Milistan multisymptom advanc

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MILESTAN MULTISYMPTOMATIC ADVANCE (MILISTAN MULTISYMPTOMATIC ADVANCE)

Composition:

Active substances: 1 tablet contains paracetamol – 500 mg, caffeine – 30 mg, phenylephrine hydrochloride – 5 mg, chlorpheniramine maleate – 2 mg;

Excipients: maize starch, colloidal anhydrous silicon dioxide, microcrystalline cellulose, povidone, gelatin, sodium benzoate (E 211), talc, magnesium stearate, sodium starch glycolate (type A), azorubine dye 4R (E 124).

Medicinal form. Tablets.

Main physicochemical properties: round, flat, film-coated tablets of pink color with dark pink specks.

Pharmacotherapeutic group.

Analgesics and antipyretics. Paracetamol combinations without psychotropic agents.

ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics.

The pharmacological activity of the medicinal product is due to the properties of paracetamol, caffeine, phenylephrine hydrochloride, and chlorpheniramine maleate contained in its formulation. Paracetamol exerts antipyretic, analgesic, and anti-inflammatory effects. The mechanism of action is associated with inhibition of prostaglandin synthesis.

Caffeine exerts a stimulating effect on the central nervous system, primarily on the cerebral cortex, respiratory and vasomotor centers, enhances mental and physical performance, reduces drowsiness, fatigue, and attenuates the effects of agents that depress the central nervous system.

Phenylephrine hydrochloride produces vasoconstrictive effects, reducing swelling of the nasal mucosa and paranasal sinuses.

Chlorpheniramine maleate has antihistaminic and anticholinergic effects. By blocking H1-receptors, it exerts anti-allergic action, reduces vascular permeability of the mucous membranes of the upper respiratory tract, decreases lacrimation, and relieves itching in the eyes and nose.

Pharmacokinetics.

Data are lacking.

Clinical characteristics.

Indications.

Symptomatic treatment of cold and influenza accompanied by elevated body temperature, chills, headache, runny nose and nasal congestion, sneezing, malaise, and body aches.

Contraindications.

Hypersensitivity to any component of the drug or to other xanthine derivatives (theophylline, theobromine). Severe cardiovascular disorders, including conduction disorders, ventricular tachycardia, acute myocardial infarction, severe arterial hypertension, peripheral arterial thrombosis, thrombophlebitis, marked atherosclerosis, severe form of ischemic heart disease, severe arterial hypertension. Severe liver or kidney function impairment, acute pancreatitis. Congenital hyperbilirubinemia, Gilbert’s syndrome, Dubin–Johnson syndrome, hepatitis. Pheochromocytoma. Prostatic adenoma with urinary retention; bladder neck obstruction. Blood disorders, severe anemia, leukopenia. Stenosing gastric and duodenal ulcers, pyloroduodenal obstruction. Hyperthyroidism, diabetes mellitus, alcoholism. Bronchial asthma, chronic obstructive pulmonary disease, emphysema, chronic bronchitis, increased intraocular pressure, closed-angle glaucoma, glucose-6-phosphate dehydrogenase deficiency. Epilepsy, increased excitability, sleep disorders. Concomitant use with tricyclic antidepressants, ß-blockers; concomitant use with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of such agents. Advanced age.

Interaction with other medicinal products and other forms of interaction.

Metoclopramide and domperidone accelerate the absorption of paracetamol, while cholestyramine reduces its absorption rate. Probenecid affects the plasma concentration of paracetamol and its excretion.

The anticoagulant effect of warfarin and other coumarins, with an increased risk of bleeding, may be enhanced by prolonged concomitant use of paracetamol. Occasional use has no significant effect. Barbiturates reduce the antipyretic effect of paracetamol. Anticonvulsants (phenytoin, barbiturates, carbamazepine) that stimulate hepatic microsomal enzymes, alcohol, and isoniazid may enhance the hepatotoxicity of paracetamol due to increased conversion of the drug into hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic agents increases the toxic effects of the drugs on the liver.

Tetracycline increases the risk of anemia and methemoglobinemia caused by paracetamol. Paracetamol reduces the effectiveness of diuretics and may delay the elimination of antibiotics from the body.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as this combination 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 for use").

Interaction of phenylephrine hydrochloride with MAO inhibitors, tricyclic antidepressants, indomethacin, and bromocriptine may cause severe arterial hypertension; with tricyclic antidepressants (amitriptyline) – increases the risk of cardiovascular adverse effects; with digoxin and cardiac glycosides – may lead to arrhythmias and infarction. Phenylephrine combined with other sympathomimetics increases the risk of cardiovascular adverse reactions, enhances arrhythmogenicity, and may reduce the effectiveness of β-blockers and other antihypertensive agents (reserpine, methyldopa), increasing the risk of arterial hypertension and cardiovascular adverse effects.

Alkaloids of Rauwolfia reduce the therapeutic effect of phenylephrine hydrochloride.

The central nervous system depressant effect of chlorpheniramine maleate may be significantly enhanced by concomitant use with hypnotics, barbiturates, sedatives, neuroleptics, tranquilizers, anesthetics, narcotic analgesics, and alcohol. Do not use concomitantly with alcohol. Chlorpheniramine maleate and alcohol potentiate each other’s effects when used together. Like other antihistamines, chlorpheniramine maleate enhances the sedative effect caused by central nervous system depressants when used concomitantly and enhances the anticholinergic effects of atropine, spasmolytics, tricyclic antidepressants, and antiparkinsonian agents.

Maprotiline (a tetracyclic antidepressant) and other anticholinergic drugs: the anticholinergic effect of these drugs or of antihistamines such as chlorpheniramine may be intensified.

Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents and potentiates the effects of xanthine derivatives, α- and β-adrenergic agonists, and psychostimulants.

Cimetidine, hormonal contraceptives, and 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 drugs that depress the central nervous system (CNS), and as a competitive antagonist of adenosine and adenosine triphosphate (ATP) agents. Concomitant use of caffeine with ergotamine improves ergotamine absorption in the gastrointestinal tract; with thyrotropic agents – increases thyroid effect. Caffeine reduces lithium concentration in blood.

Special precautions for use.

Do not exceed the recommended dose or duration of treatment.

Use with caution in patients with urinary disorders, benign prostatic hyperplasia, or cardiac arrhythmias.

Prior to administration, consult a physician if the patient has mild to moderate liver or kidney disease. In patients with hepatic disorders, the risk of hepatotoxic effects of paracetamol is increased.

Consult a physician before using this medicine if the patient is taking warfarin or similar anticoagulant agents. It should be noted that the risk of paracetamol-induced hepatotoxicity is increased in patients with alcohol-related non-cirrhotic liver disease. 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 risk of developing metabolic acidosis during paracetamol use is increased. 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.

If symptoms persist, consult a physician.

Concomitant use of multiple medications, alcoholism, alcoholic liver disease, sepsis, or diabetes mellitus increases the risk of hepatotoxicity with therapeutic doses of paracetamol (acetaminophen).

This medicinal product is not recommended for concomitant use with sedatives, hypnotics, or alcoholic beverages (the sedative effect of chlorpheniramine and the risk of paracetamol hepatotoxicity are enhanced). The risk of overdose is increased in patients with alcohol-related liver disease.

Do not exceed the recommended dose.

Avoid concomitant use with other medications intended for symptomatic treatment of cold and flu, or with medicinal products containing paracetamol, as this may lead to liver failure.

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

If headache becomes persistent, consult a physician. In case of high or prolonged fever lasting more than 3 days despite treatment, or if signs of superinfection appear, consult a physician.

If the drug is used long-term as directed by a physician, monitoring of liver function and peripheral blood picture is required.

Severe skin reactions have been reported very rarely. If skin redness, rash, blisters, or peeling occur, discontinue the drug immediately and seek urgent medical attention.

Consult a physician before using this medicine if you are taking warfarin or similar anticoagulant agents.

Use with caution in patients with compensated heart failure, in those at risk of seizures, or in patients with congenital prolonged QT interval or those undergoing long-term treatment with drugs that may prolong the QT interval.

Avoid excessive consumption of coffee, strong tea, other stimulant beverages, and medicinal products containing caffeine during treatment. This may cause sleep disturbances, tremor, tension, irritability, and palpitations.

The drug may affect laboratory test results for blood glucose and uric acid levels; chlorpheniramine may mask hypersensitivity symptoms and interfere with skin test results. Therefore, discontinue the drug several days before such procedures.

Keep the medicine out of sight and reach of children.

Use during pregnancy or breastfeeding.

Milistan Multisymptom Advanced is contraindicated during pregnancy. Breastfeeding should be discontinued during treatment with this medicine.

Standard studies using currently accepted methods to evaluate reproductive and ontogenetic toxicity have not been conducted.

Extensive data on the use of paracetamol in pregnant women do not indicate any malformative or fetal/neonatal toxicity. Epidemiological studies on the development of the nervous system in children exposed to paracetamol in utero show inconclusive results.

Ability to affect reaction speed when driving or operating machinery.

During treatment, avoid driving, operating machinery, or engaging in other potentially hazardous activities.

Dosage and Administration.

For adults and children aged 12 years and older, administer 1 tablet every 3–4 hours, but not more than 4 tablets per day. The treatment course is usually 3 days, but should not exceed 5 days.

Children.

The medicinal product is contraindicated in children under 12 years of age.

Overdose.

In patients with risk factors, therapeutic doses of paracetamol may cause symptoms of overdose when used concomitantly with certain drugs or in diseases that increase oxidative stress and deplete hepatic glutathione stores (prolonged fasting, sepsis, diabetes mellitus).

In paracetamol overdose, pallor, nausea, vomiting, anorexia, and abdominal pain may appear within the first 24 hours. Following large doses, disorientation, agitation, dizziness, sleep disturbances, cardiac arrhythmias, and pancreatitis may occur.

In isolated cases, nephrotoxicity has been observed, including renal colic, interstitial nephritis, and acute renal failure with tubular necrosis, manifesting as lumbar pain, hematuria, and proteinuria.

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., gastrointestinal disorders, HIV infection, fasting, cystic fibrosis, cachexia), ingestion of 5 g or more of paracetamol may lead to liver damage.

Ingestion of 10 g or more of paracetamol by adults, especially when combined with alcohol, or ingestion of more than 150 mg of paracetamol per kg body weight by children may result in hepatocellular necrosis, leading to encephalopathy, hepatic coma, and fatal outcome. The first clinical signs of hepatonecrosis may appear 12–48 hours after overdose. Disturbances in glucose metabolism and metabolic acidosis (including lactic acidosis) may occur, along with elevated liver transaminase activity, increased bilirubin levels, prolonged prothrombin index, and hemorrhages.

Arrhythmias (cardiac rhythm disturbances) and pancreatitis have also been reported. Following large doses, disturbances in orientation may develop due to central nervous system involvement.

With prolonged use of high doses, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia are possible.

In case of overdose, prompt medical assistance is required. The patient should be immediately transported to a hospital, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of the overdose or the risk of organ damage. Administration of activated charcoal should be considered if the excessive dose of paracetamol was ingested within the past hour. Gastric lavage should be performed within the first hours after suspected overdose. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours after ingestion. The efficacy of the antidote decreases sharply after this time. If necessary, intravenous N-acetylcysteine should be administered according to current guidelines. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

In overdose of phenylephrine hydrochloride, symptoms include hyperhidrosis, psychomotor agitation or CNS depression, headache, dizziness, drowsiness, impaired consciousness, arrhythmias, tremor, hyperreflexia, seizures, nausea, vomiting, irritability, restlessness, tachycardia, extrasystoles, and arterial hypertension.

In overdose of chlorpheniramine maleate, the condition may range from CNS depression to excitation (restlessness and seizures). Anticholinergic-like symptoms may occur: mydriasis, photophobia, dry skin and mucous membranes, elevated body temperature, and intestinal atony. CNS depression may be accompanied by respiratory depression and cardiovascular disturbances (reduced pulse rate, decreased arterial pressure up to circulatory failure).

Large doses of caffeine may cause epigastric pain, vomiting, increased diuresis, rapid breathing, extrasystoles, tachycardia or cardiac arrhythmia, and effects on the central nervous system (dizziness, insomnia, nervous excitation, irritability, emotional lability, anxiety, tremor, convulsions). Clinically significant symptoms of caffeine overdose may also be associated with liver damage caused by paracetamol.

There is no specific antidote; however, supportive measures such as the use of beta-adrenergic antagonists may alleviate cardiotoxic effects. Gastric lavage is required. Oxygen therapy is recommended, and diazepam should be administered in case of seizures. Symptomatic therapy.

Adverse Reactions.

Skin and subcutaneous tissue disorders: allergic skin reactions, skin and mucosal rashes (usually generalized, erythematous, urticarial), pruritus, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Immune system disorders: hypersensitivity reactions, including anaphylactic shock, angioneurotic edema.

Nervous system disorders: headache, dizziness, psychomotor agitation and disorientation, restlessness, excitement, fear, anxiety, irritability, sleep disturbances, insomnia, somnolence, confusion, hallucinations, depressive states, tremor, paresthesia and heaviness in limbs, tinnitus, in isolated cases – coma, seizures, dyskinesia, behavioral changes, general weakness, increased sweating.

Respiratory system disorders: bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs), dryness of mucous membranes.

Eye disorders: visual disturbances and accommodation disorders, mydriasis, increased intraocular pressure, dry eyes.

Gastrointestinal disorders: nausea, vomiting, heartburn, dry mouth, epigastric discomfort and pain, diarrhea, hypersalivation, loss of appetite, exacerbation of peptic ulcer, flatulence, constipation.

Hepatobiliary disorders: hepatotoxic effects, liver function disturbances, increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (with high-dose use).

Endocrine system disorders: hypoglycemia, up to hyperglycemic coma.

Blood and lymphatic system disorders: anemia, including hemolytic anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), bruising or bleeding. With prolonged use at high doses – aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia.

Renal and urinary system disorders: with high-dose use – nephrotoxicity, interstitial nephritis, papillary necrosis, renal colic, micturition disorders, dysuria, urinary retention and difficulty in urination, increased creatinine clearance, increased excretion of sodium and calcium, aseptic pyuria.

Cardiovascular system disorders: elevated blood pressure, tachycardia or reflex bradycardia, arrhythmia, dyspnea, chest pain.

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

Concomitant use of the medicinal product at recommended doses with caffeine-containing products may enhance caffeine-related adverse effects such as dizziness, increased excitability, insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and tachycardia.

Description of selected adverse reactions

Metabolic acidosis with high anion gap

Metabolic acidosis with high anion gap as a result of pyroglutamic acidosis has been observed in patients with risk factors who used paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Shelf life. 4 years.

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

Keep out of reach of children.

Packaging.

Pack No. 4: 4 tablets in a blister; 1 blister per cardboard box.

Pack No. 100: 4 tablets in a blister; 1 blister per cardboard box; 25 cardboard boxes No. 4 in a cardboard outer box.

Pack No. 12: 12 tablets in a blister; 1 blister per cardboard box.

Prescription status.

Over-the-counter – tablets No. 4, No. 12.

By prescription only – tablets No. 100.

Manufacturer.

Mepro Pharmaceuticals Private Limited / Mepro Pharmaceuticals Private Limited.

Address.

Unit II, Q-Road, Phase IV, GIDC, Wadhwan, Surendranagar, Gujarat, 363 035, India /
Unit II, Q-Road, Phase IV, GIDC, Wadhwan, Surendranagar, Gujarat, 363 035, India.

Marketing Authorization Holder.

Mili Healthcare Limited / Mili Healthcare Limited.

Address.

Fairfax House 15, Fulwood Place, London, WC1V 6AY, Great Britain /
Fairfax House 15, Fulwood Place, London, WC1V 6AY, Great Britain.