Acetaminophen, aspirin, and caffeine

Use this medication exactly as directed on the label, or as it has been prescribed by your doctor. Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death.

Take the medicine with food or milk if it makes your stomach upset.

Call your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever lasting longer than 3 days, or any swelling or pain lasting longer than 10 days.

This medication can cause unusual results with certain lab tests for glucose (sugar) in the urine. Tell any doctor who treats you that you are using acetaminophen, aspirin, and caffeine.

If you need surgery, tell the surgeon ahead of time that you are using acetaminophen, aspirin, and caffeine. You may need to stop using the medicine for a short time.

Store at room temperature away from moisture and heat.

Avoid drinking alcohol while you are taking this medication. Alcohol may increase your risk of stomach bleeding while taking aspirin, or liver damage while taking acetaminophen.

Ask a doctor or pharmacist before using any other cough, cold, allergy, pain, menstrual symptom, or fever medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose. Aspirin and caffeine are also contained in many combination medicines. Check the label to see if a medicine contains acetaminophen, APAP, aspirin, or caffeine.

Avoid taking another NSAID (nonsteroidal anti-inflammatory drug) such as aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

Avoid coffee, tea, cola, energy drinks or other sources of caffeine while taking this medication. They can add to the side effects of the caffeine in the medication.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

In rare cases, acetaminophen may cause a severe skin reaction that can be fatal. This could occur even if you have taken acetaminophen in the past and had no reaction. Stop taking this medicine and call your doctor right away if you have skin redness or a rash that spreads and causes blistering and peeling. If you have this type of reaction, you should never again take any medicine that contains acetaminophen.

Stop using this medicine and call your doctor at once if you have:

• severe anxiety, agitation, confusion, panic;

• easy bruising or bleeding;

• a light-headed feeling, like you might pass out;

• if you feel very thirsty or hot, are unable to urinate, and have heavy sweating or hot and dry skin;

• symptoms of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

• high potassium--slow heart rate, weak pulse, muscle weakness, tingly feeling; or

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

Common side effects may include:

• upset stomach, heartburn;

• depressed mood, feeling anxious or restless; or

• sleep problems (insomnia).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other drugs may interact with acetaminophen, aspirin, and caffeine, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Applies to acetaminophen / aspirin / caffeine: oral powder for reconstitution, oral tablet

Hepatic

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.

One study has suggested that acetaminophen may precipitate acute biliary pain and cholestasis. The mechanism of this effect may be related to inhibition of prostaglandin and alterations in the regulation of the sphincter of Oddi.

Cases of acute pancreatitis have been reported rarely with the use of acetaminophen.

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

Hepatic side effects including hepatotoxicity and hepatitis have been reported.

In alcoholic patients, severe and sometimes fatal dose dependent hepatitis has been reported with acetaminophen use. Hepatotoxicity has been increased during fasting.

Cases of aspirin induced hepatotoxicity and cholestatic hepatitis, particularly at high doses, have been reported rarely.[Ref]

Gastrointestinal

Endoscopically identifiable gastric mucosal lesions occur in most patients who receive a single dose of aspirin. Clinically evident gastrointestinal bleeding has been reported in as many as 3% of treated elderly patients. Anorectal ulceration and rectal stenosis have been reported in patients who abuse aspirin containing rectal suppositories. One case controlled study has suggested that an association between aspirin (and other NSAID) consumption and appendicitis may exist.[Ref]

Gastrointestinal side effects have been common and have included epigastric distress (in as many as 83% of patients treated with regular aspirin), abdominal discomfort or pain, endoscopically identifiable gastric mucosal lesions, nausea, and vomiting. More serious gastrointestinal effects include hemorrhage, peptic ulcers, perforation, and esophageal ulcerations.

In clinical trials of caffeine citrate, five cases of necrotizing enterocolitis were reported among the 46 infants exposed to the caffeine citrate injection.

Gastrointestinal side effects have been rare with the use of acetaminophen, except in alcoholics and after overdose.[Ref]

General

General side effects including caffeinism have been reported. Consumption of higher doses of caffeine (>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 PMS.

In general, many side effects noted with aspirin use are dose-related.[Ref]

Renal

The mechanism of an aspirin induced decrease in renal function may be related to inhibition of renal prostaglandin synthesis with consequent decreases in renal blood flow. Vasodilating renal prostaglandins may be particularly important in patients who exhibit arterial underfilling (i.e. heart failure, cirrhosis). The administration of high doses of NSAIDs to such patients has produced acute renal failure in rare instances.

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

A case control 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 more than two pills per day.[Ref]

Renal side effects of aspirin have included reduction in glomerular filtration rate (particularly in patients who are sodium restricted or who exhibit diminished effective arterial blood volume, such as patients with advanced heart failure or cirrhosis), interstitial nephritis, papillary necrosis, elevations in serum creatinine, elevations in blood urea nitrogen, proteinuria, hematuria, and renal failure.

Renal side effects have been rare with acetaminophen use and have included 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.[Ref]

Hypersensitivity

Hypersensitivity side effects of aspirin have included bronchospasm, rhinitis, conjunctivitis, urticaria, angioedema, and anaphylaxis. Approximately 10% to 30% of asthmatics are aspirin sensitive (with the clinical triad of aspirin sensitivity, bronchial asthma, and nasal polyps).

Hypersensitivity reactions such as anaphylaxis and fixed drug eruptions have rarely been reported in association with acetaminophen use.[Ref]

The mechanism of aspirin induced hypersensitivity may be related to an up-regulation of the 5-lipoxygenase pathway of arachidonic acid metabolism with a resulting increase in the products of 5-lipoxygenase (such as leukotrienes).[Ref]

Hematologic

Hematologic side effects of aspirin (in addition to predictable antiplatelet effects which may result in hemorrhage) have included increased blood fibrinolytic activity. In addition, hypoprothrombinemia, thrombocytopenia, thrombocyturia, megaloblastic anemia, and pancytopenia have been reported rarely. Aplastic anemia has also been reported.

Rare cases of thrombocytopenia associated with acetaminophen have been reported. Methemoglobinemia with resulting cyanosis has also been observed in the setting of acute overdose.[Ref]

Dermatologic

Dermatologic side effects from the use of aspirin including Stevens-Johnson syndrome and a lichenoid eruption have been reported rarely.

Dermatologic side effects associated with acetaminophen includes the risk of rare but potentially fatal serious skin reactions known as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP). Erythematous skin rashes associated with acetaminophen have been reported, but are rare. Acetaminophen associated bullous erythema and purpura fulminans have been reported.[Ref]

Respiratory

Respiratory side effects including hyperpnea, pulmonary edema, and tachypnea have occurred in patients receiving aspirin.

A case of acetaminophen induced eosinophilic pneumonia has been reported.[Ref]

Cardiovascular

Two cases 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 episode.[Ref]

Cardiovascular side effects of aspirin have been reported rarely and have included salicylate induced variant angina, ventricular ectopy, conduction abnormalities, and hypotension, particularly during salicylate toxicity.

Several cases of hypotension have been reported following the administration of acetaminophen.[Ref]

Metabolic

Metabolic side effects of aspirin have included dehydration and hyperkalemia. Respiratory alkalosis and metabolic acidosis, particularly during salicylate toxicity, have been reported. A case of hypoglycemia has also been reported in a patient on hemodialysis.[Ref]

Nervous system

Nervous system side effects in patients receiving aspirin have included agitation, cerebral edema, coma, confusion, dizziness, headache, cranial hemorrhage, lethargy, and seizures. Some investigators have reported that modest doses may result in decreased frequency selectivity and may therefore impair hearing performance, particularly in the setting of background noise.[Ref]

Regarding the use of aspirin, some investigators have suggested that tinnitus may be a less reliable indicator of salicylate toxicity than previously believed. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In a study of rheumatoid arthritis patients, those with tinnitus had no greater salicylate levels than those without tinnitus. Elderly patients may be less likely to perceive tinnitus than younger patients.[Ref]

Other

Other side effect have also been reported. In one study of the effects of caffeine, 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.

Reye's syndrome, although rare, has been associated with aspirin use in children with an acute viral illness. Reye's syndrome has also been reported even more rarely in adults.

Prolonged labor and pregnancy, decreased infant birth weight and stillborn births, antepartum and postpartum bleeding have occurred due to aspirin use by women during the third trimester of pregnancy.[Ref]

Reye's syndrome typically involves vomiting, neurologic dysfunction, and hepatic dysfunction during or shortly after an acute viral infection.[Ref]

Musculoskeletal

Musculoskeletal side effects including rhabdomyolysis have occurred in patients receiving aspirin.[Ref]

Endocrine

Endocrine side effects of aspirin use have included hypoglycemia and hyperglycemia.[Ref]

Ocular

Ocular side effects including cases of localized periorbital edema have been reported rarely in patients receiving aspirin.[Ref]

Oncologic

Oncologic side effects have been reported. Several epidemiologic studies have suggested that chronic aspirin use may decrease the risk of large bowel neoplasms. However, other studies have not found this beneficial effect.[Ref]

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

Up to a total of 650 of acetaminophen and aspirin combined every 4-6 hours as needed.

Use acetaminophen with caution in patients with liver disease. Chronic use of acetaminophen is not recommended in patients with liver disease.

The use of aspirin in patients with severe hepatic impairment is not recommended due to the potential for increased risk of clinically significant bleeding and other adverse effects.

One small study has reported that following a 1000 mg dose of acetaminophen to nursing mothers, nursing infants receive less than 1.85% of the weight-adjusted maternal oral dose.

Aspirin is excreted into human milk in small amounts. Peak milk salicylate levels have been reported at nine hours after maternal dosing (and measured at 1.1 mg/dL). Use of large doses of aspirin can result in rashes, platelet abnormalities, and bleeding in nursing infants. Because of a single case report of metabolic acidosis, the American Academy of Pediatrics characterizes aspirin as a drug that has been "associated with significant effects on some nursing infants and should be given to nursing mothers with caution." Acetaminophen is excreted into human milk in small concentrations. One case of a rash has been reported in a nursing infant. Acetaminophen is considered compatible with breast-feeding by the American Academy of Pediatrics. Caffeine is excreted into human milk in small amounts. Adverse effects in the nursing infant are unlikely. However, irritability and poor sleep patterns have been reported in nursing infants. The amount of caffeine generally found in caffeinated beverages is considered to usually be compatible with breast-feeding by the American Academy of Pediatrics. Because caffeine is excreted into human milk and because caffeine is metabolized slowly by nursing infants, consumption of more than moderate levels of caffeine by nursing mothers is not recommended.