1 Name of Medicine
Paracetamol and caffeine.
2 Qualitative and Quantitative Composition
Each tablet contains paracetamol 500 mg and caffeine 65 mg.
Excipients with known effect.
Potassium sorbate.
For the full list of excipients, see Section 6.1 List of Excipients.3 Pharmaceutical Form
White colour, capsule shaped film coated tablets debossed "PC 65" on one side and scored on other side.
4.1 Therapeutic Indications
For the temporary relief of pain and discomfort associated with headache, tension headache, migraine headache, osteoarthritis, arthritis, cold and flu symptoms, toothache, dental procedures, muscular aches, sore throat and period pain. Reduces fever.
4.2 Dose and Method of Administration
Dosage.
For adults and children 12 years and older.
2 tablets every 4 to 6 hours (as required) with water. Maximum of 8 tablets in 24 hours. Not recommended in children under the age of 12 years.4.3 Contraindications
This medication is contraindicated in patients who are hypersensitive to paracetamol, caffeine or to any of the excipients of this medicine. It must not be used in patients with known glucose-6-phosphate-dehydrogenace deficiency. This medicine must not be used in patients with impaired liver function.
4.4 Special Warnings and Precautions for Use
This medication may be dangerous when used in large amounts or for long periods. Hepatotoxicity may occur with paracetamol even at therapeutic doses, after short treatment duration and in patients without pre-existing liver dysfunction. Hepatotoxicity may develop following as little as 10 to 15 g of paracetamol and hepatic failure is known to occur occasionally with long term use of paracetamol.
To avoid the risk of overdose.
Check that paracetamol is absent from the composition of other medicinal products taken concomitantly.
Patients with known analgesic intolerance or known bronchial asthma must only use this medication after having consulted a physician (hypersensitivity reactions including bronchospasm possible).
Caution is advised in patients with underlying sensitivity to aspirin and/or to non-steroidal anti-inflammatory drugs (NSAIDs).
Severe cutaneous adverse reactions (SCARs).
Life threatening cutaneous reactions Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported with the use of paracetamol. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If symptoms or signs of SJS and TEN (e.g. progressive skin rash often with blisters or mucosal lesions) occur, patients should stop paracetamol treatment immediately and seek medical advice.
Paracetamol should be used upon medical advice in patients with:
severe renal insufficiency;
chronic alcohol use including recent cessation of alcohol intake;
low glutathione reserves;
Gilbert's syndrome.
Excessive intake of caffeine (e.g. coffee, tea and some canned drinks) should be avoided while taking this product. If symptoms persist, medical advice must be sought.
Keep out of sight and reach of children.
Use in hepatic impairment.
This medication should not be administered to patients with hepatic dysfunction (see Section 4.3 Contraindications).
Use in renal impairment.
This medication should not be administered to patients with renal dysfunction (see Section 4.3 Contraindications).
Use in the elderly.
No data available.
Paediatric use.
Not recommended in children under the age of 12 years.
Effects on laboratory tests.
Uric acid and blood glucose.
Intake of paracetamol may affect the laboratory determination of uric acid by phosphotungstic acid and of blood glucose by glucose oxidase-peroxidase.4.5 Interactions with Other Medicines and Other Forms of Interactions
Paracetamol may increase the risk of bleeding in patients taking warfarin and other antivitamin K. Anticoagulant dosage may require reduction and patients should be monitored for appropriate coagulation and bleeding complications.
Paracetamol absorption is increased by drugs which increase gastric emptying e.g. metoclopramide and domperidone and decreased by drugs which decrease gastric emptying e.g. propantheline, antidepressants with anticholinergic properties, narcotic analgesics.
Paracetamol may increase chloramphenicol concentrations by slowing down excretion, entailing the risk of increased toxicity. The risk of paracetamol toxicity may be increased in patients receiving other potentially hepatoxic drugs or drugs that induce liver microsomal enzymes, such as antiepileptics (such as phenobarbital, phenytoin, carbamazepine, topiramate), barbiturates, hypnotics, rifampicin and alcohol.
Paracetamol excretion may be affected and plasma concentrations altered when given probenecid.
Cholestyramine reduces the absorption of paracetamol if given within 1 hour of paracetamol. Chelating resins can decrease the intestinal absorption of paracetamol and potentially decrease its efficacy if taken simultaneously. In general, there must be an interval of more than 2 hours between taking the resin and taking paracetamol, if possible.
Co-administration of flucloxacillin with paracetamol may lead to metabolic acidosis, particularly in patients presenting risk factors of glutathione depletion, such as sepsis, malnutrition or chronic alcoholism.
When used concurrently with zidovudine, an increased tendency for neutropenia may develop. Combination of paracetamol and zidovudine should be avoided.
Caffeine undergoes extensive metabolism by hepatic microsomal cytochrome P450 isoenzyme CYP1A2, and is subject to numerous interactions with other drugs and substances which enhance or reduce its metabolic clearance.
No potentially hazardous interactions with caffeine have been reported. However, patients who take medicines that decrease caffeine elimination may need to limit caffeine intake to avoid adverse events.
Caffeine may increase the elimination of lithium from the body. Concomitant use is therefore not recommended.
4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
No data available.
(Category A)
Both paracetamol and caffeine have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations.
Animal studies have shown an association between caffeine intake and foetal abnormalities, but only at very high doses that are not considered relevant to human consumption.
There is limited evidence that maternal caffeine intake during pregnancy may reduce birthweight. One review article indicated a correlation between caffeine consumption during pregnancy and a decrease in birthweight due to the vasoconstrictive effect of caffeine on placental circulation. Other reviews have found no correlation between caffeine intake in pregnancy and birthweight.
Paracetamol/ caffeine is not recommended for use during pregnancy due to the possible increased risk of spontaneous abortion associated with caffeine consumption.
Paracetamol is excreted in breast milk. The amount available for ingestion by the infant has been reported variously as less than 0.1% of a single dose of paracetamol 500 mg and as 0.04 to 0.23% of a single 650 mg dose. Maternal ingestion of paracetamol in usual analgesic doses does not appear to present a risk to the nursing infant.
Caffeine is excreted in breast milk. Studies examining the transfer of caffeine into breast milk after oral doses of 35 to 336 mg of caffeine have recorded peak maternal plasma concentrations of 2.4 to 4.7 microgram/mL, peak maternal saliva concentrations of 1.2 to 9.2 microgram/mL, and peak breast milk concentrations of 1.4 to 7.2 microgram/mL. At these concentrations in breast milk, the calculated daily caffeine ingestion by breastfed infants ranged from 1.3 to 3.1 mg, which was not thought to present a hazard, although irritability and a poor sleeping pattern have been reported. The American Academy of Pediatrics states that caffeine is excreted slowly by the infant and may be associated with irritability and poor sleeping pattern when ingested by breastfeeding mothers. However, no effects occur with moderate intake of caffeinated beverages (2 to 3 cups daily) and caffeine is usually compatible with breastfeeding.
Caffeine in breast milk may potentially have a stimulating effect on breast fed infants but significant toxicity has not been observed.4.7 Effects on Ability to Drive and Use Machines
This medication has no influence on the ability to drive or use machines.
4.8 Adverse Effects (Undesirable Effects)
Events reported from extensive post marketing experience at therapeutic/ labelled dose and considered attributable are listed below by system organ class and frequency.
The following convention has been utilised for the classification of undesirable effects: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), not known (cannot be estimated from available data).
Adverse event frequencies have been estimated from spontaneous reports received through post marketing data.
Paracetamol.
Blood and lymphatic system disorders.
Very rare: thrombocytopenia.
Immune system disorders.
Very rare: anaphylaxis, cutaneous hypersensitivity reactions including skin rashes, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN).
Respiratory, thoracic and mediastinal disorders.
Very rare: bronchospasm, especially in patients sensitive to aspirin and other NSAIDs.
Hepatobiliary disorders.
Very rare: hepatic dysfunction.
Caffeine.
Central nervous system.
Not known: nervousness, dizziness.
When the recommended paracetamol/caffeine dosing regimen is combined with dietary caffeine intake, the resulting higher dose of caffeine may increase the potential for caffeine related adverse effects such as insomnia, restlessness, anxiety, irritability, headaches, gastrointestinal disturbances and palpitations.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.4.9 Overdose
Paracetamol.
Elderly persons, small children, patients with liver disorders, chronic alcohol consumption or chronic malnutrition, as well as patients concomitantly treated with enzymes-inducing drugs are at an increased risk of intoxication, including fatal outcome.
Symptoms. Toxic symptoms include vomiting, abdominal pain, hypotension and sweating. Nausea, vomiting, anorexia, pallor and abdominal pain generally appear during the first 24 hours of overdosage with paracetamol. Overdosage with paracetamol may cause hepatic cytolysis which can lead to hepatocellular insufficiency, gastrointestinal bleeding, metabolic acidosis, encephalopathy, disseminated intravascular coagulation, coma and death. Increased levels of hepatic transaminases, lactate dehydrogenase and bilirubin with a reduction in prothrombin level can appear 12 to 48 hours after acute overdosage. Overdosage can also lead to pancreatitis acute renal failure and pancytopenia. The most serious adverse effect of acute overdosage of paracetamol is a dose-dependent, potentially fatal hepatic necrosis. In adults, hepatotoxicity may occur after ingestion of a single dose of 12 g (24 tablets) of paracetamol; a dose of 25 g (50 tablets) or more is potentially fatal. Symptoms during the first 2 days of acute poisoning by paracetamol do not reflect the potential seriousness of the intoxication. Major manifestations of liver failure such as jaundice, hypoglycaemia and metabolic acidosis may take at least 3 days to develop.
Treatment. Despite lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention.
Determinations of the plasma concentration of paracetamol are recommended. Plasma concentration of paracetamol should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable).
Where paracetamol intoxication is suspected, intravenous administration of SH group donators such as acetylcysteine within the first 10 hours after ingestion is indicated. Although acetylcysteine is most effective if initiated within this period, it can still offer some degree of protection if given as late as 48 hours after ingestion; in this case it is taken for longer.
If the history suggests that 12 g paracetamol or more has been ingested, administer one of the following antidotes:
Acetylcysteine 20% iv.
Administer intravenously, 20% acetylcysteine immediately without waiting for positive urine test or plasma level results. For dosage instructions refer to the acetylcysteine 20% iv product information.
Oral methionine.
For dosage instructions refer to the methionine product information.
Further measures will depend on the severity, nature and course of clinical symptoms of intoxication and should follow standard intensive care protocols.
Caffeine.
Overdose of caffeine may result in epigastric pain, vomiting, diuresis, tachycardia or cardiac arrhythmia, CNS stimulation (insomnia, restlessness, excitement, agitation, anxiety, tremors and convulsions).
For clinically significant symptoms of caffeine overdose to occur, the amount ingested would be associated with serious paracetamol-related liver toxicity.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Paracetamol is a para-aminophenol derivative that exhibits analgesic and antipyretic activity. It inhibits prostaglandin synthetase in the hypothalamus, prevents synthesis of spinal prostaglandin and inhibits inducible nitric oxide synthesis in macrophages. Paracetamol has minimal anti-inflammatory action. Caffeine acts as an analgesic adjuvant which enhances the efficacy of paracetamol.
Clinical trials.
A meta-analysis to determine the analgesic effect of the combined dosage of paracetamol (1000 mg) and caffeine (130 mg) versus paracetamol (1000 mg) alone has been undertaken. The primary outcome of the meta-analysis was to determine whether the use of paracetamol plus caffeine provided significantly superior analgesia over paracetamol alone in acute pain states.
Inclusion criteria were full journal publications reporting the results of randomised, controlled, double blind trials comparing the two treatments.
The clinical measure selected was the > 50% max TOTPAR (i.e. the number of patients in the two groups who achieved at least 50% of the maximal pain relief). The dichotomous descriptor of > 50% max TOTPAR was chosen because it is a simple clinical end point of half pain relieved. It is a well defined clinical measure of pain relief and can be used to evaluate the comparative benefit of contrasting medications.
Of the seven papers describing double blind trials, four papers met the inclusion criteria for the meta-analysis and contained eight separate studies. These eight studies spanned a number of different pain states; postpartum pain (n = 3), headache (n = 2), dental pain (n = 2) and dysmenorrhoea (n = 1).
All of the eight studies included in the meta-analysis provided efficacy results as mean TOTPAR values over 0-4 hours. The total number of patients evaluated was 1265 (paracetamol plus caffeine) and 1268 (paracetamol alone). Using the endpoint of at least half pain relief achieved (at least 50% max TOTPAR), the odds ratio of a greater likelihood of effect of the paracetamol/ caffeine combination compared to paracetamol alone is 1.34 (95% CI 1.14, 1.58). This corresponds to a relative benefit of 1.12 (95% CI 1.05-1.19). Analgesic efficacy has also been determined as the number needed to treat (NNT). For the comparison of the paracetamol/ caffeine combination with paracetamol alone, the NNT for at least 50% pain relief achieved over 0-4 hours is 14.
Compared with placebo, the relative benefit for the paracetamol/ caffeine combination is 1.42 (95% CI 1.29-1.56) and the NNT for at least 50% pain relief achieved over 0-4 hours is 5. For paracetamol alone compared with placebo, the relative benefit is 1.27 (95% CI 1.15-1.40) and the NNT is 81.
The meta-analysis indicated that the combination of paracetamol and caffeine has an added benefit in analgesic activity compared to paracetamol alone.
Time effect curves for pain relief were presented in all eight of the studies included in the meta-analysis. Overall, these studies suggested that combining paracetamol with caffeine results in an earlier analgesic effect than is achieved with paracetamol alone.
1 Palmer H, Graham G, Williams and Day R (2010). A risk-based assessment of paracetamol (acetaminophen) combined with caffeine. Pain Medicine 11: 951-965'.
5.2 Pharmacokinetic Properties
Absorption.
After oral administration, paracetamol is absorbed rapidly and completely from the small intestine; peak plasma levels occur 10 to 60 minutes after administration. Food intake delays paracetamol absorption.
Caffeine is absorbed readily after oral administration. Maximal plasma concentrations are achieved in adults within one hour and the plasma half-life is about 3 to 7 hours.
Distribution.
Paracetamol is uniformly distributed throughout most body fluids; the apparent volume of distribution is 1 to 1.2 L/kg. Paracetamol can cross the placenta and is excreted in breast milk. Plasma protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.
Metabolism.
Paracetamol is metabolised by the hepatic microsomal enzyme system. In adults at therapeutic doses, paracetamol is mainly conjugated with glucuronide (45 to 55%) or sulfate (20 to 30%). A minor proportion (less than 20%) is metabolised to catechol derivatives and mercapturic acid compounds via oxidation. Paracetamol is metabolised differently by infants and children compared to adults, the sulfate conjugate being predominant.
Caffeine is almost completely metabolised in the liver by oxidation, demethylation and acetylation to various xanthine derivatives.
Excretion.
Paracetamol is excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol with 85 to 90% of the administered dose eliminated in the urine within 24 hours of ingestion. The elimination half-life is about 1 to 4 hours. The various xanthine derivatives or caffeine are excreted in the urine.
5.3 Preclinical Safety Data
Genotoxicity.
No data available.
Carcinogenicity.
No data available.6 Pharmaceutical Particulars
6.1 List of Excipients
Croscarmellose sodium, maize starch, potassium sorbate, povidone, purified talc, stearic acid, hypromellose, propylene glycol, macrogol 6000 and titanium dioxide.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C.
6.5 Nature and Contents of Container
PVC-PVDC/Aluminium blister packs of 10, 18, 20, 36, 40, 64, or 72 tablets.
Not all pack sizes may be marketed.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Chemical structure.
Chemical name: Paracetamol: N-(4-Hydroxyphenyl) acetamide.
Caffeine: 1,3,7-Trimethyl-3,7-dihydro-1H-purine-2,6-dione.
Structural formula:
Molecular formula: Paracetamol: C8H9NO2.
Caffeine: C8H10N4O2.
Molecular weight: Paracetamol: 151.17.
Caffeine: 194.20.
CAS number.
Paracetamol.
103-90-2.
Caffeine.
58-08-2.7 Medicine Schedule (Poisons Standard)
Packs of 10 - Not scheduled.
Packs of 18, 20, 36, 40 - S2, Pharmacy Medicine.
Packs of 64, 72 - S3, Pharmacist Only Medicine.
Summary Table of Changes
