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This medication contains important usage instructions, warnings, and side effect information that you should review before use.
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME, CYTOCHROME P450 3A4 INTERACTION; HEPATOTOXICITY, and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
ADDICTION, ABUSE, AND MISUSE: RISK EVALUATION AND MITIGATION STRATEGY (REMS)
Oxycodone and Acetaminophen Tablets exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Oxycodone and Acetaminophen Tablets, and monitor all patients regularly for the development of these behaviors and conditions [see WARNINGS].
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS):
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [see Warnings]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to
complete a REMS-compliant education program,
counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
consider other tools to improve patient, household, and community safety.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of Oxycodone and Acetaminophen Tablets. Monitor for respiratory depression, especially during initiation of Oxycodone and Acetaminophen Tablets or following a dose increase [see WARNINGS].
Accidental Ingestion
Accidental ingestion of Oxycodone and Acetaminophen Tablets, especially by children, can result in a fatal overdose of Oxycodone and Acetaminophen Tablets [see WARNINGS].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of Oxycodone and Acetaminophen Tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see WARNINGS].
Cytochrome P450 3A4 Interaction
The concomitant use of Oxycodone Tablets with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving Oxycodone and Acetaminophen Tablets and any CYP3A4 inhibitor or inducer [see CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS; Drug Interactions].
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 mg per day, and often involve more than one acetaminophen-containing product.
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings, Precautions: Drug Interactions].
• Reserve concomitant prescribing of Oxycodone and Acetaminophen Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.
Oxycodone and Acetaminophen Tablets is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
Limitations of Use
Because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses [see WARNINGS], reserve Oxycodone and Acetaminophen Tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]
• Have not been tolerated, or are not expected to be tolerated,
• Have not provided adequate analgesia, or are not expected to provide adequate analgesia
Important Dosage and Administration Instructions
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings].
Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see WARNINGS].
Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Oxycodone and Acetaminophen Tablets and adjust the dosage accordingly [see WARNINGS].
Initial Dosage
Initiating Treatment with Oxycodone and Acetaminophen Tablets
The usual adult dosage is one tablet every 6 hours as needed for pain. 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
Conversion from Oxycodone Hydrochloride and Acetaminophen to Extended-Release Oxycodone
The relative bioavailability of Oxycodone and Acetaminophen Tablets compared to extended-release oxycodone is unknown, so conversion to extended-release oxycodone must be accompanied by close observation for signs of excessive sedation and respiratory depression.
Titration and Maintenance of Therapy
Individually titrate Oxycodone and Acetaminophen Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Oxycodone and Acetaminophen Tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see WARNINGS]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.
If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Oxycodone and Acetaminophen Tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
Discontinuation of Oxycodone and Acetaminophen Tablets
When a patient who has been taking Oxycodone and Acetaminophen Tablets regularly and may be physically dependent no longer requires therapy with Oxycodone and Acetaminophen Tablets, use a gradual downward titration of the dosage to prevent signs and symptoms of withdrawal. Do not stop Oxycodone and Acetaminophen Tablets abruptly [see WARNINGS, DRUG ABUSE AND DEPENDENCE].
Oxycodone and Acetaminophen Tablets is contraindicated in patients with:
• Significant respiratory depression [see WARNINGS]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative
equipment [see WARNINGS]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS]
• Hypersensitivity to oxycodone, acetaminophen, or any other component of the product (e.g.,
anaphylaxis) [see WARNINGS, ADVERSE REACTIONS]
The following adverse reactions have been identified during post approval use of Oxycodone and Acetaminophen Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serious adverse reactions that may be associated with oxycodone and acetaminophen 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 oxycodone and acetaminophen 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
• Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
• Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
• Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Oxycodone and Acetaminophen Tablets.
• Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology].
Following an acute overdosage, toxicity may result from the oxycodone or the acetaminophen.
Clinical Presentation
Acute overdosage with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.
Acetaminophen
Dose-dependent potentially fatal hepatic necrosis is the most serious adverse effect of acetaminophen overdosage. Renal tubular necrosis, hypoglycemic coma, and coagulation defects 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.
Treatment of Overdose
Oxycodone
In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.
The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to oxycodone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose.
Because the duration of opioid reversal is expected to be less than the duration of action of oxycodone in Oxycodone and Acetaminophen Tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.
Acetaminophen
Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration.
Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication
Oxycodone (ox" i koe' done ) and Acetaminophen (a seet" a min' oh fen) Tablets, CII
Oxycodone and Acetaminophen Tablets are:
• A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain, severe enough to require an opioid analgesic and for which alternative treatments are inadequate and when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
• An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
Important information about Oxycodone and Acetaminophen Tablets:
• Get emergency help right away if you take too much Oxycodone and Acetaminophen Tablets (overdose). When you first start taking Oxycodone and Acetaminophen Tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Taking Oxycodone and Acetaminophen Tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
• Never give anyone else your Oxycodone and Acetaminophen Tablets. They could die from taking it. Store Oxycodone and Acetaminophen Tablets away from children and in a safe place to prevent stealing or abuse. Selling or giving away Oxycodone and Acetaminophen Tablets are against the law.
Do not take Oxycodone and Acetaminophen Tablets if you have:
• Severe asthma, trouble breathing, or other lung problems.
• A bowel blockage or have narrowing of the stomach or intestines
• known hypersensitivity to oxycodone, acetaminophen, or any ingredient in Oxycodone and Acetaminophen Tablets
Before taking Oxycodone and Acetaminophen Tablets, tell your healthcare provider if you have a history of:
• Head injury, seizures
• Liver, kidney, thyroid problems
• Problems urinating
• Pancreas or gallbladder problems
• Abuse of street or prescription drugs, alcohol addiction, or mental health problems
Tell your healthcare provider if you are:
• Pregnant or planning to become pregnant. Prolonged use of Oxycodone and Acetaminophen Tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
• Breastfeeding. Oxycodone and Acetaminophen Tablets passes into breast milk and may harm your baby.
• Taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Oxycodone and Acetaminophen Tablets with certain other medicines can cause serious side effects that could lead to death.
When taking Oxycodone and Acetaminophen Tablets:
• Do not change your dose. Take Oxycodone and Acetaminophen Tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
• Take your prescribed dose every 6 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.
• Call your healthcare provider if the dose you are taking does not control your pain.
• If you have been taking Oxycodone and Acetaminophen Tablets regularly, do not stop taking Oxycodone and Acetaminophen Tablets without talking to your healthcare provider.
• After you stop taking Oxycodone and Acetaminophen Tablets, dispose of unused tablets by flushing them down the toilet.
While taking Oxycodone and Acetaminophen Tablets DO NOT:
• Drive or operate heavy machinery, until you know how Oxycodone and Acetaminophen Tablets affects you. Oxycodone and Acetaminophen Tablets can make you sleepy, dizzy, or lightheaded.
• Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Oxycodone and Acetaminophen Tablets may cause you to overdose and die.
The possible side effects of Oxycodone and Acetaminophen Tablets:
• Constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.
Get emergency medical help if you have:
• Trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.
These are not all the possible side effects of Oxycodone and Acetaminophen Tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
For more information go to dailymed.nlm.nih.gov.
Distributed by: Camber Pharmaceuticals, Inc, Piscataway, NJ 08854 or call 1-800-495-8330
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 01/17
Oxycodone Hydrochloride and Acetaminophen is available in tablets for oral administration.
Each tablet, for oral administration contains:
Oxycodone hydrochloride, USP………………………………………………….. 2.5 mg*
(*2.5 mg oxycodone Hydrochloride is equivalent to 2.2409 mg of oxycodone.)
Acetaminophen, USP……………………………………………………………… 325 mg
Oxycodone hydrochloride, USP …………………………………………………. 5 mg*
(*5 mg oxycodone Hydrochloride is equivalent to 4.4815 mg of oxycodone.)
Acetaminophen, USP …………………………………………………………….. 325 mg
Oxycodone hydrochloride, USP………………………………………………….. 7.5 mg*
(*7.5 mg oxycodone Hydrochloride is equivalent to 6.7228 mg of oxycodone.)
Acetaminophen, USP……………………………………………………………… 325 mg
Oxycodone hydrochloride, USP…………………………………………………… 10 mg*
(*10 mg oxycodone Hydrochloride is equivalent to 8.9637 mg of oxycodone.)
Acetaminophen, USP ……………………………………………………………... 325 mg
Inactive Ingredients
The tablets contain: colloidal silicon dioxide, croscarmellose sodium, crospovidone, microcrystalline cellulose, povidone, pregelatinized starch, and stearic acid.
Oxycodone and Acetaminophen Tablets contain oxycodone, 14-hydroxydihydrocodeinone, a semisynthetic opioid analgesic which occurs as a white to off-white fine crystalline powder. The molecular formula for oxycodone hydrochloride is C18H21NO4 ∙ HCl and the molecular weight is 381.82. It is derived from the opium alkaloid, thebaine, and may be represented by the following structural formula:
[structure1]
Oxycodone and Acetaminophen Tablets contain acetaminophen, 4'-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic which occurs as a white, odorless, crystalline powder. The molecular formula for acetaminophen is C8H9NO2 and the molecular weight is 151.17. It may be represented by the following structural formula:
[structure2]
[image: img_90a4ba41-9a4a-1c24-e053-2995a90ad8f6]
HOW SUPPLIED
Oxycodone and Acetaminophen Tablets, USP:
2.5 mg/325 mg
White to Off-white color capsule shaped tablets debossed with ‘T 191’ on one side and plain on other side.
Bottles of 100 Bottles of 500
5 mg/325 mg
White to off-white color round, biconvex tablets having break line on one side and debossed with ‘T 192’ on other side.
Bottles of 100 Bottles of 500
7.5 mg/325 mg
White to Off-white color capsule shaped tablets debossed with ‘T 193’ on one side and plain on other side.
Bottles of 100 Bottles of 500
10 mg/325 mg
White to off-white color capsule shaped tablets debossed with ‘T 194’ on one side plain and plain on other side.
Bottles of 100 Bottles of 500
Store at 20° to 25°C (68° to 77°F). [see USP Controlled Room Temperature]. Protect from moisture.
Dispense in a tight, light-resistant container as defined in the USP.
Manufactured by:
Ascent Pharmaceuticals, Inc.
Central Islip, NY 11722
Manufactured for:
Camber Pharmaceuticals, Inc.
Piscataway, NJ 08854
Rev 02/19
Photos of the product and/or packaging supplied by the manufacturer.
Mechanism of Action
Oxycodone is a full opioid agonist with relative selectivity for the mu-opioid receptor, although it can interact with other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.
The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.
The precise mechanism of the analgesic properties of acetaminophen is not established but is thought to involve central actions.
Pharmacodynamics
Effects on the Central Nervous System
Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.
Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects on the Cardiovascular System
Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as symptoms as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see ADVERSE REACTIONS].
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
Concentration–Efficacy Relationships
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration].
Concentration–Adverse Reaction Relationships
There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration].
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.
Metabolism and Elimination
Oxycodone
In humans, oxycodone is extensively metabolized to noroxycodone by means of CYP3A-mediated N-demethylation, oxymorphone by means of CYP2D6-mediated O-demethylation, and their glucuronides [see PRECAUTIONS; Drug Interactions].
Acetaminophen
Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. A small fraction (10-25%) of acetaminophen is bound to plasma proteins. 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. Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways. 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.
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