Paracetamol Reneval, tablets 500 mg 10 pcs

Pharmacotherapeutic group: analgesic non-narcotic.

The ATX code: N02BE01

Pharmacological properties

Pharmacodynamics

Paracetamol has antipyretic and analgesic effects. A non-narcotic analgesic, it blocks cyclooxygenase (COX) I and II mainly in the central nervous system, affecting the centers of pain and thermoregulation. In inflamed tissues, cellular peroxidases neutralize the effect of paracetamol on COX, which explains the almost complete lack of anti-inflammatory effect. Since paracetamol has an extremely small effect on prostaglandin synthesis in periphytic tissues, it does not alter water-electrolyte metabolism and does not cause damage to the mucosa of the gastrointestinal tract. Thus, paracetamol is particularly suitable for patients with a history of gastrointestinal disease (such as patients with a history of gastrointestinal bleeding or elderly patients) or for patients taking concomitant medications when inhibition of peripheral prostaglandins may be undesirable.

Pharmacokinetics

Absorption

Absorption is high; the drug is rapidly and almost completely absorbed from the gastrointestinal tract. TC_max is reached in 0.5-2 hours; C_max is 5-20 µg/ml. Binding with plasma proteins is 15%. It penetrates through the blood-brain barrier. Less than 1% of the dose of paracetamol taken by a nursing mother penetrates into breast milk. The therapeutically effective plasma concentration of paracetamol is achieved when administered at a dose of 10-15 mg/kg.

Metabolism

Metabolized in the liver (90-95%): 80% enters into conjugation reactions with glucuronic acid and sulfates to form inactive metabolites; 17% undergoes hydroxylation to form 8 active metabolites, which conjugate with glutathione to form already inactive metabolites. In case of glutathione deficiency these metabolites can block enzyme systems of hepatocytes and cause their necrosis. CYP2E1, CYP1A2 isoenzymes and, to a lesser extent, CYP3A4 isoenzyme are also involved in metabolism of the drug. Additional metabolic pathways are hydroxylation to 3-hydroxyparacetamol and methoxylation to 3-methoxyparacetamol, which are subsequently conjugated to glucuronides or sulfates. In adults, glucuronidation predominates; in newborns (including premature infants) and young children, sulfation predominates. Conjugated metabolites of paracetamol (glucuronides, sulfates and conjugates with glutathione) have low pharmacological (including toxic) activity.

Elimation

The elimination half-life (T_1/2) is 1-4 hours. Excreted by the kidneys as metabolites, mainly conjugates, only 3% unchanged. In elderly patients, the clearance of paracetamol is decreased and the elimination half-life is increased.

Indications

Active ingredient

Composition

Active ingredient: Paracetamol – 500.0 mg

Excipients:

Potato starch – 30.2 mg

povidone K 30 – 14.3 mg

How to take, the dosage

Overly, with plenty of fluid, 1-2 hours after a meal (taking immediately after a meal leads to delayed onset of action).

Adults (including the elderly) and children over 12 years of age (body weight over 40 kg) 500 mg – 1 g up to 4 times a day, if necessary.

The single dose is 500 mg (1 tablet). The maximum single dose is 1 g (2 tablets). Maximum daily dose is 4 g (8 tablets). The interval between doses is at least 4 hours.

Children from 6 to 12 years old the dose is calculated on the basis of the child’s body weight: maximum single dose is 15 mg/kg (1/2 tablet-1 tablet) of body weight 4 times a day, maximum daily dose is 60 mg/kg (4 tablets) of body weight. The interval between doses is at least 4 hours.

In adults, paracetamol should not be used for more than 5 days as an analgesic and for more than 3 days as an antipyretic without a physician’s prescription and supervision.

In children, paracetamol is not recommended for more than 3 days without a doctor’s prescription and supervision. Do not exceed the indicated dose.

In patients with chronic or decompensated liver disease, with liver failure, chronic alcoholism, in emaciated patients and in dehydration, the daily dose should not exceed 3 g.

Do not exceed the stated dose. The lowest dose necessary to achieve an effect should be taken. The interval between doses should be at least 4 hours. The drug should not be taken simultaneously with other paracetamol-containing drugs. Increase the daily dose of paracetamol or the duration of treatment only under medical supervision.

Interaction

If you or your child is already taking other medicines, you should consult a doctor before starting to take paracetamol.

. Inducers of microsomal liver enzymes or potentially hepatotoxic substances (such as alcohol, rifampicin, isoniazid, sleeping pills, and antiepileptics, including phenobarbital, phenytoin, and carbamazepine) increase paracetamol toxicity and can lead to liver damage even with non-toxic doses of paracetamol, so liver function should be monitored.

Phenytoin reduces the effectiveness of paracetamol; therefore, patients taking phenytoin should avoid frequent use of paracetamol, especially in high doses.

Decreases the effectiveness of uricosuric drugs.

Chloramphenicol

Paracetamol may increase the risk of elevated chloramphenicol concentrations.

Zidovudine

Paracetamol may increase the risk of neutropenia, and therefore hematologic parameters should be monitored. Simultaneous use is only possible after consultation with a physician.

Probenecid

Probenecid almost halves the clearance of paracetamol, which requires reducing the dose of paracetamol.

Indirect anticoagulants

Multiple administration of paracetamol for more than 4 days increases the anticoagulant effect. International normalized ratio (INR) should be monitored during and after concomitant use of paracetamol (especially in high doses and/or for a long time) and coumarin derivatives. Irregular administration of paracetamol has no significant effect. Propantelin and other drugs that slow down the evacuation from the stomach decrease the rate of absorption of paracetamol, which may delay or reduce the onset of effect.

Methoclopramide and domperidone increase the rate of absorption of paracetamol and therefore the onset of analgesic and antipyretic effects.

Long-term use of barbiturates reduces the effectiveness of paracetamol.

Ethanol promotes acute pancreatitis.

Long-term co-use of paracetamol and other NSAIDs increases the risk of developing “analgesic” nephropathy and renal papillary necrosis, the onset of terminal renal failure.

The simultaneous long-term prescription of paracetamol in high doses and salicylates increases the risk of developing kidney or bladder cancer.

Diflunisal increases plasma concentrations by 50% – risk of hepatotoxicity.

Myelotoxic drugs increase the manifestations of hematotoxicity of the drug.

Special Instructions

If no improvement is seen with paracetamol or if the headache becomes permanent, a physician should be consulted. If the febrile syndrome persists after using paracetamol for more than 3 days and the pain syndrome persists for more than 5 days, a physician should be consulted.

Patients with glutathione deficiency are prone to overdose, precautions must be taken. Glutathione deficiency due to eating disorders, cystic fibrosis, HIV infection, starvation, and exhaustion makes it possible to develop severe liver damage in small overdoses of paracetamol (5 g or more). Cases of liver failure and liver function abnormalities have been reported in patients with low glutathione levels, particularly in extremely emaciated patients with anorexia, chronic alcoholism, or in patients with a low body mass index. The risk of liver damage increases in patients with liver damage from alcoholism.

The administration of paracetamol affects laboratory values in the quantification of plasma glucose and uric acid. During long-term treatment it is necessary to monitor peripheral blood count and liver function.

Paracetamol may cause serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, which may be fatal. At the first manifestation of rash or other hypersensitivity reactions, the use of the drug should be discontinued, you should immediately consult a physician.

If a patient is found to have acute viral hepatitis, the drug should be discontinued. Do not take simultaneously with other drugs containing paracetamol.

To avoid toxic liver damage, paracetamol should not be combined with the intake of alcoholic beverages and should not be taken by persons prone to chronic alcohol consumption.

Impact on the ability to drive vehicles, mechanisms

There are no data on the effect of paracetamol on the ability to drive vehicles or other mechanisms. However, given the possible adverse reactions, caution is recommended when taking paracetamol to drive vehicles or operate other mechanisms.

Synopsis

Contraindications

Hypersensitivity to paracetamol or any other ingredient of the drug;

With caution

. Renal and hepatic insufficiency of mild to moderate severity, benign hyperbilirubinemia (including Gilbert syndrome), enzyme deficiency of glucose-6-phosphate dehydrogenase, dehydration, hypovolemia, anorexia, bulimia and cachexia (insufficient glutathione reserve in the liver), viral hepatitis, alcoholic liver damage, alcoholism, pregnancy, breastfeeding period, advanced age.

In these cases, consult a physician before taking the drug.

Side effects

The following criteria were used to assess the frequency of adverse reactions (ARs): “frequent” (≥ 1/100, < 1/10); “infrequent” (≥ 1/1000, < 1/100); “rare” (≥ 1/10000, < 1/1000); “very rare” (< 1/10000); “frequency unknown” (cannot be estimated from available data). HAs are grouped according to the system-organ classes of the MedDRA Regulatory Medical Dictionary as well as the recommendations of the World Health Organization.

In recommended doses, paracetamol is generally well tolerated. The following side effects were detected spontaneously during post-registration use.

Blood and lymphatic system disorders

often: postoperative bleeding;

very rarely: Anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia;

frequency unknown: pancytopenia, sulfohemoglobinemia, methemoglobinemia.

Immune system disorders

rare rare: allergic reactions (including skin rash, pruritus, urticaria, angioedema);

very rare: Acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), anaphylaxis.

Mental disorders

often: insomnia, anxiety.

Nervous system disorders

often: headache;

frequency unknown: dystonia, dizziness, psychomotor agitation, disorientation (when taking high doses).

Visual disorders

often: periorbital edema.

Cardiac disorders

often: tachycardia, chest pain.

Vascular disorders

often: peripheral edema, hypertension;

rarely: decreased blood pressure.

Disorders of the respiratory system, thoracic and mediastinal organs

often: dyspnea, abnormal breathing, pulmonary edema, hypoxia, pleural effusion, wheezing, shortness of breath, cough;

very rarely: bronchospasm (in patients with hypersensitivity to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs).

Gastrointestinal disorders

often: Diarrhea, constipation, dyspepsia, bloating;

rarely: abdominal pain, nausea, vomiting;

frequency unknown: dry mouth.

Hepatic and biliary tract disorders

rarely: increased liver enzyme activity;

frequency unknown: liver failure, hepatitis, liver necrosis.

Skin and subcutaneous tissue disorders

incidence unknown: exanthema.

Musculoskeletal and connective tissue disorders

often: muscle cramps, trismus.

Renal and urinary tract disorders

often: oliguria;

frequency unknown: Renal colic, nonspecific bacteriuria, interstitial nephritis, papillary necrosis.

General disorders and disorders at the site of administration

often: pyrexia, feeling of fatigue;

rarely: general malaise/weakness.

Influence on laboratory and instrumental findings

often: hypokalemia, hyperglycemia;

rarely: decreased or increased prothrombin index;

incidence unknown: increased creatinine (mostly secondary to hepatorenal syndrome).

In case of any of the above side effects, stop taking paracetamol and consult a physician immediately.

Overdose

Symptoms

The clinical picture of acute overdose develops within 24 hours after taking paracetamol. Gastrointestinal disorders (nausea, vomiting, decreased appetite, feeling of discomfort in the abdomen and (or) abdominal pain), pale skin. When administered to adults 7.5 g or more or to children more than 140 mg/kg, cytolysis of hepatocytes with complete and irreversible liver necrosis, development of hepatic failure, metabolic acidosis and encephalopathy occurs, which may lead to coma and death. Oral administration of 5 g or more of paracetamol may lead to liver damage in the presence of risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort or other drugs that are inducers of microsomal liver enzymes; ethanol abuse, glutathione deficiency, digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia). In 12-48 hours after paracetamol administration, increased activity of microsomal liver enzymes, lactate dehydrogenase, bilirubin concentration and decreased prothrombin content are noted. Clinical symptoms of liver damage appear 2 days after drug overdose and reach their maximum on the 4th-6th day. In overdose intoxication is possible, especially in elderly patients, children, patients with liver diseases (caused by chronic alcoholism), in patients with nutritional disorders, as well as in patients taking microsomal liver enzyme inducers, with lightning hepatitis, liver failure, cholestatic hepatitis, cytolytic hepatitis may develop, sometimes with fatal outcome. In severe cases of overdose as a result of liver failure may develop encephalopathy (brain dysfunction), cerebral edema, bleeding, hypoglycemia, up to death. Acute renal failure with acute tubular necrosis may develop, characterized by pain in the lumbar region, hematuria (blood or red blood cells in the urine), proteinuria (high protein content in the urine), while severe liver damage may be absent. There have been cases of abnormal heart rhythm, pancreatitis.

Treatment

Hospitalization immediately. If an overdose is suspected, even if there are no pronounced first symptoms, paracetamol should be stopped and medical attention should be sought immediately. Paracetamol plasma levels should be determined, but not earlier than 4 hours after overdose (earlier results are unreliable). Laboratory tests of microsomal liver enzyme activity should be performed at the beginning of treatment and then every 24 hours. Administration of SH-group donators and precursors of glutathione-methionine and acetylcysteine synthesis is most effective in the first 8 hours.

Symptomatic treatment: In 1 hour after overdose gastric lavage and taking enterosorbents (activated charcoal and others) is recommended. In most cases, the activity of microsomal liver enzymes is normalized within 1-2 weeks. Liver transplantation may be necessary in very severe cases. Administration of acetylcysteine within 24 hours after overdose. Maximum protective effect is provided during the first 8 hours after overdose, with time the effectiveness of the antidote decreases sharply. If necessary, acetylcysteine is administered intravenously. In the absence of vomiting before the patient is admitted to the hospital, methionine may be administered. The need for additional therapeutic measures (further administration of methionine, intravenous administration of acetylcysteine) is determined depending on the concentration of paracetamol in the blood, as well as on the time elapsed after its administration. Treatment of patients with severe liver dysfunction 24 hours after paracetamol ingestion should be done in conjunction with specialists from a toxicology center or a specialized department of liver disease.

Pregnancy use

Pregnancy

In animal studies and studies conducted in humans, no risks of using the drug in pregnant women or harmful effects of the drug on the development of the embryo and fetus have been found. Paracetamol can be used during pregnancy, but it is advisable to use the lowest effective dose and the shortest possible course.

Breastfeeding period

In small amounts it penetrates into breast milk. Studies have not found harmful effects of paracetamol on the baby during breastfeeding, however, should be used with caution.

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