PACKAGE LABEL. PRINCIPAL DISPLAY PANEL

BOXED WARNING

WARNING

Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product.

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

Oxycodone and acetaminophen tablets should not be administered to patients with known hypersensitivity to oxycodone, acetaminophen, or any other component of this product.

Oxycodone is contraindicated in any situation where opioids are contraindicated including patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe bronchial asthma or hypercarbia. Oxycodone is contraindicated in the setting of suspected or known paralytic ileus.

ADVERSE REACTIONS

Serious adverse reactions that may be associated with oxycodone and acetaminophen tablet use include respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, and shock (see OVERDOSAGE).

The most frequently observed non-serious adverse reactions include lightheadedness, dizziness, drowsiness or 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 euphoria, dysphoria, constipation, and pruritus.

Hypersensitivity reactions may include: Skin eruptions, urticarial, erythematous skin reactions. Hematologic reactions may include: Thrombocytopenia, neutropenia, pancytopenia, hemolytic anemia. Rare cases of agranulocytosis have likewise been associated with acetaminophen use. In high doses, the most serious adverse effect is a dose-dependent, potentially fatal hepatic necrosis. Renal tubular necrosis and hypoglycemic coma also may occur.

Other adverse reactions obtained from postmarketing experiences with oxycodone and acetaminophen tablets are listed by organ system and in decreasing order of severity and/or frequency as follows:

Body as a Whole

Anaphylactoid reaction, allergic reaction, malaise, asthenia, fatigue, chest pain, fever, hypothermia, thirst, headache, increased sweating, accidental overdose, non-accidental overdose

Cardiovascular

Hypotension, hypertension, tachycardia, orthostatic hypotension, bradycardia, palpitations, dysrhythmias

Central and Peripheral Nervous System

Stupor, tremor, paraesthesia, hypoaesthesia, lethargy, seizures, anxiety, mental impairment, agitation, cerebral edema, confusion, dizziness

Fluid and Electrolyte

Dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis

Gastrointestinal

Dyspepsia, taste disturbances, abdominal pain, abdominal distention, sweating increased, diarrhea, dry mouth, flatulence, gastro-intestinal disorder, nausea, vomiting, pancreatitis, intestinal obstruction, ileus

Hepatic

Transient elevations of hepatic enzymes, increase in bilirubin, hepatitis, hepatic failure, jaundice, hepatotoxicity, hepatic disorder

Hearing and Vestibular

Hearing loss, tinnitus

Hematologic

Thrombocytopenia

Hypersensitivity

Acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria, anaphylactoid reaction

Metabolic and Nutritional

Hypoglycemia, hyperglycemia, acidosis, alkalosis

Musculoskeletal

Myalgia, rhabdomyolysis

Ocular

Miosis, visual disturbances, red eye

Psychiatric

Drug dependence, drug abuse, insomnia, confusion, anxiety, agitation, depressed level of consciousness, nervousness, hallucination, somnolence, depression, suicide

Respiratory System

Bronchospasm, dyspnea, hyperpnea, pulmonary edema, tachypnea, aspiration, hypoventilation, laryngeal edema

Skin and Appendages

Erythema, urticaria, rash, flushing

Urogenital

Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, urinary retention

DRUG/DRUG INTERACTIONS WITH ACETAMINOPHEN

Alcohol, ethyl – Hepatotoxicity has occurred in chronic alcoholics following various dose levels (moderate to excessive) of acetaminophen.

Anticholinergics – The onset of acetaminophen effect may be delayed or decreased slightly, but the ultimate pharmacological effect is not significantly affected by anticholinergics.

Oral Contraceptives – Increase in glucuronidation resulting in increased plasma clearance and a decreased half-life of acetaminophen.

Charcoal (activated) – Reduces acetaminophen absorption when administered as soon as possible after overdose.

Beta Blockers (Propanolol) – Propanolol appears to inhibit the enzyme systems responsible for the glucuronidation and oxidation of acetaminophen. Therefore, the pharmacologic effects of acetaminophen may be increased.

Loop Diuretics – The effects of the loop diuretic may be decreased because acetaminophen may decrease renal prostaglandin excretion and decrease plasma renin activity.

Lamotrigine – Serum lamotrigine concentrations may be reduced, producing a decrease in therapeutic effects.

Probenecid – Probenecid may increase the therapeutic effectiveness of acetaminophen slightly.

Zidovudine – The pharmacologic effects of zidovudine may be decreased because of enhanced nonhepatic or renal clearance of zidovudine.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Carcinogenesis – Animal studies to evaluate the carcinogenic potential of oxycodone and acetaminophen have not been performed.

Mutagenesis – The combination of oxycodone and acetaminophen has not been evaluated for mutagenicity. Oxycodone alone was negative in a bacterial reverse mutation assay (Ames), an in vitro chromosome aberration assay with human lymphocytes without metabolic activation and an in vivo mouse micronucleus assay. Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation and in the mouse lymphoma assay with or without metabolic activation.

Fertility – Animal studies to evaluate the effects of oxycodone on fertility have not been performed.

DESCRIPTION

Each tablet, for oral administration, contains oxycodone hydrochloride and acetaminophen in the following strengths:

Oxycodone Hydrochloride USP ..........................................................................5 mg*
Acetaminophen USP ........................................................................................325 mg
*5 mg oxycodone HCl is equivalent to 4.4815 mg of oxycodone.

Oxycodone Hydrochloride USP .......................................................................7.5 mg*
Acetaminophen USP ........................................................................................325 mg
*7.5 mg oxycodone HCl is equivalent to 6.7228 mg of oxycodone.

Oxycodone Hydrochloride USP .........................................................................10 mg*
Acetaminophen USP .........................................................................................325 mg
*10 mg oxycodone HCl is equivalent to 8.9637 mg of oxycodone.

All strengths of oxycodone and acetaminophen tablets USP also contain the following inactive ingredients: crospovidone, microcrystalline cellulose, povidone, pregelatinized starch, silicon dioxide and stearic acid.

Oxycodone, 4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride, is a semisynthetic opioid analgesic which occurs as a white, odorless, crystalline powder having a saline, bitter taste. It is derived from the opium alkaloid thebaine. Oxycodone hydrochloride may be represented by the following structural formula:

[Oxycodone Chemical Structure]

Acetaminophen, 4'-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste. It may be represented by the following structural formula:

[Acetaminophen Chemical Structure]

CESSATION OF THERAPY

In patients treated with oxycodone and acetaminophen tablets for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.

PHARMACOKINETICS

Absorption and Distribution – The mean absolute oral bioavailability of oxycodone in cancer patients was reported to be about 87%. Oxycodone has been shown to be 45% bound to human plasma proteins in vitro. The volume of distribution after intravenous administration is 211.9 ± 186.6 L.

Absorption of acetaminophen is rapid and almost complete from the GI tract after oral administration. With overdosage, absorption is complete in 4 hours. Acetaminophen is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable; only 20% to 50% may be bound at the concentrations encountered during acute intoxication.

GENERAL

Opioid analgesics should be used with caution when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension.

Acute Abdominal Conditions – The administration of oxycodone and acetaminophen tablets or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Oxycodone and acetaminophen tablets should be given with caution to patients with CNS depression, elderly or debilitated patients, patients with severe impairment of hepatic, pulmonary, or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, urethral stricture, acute alcoholism, delirium tremens, kyphoscoliosis with respiratory depression, myxedema, and toxic psychosis.

Oxycodone and acetaminophen tablets may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Following administration of oxycodone and acetaminophen tablets, anaphylactic reactions have been reported in patients with a known hypersensitivity to codeine, a compound with a structure similar to morphine and oxycodone. The frequency of this possible cross-sensitivity is unknown.

INTERACTIONS WITH MIXED AGONIST/ANTAGONIST OPIOID ANALGESICS

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these patients.

INFORMATION FOR PATIENTS/CAREGIVERS

Do not take oxycodone and acetaminophen tablets USP if you are allergic to any of its ingredients.
If you develop signs of allergy such as a rash or difficulty breathing stop taking oxycodone and acetaminophen tablets USP and contact your healthcare provider immediately.
Do not take more than 4000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose.
Patients should be aware that oxycodone and acetaminophen tablets contain oxycodone, which is a morphine-like substance.
Patients should be instructed to keep oxycodone and acetaminophen tablets in a secure place out of the reach of children. In the case of accidental ingestions, emergency medical care should be sought immediately.
When oxycodone and acetaminophen tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet.
Patients should be advised not to adjust the medication dose themselves. Instead, they must consult with their prescribing physician.
Patients should be advised that oxycodone and acetaminophen tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).
Patients should not combine oxycodone and acetaminophen tablets with alcohol, opioid analgesics, tranquilizers, sedatives, or other CNS depressants unless under the recommendation and guidance of a physician. When co-administered with another CNS depressant, oxycodone and acetaminophen tablets can cause dangerous additive central nervous system or respiratory depression, which can result in serious injury or death.
The safe use of oxycodone and acetaminophen tablets during pregnancy has not been established; thus, women who are planning to become pregnant or are pregnant should consult with their physician before taking oxycodone and acetaminophen tablets.
Nursing mothers should consult with their physicians about whether to discontinue nursing or discontinue oxycodone and acetaminophen tablets because of the potential for serious adverse reactions to nursing infants.
Patients who are treated with oxycodone and acetaminophen tablets for more than a few weeks should be advised not to abruptly discontinue the medication. Patients should consult with their physician for a gradual discontinuation dose schedule to taper off the medication.
Patients should be advised that oxycodone and acetaminophen tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.

LABORATORY TESTS

Although oxycodone may cross-react with some drug urine tests, no available studies were found which determined the duration of detectability of oxycodone in urine drug screens. However, based on pharmacokinetic data, the approximate duration of detectability for a single dose of oxycodone is roughly estimated to be one to two days following drug exposure.

Urine testing for opiates may be performed to determine illicit drug use and for medical reasons such as evaluation of patients with altered states of consciousness or monitoring efficacy of drug rehabilitation efforts. The preliminary identification of opiates in urine involves the use of an immunoassay screening and thin-layer chromatography (TLC). Gas chromatography/mass spectrometry (GC/MS) may be utilized as a third-stage identification step in the medical investigational sequence for opiate testing after immunoassay and TLC. The identities of 6-keto opiates (e.g., oxycodone) can further be differentiated by the analysis of their methoxime- trimethylsilyl (MO-TMS) derivative.

DRUG/LABORATORY TEST INTERACTIONS

Depending on the sensitivity/specificity and the test methodology, the individual components of oxycodone and acetaminophen tablets may cross-react with assays used in the preliminary detection of cocaine (primary urinary metabolite, benzoylecgonine) or marijuana (cannabinoids) in human urine. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. The preferred confirmatory method is gas chromatography/mass spectrometry (GC/MS). Moreover, clinical considerations and professional judgment should be applied to any drug-of-abuse test result, particularly when preliminary positive results are used.

Acetaminophen may interfere with home blood glucose measurement systems; decreases of > 20% in mean glucose values may be noted. This effect appears to be drug, concentration and system dependent.

PREGNANCY

Teratogenic Effects. Pregnancy Category C – Animal reproductive studies have not been conducted with oxycodone and acetaminophen. It is also not known whether oxycodone and acetaminophen tablets can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Oxycodone and acetaminophen tablets should not be given to a pregnant woman unless in the judgment of the physician, the potential benefits outweigh the possible hazards.

Nonteratogenic Effects – Opioids can cross the placental barrier and have the potential to cause neonatal respiratory depression. Opioid use during pregnancy may result in a physically drug-dependent fetus. After birth, the neonate may suffer severe withdrawal symptoms.

LABOR AND DELIVERY

Oxycodone and acetaminophen tablets are not recommended for use in women during and immediately prior to labor and delivery due to its potential effects on respiratory function in the newborn.

NURSING MOTHERS

Ordinarily, nursing should not be undertaken while a patient is receiving oxycodone and acetaminophen tablets because of the possibility of sedation and/or respiratory depression in the infant. Oxycodone is excreted in breast milk in low concentrations, and there have been rare reports of somnolence and lethargy in babies of nursing mothers taking an oxycodone/acetaminophen product. Acetaminophen is also excreted in breast milk in low concentrations.

PEDIATRIC USE

Safety and effectiveness in pediatric patients have not been established.

GERIATRIC USE

Special precaution should be given when determining the dosing amount and frequency of oxycodone and acetaminophen tablets for geriatric patients, since clearance of oxycodone may be slightly reduced in this patient population when compared to younger patients.

DRUG ABUSE AND DEPENDENCE

Oxycodone and acetaminophen tablets are a Schedule II controlled substance. Oxycodone is a mu-agonist opioid with an abuse liability similar to morphine. Oxycodone, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion.

Drug addiction is defined as an abnormal, compulsive use, use for non-medical purposes of a substance despite physical, psychological, occupational or interpersonal difficulties resulting from such use, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common. Opioid addiction is relatively rare in patients with chronic pain but may be more common in individuals who have a past history of alcohol or substance abuse or dependence. Pseudoaddiction refers to pain relief seeking behavior of patients whose pain is poorly managed. It is considered an iatrogenic effect of ineffective pain management. The health care provider must assess continuously the psychological and clinical condition of a pain patient in order to distinguish addiction from pseudoaddiction and thus, be able to treat the pain adequately.

Physical dependence on a prescribed medication does not signify addiction. Physical dependence involves the occurrence of a withdrawal syndrome when there is sudden reduction or cessation in drug use or if an opiate antagonist is administered. Physical dependence can be detected after a few days of opioid therapy. However, clinically significant physical dependence is only seen after several weeks of relatively high dosage therapy. In this case, abrupt discontinuation of the opioid may result in a withdrawal syndrome. If the discontinuation of opioids is therapeutically indicated, gradual tapering of the drug over a 2-week period will prevent withdrawal symptoms. The severity of the withdrawal syndrome depends primarily on the daily dosage of the opioid, the duration of therapy and medical status of the individual.

The withdrawal syndrome of oxycodone is similar to that of morphine. This syndrome is characterized by yawning, anxiety, increased heart rate and blood pressure, restlessness, nervousness, muscle aches, tremor, irritability, chills alternating with hot flashes, salivation, anorexia, severe sneezing, lacrimation, rhinorrhea, dilated pupils, diaphoresis, piloerection, nausea, vomiting, abdominal cramps, diarrhea and insomnia, and pronounced weakness and depression.

“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 infection.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, 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. Oxycodone, like other opioids, has been diverted for non-medical use. Careful 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.

Like other opioid medications, oxycodone and acetaminophen tablets are subject to the Federal Controlled Substances Act. After chronic use, oxycodone and acetaminophen tablets should not be discontinued abruptly when it is thought that the patient has become physically dependent on oxycodone.

OVERDOSAGE

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

DOSAGE AND ADMINISTRATION

Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the- clock schedule. Oxycodone and acetaminophen tablets are given orally.

The total daily dose of acetaminophen should not exceed 4 grams.

Strength Usual
Adult Dosage Maximal
Daily Dose
Oxycodone and acetaminophen tablets
5 mg/325 mg 1 tablet every 6 hours as needed for pain 12
Tablets
Oxycodone and acetaminophen tablets
7.5 mg/325 mg 1 tablet every 6 hours
as needed for pain 8
Tablets
Oxycodone and acetaminophen tablets
10 mg/325 mg 1 tablet every 6 hours
as needed for pain 6
Tablets

HOW SUPPLIED

Each oxycodone and acetaminophen tablet USP 5 mg/325 mg contains oxycodone hydrochloride 5 mg (equivalent to 4.4815 mg oxycodone) and acetaminophen 325 mg. It is available as a round, white scored tablet debossed with a 512 identification number.

Bottles of 100 . . . . . . . . . . . . . . . . . . . . . NDC 0406-0512-01
Bottles of 500 . . . . . . . . . . . . . . . . . . . . . NDC 0406-0512-05
Unit Dose (10 x 10). . . . . . . . . . . . . . . . . NDC 0406-0512-62

Each oxycodone and acetaminophen tablet USP 7.5 mg/325 mg contains oxycodone hydrochloride 7.5 mg (equivalent to 6.7228 mg oxycodone) and acetaminophen 325 mg. It is available as a white to off-white caplet shaped tablet debossed with “M522” on one side and “7.5/325” on the other side.

Bottles of 100 . . . . . . . . . . . . . . . . . . . . . NDC 0406-0522-01
Bottles of 500 . . . . . . . . . . . . . . . . . . . . . NDC 0406-0522-05
Unit Dose (10 x 10). . . . . . . . . . . . . . . . . NDC 0406-0522-62

Each oxycodone and acetaminophen tablet USP 10 mg/325 mg contains oxycodone hydrochloride 10 mg (equivalent to 8.9637 mg oxycodone) and acetaminophen 325 mg. It is available as a white to off-white caplet shaped tablet debossed with “M523” on one side and “10/325” on the other side.

Bottles of 100 . . . . . . . . . . . . . . . . . . . . . NDC 0406-0523-01
Bottles of 500 . . . . . . . . . . . . . . . . . . . . . NDC 0406-0523-05
Unit Dose (10 x 10). . . . . . . . . . . . . . . . . NDC 0406-0523-62

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

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

DEA Order Form Required.

Mallinckrodt, the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company.

© 2015 Mallinckrodt.

Mallinckrodt Inc.
Hazelwood, MO 63042 USA

Printed in U.S.A.

Rev 11/2015

Mallinckrodt™
Pharmaceuticals