Pharmadol® max

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

Composition:

Active substances: acetylsalicylic acid, paracetamol, caffeine;

One film-coated tablet contains: acetylsalicylic acid 250 mg, paracetamol 250 mg, caffeine 65 mg;

Excipients: microcrystalline cellulose, low-substituted hydroxypropylcellulose, stearic acid, hydroxypropylcellulose;

Film coating: hypromellose, titanium dioxide (E 171), macrogol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: elongated, biconvex film-coated tablets, white or almost white in colour.

Pharmacotherapeutic group.

Analgesics and antipyretics. Acetylsalicylic acid combinations without psychotropic agents.

ATC code N02B A51.

Pharmacological Properties

Pharmacodynamics

In the combination of paracetamol, acetylsalicylic acid, and caffeine, paracetamol acts as an analgesic and antipyretic agent. Acetylsalicylic acid (ASA) exerts analgesic, antipyretic, and anti-inflammatory effects through inhibition of prostaglandin synthesis. Caffeine enhances the analgesic effects of both paracetamol and ASA.

Pharmacokinetics

Acetylsalicylic acid (ASA)

Rapidly and completely absorbed after oral administration. Hydrolyzed in blood plasma to salicylic acid, which is then metabolized primarily in the liver and excreted via the kidneys along with its metabolites.

Paracetamol

Paracetamol is rapidly and almost completely absorbed in the gastrointestinal tract. Plasma protein binding is negligible when administered at therapeutic doses. Paracetamol is metabolized in the liver and primarily excreted in the urine as glucuronide and sulfate conjugates. Less than 5% is excreted unchanged.

Caffeine

Caffeine is rapidly and completely absorbed in the gastrointestinal tract, with peak plasma concentrations observed between 5 and 120 minutes after administration. Data regarding its presystemic metabolism are lacking. Caffeine is uniformly distributed in all body fluids. Mean plasma protein binding is 35%. In adults, it is almost entirely metabolized in the liver. Elimination rate in adults is individual. The mean elimination half-life from plasma is 4.9 hours, with a range of 1.9–12.2 hours.

Caffeine is almost entirely metabolized via oxidation, demethylation, and acetylation, and is excreted in urine. Its main metabolites are 1-methylxanthine, 7-methylxanthine, and 1,7-dimethylxanthine (paraxanthine). Minor metabolites include 1-methyluric acid and 5-acetylamino-6-formylamino-3-methyluracil (AMFU).

No cross-interaction between the three active components, nor increased risk of interaction with other drugs when the active components are used in combination, has been observed. Due to the combination of the three active substances, the content of each is low, thereby reducing the drug's toxicity.

Clinical Study Data

Clinical studies have demonstrated the efficacy of the medicinal product in the treatment of acute migraine attacks, resulting in relief of migraine symptoms such as headache, nausea, photophobia, phonophobia, and functional impairment. The effect of the medicinal product in reducing migraine symptoms has been shown to begin within 30 minutes.

The efficacy of the medicinal product in treating headache has also been demonstrated. Headache relief was reported by patients within 15 minutes and sustained for up to 4 hours after administration.

Preclinical Study Data

There are no data from studies using modern standards to assess the toxic effects of paracetamol on fertility and fetal development.

Clinical characteristics.

Indications.

Emergency treatment of headache and migraine attacks with or without aura.

Contraindications.

• Hypersensitivity to the active substances of the medicinal product or to any of its components; history of asthma attacks, bronchospasm, angioedema, urticaria, or acute rhinitis induced by acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs);
• Active peptic ulcer or history of gastric ulcer; gastrointestinal bleeding or perforation associated with NSAID therapy;
• Hemophilia, hyperbilirubinemia, or other blood coagulation disorders;
• Renal failure (glomerular filtration rate (GFR) < 15 mL/min/1.72 m²);
• Hepatic insufficiency, history of gout;
• Hypersensitivity to other xanthine derivatives (theophylline, theobromine), other salicylates; glucose-6-phosphate dehydrogenase deficiency;
• Blood disorders; severe anemia; leukopenia; conditions of increased excitation; sleep disturbances; elderly age; glaucoma; alcoholism;
• Period of using monoamine oxidase inhibitors (MAOIs), as well as within 2 weeks after discontinuation of these drugs; severe cardiovascular diseases, including cardiac arrhythmias;
• Severe atherosclerosis;
• Severe form of ischemic heart disease;
• Severe heart failure;
• Severe arterial hypertension;
• Use of more than 15 mg of methotrexate per week;
• Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

The medicinal product should not be used with other NSAIDs, including acetylsalicylic acid (ASA) and specific cyclooxygenase-2 (COX-2) inhibitors, as this increases the risk of adverse reactions.

Possible interactions of active ingredients

Acetylsalicylic acid (ASA)

Paracetamol

Caffeine

Effect on laboratory test results

• The use of high doses of acetylsalicylic acid (ASA) may affect the results of several clinical chemical laboratory tests.
• The use of paracetamol may affect the results of uric acid determination when the test is performed using phosphotungstic acid reagent, and may also affect blood glucose determination results when the test is performed using the glucose oxidase/peroxidase method.
• Caffeine may counteract the effect of dipyridamole on myocardial blood flow and thus influence the results of this test. It is recommended to discontinue caffeine intake 8–12 hours before the start of this test.

Special precautions for use.

• Keep the medicinal product out of reach and sight of children.
• Use with caution in patients suspected of migraine in whom migraine has not previously been diagnosed or whose symptoms are atypical, in order to exclude possible serious neurological conditions.
• Do not use the medicinal product Pharmadol***®*** Max in patients in whom > 20% of migraine attacks are accompanied by vomiting or in whom > 50% of migraine attacks require bed rest.
• If the patient with migraine does not experience symptom improvement after taking the first 2 tablets, they should consult a physician.
• Do not use this medicinal product in patients who have experienced headaches more than 10 days per month over the past 3 or more months.
• Use this medicinal product with caution in patients at risk of dehydration (e.g., due to vomiting, diarrhea, or before or after major surgery).
• Due to its pharmacodynamic properties, the medicinal product Pharmadol***®*** Max may mask signs and symptoms of infection.
• Use the medicinal product Pharmadol***®*** Max with caution in patients with mild or moderate renal impairment.
• The medicinal product contains benzoic acid, which increases the risk of jaundice in newborns.

Due to acetylsalicylic acid content

• Do not use this medicinal product concomitantly with products containing acetylsalicylic acid (ASA) or other systemic NSAIDs, including selective COX-2 inhibitors, due to the potential for additional adverse reactions.
• The medicinal product Pharmadol***®*** Max may provoke bronchospasm and cause serious hypersensitivity reactions or anaphylaxis in patients with a history of bronchial asthma, allergic disorders, or nasal polyps.
• Do not use the medicinal product Pharmadol***®*** Max in children and adolescents during or immediately after varicella (chickenpox), influenza, or other viral infections without medical prescription, as there may be an association between ASA therapy in children during or immediately after viral infections and the development of Reye’s syndrome.
• Use the medicinal product Pharmadol***®*** Max with caution in patients with uncontrolled hypertension (in whom blood pressure cannot be measured), renal or hepatic dysfunction, dehydration, or diabetes mellitus.
• Acetylsalicylic acid may cause sodium and water retention in the body, which may worsen conditions such as arterial hypertension, chronic heart failure, and renal dysfunction.
• ASA inhibits platelet aggregation and prolongs bleeding time; therefore, use of the medicinal product increases the risk of hematological and hemorrhagic effects, which may be severe. Unusual bleeding should be reported to a physician.
• Do not use the medicinal product Pharmadol***®*** Max concomitantly with anticoagulants or other medicinal products that inhibit platelet aggregation without medical supervision. Patients with coagulation disorders should be closely monitored. The medicinal product should be used with caution in cases of metrorrhagia or menorrhagia.
• With the use of all NSAIDs, cases of gastrointestinal bleeding, ulceration, or perforation have been reported, which may be fatal and can occur at any stage of treatment, regardless of a history of gastrointestinal disorders. These cases are more severe in elderly individuals.
• ASA intake may affect laboratory test results for thyroid function, causing pseudolow concentrations of levothyroxine (T4) or triiodothyronine (T3).
• Intake of more than 1 g of ASA per day may cause acute hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.

Due to paracetamol content

• Do not use the medicinal product Pharmadol***®*** Max concomitantly with other medicinal products containing paracetamol, as this may lead to overdose. Paracetamol overdose may cause liver failure, which may require liver transplantation or result in death.
• In patients with liver disease, the risk of hepatotoxic effects of paracetamol is increased. The benefit-risk ratio should be evaluated before prescribing the medicinal product to patients with liver or kidney disease.
• Cases of impaired liver function/liver failure have been reported in patients with reduced glutathione levels, such as in severe malnutrition, anorexia, low body mass index, chronic alcoholism, or sepsis. In patients with reduced glutathione levels, paracetamol intake increases the risk of metabolic acidosis.
• The risk of paracetamol toxicity may increase in patients taking other potentially hepatotoxic medicinal products or medicinal products that induce hepatic microsomal enzymes (e.g., rifampicin, isoniazid, chloramphenicol, sedatives, and antiepileptic agents, including phenobarbital, phenytoin, and carbamazepine).
• Caution is advised when using paracetamol concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis, particularly in patients with severe renal impairment, sepsis, malnutrition, or other sources of glutathione deficiency (e.g., chronic alcoholism), as well as those taking maximum daily doses of paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.

Due to caffeine content

• Use the medicinal product Pharmadol***®*** Max with caution in patients with gout or hyperthyroidism.
• During treatment with the medicinal product Pharmadol***®*** Max, patients should limit consumption of products containing caffeine (e.g., coffee, tea, and certain other beverages), as excessive caffeine concentration in the body may cause nervousness, irritability, insomnia, episodes of tachycardia, and other symptoms of caffeine overdose.

Use during pregnancy or breastfeeding

Use of the medicinal product during pregnancy is not recommended.

The medicinal product Pharmadol***®*** Max contains ASA; therefore, its use should be avoided during the first two trimesters of pregnancy, except when the expected benefit to the mother outweighs the potential risk to the fetus. If benefit to the mother outweighs risk to the fetus, it is recommended to reduce the dosage to the lowest possible level and shorten the duration of treatment. ASA is contraindicated in women during the third trimester of pregnancy due to the risk of premature closure of the ductus arteriosus, pulmonary hypertension, and impaired fetal kidney function leading to oligohydramnios. Labor may be delayed, and its duration may increase, with an increased risk of bleeding in both mother and child.

Caffeine is not recommended during pregnancy due to the risk of spontaneous abortion.

Extensive data on the use of paracetamol in pregnant women do not indicate any teratogenic effect or fetal or neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol during intrauterine life have yielded inconclusive results.

Use of the medicinal product during breastfeeding is not recommended.

ASA, paracetamol, and caffeine pass into breast milk. Due to the presence of caffeine in the product, the behavior of a breastfed infant may change (e.g., excitability, sleep disturbances). Due to the presence of ASA, the product may potentially affect platelet function in infants (possibly causing bleeding), although no such cases have been reported to date. There is also a risk of Reye’s syndrome in infants associated with ASA use.

Ability to affect reaction speed when driving or operating machinery

Studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery have not been conducted.

Dosage and Administration

The medicinal product is intended for oral use only.

Do not exceed the recommended dose.

The lowest effective dose required to achieve the therapeutic effect should be used for the shortest possible duration.

For headache

The usual recommended dose is 1 tablet; if necessary, an additional tablet may be taken after 4–6 hours. In cases of mild pain, taking 1 tablet should be sufficient.

In cases of more severe pain, 2 tablets may be taken initially; if necessary, an additional 2 tablets may be taken with intervals of 4–6 hours between doses.

The medicinal product is intended for episodic use in headache for no more than 4 days.

For migraine

At the onset of symptoms, take 2 tablets. If necessary, 2 additional tablets may be taken with intervals of 4–6 hours between doses.

The medicinal product is intended for episodic use in migraine for no more than 3 days.

For all indications: do not take more than 6 tablets in 24 hours. Each dose should be taken with a full glass of water.

Use with caution in elderly patients, particularly those with low body weight.

Children

The use of this medicinal product in children and adolescents is not recommended, as safety and efficacy have not been established in this patient group.

Overdose

Acetylsalicylic acid overdose

Salicylate poisoning usually occurs at plasma concentrations > 350 mcg/mL (2.5 mmol/L). Fatal cases have mostly occurred at concentrations > 700 mcg/mL (5.1 mmol/L) in adults. Serious poisoning is unlikely following single doses less than 100 mg/kg.

Symptoms of salicylate poisoning include: vomiting, dehydration, tinnitus, dizziness, hearing loss, increased sweating, elevated body temperature with rapid pulse, hyperventilation, and tachypnea. In most cases, acid-base imbalance occurs. In adults and children over 4 years of age, a mixed respiratory alkalosis and metabolic acidosis with normal or elevated arterial pH is usually observed. In children under 4 years of age, metabolic acidosis with low pH is more commonly observed. Acidosis may enhance salicylate transport across the blood-brain barrier.

Less common symptoms include hematemesis, hyperpyrexia, hypoglycemia, hypokalemia, thrombocytopenia, elevated international normalized ratio/prothrombin time (INR/PTR), intravascular coagulation, renal failure, and non-cardiogenic pulmonary edema.

Central nervous system disturbances, including confusion, disorientation, coma, and seizures, are less common in adults than in children.

If there is suspicion that a patient has ingested salicylates in a dose exceeding 120 mg/kg body weight within the past hour, oral activated charcoal should be administered and plasma salicylate levels monitored. Sodium bicarbonate should be administered to effectively enhance salicylate elimination from plasma. Hemodialysis is the treatment of choice when plasma salicylate concentration exceeds 700 mcg/mL in adults or lower levels in children and elderly patients, as well as in cases of severe metabolic acidosis. Further treatment should be conducted according to physician recommendations.

Paracetamol overdose

Clinical signs of liver damage typically become apparent 24–48 hours after overdose and usually peak at 4–6 days. High-risk patients include those receiving therapy with enzyme-inducing medicinal products such as carbamazepine, phenytoin, phenobarbital, rifampicin, and St. John’s wort, as well as patients with a history of alcohol dependence or malnutrition.

Paracetamol overdose may lead to liver failure, which may require liver transplantation or result in death.

Acute pancreatitis has been observed in cases of overdose, usually in conjunction with liver function abnormalities and hepatotoxicity.

Immediate medical attention is required in cases of overdose, even if symptoms are not present. If overdose is confirmed or even suspected, the patient should be taken immediately to the nearest medical facility capable of providing emergency medical care and appropriate treatment. This is necessary even in the absence of symptoms due to the risk of delayed liver injury. If required, treatment with N-acetylcysteine or methionine should be administered.

Caffeine overdose

Caffeine overdose may cause epigastric pain, vomiting, diuresis, tachycardia or cardiac arrhythmia, and effects on the central nervous system (insomnia, restlessness, nervous excitation, agitation, anxiety, tremor, seizures). Clinically significant symptoms of caffeine overdose may also be associated with severe liver injury due to paracetamol.

There is no specific antidote; however, supportive measures such as the use of beta-adrenergic antagonists may help alleviate cardiotoxic effects.

Adverse reactions.

The frequency of the adverse reactions listed below, which were reported during post-marketing surveillance, cannot be precisely determined from the available data; however, they are most likely to be isolated or rare (< 1/1000).

Adverse reactions associated with acetylsalicylic acid

Blood and lymphatic system disorders (frequency not known): prolonged bleeding, thrombocytopenia, bruising.

Immune system disorders (frequency not known): hypersensitivity reactions (e.g., anaphylaxis, angioedema, bronchospasm, urticaria, skin reactions or rhinitis).

Metabolism and nutrition disorders (frequency not known): sodium and fluid retention.

Ear and labyrinth disorders (frequency not known): temporary hearing loss, tinnitus.

Gastrointestinal disorders (frequency not known): gastrointestinal bleeding (including upper gastrointestinal bleeding, gastric bleeding, gastric ulcers, duodenal ulcers, rectal bleeding), gastrointestinal ulceration (including gastric, duodenal, and colonic ulcers), vomiting, gastritis, nausea, and dyspepsia.

Hepatobiliary disorders (frequency not known): Reye's syndrome, increased concentration of aminotransferases.

Renal and urinary disorders (frequency not known): renal dysfunction, increased blood uric acid concentration.

Adverse reactions associated with paracetamol

Blood and lymphatic system disorders (rare): thrombocytopenia.

Immune system disorders (rare): anaphylaxis, skin hypersensitivity reactions, including but not limited to skin rash, angioedema, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Respiratory, thoracic and mediastinal disorders (rare): bronchospasm in patients sensitive to ASA and other NSAIDs.

Hepatobiliary disorders (rare): liver function abnormalities.

Adverse reactions associated with caffeine

Nervous system disorders (frequency not known): nervousness, dizziness.

Cardiac disorders (frequency not known): tachycardia.

Psychiatric disorders (frequency not known): insomnia, restlessness, anxiety and irritability, nervousness.

Gastrointestinal disorders (frequency not known): gastrointestinal discomfort.

Additional adverse reactions reported for the medicinal product include:

In addition, the following adverse reactions were observed (frequency unknown): migraine, somnolence, arterial hypotension, dyspnea, asthma, abdominal pain, upper abdominal pain, hepatic failure, increased liver enzyme activity, erythema, rash, angioneurotic edema, erythema multiforme, malaise, pain.

The likelihood of adverse reactions increases with increasing dose and duration of drug use.

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the drug. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets per blister. 1 blister per carton.

Availability. Over-the-counter.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of its business activities.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.