TYLENOL & CODEINE 500/60mg. Capsules.

BOXED WARNING

As with other opioid agonists, products containing codeine should be avoided in patients with severe pulmonary disease. Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as this significantly increases the risk for respiratory depression, low blood pressure, and death. Acetaminophen; codeine should be used cautiously in patients with asthma. In addition, codeine should be avoided in patients with severe pulmonary disease such as acute or severe bronchial asthma, chronic obstructive pulmonary disease (COPD), or upper airway obstruction, patients with decreased respiratory reserve or in patients with significant respiratory depression due to potential additive affects.

Acetaminophen has the potential for overdose or poisoning causing acute liver failure, at times resulting in liver transplant and death. Most cases of liver injury are associated with the use of acetaminophen at doses exceeding 4 grams per day and often involve the use of more than one acetaminophen-containing product. Advise patients receiving acetaminophen to carefully read OTC and prescription labels, to avoid excessive and/or duplicate medications, and to seek medical help immediately if more than 4 grams of acetaminophen is ingested in 1 day, even if they feel well. It is important to note that the risk of acetaminophen-induced hepatotoxicity is increased in patients with pre-existing hepatic disease (e.g., hepatitis), those who ingest alcohol (e.g., ethanol intoxication, alcoholism), those with chronic malnutrition, and those with severe dehydration. In patients with chronic hepatic disease, acetaminophen can be used safely in recommended doses and is often preferred to nonsteroidal anti-inflammatory drugs (NSAIDs) due to the absence of platelet impairment, gastrointestinal toxicity, and nephrotoxicity. Though the half-life of acetaminophen may be prolonged, repeated dosing does not result in drug or metabolite accumulation. In addition, cytochrome P450 activity is not increased and glutathione stores are not depleted in hepatically impaired patients taking therapeutic doses, therefore toxic metabolite formation and accumulation is not altered. Although it is always prudent to use the smallest dose of acetaminophen for the shortest duration necessary, courses less than 2 weeks in length have been administered safely to adult patients with stable chronic liver disease. Further, patients with severe hepatic disease may experience increased toxicity and reduced analgesic effects from codeine. Codeine is primarily metabolized by the liver, and conversion to morphine is necessary for analgesic effects. Codeine may not be a good analgesic choice for patients with severe hepatic impairment. In acute situations, lower doses and/or less frequent dosing intervals may be needed. Carefully monitor patients for codeine efficacy and toxicity.

Because codeine is an opiate agonist, acetaminophen; codeine is subject to substance abuse and psychologic dependence (i.e., drug addiction) or criminal diversion. Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk for harm. Patients with a previous history of substance abuse may be at increased risk of relapse if treated with acetaminophen; codeine. Abuse and addiction are separate and distinct from physiologic dependence and tolerance. Physicians should be aware that psychologic dependence may not be accompanied by concurrent tolerance and symptoms of physiologic dependence. In addition, abuse of opiate agonists can occur in the absence of true psychologic dependence and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Health care professionals should not let concerns over psychologic dependence deter them from using adequate amounts of opiate agonists in the management of severe pain. Patients should also be counseled regarding misconceptions regarding the use of opiate agonists for pain management. Acetaminophen; codeine is not approved for the management of substance abuse (alcohol or drug dependence). The use of acetaminophen; codeine in patients with alcohol or drug dependence, either active or in remission, is for the treatment of pain requiring opiate agonist analgesia. Patients receiving opiate substitution therapy for opiate substance abuse will have increased tolerance to the analgesic effects of opiate agonists used for acute pain, and will require higher and more frequent dosing to control their pain. Opiate substitution therapy does not adequately treat pain.

Acetaminophen; codeine is classified as a FDA pregnancy risk category C drug. No adequate and well-controlled studies in pregnant women have been performed. Some experts suggest increased risk of codeine if used for prolonged periods or at high doses near term. Prolonged use of opioids, such as codeine, during pregnancy may cause neonatal opioid withdrawal syndrome (NOWS). This syndrome can be life-threatening. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the newborn for withdrawal symptoms including irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Higher doses and doses administered close to obstetric delivery may also increase the risk for respiratory depression in the newborn. Newborns of mothers who receive acetaminophen; codeine during labor or delivery should be observed for signs of respiratory depression. Opioid analgesics can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. This effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Acetaminophen; codeine should be avoided during labor if delivery of a premature newborn is expected. No overall increase in fetal mortality, as determined by pregnancy outcomes of mothers that overdosed on various amounts of acetaminophen, was apparent amongst 300 women. Treatment with acetylcysteine or methionine did not appear to affect fetal or neonatal toxicity. Of 235 babies exposed to an overdose of only acetaminophen, 168 were normal, 8 had malformations, 16 were spontaneously aborted, and 43 were electively terminated. Of 67 babies exposed to an overdose of a combination acetaminophen product, 51 were normal, 3 had malformations, 2 were spontaneously aborted (late fetal deaths), and 11 were electively terminated. None of the babies with malformations were exposed during the first trimester, but all of the spontaneous abortions and one of the late fetal deaths were subsequent to first trimester exposure.

Acetaminophen; codeine is contraindicated in neonates, infants, and children younger than 12 years and for postoperative pain management in pediatric patients younger than 18 years after a tonsillectomy and/or adenoidectomy. The American Academy of Pediatrics (AAP) recommends against the use of codeine in all pediatric patients for any indication. Avoid use in patients 12 to 18 years of age who have other risk factors for respiratory depression unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, respiratory infection, asthma, severe pulmonary disease, neuromuscular disease, and concomitant use of other respiratory depressants. When prescribing codeine for adolescents, choose the lowest effective dose for the shortest period of time and inform patients and caregivers of the risks and the signs of opioid overdose. Codeine metabolism is highly variable and unpredictable, particularly in children younger than 12 years; therapeutic response to recommended doses can range from lack of effect in poor metabolizers to fatality in ultra-rapid metabolizers. Ultra-rapid metabolizers are more likely to convert codeine to morphine quickly, leading to excessive morphine blood concentrations that can result in fatal respiratory depression. Because some children who are normal metabolizers can convert codeine to morphine at rates similar to ultra-metabolizers, this concern extends to all pediatric patients.

DEA CLASS

Rx, schedule III, schedule V

DESCRIPTION

Acetaminophen is a non-salicylate; codeine is an opiate agonist
Used for mild to moderate pain; combination produces additive analgesia
Codeine metabolism is highly variable and unpredictable; use in patients younger than 12 years is contraindicated

COMMON BRAND NAMES

Capital and Codeine, Tylenol with Codeine No.3, Tylenol with Codeine No.4

HOW SUPPLIED

Acetaminophen, Codeine Phosphate Oral Liq: 5mL, 120-12mg
Acetaminophen, Codeine Phosphate Oral Sol: 5mL, 120-12mg
Acetaminophen, Codeine Phosphate/Tylenol with Codeine No.3/Tylenol with Codeine No.4 Oral Tab: 300-15mg, 300-30mg, 300-60mg

DOSAGE & INDICATIONS

†Indicates off-label use

MAXIMUM DOSAGE

NOTE: For combination products containing acetaminophen, total daily intake of acetaminophen from all sources should be considered and may be the dose-limiting consideration for acetaminophen; codeine products.

DOSING CONSIDERATIONS

Dosage should be modified depending upon the clinical response and degree of hepatic impairment. No quantitative recommendations are available.

Dosage should be modified depending upon the clinical response and degree of renal impairment. No quantitative recommendations are available.

ADMINISTRATION

Administer with a full glass of water. May be taken with food or milk to minimize GI irritation.
Acetaminophen; codeine should be titrated to the dose required to relieve the patient’s pain keeping in mind the maximum daily dose of acetaminophen. Careful titration in opioid-naive patients is required until tolerance develops to some of the side effects (i.e., drowsiness, respiratory depression).

STORAGE

Generic:
– Store at controlled room temperature (between 68 and 77 degrees F)
Capital and Codeine:
– Store at controlled room temperature (between 68 and 77 degrees F)
Cocet:
– Store at controlled room temperature (between 68 and 77 degrees F)
Cocet Plus:
– Store at controlled room temperature (between 68 and 77 degrees F)
Tylenol with Codeine No.3:
– Store at controlled room temperature (between 68 and 77 degrees F)
Tylenol with Codeine No.4:
– Store at controlled room temperature (between 68 and 77 degrees F)

CONTRAINDICATIONS / PRECAUTIONS

NOTE: This monograph discusses the contraindications/precautions of acetaminophen; codeine combination products. Clinicians may wish to consult the individual monographs for more information about each agent.

Acetaminophen; codeine combinations are contraindicated in patients with known acetaminophen hypersensitivity. Acetaminophen hypersensitivity reactions are rare, but severe sensitivity reactions are possible. Although true opiate agonist hypersensitivity is rare, use of acetaminophen; codeine is contraindicated in patients who have demonstrated a prior codeine hypersensitivity reaction. Such patients should not receive other opioid agonists of the phenanthrene subclass including morphine, oxycodone, and hydromorphone. Use caution in patients with sulfite hypersensitivity, as some acetaminophen; codeine tablets contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible patients. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

Due to the effects of opiate agonists on the gastrointestinal tract, acetaminophen; codeine should be used cautiously in patients with GI disease including GI obstruction or ileus, ulcerative colitis, or pre-existing constipation. Opiate agonists may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Use acetaminophen; codeine with caution in patients who have or are suspected of having a paralytic ileus. Patients with acute ulcerative colitis or other inflammatory bowel disease may be more sensitive to the constipating effects of opiate agonists. Although opiate agonists may worsen systemic symptoms and/or lengthen disease course in cases of diarrhea secondary to poisoning or infectious diarrhea, antimotility agents have been used successfully in these patients. If possible, opiate agonists should not be given until the toxic substance has been eliminated.

As with other opioid agonists, products containing codeine should be avoided in patients with severe pulmonary disease. Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as this significantly increases the risk for respiratory depression, low blood pressure, and death. Acetaminophen; codeine should be used cautiously in patients with asthma. In addition, codeine should be avoided in patients with severe pulmonary disease such as acute or severe bronchial asthma, chronic obstructive pulmonary disease (COPD), or upper airway obstruction, patients with decreased respiratory reserve or in patients with significant respiratory depression due to potential additive affects.

Abrupt discontinuation of prolonged acetaminophen; codeine therapy can result in withdrawal symptoms (see Adverse Reactions). Patients should be gradually tapered off acetaminophen; codeine to avoid a withdrawal reaction. Generally, a 50% decrease every 1—2 days of the daily acetaminophen; codeine dose will prevent withdrawal symptoms in patients who have been receiving large daily doses of codeine.

Acetaminophen has the potential for overdose or poisoning causing acute liver failure, at times resulting in liver transplant and death. Most cases of liver injury are associated with the use of acetaminophen at doses exceeding 4 grams per day and often involve the use of more than one acetaminophen-containing product. Advise patients receiving acetaminophen to carefully read OTC and prescription labels, to avoid excessive and/or duplicate medications, and to seek medical help immediately if more than 4 grams of acetaminophen is ingested in 1 day, even if they feel well. It is important to note that the risk of acetaminophen-induced hepatotoxicity is increased in patients with pre-existing hepatic disease (e.g., hepatitis), those who ingest alcohol (e.g., ethanol intoxication, alcoholism), those with chronic malnutrition, and those with severe dehydration. In patients with chronic hepatic disease, acetaminophen can be used safely in recommended doses and is often preferred to nonsteroidal anti-inflammatory drugs (NSAIDs) due to the absence of platelet impairment, gastrointestinal toxicity, and nephrotoxicity. Though the half-life of acetaminophen may be prolonged, repeated dosing does not result in drug or metabolite accumulation. In addition, cytochrome P450 activity is not increased and glutathione stores are not depleted in hepatically impaired patients taking therapeutic doses, therefore toxic metabolite formation and accumulation is not altered. Although it is always prudent to use the smallest dose of acetaminophen for the shortest duration necessary, courses less than 2 weeks in length have been administered safely to adult patients with stable chronic liver disease. Further, patients with severe hepatic disease may experience increased toxicity and reduced analgesic effects from codeine. Codeine is primarily metabolized by the liver, and conversion to morphine is necessary for analgesic effects. Codeine may not be a good analgesic choice for patients with severe hepatic impairment. In acute situations, lower doses and/or less frequent dosing intervals may be needed. Carefully monitor patients for codeine efficacy and toxicity.

Because codeine is an opiate agonist, acetaminophen; codeine is subject to substance abuse and psychologic dependence (i.e., drug addiction) or criminal diversion. Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk for harm. Patients with a previous history of substance abuse may be at increased risk of relapse if treated with acetaminophen; codeine. Abuse and addiction are separate and distinct from physiologic dependence and tolerance. Physicians should be aware that psychologic dependence may not be accompanied by concurrent tolerance and symptoms of physiologic dependence. In addition, abuse of opiate agonists can occur in the absence of true psychologic dependence and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Health care professionals should not let concerns over psychologic dependence deter them from using adequate amounts of opiate agonists in the management of severe pain. Patients should also be counseled regarding misconceptions regarding the use of opiate agonists for pain management. Acetaminophen; codeine is not approved for the management of substance abuse (alcohol or drug dependence). The use of acetaminophen; codeine in patients with alcohol or drug dependence, either active or in remission, is for the treatment of pain requiring opiate agonist analgesia. Patients receiving opiate substitution therapy for opiate substance abuse will have increased tolerance to the analgesic effects of opiate agonists used for acute pain, and will require higher and more frequent dosing to control their pain. Opiate substitution therapy does not adequately treat pain.

Patients with head trauma or with increased intracranial pressure should be given acetaminophen; codeine with extreme caution, because these drugs can make it difficult to evaluate neurologic parameters. Hypoventilation due to the codeine component can produce cerebral hypoxia and raise CSF pressure, exaggerating the injury.

Opiate agonists, such as codeine, produce cholinergic side effects (by stimulating medullary vagal nuclei) causing bradycardia and vasovagal syncope, and induce the release of histamine, causing peripheral vasodilatation and orthostatic hypotension. These effects can cause problems in patients with cardiac disease. Acetaminophen; codeine should be used with caution in patients with cardiac arrhythmias, hypotension, or hypovolemia.

Acetaminophen; codeine is classified as a FDA pregnancy risk category C drug. No adequate and well-controlled studies in pregnant women have been performed. Some experts suggest increased risk of codeine if used for prolonged periods or at high doses near term. Prolonged use of opioids, such as codeine, during pregnancy may cause neonatal opioid withdrawal syndrome (NOWS). This syndrome can be life-threatening. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the newborn for withdrawal symptoms including irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Higher doses and doses administered close to obstetric delivery may also increase the risk for respiratory depression in the newborn. Newborns of mothers who receive acetaminophen; codeine during labor or delivery should be observed for signs of respiratory depression. Opioid analgesics can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. This effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Acetaminophen; codeine should be avoided during labor if delivery of a premature newborn is expected. No overall increase in fetal mortality, as determined by pregnancy outcomes of mothers that overdosed on various amounts of acetaminophen, was apparent amongst 300 women. Treatment with acetylcysteine or methionine did not appear to affect fetal or neonatal toxicity. Of 235 babies exposed to an overdose of only acetaminophen, 168 were normal, 8 had malformations, 16 were spontaneously aborted, and 43 were electively terminated. Of 67 babies exposed to an overdose of a combination acetaminophen product, 51 were normal, 3 had malformations, 2 were spontaneously aborted (late fetal deaths), and 11 were electively terminated. None of the babies with malformations were exposed during the first trimester, but all of the spontaneous abortions and one of the late fetal deaths were subsequent to first trimester exposure.

Breast-feeding is not recommended when taking acetaminophen; codeine due to the risk of serious adverse reactions including excessive sedation and respiratory depression in the breastfed infant. If an infant is exposed to codeine through breast milk, they should be monitored for excessive sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal use of an opioid is stopped or when breast-feeding is stopped. Alternative analgesics that previous American Academy of Pediatrics recommendations considered as usually compatible with breast-feeding include acetaminophen, ibuprofen, and morphine. There is no information on the effects of codeine on milk production. Codeine and its active metabolite, morphine, are excreted into human milk. An infant nursing from an ultra-rapid metabolizer mother taking codeine could potentially be exposed to high metabolite concentrations and experience life-threatening respiratory depression. At least one death has been reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent.

Codeine can cause urinary retention and oliguria, due to increasing the tension of the detrusor muscle. Patients more prone to these effects include those with prostatic hypertrophy, urethral stricture, bladder obstruction or pelvic tumors. Drug accumulation or prolonged duration of action can occur in patients with renal impairment, renal failure, or renal disease. Three patients, a 25-year-old male, a 65-year-old woman, and a 75-year-old male, with normal hepatic function and chronic renal failure (on hemodialysis) developed narcosis a few days after getting codeine 60 mg up to 4 times a day. In addition, chronic acetaminophen administration should be avoided in patients with underlying renal disease; however it may be used for episodic pain. In acute situations, patients require close monitoring to avoid excessive toxicity. Patients with renal impairment may require lower doses and/or less frequent dosing intervals.

Geriatric patients are more sensitive to adverse reactions from opiate agonists such as codeine; especially sedation and respiratory depression probably as a result of altered distribution of the drug and decreased elimination. Initial doses of opiate agonists may need to be reduced and doses should be carefully titrated taking into account analgesic effects and adverse reactions. According to the Beers Criteria, opiate agonists are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these populations, with the exception of pain management due to recent fractures or joint replacement, since opiates can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an opiate must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk.

Acetaminophen; codeine is contraindicated in neonates, infants, and children younger than 12 years and for postoperative pain management in pediatric patients younger than 18 years after a tonsillectomy and/or adenoidectomy. The American Academy of Pediatrics (AAP) recommends against the use of codeine in all pediatric patients for any indication. Avoid use in patients 12 to 18 years of age who have other risk factors for respiratory depression unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, respiratory infection, asthma, severe pulmonary disease, neuromuscular disease, and concomitant use of other respiratory depressants. When prescribing codeine for adolescents, choose the lowest effective dose for the shortest period of time and inform patients and caregivers of the risks and the signs of opioid overdose. Codeine metabolism is highly variable and unpredictable, particularly in children younger than 12 years; therapeutic response to recommended doses can range from lack of effect in poor metabolizers to fatality in ultra-rapid metabolizers. Ultra-rapid metabolizers are more likely to convert codeine to morphine quickly, leading to excessive morphine blood concentrations that can result in fatal respiratory depression. Because some children who are normal metabolizers can convert codeine to morphine at rates similar to ultra-metabolizers, this concern extends to all pediatric patients.

Patients with G6PD deficiency who overdose with acetaminophen; codeine may be at increased risk for drug-induced hemolysis due to the acetaminophen component. During acetaminophen overdose, cyanosis may not be apparent in patients with pre-existing anemia, in spite of dangerously high blood concentrations of methemoglobin.

Symptoms of acute infection (e.g., fever, pain) can be masked during treatment with acetaminophen; codeine in patients who have bone marrow suppression or immunosuppression.

Any patient receiving acetaminophen; codeine should be warned about the possibility of sedation and to use caution when driving or operating machinery.

When prescribing codeine-containing products, consider the race-related prevalence of altered codeine metabolism, including that of Asian patients, Black patients, Caucasian patients, Hispanic patients, and Middle Eastern patients. Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6 genotype (gene duplications noted as *1/*1xN or *1/*2xN). People who are ultra-rapid metabolizers should not use codeine-containing products. Ultra-rapid metabolizers convert codeine into morphine more rapidly and completely than other people. Higher than expected serum morphine concentrations occur due to the rapid conversion and serious toxicity, including life-threatening or fatal respiratory depression, may occur. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1% to 10% in Caucasians, 3% to 4% in Blacks (African Americans), 1% to 2% in East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (e.g., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). In contrast, patients who are poor metabolizers of CYP2D6 may not adequately convert codeine to morphine and may not experience the expected therapeutic response to codeine. Approximately 7% to 10% of the Caucasian population lacks functional CYP2D6 activity.

Use codeine with caution in patients with adrenal insufficiency (i.e., Addison’s disease), hypothyroidism, or myxedema. Such patients may be at increased risk of adverse events. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH); however, the thyroid stimulating hormone may be either stimulated or inhibited by opioids. Rarely, adrenal insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency. In addition, chronic opioid use may lead to symptoms of hypogonadism, resulting from changes in the hypothalamic-pituitary-gonadal axis. Monitor patients for symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.

Use of codeine is contraindicated in patients who are receiving or who have received MAOI therapy within the past 14 days. Additive CNS depression, drowsiness, dizziness, or hypotension may occur.

Accidental exposure to acetaminophen; codeine, especially by children, can result in respiratory depression and death due to overdose of codeine. Keep out of the reach of children. Instruct patients to store their medication securely and properly dispose of unused drug in accordance with local state guidelines and/or regulations.