Lekofen Combo (Tablets) Instructions for Use

Marketing Authorization Holder

Sandoz, d.d. (Slovenia)

Manufactured By

Rontis Hellas Medical And Pharmaceutical Products, S.A. (Greece)

Contact Information

SANDOZ AO (Russia)

ATC Code

M01AE51 (Ibuprofen in combination with other drugs)

Active Substances

Ibuprofen (Rec.INN registered by WHO)

Paracetamol (Rec.INN registered by WHO)

Dosage Form

Lekofen Combo

Film-coated tablets, 200 mg+500 mg: 6, 8, 10, 12, 16, 18, 20, 24 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, oval, biconvex.

Excipients* corn starch – 108.8 mg, crospovidone (type A) – 18.6 mg, colloidal anhydrous silicon dioxide – 9 mg, povidone K30 – 40 mg, pregelatinized starch – 41.6 mg, talc – 8 mg, stearic acid – 4 mg.

Tablet coating composition* (Opadry II white, 85F18422): polyvinyl alcohol – 11.16 mg, talc – 4.129 mg, macrogol 3350 – 5.636 mg, titanium dioxide – 6.975 mg.

* The solvent (purified water) evaporates during the manufacturing process and is absent in the finished product.

6 pcs. – blisters (1) – cardboard packs.
6 pcs. – blisters (2) – cardboard packs.
6 pcs. – blisters (3) – cardboard packs.
8 pcs. – blisters (1) – cardboard packs.
8 pcs. – blisters (2) – cardboard packs.
8 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

NSAID in combination with an analgesic-antipyretic

Pharmacotherapeutic Group

Combined analgesic agent (NSAID + non-narcotic analgesic agent)

Pharmacological Action

Pharmacodynamics

A combined drug, the action of which is due to its constituent components. It has a targeted effect against pain (analgesic), antipyretic and anti-inflammatory action. Ibuprofen and Paracetamol differ in their mechanism and site of action. As a result of their mutually reinforcing action, a more pronounced reduction in pain sensitivity and enhancement of the antipyretic effect is achieved than individually.

Ibuprofen – a propionic acid derivative from the NSAID group, has anti-inflammatory, including anti-edema, analgesic and antipyretic effects. The mechanism of action of ibuprofen is due to inhibition of the synthesis of prostaglandins – mediators of pain, inflammation and hyperthermic reaction, through non-selective inhibition of COX-1 and COX-2 activity. The analgesic effect of ibuprofen is provided by its inhibitory action at the peripheral level. The antipyretic effect of ibuprofen is associated with the central inhibition of prostaglandin synthesis in the hypothalamus. Ibuprofen inhibits the migration of leukocytes to the site of inflammation, reversibly suppresses platelet aggregation.

Paracetamol – a non-narcotic analgesic agent, has analgesic, antipyretic and weak anti-inflammatory effects. It non-selectively blocks COX-2, mainly in the CNS. Paracetamol can also stimulate the activity of descending serotonin pathways, leading to the relief of pain impulse transmission in the spinal cord. At the peripheral level, Paracetamol has a weak effect on COX-1 and COX-2.

The drug Lekofen Combo has a faster therapeutic effect and a more pronounced analgesic effect than Ibuprofen and Paracetamol individually. After taking one tablet, the analgesic effect is noted on average 15 minutes after taking the drug, a clinically significant analgesic effect is achieved after 40 minutes and lasts for 8 hours. After taking 2 tablets, the analgesic effect is noted on average 18 minutes after taking the drug, a clinically significant analgesic effect is achieved after 45 minutes and lasts for 9 hours.

Pharmacokinetics

Ibuprofen

Absorption

Absorption is high, rapidly and almost completely absorbed from the gastrointestinal tract. Detected in blood plasma 5 minutes after taking the drug on an empty stomach. T_max after oral administration is about 1-2 hours. Taking the drug with food may increase T_max by 25 minutes, but the overall extent of absorption is equivalent.

Distribution

Plasma protein binding is 90%. It slowly penetrates into the joint cavity, accumulates in the synovial fluid, creating higher concentrations in it than in the blood plasma. There is evidence that Ibuprofen was detected in breast milk in insignificant concentrations.

Metabolism

It is metabolized in the liver. After absorption, about 60% of the pharmacologically inactive R-form is slowly transformed into the active S-form.

Elimination

It is mainly excreted by the kidneys in the form of metabolites (unchanged no more than 1%) and to a lesser extent with bile in the form of metabolites and their conjugates. T_1/2 is about 2 hours.

In elderly people, no significant differences in the pharmacokinetic profile of ibuprofen were found compared to younger people.

Paracetamol

Absorption

Absorption is high, rapidly absorbed from the gastrointestinal tract. Detected in blood plasma 5 minutes after taking the drug on an empty stomach. T_max after oral administration is 30-40 minutes. C_max is 5-20 µg/ml. When taking the drug Lekofen Combo with food, a lower plasma concentration is determined, which is achieved 55 minutes later, but the overall extent of absorption is equivalent.

Distribution

Plasma protein binding is less than 10% when taken in therapeutic doses, slightly increases in overdose. It is distributed fairly evenly in body fluids. Penetrates the blood-brain barrier.

Metabolism

About 90-95% of paracetamol is metabolized in the liver to form inactive conjugates with glucuronic acid (60%), taurine (35%) and cysteine (3%), as well as a small amount of hydroxylated and deacetylated metabolites. A small part of the drug is hydroxylated by microsomal enzymes to form highly active N-acetyl-p-benzoquinone imine, which binds to the sulfhydryl groups of glutathione. When liver glutathione stores are depleted (in case of overdose), hepatocyte enzyme systems can be blocked, leading to tissue damage.

Elimination

It is excreted by the kidneys mainly in the form of glucuronides and sulfated conjugates with the formation of about 10% glutathione conjugates (less than 5% is excreted unchanged). T_1/2 is 3 hours.

In elderly people, no significant differences in the pharmacokinetic profile of paracetamol were found compared to younger people.

The bioavailability and pharmacokinetic parameters of ibuprofen and paracetamol taken as part of this combined drug do not change with either single or multiple use. The drug is developed using technology that allows ibuprofen and paracetamol to be released simultaneously, so that the active ingredients provide a combined effect.

Indications

• Back pain;
• Joint pain;
• Muscular and rheumatic pains;
• Neuralgia;
• Headache;
• Migraine;
• Toothache;
• Algodysmenorrhea;
• Sore throat, febrile condition, symptoms of cold and flu.

The drug is especially indicated for the symptomatic treatment of pain requiring a more pronounced analgesic effect than Ibuprofen and Paracetamol individually.

ICD codes

Dosage Regimen

Orally, before meals or 2-3 hours after meals, 1 tablet up to 3 times/day, with water. The interval between doses of the drug should be at least 6 hours.

For short-term use only.

Maximum single dose: 2 tablets (corresponding to 400 mg ibuprofen, 1000 mg paracetamol).

Maximum daily dose: 6 tablets (corresponding to 1200 mg ibuprofen, 3000 mg paracetamol).

The recommended duration of treatment is no more than 3 days. If symptoms persist or worsen while taking the drug for 3 days, it is necessary to stop treatment and consult a doctor.

Adverse Reactions

The risk of adverse reactions can be minimized by using the drug in a short course, at the minimum effective dose necessary to relieve symptoms.

In elderly people, there is an increased frequency of adverse reactions (AR) against the background of NSAID use, especially gastrointestinal bleeding and perforations, in some cases with a fatal outcome. ARs are predominantly dose-dependent. In particular, the risk of gastrointestinal bleeding depends on the dose range and duration of treatment.

The ARs listed below were noted with short-term use of ibuprofen at doses of 1200 mg/day, paracetamol at doses of 3000 mg/day (6 tablets). When treating chronic conditions and with long-term use, other side effects may occur.

According to WHO, adverse events are classified according to their frequency of occurrence as follows: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Blood and lymphatic system disorders very rare – hematopoietic disorders (anemia, leukopenia, neutropenia, aplastic anemia, hemolytic anemia, thrombocytopenia, pancytopenia, agranulocytosis). The first symptoms of such disorders may be fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe weakness, nosebleeds and subcutaneous hemorrhages, bleeding and bruising of unknown origin.

Immune system disorders uncommon – hypersensitivity reactions (non-specific allergic reactions and anaphylactic reactions, allergic rhinitis, eosinophilia); very rare – severe hypersensitivity reactions, including swelling of the face, tongue and larynx, shortness of breath, tachycardia, decreased blood pressure (anaphylaxis, angioedema or severe anaphylactic shock).

Nervous system disorders uncommon – headache, dizziness; very rare – paresthesia, optic neuritis, drowsiness, aseptic meningitis (in patients with autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease, during treatment with ibuprofen, isolated cases of symptoms of aseptic meningitis were observed: neck stiffness, headache, nausea, vomiting, fever and disorientation, confusion, depression, hallucinations).

Eye disorders very rare – visual impairment.

Ear and labyrinth disorders : very rare – tinnitus and vertigo.

Cardiac disorders very rare – heart failure, with long-term use increased risk of thrombotic complications (e.g., myocardial infarction).

Vascular disorders very rare – peripheral edema, increased blood pressure.

Respiratory, thoracic and mediastinal disorders very rare – bronchial asthma, including exacerbation, bronchospasm, shortness of breath.

Gastrointestinal disorders common – abdominal pain, diarrhea, dyspepsia, nausea, abdominal discomfort, vomiting; uncommon – flatulence and constipation, gastric ulcer, perforation or gastrointestinal bleeding, melena, vomiting blood, in some cases with a fatal outcome, especially in elderly patients, ulcerative stomatitis, exacerbation of ulcerative colitis and Crohn’s disease; uncommon – gastritis, pancreatitis.

Hepatobiliary disorders very rare – impaired liver function (especially with long-term use), increased activity of liver transaminases, hepatitis, jaundice.

Renal and urinary disorders very rare – acute renal failure (compensated and decompensated), especially with long-term use, in combination with an increase in plasma urea concentration and the appearance of edema, papillary necrosis, hematuria and proteinuria, nephritic syndrome, nephrotic syndrome, interstitial nephritis, cystitis.

Skin and subcutaneous tissue disorders : common – hyperhidrosis (increased sweating); uncommon – skin rash, acute generalized exanthematous pustulosis; very rare – exfoliative and bullous dermatoses, including toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, erythema multiforme.

Investigations common – increased ALT activity, GGT, increased plasma creatinine and urea concentration, changes in liver function parameters (outside the normal range); uncommon – increased AST activity, ALP, CPK, decreased hemoglobin concentration, increased platelet count.

If side effects occur, you should stop taking the drug and consult a doctor.

Contraindications

• Increased individual sensitivity to ibuprofen, paracetamol or other components of the drug;
• Simultaneous use with other agents containing NSAIDs, including Paracetamol, selective COX-2 inhibitors and doses of acetylsalicylic acid over 75 mg/day – the risk of adverse reactions increases;
• Complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance to acetylsalicylic acid or other NSAIDs (including in history);
• Erosive and ulcerative diseases of the gastrointestinal tract (including peptic ulcer of the stomach and duodenum, Crohn’s disease, ulcerative colitis) or ulcerative bleeding/perforation of a gastrointestinal ulcer in the active phase or in history, including those provoked by the use of NSAIDs (2 or more confirmed episodes of peptic ulcer or ulcer bleeding);
• Severe heart failure (class IV according to NYHA – New York Heart Association classification);
• Severe hepatic failure or active liver disease;
• Severe renal failure (CC <30 ml/min);
• Confirmed hyperkalemia;
• Decompensated heart failure, the period after coronary artery bypass grafting;
• Cerebrovascular or other bleeding;
• Hemophilia or other blood clotting disorders (including hypocoagulation), hemorrhagic diatheses;
• Pregnancy over 20 weeks;
• Age under 18 years.

With caution

In the presence of the conditions listed in this section, you should consult a doctor before using the drug

• Simultaneous use of other NSAIDs;
• History of a single episode of gastric and duodenal ulcer or gastrointestinal ulcer bleeding, presence of Helicobacter pylori infection, gastritis, enteritis, colitis, ulcerative colitis, Crohn’s disease;
• Bronchial asthma or allergic diseases in the acute stage or in history – bronchospasm may develop;
• Systemic lupus erythematosus or mixed connective tissue disease (Sharp’s syndrome) – increased risk of aseptic meningitis;
• Renal failure, including with dehydration (CC 30-60 ml/min), nephrotic syndrome;
• Hepatic failure, liver cirrhosis with portal hypertension, alcoholic liver damage without cirrhosis, benign hyperbilirubinemia;
• Arterial hypertension and/or congestive heart failure, cerebrovascular diseases, peripheral artery diseases, coronary artery disease;
• Blood diseases of unknown etiology (leukopenia and anemia);
• Dyslipidemia/hyperlipidemia;
• Diabetes mellitus;
• Simultaneous use with drugs that may increase the risk of ulcers or bleeding, in particular, with oral corticosteroids (including prednisolone), anticoagulants (including warfarin), antiplatelet agents (including clopidogrel), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline);
• Elderly age;
• Pregnancy (I-II trimester);
• Breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

There are no data on the use of the drug during pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic-fetal development. Data obtained from epidemiological studies indicate that the use of prostaglandin synthesis inhibitors leads to an increased risk of spontaneous abortion, congenital heart defects and anterior abdominal wall defects.

The use of prostaglandin synthesis inhibitors in the III trimester of pregnancy can cause signs of toxic effects on the heart and lungs in the fetus (premature closure of the ductus arteriosus and pulmonary hypertension), increases the likelihood of prolonged bleeding, has an antiplatelet effect even in low doses and can inhibit uterine contractions, thereby leading to a delay or increase in the duration of labor and is therefore contraindicated. NSAIDs should not be used by women from the 20th week of pregnancy due to the development of oligohydramnios and/or kidney pathology in newborns (neonatal renal dysfunction).

The use of the drug in the first and second trimesters of pregnancy should be avoided unless absolutely necessary. If it is necessary to take the drug during these stages of pregnancy, a doctor should be consulted.

To date, no negative effects of paracetamol in recommended doses on the fetus have been observed.

Breastfeeding period

There is evidence that Ibuprofen may pass into breast milk in small amounts without any negative consequences for the health of the breastfed infant; therefore, short-term use usually does not necessitate discontinuation of breastfeeding. Paracetamol is excreted in breast milk; however, it does not produce a clinically significant effect. If long-term use of the drug is necessary, a doctor should be consulted to decide on discontinuing breastfeeding during the period of drug use.

Fertility

The active substances contained in the drug Lekofen Combo inhibit COX and prostaglandin synthesis, affect ovulation, and may impair female reproductive function (reversible after discontinuation of treatment).

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency or active liver disease. Use with caution in hepatic insufficiency, liver cirrhosis with portal hypertension, alcoholic liver disease without cirrhosis, benign hyperbilirubinemia.

Use in Renal Impairment

Contraindicated in severe renal failure (CrCl <30 ml/min). Use with caution in renal failure, including dehydration (CrCl 30-60 ml/min), nephrotic syndrome.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Special Precautions

The drug should be used for the shortest possible course and at the minimum effective dose necessary to relieve symptoms.

When using ibuprofen/paracetamol, the symptoms of infectious diseases may be less pronounced, which may lead to a delay in initiating appropriate treatment and a worsening outcome of the infectious disease. Worsening has been observed in the context of community-acquired bacterial pneumonia and with bacterial complications of chickenpox. In case of using ibuprofen/paracetamol for an infectious disease to reduce body temperature or relieve pain, careful monitoring of the course of the infection is recommended. In outpatient settings, if symptoms persist or worsen, the patient should consult a doctor.

In patients with bronchial asthma or allergic diseases in the acute phase, as well as in patients with a history of bronchial asthma/allergic disease, the drug may provoke bronchospasm.

The use of the drug in patients with systemic lupus erythematosus or mixed connective tissue disease is associated with an increased risk of aseptic meningitis.

During long-term treatment, monitoring of peripheral blood counts and the functional state of the liver and kidneys is necessary. If symptoms of gastropathy appear, careful monitoring is indicated, including esophagogastroduodenoscopy, complete blood count (hemoglobin determination), and stool test for occult blood.

Ethanol consumption is not recommended during treatment.

Patients with renal insufficiency should consult a doctor before using the drug, as there is a risk of worsening renal function.

Patients with hypertension, including a history of it, and/or with chronic heart failure should consult a doctor before using the drug, as the drug may cause fluid retention, increased blood pressure, and edema.

In patients with uncontrolled arterial hypertension, congestive heart failure NYHA class II-III, coronary artery disease, peripheral arterial disease and/or cerebrovascular disease, the drug should be prescribed only after a thorough benefit-risk assessment, and the use of high doses of ibuprofen (≥2400 mg/day) should be avoided.

The use of NSAIDs in patients with chickenpox may be associated with an increased risk of severe purulent complications of infectious and inflammatory diseases of the skin and subcutaneous tissue (e.g., necrotizing fasciitis). Therefore, it is recommended to avoid using the drug for chickenpox.

To avoid possible damaging effects on the liver during the use of the drug, alcohol should not be consumed.

The drug may distort the results of laboratory tests in the quantitative determination of glucose, uric acid in blood serum, 17-ketosteroids (discontinuation of the drug 48 hours before the test is necessary). It should not be taken with any other drugs containing Paracetamol. If this occurs, seek medical help immediately, even if feeling well, as this may lead to overdose.

Effect on the ability to drive vehicles and machinery

When adhering to the recommended dosage regimen and duration of use, the drug does not affect the ability to drive vehicles and machinery, or to engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Ibuprofen

In adults, the dose-dependent effect of overdose is less pronounced. The T_1/2 of the drug in overdose is 1.5-3 hours.

Symptoms nausea, vomiting, epigastric pain or, less commonly, diarrhea, tinnitus, headache, and gastrointestinal bleeding. In more severe cases, manifestations from the central nervous system are observed: drowsiness, rarely – agitation, convulsions, disorientation, coma. In cases of severe poisoning, metabolic acidosis and increased prothrombin time, renal failure, liver tissue damage, decreased blood pressure, respiratory depression, and cyanosis may develop. In patients with bronchial asthma, an exacerbation of this disease is possible.

Treatment symptomatic, with mandatory maintenance of airway patency, monitoring of ECG and basic vital signs until the patient’s condition normalizes. Oral administration of activated charcoal or gastric lavage within 1 hour after ingestion of a potentially toxic dose of ibuprofen is recommended. If Ibuprofen has already been absorbed, alkaline fluids may be prescribed to promote the excretion of the acidic derivative of ibuprofen by the kidneys, along with forced diuresis. Frequent or prolonged convulsions should be controlled with intravenous administration of diazepam or lorazepam. If bronchial asthma worsens, the use of bronchodilators is recommended.

Paracetamol

Symptoms of paracetamol overdose within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may appear 12-48 hours after ingestion, so a doctor should be consulted even in the absence of symptoms. Impaired glucose metabolism and metabolic acidosis are possible. In severe poisonings, liver failure may progress with complications such as encephalopathy, hemorrhage, hypoglycemia, cerebral edema, and death. Acute renal failure with acute tubular necrosis (identified by low back pain, hematuria, and proteinuria) may develop even in the absence of severe liver damage. There are reports of cardiac arrhythmias and pancreatitis.

Treatment immediate treatment is necessary for paracetamol overdose. Despite the lack of significant early symptoms, patients should be urgently taken to a hospital for immediate medical examination. Symptoms may be limited to nausea or vomiting and may not reflect the severity of the overdose or the risk of organ damage. Treatment with activated charcoal should be considered if the excessive dose was taken less than 1 hour ago. The plasma concentration of paracetamol should be measured at 4 hours or more after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine can be administered up to 24 hours after paracetamol ingestion, but the maximum protective effect is achieved about 8 hours after drug ingestion. The effectiveness of the antidote gradually decreases after this time. If necessary, N-acetylcysteine is administered intravenously according to the established regimen. Outside the hospital, if there is no vomiting, methionine can be taken orally. Patients presenting with serious liver dysfunction 24 hours after drug ingestion should be referred to a poison control specialist.

Additional information for special patient groups

An increased risk of liver damage from paracetamol overdose is most likely in

• Patients receiving long-term treatment with enzyme-inducing agents (such as carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, and St. John’s wort);
• Patients who consume alcohol in amounts above the recommended limits;
• Patients with glutathione depletion (e.g., patients with eating disorders, cystic fibrosis, HIV infection, cachexia, starvation).

Drug Interactions

Ibuprofen

Concomitant use of ibuprofen with the following drugs should be avoided

– acetylsalicylic acid, except for low doses of acetylsalicylic acid – (not more than 75 mg/day) prescribed by a doctor, since concomitant use may increase the risk of side effects. When used concomitantly, Ibuprofen reduces the anti-inflammatory and antiplatelet effect of acetylsalicylic acid (an increase in the frequency of acute coronary insufficiency is possible in patients receiving low doses of acetylsalicylic acid as an antiplatelet agent after starting ibuprofen);

– other NSAIDs, in particular, selective COX-2 inhibitors: the simultaneous use of two or more drugs from the NSAID group should be avoided due to a possible increase in the risk of adverse reactions.

Use with caution concomitantly with the following drugs

– anticoagulants and thrombolytic drugs: NSAIDs may enhance the effect of anticoagulants, in particular warfarin, and thrombolytic drugs (alteplase, streptokinase, urokinase);

• antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists and diuretics) NSAIDs may reduce the effectiveness of drugs in these groups in some patients with impaired renal function (e.g., in dehydrated patients or elderly patients with impaired renal function) concomitant administration of ACE inhibitors or angiotensin II receptor antagonists and agents that inhibit COX may lead to deterioration of renal function, including the development of acute renal failure (usually reversible). Therefore, the concomitant use of the aforementioned agents should be prescribed with caution, especially in the elderly. Dehydration in patients should be prevented, and consideration should be given to monitoring renal function after initiation of such combined therapy and periodically thereafter. Diuretics and ACE inhibitors may increase the nephrotoxicity of NSAIDs;
• glucocorticosteroids increased risk of erosive and ulcerative lesions of the gastrointestinal tract and gastrointestinal bleeding;
• antiplatelet agents and selective serotonin reuptake inhibitors increased risk of gastrointestinal bleeding;
• cardiac glycosides concomitant administration of NSAIDs and cardiac glycosides may lead to worsening of heart failure, decreased glomerular filtration rate, and increased plasma concentration of cardiac glycosides;
• lithium preparations there is evidence of a probable increase in plasma lithium concentration during the use of NSAIDs;
• methotrexate there is evidence of a probable increase in plasma methotrexate concentration during the use of NSAIDs;
• cyclosporine, tacrolimus an increased risk of nephrotoxicity is possible with concomitant administration with NSAIDs;
• mifepristone NSAIDs should be started no earlier than 8-12 days after finishing mifepristone, as NSAIDs may reduce the effectiveness of mifepristone;
• zidovudine concomitant use of NSAIDs and zidovudine may lead to increased hematotoxicity. There is evidence of an increased risk of hemarthrosis and hematoma in HIV-positive patients with hemophilia receiving combined treatment with zidovudine and ibuprofen;
• quinolone antibiotics in patients receiving combined treatment with NSAIDs and quinolone antibiotics, an increased risk of convulsions is possible;
• Myelotoxic drugs enhance the manifestations of hematotoxicity of the drug;
• Caffeine enhances the analgesic effect;

Paracetamol

• antiemetics reduced rate of absorption of paracetamol when used concomitantly with metoclopramide or domperidone;
• anticoagulants long-term use of drugs containing Paracetamol may enhance the effect of anticoagulants, in particular warfarin, and increase the risk of bleeding;
• cholestyramine reduces the rate of absorption of paracetamol when used concomitantly;
• chloramphenicol : Paracetamol increases the plasma concentration of chloramphenicol.

Paracetamol falsely increases continuous glucose monitoring (CGM) system readings compared to glucometer readings. This applies to patients using CGM devices that contain or do not contain an automatic insulin pump, i.e., with type I diabetes. Caution should be exercised when using paracetamol and flucloxacillin concomitantly, as this is associated with an increased risk of developing metabolic acidosis with a high anion gap, especially in patients with risk factors for glutathione deficiency (including patients with severe renal failure, sepsis, malnutrition, and chronic alcoholism). Careful monitoring is recommended to detect signs of acid-base imbalance, namely metabolic acidosis with a high anion gap, including determination of urinary 5-oxoproline.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date.

Dispensing Status

The drug is available without a prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.