Acetaminophen and codeine

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Capital® may be confused with Capitrol®
Tylenol® may be confused with atenolol, timolol, Tuinal®, Tylox®

T3 is an error-prone abbreviation (mistaken as liothyronine)

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Duplicate therapy issues: This product contains acetaminophen, which may be a component of other combination products. Do not exceed the maximum recommended daily dose of acetaminophen.

SPECIAL ALERTS
Tylenol® With Codeine: Health Canada Issues Warning Concerning Potentially Increased Morphine Levels In Milk of Nursing Mothers - October 9, 2008

Janssen-Ortho Inc, in conjunction with Health Canada, has issued a "Dear Healthcare Professional" letter concerning use of Tylenol® with Codeine (acetaminophen with codeine) products and the risk of elevated morphine levels in the serum and breast milk of nursing women who are ultra-rapid metabolizers of codeine. Consequently, infants of nursing mothers with a certain CYP2D6 (converts codeine to morphine) genotype, may be exposed to potentially dangerous serum levels of morphine as well.

Available data indicates the incidence of this CYP2D6 genotype in the general population varies and is estimated to occur in the following populations as follows: North African, Ethiopian, and Arab (16% to 28%); Chinese, Japanese, and Hispanic (0.5% to 1%); Caucasian (1% to 10%); African American (3%).

When using codeine in nursing women, healthcare providers are urged to prescribe and administer the lowest possible dose for the shortest time necessary to achieve adequate clinical effect. Nursing women should be advised of signs/symptoms of morphine toxicity for themselves (extreme sedation, confusion, shallow breathing) and for their infants (sedation, dyspnea, decreased tone, difficult breastfeeding). The manufacturer will be updating the product labeling to include these new warnings and precautions. A similar warning had previously been released in the U.S. in August 2007.

Additional information can be found at the following websites:
Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/tylenol_codeine_hpc-cps-eng.php
U.S.: http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm124889.htm

U.S. BRAND NAMES — Capital® and Codeine; Tylenol® with Codeine No. 3; Tylenol® with Codeine No. 4

PHARMACOLOGIC CATEGORY
Analgesic, Opioid

DOSING: ADULTS — Doses should be adjusted according to severity of pain and response of the patient. Adult doses ≥ 60 mg codeine fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciably increased incidence of side effects.

Cough (Antitussive): Oral: Based on codeine (15-30 mg/dose) every 4-6 hours (maximum: 360 mg/24 hours based on codeine component)

Pain (Analgesic): Oral: Based on codeine (30-60 mg/dose) every 4-6 hours (maximum: 4000 mg/24 hours based on acetaminophen component)
1-2 tablets every 4 hours to a maximum of 12 tablets/24 hours

DOSING: PEDIATRIC

(For additional information see "Acetaminophen and codeine: Pediatric drug information")
Analgesic: Oral:
Codeine: 0.5-1 mg codeine/kg/dose every 4-6 hours
Acetaminophen: 10-15 mg/kg/dose every 4 hours up to a maximum of 2.6 g/24 hours for children <12 years; alternatively, the following can be used:
3-6 years: 5 mL 3-4 times/day as needed of elixir
7-12 years: 10 mL 3-4 times/day as needed of elixir
Children >12 years: 15 mL every 4 hours as needed of elixir

DOSING: ELDERLY — Doses should be titrated to appropriate analgesic effect.

1 Tylenol® [#3] or 2 Tylenol® [#2] tablets every 4 hours; do not exceed 4 g/day acetaminophen.

DOSING: RENAL IMPAIRMENT — See individual agents.

DOSING: HEPATIC IMPAIRMENT — Use with caution. Limited, low-dose therapy is usually well tolerated in hepatic disease/cirrhosis; however, cases of hepatotoxicity at daily acetaminophen dosages <4 g/day have been reported. Avoid chronic use in hepatic impairment.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product; [CAN] = Canadian brand name

Caplet:
ratio-Lenoltec No. 1 [CAN], Tylenol No. 1 [CAN]: Acetaminophen 300 mg, codeine phosphate 8 mg, and caffeine 15 mg [not available in the U.S.]
Tylenol No. 1 Forte [CAN]: Acetaminophen 500 mg, codeine phosphate 8 mg, and caffeine 15 mg [not available in the U.S.]

Solution, oral [C-V]: Acetaminophen 120 mg and codeine phosphate 12 mg per 5 mL (5 mL, 10 mL, 12.5 mL, 15 mL, 120 mL, 480 mL) [contains alcohol 7%]
Tylenol Elixir with Codeine [CAN]: Acetaminophen 160 mg and codeine phosphate 8 mg per 5 mL (500 mL) [contains alcohol 7%, sucrose 31%; cherry flavor; not available in the U.S.]

Suspension, oral [C-V] (Capital® and Codeine): Acetaminophen 120 mg and codeine phosphate 12 mg per 5 mL (480 mL) [alcohol free; contains propylene glycol, sodium benzoate; fruit punch flavor]

Tablet [C-III]: Acetaminophen 300 mg and codeine phosphate 15 mg; acetaminophen 300 mg and codeine phosphate 30 mg; acetaminophen 300 mg and codeine phosphate 60 mg
ratio-Emtec [CAN], Triatec-30 [CAN]: Acetaminophen 300 mg and codeine phosphate 30 mg [not available in the U.S.]
ratio-Lenoltec No. 1 [CAN]: Acetaminophen 300 mg, codeine phosphate 8 mg, and caffeine 15 mg [not available in the U.S.]
ratio-Lenoltec No. 2 [CAN], Tylenol No. 2 with Codeine [CAN]: Acetaminophen 300 mg, codeine phosphate 15 mg, and caffeine 15 mg [not available in the U.S.]
ratio-Lenoltec No. 3 [CAN], Tylenol No. 3 with Codeine [CAN]: Acetaminophen 300 mg, codeine phosphate 30 mg, and caffeine 15 mg [not available in the U.S.]
ratio-Lenoltec No. 4 [CAN], Tylenol No. 4 with Codeine [CAN]: Acetaminophen 300 mg and codeine phosphate 60 mg [not available in the U.S.]
Triatec-8 [CAN]: Acetaminophen 325 mg, codeine phosphate 8 mg, and caffeine 30 mg [not available in the U.S.]
Triatec-8 Strong [CAN]: Acetaminophen 500 mg, codeine phosphate 8 mg, and caffeine 30 mg [not available in the U.S.]
Tylenol® with Codeine No. 3: Acetaminophen 300 mg and codeine phosphate 30 mg [contains sodium metabisulfite]
Tylenol® with Codeine No. 4: Acetaminophen 300 mg and codeine phosphate 60 mg [contains sodium metabisulfite]

DOSAGE FORMS: CONCISE — [CAN] = Canadian brand name

Caplet:
ratio-Lenoltec No. 1 [CAN], Tylenol No. 1 [CAN]: Acetaminophen 300 mg, codeine 8 mg, and caffeine 15 mg [not available in the U.S.]
Tylenol No. 1 Forte [CAN]: Acetaminophen 500 mg, codeine 8 mg, and caffeine 15 mg [not available in the U.S.]

Solution, oral [C-V]: Acetaminophen 120 mg and codeine 12 mg per 5 mL
Tylenol Elixir with Codeine [CAN]: Acetaminophen 160 mg and codeine 8 mg per 5 mL [not available in the U.S.]

Suspension, oral [C-V]: Acetaminophen 120 mg and codeine 12 mg per 5 mL
Capital® and Codeine [C-V]: Acetaminophen 120 mg and codeine 12 mg per 5 mL

Tablet [C-III]: Acetaminophen 300 mg and codeine 15 mg; acetaminophen 300 mg and codeine 30 mg; acetaminophen 300 mg and codeine 60 mg
ratio-Emtec [CAN], Triatec-30 [CAN]: Acetaminophen 300 mg and codeine 30 mg [not available in the U.S.]
ratio-Lenoltec No. 1 [CAN]: Acetaminophen 300 mg, codeine 8 mg, and caffeine 15 mg [not available in the U.S.]
ratio-Lenoltec No. 2 [CAN], Tylenol No. 2 with Codeine [CAN]: Acetaminophen 300 mg, codeine 15 mg, and caffeine 15 mg [not available in the U.S.]
ratio-Lenoltec No. 3 [CAN], Tylenol No. 3 with Codeine [CAN]: Acetaminophen 300 mg, codeine 30 mg, and caffeine 15 mg [not available in the U.S.]
ratio-Lenoltec No. 4 [CAN], Tylenol No. 4 with Codeine [CAN]: Acetaminophen 300 mg and codeine 60 mg [not available in the U.S.]
Triatec-8 [CAN]: Acetaminophen 325 mg, codeine 8 mg, and caffeine 30 mg [not available in the U.S.]
Triatec-8 Strong [CAN]: Acetaminophen 500 mg, codeine 8 mg, and caffeine 30 mg [not available in the U.S.]
Tylenol® with Codeine No. 3: Acetaminophen 300 mg and codeine 30 mg
Tylenol® with Codeine No. 4: Acetaminophen 300 mg and codeine 60 mg

GENERIC EQUIVALENT AVAILABLE — Yes

USE — Relief of mild-to-moderate pain

ADVERSE REACTIONS SIGNIFICANT
>10%:
Central nervous system: Dizziness, lightheadedness, sedation
Gastrointestinal: Nausea, vomiting
Respiratory: Dyspnea

1% to 10%:
Central nervous system: Dysphonia, euphoria
Dermatologic: Pruritus
Gastrointestinal: Abdominal pain, constipation
Miscellaneous: Histamine release

<1% (Limited to important or life-threatening): Antidiuretic hormone release, biliary tract spasm, bradycardia, hypotension, intracranial pressure increased, miosis, palpitation, peripheral vasodilation, physical and psychological dependence, respiratory depression, urinary retention

CONTRAINDICATIONS — Hypersensitivity to acetaminophen, codeine, or any component of the formulation; significant respiratory depression (in unmonitored settings); acute or severe bronchial asthma; hypercapnia; paralytic ileus

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Hepatotoxicity: May cause severe hepatic toxicity on acute overdose; in addition, chronic daily dosing in adults has resulted in liver damage in some patients. Hypotension: May cause hypotension; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).

Disease-related concerns: Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions. Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addison's disease. CNS depression/coma: Use with caution in patients with CNS depression or coma. Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use. Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥ 3 alcoholic drinks/day may increase the risk of liver damage. G6PD deficiency: Use with caution in patients with known G6PD deficiency. Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur. Hepatic impairment: Use with caution in patients with severe hepatic impairment. Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture. Renal impairment: Use with caution in patients with renal impairment. Respiratory disease: Use with caution in patients with pre-existing respiratory compromise (hypoxia and/or hypercapnia), COPD or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages. Seizure disorder: Use with caution in patients with a history of seizure disorder. Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues: Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations: CYP2D6 "ultrarapid metabolizers": Use caution in patients with two or more copies of the variant CYP2D6*2 allele; may have extensive conversion to morphine and thus increased opioid-mediated effects. Debilitated patients: Use with caution in debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Decrease initial dose.

Dosage form specific issues: Metabisulfite: Tablets contain metabisulfite which may cause allergic reactions. Non-U.S. formulations: Some non-U.S. formulations (including most Canadian formulations) may contain caffeine as an additional ingredient. Caffeine may cause CNS and cardiovascular stimulation, as well as GI irritation in high doses. Use with caution in patients with a history of peptic ulcer or GERD; avoid in patients with symptomatic cardiac arrhythmias.

Other warnings/precautions: Dosage limit: Limit total acetaminophen dose to <4 g/day. Withdrawal: Concurrent use of agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms.

RESTRICTIONS — C-III; C-V

Note: In countries outside of the U.S., some formulations of Tylenol® with Codeine (eg, Tylenol® No. 3) include caffeine.

METABOLISM / TRANSPORT EFFECTS — Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

DRUG INTERACTIONS
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

Ammonium Chloride: May increase the excretion of Analgesics (Opioid). Risk C: Monitor therapy

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Risk C: Monitor therapy

Anticonvulsants (Hydantoin): May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk D: Consider therapy modification

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Imatinib: May increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy

Somatostatin Analogs: May decrease the metabolism of Codeine. The formation of two major codeine metabolites (morphine and norcodeine) may be impaired by somatostatin analogs. Risk C: Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Risk C: Monitor therapy

Thiazide Diuretics: Analgesics (Opioid) may enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: Excessive intake of ethanol may increase the risk of acetaminophen-induced hepatotoxicity. Avoid ethanol or limit to <3 drinks/day.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Refer to Codeine monograph.

LACTATION — Enters breast milk/use caution

BREAST-FEEDING CONSIDERATIONS — Refer to Codeine monograph.

DIETARY CONSIDERATIONS — May be taken with food.

PRICING — (data from drugstore.com)
Solution (Acetaminophen-Codeine)
120-12 mg/5 mL (118): $8.99
120-12 mg/5 mL (240): $13.99

Tablets (Acetaminophen-Codeine #2)
300-15 mg (30): $7.99

Tablets (Acetaminophen-Codeine #3)
300-30 mg (30): $11.99

Tablets (Acetaminophen-Codeine #4)
300-60 mg (30): $13.99

Tablets (Tylenol/Codeine #3)
300-30 mg (30): $30.76

Tablets (Tylenol/Codeine #4)
300-60 mg (30): $49.38

MONITORING PARAMETERS — Relief of pain, respiratory and mental status, blood pressure, bowel function

CANADIAN BRAND NAMES — ratio-Emtec; ratio-Lenoltec; Triatec-30; Triatec-8; Triatec-8 Strong; Tylenol Elixir with Codeine; Tylenol No. 1; Tylenol No. 1 Forte; Tylenol No. 2 with Codeine; Tylenol No. 3 with Codeine; Tylenol No. 4 with Codeine

INTERNATIONAL BRAND NAMES — Algimide (CO); Algimide F (CO); Chemists Own Dolased Day Pain Relief (AU); Citodon (SE); Claradol Codeine (FR); Co-Cadamol (SG); Cod-Acamol Forte (IL); Codabrol (IL); Codalgin (AU); Codapane (AU); Codeidol (CO); Codeidol F (CO); Codeipar (CN); Codicet (TH); Codilprane Enfant (FR); Codipar (GB, IE); Coditam (ID); Codoliprane (FR); Codoliprane Enfant (FR); Codral Pain Relief (AU, NZ); Dafalgan Codeine (FR); Dolaforte (AU); Dolorol Forte (ZA); Dymadon Co (AU); Dymadon Forte (AU, NZ); Efferalgan Codeine (PY); Febricod (AU); Hexal Comfarol Plus (AU); Liquigesic Co (AU, NZ); Maxadol (ZA); Nasa w/codeine (TH); Paceco (MY, SG); Panadeine (BB, BM, BS, BZ, CZ, GY, HK, HN, JM, MY, NL, NZ, SR, TT); Panadeine Co (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Panadeine Forte (AU, NZ); Panadiene (AU, BB, BM, BS, BZ, CZ, GY, HK, HN, JM, JP, MY, NL, NZ, SR, TT); Panado-Co Caplets (ZA); Panadol Duo (FI); Panadol Ultra (HK); Panamax (AU, NZ); Paracodol (ZA); Paradine (MY); Paramax (EE); Parcono (TH); Parcoten (HK); Perdolan codeine (BE); Prodeine Forte (AU); Prodeine-15 (AU); Rokamol Plus (IL); Solpadeine (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Solpadol (GB, IE); TWC 30 (IN); Tylex CD (CR, DO, GT, HN, MX, NI, PA, SV); Winadol Forte (CO); Zapain (GB, IE)

MECHANISM OF ACTION — Inhibits the synthesis of prostaglandins in the central nervous system and peripherally blocks pain impulse generation; produces antipyresis from inhibition of hypothalamic heat-regulating center; binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; causes cough supression by direct central action in the medulla; produces generalized CNS depression. Caffeine (contained in some non-U.S. formulations) is a CNS stimulant; use with acetaminophen and codeine increases the level of analgesia provided by each agent.

PHARMACODYNAMICS / KINETICS — See individual agents.