Citramon-m

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYTRAMON-M (CITRAMON-M)

Composition:

Active substances: acetylsalicylic acid, paracetamol, caffeine;

One tablet contains: acetylsalicylic acid – 240 mg, paracetamol – 180 mg, caffeine – 30 mg;

Excipients: citric acid, potato starch, povidone, ascorbic acid, calcium stearate, cocoa powder.

Pharmaceutical form. Tablets.

Main physicochemical properties: light brown, flat cylindrical tablets with a score line and bevel, containing specks.

Pharmacotherapeutic group.

Analgesics and antipyretics. Acetylsalicylic acid and combinations without psychotropic agents.

ATC code N02BA51.

Pharmacological properties.

Pharmacodynamics.

Acetylsalicylic acid, paracetamol, and caffeine in the composition of Citramon-M tablets exert analgesic, antipyretic, and moderately expressed anti-inflammatory effects. The antipyretic effect of acetylsalicylic acid is mediated in the central nervous system by inhibition of PGF2 synthesis in the hypothalamus in response to the action of endogenous pyrogens; the analgesic effect has both peripheral and central origins. The peripheral effect is due to inhibition of prostaglandin synthesis in inflamed tissues; the central effect results from action on hypothalamic centers. Paracetamol affects the thermoregulatory center in the hypothalamus and reduces transmission of pain impulses. Caffeine enhances the pharmacotherapeutic effects of acetylsalicylic acid and paracetamol, increases reflex excitability of the spinal cord, and of the respiratory and vasomotor centers in the medulla oblongata, dilates blood vessels in skeletal muscles, brain, heart, and kidneys, reduces drowsiness and feelings of fatigue, enhances mental and physical performance, and accelerates blood flow.

Pharmacokinetics.

The drug is rapidly and almost completely absorbed in the upper gastrointestinal tract. Antipyretic effects appear within 30 minutes after administration, analgesic effects within 50–60 minutes. Maximum concentration of Citramon-M is reached within 2–2.5 hours.

Clinical characteristics.

Indications.

Mild or moderately expressed pain syndrome (headache, migraine, toothache, neuralgias, primary dysmenorrhea); infectious-inflammatory diseases accompanied by hyperthermic syndrome.

Contraindications.

Hypersensitivity to the components of the drug, to other xanthine derivatives (theophylline, theobromine), or to other salicylates; bronchial asthma caused by salicylates or other nonsteroidal anti-inflammatory agents in medical history; congenital hyperbilirubinemia; Gilbert’s syndrome; congenital glucose-6-phosphate dehydrogenase deficiency; blood disorders; leukopenia; anemia; hemorrhagic diathesis; severe renal insufficiency; severe hepatic insufficiency; severe cardiovascular diseases, including cardiac arrhythmias, severe atherosclerosis, severe form of ischemic heart disease, severe heart failure, severe arterial hypertension; conditions of increased excitation, sleep disturbances; elderly age; glaucoma; alcoholism. The drug is contraindicated during the use of monoamine oxidase inhibitors, as well as within 2 weeks after discontinuation of their use. Combination with methotrexate at doses of 15 mg/week or higher is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations.

Methotrexate – when used concomitantly with salicylates at doses of 15 mg/week or higher, hematological toxicity of methotrexate increases due to reduced renal clearance of methotrexate by anti-inflammatory agents and its displacement from plasma protein binding. Therefore, this combination is contraindicated.

MAO inhibitors – concomitant use with caffeine may lead to dangerous increase in blood pressure; therefore, this combination is contraindicated.

Combinations requiring caution.

Paracetamol: antidepressants and other stimulators of microsomal oxidation – these drugs increase the production of hydroxylated active metabolites affecting liver function, increasing the risk of severe intoxication even with minor overdoses of the drug. Paracetamol enhances the therapeutic effect of acetylsalicylic acid, pyrazolone, caffeine, and codeine, while decreasing paracetamol toxicity. It increases the effect of indirect anticoagulants and the risk of liver damage by hepatotoxic drugs, potentiates the action of spasmolytics, and enhances the toxicity of chloramphenicol. When used concomitantly with barbiturates, the activity of paracetamol decreases. The absorption rate of paracetamol may increase when used simultaneously with metoclopramide and domperidone, and decrease when used with cholestyramine. Paracetamol reduces the effectiveness of diuretics. Long-term use of paracetamol increases the risk of bleeding when used with coumarin derivatives (warfarin). Under the influence of paracetamol, the half-life of chloramphenicol increases fivefold.

Caution should be exercised when using paracetamol concomitantly with flucloxacillin, as such concomitant use has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions").

Caffeine: cimetidine, hormonal contraceptives, isoniazid enhance the effect of caffeine. Caffeine enhances the action of non-narcotic analgesics, cardiac glycosides, and ergotamine. Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; it acts as an antagonist of anesthetic agents and other drugs that suppress the central nervous system, and as a competitive antagonist of adenosine and adenosine triphosphate drugs. When used concomitantly with ergotamine, caffeine improves the absorption of ergotamine from the gastrointestinal tract; when used with thyrotropic agents, it enhances the thyroid effect. Caffeine increases the urinary excretion of lithium preparations and reduces lithium concentration in blood. Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic drugs, potentiates the effects of xanthine derivatives, α- and β-adrenomimetics, and psychostimulants. It reduces calcium absorption in the gastrointestinal tract.

Acetylsalicylic acid: concomitant use with uricosuric agents such as benzbromarone and probenecid reduces uric acid excretion effect (due to competition for renal tubular excretion of uric acid). When used concomitantly with digoxin, its plasma concentration increases due to reduced renal excretion. Angiotensin-converting enzyme inhibitors in combination with high doses of acetylsalicylic acid cause reduced glomerular filtration due to inhibition of vasodilatory prostaglandins and reduced antihypertensive effect. Concomitant use with nonsteroidal anti-inflammatory drugs increases both therapeutic and adverse effects of the latter; with oral hypoglycemic agents – enhances their hypoglycemic effect.

Selective serotonin reuptake inhibitors (SSRIs): risk of upper gastrointestinal bleeding increases due to possible synergistic effect. When used concomitantly with valproic acid, acetylsalicylic acid displaces it from plasma protein binding, increasing its toxicity. It diminishes the effect of antihypertensive agents, spironolactone, and furosemide.

The drug enhances the effect of agents that reduce blood coagulation and platelet aggregation, and increases the adverse effects of corticosteroids, sulfonylureas, and methotrexate. Combinations with barbiturates, anticonvulsants, salicylates, rifampicin, and alcohol should be avoided.

Special precautions for use.

In patients with allergic complications, including bronchial asthma, allergic rhinitis, urticaria, skin pruritus, mucosal edema, and nasal polyposis, as well as in combination with chronic respiratory tract infections and in patients hypersensitive to NSAIDs, treatment with the medicinal product may lead to bronchospasm or an asthma attack.

Acetylsalicylic acid irritates the gastric mucosa; therefore, Citramon-M should be taken only after meals, with water or alkaline mineral waters.

Do not use the drug with other products containing paracetamol or acetylsalicylic acid. Do not exceed the recommended doses. Use the drug with caution in patients with a history of peptic ulcers, including chronic or recurrent peptic ulcer disease, gastrointestinal bleeding in the past; when used concomitantly with anticoagulants; in patients with impaired blood coagulation, or renal and/or hepatic dysfunction. Pre-existing liver diseases increase the risk of hepatotoxicity from paracetamol. The risk of overdose is higher in patients with non-cirrhotic alcoholic liver disease. During surgical procedures (including dental surgery), the use of drugs containing acetylsalicylic acid increases the likelihood of bleeding or increased bleeding due to inhibition of platelet aggregation, which persists for some time after administration of acetylsalicylic acid. Use of the drug may reduce the excretion of uric acid, potentially leading to gout in patients with reduced uric acid excretion. During treatment, avoid consuming excessive amounts of beverages containing caffeine (e.g., coffee, tea), as this may cause sleep disturbances, tremor, feelings of tension, irritability, and retrosternal discomfort due to palpitations. Alcohol consumption should be avoided during treatment.

It is not recommended to use the medicinal product without consulting a physician for more than 5 days as an analgesic or more than 3 days as an antipyretic.

In patients with impaired renal or hepatic function, the interval between doses should be at least 8 hours.

Paracetamol

Consult a physician before using the drug if the patient is taking warfarin or similar agents with anticoagulant effects. The drug may affect laboratory test results for blood glucose and uric acid levels.

Patients who take analgesics daily for mild forms of arthritis should consult a physician. In patients with severe infections such as sepsis, associated with reduced glutathione levels, the use of paracetamol increases the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Immediate medical attention is required if these symptoms occur.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, as well as in patients with inadequate nutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who were treated with paracetamol at therapeutic doses over a prolonged period or in combination with flucloxacillin. If high anion gap metabolic acidosis due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with close monitoring of the patient. Measurement of 5-oxoproline levels in urine may be helpful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

If symptoms do not resolve, consult a physician.

If headaches become persistent, consult a physician.

Keep the medicinal product out of sight and reach of children.

Acetylsalicylic acid

Use with caution in patients hypersensitive to analgesic, anti-inflammatory, or antirheumatic drugs, when used concomitantly with anticoagulants, and in patients with circulatory disorders (e.g., renal vascular pathology, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding), as acetylsalicylic acid may increase the risk of renal dysfunction and acute renal failure. Ibuprofen may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation. If Citramon-M is used prior to starting ibuprofen as an analgesic, the patient should consult a physician.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy and breastfeeding.

Acetylsalicylic acid has teratogenic effects; its use during the first trimester of pregnancy may cause congenital malformations such as cleft palate, and during the third trimester may inhibit labor activity (by inhibiting prostaglandin synthesis), lead to closure of the fetal arterial duct, resulting in pulmonary vascular hyperplasia and pulmonary hypertension in the fetal circulation, impair renal function with possible subsequent development of renal failure associated with oligohydramnios, and prolong bleeding time. Anti-aggregatory effects may occur even after administration of very low doses.

Acetylsalicylic acid and paracetamol pass into breast milk, increasing the risk of bleeding in the infant due to impaired platelet function.

Current data on paracetamol use in pregnant women indicate no disturbances in fetal development or fetotoxic/neonatal toxicity when used appropriately.

Caffeine increases the risk of spontaneous abortion.

Ability to affect reaction speed when driving or operating machinery.

Due to the presence of caffeine in the formulation, individuals with increased excitability may experience insomnia or feelings of anxiety. Therefore, during treatment, patients should refrain from driving vehicles or performing tasks requiring high attention and rapid reaction speed.

Method of Administration and Dosage

The drug should be administered to adults at a dose of 1 tablet 2–3 times daily after meals. The maximum daily dose is 6 tablets (taken in 3 doses). Citramon-M tablets should not be taken for more than 5 days as an analgesic and for more than 3 days as an antipyretic.

Do not exceed the recommended dose. Do not take together with other medicinal products containing paracetamol.

Children.

The drug is contraindicated in children due to the risk of Reye's syndrome development during hyperthermia associated with viral infections (hyperpyrexia, metabolic acidosis, neurological and psychiatric disturbances, vomiting, liver function impairment).

Overdose.

Symptoms of overdose may occur with prolonged use of the drug or when used in doses many times higher than recommended.

Symptoms of overdose within the first 24 hours, caused by paracetamol.

Liver damage is possible in adults who have ingested 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight. Liver injury may manifest 12–48 hours after administration of excessive doses. Within the first 24 hours: pallor, loss of appetite, nausea, vomiting, anorexia, abdominal pain, hepatonecrosis, increased activity of liver transaminases, prolonged prothrombin index. Disorders of glucose metabolism and metabolic acidosis may also occur. In severe poisoning, liver failure may progress and lead to toxic encephalopathy with impaired consciousness, hemorrhages, hypoglycemia, coma, and in some cases, fatal outcome. Acute renal failure with acute tubular necrosis may present with severe lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe kidney damage. Cardiac arrhythmia and pancreatitis have also been reported. With long-term use of high doses, aplastic anemia, thrombocytopenia, pancytopenia, agranulocytosis, neutropenia, and leukopenia may develop from the hematopoietic system side. When large doses are taken, central nervous system effects may include dizziness, psychomotor agitation, and disorientation; from the urinary system — nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).

In patients with risk factors (long-term use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; alcohol abuse; glutathione system deficiency, e.g., digestive disorders, HIV infection, fasting, cystic fibrosis, cachexia), ingestion of 5 g or more of paracetamol may lead to liver damage.

In case of overdose, prompt medical assistance is required. The patient should be immediately hospitalized, even if early symptoms of overdose are absent.

In overdose, nausea, vomiting, excessive sweating, psychomotor agitation or central nervous system depression, drowsiness, impaired consciousness, cardiac rhythm disturbances, tachycardia, extrasystoles, tremor, hyperreflexia, seizures may occur, or the severity of overdose or risk of organ damage may not be apparent. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier measurement is unreliable).

Treatment: gastric lavage followed by administration of activated charcoal (if the excessive dose of paracetamol was taken within 1 hour), symptomatic therapy. The specific antidote for paracetamol overdose is N-acetylcysteine. In the absence of vomiting, oral methionine or intravenous N-acetylcysteine may be used, which is effective within 24 hours, but maximum protective effect is achieved when administered within 8 hours after overdose. The efficacy of the antidote sharply decreases after this time. General supportive measures should also be taken. If necessary, α-adrenoblockers should be used.

Symptoms of caffeine overdose.

Large doses of caffeine may cause epigastric pain, vomiting, diuresis, rapid breathing, extrasystoles, tachycardia, or cardiac arrhythmia, and effects on the central nervous system (dizziness, insomnia, irritability, nervous excitement, affective state, anxiety, tremor, seizures).

Treatment: gastric lavage, repeated administration of activated charcoal, forced alkaline diuresis, oxygen therapy, hemodialysis in severe cases, fluid and electrolyte infusion. Symptomatic therapy. In case of seizures, diazepam should be administered.

Symptoms of acetylsalicylic acid overdose.

Salicylate overdose may occur due to chronic intoxication resulting from prolonged therapy (use of more than 100 mg/kg/day for over 2 days may cause toxic effects), as well as due to acute, life-threatening intoxication (overdose), which may result from accidental ingestion or unintentional overdose. Chronic salicylate intoxication may have a hidden course, as its signs are nonspecific. Moderate chronic intoxication caused by salicylates, or salicylism, usually occurs only after repeated administration of large doses.

Symptoms. Loss of balance, dizziness, tinnitus, deafness, decreased visual acuity, increased sweating, dehydration, nausea and vomiting, headache, confusion, carbohydrate metabolism disturbances, coma. These symptoms can be controlled by dose reduction. Tinnitus may occur at plasma salicylate concentrations between 150 and 300 mcg/mL. More serious adverse reactions occur at plasma salicylate concentrations exceeding 300 mcg/mL. Acute intoxication is characterized by marked acid-base imbalance, which may vary depending on age and severity of intoxication. Metabolic acidosis is a common sign in children. The severity of the condition cannot be determined solely by plasma salicylate concentration. Absorption of acetylsalicylic acid may be delayed due to delayed gastric emptying, formation of concretions in the stomach, or use of enteric-coated formulations.

Emergency management of acetylsalicylic acid poisoning depends on the severity, stage, and clinical symptoms and follows standard methods for treating poisoning. Initial measures should aim at accelerating drug elimination and restoring electrolyte and acid-base balance. Due to complex pathophysiological effects of salicylate poisoning, certain symptoms and laboratory changes may occur.

Mild to moderate poisoning: tachypnea, hyperventilation, respiratory alkalosis, increased sweating, nausea, vomiting. Laboratory findings: alkalosis, alkaline urine reaction.

Severe poisoning: respiratory alkalosis with compensatory metabolic acidosis, hyperpyrexia, tinnitus, deafness. Respiratory system: from hyperventilation and non-cardiogenic pulmonary edema to respiratory arrest and asphyxia. Laboratory findings: alkalosis, alkaline urine reaction. Cardiovascular system: from cardiac rhythm disturbances and arterial hypotension to cardiac arrest. Fluid and electrolyte loss: dehydration, oliguria, renal failure. Laboratory findings: hypokalemia, hypernatremia, hyponatremia, impaired kidney function. Glucose metabolism disturbances and ketosis manifest in laboratory tests as hyperglycemia, hypoglycemia (especially in children), elevated ketone bodies. Gastrointestinal tract: gastrointestinal bleeding. Blood: from platelet function suppression to coagulopathies. Laboratory findings: prolonged prothrombin time, hypoprothrombinemia. Neurological: toxic encephalopathy and CNS depression ranging from lethargy and impaired consciousness to coma and seizures.

Treatment. Prompt medical assistance is required in case of overdose, even if symptoms are absent. Administration of oral methionine or intravenous acetylcysteine may have a positive effect within 48 hours after overdose. General supportive measures and symptomatic therapy, including use of beta-adrenoreceptor antagonists to counteract cardiotoxic effects, should also be applied.

Side effects

Immune system disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, rhinitis, nasal congestion;

Skin and subcutaneous tissue disorders: skin pruritus, skin and mucous membrane rashes, including generalized and erythematous rashes, urticaria, angioneurotic edema; erythema multiforme; Stevens–Johnson syndrome; toxic epidermal necrolysis (Lyell’s syndrome);

Gastrointestinal disorders: dyspeptic disorders, including nausea, vomiting, epigastric discomfort and pain, heartburn, abdominal pain; gastrointestinal tract inflammation; erosive-ulcerative lesions of the gastrointestinal tract, which in rare cases may lead to gastrointestinal bleeding and perforation, with corresponding laboratory and clinical manifestations;

Hepatobiliary disorders: liver function abnormalities, increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (dose-dependent effect), hepatotoxicity;

Endocrine disorders: hypoglycemia, up to hypoglycemic coma;

Nervous system disorders: headache, dizziness, tremor, paresthesia, fear, anxiety, excitement, irritability, sleep disturbances, insomnia, restlessness, general weakness, tinnitus;

Cardiac disorders: tachycardia, palpitations, arterial hypertension, arrhythmia;

Renal and urinary system disorders: nephrotoxicity, aseptic pyuria, renal colic;

Blood and lymphatic system disorders: anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia. Due to the antiplatelet effect of acetylsalicylic acid, the risk of bleeding is increased. Bleeding events observed include intraoperative hemorrhages, hematomas, genitourinary tract bleeding, epistaxis, gingival bleeding; gastrointestinal bleeding and cerebral hemorrhages;

Respiratory system disorders: bronchospasm;

Other: bleeding may lead to acute and chronic post-hemorrhagic/iron-deficiency anemia (due to so-called occult microbleeding), with corresponding laboratory findings and clinical symptoms such as asthenia, pallor of the skin, hypoperfusion; non-cardiogenic pulmonary edema;

Metabolism and nutrition disorders: metabolic acidosis with high anion gap (frequency unknown).

Description of selected adverse reactions

Metabolic acidosis with high anion gap. Cases of metabolic acidosis with high anion gap due to pyroglutamic acidosis have been observed in patients with risk factors taking paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

6 or 10 tablets in blisters.

1 blister of 6 or 10 tablets, or 10 blisters of 10 tablets per cardboard box.

Prescription status.

Over-the-counter: No. 6, No. 6 (6x1); No. 10, No. 10 (10x1).

By prescription: No. 100 (10x10).

Manufacturer: JSC "CHEMICAL PHARMACEUTICAL PLANT "CHERVONA ZIRKA".

Manufacturer's address and place of business:

1 Gordienkivska Street, Kharkiv, Kharkiv Oblast, 61010, Ukraine.