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TYLENOL® with CODEINE Preparations Janssen-Ortho/McNeil Consumer Healthcare Acetaminophen--Codeine Phosphate Compound Analgesic--Antipyretic
Action and Clinical

Tylenol acetaminophen with codeine combines the analgesic effects of the centrally acting analgesic codeine, with a peripherally acting analgesic, acetaminophen. Caffeine stimulates the CNS at all levels including the cortex. In addition, it acts on the kidney to produce diuresis, stimulates cardiac muscle and depresses smooth muscle.

Both acetaminophen and codeine are well absorbed orally.

Acetaminophen is distributed throughout most tissues of the body. Acetaminophen is metabolized primarily in the liver. Little unchanged drug is excreted in the urine, but most metabolic products appear in the urine within 24 hours.

Codeine retains at least one-half of its analgesic activity when administered orally. A reduced first-pass metabolism of codeine by the liver accounts for the greater oral potency of codeine when compared to most other morphine-like narcotics. Following absorption, codeine is metabolized by the liver and metabolic products are excreted in the urine. Approximately 10% of the administered codeine is demethylated to morphine, which may account for its analgesic activity.

Caffeine is rapidly distributed and appears in all tissues within 5 minutes with peak plasma levels being reached in 30 minutes. It is almost completely metabolized via oxidation, demethylation and acetylation, with only about 1% of caffeine excreted via the urine. The principal metabolites in man are methyluric acid, 1-methylxanthine, paraxanthine and theobromine.

Pharmacokinetics: Following oral administration of acetaminophen in combination with codeine, both drugs are rapidly absorbed with peak plasma levels occurring within 60 minutes. Given 2 tablets of Tylenol with codeine NO. 3, acetaminophen 600 mg produces a peak plasma level of 6.25 µg/mL within 40 minutes, codeine phosphate 60 mg produces a peak plasma level of 150 ng/mL within 60 minutes.

Following oral administration, caffeine is rapidly absorbed with a peak plasma level occurring within 60 minutes. Given an oral dose of 100 mg, peak plasma caffeine concentrations of 1.5 to 1.8 µg/mL are reached within 60 minutes.

The plasma elimination half-life (t 1/2) ranges from 1.5 to 3.5 hours for acetaminophen, 1.5 to 4 hours for codeine and from 2.5 to 4.5 hours for caffeine. Metabolism is rapid, the principle metabolites are conjugates of glucuronic acid which are excreted in the urine. Less than 1% of an administered dose of codeine or caffeine, and less than 4% of an administered dose of acetaminophen, is excreted unchanged in the urine.

Indications and Clinical Uses:

For the relief of mild to moderate pain associated with conditions such as headache, dental pain, myalgia, dysmenorrhea, pain following trauma and pain following operative procedures. May also be effective in relieving the pain associated with various forms of arthritis, but is not indicated as primary therapy for rheumatoid arthritis and similar inflammatory conditions.

The elixir is useful as an analgesic/antipyretic in the symptomatic treatment of mild to moderate pain and fever in children. Tylenol with Codeine No. 4 tablets are indicated for the relief of moderate to severe pain in adults only.


Patients who have previously exhibited hypersensitivity to acetaminophen, codeine or caffeine.

Warnings in Clinical State and Precautions:

As with any other nonprescription analgesic drug, physicians should be cognisant of and supervise the use of acetaminophen in patients with alcoholism, serious kidney or serious liver disease. Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive acetaminophen use, although reports of this event are rare. Reports usually involve cases of severe chronic alcoholics and the dosages of acetaminophen most often exceed recommended doses and often involve substantial overdose. Physicians should alert their patients who regularly consume large amounts of alcohol not to exceed the recommended doses of acetaminophen.

Patients should be counseled to consult a physician if redness or swelling is present in an area of pain, if symptoms do not improve or if they worsen, or if new symptoms such as high fever, rash or headache occur, as these may be signs of a condition which requires medical attention.

Acetaminophen should not be taken for pain for more than 5 days or for fever for more than 3 days, unless directed by a physician. As with any drug, patients who are pregnant or nursing a baby should consult a physician before taking this product.

Do not use with other products containing acetaminophen. Keep out of the reach of children.

General: Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries.

Acute Abdominal Conditions: The administration of these drugs or other narcotics may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Special Risk Patients: These drugs should be given with caution to certain patients such as the elderly or debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, and prostatic hypertrophy or urethral stricture.

Occupational Hazards: Codeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks. Patients using this drug should be cautioned about driving a car or operating potentially hazardous machinery if they become drowsy or show impaired mental or physical abilities while taking this medication.

The patient should understand the single-dose and 24 hour dose limits, and the time interval between doses. Like other narcotic-containing medications, these drugs are subject to the Controlled Drugs and Substances Act.

Drug Interactions :

Patients receiving other narcotic analgesics, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol) concomitantly with this drug may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

The concurrent use of anticholinergics with codeine may produce paralytic ileus.

Pregnancy: Teratogenic Effects: Codeine: A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120 mg/kg level, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In another study, a single 100 mg/kg dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring.

There are no studies in humans, and the significance of these findings to humans, if any, is not known.

Acetaminophen with codeine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: Dependence and withdrawal signs have been reported in newborns whose mothers took opiates regularly during pregnancy. These signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting and diarrhea. Signs usually appear during the first few days of life.

Labor and Delivery: Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see Overdose). The effects of codeine, if any, on the later growth, development, and functional maturation of the child is unknown.

Lactation: Acetaminophen with codeine is not recommended during lactation because safety in nursing mothers has not been established. Acetaminophen passes into breast milk but is not likely to have an adverse effect on the infant at therapeutic doses.

Some studies, but not others, have reported detectable amounts of codeine in breast milk. The levels are probably not clinically significant after usual therapeutic dosage. The possibility of clinically important amounts being excreted in breast milk in individuals abusing codeine should be considered.

Caffeine is found in breast milk following the consumption of tea or coffee. About 1% of the caffeine in these beverages is recovered in approximately 100 mL of breast milk at 4 hours.

Children: These products contain codeine and should not be administered to children except on the advice of a physician. Tablets and caplets should not be administered to children below the age of 12 years. Safe dosage of the elixir has not been established in infants below the age of 2 years.

Drug Abuse and Dependence: Codeine can produce drug dependence of the morphine type, and therefore has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of this product. These drugs should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic-containing medications.

Adverse Reactions:

:The most frequently observed adverse effects include lightheadedness, dizziness, sedation, shortness of breath, nausea and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory 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, and pruritus. The incidence and severity of gastrointestinal upset is less than that after salicylate administration.

When used as directed, acetaminophen is virtually free of toxicity or side effects. The classic gastrointestinal irritation associated with NSAIDs, including ASA does not occur with acetaminophen. Sensitivity reactions are rare. Cross-reactivity in ASA-sensitive persons has been rarely reported. If sensitivity is suspected, discontinue use of the drug.

Patients who concomitantly medicate with warfarin-type anticoagulants and regular doses of acetaminophen have occasionally been reported to have unforeseen elevations in their INR. Physicians should be cognisant of this potential interaction and monitor the INR in such patients closely while therapy is established.

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

Higher doses of caffeine lead to overstimulation of the higher centres of the CNS. Long-term use of caffeine may cause gastric disturbances and subsequent development of gastric ulcers.

Symptoms And Treatment Of Overdose :

Typical Toxidrome: Significant overdoses of acetaminophen may result in potentially fatal hepatotoxicity. The physician should be mindful that there is no early presentation that is pathognomonic for the overdose. A high degree of clinical suspicion must always be maintained.

Due to the wide availability of acetaminophen, it is commonly involved in single and mixed drug overdose situations and the practitioner should have a low threshold for screening for its presence in a patient's serum. Acute toxicity after single dose overdoses of acetaminophen can be anticipated when the overdose exceeds 150 mg/kg. Chronic alcohol abusers, cachectic individuals, and persons taking pharmacologic inducers of the hepatic P450 microsomal enzyme system may be at risk with lower exposures. There have been rare reports of chronic intoxication in persons consuming in excess of 150 mg/kg of acetaminophen daily for several days.

Specific Antidote: NAC (N-acetylcysteine) administered by either the i.v. or the oral route is known to be a highly effective antidote for acetaminophen poisoning. It is most effective when administered within 8 hours of a significant overdose but reports have indicated benefits to treatment initiated well beyond this time period. It is imperative to administer the antidote as early as possible in the time course of acute intoxication to reap the full benefits of the antidote's protective effects.

General Management: When the possibility of acetaminophen overdose exists, treatment should begin immediately and include appropriate decontamination of the GI tract, proper supportive care, careful assessment of appropriately timed serum acetaminophen estimations evaluated against the Matthew-Rumack nomogram, timely administration of NAC as required and appropriate followup care. Physicians unfamiliar with the current management of acetaminophen overdose should consult with a poison control centre immediately. Telephone numbers for local poison control centres are available in the local phone directory. Delays in initiation of appropriate therapy may jeopardize the patient's chances for full recovery.

Codeine: Typical Toxidrome: Narcotic/Opiate.

Specific Antidote: Naloxone HCl.

General Management: Stabilize the patient (A, B, C's), undertake appropriate gastrointestinal tract decontamination procedures, initiate supportive care, administer antidote as needed (see manufacturer's product monograph), consult with a Regional Poison Control Centre regarding ongoing management, and arrange for appropriate followup care.

Caffeine: Typical Toxidrome: Xanthine (theophylline-like picture), CNS excitation, skeletal muscle irritability.

Specific Antidote: None.

General Management: Stabilize the patient (A, B, C's), undertake appropriate gastrointestinal tract decontamination procedures, initiate supportive care, consult with a Regional Poison Control Centre regarding ongoing management, and arrange for appropriate follow-up care.

Dosage And Administration:

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 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.

Tablets, caplets and elixir are given orally.

Tylenol NO. 1: Adults: 1 to 2 caplets every 4 hours as required, not to exceed 12 caplets in 24 hours.

Children: when recommended by a physician or dentist: (12 to 14 years of age): 1 caplet 3 times daily. Not to exceed 1 caplet 4 times daily.

Tylenol NO. 1 Forte: Adults: 1 or 2 caplets 3 to 4 times daily as required, not to exceed 8 caplets in a 24-hour period.

Do not exceed the recommended dose unless advised by a physician. Use longer than 5 days only on the advice of a physician.

Tylenol NO. 2 and NO. 3 with Codeine: Adults: 1 or 2 tablets every 4 hours as required.

Tylenol NO. 4 with Codeine: Adults: 1 tablet every 4 hours as required.

Based on the dosage guidance, the number of tablets per dose, and the maximum number of tablets per 24 hours, should be conveyed in the prescription.

Tylenol Elixir with Codeine: Dosage should be adjusted according to severity of pain and response of the patient. As an analgesic-antipyretic, the dose is given every 4 hours as required. Not to exceed 5 doses in a 24 hour period.

Adults: 10 to 20 mL every 4 hours as required.

Children: 2 to 3 years: 3.75 to 5 mL; 4 to 5 years: 5 to 6.25 mL; 6 to 8 years: 6.25 to 8.75 mL; 9 to 10 years: 8.75 to 10 mL; 11 to 12 years: 10 to 12.5 mL.

Safe dosage of this elixir has not been established in children below the age of 2 years.

Note: The recommended dose of codeine in children is 0.5 mg/kg body weight.

Availability And Storage:

Tylenol NO. 1: Each hard, white, capsule-shaped tablet imprinted with stylized M and McNEIL on one face and imprinted NO. 1 on the other face, contains: acetaminophen 300 mg, caffeine 15 mg and codeine phosphate 8 mg. Nonmedicinal ingredients: cellulose, cornstarch, magnesium stearate and sodium starch glycolate. Energy: 0.761 kJ (0.182 kcal). Gluten-, lactose-, sodium metabisulfite- and tartrazine-free. Bottles of 30, 50 and 100 (supplied by McNeil Consumer Healthcare).

Tylenol NO. 1 Forte: Each hard, white, capsule-shaped tablet imprinted with stylized M and McNEIL on one face and imprinted NO. 1 FORTE on the opposite face, contains: acetaminophen 500 mg, caffeine 15 mg and codeine phosphate 8 mg. Nonmedicinal ingredients: cellulose, cornstarch, magnesium stearate and sodium starch glycolate. Energy: 1.645 kJ (0.391 kcal). Gluten-, lactose-, sodium metabisulfite- and tartrazine-free. Bottles of 50 (supplied by McNeil Consumer Healthcare).

Tylenol NO. 2 and NO. 3 with Codeine: Each round, hard, white tablet, flat-faced, beveled, engraved 2 or 3, respectively, on one side and has a flat-faced, special design, beveled, engraved with McNEIL the other side, contains: acetaminophen 300 mg and caffeine 15 mg, in combination with codeine phosphate 15 mg and 30 mg, respectively. Nonmedicinal ingredients: cellulose, cornstarch and magnesium stearate. Energy: NO. 2: 0.949 kJ (0.224 kcal); NO. 3: 0.976 kJ (0.232 kcal). Gluten-, lactose-, sodium metabisulfite- and tartrazine-free. Bottles of 500 (supplied by Janssen-Ortho).

Tylenol NO. 4 with Codeine: Each round, hard, white tablet, flat-faced, beveled, engraved 4 one side and flat-faced special design, beveled, engraved McNEIL the other side contains: acetaminophen 300 mg and codeine phosphate 60 mg. Nonmedicinal ingredients: cellulose, cornstarch, magnesium stearate, sodium lauryl sulfate, sodium starch glycolate and talc. Energy: 1.704 kJ (0.405 kcal). Gluten-, lactose-, sodium metabisulfite- and tartrazine-free. Bottles of 100 (supplied by Janssen-Ortho).

Tylenol Elixir with Codeine: Each 5 mL of elixir contains: acetaminophen 160 mg and codeine phosphate 8 mg in a slightly viscous, clear red liquid that tastes and smells like cherry. Nonmedicinal ingredients: alcohol, citric acid, D&C Red No. 33, flavor, polyethylene glycol, sodium benzoate, sodium cyclamate, sorbitol and sucrose. Alcohol: 6% w/v (7% v/v). Energy: 45.93 kJ (10.98 kcal)/5 mL. Sucrose: 31% w/v. Gluten-, lactose-, sodium metabisulfite- and tartrazine-free. Dark amber glass bottles of 500 mL (supplied by Janssen-Ortho). Dispense in tight and light-resistant containers.