PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

ACETAMINOPHEN AND CODEINE PHOSPHATE TABLET

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INDICATIONS & USAGE SECTION

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, even at recommended doses (seeWARNINGS), reserve acetaminophen and codeine phosphate tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics)

• Have not provided adequate analgesia, or are not expected to provide adequate analgesia,

• Have not been tolerated, or are not expected to be tolerated.

DOSAGE & ADMINISTRATION SECTION

DOSAGE AND ADMINISTRATION

Important Dosage and Administration Instructions

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (seeWARNINGS).

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 acetaminophen and codeine phosphate tablets and adjust the dosage accordingly (seeWARNINGS).

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

Initiating Treatment with Acetaminophen and Codeine Phosphate Tablets

Dosage should be adjusted according to severity of pain and response of the patient. However, it should be kept in mind that tolerance to codeine can develop with continued use and that the incidence of untoward effects is dose related. Adult doses of codeine higher than 60 mg are associated with an increased incidence of adverse reactions and are not associated with greater efficacy.

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 and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse (seeWARNINGS). 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 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.

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 dose of 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, monitor 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 a long duration 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 (seeWARNINGS,******** Withdrawal andDRUG ABUSE AND DEPENDENCE).

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BOXED WARNING SECTION

PRECAUTIONS SECTION

PRECAUTIONS

Risks of Driving and Operating Machinery

Acetaminophen and codeine phosphate tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of acetaminophen and codeine phosphate tablets and know how they will react to the medication (see PRECAUTIONS, Information for Patients/Caregivers).

Information for Patients/Caregivers

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store acetaminophen and codeine phosphate tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home (seeWARNINGS andDRUG ABUSE AND DEPENDENCE). Inform patients that leaving acetaminophen and codeine phosphate tablets unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that medicine take-back options are the preferred way to safely dispose of most types of unneeded medicines. If no take back programs or DEA-registered collectors are available, instruct patients to dispose of acetaminophen and codeine phosphate tablets by following these four steps:

• Mix acetaminophen and codeine phosphate tablets (do not crush) with an unpalatable substance such as dirt, cat litter, or used coffee grounds;

• Place the mixture in a container such as a sealed plastic bag;

• Throw the container in the household trash;

• Delete all personal information on the prescription label of the empty bottle.

Inform patients that they can visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

Addiction, Abuse, and Misuse

Inform patients that the use of acetaminophen and codeine phosphate tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death (seeWARNINGS). Instruct patients not to share acetaminophen and codeine phosphate tablets with others and to take steps to protect acetaminophen and codeine phosphate tablets from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting acetaminophen and codeine phosphate tablets or when the dosage is increased, and that it can occur even at recommended dosages.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose (seeWARNINGS, Life-Threatening Respiratory Depression).

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with acetaminophen and codeine phosphate tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) (see**WARNINGS, Life-Threatening Respiratory Depression****;**DOSAGE AND ADMINISTRATION).

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered (see OVERDOSAGE).

If naloxone is prescribed, also advise patients and caregivers:

• How to treat with naloxone in the event of an opioid overdose,
• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency,
• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death (seeWARNINGS).

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Advise caregivers that acetaminophen and codeine phosphate tablets are contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children 12 to 18 years of age receiving acetaminophen and codeine phosphate tablets to monitor for signs of respiratory depression (seeWARNINGS).

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if acetaminophen and codeine phosphate tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these drugs concomitantly unless supervised by a healthcare provider (see WARNINGS****andPRECAUTIONS, Drug Interactions).

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life- threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms and signs of serotonin syndrome and to seek medical attention right away if symptoms develop.

Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications (seePRECAUTIONS, Drug Interactions).

MAOI Interaction

Inform patients not to take acetaminophen and codeine phosphate tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking acetaminophen and codeine phosphate tablets (see PRECAUTIONS, Drug Interactions).

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non- specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms (see WARNINGS).

Important Administration Instructions

Instruct patients how to properly take acetaminophen and codeine phosphate tablets (seeDOSAGE AND ADMINISTRATION).

• Advise patients not to adjust the dose of acetaminophen and codeine phosphate tablets without consulting a physician or other healthcare professional.

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue acetaminophen and codeine phosphate tablets without first discussing a tapering plan with the prescriber (seeDOSAGE AND ADMINISTRATION).

Maximum Daily Dose of Acetaminophen

Inform patients not to take more than 4,000 milligrams of acetaminophen per day. Advise patients to call their healthcare provider if they have taken more than the recommended dose.

Hypotension

Inform patients that acetaminophen and codeine phosphate tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) (seeWARNINGS, Hypotension).

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in acetaminophen and codeine phosphate tablets. Advise patients how to recognize such a reaction, and if they develop signs of allergy such as a rash or difficulty breathing to stop taking acetaminophen and codeine phosphate tablets and seek medical attention (seeCONTRAINDICATIONS andADVERSE REACTIONS).

Pregnancy

Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of acetaminophen and codeine phosphate tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated (seePRECAUTIONS, Pregnancy).

Embryo-Fetal Toxicity
Inform female patients of reproductive potential that acetaminophen and codeine phosphate tablets can cause fetal harm and to inform the prescriber of a known or suspected pregnancy (seePRECAUTIONS, Pregnancy).

Lactation

Advise women that breastfeeding is not recommended during treatment with acetaminophen and codeine phosphate tablets (seePR********ECAUTIONS, Nursing Mothers).

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

Driving or Operating Heavy Machinery

Inform patients that acetaminophen and codeine phosphate tablets may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery and to avoid such tasks while taking this product, until they know how they will react to the medication.

Constipation
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (seeADVERSE REACTIONSand CLINICAL PHARMACOLOGY).

Drug Interactions

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 acetaminophen and codeine phosphate tablets as needed.

After stopping use of a CYP2D6 inhibitor, consider reducing the 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 cytochrome 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 (seeWARNINGS).

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 (seeCLINICAL 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 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 2D6 with resultant lower morphine levels (seeCLINICAL PHARMACOLOGY), resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence (seeWARNINGS).

After stopping a CYP3A4 inducer, as the effects of the inducer decline, codeine plasma concentrations may increase, with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels (see CLINICAL PHARMACOLOGY), which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy and signs of opioid withdrawal and consider increasing the acetaminophen and codeine phosphate tablets dosage as needed.

If a CYP3A4 inducer is discontinued, consider acetaminophen and codeine phosphate tablets dosage reduction and monitor for signs of respiratory depression and sedation at frequent intervals.

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose (seeWARNINGS).

Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Examples of these drugs include, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and monoamine oxidase (MAO) inhibitors (used to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) (seePRECAUTIONS, Information for Patients/Caregivers).

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue acetaminophen and codeine phosphate tablets immediately if serotonin syndrome is suspected.

Monoamine Oxidase Inhibitors (MAOIs)

The concomitant use of opioids and MAOIs, such as phenelzine, tranylcypromine, linezolid, may manifest as serotonin syndrome or opioid toxicity.

Advise patients taking acetaminophen and codeine phosphate tablets not to use MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

The concomitant use of opioids with other opioid analgesics, such as butorphanol, nalbuphine, pentazocine, may reduce the analgesic effect of acetaminophen and codeine phosphate tablets and/or precipitate withdrawal symptoms.

Advise patient to avoid concomitant use of these drugs.

Muscle Relaxants

Acetaminophen and codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

If concomitant use is warranted, monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of acetaminophen and codeine phosphate tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose (seeWARNINGS).

Diuretics

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

If concomitant use is warranted, monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

If concomitant use is warranted, monitor patients for signs of urinary retention or reduced gastric motility when acetaminophen and codeine phosphate tablets are used concomitantly with anticholinergic drugs.

Drug/Laboratory Test Interactions

Codeine may increase serum amylase levels.

Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies to evaluate the carcinogenic potential of the combination of codeine and acetaminophen have not been conducted.

Two-year carcinogenicity studies have been conducted in F344/N rats and B6C3F1 mice. There was no evidence of carcinogenicity in male and female rats, respectively, at dietary doses up to 70 and 80 mg/kg/day of codeine sulfate (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m2 basis) for two years. Similarly there was no evidence of carcinogenicity activity in male and female mice at dietary doses up to 400 mg/kg/day of codeine sulfate (approximately 5 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m2 basis) for two years.

Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 0.8 times the maximum human daily dose (MHDD) of 4 grams/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats that received up to 0.7 times or mice at up to 1.2 to 1.4 times the MHDD, based on a body surface area comparison.

Mutagenesis

Codeine sulfate was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary cell chromosome aberration assay.

In the published literature, acetaminophen has been reported to be clastogenic when administered at 1500 mg/kg/day to the rat model (3.6 times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.8 times the MHDD, based on a body surface area comparison), suggesting a threshold effect.

Impairment of Fertility

No nonclinical fertility studies have been conducted with codeine or the combination of codeine and acetaminophen.

In studies conducted by the National Toxicology Program, fertility assessments with acetaminophen have been completed in Swiss CD-1 mice via a continuous breeding study. There were no effects on fertility parameters in mice consuming up to 1.7 times the MHDD of acetaminophen, based on a body surface area comparison. Although there was no effect on sperm motility or sperm density in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming 1.78 times the MHDD (based on a body surface comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing.

Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 1.2 times the MHDD and greater (based on a body surface comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses. These effects appear to increase with the duration of treatment. The clinical significance of these findings is not known.

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible (seeADVERSE REACTIONS).

Pregnancy

Teratogenic Effects

Codeine
A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120 mg/kg level, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In another study a single 100 mg/kg subcutaneous dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring.

There are no adequate and well-controlled studies in pregnant women. Acetaminophen and codeine phosphate tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Fetal/Neonatal Adverse Reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly (seeWARNINGS).

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho- physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Acetaminophen and codeine phosphate tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including acetaminophen and codeine phosphate tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (seeOVERDOSAGE). The effect of codeine, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers

Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent.

There is no information on the effects of codeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with acetaminophen and codeine phosphate tablets (seeWARNINGS).

Acetaminophen is excreted in breast milk in small amounts, but the significance of its effect on nursing infants is not known. Because of the potential for serious adverse reactions in nursing infants from acetaminophen, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Clinical Considerations
If infants are exposed to acetaminophen and codeine phosphate tablets through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.

Pediatric Use

The safety and effectiveness of acetaminophen and codeine phosphate tablets in pediatric patients below the age of 18 have not been established.

Life-threatening respiratory depression and death have occurred in children who received codeine (seeWARNINGS). In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine. Because of the risk of life- threatening respiratory depression and death:

• Acetaminophen and codeine phosphate tablets are contraindicated for all children younger than 12 years of age (seeCONTRAINDICATIONS).
• Acetaminophen and codeine phosphate tablets are contraindicated for postoperative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy (seeCONTRAINDICATIONS).
• Avoid the use of acetaminophen and codeine phosphate tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression (seeWARNINGS).

Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to acetaminophen and codeine phosphate tablets. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of acetaminophen and codeine phosphate tablets slowly in geriatric patients and monitor closely for signs of central nervous system depression (see WARNINGS).

These drugs are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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DEPENDENCE SECTION

DRUG ABUSE AND DEPENDENCE

Controlled Substance

Acetaminophen and codeine phosphate tablets contain codeine. Codeine in combination with acetaminophen, is a Schedule III controlled substance.

Abuse

Acetaminophen and codeine phosphate tablets contain codeine, a substance with a high potential for abuse similar to other opioids, including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Acetaminophen and codeine phosphate tablets can be abused and are subject to misuse, addiction, and criminal diversion (seeWARNINGS).

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful, or potentially harmful, consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. 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 healthcare providers. “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers 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.

Acetaminophen and codeine phosphate tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, 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.

Risks Specific to Abuse of Acetaminophen and Codeine Phosphate Tablets

Acetaminophen and codeine phosphate tablets are for oral use only. Abuse of acetaminophen and codeine phosphate tablets poses a risk of overdose and death. The risk is increased with concurrent use of acetaminophen and codeine phosphate tablets with alcohol and other central nervous system depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. 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). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Do not abruptly discontinue acetaminophen and codeine phosphate tablets in a patient physically dependent on opioids. Rapid tapering of acetaminophen and codeine phosphate tablets in a patient physically dependent on opioids may lead to 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.

When discontinuing acetaminophen and codeine phosphate tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of acetaminophen and codeine phosphate tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper (seeDOSAGE AND ADMINISTRATION and WARNINGS).

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs (seePRECAUTIONS, Pregnancy).

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OVERDOSAGE SECTION

OVERDOSAGE

Following an acute overdosage, toxicity may result from codeine or acetaminophen.

Clinical Presentation

Codeine

Acute overdosage with codeine 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 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 serious arrhythmias will require advanced life-support measures.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to acetaminophen and codeine overdose, administer an opioid antagonist.

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 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 begun 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.

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SPL MEDGUIDE SECTION

This Medication Guide has been approved by the U.S. Food and Drug Administration.****

Issued: 08/2020
MG20A08

Mallinckrodt™

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HOW SUPPLIED SECTION

HOW SUPPLIED

Product: 53002-0102

NDC: 53002-0102-1 10 TABLET in a BOTTLE

NDC: 53002-0102-2 20 TABLET in a BOTTLE

NDC: 53002-0102-3 30 TABLET in a BOTTLE

NDC: 53002-0102-5 15 TABLET in a BOTTLE

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