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
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.
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.
Interactions with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if acetaminophen and codeine phosphate tablets is used with benzodiazepines or other CNS depressants,including alcohol, and not to use these concomitantly unless supervised by a health care provider [see WARNINGS, PRECAUTIONS; Drug Interactions] .
Inform patients that
could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms 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].
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 [TRADENAME] [see W&P or DI].
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
Important Administration Instructions
Instruct patients how to properly take Acetaminophen and Codeine Phosphate Tablets [see DOSAGE 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.
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) [see WARNINGS; Hypotension].
Inform patients that anaphylaxis has been reported with ingredients contained in Acetaminophen and Codeine Phosphate Oral Tablet. 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 Oral Tablet and seek medical attention. [see Contraindications, Adverse Reactions].
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 [see WARNINGS, PRECAUTIONS; Pregnancy]
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 [see PRECAUTIONS; Pr egnancy ].
Advise patients that nursing mothers taking codeine can have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Advise nursing mothers to watch for signs of morphine toxicity in their infants which includes increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby’s doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services) [see PRECAUTIONS; Nursing Mothers].
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.
Ultra-Rapid Metabolism of Codeine
Advise patients that some people have a genetic variation that results in codeine changing into morphine more rapidly and completely than other people. Most people are unaware of whether they are an ultra-rapid codeine metabolizer or not. These higher-than-normal levels of morphine in the blood may lead to life-threatening or fatal respiratory depression or signs of overdose such as extreme sleepiness, confusion, or shallow breathing. Children with this genetic variation who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may be at greatest risk based on reports of several deaths in this population due to respiratory depression. Codeine-containing products are contraindicated in all children who undergo tonsillectomy and/or adenoidectomy. Advise caregivers of children receiving codeine-containing products for other reasons to monitor for signs of respiratory depression.
Disposal of Unused Acetaminophen and Codeine Phosphate Tablets
1. Advise patients to properly dispose of the Acetaminophen and Codeine Phosphate 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).
2. 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 to dispose of in accordance with local state guidelines and/or regulations.
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.
If concomitant use is necessary, consider dosage adjustment of Acetaminophen and Codeine Phosphate Tablets until stable drug effects are achieved.
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. If a CYP2D6 inhibitor is discontinued, consider adjusting the Acetaminophen and Codeine Phosphate Tablets dosage until stable drug effects are achieved.
If concomitant use is necessary or if a CYP2D6 inhibitor is discontinued after concomitant use, monitor patients closely at frequent intervals. If signs and symptoms of respiratory depression or sedation occur, consider reducing the Acetaminophen and Codeine Phosphate Tablets dosage until stable drug effects are achieved.
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), can increase the plasma concentration of codeine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Acetaminophen and Codeine Phosphate Tablets is achieved. If concomitant use is necessary, consider dosage reduction of Acetaminophen and Codeine Phosphate Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the codeine plasma concentration will decrease resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine. 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.
The concomitant use of Acetaminophen and Codeine Phosphate Tablets and CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) can decrease the plasma concentration of codeine, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to codeine. If concomitant use is necessary, consider increasing the Acetaminophen and Codeine Phosphate Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the codeine plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. If a CYP3A4 inducer is discontinued, consider Acetaminophen and Codeine Phosphate Tablets dosage reduction and monitor for signs of respiratory depression.
Benzodiazepines and other Central Nervous System (CNS) Depressants
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants such as alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle
relaxants, general anesthetics, anti psychotics, and other opioids, can increases the risk of 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].
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as 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 (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome [see
PRECAUTIONS ;Information for Patients ].
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue acetaminophen and codeine phosphate tablets 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 Tablet and/or precipitate withdrawal symptoms.
Advise patient to avoid concomitant use of these drugs.
Acetaminophen and codeine tablet 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 tablet and/or the muscle relaxant as necessary.
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.
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 Tablet is 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
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 1.2-1.4 times the MHDD, based on a body surface area comparison.
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.
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].
Teratogenic Effects: Pregnancy Category C
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.
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. 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, 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.
Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine’s active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Codeine Phosphate Tablets and any potential adverse effects on the breastfed infant from Codeine Phosphate Tablets or from the underlying maternal condition.
The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine-containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Infants exposed to codeine phosphate through breast milk should be monitored for excess sedation and respiratory depression. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding (See WARNINGS; Death Related to Ultra-Rapid Metabolism of Codeine to Morphine).
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.
Infants exposed to Acetaminophen and Codeine Tablets through breast milk 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 breast-feeding is stopped.
Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme CYP2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine-containing products are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS, WARNINGS].
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 and 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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