HYDROCODONE/APAP

HYDROCODONE/APAP — hydrocodone bitartrate and acetaminophen tablet
PharmPak, Inc.

CII Rx only

Hydrocodone Bitartrate and Acetaminophen Tablets, USP are supplied in tablet form for oral administration.

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: 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:

Each Hydrocodone Bitartrate and Acetaminophen Tablet, USP contains:

In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch and stearic acid.

PharmPak Hydrocodone-APAP1 Label
(click image for full-size original)

Meets USP Dissolution Test 1.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP, contain hydrocodone bitartrate 5 mg and acetaminophen 325 mg. They are supplied as white to off-white, scored, oblong biconvex tables, debossed “lP109” on obverse and bisected on the reverse.

Clinical Pharmacology

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 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, opioids 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, N-demethylation and 6-ketoreduction to the corresponding 6-a- and 6-ß-hydroxymetabolites.
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.

HYDROCODONE/APAP Indications and Usage

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

Contraindications

Hydrocodone bitartrate and acetaminophen tablets should not be administered to patients who have previously exhibited hypersensitivity to hydrocodone or acetaminophen, or any other component of this product.
Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to hydrocodone.

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 breathing.
Head Injury and Increased Intracranial Pressure:
The respiratory depressant effects 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 pre-existing 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 opioids may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Keep this and all medications out of reach of children.

Special Risk Patients:


As with any opioid 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 opioids, caution should be exercised when hydrocodone bitartrate and acetaminophen tablets are used postoperatively and in patients with pulmonary disease.
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; 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.
In patients with severe hepatic or renal disease, effects of therfRV should be monitored with serial liver and/or renal
function tests.
Patients receiving other opioids, 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 hldrocodone preparations may increase the effect of either the antidepressant or hydrocodone.
Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.
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 Category C:
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.
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.
As with all opioids, 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.
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.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of hydrocodone bitartrate and acetaminophen 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 concomitanidisease 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 ofhydrocodone bitartrate and acetaminophen tablets and observed closely.

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