acetaminophen and codeine phosphate

INDICATIONS AND USAGE 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 or opioid combination products]: 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.

DOSAGE AND ADMINISTRATION 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 30 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. Single Doses (Range) Maximum 24-Hour Dose Codeine Phosphate 15 mg to 60 mg 360 mg Acetaminophen 300 …

CONTRAINDICATIONS 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 ] .

ADVERSE REACTIONS •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 ] • Neonatal Opioid Withdrawal Syndrome [see WARNINGS ] • Ultra-rapid Metabolizers of Codeine [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 post marketing 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). Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids, and may occur more frequently in patients taking higher doses of opioid, and/or in patients taking opioids longer term [see WARNINGS ]. Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90 day period (n=978); or 2) filled any Schedule II opioid analgesic for at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: • approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two valid …

Drug Interactions Anticoagulants Chronic oral acetaminophen use at a dose of 4000 mg/day has been shown to cause an increase in international normalized ratio (INR) in some patients who have been stabilized on sodium warfarin as an anticoagulant. As no studies have been performed evaluating the short term use of acetaminophen and codeine phosphate tablets in patients on oral anticoagulants, more frequent assessment of INR may be appropriate in such circumstances. CYP2D6 Inhibitors Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of acetaminophen and codeine phosphate tablets and CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, bupropion, quinidine) can increase the plasma concentration of codeine, but can decrease the plasma concentration of active metabolite morphine, which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of acetaminophen and codeine phosphate tablets is achieved (see CLINICAL PHARMACOLOGY ). After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the codeine plasma concentration will decrease but the active metabolite morphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression (see CLINICAL PHARMACOLOGY ). If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of acetaminophen and codeine phosphate tablets and monitor patients closely at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the dosage of acetaminophen and codeine phosphate tablets as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the dosage of acetaminophen and codeine phosphate tablets and monitor the patient for signs and symptoms of respiratory depression or sedation. CYP3A4 Inhibitors The concomitant use of acetaminophen and codeine phosphate tablets and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease inhibitors (e.g., ritonavir), may result in an increase in codeine plasma concentrations , with subsequently greater metabolism by CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of acetaminophen and codeine phosphate tablets is achieved (see WARNINGS ). After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels (see CLINICAL PHARMACOLOGY ), resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine. If concomitant use of CYP3A4 inhibitor is necessary, consider dosage reduction of acetaminophen and codeine phosphate tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the acetaminophen and codeine phosphate tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. CYP3A4 Inducers The concomitant use of acetaminophen and codeine phosphate tablets and CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) can result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels (see CLINICAL PHARMACOLOGY ), resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence (see WARNINGS ). After stopping a CYP3A4 inducer, as the effects of the inducer decline …

DESCRIPTION Acetaminophen and Codeine Phosphate Tablets, USP 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 1⁄2H 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: colloidal silicon dioxide, corn starch, croscarmellose sodium, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, stearic acid, FD&C Red #40 aluminum lake (300 mg/15 mg only), and FD&C Blue#1 aluminum lake (300 mg/60 mg only). codeine-01 codeine-02

OVERDOSAGE Following an acute overdosage, toxicity may result from codeine or acetaminophen. Clinical Presentation Codeine Acute overdose with codeine phosphate 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, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. [ see CLINICAL PHARMACOLOGY ] . Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Acetaminophen Dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect of acetaminophen overdose. Renal tubular necrosis, hypoglycemic coma, and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include; anorexia, nausea, vomiting, diaphoresis, pallor and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Treatment of Overdose Codeine 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 measures. For clinically significant respiratory or circulatory depression secondary to acetaminophen and codeine phosphate tablets overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of opioid reversal is expected to be less than the duration of action of codeine in acetaminophen and codeine phosphate tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product's prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the opioid overdose reversal agent 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 reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be begun with care and by titration with smaller than usual doses of the reversal agent. 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.

HOW SUPPLIED Each Acetaminophen and Codeine Phosphate Tablet USP 300 mg/15 mg tablet contains acetaminophen 300 mg and codeine phosphate 15 mg. It is available as a round, white to off-white tablet debossed with “2” on one side and an on the other side. Bottles of 100......................................... NDC 0406-0483-01 Each Acetaminophen and Codeine Phosphate Tablet USP 300 mg/30 mg tablet contains acetaminophen 300 mg and codeine phosphate 30 mg. It is available as a round, white to off-white tablet debossed with “3” on one side and an on the other side. Bottles of 20............................................ NDC 0406-0484-20 Bottles of 30............................................ NDC 0406-0484-03 Bottles of 50............................................ NDC 0406-0484-50 Bottles of 100......................................... NDC 0406-0484-01 Bottles of 1000....................................... NDC 0406-0484-10 Unit Dose (10 x 10)............................... NDC 0406-0484-62 Each Acetaminophen and Codeine Phosphate Tablet USP 300 mg/60 mg tablet contains acetaminophen 300 mg and codeine phosphate 60 mg. It is available as a round, white to off-white tablet debossed with “4” on one side and an on the other side. Bottles of 100......................................... NDC 0406-0485-01 Bottles of 500......................................... NDC 0406-0485-05 Blister card of 30...........................NDC 58118-0485-8 Store acetaminophen and codeine phosphate tablets 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 ). Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and are trademarks of a Mallinckrodt company. © 2020 Mallinckrodt. SpecGx LLC Webster Groves, MO 63119 USA Rev 08/2020 MallinckrodtTM Pharmaceuticals Repackaged by: Clinical Solutions Wholesale Franklin, TN 37067 An electronic copy of this medication guide can be obtained from www.mallinckrodt.com/Medguide/MG20A08.pdf or by calling 1-800-778-7898 for alternate delivery options. Boxed M Boxed M Boxed M Boxed M