TYLENOL Tablets, Capsule, Suspension, Powder Ref.[50413] Active ingredients: Paracetamol

Immediate Release

Adults and children 12 years of age and older

325 mg tablet/caplet or liquid gel capsule: Take 1 every 4 to 6 hours. If pain or fever does not respond to 1 tablet/caplet or liquid gel, take 2 tablets/caplets or liquid gels at next dose. Do not take more than 12 tablets/caplets or liquid gels per day.

500 mg caplet or tablet: 500 mg to 1000 mg every 4 to 6 hours, as required, not to exceed 1000 mg per single dose. Taken in divided doses, not greater than 4000 mg acetaminophen in 24 hours.

Doses may be administered with or without food.

Children under 12 years of age

10 to 15 mg/kg every 4 to 6 hours, as required, not to exceed 50-75 mg/kg/24 hours. For children weighing more than 53 kg do not exceed the maximum allowed daily dose of 4000 mg acetaminophen. Alternatively, the following single doses (see Table 3) may be given every 4 to 6 hours not to exceed 5 doses in 24 hours. Doses may be given with or without food (i.e. milk, formula, juices, etc.). Dose determination based on weight is preferred over dose determination based on age.

Sustained Release

TYLENOL Arthritis Pain 8H Extended Release Tablets

Adults and children 12 years of age and over: Not greater than 2 sustained release caplets (1300 mg) every 8 hours, not to exceed 6 caplets (3900 mg) in 24 hours. Swallow each caplet whole with water on an empty stomach. Do not crush, chew or dissolve the caplet.

TYLENOL Muscle and Body Extended Release Tablets

Adults and children 12 years of age and older: Not greater than 2 sustained release caplets (1300 mg) every 8 hours, not to exceed 6 caplets (3900 mg) in 24 hours. Swallow each caplet whole with water on an empty stomach. Do not crush, chew or dissolve the caplet.

Dosage in Children

^a Consumer labeling for Infants' and Children’s TYLENOL acetaminophen does not offer dosing information for children less than 4 months of age; therefore, this dose is provided as a guideline for professional recommendations to the consumer. Note: Data not available to define appropriate adjustments, if any, needed for the immediate neonatal period. Use of antipyretics in the immediate neonatal period is extremely limited.
^b TYLENOL solid dosage forms may not be appropriate for children under 2 years of age.

Children’s TYLENOL Easy Dissolve (Acetaminophen Powder 160 mg)

Children aged 6-11 years: Tear pack and pour powder on child’s tongue. Single dose may be repeated every 4 to 6 hours, as needed. Do not give more than 5 doses in 24 hours.

Symptoms and Treatment

Acetaminophen: Typical Toxidrome: Hepatic injury is the principal toxic effect of a substantial acetaminophen overdose. In adults and adolescents (12 years of age and older), hepatic toxicity may occur following ingestion of greater than 7.5 to 10 grams over a period of 8 hours or less. Fatalities are infrequent (less than 3-4% of untreated cases) and have rarely been reported with overdoses of less than 15 grams. In children (<12 years of age), an acute overdosage of less than 150 mg/kg has not been associated with hepatic toxicity. Early symptoms following a potentially hepatotoxic overdose may include: anorexia, nausea, vomiting, diaphoresis, pallor and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion¹¹⁰.

If an acetaminophen extended release product is involved, it may be appropriate to obtain an additional plasma acetaminophen level 4-6 hours following the initial acetaminophen level.

Serious toxicity or fatalities have been extremely infrequent following an acute acetaminophen overdose in young children, possibly because of differences in the way they metabolize acetaminophen¹¹⁰.

The physician should be mindful that there is no early presentation that is pathognomic for the overdose. A high degree of clinical suspicion must always be maintained.

Untreated acetaminophen overdoses may produce hepatotoxicity. Acetaminophen hepatotoxicity occurs as a threshold effect and is characterized by a lack of toxicity at lower/therapeutic doses. Acetaminophen hepatotoxicity occurs after major depletion of glutathione, an endogenous detoxifying substance. Once the threshold is exceeded, increasing acetaminophen doses may produce increasing degrees of hepatotoxicity, unless N-acetylcysteine (NAC) is administered. Situations in which acetaminophen overdose and resultant hepatotoxicity may occur include acute intentional overdose and repeated supratherapeutic overdose in adults and acute accidental ingestion or overdose and repeated supratherapeutic overdose in children.

The clinical course of acetaminophen overdose generally occurs in a three-phase sequential pattern. The first phase begins shortly after ingestion and lasts for 12 to 24 hours. The patient may manifest signs of gastrointestinal irritability, nausea, vomiting, anorexia, diaphoresis, pallor and general malaise. If toxicity continues, there is a latent phase of up to 48 hours. During this second phase, initial symptoms abate and the patient may feel better. However, hepatic enzymes, bilirubin, and prothrombin time or INR values will progressively rise. Right upper quadrant pain may develop as the liver becomes enlarged and tender. Most patients do not progress beyond this phase, especially if given N-acetylcysteine (NAC) treatment early in the course. Signs and symptoms of the third phase depend on the severity of hepatic damage and usually occur from three to five days following overdose ingestion. Symptoms may be limited to anorexia, nausea, general malaise, and abdominal pain in less severe cases or may progress to confusion, stupor and sequelae of hepatic necrosis including jaundice, coagulation defects, hypoglycemia, and encephalopathy, as well as renal failure and cardiomyopathy. Death, if it occurs, is generally the result of complications associated with fulminant hepatic failure. Mortality rates in patients with toxic plasma levels who do not receive antidote therapy range from 3% to 4%.

Due to the wide availability of acetaminophen, it is commonly involved in single and mixed drug overdose situations and the practitioner should screen 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.

Specific Antidote: Any individual presenting with a possible acetaminophen overdose should be treated with N-acetylcysteine (NAC), even if the amount of acetaminophen ingested is unknown or questionable. A blood sample for determination of the plasma acetaminophen concentration should be obtained as early as possible, but no sooner than four hours following ingestion. Do not await the results of assays for plasma acetaminophen levels before initiating treatment NAC. If the acetaminophen plasma level is found to plot above the treatment line on the acetaminophen overdose nomogram, NAC treatment should be continued for a full course of therapy. NAC is used clinically to treat acute acetaminophen overdose, and acts by interacting with the oxidative intermediate, NAPQI. NAC 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. For full prescribing information, consult the product monograph for NAC.

General Management: When the possibility of acetaminophen overdose exists, treatment should begin immediately and include appropriate decontamination of the gastrointestinal tract, proper supportive care, careful assessment of appropriately timed serum acetaminophen estimations evaluated against the Rumack-Matthew nomogram, timely administration of NAC as required and appropriate follow-up care. Liver function tests should be performed initially and repeated at 24-hour intervals.

Overdose During Pregnancy

Acetaminophen is one of the most common overdoses in pregnancy. Hepatic toxicity of acetaminophen follows the formation of the highly reactive metabolite N-acetyl-p-benzoquinoneimine produced by acetaminophen metabolism through the cytochrome P450 mixed-function oxidase system. Hepatic failure can be prevented by timely administration of NAC either orally for 72 hours, or intravenously (IV) for 20 hours^79,80.

Acetaminophen crosses the human placenta⁸¹ though the fetus is theoretically at risk when maternal overdose of acetaminophen occurs. Acetaminophen can be transformed to its toxic metabolite since the oxidative capacity of fetal microsomes is present in the fetus by 14 weeks gestation⁸².

Studies on placental transfer of NAC in rats and sheep yielded conflicting results⁸³. Placental transfer of N-acetylcysteine in humans was demonstrated in 4 women treated with NAC for acetaminophen overdose during labour. NAC blood levels in the fetuses were within the range associated with therapeutic doses of NAC administered to adults with acetaminophen poisoning⁸⁴.

Fetal toxicity and stillbirth after a large (e.g. 30 g) acetaminophen overdose has been reported, but others observed a normal outcome for the offspring after acetaminophen overdose in pregnancy. A large case series investigated the pregnancy outcome in 300 women who had overdosed with acetaminophen. In this group, 118 cases occurred in the first trimester, 103 in the second trimester and 79 in the third trimester. Forty-nine of these mothers were treated with specific antidotes (33 with NAC and 16 with methionine). There were 219 live-born infants, 11 have malformations (including minor); none had been exposed to acetaminophen during the first trimester. Nine women were treated with NAC during the first trimester; there were two elective terminations; two spontaneous abortions, and five healthy babies in this group⁸⁵.

In summary, acetaminophen overdose during pregnancy should be treated according to regular protocols in order to prevent maternal and potentially fetal toxicity. Unless severe maternal toxicity develops, an acetaminophen overdose does not increase the risk for birth defects or adverse pregnancy outcomes.

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.

The following are clinical events associated with acetaminophen overdose that if seen with overdose are considered expected, including fatal events due to fulminant hepatic failure or its sequelae.

Table 4. Adverse Drug Reactions Identified with Overdose of Acetaminophen:

Metabolism and Nutrition Disorders: Anorexia

Gastrointestinal Disorders: Vomiting, Nausea, Abdominal discomfort

Hepatobiliary disorders: Hepatic necrosis, Acute hepatic failure, Jaundice, Hepatomegaly, Liver tenderness

General disorders and Administration Site Conditions: Pallor, Hyperhidrosis, Malaise

Investigations: Blood bilirubin increased, Hepatic enzymes increased, International normalized ratio increase, Prothrombin time prolonged, Blood phosphate increased, Blood lactate increased

The following clinical events are sequelae to acute hepatic failure and may be fatal. If these events occur in the setting of acute hepatic failure^111,112 associated with acetaminophen overdose (adults and adolescents: ≥12 years of age: >7.5 g within 8 hours; children <12 years of age: >150 mg/kg within 8 hours), they are considered expected.

Table 5. Expected Sequelae to Acute Hepatic Failure Associated with Acetaminophen Overdose:

Infections and Infestations: Sepsis, Fungal infection, Bacterial infection

Blood and Lymphatic System Disorders: Disseminated intravascular coagulation, Coagulopathy, Thrombocytopenia

Metabolism and Nutrition Disorders: Hypoglycemia, Hypophosphatemia, Metabolic Acidosis, Lactic Acidosis

Nervous System Disorders: Coma (with massive acetaminophen overdose or multiple drug overdose), Encephalopathy, Brain edema

Cardiac Disorders: Cardiomyopathy

Vascular Disorders: Hypotension

Respiratory, Thoracic and Mediastinal Disorders: Respiratory failure

Gastrointestinal Disorders: Pancreatitis, Gastrointestinal hemorrhage

Renal and Urinary Disorders: Acute renal failure

General Disorders and Administration Site Conditions: Multi-organ failure

Store at room temperature (15 to 30°C). TYLENOL Rapid Release (Gelcaps) should additionally be protected from high heat and humidity. Infants' and Children’s TYLENOL Suspensions should additionally be protected from light.