Butalbital, Acetaminophen, Caffeine and Codeine Phosphate (Page 9 of 12)

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Do not abruptly discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in a patient physically dependent on opioids. Rapid tapering of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.4), Warnings and Precautions (5.16)].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

10 OVERDOSAGE

Clinical Presentation

Acute overdose with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

Signs and Symptoms

Symptoms attributable to acute barbiturate poisoning include drowsiness, confusion, and coma; respiratory depression; hypotension; and hypovolemic shock.

Toxicity from codeine poisoning includes the opioid triad of: pinpoint pupils, depression of respiration, and loss of consciousness. Convulsions may occur.

In acetaminophen overdosage: dose dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, 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, and delirium, tachycardia, and extrasystoles.

Treatment of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist.

Because the duration of opioid reversal is expected to be less than the duration of action of codeine in Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

A single or multiple drug overdose with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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. For respiratory depression due to overdosage or unusual sensitivity to codeine, parenteral naloxone is a specific and effective antagonist.

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.

11 DESCRIPTION

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are supplied in capsule form for oral administration. Each capsule contains:

Butalbital, USP 50 mg
Acetaminophen, USP 325 mg
Caffeine, USP 40 mg
Codeine phosphate, USP 30 mg

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

Chemical Structure

C11 H16 N2 O3 MW 224.26

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

Chemical Structure

C8 H9 NO2 MW 151.16

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

Chemical Structure

C8 H10 N4 O2 MW 194.19

Codeine phosphate (7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1)(salt) hemihydrate) is an opioid agonist. It has the following structural formula:

Chemical Structure
(click image for full-size original)

C18 H24 NO7 P anhydrous MW 397.37

Inactive Ingredients: Microcrystalline Cellulose, Sodium Lauryl Sulfate, Stearic Acid, Talc. The gelatin capsules are printed with edible inks containing Titanium Dioxide, Gelatin, FD&C Blue No. 1, FD&C Red No. 40, and FD&C Yellow No. 5 [see Warnings and Precautions (5.21)].

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