Codefemol n

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KODEFEMOL H (CODEFEMOL H)

Composition:

Active substances: 5 ml of syrup contains paracetamol 60 mg, pseudoephedrine hydrochloride 7.5 mg, codeine phosphate equivalent to anhydrous codeine phosphate 5 mg;

Excipients: sorbitol (E 420), glycerol, propylene glycol, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), "Raspberry" flavor (purified water, propylene glycol, ethanol 96%, alpha-tocopherol, ascorbic acid), yellow sunset FCF (E 110), purified water.

Pharmaceutical form. Syrup.

Main physicochemical properties: clear, viscous orange liquid with a characteristic fruity odor.

Pharmacotherapeutic group.

Antitussives, excluding combinations with expectorants. Opium alkaloids and derivatives. Combinations. ATC code R05D A20.

Pharmacological properties.

Pharmacodynamics.

Codefemol N is a combined medicinal product whose pharmacological effect is determined by the properties of the active components contained in its composition. The presence in the syrup of codeine, paracetamol, and pseudoephedrine provides antitussive, antipyretic, analgesic, and decongestant effects.

Codeine, included in the formulation, is a centrally-acting antitussive agent—a phenanthrene-series alkaloid; belonging to the group of narcotic analgesics, it is an opioid receptor agonist. It reduces excitability of the cough center and interrupts reflexes provoking persistent cough. It exerts analgesic and sedative effects. In small doses, it does not cause respiratory center depression, does not impair ciliary epithelium function, and does not reduce bronchial secretion.

Pseudoephedrine is a sympathomimetic agent with moderate action on α1-adrenergic receptors, causing vasoconstriction, reducing swelling, local exudative manifestations, and hyperemia of the mucous membranes of the nose, nasopharynx, and paranasal sinuses.

Paracetamol induces reduction of body temperature during fever and provides (especially in combination with codeine) a prolonged analgesic effect.

Pharmacokinetics.

Not studied.

Clinical characteristics.

Indications.

Reduction of intensity and complete relief of cough (especially exhausting dry cough) in lung and upper respiratory tract diseases (bronchitis, pneumonia), particularly when accompanied by fever and catarrhal (inflammatory) manifestations of the nasal mucosa (rhinitis, acute respiratory viral infections, influenza).

Contraindications.

Hypersensitivity to components of the medicinal product.

Severe hepatic dysfunction, severe acute or chronic kidney diseases/renal insufficiency, pulmonary insufficiency, bronchial asthma (opioids should not be used during an asthma attack), respiratory depression, congenital hyperbilirubinemia, glucose-6-phosphate dehydrogenase deficiency, alcoholism, blood disorders, Gilbert’s syndrome, severe anemia, leukopenia, severe hypertension or uncontrolled hypertension, pronounced atherosclerosis of cerebral and cardiac vessels, ischemic heart disease, hyperthyroidism, diabetes mellitus, prostatic hypertrophy, insomnia, concomitant use with monoamine oxidase inhibitors (MAOIs), as well as within 2 weeks before and after MAOI therapy, closed-angle glaucoma, pheochromocytoma, head trauma, increased intracranial pressure, postoperative period following biliary tract surgery, conditions where inhibition of peristalsis should be avoided or where abdominal distension may develop, risk of paralytic intestinal obstruction.

Codeine is contraindicated in patients who are ultra-rapid metabolizers of CYP2D6.

The medicinal product is contraindicated in women during pregnancy and lactation.

The medicinal product must not be administered to children under 12 years of age.

The medicinal product is contraindicated in children (under 18 years of age) undergoing tonsillectomy and/or adenoidectomy for the treatment of obstructive sleep apnea syndrome.

The medicinal product must not be used in children aged 12 to 18 years with compromised respiratory function due to the risk of developing serious and life-threatening adverse reactions.

Interaction with other medicinal products and other forms of interaction.

Morphine agonists and antagonists (buprenorphine, nalbuphine, pentazocine) reduce the efficacy of codeine due to competitive blockade of opioid receptors.

Barbiturates, benzodiazepines, morphine derivatives (analgesics, antitussives) increase the risk of respiratory disturbances.

Medicinal products that reduce central nervous system activity (sedative antidepressants, sedative H1-histamine receptor blockers, barbiturates, clonidine, hypnotics, neuroleptics, anxiolytics, anesthetics) increase the risk of developing central nervous system depression.

Tricyclic antidepressants may enhance the depressant effects of opioid analgesics. Concomitant use of codeine with antihypertensive agents may potentiate hypotensive effects; with antiarrhythmic agents – codeine slows the absorption of mexiletine; concomitant use of codeine and quinidine may significantly reduce the analgesic effect of codeine due to the negative influence of quinidine on its metabolism; with chloramphenicol – plasma concentration of codeine may increase due to inhibition of its metabolism; with non-narcotic analgesics – possible enhancement of analgesic effect; with antiulcer agents – cimetidine may inhibit codeine metabolism, leading to increased plasma concentration; with ciprofloxacin – premedication with opioids should be avoided, as they reduce plasma concentration of ciprofloxacin; with antidiarrheal agents, anticholinergic agents (e.g., atropine) – risk of severe constipation, which may lead to paralytic intestinal obstruction and/or urinary retention. Codeine antagonizes the effects of cisapride, metoclopramide, and domperidone on gastrointestinal motility. Concomitant use with ritonavir may increase plasma levels of opioid analgesics (including codeine).

Opioid use may interfere with assessment of gastric emptying, as opioids delay gastric evacuation, and also with hepatobiliary imaging using Technetium Tc 99m Disofenin, since opioid therapy may cause Oddi sphincter constriction and increased pressure in the biliary tract.

Alcohol enhances the sedative effect of codeine. Concomitant use of alcohol or other centrally acting sedatives with codeine should be avoided.

Metoclopramide and domperidone may increase the absorption rate of paracetamol, while cholestyramine may reduce it. The anticoagulant effect of warfarin and other coumarins may be enhanced by long-term, regular daily use of paracetamol, increasing the risk of bleeding. Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effects of paracetamol due to increased formation of hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic agents increases the risk of hepatic toxicity.

Concomitant use of high-dose paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Paracetamol reduces the efficacy of diuretics.

Caution is required when using paracetamol concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

Inhalational anesthetics, including halothane, trichloroethylene, and other hydrocarbon derivatives, increase myocardial sensitivity to pseudoephedrine.

Pseudoephedrine may partially counteract the hypotensive effects of agents affecting sympathetic activity, including bretylium, betanidine, guanethidine, debrisoquin, methyldopa, α- and β-adrenergic blockers. Use of moclobemide increases the risk of hypertensive crisis. Concomitant use with cardiac glycosides increases the risk of arrhythmias. Digitalis preparations and levodopa increase the risk of severe ventricular arrhythmias. Ergot alkaloids increase the risk of ergotism.

Concomitant use of pseudoephedrine and MAO inhibitors may cause elevated blood pressure.

Use of anorexigenic agents and oxytocin increases the risk of hypertension.

Special precautions for use

Long-term use requires monitoring of peripheral blood parameters and liver function.

Before using the medication, consult a physician if the patient is taking warfarin or similar anticoagulant agents.

If any of the following occur—hallucinations, agitation, sleep disturbances—the medication should be discontinued.

Use with caution in patients whose conditions may be exacerbated by opioids, particularly those being treated for depression or with inflammatory gastrointestinal disorders.

Paracetamol may interfere with laboratory tests for quantitative determination of glucose and uric acid in blood.

During treatment with this medication, the use of other paracetamol-containing products and alcohol consumption are not recommended. Concomitant use with other paracetamol-containing medications may lead to overdose.

Hepatic dysfunction/liver failure has been reported in patients with reduced glutathione levels, such as those with severe malnutrition, anorexia, low body mass index, or chronic alcoholism.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in critically ill patients, such as those with severe renal failure and sepsis, or in patients with malnutrition or other causes of glutathione deficiency (e.g., chronic alcoholism), who were 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 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.

Patients who take analgesics daily for mild forms of arthritis should consult their physician.

Codeine should be used with caution in patients with biliary tract disorders (particularly cholelithiasis), history of drug abuse, respiratory impairment, or asthma. Dose reduction of codeine is recommended in elderly patients, debilitated patients, patients with hypotension, hypothyroidism, inflammatory or obstructive gastrointestinal disorders (codeine reduces peristalsis, increases intestinal tone and segmentation, and may increase colonic pressure), urethral stricture, shock, seizure disorders, or myasthenia gravis.

Codeine should be used cautiously in patients who have recently undergone gastrointestinal or urinary tract surgery (due to possible reduction in gastrointestinal motility or increased risk of urinary retention caused by urethral sphincter spasm and constipation from codeine use). Discontinuation of therapy should be gradual in patients who may have physical dependence to avoid precipitating withdrawal symptoms.

Concomitant use of pethidine and other opioid analgesics in patients taking MAO inhibitors may result in severe, sometimes fatal reactions. If codeine use in patients taking MAO inhibitors is essential, MAO inhibitors should be discontinued at least 2 weeks prior to initiating codeine therapy.

Codeine may increase intracranial pressure and cause disturbances of consciousness of varying degrees, loss of appetite, drowsiness, constipation, respiratory depression, marked pupillary constriction ("pinpoint pupils"), nausea, and vomiting.

Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS)

Cases of PRES and RCVS have been reported with medications containing pseudoephedrine (see section "Adverse reactions"). The risk is increased in patients with severe or uncontrolled hypertension or with severe acute or chronic kidney disease/renal insufficiency (see section "Contraindications").

Pseudoephedrine should be discontinued and immediate medical attention sought if symptoms such as sudden severe or thunderclap headache, nausea, vomiting, confusion, seizures, and/or visual disturbances occur. Most reported cases of PRES and RCVS resolved after discontinuation of the medication and appropriate treatment.

Metabolism mediated by CYP2D6

Codeine is metabolized in the liver by the CYP2D6 enzyme into its active metabolite, morphine. If a patient has a deficiency or complete absence of this enzyme, adequate therapeutic effect may not be achieved. It has been estimated that up to 7% of the Caucasian population may have this CYP2D6 metabolic deficiency. However, if a patient is an ultra-rapid metabolizer via CYP2D6, there is an increased risk of adverse effects—symptoms of opioid toxicity—even at usual doses. In such patients, rapid conversion of codeine to morphine leads to higher-than-expected serum morphine levels.

General symptoms of opioid toxicity include confusion, drowsiness, shallow breathing, pinpoint pupils, nausea, vomiting, constipation, and loss of appetite. In severe cases, circulatory and respiratory depression may occur, which can be life-threatening and, very rarely, fatal.

Data on the prevalence of CYP2D6 ultra-rapid metabolizers in various populations are provided below:

Children with compromised respiratory function

Codeine is contraindicated in children whose respiratory function may be compromised by neuromuscular disorders, severe cardiac or respiratory diseases, infections of the upper respiratory tract or lungs, multiple trauma, or extensive surgical procedures. These factors may intensify symptoms of morphine toxicity.

When high doses of the drug are used, there is a risk of codeine dependence or development of withdrawal syndrome.

If the patient has known sensitivities to certain sugars, medical advice should be sought before taking this medicinal product.

The medicinal product contains the following excipients: methylparaben (E 218), propylparaben (E 216), and "Yellow West FCF" (E 110), which may cause allergic reactions (possibly delayed).

This medicinal product contains a small amount of ethanol (alcohol), less than 100 mg per dose.

If symptoms of illness do not begin to subside, or if the patient's condition worsens, or adverse effects occur, consult a physician regarding further use of the drug.

Do not exceed the recommended doses!

Use during pregnancy or breastfeeding.

Pregnancy

The use of this medicinal product during pregnancy is contraindicated.

There have been reports of a possible association between congenital respiratory and cardiac malformations in newborns and codeine use during the first trimester of pregnancy. Regular use of codeine during pregnancy may lead to physical dependence in the fetus, resulting in neonatal withdrawal symptoms.

Breastfeeding

The use of this medicinal product during breastfeeding is contraindicated.

When used at normal therapeutic doses, codeine and its active metabolite may be present in breast milk at very low concentrations, which are unlikely to have a negative effect on the infant. However, if the patient is an ultra-rapid metabolizer via CYP2D6, higher levels of morphine may accumulate in breast milk, and in very rare cases this may lead to potentially fatal opioid toxicity symptoms in the infant.

Ability to influence reaction speed when driving or operating machinery.

Given that adverse reactions (dizziness, disorientation) may occur in sensitive patients during use of this medicinal product, patients should refrain from driving vehicles or performing other tasks requiring concentration during treatment.

Dosage and Administration.

A measuring spoon or cup with graduations is included in the package together with the bottle.

Adults and children aged 14 years and older: 10 ml 3–4 times daily.

Children aged 12 to 14 years: 5–10 ml 3–4 times daily.

Duration of treatment: 7–10 days.

The medication may be taken again every 4–6 hours if needed.

Do not take more than 4 doses per day. Do not take more frequently than every 4 hours.

Maximum duration of use without medical advice: 3 days.

Children.

The medication is contraindicated in children under 12 years of age.

Codeine is contraindicated in children (under 18 years of age) undergoing tonsillectomy and/or adenoidectomy for the treatment of obstructive sleep apnea syndrome.

Codeine should not be used in children aged 12 to 18 years with compromised respiratory function due to the risk of serious and life-threatening adverse reactions.

Overdose.

Paracetamol

Hepatic damage is possible in adults who have ingested 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight. In patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs inducing liver enzymes; chronic excessive alcohol consumption; glutathione depletion, digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia), ingestion of 5 g or more of paracetamol may lead to hepatic damage.

Symptoms within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, cerebral edema, coma, and death. Acute renal failure with acute tubular necrosis may present with severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have also been reported.

With prolonged use of the drug in high doses, hematological disorders may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Central nervous system effects may include dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).

Prompt medical intervention is required in case of overdose. Administration of activated charcoal should be considered if the excessive dose of paracetamol was ingested within the past hour. Plasma paracetamol concentration should be measured at least 4 hours (or later) after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours after paracetamol ingestion, but its maximum protective effect is achieved when administered within 8 hours after overdose. The efficacy of the antidote decreases significantly after this time. If necessary, intravenous N-acetylcysteine should be administered according to current guidelines. Methionine may be administered orally as an alternative in remote areas outside hospital settings, provided vomiting does not occur.

Codeine

Symptoms: central nervous system depression, particularly respiratory depression (cyanosis, reduced respiratory rate). Drowsiness, dizziness, bronchospasm, skin allergic reactions, marked pupillary constriction, dry mouth, increased sweating, facial flushing, nausea and vomiting, ataxia; less commonly – pulmonary edema, respiratory arrest, miosis, seizures, collapse, urinary retention. Arterial hypotension and tachycardia are possible but unlikely. Signs of histamine release have been observed. Cases of rhabdomyolysis progressing to renal failure have been reported following opioid overdose.

Treatment: general symptomatic and supportive measures, including support of the respiratory center and monitoring of vital signs until stabilization.

Administration of activated charcoal is advisable if less than 1 hour has passed since ingestion of codeine in adults at doses exceeding 350 mg. Naloxone should be administered in cases of coma or respiratory depression. Naloxone is a competitive antagonist with a short half-life; therefore, repeated administration of high doses may be required in cases of severe poisoning. The patient should be observed for at least 4 hours after naloxone administration, or 8 hours if a prolonged-release naloxone formulation has been used.

Pseudoephedrine hydrochloride

Following overdose, adverse effects intensify, particularly excitability, thirst, urinary disturbances, restlessness, irritability, tremor, hallucinations, seizures, arterial hypertension, cardiac arrhythmia, nausea, and vomiting.

In acute overdose, gastric lavage is a necessary measure and should be performed within 4 hours after overdose. Administration of activated charcoal is effective within the first hour after overdose. In the absence of renal damage, forced diuresis accelerates elimination of the active substance. In cases of cardiotoxicity, intravenous propranolol should be administered; in cases of delirium or seizures, diazepam should be given.

Adverse reactions.

Immune system disorders: hypersensitivity reactions, including cross-sensitivity, maculopapular rash (considered a symptom of hypersensitivity syndrome associated with oral codeine administration), fever, splenomegaly, and lymphadenopathy. Allergic reactions, including pruritus, skin and mucous membrane rashes (usually erythematous, urticaria), angioneurotic edema, erythema multiforme (including Stevens–Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), anaphylaxis.

Nervous system disorders (usually with high-dose administration): dizziness, psychomotor agitation and disorientation, tremor, restlessness, increased sweating, hallucinations, sleep disturbances (including insomnia, somnolence), anxiety, irritability, headache, depression, sudden mood changes, euphoria, dysphoria, reversible posterior encephalopathy syndrome (see section "Special precautions"), reversible cerebral vasoconstriction syndrome (see section "Special precautions").

Respiratory system disorders: bronchospasm (this reaction may also occur in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs), respiratory depression.

Metabolism and nutrition disorders: metabolic acidosis with a high anion gap.

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

Gastrointestinal disorders: loss of appetite, nausea, vomiting, constipation, epigastric pain, increased liver enzyme activity (usually without development of jaundice), hepatonecrosis (a dose-dependent effect), dry mouth, diarrhea.

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

Reproductive system disorders: sexual dysfunction, erectile dysfunction, decreased libido and potency.

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

Renal and urinary system disorders (with high-dose administration): nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis), urinary retention, dysuria.

Cardiovascular system disorders: tachycardia, bradycardia, palpitations, facial flushing, orthostatic hypotension, arterial hypotension, or hypertension.

Eye disorders: miosis, photophobia, visual disturbances (including blurred vision, double vision), glaucoma.

Other: malaise, increased fatigue, hypothermia.

Shelf life. 2 years.

After opening the bottle, the shelf life of the medicinal product is 30 days, provided it is stored at a temperature not exceeding 25 °C.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

100 ml or 200 ml in a bottle with a measuring spoon or cup, in a carton.

Prescription status.

Prescription only.

Manufacturer.

Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's address and place of business.

41 Kuilikivska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.