PRECAUTIONS Risks of Driving and Operating Machinery TYLENOL ® with Codeine 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 TYLENOL ® with Codeine 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 TYLENOL ® with Codeine 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 TYLENOL ® with Codeine tablets with others and to take steps to protect TYLENOL ® with Codeine 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 TYLENOL ® with Codeine 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 TYLENOL ® with Codeine tablets securely. Advise patients to properly dispose of TYLENOL ® with Codeine 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 caregivers that TYLENOL ® with Codeine is 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 TYLENOL ® with Codeine to monitor for signs of respiratory depression (see WARNINGS ) . Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if TYLENOL ® with Codeine is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these drugs concomitantly unless supervised by a healthcare provider (see WARNINGS, 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 TYLENOL ® with Codeine tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking TYLENOL ® with Codeine 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 TYLENOL ® with Codeine tablets (see DOSAGE AND ADMINISTRATION ). Advise patients not to adjust the dose of TYLENOL ® with Codeine without consulting a physician or other healthcare professional. If patients have been receiving treatment with TYLENOL ® with Codeine tablets for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose and that abruptly discontinuing the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication (see WARNINGS ). 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 TYLENOL ® with Codeine 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) (see WARNINGS; Hypotension ). Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in TYLENOL ® with Codeine. 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 TYLENOL ® with Codeine and seek medical attention. (see CONTRAINDICATIONS, ADVERSE REACTIONS ). Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of TYLENOL ® with Codeine during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated (see WARNINGS, Pregnancy ). Embryo-Fetal Toxicity Inform female patients of reproductive potential that TYLENOL ® with Codeine can cause fetal harm and to inform the prescriber of a known or suspected pregnancy (see PRECAUTIONS; Pregnancy ). Lactation Advise women that breastfeeding is not recommended during treatment with TYLENOL ® with Codeine tablets (see PRECAUTIONS; 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 TYLENOL ® with Codeine 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 (see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY ). Disposal of Unused TYLENOL ® with Codeine Advise patients to properly dispose of TYLENOL ® with Codeine tablets. Advise patients to throw the drug in the household trash following these steps: Remove them from their original containers and mix them with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs). Place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or breaking out of a garbage bag, or dispose of unused tablets in accordance with local state guidelines and/or regulations. Drug Interactions CYP2D6 Inhibitors Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of TYLENOL ® with Codeine 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 TYLENOL ® with Codeine 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 TYLENOL ® with Codeine 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 TYLENOL ® with Codeine as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the dosage of TYLENOL ® with Codeine and monitor the patient for signs and symptoms of respiratory depression or sedation. CYP3A4 Inhibitors The concomitant use of TYLENOL ® with Codeine 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 TYLENOL ® with Codeine 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 TYLENOL ® with Codeine 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 TYLENOL ® with Codeine tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. CYP3A4 Inducers The concomitant use of TYLENOL ® with Codeine 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, 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 TYLENOL ® with Codeine dosage as needed. If a CYP3A4 inducer is discontinued, consider a TYLENOL ® with Codeine 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 (see WARNINGS ). 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 effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (used to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) (see PRECAUTIONS; Information for Patients/Caregivers ). If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue TYLENOL ® with Codeine 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 TYLENOL ® with Codeine 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 TYLENOL ® with Codeine tablets and/or precipitate withdrawal symptoms. Advise patient to avoid concomitant use of these drugs. Muscle Relaxants TYLENOL ® with Codeine tablets 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 TYLENOL ® with Codeine tablets and/or the muscle relaxant as necessary. 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 TYLENOL ® with Codeine 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/m 2 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/m 2 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 1.2–1.4 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 (see ADVERSE 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. TYLENOL ® with Codeine 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 (see WARNINGS ). 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. TYLENOL ® with Codeine is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including TYLENOL ® with Codeine, and 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 (see OVERDOSAGE ). 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 TYLENOL ® with Codeine tablets (see WARNINGS ). 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 TYLENOL ® with Codeine 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 TYLENOL ® with Codeine 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 (see WARNINGS ). 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 CYP2D6 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: TYLENOL ® with Codeine tablets are contraindicated for all children younger than 12 years of age (see CONTRAINDICATIONS ). TYLENOL ® with Codeine tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy (see CONTRAINDICATIONS ). Avoid the use of TYLENOL ® with Codeine 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 post-operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression (see WARNINGS ). Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to TYLENOL ® with Codeine 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 TYLENOL ® with Codeine 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.