Acetaminophen and Codeine Phosphate 300 mg; 30 mg Tablet, 30-count — NDC 68071-4673-3 (Billing 68071-4673-03)

WARNINGS Addiction, Abuse, and Misuse: Acetaminophen and Codeine Phosphate Tablets contains codeine, a Schedule II controlled substance. As an opioid, Acetaminophen and Codeine Phosphate Tablets exposes users to the risks of addiction, abuse, and misuse [see DRUG ABUSE and DEPENDENCE ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Acetaminophen and Codeine Phosphate Tablets.

Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Acetaminophen and Codeine Phosphate Tablets, and monitor all patients receiving Acetaminophen and Codeine Phosphate Tablets with Codeine for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).

The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Acetaminophen and Codeine Phosphate Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Acetaminophen and Codeine Phosphate Tablets along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Consider these risks when prescribing or dispensing Acetaminophen and Codeine Phosphate Tablet. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see PRECAUTIONS ; Information for Patients/Caregivers ]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS): To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed.

The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. • Consider using other tools to improve patient, household, and community safety, such as patient- prescriber agreements that reinforce patient- prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 800-503-0784, or log on to www.opioidanalgesicrems.com .

The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.

Management of resp… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS The following adverse reactions have been identified during post approval use of Acetaminophen and Codeine Phosphate Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • 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 ] 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 chronic use of opioids [see 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 decreased the plasma concentration of active metabolite morphine, particularly when an inhibitor is added after a stable dose of Acetaminophen and Codeine Phosphate Tablet 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 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 [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 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 [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, 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… [Excerpted — this section continues on DailyMed.]

Drug/Laboratory Test Interactions Codeine may increase serum amylase levels. Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.

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).

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 [see WARNINGS ]. 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 [see WARNINGS ].

Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see WARNINGS ]. Instruct patients to take steps to store acetaminophen and codeine phosphate tablets securely.

Advise patients to properly dispose of the Acetaminophen and Codeine Phosphate Tablets in accordance with local state guidelines and/or regulations. Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children: Advise patients that acetaminophen and codeine phosphate tablets should not be used in children younger than 12 years of age or in a child of any age for pain treatment after tonsillectomy and/or adenoidectomy. Advice caregivers of children ages 12-18 receiving codeine to monitor for signs of respiratory depression [see WARNINGS and PRECAUTIONS ].

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 health care provider [see WARNINGS and PRECAUTIONS ; 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 [see PRECAUTIONS ; 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 WARNINGS , 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 [see DOSAGE and ADMINISTRATION… [Excerpted — this section continues on DailyMed.]

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 is subject to misuse, addiction, and criminal diversion [see WARNINGS ]. 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 health care 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 results 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/… [Excerpted — this section continues on DailyMed.]