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RedPharm Drug, Inc.
Dosage Form
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Manufacturer
RedPharm Drug, Inc.
This medication contains important usage instructions, warnings, and side effect information that you should review before use.
BOXED WARNING
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE; HEPATOTOXICITY; CYTOCHROME P450 2D6 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Addiction, Abuse, and Misuse
Acetaminophen and Codeine Phosphate Tablets expose 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. Monitor for respiratory depression, especially during initiation of acetaminophen and codeine phosphate tablets or following a dose increase [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 tablets [see WARNINGS].
Neonatal Opioid Withdrawal Syndrome
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, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see WARNINGS].
Death Related to Ultra-Rapid Metabolism of Codeine to Morphine
Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism [see WARNINGS, PRECAUTIONS; Information for Patients/Caregivers, Nursing mothers].
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 with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product [see WARNINGS].
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.
Cytochrome P450 3A4 Interaction
The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all cytochrome P450 3A4 inhibitors or discontinuation of a cytochrome P450 3A4 inducer may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.
The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal.
Follow patients receiving Acetaminophen and Codeine Phosphate Tablets and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Acetaminophen and Codeine Phosphate Tablets is used in conjunction with inhibitors and inducers of CYP3A4 [see Warnings, Precautions, Drug Interactions].
Cytochrome P450 2D6 Interaction
The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all cytochrome P450 2D6 inhibitors may result in an increase in codeine plasma concentrations and a decrease in the plasma concentration of the active metabolite, morphine, which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal.
The discontinuation of a cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentrations and an increase in the plasma concentration of the active metabolite, morphine, which could which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.
Follow patients receiving Acetaminophen and Codeine Phosphate Tablets and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Acetaminophen and Codeine Phosphate Tablets are used in conjunction with inhibitors of CYP2D6 [see WARNINGS,PRECAUTIONS, DRUG INTERACTIONS].
Risks from concomitant use with Benzodiazepines or other CNS Depressants
Concomitant use of opiods with benzodiazepines or other central nervous system (CNS) depressants including alcohol, may result in profound sedation, respiratory depression, coma, and death. [see WARNINGS,PRECAUTIONS; Drug interactions]
• 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.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.
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, even at recommended doses [see WARNINGS], reserve acetaminophen and codeine phosphate tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]
Have not provided adequate analgesia, or are not expected to provide adequate analgesia
Have not been tolerated, or are not expected to be tolerated
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [seeWARNINGS].
Important Dosage and Administration Instructions
Initiate the dosing regimen for each patient individually; taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see WARNINGS].
Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with acetaminophen and codeine phosphate tablets and adjust the dosage accordingly [see WARNINGS].
Initial Dosage
Initiating Treatment with Acetaminophen and Codeine Phosphate Tablets
Dosage should be adjusted according to severity of pain and response of the patient. However, it should be kept in mind that tolerance to codeine can develop with continued use and that the incidence of untoward effects is dose related. Adult doses of codeine higher than 60 mg are associated with an increased incidence of adverse reactions and are not associated with greater efficacy.
The usual adult dosage is:
Acetaminophen and Codeine Phosphate Tablets (codeine 15 mg and acetaminophen 300 mg): Take 1 to 2 tablets every 4 hours as needed for pain.
Acetaminophen and Codeine Phosphate 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 1000 mg
4000 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.
The usual dose of codeine phosphate in children is 0.5 mg/kg. Doses may be repeated up to every 4 hours.
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.
Initiating Treatment with Acetaminophen and Codeine Phosphate Tablets
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.
It should be kept in mind, however, that tolerance to codeine can develop with continued use and that the incidence of untoward effects is dose related. Adult doses of codeine higher than 60 mg fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciably increased incidence of undesirable side effects. Equivalently high doses in children would have similar effects.
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 and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [seeWARNINGS]. 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 unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
Discontinuation of acetaminophen and codeine phosphate tablets
When a patient who has been taking acetaminophen and codeine phosphate tablets regularly and may be physically dependent no longer requires therapy with acetaminophen and codeine phosphate tablets,taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Acetaminophen and Codeine Phosphate Tablets in a physically-dependent patient [see WARNINGS, DRUG ABUSE AND DEPENDENCE].
Acetaminophen and codeine phosphate tablets are contraindicated in patients with:
Patients with significant respiratory depression [see WARNINGS].
Patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS].
Postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy [see WARNINGS].
Patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS].
Patients with hypersensitivity to codeine, acetaminophen, or any of the formulation excipients. (e.g., anaphylaxis) [see WARNINGS].
Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.
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 [seeWARNINGS]
• Gastrointestinal Adverse Reactions [see WARNINGS]
• Seizures [see WARNINGS]
• Withdrawal [see WARNINGS]
Serious adverse reactions associated with codeine are respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.
The most frequently observed adverse reactions with codeine administration include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation.
Other adverse reactions include allergic reactions, euphoria, dysphoria, constipation, abdominal pain, pruritus, rash, thrombocytopenia, and agranulocytosis.
Cardiovascular system: faintness, flushing, hypotension, palpitations, syncope
Digestive System: abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis
Nervous system: anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness
Skin and Appendages: rash, sweating, urticarial
• Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
• Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
• Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Acetaminophen and Codeine Phosphate Tablets.
• Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY].
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, 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 acetminophen. 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
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 arrhythmias will require advanced life-support measures.
The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to acetaminophen and codeine phosphate tablets overdose, administer an opioid antagonist. In patients who are physically dependent on any opioid agonist including Acetaminophen and Codeine Phosphate Tablets, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.
Because the duration of opioid reversal is expected to be less than the duration of action of acetaminophen and codeine phosphate in acetaminophen and codeine phosphate tablets, carefully monitor the patient until spontaneous respiration is reliably re-established. 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.
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
Acetaminophenand Codeine Phosphate Tablets, USP CIII
ass-cet-ah-MEE-noe-fenwith KOE-deen FOSS-fate
Acetaminophen and Codeine PhosphateTablets 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 codeinephosphate tablets:
Get emergency help right away if you take too much acetaminophen and codeine phosphate tablets (overdose). When you first start taking acetaminophen and codeine phosphate 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.
Acetaminophen and Codeine Phosphate Tablets can cause severe drowsiness, breathing problems (respiratory depression), coma and death when taken with benzodiazepines or other medicines that depress consciousness.
Never give anyone else your acetaminophen and codeine phosphate tablets. They could die from taking it. Store acetaminophen and codeine phosphate tablets away from children and in a safe place to prevent stealing or abuse. Selling or giving away acetaminophen and codeine phosphate tablets are against the law.
Do not take Acetaminophen and Codeine Phosphate Tablets ifyou 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 phosphatetablets, tell your healthcare providerif 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, or mental health problems.
Tell your healthcare provider if you are:
pregnant or planning to become pregnant. Prolonged use of acetaminophen and codeine phosphate tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
breastfeeding. acetaminophen and codeine phosphate passes into breast milk and may harm your baby.
taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking 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.
•Take your prescribed dose every 4 hours as needed. 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.
•After you stop taking Acetaminophen and Codeine Phosphate Tablets, to properly dispose of the Acetaminophen and Codeine Phosphate Tablets flush it down the toilet or dispose of in accordance with local state guidelines and/or regulations.
While taking acetaminophen and codeine phosphate tabletsDO NOT:
Drive or operate heavy machinery, until you know howacetaminophen and codeine phosphate tablets affects 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 phosphatetablets:
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 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 allthe possible side effects of acetaminophen and codeine phosphate tablets. Callyour doctor for medical advice about side effects. You may also request medicalinformation or to report suspected adverse reactions, contact Aurobindo PharmaUSA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088. For more information go todailymed.nlm.nih.gov
What are the ingredients in Acetaminophen and CodeinePhosphate Tablets?
Active Ingredients: acetaminophenand codeine phosphate
Inactive ingredients:colloidal silicon dioxide, croscarmellose sodium,crospovidone, magnesium stearate, microcrystalline cellulose, povidone,pregelatinized starch, sodium lauryl sulfate, and stearicacid
This Medication Guide has beenapproved by the U.S. Food and Drug Administration.
Manufacturedby:
Aurolife Pharma LLC
Dayton, NJ 08810
Manufacturedfor:
Aurobindo Pharma USA, Inc.
Dayton, NJ 08810
Revised: 12/2016
Acetaminophen 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 antipyretic. It has the following structural formula:
[chemical structure]
Codeine phosphate, 7,8-didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate, a white crystalline powder, is a narcotic analgesic and antitussive. It has the following structural formula:
[chemical structure]
Each tablet contains:
Acetaminophen............................300 mg
Codeine Phosphate........................15 mg
(Warning: May be habit forming)
OR
Acetaminophen............................300 mg
Codeine Phosphate........................30 mg
(Warning: May be habit forming)
OR
Acetaminophen............................300 mg
Codeine Phosphate........................60 mg
(Warning: May be habit forming)
In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, sodium lauryl sulfate, and stearic acid.
[image: img_5c3cda15-c9a0-c942-e053-2a91aa0af8b6] [image: img_50e99899-b78f-5855-e054-00144ff88e88]
Acetaminophen and codeine phosphate tablets, USP are supplied as follows:
300 mg/15 mg
White to off-white, round, flat-faced, beveled-edged tablets, debossed with “U35” on one side and plain on the other side.
Bottles of 30 NDC 13107-058-30
Bottles of 100 NDC 13107-058-01
Bottles of 500 NDC 13107-058-05
Bottles of 1000 NDC 13107-058-99
300 mg/30 mg
White to off-white, round, flat-faced, beveled-edged tablets, debossed with “U36” on one side and plain on the other side.
Bottles of 30 NDC 13107-059-30
Bottles of 100 NDC 13107-059-01
Bottles of 500 NDC 13107-059-05
Bottles of 1000 NDC 13107-059-99
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.
Bottles of 30 NDC 13107-060-30
Bottles of 100 NDC 13107-060-01
Bottles of 500 NDC 13107-060-05
Bottles of 1000 NDC 13107-060-99
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Keep this and all medication out of the reach of children.
Protect from moisture. Dispense in a tight, light-resistant container as described in the USP.
PROTECT FROM LIGHT
Dispense with Medication Guide availableat www.aurobindousa.com/product-medication-guides
Manufactured by:
Aurolife Pharma LLC
Dayton, NJ 08810
Manufactured for:
Aurobindo Pharma USA, Inc.
Dayton, NJ 08810
Revised: 12/2016
LM 2126
Photos of the product and/or packaging supplied by the manufacturer.
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.
Chronic use of opioids 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 potent agonist opioids. 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 readily 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; however, 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 glucurodination 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.
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