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Acetaminophen Caffeine Dihydrocodeine

Generic Name: acetaminophen, caffeine and dihydrocodeine bitartrate
Dosage Form: tablet

Acetaminophen, Caffeine and Dihydrocodeine Bitartrate Tablets
712.8 mg/60 mg/32 mg


Rx Only

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 4,000 milligrams per day, and often involve more than one acetaminophen-containing product.

DESCRIPTION:

Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets are supplied in tablet form for oral administration.
Each tablet contains:
Acetaminophen………………………….. 712.8 mg
Caffeine …………………………………….. 60 mg
Dihydrocodeine* bitartrate …………………. 32 mg
*Warning: May be habit forming

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

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

Dihydrocodeine Bitartrate (4,5α-epoxy-3-methoxy-17- methylmorphinan-6α-ol (+)-tartrate), an odorless, fine white powder is an opioid analgesic. It has the following structural formula:

In addition, each tablet also contains the following inactive ingredients: crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, stearic acid.

CLINICAL PHARMACOLOGY:

Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets contain dihydrocodeine which is a semisynthetic narcotic analgesic related to codeine, with multiple actions qualitatively similar to those of codeine; the most prominent of these involve the central nervous system and organs with smooth muscle components. The principal action of therapeutic value is analgesia.

This combination product also contains acetaminophen, a non-opiate, non-salicylate analgesic and antipyretic. This combination product contains caffeine as an analgesic adjuvant. Caffeine is also a central nervous system and cardiovascular stimulant.

INDICATIONS AND USAGE:

Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets are indicated for the relief of moderate to moderately severe pain.

CONTRAINDICATIONS:

This combination product is contraindicated in persons with hypersensitivity to dihydrocodeine, codeine, acetaminophen, caffeine, or any of the inactive components listed above, or any situation where opioids are contraindicated including significant respiratory depression (in unmonitored settings or in the absence of resuscitative equipment), acute or severe bronchial asthma or hypercapnia, and paralytic ileus.

WARNINGS:

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 4,000 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 4,000 milligrams of acetaminophen per day, even if they feel well.

Hypersensitivity/Anaphylaxis:

There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the 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 Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate Tablets immediately and seek medical care if they experience these symptoms. Do not prescribe Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate Tablets for patients with acetaminophen allergy.

Usage in Ambulatory Patients:

Dihydrocodeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.

Respiratory Depression:

Respiratory depression is the most dangerous acute reaction produced by opioid agonist preparations, although it is rarely severe with usual doses. Opioids decrease the respiratory rate, tidal volume, minute ventilation, and sensitivity to carbon dioxide. Respiratory depression occurs most frequently in elderly or debilitated patients, usually after large initial doses in nontolerant patients, or when opioids are given in conjunction with other agents that depress respiration. This combination product should be used with caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale and in patients with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or respiratory depression. In such patients, alternative non-opioid analgesics should be considered, and opioids should be administered only under careful medical supervision at the lowest effective dose.

Head Injury:

This combination product should be used cautiously in the presence of head injury or increased intracranial pressure. The effects of opioids on pupillary response and consciousness may obscure neurologic signs of increases in intracranial pressure in patients with head injuries. The respiratory depressant effects including carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions, or other causes of increased intracranial pressures.

Hypotensive Effect:

Dihydrocodeine, like all opioid analgesics, may cause hypotension in patients whose ability to maintain blood pressure has been compromised by a depleted blood volume or who receive concurrent therapy with drugs such as phenothiazines or other agents which compromise vasomotor tone. Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets may produce orthostatic hypotension in ambulatory patients. This combination product should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Drug Dependence

Dihydrocodeine can produce drug dependence of the codeine type and has the potential of being abused (See DRUG ABUSE AND DEPENDENCE).

PRECAUTIONS:

General:

Selection of patients for treatment with Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets should be governed by the same principles that apply to the use of similar opioid/non-opioid fixed combination analgesics. As with any such opioid analgesic, the dosing regimen should be adjusted for each patient (see DOSAGE AND ADMINISTRATION). This combination product should be used with caution in elderly or debilitated patients or those with any of the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addison's disease); asthma; central nervous system depression or coma; chronic obstructive pulmonary disease; decreased respiratory reserve (including emphysema, severe obesity, cor pulmonale, or kyphoscoliosis); delirium tremens; head injury; hypotension; increased intracranial pressure; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and toxic psychosis. The benefits and risks of using opioids in patients taking monoamine oxidase inhibitors and in those with a history of drug abuse should be carefully considered. The administration of an analgesic containing an opioid may obscure the diagnosis or clinical course in patients with acute abdominal conditions. This combination product may aggravate convulsions in patients with convulsive disorders and, like all opioids, may induce or aggravate seizures in some clinical settings. Acetaminophen is relatively non-toxic at therapeutic doses, but should be used with caution in patients with severe renal or hepatic disease. Care should be observed when using large doses of acetaminophen in malnourished patients or those with a history of chronic alcohol abuse because they may be more susceptible to hepatic damage similar to that observed with toxic overdosage.Caffeine in high doses may produce central nervous system and cardiovascular stimulation and gastrointestinal irritation.

Drug-Drug Interactions

Dihydrocodeine with Other Central Nervous System Depressants:

Patients receiving other opioid analgesics, sedatives or hypnotics, muscle relaxants, general anesthetics, centrally acting anti-emetics, phenothiazines or other tranquilizers, or alcohol concomitantly with this combination product may exhibit additive depressant effects on the central nervous system. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

Dihydrocodeine with Monoamine Oxidase Inhibitors:

Dihydrocodeine, like all opioid analgesics, interacts with monoamine oxidase inhibitors causing central nervous system excitation and hypertension.

Dihydrocodeine with Mixed Agonist/Antagonist Opioid Analgesics:

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) may reduce the analgesic effect of this combination product.

Acetaminophen-Drug Interactions:

Chronic and excessive consumption of alcohol may increase the hepatotoxic risk of acetaminophen. The potential for hepatotoxicity with acetaminophen also may be increased in patients receiving anticonvulsants that induce hepatic microsomal enzymes (including phenytoin, barbiturates, and carbamazepine) or isoniazide. Chronic ingestion of large doses of acetaminophen may slightly potentiate the effects of warfarin- and indandione-derivative anticoagulants. Severe hypothermia is possible in patients receiving acetaminophen concomitantly with phenothiazines.

Caffeine-Drug Interactions:

Caffeine may enhance the cardiac inotropic effects of beta-adrenergic stimulating agents. Coadministration of caffeine and disulfiram may lead to a substantial decrease in caffeine clearance. Caffeine may increase the metabolism of other drugs such as phenobarbital and aspirin. Caffeine accumulation may occur when products or foods containing caffeine are consumed concomitantly with quinolones such as ciprofloxacin.

Information for Patients/Caregivers:

Patients receiving Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets should be given the following information:

1. Patients should be advised that Acetaminophen, caffeine and dihydrocodeine bitartrate tablet may impair the mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.

2. Patients should be advised to report adverse experiences occurring during therapy.

3. Patients should be advised not to adjust the dose of Acetaminophen, caffeine and dihydrocodeine bitartrate tablet without consulting the prescribing professional.

4. Patients should not combine Acetaminophen, caffeine and dihydrocodeine bitartrate tablet with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur.

5. Women of childbearing potential who become, or are planning to become, pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.

6. Patients should be advised that Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.

7. Do not take Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate Tablets if you are allergic to any of its ingredients.

8. If you develop signs of allergy such as rash or difficulty breathing stop taking Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate Tablets and contact your healthcare provider immediately.

9. Do not take more than 4,000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose.

Pregnancy:

Teratogenic Effects – Pregnancy Category C.

Animal reproduction studies have not been conducted with Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets. It is also not known whether this combination product can cause fetal harm when administered to pregnant women or can affect reproduction capacity in males and females. This combination product should be given to pregnant women only if clearly needed, especially during the first trimester.

Labor and Delivery:

Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets are not recommended for use by women during and immediately before labor and delivery because oral opioids may cause respiratory depression in the newborn.

Nursing Mothers:

Dihydrocodeine bitartrate, acetaminophen and caffeine tablets are excreted in breast milk in small amounts, but the significance of their effects on nursing infants is not known. Because of the potential for serious adverse reactions in nursing infants from this combination product, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:

Safety and effectiveness of Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets in pediatric patients have not been established.

Geriatric Use:

Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets should be given with caution to the elderly.

Hepatic Impairment:

Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets should be given with caution to patients with hepatic insufficiency. Since dihydrocodeine is metabolized by the liver and since acetaminophen potentially causes hepatotoxicity, the effects of this combination product should be monitored closely in such patients.

Renal Impairment:

Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets should be used with caution and at reduced dosage in the presence of impaired renal function.

Pancreatic/Biliary Tract Disease:

Opioids may cause spasms of the sphincter of Oddi and should be used with caution in patients with biliary tract disease including pancreatitis.

ADVERSE REACTIONS:

Dihydrocodeine:

The most frequently observed adverse reactions include light-headedness, dizziness, drowsiness, headache, fatigue, sedation, sweating, nausea, vomiting, constipation, pruritus, and skin reactions. With the exception of constipation, tolerance develops to most of these effects. Other reactions that have been observed with dihydrocodeine or other opioids include respiratory depression, orthostatic hypotension, cough suppression, confusion, diarrhea, miosis, abdominal pain, dry mouth, indigestion, anorexia, spasm of biliary tract, and urinary retention. Physical and psychological dependence are possibilities. Hypersensitivity reactions (including anaphylactoid reactions), hallucinations, vivid dreams, granulomatous interstitial nephritis, severe narcosis and acute renal failure have been reported rarely during dihydrocodeine administration.

Acetaminophen:

Acetaminophen in therapeutic doses rarely causes adverse reactions. The most serious adverse reaction is hepatoxicity from overdosage (see OVERDOSAGE). Thrombocytopenia, leukopenia, pancytopenia, neutropenia, thrombocytopenic purpura, and agranulocytosis have been reported in patients receiving acetaminophen or p-aminophenol derivatives. Hypersensitivity reactions including urticarial or erythematous skin reactions, laryngeal edema, angioedema, or anaphylactoid reactions are rare.

Caffeine:

Adverse reactions associated with caffeine use include anxiety, anxiety neurosis, excitement, headaches, insomnia, irritability, lightheadedness, restlessness, tenseness, tremor, extrasystoles, palpitations, tachycardia, diarrhea, nausea, stomach pain, vomiting, diuresis, urticarcia, scintillating scotoma, and tinnitus.

DRUG ABUSE AND DEPENDENCE:

This combination product is subject to the provisions of the Controlled Substance Act, and has been placed in Schedule III.

Dihydrocodeine can produce drug dependence of the codeine type and therefore has the potential of being abused.

Like other opioid analgesics, dihydrocodeine may produce subjective effects other than analgesia (e.g., euphoria, relaxation), which may contribute to abuse by some patients.

Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of dihydrocodeine, and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral opioid analgesic medications.

Symptoms of dihydrocodeine withdrawal consist of irritability, restlessness, insomnia, diaphoresis, anxiety and palpitations.

Prolonged, high intake of caffeine may produce tolerance and habituation. Physical signs of withdrawal, such as headaches, irritation, nervousness, anxiety, and dizziness may occur upon abrupt discontinuation.

OVERDOSAGE:

Following an acute overdosage with Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate Tablets, toxicity may result from the dihydrocodeine or the acetaminophen. Toxicity due to the caffeine is less likely, due to the relatively small amounts in this formulation.

Signs and Symptoms:

Toxicity from dihydrocodeine poisoning includes the opioid triad of: pinpoint pupils, respiratory depression, and loss of consciousness. Convulsions, cardiovascular collapse, and death may occur. A single case of acute rhabdomyolysis associated with an overdose of dihydrocodeine has been reported.

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, delirium, tachycardia, and extrasystoles.

Because overdose information on this combination product is limited, it is unclear which of the signs and symptoms of toxicity would manifest in any particular overdose situation.

Treatment:

A single or multiple drug overdose with Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate Tablets 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 dihydrocodeine, 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.

DOSAGE AND ADMINISTRATION:

The usual adult dosage is one (1) Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets orally every four (4) hours, as needed. Dosage should be adjusted according to the severity of the pain and the response of the patient. No more than one (1) tablet should be taken in a 4-hour period. No more than five (5) doses, or five (5) tablets should be taken in a 24-hour period.

HOW SUPPLIED:

Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets, containing acetaminophen 712.8 mg, caffeine 60 mg and dihydrocodeine* bitartrate 32 mg (*Warning: May be habit-forming), are supplied in bottles of 30 tablets (NDC #64376-611-31) and 100 tablets (NDC #64376-611-01). Tablets are white, oval-shaped single scored and are debossed “Boca” on one side and “611” on the other side.

Store at 20°C to 25°C (68°F to 77°F). [see USP Controlled Room Temperature]. Protect from moisture.

Dispense in a tight, light-resistant container with a child-resistant closure.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Rx Only

Manufactured for:
Boca Pharmacal, Inc.
Coral Springs, FL 33065
www.bocapharmacal.com 1-800-354-8460

Rev. 05/2011

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

[Rev. 20]

ACETAMINOPHEN, CAFFEINE AND DIHYDROCODEINE BITARTRATE 
acetaminophen, caffeine and dihydrocodeine bitartrate tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:64376-611
Route of Administration ORAL DEA Schedule CIII    
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ACETAMINOPHEN (ACETAMINOPHEN) ACETAMINOPHEN 712.8 mg
CAFFEINE (CAFFEINE) CAFFEINE 60 mg
DIHYDROCODEINE BITARTRATE (DIHYDROCODEINE) DIHYDROCODEINE BITARTRATE 32 mg
Inactive Ingredients
Ingredient Name Strength
CROSPOVIDONE  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POVIDONE  
STARCH, CORN  
STEARIC ACID  
Product Characteristics
Color WHITE Score 2 pieces
Shape OVAL Size 19mm
Flavor Imprint Code Boca;611
Contains         
Packaging
# Item Code Package Description
1 NDC:64376-611-31 30 TABLET (CAPSULE) in 1 BOTTLE
2 NDC:64376-611-01 100 TABLET (CAPSULE) in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA040701 04/03/2007
Labeler - Boca Pharmacal, Inc. (170266089)
Registrant - Boca Pharmacal, Inc. (170266089)
Revised: 06/2011
 
Boca Pharmacal, Inc.



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