Children's Antidol 100 Mg/Ml 1 Bottle Oral Solution 90 Ml

Children's Antidol 100 Mg/Ml 1 Bottle Oral Solution 90 Ml

Paracetamol

ACTION AND MECHANISM: Paracetamol is a derivative of para-aminophenol, with analgesic and antipyretic activity.

• Analgesic effect: Its mechanism of action is not completely clarified, but it seems to be fundamentally mediated by the inhibition of cyclooxygenase at a central level, especially COX-2, decreasing the synthesis of prostaglandins. It also has a certain peripheral effect by blocking the generation of the painful nerve impulse. A possible peripheral effect is also proposed due to inhibition of prostaglandin synthesis, activation of the CB1 cannabinoid receptor, modulation of serotonergic or opiate signaling pathways, inhibition of nitric oxide synthesis or hyperalgesia induced by substance P.

• Antipyretic effect: Acts on the hypothalamic thermoregulatory center, inhibiting the synthesis of prostaglandins and the effects of endogenous pyrogen, leading to 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 an analgesic and antipyretic power similar to acetylsalicylic acid (ASA). The effects are maximum at 1-3 hours and last for 3-4 hours.

Unlike ASA and other NSAIDs, it does not present an appreciable anti-inflammatory activity, except in some non-rheumatic pathologies, although it is not important. An advantage over NSAIDs is that not only does it not inhibit the synthesis of prostaglandins at the gastric level, but it appears to increase it, so it does not give rise to gastro-injurious effects. Likewise, it lacks antiplatelet effects.

PHARMACOKINETICS:

• Oral route: rapid and complete absorption after oral administration, with a bioavailability of 75-85%. After a dose of 1000 mg, a cmax of 7.7-17.6 mcg/ml is obtained after 0.5-2 h. It presents an important saturable first pass effect from doses of 2 g.

• Effect of food: Food can reduce the rate of absorption of paracetamol, although it does not substantially modify the amount absorbed.

• Distribution: after systemic absorption, it is widely distributed throughout most tissues, reaching concentrations similar to plasma concentrations. Its Vd is approximately 1 l/kg. It tends to accumulate especially in the liver and renal medulla. Distribution is moderately rapid, with a plasma t1/2 of 1-3 h, and may be even faster in adolescents. It has low binding to plasma proteins, around 10%, and may be 20-40% in patients with acute overdose. It is capable of crossing the placenta and the blood-brain barrier, detecting concentrations in CSF of 1.5 mcg/ml after its iv infusion.

• Metabolism: it undergoes intense hepatic metabolism (90-95%) through conjugation reactions, mainly with glucuronic acid and sulfate.

The metabolization routes are saturable at high doses, especially sulfation, which causes it to be metabolized by alternative routes by cytochrome P450 (CYP2E1) that generate hepatotoxic metabolites such as N-acetyl-P-benzoquinone imine (NAPBI), which consumes glutathione. in its elimination. NAPBI is subsequently metabolized to cysteine ​​and mercapturic acid.

Enzyme inducing/inhibitory capacity: does not seem to present significant effects.

• Elimination: metabolism and subsequent elimination in urine, mainly in the form of glucuroconjugated metabolites (60-70%), and to a lesser extent conjugated with sulfate (20-30%) and cysteine ​​(3%). Small amounts are obtained unchanged in urine (<3%). Its elimination t1/2 is 1.5-3 h. It has a small excretion of bile (2.6%).

• Pharmacokinetics in special situations:

  • Children: neonates may have a somewhat longer t1/2 (4-11 h), while in older children it is similar to that in adults (around 1.5-4.2 h).
  • Elderly: may present a somewhat longer t1/2.
  • Renal failure: elimination may be reduced in patients with end-stage renal failure (ClCr < 10 ml/min).
  • Liver failure: they may present a somewhat longer t1/2, although the conjugation capacity is not modified.

INDICATIONS: Children's Antidol 100 Mg/Ml oral solution: it is indicated for adults and adolescents over 15 years of age and weighing over 50 kg.

• Symptomatic treatment of pain of mild to moderate intensity, such as headache, odontalgia, dysmenorrhea, musculoskeletal pain such as muscle contracture, torticollis, low back pain, osteoarthritis or rheumatoid arthritis, neuralgia such as sciatica, sore throat, postoperative or postpartum pain.
• Symptomatic treatment of fever.

POSOLOGY:

• Adults: The recommended dose is 500 mg - 1 g of paracetamol every 4-6 hours, as needed, according to the intensity of symptoms. In no case will more than 3 g of paracetamol be exceeded in 24 hours. Feedings should be spaced at least 4 hours apart. Avoid administering high doses of paracetamol for prolonged periods of time as the risk of liver damage increases.

  • If the pain persists for more than 5 days, the fever lasts more than 3 days, or the pain or fever worsens or other symptoms appear, the clinical situation should be evaluated.
  • For sore throat, it should not be administered more than 2 days in a row, without evaluating the clinical situation.

• Pediatric population:

  • Due to the severity of liver toxicity and death that has occurred in children who have received excessive doses of acetaminophen, dosing should be based on weight and calibrated measuring devices should be used. Advise parents that the risk of overdose and serious liver damage increases when more than one acetaminophen-containing medication is administered concomitantly.
  • The recommended daily dose of paracetamol is approximately 60 mg/kg/day, which is divided into 4 or 6 daily doses, that is, 15 mg/kg every 6 hours or 10 mg/kg every 4 hours.
  • Children between 33 kg and 42 kg in weight (approximately 10 to 12 years old): 500 mg of paracetamol per dose, every 6 hours, up to a maximum of 4 sachets per day.
  • Children between 43 kg and 50 kg in weight (approximately 12 to 15 years old): 500 mg of paracetamol per dose, every 4-6 hours as needed, up to a maximum of 5 sachets (2,500 mg) per day. Or 650 mg of paracetamol per dose, every 6 hours, up to a maximum of 4 sachets (2,600 mg) per day.
  • Adolescents over 15 years of age and weighing over 50 kg can follow the adult dosage.
  • Do not use in children for more than 3 days in a row without evaluating the clinical situation.

• Dosage in renal failure:

  • 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.

• Dosage in liver failure:

  • Use only under medical supervision, evaluating liver function at the beginning of treatment and periodically throughout it.
  • It is recommended to avoid doses greater than 2 g/24 h (orally) or 3 g (IV), with a minimum interval of at least 8 h.

RULES FOR CORRECT ADMINISTRATION: Paracetamol can be taken with or without food. Oral administration on an empty stomach accelerates the effects of paracetamol, although not its intensity.

• Oral solution: The oral solution can be administered directly or diluted in water (preferably), milk or fruit juices.

ADVICE TO THE PATIENT:

• It can be taken with or without food. Administration without food accelerates the analgesic effects, but not their intensity.
• Do not exceed the recommended doses, nor use for more than 10 days without a doctor's recommendation. Stop treatment as soon as symptoms disappear.
• Consult your doctor and/or pharmacist if the pain continues after 5-10 days of treatment (3-5 days in children; 2 days in case of pharyngeal pain), the fever lasts more than 3 days, or symptoms worsen or new ones appear.
• Those patients who regularly consume alcohol in significant quantities (3 or more drinks daily) should limit the doses of paracetamol to avoid liver damage.
• In case of overdose, consult a doctor and/or pharmacist, even if no symptoms appear.

CONTRAINDICATIONS:

• Allergy to paracetamol or any other component of the medication.
• Severe and active liver disease.

PRECAUTIONS:

• Renal failure: Patients treated with high doses for long periods of time could experience adverse renal reactions, so it is recommended to monitor renal function. Patients with end-stage renal failure (CLcr < 10 ml/min) should space their intakes at least 8 hours apart. No special problems are expected in case of occasional use.
• Hepatotoxicity: During the hepatic metabolism of paracetamol, hepatotoxic compounds such as N-acetyl-benzoquinone imine are generated. This compound is produced in small quantities through cytochrome P450 metabolism, a minor pathway for paracetamol. However, at high doses of paracetamol, saturation of the fundamental pathways (glucurone and sulfateconjugation) may occur, increasing the role of this cytochrome, and the consequent production of benzoquinone. This substance is quickly detoxified with reduced glutathione expenditure, transforming into cysteine ​​and mercapturic acid, and eliminated through urine. If benzoquinone production is excessive, glutathione depletion occurs in the hepatocyte, and consequent cellular damage, which could lead to life-threatening toxicity. This hepatotoxicity is a delayed adverse reaction; symptoms usually appear 2 days after overdose and are maximum after 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 as long as the symptoms that motivated 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 taking into account its indications and the alternative of other analgesics and antipyretics, as a general rule it is 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 glutathione levels, or treated with other hepatotoxic drugs.
• In those patients in whom this is not possible, it is suggested to use it under medical judgment, after a careful evaluation of the benefit/risk relationship. It is recommended to evaluate liver function in these patients at the beginning of treatment and periodically throughout it. Likewise, the maximum doses to be used should not exceed 2 g/24 h (po) or 3 g/24 h (iv).
• Allergy to salicylates: Patients allergic to acetylsalicylic acid do not usually present 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 related to hematological alterations such as leukopenia, agranulocytosis or neutropenia. In case of prolonged treatments, it may be necessary to perform periodic blood counts.
• Determination of pancreatic functionality: Paracetamol can interfere with the bentiromide test, because it is metabolized to arylamine, giving rise to a false increase in para-aminobenzoic acid. It is recommended to stop treatment with paracetamol at least three days before the test.
• Caution is advised if paracetamol is administered 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 who use maximum daily doses of paracetamol. Close monitoring is recommended, including measurement of urinary 5-oxoproline.
• Heart failure: fluid retention and edema have been observed in some patients, so extreme caution is recommended in patients with heart failure. Cases of Kounis syndrome have been reported in patients with this treatment. This syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitivity reaction associated with the constriction of the coronary arteries and which can lead to a myocardial infarction.

PRECAUTIONS RELATING TO EXCIPIENTS:

• This medicine contains glucose. Patients with glucose or galactose malabsorption should not take this medication.
• This medication may cause severe allergic reactions and bronchospasm because it contains ammonium sulfite caramel.
• This medicine contains azorubine as an excipient. It may cause allergic-type reactions including asthma, especially in patients with allergies to salicylates.
• This medicine contains sorbitol (E-420). Patients with hereditary fructose intolerance should not take this medication.
• This medicine contains glucose. Its use in oral liquids and pharmaceutical forms that remain in contact with the mouth for a period of time can harm the teeth.

SPECIAL WARNINGS:

• Although it does not considerably reduce inflammation, very positive effects have been obtained in knee arthritic processes, probably due to its analgesic effect.
• Monitoring:
  • Kidney 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.

INTERACTIONS: In general, interactions with paracetamol are not expected to be serious, due to its occasional use. Only in those patients treated with high doses, especially if there are other risk factors for hepatotoxicity, or in long-term treatments, it is expected that interactions will have clinical significance.

• NSAID: Paracetamol is usually used in combination with other analgesics, such as ibuprofen, for the treatment of febrile processes in children. However, it must be taken into account that its administration together with NSAIDs or salicylates at high doses and for prolonged periods of time could increase the risk of kidney damage. It is therefore recommended not to exceed the recommended doses and limit joint treatment to the essential minimum.
• 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 the case of prolonged treatments and high doses, but without reaching toxic doses, a slight hepatotoxic effect could occur, characterized by a decrease in the production of hepatic coagulation factors, so the INR of these patients could be increased. , with risk of hemorrhage.
  • Therefore, it is recommended to monitor this parameter in these patients treated with high doses. The risk seems insignificant in case of occasional treatments or in prolonged treatments with doses < 2 g/24 h.
• Busulfan: Risk of toxicity due to busulfan, as paracetamol reduces glutathione levels, a substance with which busulfan is conjugated during its elimination. It is recommended to avoid the administration of paracetamol, or limit exposure if this is not possible, in the 72 hours before and during treatment with busulfan.
• Chloramphenicol: Paracetamol could favor the accumulation of chloramphenicol by reducing its hepatic metabolism, with the risk of hematological toxicity. It is advisable to monitor the patient.
• Drugs that delay gastric emptying, such as anticholinergics or exenatide: This delay could slow the absorption of paracetamol and the onset of the effect, rather than its intensity.
• Hepatotoxic drugs: Paracetamol at high doses exerts a hepatotoxic effect. It is recommended to avoid its co-administration with other hepatotoxic drugs, as well as 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 together with a potent inducing drug of the system. hepatic microsomal. On the other hand, in case of paracetamol overdose, the inducer could increase liver toxicity as a consequence of a greater production of toxic metabolites generated by this enzymatic system.
• Enzyme inhibitors (imatinib, isoniazid, propranolol): Increases in plasma levels of paracetamol have been reported by drugs with inhibitory activity of its metabolism.
• Reverse transcriptase inhibitors (didanosine, zidovudine): Paracetamol could potentiate the hematological toxicity of zidovudine. On the other hand, both didanosine and zidovudine could promote hepatotoxicity due to paracetamol.
• Lamotrigine: Paracetamol may increase the metabolism of lamotrigine, reducing its therapeutic effects.
• Ion exchange resins (cholestyramine, colestipol): Possible decrease in the absorption of paracetamol. Distance the administration for an hour.

In the studies carried out, the absence of significant pharmacokinetic interaction with adefovir, amantadine, H2 antihistamines or proton pump inhibitors, argatroban, chloroquine, erythromycin, lithium, methotrexate, oseltamivir, sucralfate, telmisartan or zolmitriptan has been confirmed. There has also been no interaction of any kind 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 influenza vaccines, and could reduce the symptoms of their adverse reactions.

PREGNANCY:

• Safety in animals: no teratogenic effects have been reported in animal studies.

• Safety in Humans: A large amount of data in pregnant women indicates 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 malformation, heart defects, or spontaneous abortion. There is data that suggests that its use during the last two trimesters could be related to an increased risk of wheezing in the first year of the child's life.

• Some specific cases of serious adverse reactions have been recorded in children of mothers who received paracetamol during pregnancy, including severe anemia, hepatotoxicity and nephrotoxicity (the latter two fatal). However, these symptoms appeared to be due to an overdose on the mother's part.

• Oral paracetamol, at recommended doses and used promptly, is considered a safe analgesic/antipyretic during pregnancy. It has been used just before childbirth in women with fever secondary to chorioamnionitis, with a significant improvement in the fetal and newborn status observed after normalization of maternal temperature. However, its use at high doses or for longer periods of time could be related to fetal hepatotoxicity phenomena.

• On the contrary, due to the lack of safety and efficacy data in pregnant women, it is recommended to avoid its parenteral use, unless the expected benefits outweigh the possible risks.

• Effects on fertility: In animal trials, paracetamol resulted in testicular atrophy and decreased spermatogenesis at high doses. It is unknown if these data can be extrapolated to humans.

LACTATION:

• Safety in animals: no data available.
• Safety in humans: Paracetamol is excreted in small quantities with breast milk, reaching concentrations in milk of 10-15 mcg/ml (similar to plasma concentrations) within 1-2 h after a dose of 650 mg po. An estimated exposure in the child of 1-2% of the maternal dose. No paracetamol or its metabolites have been found in the urine of the infant, nor have any adverse reactions been reported in the child, 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 young children. However, as a general precautionary measure, its use in children under 3 years of age should be carried out under medical supervision, and its use should be limited to the minimum possible.

Due to the risks of serious, potentially fatal poisoning, it is recommended to closely monitor the dosage in children, avoiding doses higher than those recommended. In this way, the appropriate presentation must be used that allows precise dosing of the child, depending on his or her weight.

It is advisable to consult the dosage of the different presentations for more information on their use in children.

OLD AGE: A reduction in elimination has been recorded in elderly patients. Certain manufacturers recommend reducing the dose by 25% compared to young adults, but others do not consider this precaution necessary.

ADVERSE REACTIONS: Paracetamol is usually well tolerated, and its 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).

• ORAL RAM:
  • Hepatic: rare (increased transaminases, increased alkaline phosphatase, hyperbilirubinemia); very rare (hepatotoxicity, with jaundice).
  • Cardiovascular: rare (hypotension).
  • Neurological/psychological: dizziness, disorientation, excitability.
  • Genitourinary: very rare renal alterations such as urine turbidity and kidney disorders.
  • Allergic: very rare hypersensitivity reactions, with symptoms ranging from skin rashes and hives to anaphylaxis.
  • Hematological: very rare thrombocytopenia, agranulocytosis, leukopenia, neutropenia, hemolytic anemia, methemoglobinemia. The prothrombin time could be increased, although it does not seem significant.
  • Metabolic: very rare hypoglycemia.
  • Analytical: analytical alterations have been described such as increased lactate dehydrogenase, increased serum creatinine, increased ammonia levels, increased urea nitrogen.
  • On the other hand, paracetamol could interfere with the analytical determination of uric acid and glucose, as well as with theophylline monitoring. It can also give false positives in the determination of 5-hydroxy-indoleacetic acid when nitrosonaphthol is used as a reagent.
  • General: rare general malaise.

OVERDOSE:

• Symptoms: paracetamol can cause very serious and life-threatening poisoning. Toxicity can begin to be experienced from single doses of 6 g in adults or 100 mg/kg in children. Doses greater than 20-25 g are potentially fatal. Chronic doses greater than 4 g/24 h may result in transient hepatotoxicity. However, patients treated with other hepatotoxic drugs, enzyme inducers or with chronic alcoholism could be more susceptible to their toxic effects, requiring lower doses to produce toxicity.
• Hepatotoxicity may appear at Cp of paracetamol greater than 120 mcg/ml at 4 h and 30 mcg/ml at 12 h. Levels of 300 mcg/ml 4 hours after overdose have been related to hepatotoxicity phenomena in 90% of patients.
• Paracetamol overdose follows four characteristic clinical stages:
  • Phase I: appears a few hours after the overdose, and up to the first 24 hours. It presents with general malaise, nausea and vomiting, abdominal pain, paleness, excessive sweating and anorexia. Liver functionality and liver parameters are normal.
  • Phase II: occurs within 24-36 hours after overdose. Symptoms of liver damage begin to appear, such as abdominal pain in the right upper quadrant and increased levels of transaminases and bilirubin, and prothrombin time.
  • Phase III: occurs 72-96 hours after overdose, and coincides with the peak of hepatotoxicity, with elevations in transaminases of up to 10,000 U/L and even higher, increases in bilirubin, glucose, lactate and phosphate, as well as elevation of prothrombin time. The patient may present with encephalopathy and coma. Likewise, renal tubular necrosis and myocardial involvement have sometimes been reported. Death may occur from fulminant hepatic failure with hepatic necrosis.
  • Phase IV: occurs 7-8 days after overdose. Recovery of those patients who have survived the previous stage.
• The risk of severe paracetamol poisoning depends on the route of administration as well as the conditions of use of the drug. In this way, serious poisoning is not expected to occur in case of overdose with suppositories (yes, due to their ingestion, although this is not frequent), or in case of injectables (due to their hospital use, with health control , despite the fact that serious poisonings have occurred due to confusion of the dose in amount of paracetamol or volume of the injectable solution). However, in no case can it be ruled out.
• Treatment: in case of oral overdose, and preferably within 4 hours after ingestion, aspiration and gastric lavage will be performed, together with administration of active charcoal, reducing the absorption of paracetamol.
• N-acetylcysteine ​​is the specific antidote for paracetamol overdose. N-acetylcysteine ​​can be used 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 hours 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 route or diluted in 200 ml of 5% glucose serum, for 15 min.
    • Then 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 over 4 hours.
    • 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 hours.
    • Children: the same regimen will be administered, although the volume of the infusion solutions will be adjusted to the age and weight of the child to avoid pulmonary vascular congestion.
  • The effectiveness of parenteral treatment with N-acetylcysteine ​​is maximum when administered within 8 hours after overdose, gradually reducing thereafter until it is ineffective at 15 hours.
  • The administration of N-acetylcysteine ​​may be suspended when plasma paracetamol levels are less than 200 mcg/ml.
  • Oral route (adults only): initially 140 mg/kg, followed by 17 doses of 70 mg/kg/4 h. The dose should be diluted in water, cola drinks or orange or grape juice to a final concentration of 5%, as it has an unpleasant taste and may lead to irritation or sclerosation. If the dose is vomited within 1 hour, its administration will 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.

Package leaflet : Children's Antidol 100 Mg/Ml 1 Bottle Oral Solution 90 Ml