Acetaminophen and Codeine Phosphate

Tablets, USP CIII · Bryant Ranch Prepack

Dosage Form

Tablets, USP CIII

Manufacturer

Bryant Ranch Prepack

Important Safety Information

This medication contains important usage instructions, warnings, and side effect information that you should review before use.

Full label on DailyMed PDF Full label (ZIP)

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF ACETAMINOPHEN AND CODEINE PHOSPHATE TABLETS

Addiction, Abuse and Misuse

Because the use of Acetaminophen and codeine phosphate tablets exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing acetaminophen and codeine phosphate tablets, and monitor all patients regularly for the development of these behaviors and conditions [see WARNINGS].

Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of acetaminophen and codeine phosphate tablets, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Acetaminophen and codeine phosphate are essential [see Warnings].
Accidental Ingestion
Accidental ingestion of even one dose of Acetaminophen and codeine phosphate tablets, especially by children, can result in a fatal overdose of acetaminophen and codeine phosphate [see WARNINGS]

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of acetaminophen and codeine phosphate tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings, Drug Interactions].

Neonatal Opioid Withdrawal Syndrome (NOWS)
If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings].

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS):
Healthcare providers are strongly encouraged to complete a REMS compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings].

Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of acetaminophen and codeine phosphate tablets. Monitor for respiratory depression, especially during initiation of acetaminophen and codeine phosphate tablets or following a dosage increase [see WARNINGS].

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life- Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy and many of the children had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism [see WARNINGS, PRECAUTIONS; Information for Patients/Caregivers, Nursing Mothers]. Acetaminophen and codeine phosphate tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (see CONTRAINDICATIONS). Avoid the use of acetaminophen and codeine phosphate tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes
The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with acetaminophen and codeine phosphate tablets requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. (see WARNINGS, PRECAUTIONS: DRUG INTERACTIONS)

Hepatotoxicity
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated

Acetaminophen and codeine phosphate tablets are indicated for the management of mild to moderate pain,where treatment with an opioid is appropriate and for which alternative treatments are inadequate.

Limitations of Use

Because of the risks of addiction, abuse, and misuse, with opioids, which can occur at any dosage or duration [see WARNINGS], reserve acetaminophen and codeine phosphate tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]

· Have not been tolerated or are not expected to be tolerated.

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

Acetaminophen and codeine phosphate tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate

Important Dosage and Administration Instructions

Acetaminophen and codeine phosphate tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Acetaminophen and codeine phosphate tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.

There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings].

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Acetaminophen and codeine phosphate tablets]. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings].

Initial Dosage

Use of Acetaminophen and Codeine Phosphate Tablets as the First Opioid AnalgesicInitiate treatment with Acetaminophen and Codeine Phosphate Tablets in a dosing range of 300 mg to 600 mg of acetaminophen and 30 mg to 60 mg of codeine phosphate every 4 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Acetaminophen and Codeine Phosphate Tablets.

The usual adult dosage is:

Acetaminophen and Codeine P hosphate Tablets (codeine 30 mg and acetaminophen 300 mg): Take 1 to 2 tablets every 4 hours as needed for pain.

Acetaminophen and Codeine Phosphate Tablets (codeine 60 mg and acetaminophen 300 mg): Take one tablet every 4 hours as needed for pain.

	Single Doses (Range)	Maximum 24-Hour Dose
Codeine Phosphate	15 mg to 60 mg	360 mg
Acetaminophen	300 mg to 1,000 mg	4,000 mg

The prescriber must determine the number of tablets per dose, and the maximum number of tablets per 24 hours, based upon the above dosage guidance. This information should be conveyed in the prescription.

Conversion from Other Opioids to Acetaminophen and Codeine Phosphate Tablets

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of acetaminophen and codeine phosphate tablets. It is safer to underestimate a patient’s 24-hour acetaminophen and codeine phosphate tablets dosage than to overestimate the 24-hour acetaminophen and codeine phosphate tablets dosage and manage an adverse reaction due to overdose.

Titration and Maintenance of Therapy

Individually titrate acetaminophen and codeine phosphate tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving acetaminophen and codeine phosphate tablets to assess the maintenance of pain control signs and symptoms of opioid withdrawal, and other adverse reactions, as well as reassessing for the development of addiction, abuse, or misuse [see WARNINGS ]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the acetaminophen and codeine phosphate tablets dosage. If after increasing the dosage unacceptable opioid-related adverse reactions are observed, (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Safe Reduction and Discontinuation of acetaminophen and codeine phosphate tablets

Do not abruptly discontinue acetaminophen and codeine phosphate tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking acetaminophen and codeine phosphate tablets there are a variety of factors that should be considered, including the total daily dose of opioid (including acetaminophen and codeine phosphate tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on acetaminophen and codeine phosphate tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see WARNINGS/ Withdrawal, DRUG ABUSE AND DEPENDENCE].

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]
• Opioid-Induced Hyperalgesia and Allodynia [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 use of opioids for an extended period of time [see Clinical Pharmacology].
· Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings].
· Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800 FDA-1088 or www.fda.gov/medwatch.

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

Clinical Presentation

Codeine

Acute overdosage with codeine can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Acetaminophen

Dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect of acetaminophen overdose. Renal tubular necrosis, hypoglycemic coma, and coagulation defects may also occur.

Early symptoms following a potentially hepatotoxic overdose may include; anorexia, nausea, vomiting, diaphoresis, pallor and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.

Treatment of Overdose

Codeine

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or serious arrhythmias will require advanced life-support measures.

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

Because the duration of opioid reversal is expected to be less than the duration of action of codeine in acetaminophen and codeine phosphate tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

Acetaminophen

Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation.

Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, (NAC) should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose-dependent and occurs early in the course of intoxication.

MEDICATION GUIDE
Acetaminophen and Codeine Phosphate Tablets(ass-cet-ah-MEE-noe-fen with KOE-deen FOSS-fate), USP CIII

Acetaminophen and Codeine Phosphate Tablets are:

A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage mild to moderate pain, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

Important information about Acetaminophen and Codeine Phosphate Tablets:

Get emergency help or call 911 right away if you take too much acetaminophen and codeine phosphate tablets (overdose). When you first start taking acetaminophen and codeine tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.
Taking acetaminophen and codeine tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems coma and death
Never give anyone else your acetaminophen and codeine phosphate tablets. They could die from taking it. Selling or giving away acetaminophen and codeine phosphate tablets are against the law.
Store acetaminophen and codeine phosphate tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

Important Information Guiding Use in Pediatric Patients:

Do not give acetaminophen and codeine phosphate tablets to a child younger than 12 years of age.
Do not give acetaminophen and codeine phosphate tablets to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids.
Avoid giving acetaminophen and codeine phosphate tablets to children between 12 to 18 years of age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems.

Do not take Acetaminophen and Codeine Phosphate Tablets if you have:

severe asthma, trouble breathing, or other lung problems.
a bowel blockage or narrowing of the stomach or intestines.
previously had an allergic reaction to codeine or acetaminophen.

Before taking acetaminophen and codeine phosphate tablets, tell your healthcare provider if you have a history of:

head injury, seizures
liver, kidney, thyroid problems
problems urinating
pancreas or gallbladder problems
abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.
Have been told by your healthcare provider that you are a “rapid metabolizer” of certain medicines.

Tell your healthcare provider if you are:

noticing your pain getting worse. If your pain gets worse after you take Acetaminophen and codeine phosphate tablets, do not take more of Acetaminophen and codeine phosphate tablets without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking Acetaminophen and codeine phosphate tablets.
pregnant or planning to become pregnant. Use of acetaminophen and codeine phosphate tablets for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
breastfeeding. Not recommended; may harm your baby.Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs.
living in a household where there are small children or someone who has abused street or prescription drugs.
Taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Acetaminophen and codeine phosphate tablets with certain other medicines can cause serious side effects that could lead to death.

When taking Acetaminophen and Codeine Phosphate Tablets:

Do not change your dose. Take acetaminophen and Codeine Phosphate Tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
For acute (short-term) pain, you may only need to take Acetaminophen and codeine phosphate tablets for a few days. You may have some Acetaminophen and codeine phosphate tablets left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) unused Acetaminophen and codeine phosphate tablets.
Take your prescribed dose every 4 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose when needed.
Call your healthcare provider if the dose you are taking does not control your pain.
If you have been taking acetaminophen and codeine phosphate tablets regularly, do not stop taking acetaminophen and codeine Phosphate Tablets without talking to your healthcare provider.
Dispose of expired, unwanted, or unused acetaminophen and codeine phosphate tablets by taking your drug to an authorized DEA-registered collector or drug take-back program. If one is not available, you can dispose of acetaminophen and codeine phosphate tablets by mixing the product with dirt, cat litter, or coffee grounds; placing the mixture in a sealed plastic bag, and throwing the bag in your trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

While taking Acetaminophen and Codeine phosphate Tablets DO NOT:

Drive or operate heavy machinery, until you know how acetaminophen and codeine phosphate tablets affect you. Acetaminophen and codeine phosphate tablets can make you sleepy, dizzy, or lightheaded.
Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with acetaminophen and codeine phosphate tablets may cause you to overdose and die.

The possible side effects of Acetaminophen and Codeine Tablets:

Constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help or call 911 right away if you have:
· trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.
These are not all the possible side effects of acetaminophen and codeine phosphate tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov.

This Medication Guide has been approved by the U.S. Food and Drug Administration.
Dispense with Medication Guide available at https://www.aurobindousa.com/medication-guides/

Distributed by:
Aurobindo Pharma USA, Inc.
279 Princeton-Hightstown Road
East Windsor, NJ 08520

Revised: 12/2023

What it looks like

Photos of the product and/or packaging supplied by the manufacturer.

Package codes (NDC)

71335-0336-0
71335-0336-1
71335-0336-2
71335-0336-3
71335-0336-4
71335-0336-5
71335-0336-6
71335-0336-7
71335-0336-8
71335-0336-9

Full prescribing information (for healthcare professionals)

CLINICAL PHARMACOLOGY

Mechanism of Action
Codeine is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of codeine have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.
The precise mechanism of the analgesic properties of acetaminophen is not established but is thought to involve central actions.

Pharmacodynamics

Effects on the Central Nervous System
Codeine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.
Codeine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle
Codeine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System
Codeine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see ADVERSE REACTIONS ]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see ADVERSE REACTIONS ].

Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of codeine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see DOSAGE AND ADMINISTRATION ].

Concentration–Adverse Reaction Relationships
There is a relationship between increasing codeine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see DOSAGE AND ADMINISTRATION ].

Pharmacokinetics
The behavior of the individual components is described below.

Codeine
Codeine is rapidly absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen, and kidney. Codeine crosses the blood-brain barrier and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain. Codeine is about 7-25% bound to plasma proteins and does not accumulate in body tissues.

About 70 to 80% of the administered dose of codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (C6G) and via O-demethylation to morphine (about 5 to 10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucuronidation of codeine to C6G. Cytochrome P450 2D6 is the major enzyme responsible for conversion of codeine to morphine and P450 3A4 is the major enzyme mediating conversion of codeine to norcodeine. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Morphine and M6G are known to have analgesic activity in humans. The analgesic activity of C6G in humans is unknown. Norcodeine and M3G are generally not considered to possess analgesic properties.

The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces.

At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours.

Acetaminophen
Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. A small fraction (10-25%) of acetaminophen is bound to plasma proteins. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation via the cytochrome, P450-dependent, mixed- function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug.

See OVERDOSAGE for toxicity information.

Sign up for full access

Create a free account to view complete drug information, save medications, and more.

Full drug information and details

Save medications to your personal list

Track your medication history

Get personalized drug safety alerts

Create Free Account Sign In

Free forever · No credit card required

Important Safety Information

Serious warning (boxed)Boxed warningThe FDA's most prominent safety warning.

What this medicine is forThe uses this medicine is approved for.

How to take itDosage and administration instructions.Important Dosage and Administration Instructions Acetaminophen and codeine phosphate tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the as…

Do not use if…Contraindications.Acetaminophen and codeine phosphate tablets are contraindicated for: All children younger than 12 years of age (see WARNINGS ). Post-operative management in children younger than 18 years of age following tonsillectomy a…

Possible side effectsThe 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 no…

If you take too much (overdose)Following an acute overdosage, toxicity may result from codeine or acetaminophen. Clinical Presentation Codeine Acute overdosage with codeine can be manifested by respiratory depression, somnolence progressing to stupor…

Medication GuideMEDICATION GUIDE Acetaminophen and Codeine Phosphate Tablets(ass-cet-ah-MEE-noe-fen with KOE-deen FOSS-fate), USP CIII Acetaminophen and Codeine Phosphate Tablets are: A strong prescription pain medicine that contains an…

What's in this medicineAcetaminophen and codeine phosphate tablets, USP are for oral administration. Acetaminophen, 4’-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and an…

Package labelAcetaminophen and Codeine Phosphate Tablets 300 mg/60 mg (CIII)

How it's suppliedAcetaminophen and codeine phosphate tablets, USP are supplied as follows: 300 mg/60 mg White to off-white, round, flat-faced, beveled-edged tablets, debossed with “U37” on one side and plain on the other side. NDC: 71335…

What it looks like

Package codes (NDC)

CLINICAL PHARMACOLOGY

Sign up for full access