Safiston^® (Tablets) Instructions for Use

Marketing Authorization Holder

Atoll LLC (Russia)

Manufactured By

Ozon, LLC (Russia)

ATC Code

N02BE51 (Paracetamol in combination with other drugs, excluding psycholeptics)

Active Substances

Caffeine (Ph.Eur. European Pharmacopoeia)

Paracetamol (Rec.INN WHO Registered)

Propyphenazone (Rec.INN WHO Registered)

Dosage Form

Safiston®

Tablets 50 mg+250 mg+150 mg: 10, 20, 30, 40, 50, 60, or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets from white to white with a beige tint, round, flat-cylindrical, with a score and a bevel; slight marbling is allowed.

Excipients: microcrystalline cellulose (MCC-101 Premium) – 100 mg, croscarmellose sodium – 8 mg, sodium carboxymethyl starch – 44.8 mg, povidone K25 – 18 mg, colloidal silicon dioxide – 3.2 mg, magnesium stearate – 16 mg.

10 pcs. – contour cell packs (1) – cardboard packs.
10 pcs. – contour cell packs (2) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (4) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (10) – cardboard packs.

Clinical-Pharmacological Group

Combination analgesic-antipyretic

Pharmacotherapeutic Group

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

Pharmacological Action

Safiston^® is a combination drug, the action of which is determined by the components included in its composition. The combination of the three components of the drug leads to a mutual enhancement of their pharmacological action.

Paracetamol and Propyphenazone have analgesic and antipyretic effects. Paracetamol is a non-narcotic analgesic. It blocks cyclooxygenase (COX) only in the CNS, acting on pain and thermoregulation centers (in inflamed tissues, cellular peroxidases neutralize the effect of paracetamol on COX), which explains the almost complete absence of an anti-inflammatory effect. The lack of effect on the synthesis of prostaglandins (PG) in peripheral tissues determines the absence of its negative effect on water-salt metabolism (sodium and water retention) and the gastrointestinal mucosa.

Propyphenazone is a pyrazolone derivative. The mechanism of action is carried out by inhibiting COX, which is involved in the formation of prostaglandins from arachidonic acid.

Caffeine increases the reflex excitability of the spinal cord, excites the respiratory and vasomotor centers, dilates the blood vessels of skeletal muscles, brain, heart, kidneys, reduces platelet aggregation; reduces drowsiness, feeling of fatigue. In this combination, Caffeine in a small dose has practically no stimulating effect on the CNS, but contributes to the regulation of cerebral vascular tone, reduces drowsiness, and enhances the analgesic effect of other components of the drug.

Pharmacokinetics

Paracetamol

Absorption is high, plasma protein binding is 15%, T_max is 20-30 min. Penetrates the blood-brain barrier (BBB). Less than 1% of the dose taken by a nursing mother passes into breast milk. The therapeutic effective concentration of paracetamol in plasma is achieved when it is prescribed at a dose of 10-15 mg/kg.

Metabolized in the liver: 80% enters into a conjugation reaction with glucuronic and sulfuric acids to form inactive metabolites; 17% undergoes hydroxylation to form inactive metabolites, which conjugate with glutathione and form inactive metabolites. With a lack of glutathione, these metabolites can block the enzyme systems of hepatocytes and cause their necrosis. T_1/2 is 2-3 hours. In elderly patients, the clearance of paracetamol decreases and the half-life increases. Excreted by the kidneys unchanged 3%.

Propyphenazone

The maximum concentration of propyphenazone in plasma is reached after 30 minutes. Metabolized in the liver. T_1/2 is 1-1.5 hours. The combination with paracetamol increases its elimination time by 40%, which plays a significant role, as it allows to reduce the number of drug doses per day. Excreted by the kidneys.

Caffeine

Time to reach C_max – 1 hour; T_1/2 – 3.5 hours; 65-80% of caffeine is excreted by the kidneys mainly in the form of 1-methylxanthine, 1-methyluric acid and acetylated uracil derivatives, a small amount is converted to theophylline and theobromine.

Indications

Relief of mild to moderate pain of various origins

• Headache;
• Migraine;
• Toothache;
• Arthralgia;
• Myalgia;
• Algodysmenorrhea;

As an antipyretic for febrile conditions against the background of infectious and inflammatory diseases (ARVI, including influenza, etc.).

ICD codes

Dosage Regimen

Prescribed for adults 1-2 tablets, for children 12-18 years old – 1 tablet 1-3 times a day, preferably 1-2 hours after meals, with plenty of liquid. The maximum single dose is 2 tablets. The daily dose should not exceed 6 tablets.

The drug should not be taken for more than 5 days as an analgesic and for more than 3 days as an antipyretic without a doctor’s prescription and supervision. An increase in the daily dose or duration of treatment is possible only under medical supervision. Do not exceed the recommended dose.

Adverse Reactions

From the CNS dizziness, insomnia.

From the gastrointestinal tract nausea, vomiting, heaviness and discomfort in the stomach area;

From the hematopoietic system thrombocytopenia, agranulocytosis, hemolytic anemia.

Allergic reactions skin rash, itching, urticaria, angioedema, multiforme exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).

Contraindications

• Hypersensitivity to the components of the drug;
• Severe renal and/or hepatic insufficiency;
• Glucose-6-phosphate dehydrogenase deficiency;
• Inhibition of bone marrow hematopoiesis (leukopenia, anemia, including hemolytic);
• Acute hematoporphyria;
• Complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance to NSAIDs (including history);
• Conditions accompanied by respiratory depression;
• Intracranial hypertension;
• Acute myocardial infarction;
• Coronary heart disease;
• Arrhythmias;
• Arterial hypertension;
• Peptic ulcer of the stomach and duodenum;
• Glaucoma;
• Insomnia;
• Pregnancy;
• Lactation period;
• Children under 12 years of age.

With caution benign hyperbilirubinemia (including Gilbert, Dubin-Johnson, Rotor syndromes), old age, alcoholism, epilepsy and a tendency to convulsive seizures.

Use in Pregnancy and Lactation

The use of the drug during pregnancy and breastfeeding is contraindicated.

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency.

Use in Renal Impairment

Contraindicated in severe renal insufficiency.

Pediatric Use

Contraindicated in children under 12 years of age.

Geriatric Use

With caution in old age.

Special Precautions

With long-term use of the drug (more than 5 days), monitoring of the peripheral blood picture and the functional state of the liver is necessary.

During treatment, one should refrain from drinking alcoholic beverages (increased risk of gastrointestinal bleeding).

Excessive consumption of caffeine-containing products (coffee, tea) during treatment may cause overdose symptoms.

Taking the drug may complicate the diagnosis in acute abdominal pain syndrome.

Influence on the ability to drive vehicles and work with machinery requiring increased concentration

During the period of taking the drug, caution should be exercised when driving vehicles and engaging in other activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms (caused by paracetamol, appear after taking 10-15 g) pallor of the skin, loss of appetite, nausea, vomiting, pain in the epigastric region, hepatotoxic and nephrotoxic effects, in severe cases – liver failure, hepatonecrosis, increased activity of “liver” transaminases, increased prothrombin time, encephalopathy and coma.

Treatment gastric lavage, administration of activated charcoal, symptomatic therapy, administration of SH-group donors and glutathione synthesis precursors – methionine after 8-9 hours after overdose and N-acetylcysteine after 12 hours.

High doses of caffeine cause the following symptoms headache, tremor, irritability, gastralgia, agitation, motor restlessness, confusion, tachycardia, arrhythmia, hyperthermia, frequent urination, headache, nausea, vomiting, ringing in the ears, convulsions (in acute overdose – tonic-clonic).

Treatment gastric lavage, intake of activated charcoal, laxatives, maintenance of lung ventilation and oxygenation, for convulsions intravenous diazepam, phenobarbital, maintenance of water and electrolyte balance.

Drug Interactions

The effectiveness of the drug may decrease with simultaneous use with cholestyramine, anticholinergics, antidepressants, alkaline substances.

With simultaneous use of Safiston^® with barbiturates, anticonvulsants, ethanol, the hepatotoxic effect is significantly increased.

Metoclopramide accelerates the absorption of paracetamol.

Under the influence of paracetamol, the half-life of chloramphenicol increases by 5 times.

Simultaneous use of paracetamol in high doses enhances the effect of anticoagulants.

Myelotoxic agents enhance the manifestations of hematotoxicity of paracetamol.

Caffeine accelerates the absorption of ergotamine; reduces the absorption of calcium preparations; reduces the effect of narcotic and hypnotic drugs, increases the excretion of lithium preparations; accelerates the absorption and enhances the effect of cardiac glycosides, increases their toxicity.

Simultaneous use of caffeine with beta-blockers can lead to mutual suppression of therapeutic effects, with beta-adrenergic agonists to additional stimulation of the CNS and other toxic effects.

Caffeine may reduce the clearance of theophylline, and possibly other xanthines, increasing the possibility of additive pharmacodynamic and other toxic effects.

Monoamine oxidase inhibitors, furazolidone, procarbazine, selegiline and large doses of caffeine can cause the development of dangerous cardiac arrhythmias or a pronounced increase in blood pressure.

Nicotine increases the rate of caffeine excretion.

Caffeine is an adenosine antagonist.

Propyphenazone may enhance the effect of oral hypolipidemic agents, sulfonamide drugs, anticoagulants, the ulcerogenic effect of glucocorticosteroids, and reduce the effectiveness of potassium-sparing diuretics.

Storage Conditions

In a place protected from light at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 3 years.

Dispensing Status

Over-the-counter.

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.