ACTION AND MECHANISM

- Paracetamol: Analgesic and antipyretic.

- Caffeine: A CNS stimulant. Caffeine also increases the tone and resistance of cerebral blood vessels, which in some cases can help relieve pain in certain types of headaches.

SENIORS

No specific serious problems are anticipated in this age group. Due to its caffeine content, these patients may be more sensitive to CNS side effects. Use with caution.

PATIENT ADVICE

- It can be taken with or without food. Taking it without food accelerates the analgesic effects, but not their intensity.

Do not exceed the recommended dose, nor use for more than 10 days without a doctor's recommendation. Discontinue treatment as soon as symptoms disappear.

- Consult your doctor and/or pharmacist if pain continues after 5-10 days of treatment (3-5 days in children; 2 days in the case of throat pain), fever lasts for more than 3 days, or symptoms worsen or new ones appear.

- Patients who regularly consume significant amounts of alcohol (3 or more drinks per day) should limit their paracetamol doses to avoid liver damage.

- In case of overdose, consult a doctor and/or pharmacist, even if no symptoms appear.

- Limit the use of other medications or foods that contain caffeine.

CONTRAINDICATIONS

- [ALLERGY TO PARACETAMOL] or to caffeine or to any of the excipients included in section 6.1.

- Severe cardiovascular disorders.

- Severe uncontrolled hypertension.

PREGNANCY

Caffeine crosses the placenta and reaches tissue concentrations similar to maternal concentrations, potentially causing fetal arrhythmias with excessive use. Due to its caffeine content, it is not recommended for pregnant women.

INDICATIONS

- [PAIN]: Symptomatic relief of occasional mild to moderate pain. [FEVER]

INTERACTIONS

Paracetamol:

In general, interactions with paracetamol are not expected to be serious due to its occasional use. Clinically significant interactions are only expected in patients treated with high doses, especially if other risk factors for hepatotoxicity are present, or in long-term treatments.

- NSAIDs. Limit combined treatment to the bare minimum.

- Oral anticoagulants. INR monitoring is recommended in patients treated with high doses. The risk appears negligible in cases of short-term treatments or prolonged treatments with doses < 2 g/24 h.

- Busulfan. Risk of busulfan toxicity, as paracetamol reduces glutathione levels, a substance with which busulfan is conjugated during its elimination. It is recommended to avoid paracetamol administration, or limit exposure if this is not possible, for 72 hours before and during busulfan treatment.

- Chloramphenicol. Paracetamol may promote the accumulation of chloramphenicol by decreasing its hepatic metabolism, with a risk of hematological toxicity. Patient monitoring is advised.

- Drugs that delay gastric emptying, such as anticholinergics or exenatide. This delay could slow the absorption of paracetamol and the onset of its effect, rather than its intensity.

- Hepatotoxic drugs. Paracetamol at high doses has a hepatotoxic effect. It is recommended to avoid its combined administration with other hepatotoxic drugs, as well as with alcohol.

- Enzyme inducers (estrogenic oral contraceptives, barbiturates, carbamazepine, phenytoin, rifampicin). Paracetamol is partially metabolized by cytochrome P450, so its plasma levels and therapeutic effects could be reduced if administered with a potent inducer of the hepatic microsomal system. Furthermore, in the case of paracetamol overdose, the inducer could increase liver toxicity as a result of increased production of toxic metabolites generated by this enzyme system.

- Enzyme inhibitors (imatinib, isoniazid, propranolol). Increases in plasma levels of paracetamol have been reported with drugs that inhibit its metabolism.

- Reverse transcriptase inhibitors (didanosine, zidovudine). Paracetamol may potentiate the hematological toxicity of zidovudine. Conversely, both didanosine and zidovudine may increase the risk of hepatotoxicity from paracetamol.

- Lamotrigine. Paracetamol may increase the metabolism of lamotrigine, reducing its therapeutic effects.

- Ion exchange resins (cholestyramine, colestipol). Possible decrease in paracetamol absorption. Separate administration by one hour.

Paracetamol slightly reduces urinary excretion of diazepam, although plasma levels remain unchanged.

Paracetamol does not affect the immunogenicity of flu vaccines, and could reduce the symptoms of adverse reactions to them.

Caffeine:

- Barbiturates: Concomitant use of caffeine and barbiturates may antagonize the hypnotic or anticonvulsant effects of barbiturates.

- Bronchodilators: The simultaneous use of adrenergic bronchodilators with caffeine can lead to additive CNS stimulation, producing effects such as: increased blood pressure, arrhythmias, and cerebral hemorrhage.

- Cytochrome P450 1A2 (CYP1A2): Caffeine can interact with drugs that are substrates of the CYP1A2 enzyme, since this enzyme is involved in the metabolism of caffeine.

- Disulfiram: Alcoholic patients in recovery treatment with disulfiram should be advised to avoid the use of caffeine to prevent the possibility of alcohol withdrawal syndrome being complicated by caffeine-induced cardiovascular and cerebral excitation.

- Iron: caffeine decreases iron absorption, so its intake should be spaced at least 2 hours apart.

- Monoamine oxidase inhibitors (MAOIs), including furazolidone, linezolid, procarbazine, and selegiline, may produce hypertension, tachycardia, and a slight increase in blood pressure if caffeine is administered in small amounts.

- Mexiletine: Simultaneous use of caffeine with mexiletine may reduce caffeine elimination by 50% and may increase adverse caffeine reactions due to accumulation.

of the same.

- Products containing caffeine: Simultaneous intake of this medication with beverages containing caffeine, other medications containing caffeine, or medications that produce CNS stimulation, may cause excessive CNS stimulation with nervousness, irritability, or insomnia.

- Sympathomimetics and Thyroxine: Caffeine acts synergistically with the tachycardic effects of these medications.

- Tobacco: The breakdown or metabolism of caffeine in the liver is accelerated by tobacco.

- Erythromycin: may inhibit caffeine metabolism.

- Lithium: simultaneous use of caffeine with lithium increases urinary excretion of lithium, possibly reducing its therapeutic effect.

- Theophylline: Caffeine reduces the excretion of theophylline and increases the potential for dependence on ephedrine-like substances.

- With substances that have a broad spectrum of action (for example, benzodiazepines) interactions can vary depending on the substance and be unpredictable.

LACTATION

The use of paracetamol is acceptable during breastfeeding.

Caffeine is excreted in breast milk in very small amounts, around 1%. Occasionally, and after prolonged use of the medication, irritability and sleep disturbances have been observed in infants due to its accumulation; therefore, its intake should be avoided whenever possible for extended periods.

CHILDREN

This medicine is not recommended for use in children and adolescents under 16 years of age.

GUIDELINES FOR PROPER ADMINISTRATION

The tablets should be taken with a glass of liquid, preferably water.

POSOLOGY

Adults and adolescents over 16 years: 1 tablet every 6-24 hours. If necessary, 2 tablets may be administered per dose. Maximum dose: 3 g of paracetamol (6 tablets)/24 hours.

DOSAGE IN HEPATIC INSUFFICIENCY

Use only under medical supervision, assessing liver function at the start of treatment and periodically throughout if treatment is prolonged.

It is recommended to avoid paracetamol doses exceeding 2 g/24 h (orally), with a minimum interval of at least 8 h.

DOSAGE IN RENAL INSUFFICIENCY

Doses referring to paracetamol:

- CLcr 50-90 ml/min: no dosage adjustment required.

- CLcr 10-50 ml/min: 500 mg/6 h.

- CLcr < 10 ml/min: 500 mg/8 h.

PRECAUTIONS

Related to paracetamol:

- [RENAL INSUFFICIENCY]. Patients treated with high doses for long periods of time may experience adverse renal reactions; therefore, monitoring of renal function is recommended. Patients with end-stage renal disease (CLcr < 10 ml/min) should space doses at least 8 hours apart. No special problems are expected with occasional use.

- [HEPATOTOXICITY]. During the hepatic metabolism of paracetamol, hepatotoxic compounds such as N-acetylbenzoquinone imine are generated. This compound is produced in small amounts through cytochrome P450 metabolism, a minor pathway for paracetamol. However, at high doses of paracetamol, saturation of the main pathways (glucuronidation and sulfate conjugation) can occur, increasing the role of this cytochrome and the consequent production of benzoquinone. This substance is rapidly detoxified with reduced glutathione expenditure, transforming into cysteine ​​and mercapturic acid, which are eliminated in the urine. If benzoquinone production is excessive, glutathione depletion occurs in the hepatocyte, leading to cellular damage that could result in life-threatening toxicity. This hepatotoxicity is a delayed adverse reaction; symptoms usually appear 2 days after the overdose and peak at 4-6 days.

In general, self-medication should be limited, and paracetamol should not be used for more than 10 days without medical advice, and only as long as the symptoms that prompted its use persist. Likewise, it is not advisable to exceed the recommended daily doses of 4 g in adults or 60 mg/kg in children.

Due to its hepatotoxic effects, and considering its indications and the alternative of other analgesics and antipyretics, it is generally recommended to avoid its use in patients with liver disease, including [LIVER FAILURE], [HEPATITIS] or [LIVER CIRRHOSIS], as well as in patients with other risks of liver damage, such as [CHRONIC ALCOHOLISM], [HYPOVOLEMIA], [DEHYDRATION] or [MALNUTRITION] with low levels of glutathione, or treated with other hepatotoxic drugs.

In patients for whom this is not possible, its use is suggested under medical supervision, following a careful assessment of the benefit/risk ratio. It is recommended that liver function be evaluated in these patients at the start of treatment and periodically throughout its duration. Likewise, the maximum doses used should not exceed 2 g/24 h (po) or 3 g/24 h (iv).

- Salicylate allergy: Patients allergic to acetylsalicylic acid do not usually experience cross-hypersensitivity reactions with paracetamol. However, cases of mild bronchospasm have been reported in patients allergic to acetylsalicylic acid treated with paracetamol.

- [BLOOD DYSCRASIAS]. Paracetamol has been associated with hematological disorders such as [LEUKOPENIA], [AGRANULOCYTOSIS], or [NEUTROPENIA]. In cases of prolonged treatment, periodic blood tests may be necessary.

- Determination of pancreatic function. Paracetamol can interfere with the bentiromide test because it is metabolized to arylamine, leading to a false increase in para-aminobenzoic acid. It is recommended to discontinue paracetamol treatment at least three days before the test.

Related to caffeine:

- It should be administered under medical supervision in patients with [CARDIAC ARRHYTHMIA], [HYPERTHYROIDISM], and [ANXIETY]. In these cases, it is recommended to reduce the caffeine dose to 100 mg/day (2 tablets).

- In patients who have suffered an [ACUTE MYOCARDIAL INFARCTION], it is recommended not to administer caffeine until several weeks have passed since the event.

- [DIABETES]: Caffeine can raise blood glucose levels, so this should be taken into account in diabetic patients.

- Patients sensitive to other xanthines (aminophylline, theophylline…) may also be sensitive to caffeine and should therefore not take this medicine.

- Caution should be exercised when prescribing this medication to patients with a history of [PEPTIC ULCER] or [GASTRITIS].

- In patients with a history of [ISCHEMIC HEART DISEASE], it should be administered with caution.

- In patients with liver cirrhosis or viral hepatitis, the plasma half-life of caffeine is increased.

PRECAUTIONS RELATING TO EXCIPIENTS

This medicine contains sunset yellow FCF as an excipient. It may cause allergic-type reactions, including asthma, especially in patients with salicylate allergy.

ADVERSE REACTIONS

Paracetamol by mouth:

- Hepatic: rare [INCREASE TRANSAMINASES], [INCREASE ALKALINE PHOSPHATASE], [HYPERBILIRUBINEMIA]; very rare [HEPATOTOXICITY], with [JAUNDICE].

- Cardiovascular: rare [HYPOTENSION].

- Neurological/psychological: [DIZZINESS], [DISORIENTATION], [EXCITABILITY].

- Genitourinary: very rare renal alterations such as cloudy urine and kidney disorders.

- Allergic: very rare [HYPERSENSITIVITY REACTIONS], with symptoms ranging from [EXANTHEMATOUS ERUPTIONS] and [URTICARIA] to [ANAPHYLAXIS].

- Hematological: very rare [THROMBOCYTOPENIA], [AGRANULOCYTOSIS], [LEUKOPENIA], [NEUTROPENIA], [HEMOLYTIC ANEMIA], [METHEMOGLOBINEMIA]. Prothrombin time may be increased, although it does not appear to be significant.

- Metabolic: very rare [HYPOGLYCEMIA].

- Analytical findings: analytical alterations have been described such as [INCREASE LACTATE DEHYDROGENASE], [INCREASE SERUM CREATININE], increased ammonia levels, [INCREASE UREIC NITROGEN].

Furthermore, paracetamol may interfere with the analytical determination of uric acid and glucose, as well as with the monitoring of theophylline. It can also produce false positives in the determination of 5-hydroxyindoleacetic acid when nitrosonaphthol is used as a reagent.

- General: rare [GENERAL DISCOMFORT].

Caffeine:

- Nervous system disorders: [INSOMNIA], [AGITATION], [NERVOUSNESS], moderate delirium, [HEADACHE].

- Gastrointestinal disorders: [NAUSEA], [VOMITING], [GASTRITIS].

These adverse effects depend on sensitivity to caffeine and the daily dose. Individuals with a sensitive immune system may react to even low doses of caffeine with insomnia, restlessness, tachycardia, and possibly gastrointestinal discomfort.

High doses of caffeine can produce cardiac effects such as palpitations, arrhythmias, tachycardia, hypertension, and flushing.

ADVERSE REACTIONS RELATED TO EXCIPIENTS

- Because it contains sunset yellow (E-110) it may cause [HYPERSENSITIVITY REACTIONS].

OVERDOSE

Symptoms: Paracetamol can cause very serious and potentially fatal poisoning. Toxicity can begin to be experienced from single doses of 6 g in adults or 100 mg/kg in children. Doses above 20-25 g are potentially fatal. Chronic doses above 4 g/24 h can lead to transient hepatotoxicity. However, patients treated with other hepatotoxic drugs, enzyme inducers, or with chronic alcoholism may be more susceptible to its toxic effects, requiring lower doses to produce toxicity.

- Treatment: In case of oral overdose, and preferably within 4 hours of ingestion, gastric aspiration and lavage will be carried out, along with administration of activated charcoal, reducing the absorption of paracetamol.

N-acetylcysteine ​​is the specific antidote for paracetamol overdose. N-acetylcysteine ​​can be administered orally in adults and parenterally in adults and children.

- IV route: the dose to be administered is 300 mg/kg, over a period of 20 and 15 minutes, according to the following schedule:

* Adults: initially 150 mg/kg (equivalent to 0.75 ml/kg of 20% aqueous solution, with pH 6.5) by slow IV injection or diluted in 200 ml of 5% glucose solution, over 15 min.

Next, 50 mg/kg (0.25 ml/kg of 20% aqueous solution, with pH 6.5) diluted in 500 ml of 5% glucose serum as an IV infusion for 4 h.

Finally, 100 mg/kg (0.50 ml/kg of 20% aqueous solution, with pH 6.5) diluted in 1,000 ml of 5% glucose serum as an IV infusion for 16 h.

* Children: the same regimen will be administered, although the volume of the infusion solutions will be adjusted to the child's age and weight to avoid pulmonary vascular congestion.

The effectiveness of parenteral treatment with N-acetylcysteine ​​is at its maximum when administered within 8 hours of overdose, gradually decreasing thereafter until it is ineffective at 15 hours.

The administration of N-acetylcysteine ​​may be discontinued when plasma levels of paracetamol are below 200 mcg/ml.

- Oral administration (adults only): Initially 140 mg/kg, followed by 17 doses of 70 mg/kg every 4 hours. The dose should be diluted in water, cola, or orange or grape juice to a final concentration of 5%, as it has an unpleasant taste and may cause irritation or sclerosing. If the dose is vomited within 1 hour, it should be repeated.

If necessary, it will be administered diluted in water through a duodenal tube.

If the patient experiences symptoms of hepatotoxicity, liver function should be monitored every 24 hours.