Codeine

Codeine is available in the following forms:

• Disintegrating Tablet
• Extended Release Suspension
• Extended Release Tablet
• Injectable Solution
• Oral Capsule
• Oral Solution
• Oral Suspension
• Oral Tablet

You should not use this medicine if you are allergic to it, or if you have:

• severe asthma or breathing problems;

• a blockage in your stomach or intestines; or

• frequent asthma attacks or hyperventilation.

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.

Codeine should not be given to a child younger than 12 years old.

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

If you use codeine 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.

Do not breast-feed while taking 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;

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

• abnormal curvature of the spine that affects breathing;

• kidney disease;

• a head injury or brain tumor;

• low blood pressure;

• blockage in your digestive tract (stomach or intestines);

• a gallbladder or pancreas disorder;

• underactive thyroid;

• Addison's disease or other adrenal gland disorder;

• enlarged prostate, urination problems;

• mental illness;

• drug or alcohol addiction; or

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

Some medicines can interact with codeine and cause a serious condition called serotonin syndrome. Be sure your doctor knows if you also take medicine for depression, mental illness, Parkinson's disease, migraine headaches, serious infections, or prevention of nausea and vomiting. Ask your doctor before making any changes in how or when you take your medications.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. A codeine overdose can be fatal, especially in a child or other person using the medicine without a prescription. Overdose symptoms may include slow breathing and heart rate, severe drowsiness, muscle weakness, cold and clammy skin, pinpoint pupils, and fainting.

Usual Adult Dose for Pain:

Initial dose: 15 to 60 mg up to every 4 hours as needed
Maximum dose: 360 mg in 24 hours

Comments:
-Initial doses should be individualized taking into account severity of pain, response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse.
-Doses higher than 60 mg have not been shown to improve pain relief and are associated with an increased incidence of adverse effects.
-Because of the risks of addiction, abuse and misuse, the lowest effective dose for the shortest duration consistent with individual patient treatment goals should be used.
-Monitor patients closely for respiratory depression within the first 24 to 72 hours of initiating therapy and following any increase in dose.

Use: For the management of mild to moderate pain where treatment with an opioid is appropriate and from which alternative treatments are inadequate.

Narcotic (opioid) medication can interact with many other drugs and cause dangerous side effects or death. Be sure your doctor knows if you also use:

• other narcotic medications--opioid pain medicine or prescription cough medicine;

• drugs that make you sleepy or slow your breathing--a sleeping pill, muscle relaxer, sedative, tranquilizer, or antipsychotic medicine; or

• drugs that affect serotonin levels in your body--medicine for depression, Parkinson's disease, migraine headaches, serious infections, or prevention of nausea and vomiting.

This list is not complete. Other drugs may interact with codeine, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Opiate agonist; phenanthrene derivative.a b

Administration

Oral Administration

Administer orally.a b

Dispense a calibrated measuring device with cough preparations intended for children 2–5 years of age.10103

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as codeine phosphate and codeine sulfate; dosage expressed in terms of the salt.d e g

Pediatric Patients

Alternatively, use the following dosages as a guide based on average body weight; reduce dosage for low-weight children.10100

3 mg/kg or 100 mg/m2 daily in 6 divided doses.b Alternatively, 0.5 mg/kg or 15 mg/m2 every 4–6 hours.b f

Adults

10–20 mg every 4–6 hours.a

30 mg every 4 hours as needed; usual dosage range is 15–60 mg every 4 hours as needed.b d e

Nonopiate-containing analgesic fixed combinations: Nonopiate component may limit dosage of opiate component.117 119 120 121 Nonopiate analgesics are available in various fixed ratios with codeine and also are available in many other prescription and OTC preparations; ensure that therapy is not duplicated and that nonopiate dosage does not exceed maximum recommended dosages.117 118 119 121

Individualize initial dosage, taking into account patient's prior opiate use; concurrent drug therapy; degree of opiate tolerance; medical condition; type and severity of pain; and risk factors for addiction, abuse, and misuse.122 123

Prescribing Limits

Pediatric Patients

Adults

Maximum 120 mg daily.a

Maximum 360 mg daily.122 123

Special Populations

Geriatric Patients

Reduce dosage in older patients.a b

Ultrarapid Metabolizers of CYP2D6 Substrates

Use lowest effective dosage for shortest period of time.104 105 106 113 (See Special Populations under Pharmacokinetics.)

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 codeine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to 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 codeine in the pediatric population. Safety and efficacy have not been established.

Codeine sulfate tablets should not be used to relieve pain after surgery removal of 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 codeine in the elderly. However, elderly patients are more likely to have confusion and drowsiness, and age-related lung, liver, kidney, or heart problems, which may require caution and an adjustment in the dose for patients receiving codeine in order to avoid potentially serious side effects.

Pregnancy

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 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 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 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 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
• Imipramine
• Isoflurane
• 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
• 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

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 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 codeine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of 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 or lung problems (eg, chronic obstructive pulmonary disease [COPD], cor pulmonale, hypoxia, sleep apnea) or
• Depression, history of or
• Drug dependence, especially narcotic abuse or dependence, or history of or
• Enlarged prostate (BPH, prostatic hypertrophy) or
• Head injuries or
• Hypothyroidism (an underactive thyroid) or
• Increased pressure in your head or
• Kyphoscoliosis (curvature of spine that can cause breathing problems) or
• Mental health problems, history of or
• Problems with passing urine or
• Stomach or digestion problems—Use with caution. May increase risk for more serious side effects.

• Breathing problems (eg, asthma, hypercapnia), severe or
• Paralytic ileus (intestinal blockage) or
• Respiratory depression (hypoventilation or slow breathing)—Should not be used in patients with these conditions.

• Hypotension (low blood pressure) or
• Pancreatitis (inflammation of the pancreas) or
• Seizures, history of—Use with caution. May make these conditions worse.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Codeine Phosphate
• Codeine Sulfate
• Methylmorphine

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

Solution, Oral, as sulfate:

Generic: 30 mg/5 mL (500 mL [DSC])

Tablet, Oral, as sulfate:

Generic: 15 mg, 30 mg, 60 mg

• Analgesic, Opioid
• Antitussive

Binds to opioid receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; causes cough suppression by direct central action in the medulla; produces generalized CNS depression

Absorption

Oral: Adequate

Distribution

~3 to 6 L/kg

Metabolism

Hepatic via UGT2B7 and UGT2B4 to codeine-6-glucuronide, via CYP2D6 to morphine (active), and via CYP3A4 to norcodeine. Morphine is further metabolized via glucuronidation to morphine-3-glucuronide and morphine-6-glucuronide (active).

Excretion

Urine (~90%, ~10% of the total dose as unchanged drug); feces

Some quinolones may produce a false-positive urine screening result for opioids using commercially-available immunoassay kits. This has been demonstrated most consistently for levofloxacin and ofloxacin, but other quinolones have shown cross-reactivity in certain assay kits. Confirmation of positive opioid screens by more specific methods should be considered.

Frequency not defined.

Cardiovascular: Bradycardia, cardiac arrest, circulatory depression, flushing, hypertension, hypotension, palpitations, shock, syncope, tachycardia

Central nervous system: Abnormal dreams, agitation, anxiety, apprehension, ataxia, chills, depression, disorientation, dizziness, drowsiness, dysphoria, euphoria, fatigue, hallucination, headache, increased intracranial pressure, insomnia, nervousness, paresthesia, sedation, shakiness, taste disorder, vertigo

Dermatologic: Diaphoresis, pruritus, skin rash, urticaria

Gastrointestinal: Abdominal cramps, abdominal pain, anorexia, biliary tract spasm, constipation, diarrhea, nausea, pancreatitis, vomiting, xerostomia

Genitourinary: Urinary hesitancy, urinary retention

Hypersensitivity: Hypersensitivity reaction

Neuromuscular & skeletal: Laryngospasm, muscle rigidity, tremor, weakness

Ophthalmic: Blurred vision, diplopia, miosis, nystagmus, visual disturbance

Respiratory: Bronchospasm, dyspnea, respiratory arrest, respiratory depression

<1% (Limited to important or life-threatening): Hypogonadism (Brennan, 2013; Debono, 2011)

You should not use codeine if you are allergic to it, or if you have:

• severe asthma or breathing problems;

• a blockage in your stomach or intestines; or

• frequent asthma attacks or hyperventilation.

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.

This medicine should not be given to a child younger than 12 years old.

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

If you use codeine 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.

Do not breast-feed while taking this medicine. 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;

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

• abnormal curvature of the spine that affects breathing;

• kidney disease;

• head injury or brain tumor;

• low blood pressure;

• blockage in your digestive tract (stomach or intestines);

• a gallbladder or pancreas disorder;

• underactive thyroid;

• Addison's disease or other adrenal gland disorder;

• enlarged prostate, urination problems;

• mental illness;

• drug or alcohol addiction; or

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

Some medicines can interact with codeine and cause a serious condition called serotonin syndrome. Be sure your doctor knows if you also take medicine for depression, mental illness, Parkinson's disease, migraine headaches, serious infections, or prevention of nausea and vomiting. Ask your doctor before making any changes in how or when you take your medications.

Do not drink alcohol. Dangerous side effects or death could occur.

Codeine may impair your thinking or reactions. Avoid driving or operating machinery until you know how this medicine will affect you. Dizziness or severe drowsiness can cause falls or other accidents.

Usual Adult Dose for Pain:

Initial dose: Individualize dose based on patients prior analgesic experience
Maintenance dose: 15 to 60 mg up to every 4 hours as needed
Maximum dose: 360 mg in 24 hours

Comments: Doses higher than 60 mg have not been shown to improve pain relief and are associated with an increased incidence of adverse effects.

Individualization of dose should consider the following:
-Total daily dose, potency and specific characteristics of the opioid the patient has been previously taking
-Reliability of the relative potency estimate used to calculate the equivalent codeine dose needed
-Patient's degree of opioid tolerance
-General condition and medical status of the patient
-Concurrent medications
-Type and severity of pain
-Risk factors for abuse, addiction, or diversion, including a prior history of abuse, addiction, or diversion

Use: For the relief of mild to moderately severe pain where the use of an opioid analgesic is appropriate.

Usual Geriatric Dose for Pain:

Dose selection should be cautious, generally starting at the low end of the dosing range.

Use with caution; start with lower doses or with longer dosing intervals and titrate slowly while carefully monitoring for side effects.

• May be taken with or without food.
• May cause sedation and affect your ability to drive or operate machinery. Avoid alcohol.
• Use short-term (three days or less) only. Not recommended for long-term use.
• Do not exceed the recommended dosage.
• Tell your doctor if you experience any breathing difficulties, wheezing, rash, itching, or facial swelling.
• Tell your doctor if you think you have become addicted to codeine or the usual dosage does not appear to be working.
• Do not double up on other medications containing codeine (several cold and flu remedies also contain codeine).

Peak concentrations of codeine are reached within two hours and the analgesic activity of codeine lasts between four to six hours.

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