ACTION AND MECHANISM - Paracetamol is a derivative of para-aminophenol, with analgesic and antipyretic activity. * Analgesic effect. Its mechanism of action is not fully understood, but it appears to be primarily mediated by the central inhibition of cyclooxygenase, especially COX-2, decreasing prostaglandin synthesis. It also has some peripheral effect by blocking the generation of the painful nerve impulse. A possible peripheral effect is also proposed through inhibition of prostaglandin synthesis, activation of the CB1 cannabinoid receptor, modulation of serotonergic or opioid signaling pathways, inhibition of nitric oxide synthesis, or substance P-induced hyperalgesia. * Antipyretic effect. It acts on the hypothalamic thermoregulatory center, inhibiting the synthesis of prostaglandins and the effects of endogenous pyrogen, resulting in peripheral vasodilation, increased blood flow to the skin and increased sweating, which contribute to heat loss. At the same dose, it is considered to have similar analgesic and antipyretic potency to acetylsalicylic acid (ASA). The effects are maximum at 1-3 hours and last for 3-4 hours. Unlike aspirin and other NSAIDs, it does not exhibit appreciable anti-inflammatory activity, except in some non-rheumatic conditions, although this is not significant. One advantage over NSAIDs is that it not only does not inhibit prostaglandin synthesis in the stomach, but it appears to increase it, thus avoiding gastrointestinal side effects. Similarly, it lacks antiplatelet effects. SPECIAL WARNINGS - Although it does not significantly reduce inflammation, very positive effects have been obtained in arthritic processes of the knee, probably due to its analgesic effect. - Monitoring: * Renal function and blood count in patients treated for prolonged periods of time. * Liver function at baseline and periodically in patients at high risk of hepatotoxicity. 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 doctors 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. CONTRAINDICATIONS - [ALLERGY TO PARACETAMOL] or to any other component of the medicine. - Severe and active liver disease. ADVANCED AGE Reduced elimination has been observed in elderly patients. Some manufacturers recommend reducing the dose by 25% compared to younger adults, but others do not consider this precaution necessary. PREGNANCY Animal safety : No teratogenic effects have been observed in animal studies. Safety in humans : Extensive data in pregnant women indicate the absence of fetal/neonatal toxicity or congenital malformations. Epidemiological studies on the neurological development of children exposed to paracetamol in utero show inconclusive results. Paracetamol crosses the placental barrier. Several cohort studies have been conducted on the safety of oral paracetamol in pregnant women. These studies did not show an increased risk of congenital malformations, heart defects, or miscarriage. However, there is some evidence suggesting that its use during the last two trimesters may be associated with an increased risk of wheezing in the childs first year of life. There have been a few isolated cases of serious adverse reactions in children of mothers who received paracetamol during pregnancy, including severe anemia, hepatotoxicity, and nephrotoxicity (the latter two being fatal). However, these symptoms appeared to be due to maternal overdose. Oral paracetamol, at recommended doses and used as needed, is considered a safe analgesic/antipyretic during pregnancy. It has been used just before delivery in women with fever secondary to chorioamnionitis, with significant improvement observed in the fetal and newborn condition after the mothers temperature normalized. However, its use at high doses or for prolonged periods may be associated with fetal hepatotoxicity. Conversely, due to the lack of safety and efficacy data in pregnant women, it is recommended to avoid its use by parenteral route, unless the expected benefits outweigh the possible risks. Effects on fertility : In animal studies, paracetamol resulted in testicular atrophy and decreased spermatogenesis at high doses. It is unknown whether these findings can be extrapolated to humans. PHARMACOKINETICS - Absorption: the therapeutic concentration is around 10 mcg/ml. INDICATIONS - Symptomatic treatment of mild to moderate pain, such as [HEADACHE], [TOOTHACHE], [DYSMENORRHEA], [MUSCULOSKELETAL PAIN] such as [MUSCLE CONTRACTURE], [TORTICOLLIS], [LUMBALGIA], [OSTEOARTHRITIS] or [RHEUMATOID ARTHRITIS], [NEURALGIA] such as [SCIATICA], sore throat, [POSTOPERATIVE PAIN] or postpartum pain. - Symptomatic treatment of [FEVER]. INTERACTIONS 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. Paracetamol is commonly used in combination with other analgesics, such as ibuprofen, to treat fever in children. However, it should be noted that administering it with NSAIDs or salicylates at high doses and for prolonged periods could increase the risk of kidney damage. Therefore, it is recommended not to exceed the recommended doses and to limit combined treatment to the minimum necessary. - Oral anticoagulants. Unlike NSAIDs and acetylsalicylic acid, paracetamol does not have antiplatelet activity nor does it affect blood coagulation per se, which is why it is used as the analgesic drug of choice in patients treated with oral anticoagulants. However, in cases of prolonged treatment and high doses, but without reaching toxic levels, a slight hepatotoxic effect could occur, characterized by a decrease in the production of hepatic clotting factors, which could increase the INR of these patients, with a risk of hemorrhage. Therefore, monitoring of this parameter is recommended in these patients treated with high doses. The risk appears negligible in the case of one-off 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. Studies have shown no significant pharmacokinetic interactions with adefovir, amantadine, H2 antihistamines or proton pump inhibitors, argatroban, chloroquine, erythromycin, lithium, methotrexate, oseltamivir, sucralfate, telmisartan, or zolmitriptan. No interactions of any kind have been observed with alpha-1 adrenergic blockers (doxazosin, terazosin), furosemide, letrozole, or zanamivir. 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. LACTATION Animal safety: no data available. Safety in humans: Paracetamol is excreted in small amounts in breast milk, reaching concentrations of 10-15 mcg/ml (similar to plasma concentrations) within 1-2 hours after a 650 mg oral dose. Infant exposure is estimated at 1-2% of the maternal dose. Paracetamol and its metabolites have not been found in the infants urine, and no adverse reactions have been reported in the infant, except for one case of maculopapular rash, which resolved without sequelae when the mother discontinued paracetamol. CHILDREN Paracetamol is an analgesic-antipyretic drug commonly used in children, including toddlers. However, as a general precaution, its use in children under 3 years of age should be under medical supervision, and its use should be limited to the minimum possible. Due to the risk of severe, potentially fatal poisoning, close monitoring of dosage in children is recommended, avoiding doses exceeding those recommended. Therefore, the appropriate presentation should be used to allow for precise dosing of the child according to their weight. It is advisable to consult the dosage of the different presentations for more information on their use in children. GUIDELINES FOR PROPER ADMINISTRATION Paracetamol can be taken with or without food. However, taking it orally on an empty stomach accelerates the effects of paracetamol, although not its intensity. If a faster effect is required, it is recommended to take it without food. POSOLOGY - Adults, oral: 325-650 mg/4-6 h. Maximum dose 3.9 g/24 h. - Children and adolescents under 18 years of age, oral: * Children 6-10 years: 325 mg/4-6 h. Maximum dose 1625 mg/24 h. * Children 11 years: 325 mg/4-6 h. Maximum dose 2.6 g/24 h. * Adolescents from 12 years: 650 mg/4-6 h. Maximum dose 3.25 g/24 h. Once the symptoms disappear, the treatment will be discontinued. If pain persists (usually 5-10 days for adults and half that for children; 2 days for sore throat) or fever (usually 3 days), worsening, or the appearance of other symptoms, you should consult your doctor. DOSAGE IN HEPATIC INSUFFICIENCY Use only under medical supervision, assessing liver function at the start of treatment and periodically throughout the treatment. It is recommended to avoid doses higher than 2 g/24 h (oral) or 3 g (iv), with a minimum interval of at least 8 h. DOSAGE IN RENAL INSUFFICIENCY ORAL ADMINISTRATION - 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 - [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. Caution is advised when administering paracetamol concomitantly with flucloxacillin due to the increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition, and other sources of swallowing deficiency (e.g., chronic alcoholism), as well as those using maximum daily doses of paracetamol. Close monitoring, including measurement of 5-oxoproline in urine, is recommended. - [HEART FAILURE]: Fluid retention and edema have been observed in some patients; therefore, extreme caution is advised in patients with heart failure. Cases of Kounis syndrome have been reported in patients receiving this treatment. This syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitivity reaction associated with constriction of the coronary arteries, which may lead to myocardial infarction. ADVERSE REACTIONS Paracetamol is generally well tolerated, and adverse reactions are rare. Adverse reactions are described according to each frequency interval, being considered very common (>10%), common (1-10%), uncommon (0.1-1%), rare (0.01-0.1%), very rare (<0.01%) or of unknown frequency (cannot be estimated from the available data). 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. Hepatotoxicity can occur at paracetamol Cp levels above 120 mcg/ml at 4 h and 30 mcg/ml at 12 h. Levels of 300 mcg/ml at 4 h of overdose have been associated with hepatotoxicity in 90% of patients. Paracetamol overdose follows four characteristic clinical stages: - Phase I: appears a few hours after overdose, and lasts up to the first 24 hours. It presents with general malaise, nausea and vomiting, abdominal pain, pallor, excessive sweating and anorexia. Liver function and liver parameters are normal. - Phase II: occurs 24-36 hours after overdose. Symptoms of liver damage begin to appear, such as abdominal pain in the right hypochondrium and increased levels of transaminases and bilirubin, and prothrombin time. - Phase III: This occurs 72-96 hours after overdose and coincides with the peak of hepatotoxicity. Transaminase levels may rise to 10,000 U/L or higher, along with increases in bilirubin, glucose, lactate, and phosphate, as well as an elevated prothrombin time. The patient may present with encephalopathy and coma. Renal tubular necrosis and myocardial involvement have also been reported occasionally. Death may result from fulminant hepatic failure with hepatic necrosis. - Phase IV: occurs 7-8 days after the overdose. Recovery of those patients who have survived the previous stage. The risk of severe paracetamol poisoning depends on the route of administration and the conditions of use. Therefore, severe poisoning is not expected in cases of overdose with suppositories (though it is possible with ingestion, which is infrequent), or with injectable forms (due to their use in hospitals under medical supervision, even though severe poisoning has occurred due to confusion regarding the dose of paracetamol or the volume of the injectable solution). However, it cannot be completely ruled out. Treatment: In case of oral overdose, and preferably within 4 hours of ingestion, gastric aspiration and lavage will be performed, 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, pH 6.5) diluted in 500 ml of 5% glucose solution 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 childs 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.