ROXICET Tablet / Oral solution Ref.[10630] Active ingredients:

Misuse, Abuse and Diversion of Opioids

Oxycodone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing ROXICET in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Concerns about misuse, addiction, and diversion should not prevent the proper management of pain.

Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Administration of ROXICET (Oxycodone and Acetaminophen) should be closely monitored for the following potentially serious adverse reactions and complications:

Respiratory Depression

Respiratory depression is a hazard with the use of oxycodone, one of the active ingredients in ROXICET, as with all opioid agonists. Elderly and debilitated patients are at particular risk for respiratory depression as are non-tolerant patients given large initial doses of oxycodone or when oxycodone is given in conjunction with other agents that depress respiration. Oxycodone should be used with extreme caution in patients with acute asthma, chronic obstructive pulmonary disorder (COPD), cor pulmonale, or pre-existing respiratory impairment. In such patients, even usual therapeutic doses of oxycodone may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.

In case of respiratory depression, a reversal agent such as naloxone hydrochloride may be utilized (see OVERDOSAGE).

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Oxycodone produces effects on pupillary response and consciousness which may obscure neurologic signs of worsening in patients with head injuries.

Hypotensive Effect

Oxycodone may cause severe hypotension particularly in individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs which compromise vasomotor tone such as phenothiazines. Oxycodone, like all opioid analgesics of the morphine-type, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Oxycodone may produce orthostatic hypotension in ambulatory patients.

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. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.

Serious Skin Reactions

Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Hypersensitivity / Anaphylaxis

There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue ROXICET immediately and seek medical care if they experience these symptoms. Do not prescribe ROXICET for patients with acetaminophen allergy.

Serious adverse reactions that may be associated with ROXICET 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 has 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 ROXICET 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, gastrointestinal 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

Acute Abdominal Conditions

The administration of ROXICET (Oxycodone and Acetaminophen) or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

ROXICET 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.

ROXICET 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 ROXICET, 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 Other CNS Depressants

Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with ROXICET may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

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.

Ambulatory Surgery and Postoperative Use

Oxycodone and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with use of opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented.

Use in Pancreatic / Biliary Tract Disease

Oxycodone may cause spasm of the Sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like oxycodone may cause increases in the serum amylase level.

Tolerance and Physical Dependence

Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy).

Hepatic Impairment

In a pharmacokinetic study of oxycodone in patients with end-stage liver disease, oxycodone plasma clearance decreased and the elimination half-life increased. Care should be exercised when oxycodone is used in patients with hepatic impairment.

Renal Impairment

In a study of patients with end stage renal impairment, mean elimination half-life was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Oxycodone should be used with caution in patients with renal impairment.

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.

The following information should be provided to patients receiving ROXICET by their physician, nurse, pharmacist, or caregiver:

• Patients should be aware that ROXICET contains oxycodone, which is a morphine-like substance.
• Patients should be instructed to keep ROXICET in a secure place out of the reach of children. In the case of accidental ingestions, emergency medical care should be sought immediately.
• When ROXICET is no longer needed, the unused tablets or oral solution 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 ROXICET 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 ROXICET 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, ROXICET can cause dangerous additive central nervous system or respiratory depression, which can result in serious injury or death.
• The safe use of ROXICET during pregnancy has not been established; thus, women who are planning to become pregnant or are pregnant should consult with their physician before taking ROXICET.
• Nursing mothers should consult with their physicians about whether to discontinue nursing or discontinue ROXICET because of the potential for serious adverse reactions to nursing infants.
• Patients who are treated with ROXICET 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 ROXICET is 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.
• Do not take ROXICET if you are allergic to any of its ingredients.
• If you develop signs of allergy such as a rash or difficulty breathing stop taking ROXICET 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.

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 methoximetrimethylsilyl (MO-TMS) derivative.

Drug/Drug Interactions with Oxycodone

Opioid analgesics may enhance the neuromuscular-blocking action of skeletal muscle relaxants and produce an increase in the degree of respiratory depression.

Patients receiving CNS depressants such as other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with ROXICET may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. The concurrent use of anticholinergics with opioids may produce paralytic ileus.

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, naltrexone, and butorphanol) should be administered with caution to a patient who has received or is receiving a pure opioid agonist such as oxycodone. These agonist/antagonist analgesics may reduce the analgesic effect of oxycodone or may precipitate withdrawal symptoms.

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 (Propranolol): Propranolol 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 non-hepatic or renal clearance of zidovudine.

Category C.

Animal reproductive studies have not been conducted with ROXICET. It is also not known whether ROXICET can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. ROXICET 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.

ROXICET is 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.

Ordinarily, nursing should not be undertaken while a patient is receiving ROXICET 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.

Safety and effectiveness in pediatric patients have not been established.

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

Depending on the sensitivity/specificity and the test methodology, the individual components of ROXICET (Oxycodone and Acetaminophen) 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.

ROXICET is 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, ROXICET is subject to the Federal Controlled Substances Act. After chronic use, ROXICET should not be discontinued abruptly when it is thought that the patient has become physically dependent on oxycodone.

Interactions with Alcohol and Drugs of Abuse

Oxycodone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.