Vanatol S

HEPATOTOXICITY

ACETAMINOPHEN HAS BEEN ASSOCIATED WITH CASES OF ACUTE LIVER FAILURE, AT TIMES RESULTING IN LIVER TRANSPLANT AND DEATH. MOST OF THE CASES OF LIVER INJURY ARE ASSOCIATED WITH THE USE OF ACETAMINOPHEN AT DOSES THAT EXCEED 4000 MILLIGRAMS PER DAY, AND OFTEN INVOLVE MORE THAN ONE ACETAMINOPHEN-CONTAINING PRODUCT.

VANATOL® S (butalbital, acetaminophen and caffeine) is supplied in liquid form for oral administration.

Each 15 mL contains:

Butalbital USP.................................................... 50 mg

Warning: May be habit-forming.

Acetaminophen USP.......................................... 325 mg

Caffeine USP...................................................... 40 mg

Alcohol ............................................................... 7.368%

In addition, this drug product contains the following inactive ingredients: citric acid, ethyl maltol, liquid glucose, glycerin, methylparaben, propylene glycol, propylparaben, purified water, saccharin sodium, sorbitol solution, sucrose, with FD&C yellow #6 as coloring, and natural and artificial flavoring.

Butalbital (5-allyl-5-isobutylbarbituric acid), is a short to intermediate-acting barbiturate. It has the following structural formula:

C11H16N2O3 MW = 224.26

Acetaminophen (4'-hydroxyacetanilide), is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:

C8H9NO2 MW = 151.16

Caffeine (1,3,7-trimethylxanthine), is a central nervous system stimulant. It has the following structural formula:

C8H10N4O2 MW = 194.19

Hepatotoxcity: Butalbital is habit-forming and potentially abusable. Consequently, the extended use of this product is not recommended.

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.

Serious Skin Reactions: Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Hypersensitivity/anaphylaxis: There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue VANATOL® S immediately and seek medical care if they experience these symptoms. Do not prescribe VANATOL® S for patients with acetaminophen allergy.

Abuse and Dependence

Butalbital: Babiturates may be habit forming: Tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high doses of barbiturates. The average daily dose for the barbiturate addict is usually about 1500 mg. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than two-fold. As this occurs, the margin between an intoxication dosage and fatal dosage becomes smaller. The lethal dose of a barbiturate is far less if alcohol is also ingested. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. One method involves initiating treatment at the patient's regular dosage level and gradually decreasing the daily dosage as tolerated by the patient.

Following an acute overdosage of butalbital, acetaminophen and caffeine, toxicity may result from the barbiturate or the acetaminophen. Toxicity due to caffeine is less likely, due to the relatively small amounts in this formulation.

Signs and Symptoms: Toxicity from barbiturate poisoning include drowsiness, confusion, and coma; respiratory depression; hypotension; and hypovolemic shock.

In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necroses, hypoglycemic coma and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.

Acute caffeine poisoning may cause insomnia, restlessness, tremor, delirium, tachycardia and extrasystoles.

Treatment: A single or multiple drug overdose with this combination product is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption.

Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered.

Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication.

One or two tablespoonfuls (15 mL or 30 mL) every four hours. Total daily dosage should not exceed 6 tablespoonfuls.

Extended and repeated use of this product is not recommended because of the potential for physical dependence.