Oxycodone and Acetaminophen

OXYCODONE AND ACETAMINOPHEN — oxycodone hydrochloride and acetaminophen tablet
Lupin Pharmaceuticals,Inc.

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF

OXYCODONE AND ACETAMINOPHEN TABLETS

Addiction, Abuse, and Misuse

Because the use of 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 and reassess all patients regularly for the development of these behaviors and conditions [see WARNINGS].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of Oxycodone and Acetaminophen Tablets, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of Oxycodone and Acetaminophen Tablets are essential [see WARNINGS].

Accidental Ingestion

Accidental ingestion of even one dose of Oxycodone and Acetaminophen Tablets, especially by children, can result in a fatal overdose of Oxycodone and Acetaminophen [see WARNINGS].

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. 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 [ see WARNINGS, PRECAUTIONS: Drug Interactions].

Neonatal Opioid Withdrawal Syndrome (NOWS)

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be lifethreatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see WARNINGS].

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS):

Healthcare providers are strongly encouraged to complete a REMS compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [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.

DESCRIPTION

Oxycodone Hydrochloride and Acetaminophen is available in tablets for oral administration.

Each tablet for oral administration, contains Oxycodone Hydrochloride and Acetaminophen in the following strengths:

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

All Strengths of Oxycodone and Acetaminophen Tablets also contains the following inactive ingredients: Colloidal silicon dioxide, povidone, cross-linked povidone, corn starch, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, and stearic acid.

Oxycodone Hydrochloride 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 C18 H21 NO4 ∙ HCl and the molecular weight is 351.82. It is derived from the opium alkaloid, thebaine, and may be represented by the following structural formula:

oxy-structure

C18 H21 NO4 ·HCl MW 351.82

Oxycodone and Acetaminophen Tablets contain acetaminophen, 4′-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic which occurs as a white, free flowing granules. The molecular formula for acetaminophen is C8 H9 NO2 and the molecular weight is 151.16. It may be represented by the following structural formula:

apap-structure

C8 H9 NO2 MW 151.16

CLINICAL PHARMACOLOGY

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.

Use of opioids for an extended period of time 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 extended-release 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].

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