Solpadeine migrastop

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SOLPADERIN MIGRASTOP

Composition:

Active substances: acetylsalicylic acid, paracetamol, caffeine;

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

Excipients: low-substituted hydroxypropyl cellulose, microcrystalline cellulose, stearic acid, hypromellose, titanium dioxide (E 171), propylene glycol, benzoic acid (E 210), carnauba wax.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, elongated tablets, film-coated, with "E" engraved on one side.

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

ATC code N02BA51.

Pharmacological Properties

Pharmacodynamics

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

Pharmacokinetics

Acetylsalicylic acid

Rapidly and completely absorbed after oral administration. It is 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 excreted mainly in the urine as glucuronide and sulfate conjugates. Less than 5% is excreted unchanged as paracetamol.

Caffeine

Caffeine is rapidly and completely absorbed in the gastrointestinal tract, with peak plasma concentrations observed between 5 and 120 minutes after administration. Data on 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 plasma half-life is 4.9 hours, with a range of 1.9–12.2 hours.

Caffeine is almost completely metabolized via oxidation, demethylation, and acetylation, and is excreted in the urine. Its main metabolites are 1-methylxanthine, 7-methylxanthine, and 1,7-dimethylxanthine (paraxanthine). Among minor metabolites are 1-methyluric acid and 5-acetamino-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 three active substances, each component is present in a low amount, thereby reducing the overall toxicity of the medicinal product.

Clinical Study Data

Clinical studies have demonstrated the efficacy of Solpadeine Migrastop in the treatment of acute migraine attacks, resulting in relief of migraine symptoms such as headache, nausea, photophobia, phonophobia, and functional impairment. The onset of action in reducing migraine symptoms has been shown to occur within 30 minutes.

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

Preclinical Study Data

Data from studies using modern standards to evaluate the toxic effects of paracetamol on fertility and fetal development are not available.

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 any of its other components; history of asthma attacks, bronchospasm, angioedema, urticaria, or acute rhinitis caused by intake of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs); active peptic ulcer or history of gastric ulcer; gastrointestinal bleeding or perforation related to NSAID therapy; hemophilia, hyperbilirubinemia, or other blood coagulation disorders; renal impairment (glomerular filtration rate (GFR) < 15 ml/min/1.72 m²); hepatic impairment; history of gout; hypersensitivity to other xanthine derivatives (theophylline, theobromine), other salicylates; glucose-6-phosphate dehydrogenase deficiency; blood disorders; pronounced anemia; leukopenia; states of increased excitation; sleep disorders; elderly age; glaucoma; alcoholism; during treatment with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after their discontinuation; severe cardiovascular diseases, including arrhythmias; marked 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 types of interactions.

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

Possible interactions of active substances.

Acetylsalicylic acid (ASA)

Paracetamol

Caffeine

Effect on laboratory test results

• The use of high doses of acetylsalicylic acid may affect the results of several clinical-chemical laboratory tests.
• The use of paracetamol may affect the results of uric acid determination when the analysis is performed using phosphotungstic acid reagent, and the results of blood glucose determination when the analysis is performed using the glucose oxidase/peroxidase method.
• Caffeine may counteract the effect of dipyridamole on myocardial blood flow and thus affect 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.
• Solpadeine Migrastop should not be used 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 improvement after taking the first 2 tablets, they should seek medical advice.
• This medicinal product should not be used in patients who have experienced headaches more than 10 days per month over the past 3 or more months.
• This product should be used 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, Solpadeine Migrastop may mask signs and symptoms of infection.
• Solpadeine Migrastop should be used with caution in patients with mild or moderate renal impairment.
• The medicinal product contains benzoic acid, which increases the risk of developing jaundice in newborns.

Due to the content of acetylsalicylic acid

• The product should not be used concomitantly with medicinal products containing acetylsalicylic acid or other systemic NSAIDs, including selective cyclooxygenase-2 inhibitors, due to the potential for additional adverse reactions.
• Solpadeine Migrastop may provoke bronchospasm and cause serious hypersensitivity reactions or anaphylaxis in patients with a history of bronchial asthma, allergic disorders, or nasal polyps.
• Solpadeine Migrastop should not be used in children and adolescents during or immediately after varicella, influenza, or other viral infections without medical prescription, as there may be an association between acetylsalicylic acid therapy in children during or immediately after viral infections and the development of Reye's syndrome.
• Solpadeine Migrastop should be used with caution in patients with uncontrolled hypertension (in whom blood pressure cannot be measured), renal or hepatic impairment, dehydration, or diabetes mellitus.
• Acetylsalicylic acid may cause sodium and water retention, which may worsen conditions such as arterial hypertension, chronic heart failure, and renal dysfunction.
• Acetylsalicylic acid 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.
• Solpadeine Migrastop should not be used concomitantly with anticoagulants or other medicinal products that inhibit platelet aggregation without medical supervision. Patients with coagulation disorders should be closely monitored. The product should be used with caution in cases of metrorrhagia or menorrhagia.
• Gastrointestinal bleeding, ulceration, or perforation have been reported with the use of all NSAIDs, which may be fatal and can occur at any stage of treatment, regardless of prior gastrointestinal disorders. Such events are more severe in elderly individuals.
• Acetylsalicylic acid 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 acetylsalicylic acid per day may cause acute hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.

Due to the content of paracetamol

• Solpadeine Migrastop should not be used concomitantly with other products containing paracetamol, as this may lead to overdose. Paracetamol overdose may cause liver failure, which may require liver transplantation or result in death.
• The risk of hepatotoxic effects of paracetamol is increased in patients with hepatic disease. The benefit-risk ratio should be evaluated before prescribing the medicinal product to patients with hepatic or renal disease.
• Cases of hepatic dysfunction / 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.

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, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin.

If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring of the patient.

Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

• The risk of paracetamol toxicity may be increased in patients taking other potentially hepatotoxic medicinal products or agents that induce hepatic microsomal enzymes (e.g., rifampicin, isoniazid, chloramphenicol, sedatives, and antiepileptic drugs, including phenobarbital, phenytoin, and carbamazepine).

Due to the content of caffeine

• Solpadeine Migrastop should be used with caution in patients with gout or hyperthyroidism.
• During treatment with Solpadeine Migrastop, patients should limit consumption of products containing caffeine (e.g., coffee, tea, and certain other beverages), as excessive caffeine concentrations may cause nervousness, irritability, insomnia, episodic tachycardia, and other symptoms of caffeine overdose.

Use during pregnancy or breastfeeding

Use of the medicinal product during pregnancy is not recommended.

Solpadeine Migrastop contains acetylsalicylic acid; therefore, its use should be avoided during the first two trimesters of pregnancy, except when the benefit to the mother outweighs the risk to the fetus. If the benefit to the mother outweighs the risk to the fetus, the dose should be reduced to the lowest possible level and the duration of treatment shortened. Acetylsalicylic acid 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 renal function leading to oligohydramnios. Labour may be delayed, its duration prolonged, and the risk of bleeding increased 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 the development of the nervous system in children exposed to paracetamol in utero have yielded inconclusive results.

Use of the medicinal product during breastfeeding is not recommended.

Acetylsalicylic acid, paracetamol, and caffeine pass into breast milk. Due to the caffeine content, the behaviour of an infant breastfed by a woman taking the product may change (e.g., excitability, sleep disturbances). Due to the acetylsalicylic acid content, 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 acetylsalicylic acid use.

Ability to affect reaction speed when driving or operating machinery. Studies on the effect on the ability to drive vehicles or operate machinery have not been conducted.

Method of Administration and Dosage

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 intense pain, 2 tablets may be taken; if necessary, an additional 2 tablets may be taken at intervals of 4–6 hours between doses.

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

For migraine:

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

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

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

Use with caution in elderly patients, especially 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 typically occurs when plasma concentrations exceed 350 mcg/mL (2.5 mmol/L). Fatal cases have mostly occurred at concentrations exceeding 700 mcg/mL (5.1 mmol/L) in adults. Single doses below 100 mg/kg are unlikely to cause serious poisoning.

Symptoms of salicylate poisoning include vomiting, dehydration, tinnitus, dizziness, hearing loss, sweating, elevated body temperature with increased pulse rate, rapid breathing, and hyperventilation. In most cases, acid-base balance is disturbed. In adults and children aged 4 years and older, a mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH is usually observed. In children under 4 years of age, metabolic acidosis with low pH is more commonly observed. Acidosis may enhance the transfer of salicylates 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 last hour, oral activated charcoal should be administered and plasma salicylate levels should be monitored. Sodium bicarbonate should be administered to effectively eliminate salicylates 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 carried out according to physician recommendations.

Paracetamol overdose

Clinical signs of liver damage usually become apparent 24–48 hours after overdose and typically peak within 4–6 days. Patients at high risk include those receiving treatment with enzyme-inducing medicinal products such as carbamazepine, phenytoin, phenobarbital, rifampicin, and St. John's wort (Hypericum perforatum), 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 dysfunction and hepatotoxicity.

Immediate medical attention is required in cases of overdose, even if no symptoms are present. If overdose is confirmed or even suspected, the patient should be taken immediately to the nearest medical facility where emergency medical care and expert treatment can be provided. This is necessary even in the absence of symptoms due to the risk of delayed liver injury. If indicated, 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 caused by paracetamol.

There is no specific antidote, but 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, reported during post-marketing surveillance, cannot be precisely determined from the available data; however, they are most likely isolated or rare cases (< 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 tract, 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 concentrations of aminotransferases.

Renal and urinary disorders (frequency not known): impaired kidney function, increased blood uric acid concentration.

Adverse reactions associated with paracetamol

Blood and lymphatic system disorders (rare, <1/10,000): thrombocytopenia.

Immune system disorders (rare, <1/10,000): anaphylaxis, skin hypersensitivity reactions, including rash, angioedema, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Respiratory, thoracic and mediastinal disorders (rare, <1/10,000): bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.

Hepatobiliary disorders (rare, <1/10,000): impaired liver function.

Description of selected adverse reactions

Metabolism and nutrition disorders (frequency not known): metabolic acidosis with high anion gap.

Cases of metabolic acidosis with high anion gap, resulting from pyroglutamic acidosis, have been observed in patients with risk factors who were treated with paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Adverse reactions associated with caffeine

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

Cardiac disorders (frequency not known): tachycardia.

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

Gastrointestinal disorders (frequency not known): gastrointestinal discomfort.

Other adverse reactions reported for the medicinal product include:

In addition, the following adverse reactions (frequency unknown) were observed: headache, somnolence, 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 treatment.

Shelf life. 3 years.

Storage conditions. Store out of reach of children at a temperature not exceeding 25 °C.

Packaging. 10 film-coated tablets in a blister. 1 or 2 blisters per carton.

Availability. Over-the-counter.

Manufacturer.

Famar Italia S.p.A. / Famar Italia S.p.A.

Manufacturer's address.

Via Zambeletti 25, 20021 - Baranzate (MI), Italy / Via Zambeletti 25, 20021 - Baranzate (MI), Italy.