.
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 pre-existing 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.
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 sticture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind.
Information for Patients: Hydrocodone Bitartrate and Acetaminophen Tablets, 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.
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.
Drug Interactions: Patients receiving other narcotic analgesics, 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.
Usage in Pregnancy
1. Teratogenic Effects: Pregnancy Catergory 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.
2. 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 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 Hydrocodone Bitartate and Acetaminophen Tablets 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: 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 Hydrocodone Bitartrate and Acetaminophen Tablets, 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 children have not been established.
The most frequently observed adverse reactions include 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: 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 anti-analgesic 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 vesicle sphincters and urinary retention have been reported.
Respiratory Depression: Hydrocodone bitartrate 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. If significant respiratory depression occurs, it may be antagonized by the use of naloxone hydrochloride. Apply other supportive measures when indicated.
Hydrocodone Bitartrate and Acetaminophen Tablets are subject to the Federal Controlled Substances Act (schedule II). Psychic dependence, physical dependence and tolerance may develop upon repeated administration of narcotics; therefore, Hydrocodone bitartrate and Acetaminophen Tablets 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 short-ended duration of analgesic effect, and subsequently by decreases in the intensity of analgesia. The rate of development of tolerance varies among patients.
Acetaminophen
Signs and Systems: 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. In adults, hepatic toxicity has rarely been reported with acute overdose of less than 10 grams and fatalities with less than 15 grams. Importantly, young children seem to be more resistant than adults to the hepatotoxic effect of an acetaminophen overdose. Despite this, the measures outlined below should be initiated in any adult or child suspected of having ingested an acetaminophen overdose. Early symptoms following a potentially hepatototoxic 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.
Treatment: The stomach should be emptied promptly by lavage or by induction of emesis with syrup of ipecac. Patients’ estimates of the quantity of a drug ingested are notoriously unreliable. Therefore, if an acetaminophen overdose is suspected, a serum acetaminophen assay should be obtained as early as possible, but no sooner than four hours following ingestion. Liver function studies should be obtained initially and repeated at 24 hour intervals.
The antidote, N-acetylcysteine, should be administered as early as possible, preferably within 16 hours of the overdose ingestion for optimal results, but in any case, within 24 hours. Following recovery, there are no residual, structural or functional hepatic abnormalities.
Hydrocodone
Signs and Symptoms: Serious overdose with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and or tidal volume, CheyneStokes 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 patent airway and the institution of assisted or controlled ventilation. The narcotic antagonist naloxone is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to narcotics, including hydrocodone. Therefore, an appropriate dose of naloxone hydrochloride (see package insert) should be administered, preferably by the intravenous route, and simultaneously with efforts at respiratory resuscitation. Since the duration of action of hydrocodone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration.
An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Oxygen, intravenous fluids, vaso-pressors and other supportive measures should be employed as indicated.
Gastric emptying may be useful in removing unabsorbed drug.
Dosage should be adjusted accordingly to the severity of the pain and the 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 untowared effects is dose related.
The usual adult dosage is show in the table below.
Hydrocodone Bitartrate (WARNING: May be habit forming) and Acetaminophen Tablets are available in the following strengths:
2.5mg/500
2.5 mg hydrocodone bitartrate and 500 mg acetaminophen oblong, white tablets bisected on one side and debossed with Watson 388 on the other side.
- Bottles of 30 NDC 52544-388-30
- Bottles of 100 NDC 52544-388-01
- Bottles of 500 NDC 52544-388-05
- Bottles of 1000 NDC 52544-388-10
5 mg/500mg
5 mg hydrocodone bitartrate and 500 mg acetaminophen, capsule-shaped white tablets besected on one side and debossed with Watson 349 on the other side.
- Bottles of 30 NDC 52544-349-30
- Bottles of 100 NDC 52544-349-01
- Bottles of 500 NDC 52544-349-05
7.5 mg/500
7.5 mg hydrocodone bitartrate and 500 mg acetaminophen capsule-shaped, white tablets bisected on one side and debossed with Watson 385 on the other side.
- Bottles of 30 NDC 52544-385-30
- Bottles of 100 NDC 52544-385-01
- Bottles of 500 NDC 52544-385-05
- Bottles of 1000 NDC 52544-385-10
7.5 mg/750 mg
7.5 mg hydrocodone bitartrate and 750 mg acetaminophen, oblong, white tablets bisected on one side and debossed with Watson 387 on the other side
- Bottles of 30 NDC 52544-387-30
- Bottles of 100 NDC 52544-387-01
- Bottles of 500 NDC 52544-387-05
- Bottles of 1000 NDC 52544-387-10
Store at controlled room temperture, 15-30 degrees Celcius (59-86 degrees Farenheit).
Dispense in a tight, light-light resistant container with a child-resistant closure.
Watson Laboratories
Corona, CA 91720
11728-2
Revised December 10, 1992