FARMADOL®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FARMADOL® (FARMADOL)

Composition:

Active substances: 1 tablet contains acetylsalicylic acid 300 mg, paracetamol 100 mg, caffeine 50 mg;

Excipients: citric acid monohydrate; potato starch; lactose monohydrate; povidone; sodium croscarmellose; microcrystalline cellulose; calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets with flat surface, scored and beveled edge, white or almost white, with a slight specific odor. Marbling and specks on the tablet surface are permissible.

Pharmacotherapeutic group.

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

ATC code N02B A51.

Pharmacological properties.

Pharmacodynamics.

Fardol® is a combination drug with anti-inflammatory, antipyretic, and analgesic effects. The drug's action is determined by its components.

The antipyretic effect of acetylsalicylic acid is mediated through the central nervous system by inhibiting the synthesis of prostaglandin PGE2 in the hypothalamus in response to endogenous pyrogens. Its analgesic efficacy arises both peripherally (by inhibiting prostaglandin synthesis at the site of inflammation, preventing sensitization of pain receptors to mechanical and chemical stimuli) and centrally (by acting on hypothalamic centers without suppressing consciousness through hypnotic effects or lowering the psychological pain threshold).

The analgesic and antipyretic effects of paracetamol are due to inhibition of prostaglandin synthesis and predominant action on the thermoregulatory center in the hypothalamus. Paracetamol is a considerably weaker inhibitor of the peripheral prostaglandin biosynthesis system, which plays an important role in the development of inflammatory responses.

The mechanism of action of caffeine is based on inhibition of phosphodiesterase activity, leading to accumulation of cAMP. An important component of caffeine's mechanism of action is its interaction with purine receptors in the brain. Caffeine enhances the analgesic effects of acetylsalicylic acid and paracetamol and accelerates the onset of their action.

Pharmacokinetics.

Not studied.

Clinical characteristics.

Indications.

Mild or moderate pain syndrome (headache, migraine, toothache, neuralgias, arthralgia, primary dysmenorrhea); conditions associated with hyperthermic syndrome (as an antipyretic agent).

Contraindications.

Hypersensitivity to components of the drug, other xanthine derivatives (theophylline, theobromine), or other salicylates; bronchial asthma caused by salicylates or other nonsteroidal anti-inflammatory drugs (NSAIDs) in medical history; congenital hyperbilirubinemia, congenital glucose-6-phosphate dehydrogenase deficiency, blood disorders, leukopenia, anemia, thrombosis, thrombophlebitis, acute gastrointestinal ulcers, hemorrhagic diathesis, severe renal impairment, severe hepatic impairment, severe cardiovascular diseases including arrhythmias, severe atherosclerosis, severe form of ischemic heart disease, severe heart failure, severe arterial hypertension, tendency to vascular spasm; acute pancreatitis, prostate hyperplasia, severe forms of diabetes mellitus; conditions of increased excitation, sleep disorders, epilepsy, hyperthyroidism, glaucoma, alcoholism. The period of monoamine oxidase inhibitors (MAOIs) use, as well as the 2-week period following discontinuation of their use, is contraindicated in patients taking tricyclic antidepressants or beta-blockers. Combination with methotrexate at doses of 15 mg/week or higher.

Interaction with other medicinal products and other types of interactions.

Contraindicated combinations.

Methotrexate – when used concomitantly with salicylates at doses of 15 mg per 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.

Barbiturates reduce the antipyretic effect of paracetamol.

Due to the presence of acetylsalicylic acid, the drug may enhance the hypoglycemic effect of oral antidiabetic agents.

Combinations requiring caution.

Paracetamol: antidepressants and other stimulators of microsomal oxidation – these drugs increase the production of hydroxylated active metabolites affecting liver function, which may lead to the development of severe intoxications even with minor overdoses of the drug. The absorption rate of paracetamol may increase when used concomitantly 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. Concurrent use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome.

Caffeine: cimetidine, hormonal contraceptives, isoniazid enhance the effect of caffeine. Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; it acts as an antagonist of anesthetic agents and other central nervous system (CNS) depressants (competitive antagonist of CNS depressants), and as a competitive antagonist of adenosine and adenosine triphosphate (ATP) drugs. Concurrent use of caffeine with ergotamine improves ergotamine absorption from the gastrointestinal tract; with thyrotropic agents – increases thyroid effect. Caffeine reduces blood lithium concentration. Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic drugs, potentiates the effects of xanthine derivatives, alpha- and beta-adrenomimetics, psychostimulants. Concurrent use of caffeine with MAO inhibitors may cause a dangerous increase in blood pressure.

Acetylsalicylic acid: concomitant use with uricosuric agents such as benzbromarone, probenecid reduces the 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. ACE inhibitors in combination with high doses of acetylsalicylic acid cause reduced glomerular filtration due to inhibition of vasodilatory prostaglandins and reduced antihypertensive effect. Selective serotonin reuptake inhibitors: increase the risk of upper gastrointestinal bleeding due to possible synergistic effect. When used concomitantly with valproic acid, acetylsalicylic acid displaces it from plasma protein binding, increasing its toxicity.

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

Special precautions.

Do not use this medicine together with other products containing paracetamol or acetylsalicylic acid. Do not exceed the recommended doses.

Pre-existing liver disease increases the risk of liver damage caused by paracetamol.

Allergic reactions or exacerbation of the underlying disease may occur in patients with bronchial asthma, allergic disorders, or hypersensitivity to NSAIDs. The medicine should be used with caution in elderly patients.

During treatment, it is not recommended to consume excessive amounts of beverages containing caffeine (e.g., coffee, tea), as this may cause sleep disturbances, tremor, or discomfort in the chest due to palpitations.

Alcoholic beverages should not be consumed during treatment.

Paracetamol should be used with caution when administered concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition, or other sources of glutathione deficiency (e.g., chronic alcoholism), especially when the maximum daily dose of paracetamol is used.

After concomitant use of paracetamol and flucloxacillin, careful monitoring is recommended to detect acid-base disturbances, specifically high anion gap metabolic acidosis, including detection of 5-oxoproline in urine.

Use with caution in the following cases:

• Hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as well as allergy to other substances;
• Gastrointestinal ulcers, including chronic or recurrent peptic ulcer disease or gastrointestinal bleeding in medical history;
• Concomitant use of anticoagulants;
• Impaired kidney function or disturbances in cardiovascular circulation (e.g., renal vascular disease, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding), since acetylsalicylic acid may increase the risk of renal dysfunction and acute kidney injury;
• Severe glucose-6-phosphate dehydrogenase deficiency — acetylsalicylic acid may cause hemolysis or hemolytic anemia, especially in the presence of risk factors for hemolysis such as high drug doses, fever, or acute infection;
• Impaired liver function.

Acetylsalicylic acid may provoke bronchospasm, asthma attacks, or other hypersensitivity reactions. Risk factors include history of asthma, hay fever, nasal polyps, or chronic respiratory disease, and allergic reactions (e.g., skin reactions, pruritus, urticaria) to other substances in the past.

Due to the inhibitory effect of acetylsalicylic acid on platelet aggregation, which persists for several days after administration, the use of medicines containing acetylsalicylic acid increases the likelihood of increased bleeding during surgical procedures (including minor surgeries such as tooth extraction).

When low doses of acetylsalicylic acid are used, excretion of uric acid may be reduced. This may trigger gout attacks in predisposed patients.

Medicines containing acetylsalicylic acid should not be used in children and adolescents with acute respiratory viral infections (ARVI), whether or not accompanied by fever, without prior consultation with a physician. In certain viral illnesses, particularly influenza A, influenza B, and varicella, there is a risk of developing Reye's syndrome—a very rare but life-threatening condition requiring urgent medical intervention. The risk may be increased if acetylsalicylic acid is used as an adjunctive treatment; however, a causal relationship has not been definitively established. Persistent vomiting during these conditions may be a manifestation of Reye's syndrome.

If symptoms do not resolve, consult a physician.

If headache becomes persistent, consult a physician.

Patients who take analgesics daily for mild forms of arthritis should consult a physician. In patients with severe infections such as sepsis, which are 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 should be sought if these symptoms occur.

This medicine contains lactose. Therefore, it should not be used in patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Do not use.

Ability to affect reaction speed when driving or operating machinery.

If dizziness occurs, potentially hazardous activities, including driving a vehicle and/or performing tasks requiring high attention and rapid psychomotor reactions, should be avoided.

Dosage and Administration.

For adults, take Pharmadol® orally, 1–2 tablets 2–3 times daily after meals, with a large amount of liquid. The maximum daily dose is 6 tablets, divided into 3 doses.

The drug should not be used for more than 5 days as an analgesic or more than 3 days as an antipyretic.

Children. Do not use the drug in children due to the risk of Reye's syndrome (hyperpyrexia, metabolic acidosis, neurological and psychiatric disturbances, vomiting, liver dysfunction) associated with hyperthermia during viral infections.

Overdose.

Symptoms of paracetamol overdose.

Liver damage may occur in adults who have ingested 10 g or more of paracetamol, and in children who have taken more than 150 mg/kg body weight. Liver injury may manifest 12–48 hours after ingestion of excessive doses. During the first 24 hours, symptoms may include pallor, nausea, vomiting, anorexia, abdominal pain, hepatonecrosis, elevated activity of liver transaminases, and increased prothrombin index. In severe poisoning, liver failure may lead to encephalopathy, coma, and 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. Pancreatitis has also been reported. Glucose metabolism disturbances and metabolic acidosis may occur. Cardiac arrhythmias have also been observed. With prolonged use of high doses, aplastic anemia, thrombocytopenia, pancytopenia, agranulocytosis, neutropenia, and leukopenia may develop.

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

With large doses, central nervous system (CNS) effects may include dizziness, psychomotor agitation, and disorientation. Effects on the urinary system may include nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

Treatment with N-acetylcysteine can be administered within 24 hours after paracetamol ingestion, but the maximum protective effect is achieved when administered within 8 hours after overdose. The efficacy of the antidote decreases sharply after this time.

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), or due to acute, life-threatening intoxication (overdose), which may result from accidental ingestion, particularly in children, or unintentional overdose.

Chronic salicylate poisoning may have a hidden course, as its signs are nonspecific. Moderate chronic intoxication caused by salicylates, or salicylism, usually occurs only after repeated ingestion of large doses. Main symptoms include: loss of balance, dizziness, tinnitus, hearing loss, excessive sweating, nausea and vomiting, headache, confusion. These symptoms can be managed by reducing the dose. Tinnitus may occur at plasma salicylate concentrations above 150–300 µg/mL. Severe adverse reactions occur at plasma salicylate concentrations above 300 µg/mL. Acute intoxication is characterized by significant disturbances in acid-base balance, which may vary depending on the patient's age and severity of intoxication. The severity of the condition cannot be determined solely based on plasma salicylate concentration.

Due to complex pathophysiological effects, symptoms of salicylate poisoning may include:

• Mild to moderate intoxication may be accompanied by: tachypnea, hyperventilation, respiratory alkalosis (alkalemia, alkaluria); increased sweating; nausea, vomiting.
• Moderate to severe intoxication may be accompanied by: respiratory alkalosis with compensatory metabolic acidosis (acidemia, aciduria); hyperpyrexia; respiratory disorders: hyperventilation, non-cardiogenic pulmonary edema, respiratory failure, asphyxia; cardiovascular disorders: arrhythmia, arterial hypotension, cardiovascular failure; fluid and electrolyte loss: dehydration, oliguria, renal failure; glucose metabolism disturbances, ketoacidosis; tinnitus, hearing loss; gastrointestinal bleeding; hematological disorders: platelet inhibition, coagulopathy; neurological disorders: toxic encephalopathy and CNS depression, manifesting as lethargy, confusion, coma, and seizures.

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, nervous excitation, irritability, emotional lability, anxiety, tremor, seizures).

Treatment.

Treatment is determined by the severity and clinical symptoms and is provided by standard methods. In case of overdose, prompt medical assistance is required, even if symptoms of overdose are absent. Oral administration of methionine or intravenous administration of acetylcysteine may be effective within 48 hours after overdose. General supportive measures and symptomatic therapy should also be implemented, including the use of beta-adrenergic receptor antagonists, which may counteract cardiotoxic effects.

Side effects.

Allergic reactions: skin rashes (usually erythematous, urticaria), itching, angioedema, Stevens-Johnson syndrome (including other forms of exudative multiform erythema), toxic epidermal necrolysis, non-cardiogenic pulmonary edema, asthma.

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

Hepatobiliary system disorders: increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (dose-dependent effect).

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

Hematologic disorders: sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, thrombocytopenia, agranulocytosis, perioperative hemorrhages, hematomas, genitourinary system hemorrhages, epistaxis, gingival bleeding, cerebral hemorrhages.

Hemorrhages 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.

Immune system disorders: angioedema, anaphylactic shock, which may be accompanied by cardiorespiratory failure, hypersensitivity reactions, rhinitis, nasal congestion, bronchospasm.

Cardiovascular disorders: transient arterial hypertension, tachycardia, arrhythmia.

Central nervous system disorders: dizziness, insomnia, restlessness, tinnitus.

Renal and urinary system disorders: impaired kidney function and cases of acute renal failure have been reported.

Concomitant use of the drug at recommended doses with products containing caffeine may enhance caffeine-related side effects such as increased excitability, anxiety, irritability, headache, gastrointestinal disturbances, and tachycardia.

Shelf life.

2 years.

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

Storage conditions.

Store in a light-protected place at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per blister. 1, 3, or 5 blisters per carton.

Availability. Over-the-counter.

Manufacturer: JSC "Farmak".

Manufacturer's name and address of place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.