Get your patient on Acetaminophen And Codeine Phosphate - Acetaminophen And Codeine Phosphate tablet (Acetaminophen And Codeine Phosphate)

Acetaminophen and codeine phosphate tablets are indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate.

Limitations of Use:

Because of the risks of addiction, abuse, and misuse, with opioids, which can occur at any dosage or duration [see Warnings] , reserve acetaminophen and codeine phosphate 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

Acetaminophen and codeine phosphate tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

Important Dosage and Administration Instructions

Acetaminophen and codeine phosphate tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of acetaminophen and codeine phosphate tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.

There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings].

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with acetaminophen and codeine phosphate tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with acetaminophen and codeine phosphate tablets [see Warnings, Life-Threatening Respiratory Depression; Precautions, Information for Patients/Caregivers].

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing regulations (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings, Addiction, Abuse, and Misuse, Life-Threatening Respiratory Depression, Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants].

Consider prescribing naloxone when the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

Initial Dosage

Use of Acetaminophen and Codeine Phosphate Tablets as the First Opioid Analgesic

Initiate treatment with acetaminophen and codeine phosphate tablets in a dosing range of 300 mg to 600 mg of acetaminophen and 15 mg to 60 mg of codeine phosphate every 4 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of acetaminophen and codeine phosphate tablets

The usual adult dosage is:

Acetaminophen and Codeine Phosphate Tablets (codeine 15 mg and acetaminophen 300 mg): Take 1 to 2 tablets every 4 hours as needed for pain.

Acetaminophen and Codeine Phosphate Tablets (codeine 30 mg and acetaminophen 300 mg): Take 1 to 2 tablets every 4 hours as needed for pain.

Acetaminophen and Codeine Phosphate Tablets (codeine 60 mg and acetaminophen 300 mg): Take one tablet every 4 hours as needed for pain.

The prescriber must determine the number of tablets per dose, and the maximum number of tablets per 24 hours, based upon the above dosage guidance. This information should be conveyed in the prescription.

Conversion from Other Opioids to Acetaminophen and Codeine Phosphate Tablets

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of acetaminophen and codeine phosphate tablets. It is safer to underestimate a patient's 24-hour acetaminophen and codeine phosphate tablets dosage than to overestimate the 24-hour acetaminophen and codeine phosphate tablets dosage and manage an adverse reaction due to overdose.

Titration and Maintenance of Therapy

Individually titrate acetaminophen and codeine phosphate tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving acetaminophen and codeine phosphate tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess 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 acetaminophen and codeine phosphate tablets dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Safe Reduction or Discontinuation of Acetaminophen and Codeine Phosphate Tablets

Do not abruptly discontinue Acetaminophen and Codeine Phosphate Tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Acetaminophen and Codeine Phosphate Tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including acetaminophen and codeine phosphate tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Acetaminophen and Codeine Phosphate Tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings/Withdrawal, Drug Abuse and Dependence].

Acetaminophen and codeine phosphate tablets are contraindicated for:

• All children younger than 12 years of age [see Warnings].
• Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings].
• Acetaminophen and codeine phosphate tablets are 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].
• concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings].
• known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings].
• hypersensitivity to codeine, acetaminophen, or any of the formulation excipients (e.g., anaphylaxis) [see Warnings].

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Addiction, Abuse, and Misuse [see Warnings]
• Life-Threatening Respiratory Depression [see Warnings]
• Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings]
• Neonatal Opioid Withdrawal Syndrome [see Warnings]
• Interactions with CNS Depressants [see Warnings]
• Severe Hypotension [see Warnings]
• Gastrointestinal Adverse Reactions [see Warnings]
• Seizures [see Warnings]
• Withdrawal [see Warnings]
• Opioid-Induced Hyperalgesia and Allodynia [See Warnings]

The following adverse reactions associated with the use of codeine were identified in postmarketing reports. Because some of these reactions were 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 associated with codeine are respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.

The most frequently observed adverse reactions with codeine administration include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation.

Other adverse reactions include allergic reactions, euphoria, dysphoria, abdominal pain, pruritus, rash, thrombocytopenia, and agranulocytosis

Other less frequently observed adverse reactions expected from opioid analgesics, including Acetaminophen and Codeine phosphate Tablets:

Cardiovascular system: faintness, flushing, hypotension, palpitations, syncope.

Digestive System: abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis

Nervous system: anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness

Skin and Appendages: rash, sweating, urticarial.

• 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 acetaminophen and codeine phosphate tablets.
• Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology].
• Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings].
• Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

To report SUSPECTED ADVERSE REACTIONS, contact Strides Pharma Inc. at 1-877-244-9825 or go to or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Acetaminophen and codeine phosphate tablets are supplied in tablet form for oral administration.

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:

C ₈ H ₉ NO ₂ M.W. 151.16

Codeine phosphate, 7,8-didehydro-4, 5α-epoxy-3-methoxy-17-methylmorphinan-6α- ol phosphate (1:1) (salt) hemihydrate, a white crystalline powder, is a narcotic analgesic and antitussive. It has the following structural formula:

C ₁₈ H ₂₁ NO ₃ •H ₃ PO ₄ •1/2 H ₂ O  M.W. 406.37

Each Acetaminophen and Codeine Phosphate Tablet, USP (300 mg/15 mg) contains:

Acetaminophen USP………………..…300 mg

Codeine Phosphate USP……………….15 mg

Each Acetaminophen and Codeine Phosphate Tablet, USP (300 mg/30 mg) contains:

Acetaminophen USP…………………300 mg

Codeine Phosphate USP………………30 mg

Each Acetaminophen and Codeine Phosphate Tablet, USP (300 mg/60 mg) contains:

Acetaminophen USP…………………300 mg

Codeine Phosphate USP………………60 mg

In addition, each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, povidone, pregelatinized corn starch, sodium metabisulfite, sodium starch glycolate and stearic acid.

Mechanism of Action

Codeine is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of codeine have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.

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

Codeine 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.

Codeine 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.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Codeine 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

Codeine 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 low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical 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 opioid agonists. The minimum effective analgesic concentration of codeine 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 codeine 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

The behavior of the individual components is described below.

Codeine

Codeine is rapidly absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen, and kidney. Codeine crosses the blood-brain barrier and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain. Codeine is about 7-25% bound to plasma proteins and does not accumulate in body tissues.

About 70 to 80% of the administered dose of codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (C6G) and via O-demethylation to morphine (about 5 to 10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucuronidation of codeine to C6G. Cytochrome P450 2D6 is the major enzyme responsible for conversion of codeine to morphine and P450 3A4 is the major enzyme mediating conversion of codeine to norcodeine. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Morphine and M6G are known to have analgesic activity in humans. The analgesic activity of C6G in humans is unknown. Norcodeine and M3G are generally not considered to possess analgesic properties.

The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces.

At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours.

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.

Acetaminophen and Codeine Phosphate Tablets 300 mg/15 mg are white, round, flatfaced, beveled edge, scored (bisect bar) tablets, debossed "2063" and "V" on one side and debossed "2" on the reverse side. They are supplied in:

• Bottles of 100: NDC 64380-448-01

Acetaminophen and Codeine Phosphate Tablets, USP 300 mg/30 mg are white, round, flat-faced, beveled edge, scored (bisect bar) tablets, debossed "2064" and "V" on one side and debossed "3" on the reverse side. They are available as follows:

• Bottles of 100: NDC 64380-446-01
• Bottles of 500: NDC 64380-446-03
• Bottles of 1000: NDC 64380-446-02

Acetaminophen and Codeine Phosphate Tablets, USP 300 mg/60 mg are white, round, flat-faced, beveled edge, scored (bisect bar) tablets, debossed "2065" and "V" on one side and debossed "4" on the reverse side. They are available as follows:

• Bottles of 100: NDC 64380-447-01
• Bottles of 500: NDC 64380-447-02

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

Dispense in tight, light-resistant container as defined in the USP.

Store Acetaminophen and Codeine Phosphate Tablets securely and dispose of properly [see PRECAUTIONS/Information for Patients].

Distributed by: Strides Pharma Inc.

East Brunswick, NJ 08816

Revised: 03/2024