Acetaminophen / caffeine / dihydrocodeine Side Effects

Some side effects of acetaminophen / caffeine / dihydrocodeine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

For the Consumer

Applies to acetaminophen / caffeine / dihydrocodeine: oral capsule, oral tablet

Get emergency medical help if you have any of these signs of an allergic reaction while taking acetaminophen / caffeine / dihydrocodeine: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using acetaminophen, caffeine, and dihydrocodeine and call your doctor at once if you have a serious side effect such as:

• shallow breathing, slow heartbeat;

• fast or pounding heart rate, feeling light-headed, fainting;

• confusion, hallucinations, unusual thoughts or behavior;

• muscle twitching;

• problems with urination;

• easy bruising or bleeding; or

• nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Less serious side effects include:

• feeling dizzy or drowsy, shaky or agitated;

• mild nausea, vomiting, upset stomach; constipation, diarrhea;

• mood changes, sleep problems (insomnia);

• sweating, urinating more than usual;

• ringing in your ears, blurred vision; or

• dry mouth.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

For Healthcare Professionals

Applies to acetaminophen / caffeine / dihydrocodeine: oral capsule, oral tablet

Respiratory

Respiratory side effects of dihydrocodeine have included respiratory depression and cough suppression.

Hepatic

Hepatic side effects of acetaminophen have included severe and sometimes fatal dose dependent hepatitis in alcoholic patients. Hepatotoxicity has been increased during fasting. Several cases of hepatotoxicity from chronic acetaminophen therapy at therapeutic doses have also been reported despite a lack of risk factors for toxicity.

Alcoholic patients may develop hepatotoxicity after even modest doses of acetaminophen. In healthy patients, approximately 15 grams of acetaminophen is necessary to deplete liver glutathione stores by 70% in a 70 kg person. However, hepatotoxicity has been reported following smaller doses. Glutathione concentrations may be repleted by the antidote N-acetylcysteine. One case report has suggested that hypothermia may also be beneficial in decreasing liver damage during overdose.

In a recent retrospective study of 306 patients admitted for acetaminophen overdose, 6.9% had severe liver injury but all recovered. None of the 306 patients died.

A 19-year-old female developed hepatotoxicity, reactive plasmacytosis and agranulocytosis followed by a leukemoid reaction after acute acetaminophen toxicity.

Cardiovascular

Two cases of hypotension have been reported following the administration of acetaminophen. Both patients experienced significant decreases in blood pressure. One of the two patients required pressor agents to maintain adequate mean arterial pressures. Neither episode was associated with symptoms of anaphylaxis. Neither patient was rechallenged after resolution of the initial dose.

Cardiovascular side effects of acetaminophen have included two cases of hypotension.

Cardiovascular side effects of caffeine have included extrasystole, palpitation, and tachycardia.

Cardiovascular side effects of dihydrocodeine have included orthostatic hypotension.

Metabolic

In a case of metabolic acidosis, causality is uncertain as more than one drug was ingested. The case of metabolic acidosis followed the ingestion of 75 grams of acetaminophen, 1.95 grams of aspirin, and a small amount of a liquid household cleaner. The patient also had a history of seizures which the authors reported may have contributed to an increased lactate level indicative of metabolic acidosis.

Metabolic side effects of acetaminophen have included metabolic acidosis following a massive overdose of acetaminophen.

Dermatologic

Dermatologic side effects of acetaminophen have rarely included erythematous skin rashes. Acetaminophen associated bullous erythema and purpura fulminans have been reported. One case of toxic epidermal necrolysis associated with acetaminophen administered to a pediatric patient has been reported.

Dermatologic side effects of caffeine have included urticaria.

Gastrointestinal

Gastrointestinal side effects of acetaminophen have rarely included acute pancreatitis in alcoholics and after overdose.

Gastrointestinal side effects of caffeine have included nausea, diarrhea, stomach pain, and vomiting.

Gastrointestinal side effects of dihydrocodeine have included nausea, vomiting, constipation, diarrhea, abdominal pain, dry mouth, indigestion, and anorexia.

General

In general, acetaminophen is well tolerated when administered in therapeutic doses.

General side effects of caffeine have included irritability and restlessness. Consumption of higher doses of caffeine (less than 600 mg/day) has been reported to have lead to caffeinism. Caffeinism is a syndrome characterized by anxiety, restlessness, and sleep disorders (similar to anxiety states). It has also been reported that chronic, heavy caffeine ingestion may be associated with depression. Caffeine may cause anxiety and panic in panic disorder patients and may aggravate premenstrual syndrome (PMS).

General side effects of dihydrocodeine have included sweating and tolerance.

Renal

Acute tubular necrosis usually occurs in conjunction with liver failure, but has been observed as an isolated finding in rare cases of acetaminophen use. A possible increase in the risk of renal cell carcinoma has been associated with chronic acetaminophen use as well.

One case-controlled study of patients with end-stage renal disease suggested that long term consumption of acetaminophen may significantly increase the risk of end-stage renal disease particularly in patients taking multiple doses per day.

However, a cohort study of analgesia use in initially healthy men concluded that moderate use of analgesics including acetaminophen was not associated with increased risk of renal disease.

Renal side effects of acetaminophen have rarely included acute renal failure, acute tubular necrosis, and interstitial nephritis. Adverse renal effects are most often observed after overdose, after chronic abuse (often with multiple analgesics), or in association with acetaminophen-related hepatotoxicity.

Renal side effects of caffeine have included increased urine flow rate, creatinine clearance, sodium and calcium excretion.

Renal side effects of dihydrocodeine have included granulomatous interstitial nephritis and acute renal failure.

Hematologic

Hematologic side effects of acetaminophen have included thrombocytopenia, thrombocytopenia purpura, leukopenia, pancytopenia, neutropenia, and agranulocytosis.

Hypersensitivity

Hypersensitivity side effects of acetaminophen have rarely included urticaria, erythematous skin reaction, laryngeal edema, angioedema, and anaphylaxis.

Hypersensitivity side effects of dihydrocodeine have included anaphylaxis.

Musculoskeletal

Musculoskeletal side effects of caffeine have included tenseness and tremor.

Psychiatric

Psychiatric side effects of caffeine have included anxiety and anxiety neurosis.

Psychiatric side effects of dihydrocodeine have included severe narcosis, hallucinations, and vivid dreams.

Endocrine

Endocrine side effects of caffeine have rarely included alterations in serum glucose such as hypoglycemia and hyperglycemia.

Several studies report a decrease in insulin sensitivity in individuals following caffeine consumption. The mechanism leading to this effect is unknown but may be related to elevated serum epinephrine levels.

A few studies report a possible decreased risk of type 2 diabetes mellitus in individuals who consume coffee.

Nervous system

Nervous system side effects of caffeine have included central nervous system stimulation such as irritability, restlessness, jitteriness, headache, insomnia, and lightheadedness.

Nervous system side effects of dihydrocodeine have included lightheadedness, dizziness, drowsiness, headache, sedation, and confusion.

Ocular

Ocular side effects of caffeine have included scintillating scotoma.

Other

Other side effects of caffeine have included fibrocystic breast disease in women. One study has reported that while favorable subjective and performance-enhancing stimulant effects occur at low to intermediate caffeine doses, the unfavorable subjective and somatic effects, as well as performance disruption from high doses of caffeine may intrinsically limit the doses of caffeine used in the general population.

In one study of 634 women with fibrocystic breast disease (compared to 1066 women without the disease), the occurrence of fibrocystic breast disease was positively associated with average daily consumption of caffeine. Women who consumed 31 to 250 mg/day of caffeine were reported to have a 1.5 times increase in odds to have the disease. Women who consumed over 500 mg/day of caffeine were reported to have a 2.3 times increase in odds.

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