Acetaminophen and codeine

Name: Acetaminophen and codeine

What should I discuss with my healthcare provider before taking acetaminophen and codeine?

You should not use this medicine if you are allergic to acetaminophen or codeine, or if you have recently used alcohol, sedatives, tranquilizers, or other narcotic medications.

Do not use this medicine if you have taken an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, phenelzine, rasagiline, selegiline, and tranylcypromine.

In some people, codeine breaks down rapidly in the liver and reaches higher than normal levels in the body. This can cause dangerously slow breathing and may cause death, especially in a child.

Acetaminophen and codeine should not be given to a child younger than 12 years old.

Do not give this medicine to anyone younger than 18 years old who recently had surgery to remove the tonsils or adenoids.

Do not breast-feed while taking acetaminophen and codeine. This medicine can pass into breast milk and cause drowsiness, breathing problems, or death in a nursing baby.

To make sure this medicine is safe for you, tell your doctor if you have ever had :

  • liver disease, cirrhosis, or if you drink alcohol;

  • alcoholism or drug addiction;

  • diarrhea, inflammatory bowel disease, bowel obstruction;

  • kidney disease;

  • a head injury, brain tumor, or stroke;

  • asthma, sleep apnea, or other breathing disorders; or

  • if you use a sedative like Valium (diazepam, alprazolam, lorazepam, Ativan, Klonopin, Restoril, Tranxene, Versed, Xanax, and others).

If you use this medicine while you are pregnant, your baby could become dependent on the drug. This can cause life-threatening withdrawal symptoms in the baby after it is born. Babies born dependent on habit-forming medicine may need medical treatment for several weeks. Tell your doctor if you are pregnant or plan to become pregnant.

Commonly used brand name(s)

In the U.S.

  • APAP w/Codeine
  • Capital w/Codeine
  • Pyregesic-C
  • Tylenol w/Codeine
  • Tylenol w/Codeine #3
  • Tylenol w/Codeine #4
  • Tylenol with Codeine No. 3
  • Vopac

Available Dosage Forms:

  • Tablet
  • Capsule
  • Elixir
  • Suspension
  • Solution

Therapeutic Class: Opioid/Acetaminophen Combination

Chemical Class: Codeine

Before Using acetaminophen and codeine

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For acetaminophen and codeine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to acetaminophen and codeine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of acetaminophen and codeine oral suspension in children younger than 3 years of age. Safety and efficacy have not been established.

No information is available on the relationship of age to the effects of acetaminophen and codeine tablets in the pediatric population. Safety and efficacy have not been established.

Tylenol® with codeine should not be used to relieve pain after surgery to remove tonsils and/or adenoids in any children. Severe breathing problems and deaths have been reported in some children who received codeine after tonsil or adenoid surgery.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of acetaminophen and codeine in the elderly. However, elderly patients are more likely to have age-related kidney or liver problems, which may require caution and an adjustment in the dose for patients receiving acetaminophen and codeine.

Pregnancy

Pregnancy Category Explanation
All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using acetaminophen and codeine.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking acetaminophen and codeine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using acetaminophen and codeine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

  • Furazolidone
  • Iproniazid
  • Isocarboxazid
  • Linezolid
  • Methylene Blue
  • Moclobemide
  • Nalmefene
  • Naltrexone
  • Nialamide
  • Phenelzine
  • Procarbazine
  • Rasagiline
  • Safinamide
  • Selegiline
  • Toloxatone
  • Tranylcypromine

Using acetaminophen and codeine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Acepromazine
  • Alfentanil
  • Almotriptan
  • Alprazolam
  • Amineptine
  • Amisulpride
  • Amitriptyline
  • Amitriptylinoxide
  • Amobarbital
  • Amoxapine
  • Amphetamine
  • Anileridine
  • Aripiprazole
  • Asenapine
  • Baclofen
  • Benperidol
  • Benzphetamine
  • Bromazepam
  • Bromopride
  • Brompheniramine
  • Buprenorphine
  • Bupropion
  • Buspirone
  • Butabarbital
  • Butorphanol
  • Carbamazepine
  • Carbinoxamine
  • Carisoprodol
  • Carphenazine
  • Chloral Hydrate
  • Chlordiazepoxide
  • Chlorpheniramine
  • Chlorpromazine
  • Chlorzoxazone
  • Citalopram
  • Clobazam
  • Clomipramine
  • Clonazepam
  • Clorazepate
  • Clozapine
  • Cocaine
  • Conivaptan
  • Cyclobenzaprine
  • Darunavir
  • Desipramine
  • Desmopressin
  • Dexmedetomidine
  • Dextroamphetamine
  • Dextromethorphan
  • Dezocine
  • Diazepam
  • Dibenzepin
  • Dichloralphenazone
  • Difenoxin
  • Dihydrocodeine
  • Diphenhydramine
  • Diphenoxylate
  • Dolasetron
  • Donepezil
  • Doxepin
  • Doxylamine
  • Droperidol
  • Duloxetine
  • Eletriptan
  • Enflurane
  • Escitalopram
  • Estazolam
  • Eszopiclone
  • Ethchlorvynol
  • Ethopropazine
  • Ethylmorphine
  • Fentanyl
  • Flibanserin
  • Fluoxetine
  • Fluphenazine
  • Flurazepam
  • Fluspirilene
  • Fluvoxamine
  • Fospropofol
  • Frovatriptan
  • Granisetron
  • Haloperidol
  • Halothane
  • Hexobarbital
  • Hydrocodone
  • Hydromorphone
  • Hydroxytryptophan
  • Hydroxyzine
  • Imatinib
  • Imipramine
  • Isoflurane
  • Isoniazid
  • Ketamine
  • Ketazolam
  • Ketobemidone
  • Levomilnacipran
  • Levorphanol
  • Lisdexamfetamine
  • Lithium
  • Lofepramine
  • Lorazepam
  • Lorcaserin
  • Loxapine
  • Meclizine
  • Melitracen
  • Melperone
  • Meperidine
  • Mephobarbital
  • Meprobamate
  • Meptazinol
  • Mesoridazine
  • Metaxalone
  • Methadone
  • Methamphetamine
  • Methdilazine
  • Methocarbamol
  • Methohexital
  • Methotrimeprazine
  • Midazolam
  • Milnacipran
  • Mirtazapine
  • Molindone
  • Moricizine
  • Morphine
  • Morphine Sulfate Liposome
  • Nalbuphine
  • Naratriptan
  • Nefazodone
  • Netupitant
  • Nicomorphine
  • Nitrazepam
  • Nitrous Oxide
  • Nortriptyline
  • Olanzapine
  • Ondansetron
  • Opipramol
  • Opium
  • Opium Alkaloids
  • Orphenadrine
  • Oxazepam
  • Oxycodone
  • Oxymorphone
  • Palonosetron
  • Papaveretum
  • Paregoric
  • Paroxetine
  • Pentazocine
  • Pentobarbital
  • Perampanel
  • Perazine
  • Periciazine
  • Perphenazine
  • Phenobarbital
  • Piperacetazine
  • Pipotiazine
  • Piritramide
  • Pixantrone
  • Pneumococcal 13-Valent Vaccine, Diphtheria Conjugate
  • Prazepam
  • Primidone
  • Prochlorperazine
  • Promazine
  • Promethazine
  • Propofol
  • Protriptyline
  • Quazepam
  • Quetiapine
  • Ramelteon
  • Remifentanil
  • Remoxipride
  • Rizatriptan
  • Secobarbital
  • Sertindole
  • Sertraline
  • Sibutramine
  • Sodium Oxybate
  • St John's Wort
  • Sufentanil
  • Sulpiride
  • Sumatriptan
  • Suvorexant
  • Tapentadol
  • Temazepam
  • Thiethylperazine
  • Thiopental
  • Thiopropazate
  • Thioridazine
  • Tianeptine
  • Tilidine
  • Tizanidine
  • Tolonium Chloride
  • Topiramate
  • Tramadol
  • Trazodone
  • Triazolam
  • Trifluoperazine
  • Trifluperidol
  • Triflupromazine
  • Trimeprazine
  • Trimipramine
  • Tryptophan
  • Venlafaxine
  • Vilazodone
  • Vortioxetine
  • Zaleplon
  • Ziprasidone
  • Zolmitriptan
  • Zolpidem
  • Zopiclone
  • Zotepine

Using acetaminophen and codeine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Acenocoumarol
  • Carbamazepine
  • Fosphenytoin
  • Lixisenatide
  • Phenytoin
  • Warfarin
  • Zidovudine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using acetaminophen and codeine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use acetaminophen and codeine, or give you special instructions about the use of food, alcohol, or tobacco.

  • Ethanol
  • Tobacco

Using acetaminophen and codeine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use acetaminophen and codeine, or give you special instructions about the use of food, alcohol, or tobacco.

  • Cabbage
  • Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of acetaminophen and codeine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Addison's disease (adrenal gland problem) or
  • Alcohol abuse, history of or
  • Brain tumor or
  • Breathing problems (eg, chronic obstructive pulmonary disease [COPD], cor pulmonale, hypoxia, sleep apnea, respiratory depression) or
  • CNS depression or
  • Drug abuse or dependence, or history of or
  • Enlarged prostate or
  • Head injuries or
  • Hypothyroidism (underactive thyroid) or
  • Increased pressure in the head or
  • Mental illness, history of or
  • Problems with passing urine or
  • Weakened physical condition—Use with caution. May increase risk for more serious side effects.
  • Allergy to sulfites or
  • Asthma—Tylenol® with codeine tablets contains sodium metabisulfite, which can cause allergic reactions in patients with these conditions.
  • Asthma, acute or severe or
  • Respiratory depression (serious breathing problem) or
  • Stomach or bowel blockage (eg, paralytic ileus) or
  • Surgery (eg, nasopharyngeal tonsils, tonsils)—Should not be used in patients with these conditions.
  • Kidney disease or
  • Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Acetaminophen and Codeine - 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.

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 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 to 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 to 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.

Adverse Reactions

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)

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, pruritis, 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 chronic use of opioids (see CLINICAL PHARMACOLOGY).

 

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Oral:

Generic: Acetaminophen 120 mg and codeine phosphate 12 mg per 5 mL (5 mL, 12.5 mL, 118 mL, 120 mL [DSC], 473 mL)

Suspension, Oral:

Capital/Codeine: Acetaminophen 120 mg and codeine phosphate 12 mg per 5 mL (473 mL [DSC]) [fruit punch flavor]

Tablet, Oral:

Tylenol with Codeine #3: Acetaminophen 300 mg and codeine phosphate 30 mg [contains corn starch, sodium metabisulfite]

Tylenol with Codeine #4: Acetaminophen 300 mg and codeine phosphate 60 mg [contains corn starch, sodium metabisulfite]

Generic: Acetaminophen 300 mg and codeine phosphate 15 mg, Acetaminophen 300 mg and codeine phosphate 30 mg, Acetaminophen 300 mg and codeine phosphate 60 mg

Use Labeled Indications

Pain management: Management of mild to moderate pain where treatment with an opioid is appropriate and for which alternative treatments are inadequate.

Limitations of use: Reserve for use in patients for whom alternative treatment options (eg, nonopioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate.

Contraindications

Hypersensitivity (eg, anaphylaxis) to acetaminophen, codeine, or any component of the formulation; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy; significant respiratory depression; GI obstruction, including paralytic ileus (known or suspected); concurrent use with monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.

Canadian labeling: Additional contraindications (not in US labeling): Mechanical GI obstruction (eg, bowel obstruction, strictures) or any disease/condition that affects bowel transit (known or suspected); suspected surgical abdomen (eg, acute appendicitis, pancreatitis); severe hepatic impairment or severe active liver disease; acute or severe bronchial asthma, chronic obstructive airway disease; status asthmaticus; hypercapnia; cor pulmonale; acute alcoholism; delirium tremens; seizure disorder; severe CNS depression; increased cerebrospinal or intracranial pressure; head injury; pregnancy; use during labor and delivery; use in pediatric patients <12 years. Some products may contraindicate use in patients <18 years (refer to specific product labeling).

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Side effects

The most frequently observed adverse reactions include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea and vomiting. These effects seem to be more prominent in ambulatory than in non-ambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down.

Other adverse reactions include allergic reactions, euphoria, dysphoria, constipation, abdominal pain, pruritus, rash, thrombocytopenia, and agranulocytosis.

At higher doses, codeine has most of the disadvantages of morphine including respiratory depression.

Drug Abuse And Dependence

Controlled Substance

TYLENOL® with Codeine (acetaminophen and codeine phosphate) tablets are classified as a Schedule III controlled substance.

Abuse and Dependence

Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic medications.

Patient information

Codeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while taking this product.

Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this combination product, and should be avoided.

Codeine may be habit forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine, which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer.

Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services).

Acetaminophen and Codeine Brand Names

Acetaminophen and Codeine may be found in some form under the following brand names:

  • Tylenol and Codeine

Acetaminophen and Codeine Drug Class

Acetaminophen and Codeine is part of the drug class:

  • Anilides

Acetaminophen and Codeine and Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Acetaminophen/codeine falls into category C. This medication may be given to a pregnant woman if her healthcare provider believes that its benefits to the pregnant woman outweigh any possible risks to her unborn baby.

It is not known if acetaminophen/codeine will harm your unborn baby.

Other Requirements

  • Store acetaminophen/codeine at room temperature.
  • Shake suspension well before use.
  • Keep this and all medicines out of the reach of children.

For Healthcare Professionals

Applies to acetaminophen / codeine: oral capsule, oral liquid, oral suspension, oral tablet

General

The most frequently observed adverse reactions include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, and vomiting.[Ref]

Nervous system

Acetaminophen-codeine:
Common (1% to 10%): Drowsiness, dizziness
Frequency not reported: Lightheadedness, sedation, medication over-use headache

Acetaminophen:
Frequency not reported: Drowsiness, impaired mental functions

Opioids:
Frequency not reported: Confusion, drowsiness, vertigo, dizziness, CNS excitation (restlessness/excitement), convulsions, headache, raised intracranial pressure[Ref]

Gastrointestinal

Acetaminophen-codeine:
Frequency not reported: Nausea, vomiting, constipation, abdominal pain

Acetaminophen:
Very rare (less than 0.01%): Pancreatitis
Frequency not reported: Dyspepsia

Opioids:
Frequency not reported: Constipation, GI irritation, biliary spasm, nausea, vomiting, loss of appetite, dry mouth, paralytic ileus, toxic megacolon[Ref]

Hepatic

Acetaminophen:
Frequency not reported: Acute liver failure, hepatotoxicity, chronic hepatic necrosis, cytolytic hepatitis[Ref]

Psychiatric

Acetaminophen-codeine:
Frequency not reported: Euphoria, dysphoria

Opioid:
Frequency not reported: Confusion, changes in mood, hallucinations, mental depression, trouble sleeping or nightmares, tolerance or dependence[Ref]

Renal

Acetaminophen-codeine:
Frequency not reported: Renal failure, uremia

Acetaminophen:
Frequency not reported: Nephrotoxicity, papillary necrosis[Ref]

Hypersensitivity

Acetaminophen-codeine:
Frequency not reported: Allergic reactions

Acetaminophen:
Rare (less than 0.1%): Allergic reactions including skin rash, drug fever, mucosal lesions
Postmarketing reports: Hypersensitivity including swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting, anaphylaxis, angioedema

Opioids:
Frequency not reported: Rash, urticaria, difficulty breathing, increased sweating, redness, redness or flushed face[Ref]

Cardiovascular

Acetaminophen:
Frequency not reported: Toxic myocarditis, Kounis syndrome

Opioids:
Frequency not reported: Bradycardia, palpitations, hypotension[Ref]

Genitourinary

Acetaminophen-codeine:
Frequency not reported: Urinary retention or hesitance

Opioids:
Frequency not reported: Urinary retention, ureteral spasm, antidiuretic effect[Ref]

Hematologic

Acetaminophen-codeine:
Frequency not reported: Thrombocytopenia, agranulocytosis, anemia

Acetaminophen:
Very rare (less than 0.01%): Thrombocytopenia, neutropenia, leucopenia
Frequency not reported: Agranulocytosis, methemoglobinemia, pancytopenia, thrombocytopenia purpura, hemolytic anemia[Ref]

Dermatologic

Acetaminophen-codeine:
Frequency not reported: Pruritus, rash

Acetaminophen:
Rare (less than 0.1%): Serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN)
Frequency not reported: Sweating, fixed drug eruption[Ref]

Respiratory

In patients with a tendency of analgesic asthma acetaminophen-use has triggered bronchospasms.[Ref]

Acetaminophen-codeine:
Frequency not reported: Shortness of breath

Acetaminophen:
Frequency not reported: Bronchospasm

Codeine:
Frequency not reported: Respiratory depression[Ref]

Ocular

Opioids:
Frequency not reported: Blurred or double vision[Ref]

Some side effects of acetaminophen / codeine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Renal Dose Adjustments

Severe renal impairment: Use with caution; monitor therapy with renal function tests

Acetaminophen / codeine Breastfeeding Warnings

Acetaminophen (paracetamol) is present in breast milk in quantities much less than doses usually given to infants. Codeine is present in breast milk and for women with normal codeine metabolism (normal CYP450 2D6 activity) the amount of codeine secreted is low and dose-dependent; however, in women who are ultra-rapid metabolizers of codeine (those with a specific CYP2D6 genotype) higher-than-expected serum levels of morphine, codeine's active metabolite, may be present in breast milk which may lead to dangerously high serum morphine levels in their breastfed infants. In most cases, a person's specific CYP2D6 genotype is unknown. Several small series and 1 small retrospective study suggest that codeine may be causative in episodes of apnea, bradycardia, and cyanosis in the first week of life. A death of a breastfeed infant due to respiratory depression has been reported; the mother was found to be a CYP450 2D6 ultrarapid metabolizer.

Not recommended Excreted into human milk: Yes Comments: -Breastfeeding is not recommended due to the risks of serious adverse reactions in breastfed infants such as excess sleepiness, difficulty breastfeeding, and serious breathing problems that may result in death.

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