EXTRA STRENGTH TYLENOL NIGHTTIME

1 Dosing Considerations • Evidence from clinical studies suggests that acetaminophen is safe for use in elderly patients.

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September 2020 EXTRA STRENGTH TYLENOL® NIGHTTIME Acetaminophen / Diphenhydramine Hydrochloride Caplets Page 5 of 42 Because of the diphenhydramine hydrochloride component, EXTRA STRENGTH TYLENOL® NIGHTTIME should not be used by elderly patients who experience confusion at night time as this drug may produce excitation rather than sedation in the elderly.

2 Recommended Dose and Dosage Adjustment Adult use only (16 years and older): EXTRA STRENGTH TYLENOL® NIGHTTIME is to be taken as a single dose of 2 caplets at bedtime, or as directed by a physician. Do not exceed 2 caplets in 24 hours.

Do not take for more than 5 consecutive nights unless directed by a physician. Health Canada has not authorized an indication for pediatric use. 1 Pediatrics above. 5 Missed Dose Take once at night before bedtime. Do not take twice the recommended dose after a missed dose.

1 Adverse Reaction Overview Results of clinical trials conducted with Extra Strength TYLENOL® Nighttime caplets have shown that this combination product presents no additional risk compared to its individual active ingredients.

Adverse Drug Reactions of Acetaminophen Central Nervous System Effects:

Acetaminophen at recommended doses has no obvious effects on central nervous system function. In an overdose situation, central nervous system effects are Product Monograph Master Template Template Date: September 2020 EXTRA STRENGTH TYLENOL® NIGHTTIME Acetaminophen / Diphenhydramine Hydrochloride Caplets Page 15 of 42 uncommon.

Gastrointestinal Effects:

Acetaminophen at recommended doses does not cause gastric irritation, gastric erosions, occult or overt gastrointestinal blood loss or ulcers (Hoftiezer 1982, Johnson and Driscoll 1981). Blot and McLaughlin (2000) conducted an independent analysis of case-control data from a study conducted by the American College of Gastroenterology.

The risk of gastrointestinal bleeding increased two to three-fold among recent users of ASA, ibuprofen and other NSAIDs at OTC doses, and the risk was also dose-related. In contrast, the use of acetaminophen was not associated with an increased risk of gastrointestinal bleeding.

Hematologic Effects:

Acetaminophen does not have any immediate or delayed effects on small vessel hemostasis, as measured by bleeding time. In normal volunteers receiving a single dose of acetaminophen (975 or 1950 mg) or multiple doses of acetaminophen (1950 mg daily for 6 weeks), no change in bleeding time or platelet aggregation was observed (Mielke 1976).

In another study, a single 1000 mg dose of acetaminophen was given to normal volunteers and did not affect bleeding time or platelet aggregation (Seymour 1984). Patients with hemophilia receiving multiple doses of acetaminophen showed no significant changes in bleeding time (Kasper and Rapaport 1972, Mielke 1981).

Hematological reactions including thrombocytopenia, leucopenia, pancytopenia, neutropenia, and agranulocytosis have been reported, although these are rare and causality has not been established.

Hepatic Effects:

As an illustration of the margin of safety of acetaminophen at supratherapeutic doses, a comparison of serum concentrations of acetaminophen over time for a standard 15 mg/kg dose and for a dose exceeding the standard by a multiple of 5 (75 mg/kg) are shown in Figure 1.

The serum concentrations are drawn relative to the risk line for hepatotoxicity and treatment line of the Rumack- Matthew nomogram used to manage acute overdoses. The mean plasma concentrations for this supratherapeutic dose are well below the risk and treatment lines of the nomogram at all times.

However, to minimize the risk for adverse effects, the maximum recommended dose should not be exceeded. 6 g, 75 mg/kg) Dose Relative to Risk and Treatment Lines of the Acetaminophen Nomogram Acetaminophen in overdosage may cause hepatotoxicity.

In adults and adolescents, hepatotoxicity may occur following ingestion of greater than 150 mg/kg over a period of 8 hours or less. 5 g. In children, amounts less than 150 mg/kg are unlikely to produce hepatotoxicity. In both adults and children, toxicity associated with acetaminophen is usually caused by ingestion of quantities of the drug that are significantly above the recommended dosage range.

Hepatotoxicity, ranging from transient sharp transaminase elevations to fatal, fulminant hepatic failure, is the most common result of clinically significant overdosage (Linden and Rumack 1984). In a double-blind, placebo-controlled clinical study, healthy adults were given 4, 6 and 8 g/d of acetaminophen over 3 days (Gelotte 2003).

Plasma concentrations did not accumulate with repeat doses. Clinically all doses were well tolerated by the subjects and aminotransferase values stayed within normal limits throughout the study. These data provide information related to the margin of safety but are not intended to support dosing beyond the maximum recommended dose of 4 g/day.

A report has suggested that hepatotoxicity following greater than the recommended dose of acetaminophen may be enhanced by both prolonged fasting and/or chronic alcohol abuse (Whitcomb and Block 1994).

Acute Alcohol Use:

Acute alcohol ingestion refers to the occasional or intermittent use of alcohol. When taken together, alcohol competes with acetaminophen for CYP2E1. CYP2E1 accepts alcohol more readily than acetaminophen; therefore, less NAPQI is produced (Forrest 1982).

In the presence of alcohol, acetaminophen may be diverted to the glucuronidation and sulfation pathways. The overall result is that a smaller percentage of acetaminophen may be expected to be metabolized to the toxic intermediate, NAPQI, than would otherwise be the case (Rumack 2002).

NAPQI production is increased above baseline for the period up to 18-24 hours post ethanol clearance from the body. In healthy adults, at normal labeled doses of acetaminophen, the temporary increase in NAPQI production is more than accommodated by normal glutathione stores in the liver.

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September 2020 EXTRA STRENGTH TYLENOL® NIGHTTIME Acetaminophen / Diphenhydramine Hydrochloride Caplets Page 17 of 42 Hypersensitivity: Sensitivity reactions are rare and may manifest as rash, urticaria, dyspnea, hypotension, laryngeal edema, angioedema, bronchospasm, or anaphylaxis.

Cross-reactivity in ASA- sensitive persons has been rarely reported. If sensitivity is suspected, discontinue use of the drug.

Renal Effects:

Acute […]

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX. General Acetaminophen–containing products should be kept out of the reach of children. Packages contain enough medication to seriously harm a child. Consumers should not exceed 4 g/day of acetaminophen or use two or more acetaminophen- containing products together.

This includes combination products that contain acetaminophen. Do not use with other products containing salicylates or any other pain or fever medicine, or with any other product containing diphenhydramine, even one used on skin. Physicians should be cognizant of and supervise the use of acetaminophen in patients with chronic alcoholism, serious kidney or serious liver disease.

Physicians should alert their patients who regularly consume large amounts of alcohol not to exceed the recommended doses of acetaminophen.

Alcohol warning:

Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive doses of acetaminophen and should ask their doctor whether they should take acetaminophen or other pain relievers or fever reducers. Extra Strength TYLENOL® Nighttime should not be taken for pain for more than 5 days without consulting a physician.

Patients should 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 wheezing, rash, itching or persistent headache occur, as these may be signs of a condition that requires medical attention.

Patients with the following conditions should be advised to consult a physician before using diphenhydramine: a respiratory condition such as emphysema, chronic bronchitis, or acute or chronic bronchial asthma or chronic pulmonary disease; glaucoma; difficulty in urination due to enlargement of the prostate gland.

Diphenhydramine may enhance the sedative effects of central nervous system depressants including alcohol, sedatives, and tranquilizers resulting in marked drowsiness. While taking this product, consumers should be advised to avoid alcoholic beverages and consult their healthcare professional prior to taking with central nervous system depressants.

1 aluminum lake, hypromellose, magnesium stearate, polyethylene glycol, polysorbate 80, sodium citrate, sodium starch glycolate, titanium dioxide.

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September 2020 EXTRA STRENGTH TYLENOL® NIGHTTIME Acetaminophen / Diphenhydramine Hydrochloride Caplets Page 11 of 42 or pyloroduodenal obstruction. Hepatic/Biliary/Pancreatic Slower metabolism of acetaminophen, increased activity of the cytochrome P450 enzyme system, or depleted glutathione stores are cited as theoretical risk factors for acetaminophen hepatotoxicity in patients with chronic liver disease.

However, acetaminophen has been studied in both adults and children with a wide variety of liver diseases including various types of cirrhosis, hepatitis (including hepatitis C), nodular transformation, congenital hepatic fibrosis, and α1-antitrypsin deficiency.

In none of these conditions is there evidence of an increased risk for hepatotoxicity at currently recommended acetaminophen doses but the studies were insufficiently powered to definitely establish the extent of risk. Forrest et al (1979) compared acetaminophen metabolism following a single 1500 mg dose in normal subjects, patients with mild liver disease, and patients with severe liver disease.

There were no significant differences in overall 24-hour urinary excretion of acetaminophen and glucuronide, sulfate, cysteine, and mercapturic acid conjugates, evidence that acetaminophen metabolism was similar to that in normal subjects.

However, the elimination half-life was significantly prolonged in patients with severe liver disease. At the currently recommended doses acetaminophen is a suitable analgesic choice for use in patients with chronic stable liver disease when used under physician supervision.

g. g. overdosing when pain relief is not satisfactory), simultaneous use of multiple acetaminophen-containing preparations, accidental overdose or in very rare cases, after recommended doses, although causality has not been determined.

The hepatotoxic reaction can be severe and life-threatening. Early symptoms following a hepatotoxic overdose may include nausea, vomiting, diaphoresis, lethargy, and general malaise. If appropriate treatment is not instituted, these may progress to upper quadrant pain, confusion, stupor, and sequelae of hepatic necrosis, such as jaundice, coagulation defects, hypoglycemia, and encephalopathy.

Renal failure and cardiomyopathy may also occur. In the event of known or suspected overdosage, treatment with N-acetyl cysteine should be instituted immediately (see 5 OVERDOSAGE), even when there are no obvious symptoms. Failure to promptly treat acetaminophen hepatotoxicity with N-acetyl cysteine can result in liver failure, leading to liver transplantation and/or death.

Chronic Alcohol Use:

Excessive alcohol use may increase risk of liver toxicity from acetaminophen overdose (acute or chronic) (Critchley 1982 and 1983, Kuffner 1997). Prospective data from Kuffner et al (1997, 2001) demonstrate that chronic alcoholics can take recommended doses of acetaminophen without the added risk of liver injury.

In these prospective, placebo-controlled studies; the researchers evaluated an actively drinking group of alcoholics with a high prevalence of malnourishment. The study participants abruptly stopped their daily alcohol intake and took acetaminophen the next day.

This should theoretically make them vulnerable to acetaminophen injury because their CYP2E1 […]

EXTRA STRENGTH TYLENOL® NIGHTTIME is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.