Milistan multisymptom

INSTRUCTION for medical use of the medicinal product MILISTAN MULTISYMPTOMATIC (MILISTAN MULTISYMPTOMATIC)

Composition:
Active substances: 1 tablet contains paracetamol 325 mg, cetirizine hydrochloride 10 mg, chlorpheniramine maleate 2 mg, dextromethorphan hydrobromide 15 mg.
Excipients: maize starch, microcrystalline cellulose, methylparaben (E 218), propylparaben (E 216), magnesium stearate, talc, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, sodium starch glycolate (type A), hypromellose, propylene glycol, polyethylene glycol 4000, titanium dioxide (E 171).

Medicinal form:
Film-coated tablets.

Main physicochemical properties:
White or almost white, oval-shaped, biconvex film-coated tablets with a score line on one side.

Pharmacotherapeutic group:
Analgesics and antipyretics. Paracetamol in combination with other drugs (excluding psychotropic agents).
ATC code: N02B E51.

Pharmacological properties

Pharmacodynamics:
Paracetamol has analgesic, antipyretic, and anti-inflammatory properties. The mechanism of paracetamol's analgesic effect is associated with inhibition of prostaglandin biosynthesis. By inhibiting cyclooxygenase, it prevents the formation of prostaglandins E2 and F2, which play an important role in nociceptor perception of pain stimuli and transmission of excitation to the central nervous system (CNS). Paracetamol more effectively inhibits cyclooxygenase in CNS cells and significantly less so in peripheral tissues. The absence of paracetamol's effect on prostaglandin synthesis in peripheral tissues explains its lack of negative impact on water-salt metabolism and gastrointestinal mucosa.

The antipyretic effect of paracetamol is due to inhibition of prostaglandin biosynthesis directly in the hypothalamus, where they act as mediators of the thermoregulatory center.

Cetirizine hydrochloride is a selective antagonist of peripheral H1-histamine receptors and a metabolite of hydroxyzine. It prevents the development and alleviates allergic reactions, has antipruritic and anti-exudative effects. It exerts anti-allergic action by inhibiting the late phase of migration of cells involved in the inflammatory response (mainly eosinophils); it also reduces the expression of adhesion molecules such as ICAM-1 and VCAM-1, which are markers of allergic inflammation. It inhibits the action of other mediators and inducers of histamine secretion, such as PAF (platelet-activating factor) and substance P. It has virtually no anticholinergic or anti-serotonergic effects. It reduces capillary permeability, prevents tissue edema, and relieves smooth muscle spasm. It has virtually no anticholinergic or anti-serotonergic activity. At therapeutic doses, it has no sedative effect.

Dextromethorphan hydrobromide is an antitussive agent effective for non-productive bronchial cough. Its mechanism of action is associated with suppression of afferent impulses from the mucous membranes of the respiratory tract and increased sensitivity threshold of the cough center in the medulla oblongata. At therapeutic doses, dextromethorphan does not cause analgesic or sedative effects, does not suppress respiration, does not cause dependence, and does not inhibit ciliary epithelial activity.

Chlorpheniramine maleate is an antiallergic agent, an H1-histamine receptor blocker, with antiallergic action. It reduces capillary permeability, constricts blood vessels, eliminates edema and hyperemia of the nasal mucosa, nasopharynx, and paranasal sinuses; reduces local exudative manifestations, and suppresses symptoms of allergic rhinitis (sneezing, rhinorrhea, itching of eyes, nose, and throat). It causes a moderately pronounced sedative effect.

Pharmacokinetics:
Absorption: After oral administration, the drug is rapidly and almost completely absorbed from the gastrointestinal tract.

Elimination: The elimination half-life of paracetamol is 1–4 hours. In patients with liver cirrhosis, the elimination half-life is prolonged. Plasma protein binding is variable. Renal clearance of paracetamol is 5%. It is excreted in urine mainly as glucuronide and sulfate conjugates.

After single oral administration, the elimination half-life of cetirizine hydrochloride is approximately 10 hours; about 2/3 of the drug is excreted unchanged by the kidneys and about 10% in feces. Systemic clearance is 53 ml/min.

The elimination half-life of dextromethorphan hydrobromide is approximately 4 hours. The drug is excreted via the kidneys in unchanged form and as demethylated metabolites (including dextrorphan).

The active substances of the drug penetrate through the placenta and into breast milk.

Clinical characteristics

Indications:
Symptomatic treatment of influenza and other acute respiratory viral infections accompanied by dry, irritating cough, elevated body temperature, muscle and joint pain, headache, nasal congestion, rhinorrhea, lacrimation; including those associated with allergy.

Contraindications:
Hypersensitivity to the components of the drug, to hydroxyzine, or to any piperazine derivative or other antihistamine agents.
Severe renal impairment.
Severe hepatic impairment, congenital hyperbilirubinemia, alcoholism, Gilbert's syndrome.
Blood disorders, glucose-6-phosphate dehydrogenase deficiency, severe anemia, leukopenia, hypocoagulation.
Closed-angle glaucoma.
Risk of urinary retention due to urethral or prostate diseases, bladder neck obstruction.
Pyloroduodenal stenosis, intestinal obstruction.
Severe course of hypertension, coronary artery disease, arrhythmias.
Diabetes mellitus, hyperthyroidism.
Epilepsy.
Patients at risk of developing respiratory insufficiency.
Do not use together with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs, or with antidepressants that inhibit serotonin reuptake (fluoxetine, paroxetine).

Interaction with other medicinal products and other forms of interaction:
Avoid simultaneous use of the drug with other medicinal products containing paracetamol or other active substances present in Milistan Multisymptomatic. Interactions are determined by the properties of its components.

Paracetamol:
The absorption rate of paracetamol may be increased by metoclopramide and domperidone and decreased by cholestyramine. The anticoagulant effect of warfarin and other coumarins, with an increased risk of bleeding, may be enhanced by long-term simultaneous use of paracetamol. Occasional use has no significant effect. Barbiturates reduce the antipyretic effect of paracetamol. Anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the toxic effect of paracetamol on the liver due to increased conversion of the drug into hepatotoxic metabolites. Simultaneous use of paracetamol with hepatotoxic agents increases the toxic effect of the drugs on the liver. Simultaneous use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics. Do not use simultaneously with alcohol. Caffeine may potentiate the analgesic effect of paracetamol. Be cautious when using paracetamol simultaneously with flucloxacillin, as such co-administration 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").

Cetirizine hydrochloride:
In a study of multiple-dose administration of theophylline (400 mg once daily) and cetirizine, a slight (16%) reduction in cetirizine clearance was observed, while the disposition of theophylline was not increased with concomitant administration of cetirizine. In a study of multiple-dose administration of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), exposure to cetirizine increased by approximately 40%, while the disposition of ritonavir was slightly disturbed (-11%) with concomitant administration of cetirizine. There are no data on enhanced effects of sedatives when cetirizine is used at therapeutic doses. However, the use of sedatives should be avoided during cetirizine administration. The extent of cetirizine absorption is not reduced by food intake, although the rate of absorption is delayed by 1 hour. Simultaneous use of the drug with alcohol or other agents that depress the central nervous system may additionally impair attention and work capacity, although cetirizine does not potentiate the effect of alcohol (at blood alcohol levels of 0.5 g/l).

Chlorpheniramine maleate:
Alcoholic beverages or agents that depress the central nervous system may enhance the depressant effect of similar or antihistamine agents such as chlorpheniramine, potentially causing symptoms of overdose. Chlorpheniramine inhibits phenytoin metabolism and may lead to phenytoin toxicity. Contraindicated with MAO inhibitors. Monoamine oxidase inhibitors (MAOIs), including furazolidone (an antibacterial agent) and procarbazine (an antineoplastic agent): concomitant use is not recommended, as it may prolong and intensify the anticholinergic effect and central nervous system depression characteristic of antihistamine agents. Tricyclic antidepressants or maprotiline (a tetracyclic antidepressant) and other agents with anticholinergic effects: the anticholinergic effect of these agents or antihistamine agents such as chlorpheniramine may be enhanced. If gastrointestinal side effects occur, patients should seek medical advice as soon as possible, as this may lead to paralytic intestinal obstruction. Ototoxic agents may mask symptoms of ototoxicity such as tinnitus, dizziness, and fainting. Photosensitizing agents may cause additional photosensitizing effects. The drug should not be used simultaneously with antitussive agents that suppress the cough reflex (e.g., codeine), especially before sleep. Such combined use of drugs hinders expectoration.

Dextromethorphan hydrobromide:
When dextromethorphan, included in the drug, is used simultaneously with other medicinal products, the following interactions are possible:
With MAO inhibitors, drugs for Parkinson's disease, specific serotonin reuptake inhibitors, and other antidepressants – enhancement of the effects of the latter; concomitant use of the drug with these medicinal products is contraindicated;
With amiodarone, quinidine – increased plasma concentrations of dextromethorphan.
Alcohol may enhance the adverse reactions of dextromethorphan.

Special precautions for use:
Do not exceed the recommended dose. Keep the drug out of sight and reach of children. If hemolysis of erythrocytes or drug-induced hemolytic anemia occurs during use of Milistan Multisymptomatic, the drug should be discontinued immediately. If skin rashes occur, the use of the drug should be stopped. During prolonged use, liver and kidney function and hematopoietic system status should be monitored. If symptoms do not disappear, consult a physician. If the disease is caused by a bacterial infection, concomitant antibiotic therapy is recommended. Alcohol consumption is prohibited during use of the drug!

Related to paracetamol:
In liver or kidney diseases, consult a physician before using the drug. Consult a physician before use if the patient is taking warfarin or similar drugs with anticoagulant effects. It should be noted that in patients with alcoholic non-cirrhotic liver damage, the risk of hepatotoxic action of paracetamol is increased; the drug may affect laboratory test results for blood glucose and uric acid levels. Patients who take analgesics daily for mild arthritis should consult a physician. In patients with severe infections such as sepsis, accompanied by reduced glutathione levels, the risk of metabolic acidosis increases when taking paracetamol. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Seek immediate medical attention if these symptoms occur. Cases of metabolic acidosis with a high anion gap due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, or in patients with inadequate nutrition or other causes of glutathione deficiency (e.g., chronic alcoholism), who were treated with paracetamol at therapeutic doses for a prolonged period or in combination with paracetamol and flucloxacillin. If metabolic acidosis with a high anion gap due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and careful monitoring of the patient's condition are recommended. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the primary cause of metabolic acidosis with a high anion gap in patients with multiple risk factors. Do not take the drug simultaneously with other agents containing paracetamol. If symptoms do not disappear, consult a physician. If headache becomes persistent, consult a physician.

Related to cetirizine hydrochloride:
No clinically significant interactions with alcohol (at blood alcohol levels of 0.5 g/l) have been observed when used at therapeutic doses. However, simultaneous use of the drug with alcohol is not recommended. The drug should be prescribed with caution to patients with epilepsy and patients at risk of seizures. Use with caution in patients prone to urinary retention (spinal cord injury, prostate hyperplasia), as cetirizine may increase the risk of urinary retention. Antihistamine agents suppress skin allergy tests; therefore, drug intake should be discontinued 3 days before testing (elimination period).

Related to chlorpheniramine maleate:
Chlorpheniramine, like other agents with anticholinergic effects, should be used with caution in epilepsy; high intraocular pressure, including glaucoma, prostatic hyperplasia, severe hypertension or cardiovascular diseases, bronchitis, bronchiectasis or asthma; hepatic and renal insufficiency. In children and elderly patients, adverse reactions from the nervous system such as anticholinergic effects and paradoxical excitation (increased energy, restlessness, nervousness) may occur more frequently during therapy with chlorpheniramine. The anticholinergic properties of chlorpheniramine may cause drowsiness, dizziness, blurred vision, and impaired psychomotor reactions in some patients, which may seriously affect the ability to drive vehicles and operate machinery. Simultaneous use of chlorpheniramine with alcohol should be avoided, as the effect of the latter is enhanced. Do not use chlorpheniramine with other antihistamine agents.

Related to dextromethorphan hydrobromide:
Patients with chronic cough caused by smoking or bronchial asthma or cough due to acute asthma attack should consult a physician before using dextromethorphan hydrobromide. Consultation with a physician is also required before use in patients whose cough is accompanied by excessive sputum production. If cough persists for more than 7 days or is accompanied by fever, rash, or headache, appropriate examination of the patient is necessary to identify the underlying disease. There are reports of abuse of dextromethorphan hydrobromide. This should be considered when prescribing the drug to adolescents and young people, as well as to patients with a history of drug or psychotropic substance abuse. Dextromethorphan is metabolized in the liver by cytochrome P450 2D6. The activity of this enzyme is genetically determined. Approximately 10% of the population are poor metabolizers of the CYP2D6 enzyme. In such individuals, as well as in patients receiving therapy with CYP2D6 inhibitors, signs of overdose and/or prolonged effect of dextromethorphan may occur. Therefore, caution should be exercised when using the drug in patients who are poor metabolizers of CYP2D6 or who use CYP2D6 inhibitors.

Excipients:
The drug contains methylparaben (E 218) and propylparaben (E 216), therefore it may cause allergic reactions (possibly delayed).

Use during pregnancy or breastfeeding:

Pregnancy:
Do not use the drug during pregnancy.

Breastfeeding:
It is advisable to avoid using the drug during breastfeeding or decide to discontinue breastfeeding if the use of the drug is necessary.

Data on paracetamol:
Standard studies using currently accepted standards for assessing reproductive and ontogenetic toxicity are lacking. A large amount of data on pregnant women does not indicate teratogenic or fetal/neonatal toxicity. Epidemiological studies on the development of the nervous system in children exposed to intrauterine paracetamol do not provide convincing results.

Ability to affect reaction speed when driving vehicles or operating other machinery:
If neurological disorders occur (drowsiness, dizziness, vision disturbances), refrain from driving vehicles or operating other machinery.

Method of administration and dosage:
For adults and children over 12 years of age, take 1 tablet orally once daily. Maximum duration of treatment – 5–7 days. Maximum duration of use for children without consulting a physician – 3 days. In patients with moderate renal impairment, the drug should be used at half the dose. For elderly patients with normal renal function, dose adjustment is not required.

Children:
Contraindicated for children under 12 years of age.

Overdose:

Symptoms:
Signs and symptoms of overdose of individual components of Milistan Multisymptomatic can be categorized as follows:

Related to paracetamol:
Liver damage is possible in adults who have taken 10 g or more of paracetamol and in children who have taken more than 150 mg/kg body weight. In patients with risk factors (long-term use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort or other agents inducing liver enzymes; alcohol abuse; glutathione system deficiency, e.g., digestive disorders, HIV infection, starvation, cystic fibrosis, cachexia), intake of 5 g or more of paracetamol may lead to liver damage. Symptoms of overdose in the first 24 hours: pallor, nausea, vomiting, loss of appetite, and abdominal pain. Liver damage may become apparent 12–48 hours after overdose. Disorders of glucose metabolism and metabolic acidosis may occur. In severe poisoning, liver failure may progress to encephalopathy, hemorrhages, hypoglycemia, coma, and may be fatal. Acute renal failure with acute tubular necrosis may manifest as severe lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmia and pancreatitis have also been reported. With prolonged use in high doses, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia may develop from the hematopoietic system. With intake of large doses, dizziness, psychomotor excitation, and disorientation may occur from the central nervous system; nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis) from the urinary system.

Related to cetirizine hydrochloride:
Overdose of cetirizine is mainly associated with effects on the CNS or effects indicating anticholinergic action. Adverse effects reported after intake of a dose exceeding the recommended daily dose by at least 5 times include: confusion, diarrhea, dizziness, fatigue, headache, malaise, mydriasis, itching, restlessness, sedative effect, drowsiness, stupor, tachycardia, tremor, and urinary retention.

Related to chlorpheniramine maleate:
The expected lethal dose of chlorpheniramine is 25 to 50 mg/kg body weight. In overdose, the condition may vary from depressed to excited (restlessness and seizures). Atropine-like symptoms may be observed, including mydriasis, photophobia, dryness of skin and mucous membranes, elevated body temperature, intestinal atony; CNS depression is accompanied by respiratory disorders and cardiovascular system disturbances.

Related to dextromethorphan hydrobromide:
Symptoms of dextromethorphan hydrobromide overdose: nausea and vomiting, CNS depression, dizziness, dysarthria, ataxia, blurred vision, myoclonus, nystagmus, drowsiness, tremor, excitement, hyperactivity, confusion, psychotic disorders (psychosis), and respiratory depression.

Treatment:
In case of overdose, immediate medical assistance is required. The patient should be taken to a hospital immediately, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. Consider treatment with activated charcoal if an excessive dose of the drug was taken within 1 hour. Paracetamol plasma concentration should be measured 4 hours or later after intake (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours after drug intake, but maximum protective effect is achieved when administered within 8 hours after intake. The effectiveness of the antidote decreases sharply after this time. If necessary, N-acetylcysteine should be administered intravenously according to current recommendations. In the absence of vomiting, methionine may be administered orally as an appropriate alternative in remote areas outside the hospital. In addition to the above, symptomatic or supportive therapy is recommended.

Adverse reactions:
From the skin and subcutaneous tissue: skin rashes, including generalized, maculopapular, erythematous; urticaria, mucosal rashes, hyperemia, skin itching, angioedema, multiform exudative erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, persistent drug erythema, angioedema, exfoliative dermatitis, photosensitivity.

From the immune system: hypersensitivity reactions, including allergic reactions, anaphylaxis, anaphylactic reactions, anaphylactic shock, skin itching, rashes on skin and mucous membranes (usually generalized rashes, erythematous, urticaria), angioedema, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

From the gastrointestinal tract: dyspeptic disorders, gastrointestinal disorders, nausea, vomiting, epigastric pain, abdominal pain, dry mouth, diarrhea, gastritis, heartburn, diarrhea, constipation, flatulence.

From the hepatobiliary system: liver function disorders, increased activity of "liver" enzymes (transaminases, alkaline phosphatase, GGT), usually without development of jaundice, hyperbilirubinemia, hepatitis, jaundice. With prolonged use, especially in large doses, hepatotoxic action is not excluded.

From the endocrine system: hypoglycemia, up to hypoglycemic coma.

From metabolism: increased appetite, anorexia, metabolic acidosis with a high anion gap (frequency unknown).

From the blood and lymphatic system: anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), aplastic anemia, hemolytic anemia; agranulocytosis, thrombocytopenia, leukopenia, bruises or bleeding, pathological changes in blood.

From the respiratory system: pharyngitis, rhinitis, bronchospasm in patients sensitive to acetylsalicylic acid and other NSAIDs, nasal congestion, thickening of bronchial wall due to increased bronchial secretion.

From the nervous system: dizziness, headache, possible paradoxical stimulation of the CNS, excitement, sedative effect, paresthesia, seizures, movement disorders, dysgeusia, loss of consciousness, syncope, tremor, impaired muscle tone (dystonia), dyskinesia, impaired coordination, increased fatigue, confusion, anxiety, nervousness, tremor, irritability, insomnia, euphoria, paresthesia, neurosis, neuritis, seizures; drowsiness, coma, behavioral changes, memory impairment, amnesia, attention disorders.

From the organs of hearing and balance: vertigo, dizziness, impaired coordination, tinnitus, ringing in the ears, acute labyrinthitis.

From the urinary system: difficulty and urinary retention (see section "Special precautions for use"), dysuria, enuresis.

From the organs of vision: impaired accommodation of the eye, blurred vision, decreased visual acuity, involuntary eye movements, clouding, diplopia, increased intraocular pressure, mydriasis, photophobia.

Psychiatric disorders: nervous excitement, confusion, irritability, anxiety, aggression, confusion, depression, suicidal thoughts, hallucinations, insomnia, drowsiness, nightmares, nervous tic.

From the cardiovascular system: tachycardia, arrhythmia, sensation of rapid heartbeat, fluctuations in blood pressure, hypotension.

From the musculoskeletal and connective tissue: muscle twitching, muscle weakness.

General disorders: asthenia, increased fatigue, malaise, swelling, feeling of chest tightness.

Laboratory tests: increased body weight.

From the reproductive system: menstrual cycle disorders; impotence.

Others: dryness of mucous membranes, increased sweating, increased fatigue.

Description of individual adverse reactions:
Metabolic acidosis with a high anion gap. Cases of metabolic acidosis with a high anion gap due to pyroglutamic acidosis have been observed in patients with risk factors taking paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Shelf life:
3 years.

Storage conditions:
Store at a temperature not exceeding 25 °C in the original packaging, out of reach of children.

Packaging:
12 tablets per blister in a cardboard pack.

Category of release:
Over-the-counter.

Manufacturer:
Mepro Pharmaceuticals Private Limited.
Manufacturer's location and address of business activity: Unit II, Q-Road, Phase IV, GIDC, Vadodhan, Surendranagar, Gujarat, 363 035, India.

or

Manufacturer:
Xcel Laboratories Pvt. Ltd.
Manufacturer's location and address of business activity: E-1223, Phase-I, Ext. (Ghatai) RIICO Industrial Area, Bhiwadi, Dist. Alwar (Rajasthan), India.

Applicant:
Mili Healthcare Limited.
Applicant's location: 2nd floor, office premises, 4 Charterfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, United Kingdom.