Codepsin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KODEPSIN (CODEPSIN)

Composition:

Active substances: terpin hydrate, sodium bicarbonate, codeine phosphate;

One tablet contains: terpin hydrate 250 mg, sodium bicarbonate 250 mg, codeine phosphate
(expressed as codeine base) 8 mg;

Excipients: microcrystalline cellulose, povidone, crospovidone, colloidal hydrated silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: flat cylindrical, round tablets, white or almost white in color, with beveled edges and a groove; marbling is permissible. Tablets have a specific odor.

Pharmacotherapeutic group.
Medicinal products used for cough and colds. Opioid derivatives and expectorants.
ATC code R05FA02.

Pharmacological properties.

Pharmacodynamics.

Codepsin is a combination drug with antitussive and expectorant effects. Codeine is an opioid receptor agonist and exerts a central antitussive action (by suppressing the excitability of the cough center). Hydrotropic terpin acts as an expectorant. Sodium bicarbonate reduces sputum viscosity by increasing pH.

Pharmacokinetics.

After oral administration, codeine and other components of the drug are well absorbed from the gastrointestinal tract. In the body, due to its lipophilicity, codeine rapidly crosses the blood-brain barrier; it accumulates in fatty tissue and, to a lesser extent, in the lungs, liver, kidneys, and spleen. Maximum effect is observed within 30–60 minutes and lasts for 2–6 hours. Hydrotropic terpin and sodium bicarbonate are excreted by the kidneys and through the respiratory tract with bronchial secretions.

Clinical characteristics.

Indications.

Non-productive cough associated with diseases of the lungs and respiratory tract.

Contraindications.

Hypersensitivity to codeine or to other opioid analgesics, or to any component of the medicinal product; acute respiratory depression, pulmonary insufficiency, obstructive respiratory diseases, bronchial asthma (opioids should not be used during an asthma attack), marked arterial hypotension, arrhythmias, epilepsy, head injuries or conditions associated with increased intracranial pressure (in addition to the risk of respiratory depression and increased intracranial pressure, codeine may affect pupillary response and other vital signs when assessing neurological status); severe hepatic and renal diseases, postoperative period after surgery on the biliary tract; conditions where inhibition of peristalsis should be avoided or conditions associated with abdominal distension; risk of paralytic intestinal obstruction; alcohol intoxication, alcoholism.

The use of this medicinal product is contraindicated in the following patient groups:

• children under 12 years of age;
• children aged 12 to 18 years with compromised respiratory function;
• women during pregnancy or breastfeeding;
• patients of any age who are ultra-rapid metabolizers via CYP2D6.

Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs.

Interaction with other medicinal products and other forms of interactions.

Adsorbents, astringents, and coating agents may reduce the absorption of the components of the medicinal product in the gastrointestinal tract.

Antidepressants: tricyclic antidepressants may enhance the depressant effects of opioid analgesics.

The use of monoamine oxidase inhibitors (MAOIs) in combination with meperidine has been associated with severe excitation/depression of the central nervous system (including arterial hypertension/hypotension). Although such effects have not been documented with codeine, such an interaction cannot be ruled out. Therefore, codeine should not be used concomitantly with MAOIs or within 2 weeks after discontinuation of MAOIs.

Alcohol: possible enhancement of hypotensive and sedative effects of alcohol, as well as increased respiratory depression caused by alcohol.

Anesthetics, sodium oxybate: possible enhancement of central nervous system depression and/or respiratory depression and/or arterial hypotension.

Neuroleptics: enhanced sedative and hypotensive effects.

Anxiolytics, sedatives, and hypnotics: enhanced sedative effect and increased risk of respiratory depression.

Antihistamines: concomitant use of codeine and antihistamines with sedative properties may lead to enhanced central nervous system depression and/or respiratory depression and/or arterial hypotension.

Antihypertensive agents: enhanced hypotensive effect.

Anticholinergic agents (e.g., atropine): risk of severe constipation, which may lead to paralytic intestinal obstruction and/or urinary retention.

Antiarrhythmic agents: codeine delays the absorption of mexiletine. When codeine is used concomitantly with quinidine, the pharmacological effect of codeine is likely to be significantly reduced due to the negative effect of quinidine on its metabolism.

Cisapride, metoclopramide, domperidone: codeine antagonizes the effects of cisapride, metoclopramide, and domperidone on gastrointestinal motility.

Cardiac glycosides (digoxin and others): when codeine is used in high doses, the effect of cardiac glycosides may be enhanced.

Antidiarrheal agents: increased risk of severe constipation, which may lead to intestinal obstruction.

Non-narcotic analgesics: enhanced analgesic effect.

Opioid antagonists (e.g., buprenorphine, naltrexone, naloxone): possible acceleration of withdrawal syndrome development.

Chloramphenicol: increased plasma concentration of codeine due to inhibition of its metabolism.

Cyprofloxacin: opioids reduce the plasma concentration of cyprofloxacin.

Ritonavir: possible increase in plasma levels of opioid analgesics (particularly codeine).

Anti-ulcer agents: cimetidine may inhibit codeine metabolism, leading to increased plasma concentration.

Effect on diagnostic procedures: opioid use may interfere with gastric emptying studies, as opioids delay gastric emptying, and hepatobiliary imaging using Technetium Tc 99m Disofenin, since opioid therapy may cause Oddi sphincter constriction and increased pressure in the biliary tract.

Concomitant use of the medicinal product Codepsin with bronchodilators and antibacterial agents is possible during treatment of colds and respiratory infections.

Special precautions for use

The medicinal product should be used with caution in patients with a history of drug abuse, or with impaired renal or hepatic function (see section "Contraindications"). In patients with impaired renal function, elimination of codeine is slowed; therefore, it is recommended to prolong the intervals between doses. The dose of the medicinal product should be reduced in debilitated patients, in patients with arterial hypotension (see section "Contraindications"), hypothyroidism, prostatic hypertrophy, adrenal insufficiency (e.g., Addison's disease), inflammatory bowel diseases (codeine reduces peristalsis, increases intestinal tone and segmentation, and may increase pressure in the colon) (see section "Contraindications"), urethral stricture, seizure disorders, myasthenia gravis, and in patients in shock. In elderly patients, metabolism and elimination of codeine may be slower; therefore, a reduced dose of codeine may be appropriate. The medicinal product should be used with caution in patients who have recently undergone gastrointestinal surgery (due to possible reduction in gastrointestinal motility) or surgery on the urinary tract (such patients are more prone to urinary retention caused directly by urethral sphincter spasm and constipation due to codeine use). The medicinal product should be used with caution in patients with phaeochromocytoma (opioids may stimulate catecholamine release by inducing release of endogenous histamine). Patients with biliary tract disorders (particularly biliary calculi) should avoid the use of opioid analgesics or use them in combination with spasmolytics.

Administration of pethidine or other opioid analgesics to patients receiving monoamine oxidase inhibitors (MAO inhibitors) may result in severe reactions, sometimes with fatal outcomes. If administration of codeine to patients receiving MAO inhibitors is clinically necessary, MAO inhibitors should be discontinued at least 2 weeks prior to initiating codeine therapy (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").

In patients who may have physical dependence, discontinuation of treatment should be carried out gradually to avoid precipitating withdrawal symptoms.

Metabolism involving CYP2D6

Codeine is converted in the liver to its active metabolite—morphine—by the CYP2D6 enzyme. If a patient has a deficiency or complete absence of this enzyme, adequate therapeutic effect will not be achieved. It has been established that up to 7% of Caucasian populations may have this CYP2D6 metabolic characteristic. 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, miosis (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 ultra-rapid metabolizers via CYP2D6 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, upper respiratory tract infections or lung infections, multiple trauma, or major surgical interventions. These factors may intensify symptoms of morphine toxicity.

Opioid analgesics reduce salivary secretion, which may promote the development of dental caries and oral mucosal candidiasis.

The use of codeine requires regular assessment by a physician of the benefit-risk ratio.

Alcohol consumption is prohibited during treatment with this medicinal product.

The medicinal product should not be used for prolonged periods due to the potential for development of codeine dependence.

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 infants 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 abstinence syndrome. Codeine use during labor may cause respiratory depression in the newborn. Opioid analgesics may cause gastric stasis during labor, increasing the risk of aspiration pneumonia in the mother.

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, making it 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 affect reaction speed when driving or operating machinery.

During treatment, patients should refrain from driving or operating machinery due to the possible occurrence of effects such as confusion, drowsiness, dizziness, hallucinations, visual disturbances, or seizures. The effects of alcohol are enhanced by opioid analgesics.

Method of Administration and Dosage

The drug should be taken orally. For adults and children aged 12 years and older, the recommended dose is 1 tablet 2–3 times daily. The treatment duration is 5 days; in exceptional cases, the treatment period may be extended after consultation with a physician.

Children

Do not use in children under 12 years of age.

Due to the presence of codeine in the formulation, the drug is contraindicated in children undergoing tonsillectomy and/or adenoidectomy for the management of obstructive sleep apnea syndrome. The drug is not recommended for use in children who may have respiratory dysfunction.

Overdose

Severe central nervous system depression, including respiratory depression, may occur with concomitant use of other sedative agents (including alcohol) or with significant overdose of codeine. The clinical triad of opioid overdose consists of coma, pinpoint pupils, and respiratory depression (which may lead to cyanosis), followed by pupillary dilation as hypoxia develops. Other symptoms of opioid overdose include hypothermia, slowed or labored breathing, seizures (especially in children), severe dizziness, impaired ocular coordination, headache, pronounced drowsiness, marked weakness, nervousness or restlessness, emotional excitement, sedation, hallucinations, confusion, arterial hypotension and tachycardia (less likely), bradycardia, circulatory failure, increased sweating, facial flushing, dry mouth, constipation, and urinary bladder atony. Dyspnea, apnea, collapse, and urinary retention may occur; nausea and vomiting are common. Rarely, pulmonary edema may develop. Signs of histamine release may be observed. Cases of rhabdomyolysis progressing to renal failure have been reported following opioid overdose.

Treatment: General symptomatic and supportive measures, including maintenance of the respiratory center and monitoring of vital signs until the patient's condition stabilizes.

Administration of activated charcoal is advisable if less than 1 hour has passed since ingestion of codeine in doses exceeding 350 mg in adults or 5 mg/kg body weight in children. Further management should include symptomatic therapy. An important additional procedure is urinary bladder catheterization and, if necessary, administration of antibiotics. In cases of severe poisoning, hospitalization is required. Naloxone should be administered in cases of coma or respiratory depression. Naloxone is a competitive antagonist with a short elimination half-life; therefore, repeated administration of high doses may be necessary in patients with severe poisoning. The patient should be observed for at least 4 hours after naloxone administration, or for 8 hours if a prolonged-release naloxone formulation is used.

Adverse reactions.

Immune system disorders: allergic reactions, including angioneurotic edema; maculopapular rash considered as a symptom of hypersensitivity syndrome associated with oral codeine administration; fever, splenomegaly, lymphadenopathy, dyspnea.

Psychiatric disorders: depression, hallucinations, nightmares, restlessness, confusion, sudden mood swings, euphoria, dysphoria.

Nervous system disorders: drowsiness, dizziness, seizures (especially in infants and children), headache, increased intracranial pressure, development of tolerance or dependence, sedative effect.

Eye disorders: miosis, blurred vision, photophobia, visual disturbances (including blurred outlines of visible objects), miosis.

Ear and labyrinth disorders: vertigo.

Cardiovascular disorders: orthostatic hypotension, tachycardia, palpitations, bradycardia, facial skin hyperemia, arterial hypotension (with large doses).

Respiratory system disorders: dyspnea, respiratory depression (with large doses), bronchospasm.

Gastrointestinal disorders: dry mouth, dyspepsia, nausea, vomiting, constipation, stomach cramps, pancreatitis, epigastric pain.

Hepatobiliary disorders: biliary tract spasm, which may be associated with changes in liver enzyme levels.

Endocrine disorders: hyperglycemia.

Metabolism and nutrition disorders: anorexia.

Skin and subcutaneous tissue disorders: allergic reactions such as rash, urticaria, pruritus, increased sweating, facial swelling.

Musculoskeletal system disorders: uncontrolled muscle movements, muscle rigidity (with large doses).

Renal and urinary disorders: bladder sphincter spasm, ureter spasm, difficulty in urination, urinary retention, dysuria, antidiuretic effect.

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

General disorders: flushing, malaise, increased fatigue, hypothermia.

Tolerance and some of the most common adverse effects—drowsiness, nausea, vomiting, confusion—usually develop during prolonged use of codeine.

Regular long-term use of codeine leads to dependence, tolerance, and the emergence of restlessness and irritability after discontinuation of treatment. It should be remembered that tolerance decreases rapidly after cessation of codeine intake; therefore, re-administration of a previously tolerated dose may be fatal.

Withdrawal syndrome: sudden discontinuation of codeine treatment may cause withdrawal syndrome. Possible symptoms include insomnia, restlessness, irritability, anxiety, depression, weakness, loss of appetite, nausea, vomiting, diarrhea, dehydration, excessive sweating, lacrimation, rhinorrhea, sneezing, yawning, goosebumps, fever, mydriasis, tremor, muscle spasms, increased heart rate, respiratory rate, and elevated blood pressure.

Shelf life.

2 years.

Storage conditions.

Store in a place inaccessible to children, in the original packaging at a temperature not exceeding 25 °C.

Packaging.

10 tablets per blister; 1 blister per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

LLC "Pharma Start".

Manufacturer's address and location of business activity.

8, Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.