Codelmicst^® (Tablets) Instructions for Use

Marketing Authorization Holder

Rusan Pharma, Ltd. (India)

ATC Code

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

Active Substances

Paracetamol (Rec.INN WHO registered)

Codeine (Ph.Eur. European Pharmacopoeia)

Dosage Form

Codelmicst®

Tablets 500 mg+8 mg: 20 pcs.

Dosage Form, Packaging, and Composition

Tablets are white, round, flat, with beveled edges and a score on one side.

Excipients: pregelatinized starch, corn starch, magnesium stearate, sodium disulfite, povidone K-30.

10 pcs. – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Combination analgesic-antipyretic

Pharmacotherapeutic Group

Opioid analgesic + non-narcotic analgesic agent

Pharmacological Action

A combined drug, the action of which is due to the effects of its constituent components.

Paracetamol is a non-opioid analgesic with analgesic and antipyretic effects.

It blocks COX-1 and COX-2 primarily in the CNS, affecting the centers of pain and thermoregulation.

In inflamed tissues, cellular peroxidases neutralize the effect of paracetamol on COX, which explains the almost complete absence of an anti-inflammatory effect.

The absence of a blocking effect on the synthesis of prostaglandins in peripheral tissues means it does not have a negative effect on water-salt metabolism (sodium and water retention) and the gastrointestinal mucosa.

Codeine has a central antitussive effect (by suppressing the excitability of the cough center), as well as an analgesic effect due to the excitation of opioid receptors in various parts of the CNS and peripheral tissues, leading to stimulation of the antinociceptive system and a change in the emotional perception of pain.

It depresses respiration less than morphine and less frequently causes miosis, nausea, vomiting, and constipation (activation of opioid receptors in the intestine causes relaxation of smooth muscles, decreased peristalsis, and spasm of all sphincters).

The duration of the analgesic effect is 4 hours, and the antitussive effect is 4-6 hours.

Pharmacokinetics

Paracetamol

Absorption and Distribution

Paracetamol is well and completely absorbed from the gastrointestinal tract.

C_max is reached within 0.5-2 hours and is 5-20 µg/ml.

Plasma protein binding is 15%. It penetrates the blood-brain barrier. Less than 1% of the paracetamol dose taken by a nursing mother passes into breast milk.

Therapeutically effective plasma concentration of paracetamol is achieved when administered at a dose of 10-15 mg/kg.

Metabolism and Excretion

It is metabolized in the liver (90-95%): 80% undergoes conjugation reactions with glucuronic acid and sulfates to form inactive metabolites; 17% undergoes hydroxylation to form 8 active metabolites, which conjugate with glutathione to form inactive metabolites.

With a deficiency of glutathione, these metabolites can block the enzyme systems of hepatocytes and cause their necrosis. The isoenzyme CYP2E1 is also involved in the metabolism of the drug.

T_1/2 is 1-4 hours. It is excreted by the kidneys in the form of metabolites, mainly conjugates, with only 3% unchanged.

Pharmacokinetics in Special Clinical Cases

In elderly patients, the clearance of the drug decreases and T_1/2 increases.

Codeine

Absorption and Distribution

Codeine is rapidly absorbed from the gastrointestinal tract after oral administration.

Plasma protein binding is 30%. C_max is reached within 2-4 hours.

Metabolism and Excretion

It is metabolized in the liver to active metabolites; the isoenzyme CYP 2D6 is involved in the drug’s metabolism. 10% is converted to morphine via demethylation.

It is excreted by the kidneys (5-15% unchanged and 10% as morphine and its metabolites) and with bile. T_1/2 is 2.5-4 hours.

Indications

Mild to moderate pain syndrome

• Headache;
• Migraine;
• Myalgia;
• Neuralgia;
• Arthralgia;
• Dysmenorrhea;
• Toothache;
• Post-traumatic pain.

Colds, influenza (as an antipyretic and antitussive agent).

ICD codes

Dosage Regimen

Administer orally to adults and children over 12 years.

Take 1-2 tablets every 4 hours as needed for pain relief.

Do not exceed 8 tablets in any 24-hour period.

For use as an antipyretic, limit treatment to 3 days unless directed by a physician.

For use as an analgesic, limit treatment to 5 days unless directed by a physician.

Adhere strictly to the maximum daily dose to avoid the risk of severe liver toxicity from paracetamol.

Use the lowest effective dose for the shortest duration necessary to control symptoms.

Space doses evenly to maintain consistent pain control.

Swallow tablets whole with a sufficient amount of water.

Do not crush or chew the tablets.

Consult a physician if symptoms persist or worsen.

Exercise caution due to the potential for codeine-induced dependence and tolerance with prolonged use.

Adverse Reactions

From the central and peripheral nervous system often – drowsiness; sometimes – blurred vision, diplopia, feeling of fatigue, headache, dizziness, convulsions, involuntary muscle contractions or muscle rigidity, hallucinations, nightmares, depression, malaise, euphoria.

From the digestive system often – constipation; sometimes – nausea, vomiting, dry mouth, epigastric pain, anorexia.

Allergic reactions sometimes – skin rash, itching, angioedema.

From the cardiovascular system: sometimes – facial flushing, bradycardia/tachycardia, arterial hypotension.

From the hematopoietic system rarely – anemia, thrombocytopenia, methemoglobinemia.

Other sometimes – sweating, difficulty breathing; rarely – impaired liver and kidney function.

With long-term use of Codelmicst^®, its effectiveness decreases. Addiction may also develop due to the codeine it contains. Upon discontinuation of treatment, symptoms of anxiety and irritability may appear.

Contraindications

• Severe renal failure;
• Severe hepatic failure;
• Impaired hematopoiesis;
• Genetically determined glucose-6-phosphate dehydrogenase deficiency;
• Respiratory depression due to depression of the respiratory center;
• Bronchial asthma;
• Pulmonary insufficiency;
• Heart failure;
• Increased intracranial pressure;
• History of traumatic brain injury;
• Acute abdominal pain of unclear etiology;
• Risk of functional intestinal obstruction;
• Concomitant use of drugs containing Paracetamol;
• Concomitant use of MAO inhibitors within the last 14 days;
• Alcoholism;
• Pregnancy;
• Lactation period;
• Children under 12 years of age;
• Hypersensitivity to the components of the drug.

With caution, the drug should be prescribed for arterial hypotension, arrhythmias, cholelithiasis, myasthenia gravis, adrenal diseases, prostatic hyperplasia, convulsions, drug dependence (including history), as well as to elderly patients.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and lactation.

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency.

Use in Renal Impairment

Contraindicated in severe renal insufficiency.

Pediatric Use

The use of the drug is contraindicated in children under 12 years of age.

Geriatric Use

With caution, the drug should be prescribed to elderly patients.

Special Precautions

The drug should not be taken for more than 3 days without consulting a doctor.

Codeine contained in Codelmicst^® may cause addiction.

Alcohol consumption should be avoided during treatment with Codelmicst^®, as Codeine enhances the effect of ethanol.

Concomitant use of Codelmicst^® with other drugs containing Paracetamol, as well as with expectorants, should be avoided.

Effect on the ability to drive vehicles and machinery

During the treatment period, caution must be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, as there is a risk of drowsiness.

Overdose

Symptoms agitation, nausea, heaviness in the head, insomnia, hypoglycemia, hemolytic anemia, cyanosis, bronchospasm, accelerated development of severe respiratory failure may occur.

When paracetamol is used in high doses (more than 10 g/day) or with prolonged use of 3-4 g/day, liver necrosis and kidney damage occur.

In high doses, Paracetamol is metabolized to N-acetyl-p-benzoquinone, which causes liver damage.

Treatment gastric lavage, intake of activated charcoal.

Drug Interactions

Concomitant use of Codelmicst with MAO inhibitors causes ataxia, arterial hypotension, paresthesia, and accommodation disturbance.

Codelmicst^® enhances the effect of antiplatelet agents when used concomitantly, which may lead to adverse reactions.

Long-term regular use of paracetamol enhances the anticoagulant effect of warfarin and other coumarins, which may increase the risk of bleeding; a single dose does not have a significant effect.

Codeine enhances the effect of ethanol on psychomotor function.

Codeine may slow the absorption of mexiletine and quinidine, thus reducing its antiarrhythmic effect.

Concomitant use of metoclopramide, cisapride, or domperidone may increase the absorption rate of paracetamol.

Cholestyramine reduces the absorption of paracetamol.

Drugs that depress the central nervous system enhance the sedative effect and the depressant effect of codeine on the respiratory center.

Inducers of microsomal oxidation (barbiturates, antiepileptic drugs, rifampicin, and ethanol) when used concomitantly with Codelmicst increase the risk of hepatotoxicity.

Oral contraceptives reduce the rate of paracetamol metabolism by 20-30%.

Storage Conditions

The drug should be stored in a dry, light-protected place, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.