Codterpin ic®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KODTERPIN IS® (CODTERPIN IS)

Composition:

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

1 tablet contains codeine phosphate hemihydrate 10.9 mg (equivalent to 8 mg of codeine base), terpin hydrate 250 mg, sodium bicarbonate 250 mg;

Excipients: potato starch, povidone, sodium croscarmellose, microcrystalline cellulose, calcium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white, flat cylindrical tablets with bevelled edges; the trade mark of the manufacturer is imprinted on one side of the tablet, a score line on the other.

Pharmacotherapeutic group.

Combination preparations containing antitussives and expectorants. Opium derivatives and expectorants. ATC code: R05FA02.

Pharmacological properties.

Pharmacodynamics.

Codterpin IS® is a combination medicinal product with antitussive and expectorant effects.

Codeine is an opioid receptor agonist that exerts a central antitussive effect (by suppressing the excitability of the cough center), as well as 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.

Terpin hydrate produces an expectorant effect.

Sodium bicarbonate reduces sputum viscosity by increasing pH.

Pharmacokinetics.

Codeine and other components of the medicinal product are well absorbed in the gastrointestinal tract. After oral administration, maximum plasma concentration of codeine is reached within 1 hour. Due to its lipophilicity, codeine rapidly crosses the blood-brain barrier, accumulates in fatty tissue, and to a lesser extent in tissues with high perfusion rates (lungs, liver, kidneys, and spleen). The elimination half-life from plasma is 3–4 hours. It is metabolized in the liver by O- and N-demethylation, forming morphine and norcodeine. Codeine and its metabolites are excreted by the kidneys, mainly as glucuronide conjugates. Most excretion products are eliminated in urine within 6 hours, and up to 86% of the dose is excreted from the body within 24 hours. Approximately 70% of the dose is excreted as free codeine, 10% as free and conjugated morphine, and another 10% as free or conjugated norcodeine. Only trace amounts of excretion products are found in feces.

Terpin hydrate and sodium bicarbonate are excreted by the kidneys and through the respiratory tract with bronchial secretions.

Clinical characteristics.

Indications.

Non-productive cough associated with lung and respiratory tract diseases.

Contraindications.

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

adolescents aged 12 to 18 years with compromised respiratory function;

pregnant or breastfeeding women;

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 interaction.

Adsorbents, astringents, and demulcents may reduce the gastrointestinal absorption of the components of the medicinal product.

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 or 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 simultaneously with MAOIs or within 2 weeks after their discontinuation.

Alcohol: possible potentiation 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 and quinidine are used concomitantly, the pharmacological effect of codeine is likely to be significantly reduced due to the negative influence 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-opioid 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.

Ciprofloxacin: opioids reduce the plasma concentration of ciprofloxacin.

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

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

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

Concomitant use of the medicinal product Codterpin IS® with bronchodilators and antibacterial agents is possible during treatment of cold-related illnesses.

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 of the medicinal product. The dose of the medicinal product should be reduced in debilitated patients, patients with arterial hypotension (see section "Contraindications"), hypothyroidism, prostatic hypertrophy, adrenal insufficiency (e.g., Addison's disease), inflammatory bowel disorders (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 patients in shock. In elderly patients, metabolism and elimination of codeine may occur more slowly; 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 gallstone disease) should avoid the use of opioid analgesics or use them in combination with spasmolytics.

Administration of meperidine and possibly other opioid analgesics to patients taking monoamine oxidase inhibitors (MAOIs) may result in severe, and sometimes fatal, reactions. If administration of codeine to patients taking MAO inhibitors is essential, 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 be physically dependent, discontinuation of treatment should be performed gradually to avoid precipitating withdrawal syndrome symptoms.

Metabolism involving CYP2D6

Codeine is converted to its active metabolite – morphine – in the liver by the CYP2D6 enzyme. If a patient has a deficiency of this enzyme or if CYP2D6 is completely absent, 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 when standard doses are administered. In such patients, conversion of codeine to morphine occurs rapidly, leading to higher serum morphine levels than expected.

General symptoms of opioid toxicity: confusion, drowsiness, shallow breathing, pinpoint pupils, nausea, vomiting, constipation, loss of appetite. In severe cases, symptoms of 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, upper respiratory tract infections or lung infections, multiple trauma, or extensive surgical procedures. These factors may intensify symptoms of morphine toxicity.

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

The use of codeine requires regular physician assessment 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 the occurrence of congenital respiratory and cardiac malformations in infants and the use of codeine 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 suppress respiration 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 standard 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 with this medicinal product, driving vehicles or operating machinery should be avoided due to possible effects such as confusion, drowsiness, dizziness, hallucinations, visual disturbances, or seizures. The effects of alcohol are enhanced by opioid analgesics.

Dosage and Administration

The medicinal product should be taken orally.

Adults and children aged 12 years and older: 1 tablet 2–3 times daily. The duration of treatment is 5 days; in exceptional cases, the treatment period may be extended.

Children.

The use of this medicinal product is contraindicated in children under 12 years of age due to the risk of developing serious and life-threatening adverse reactions resulting from the variable and unpredictable metabolism of codeine into morphine in this age group (see section "Contraindications").

Codeine must 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 (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Codeine must not be used in children aged 12 to 18 years who are ultra-rapid metabolizers via CYP2D6 (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Overdose.

Severe central nervous system depression, including respiratory depression, may occur when codeine is used concomitantly with other sedative agents (including alcohol) or when codeine is taken in significantly excessive doses. The classic 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 eye coordination, headache, pronounced drowsiness, marked weakness, nervousness or restlessness, sedation, hallucinations, confusion, arterial hypotension and tachycardia (less likely), bradycardia, circulatory failure, increased sweating, facial flushing, dry mouth, constipation, and urinary retention. Dyspnea, apnea, and collapse may also occur; nausea and vomiting are common, pulmonary edema is rare. Signs of histamine release may be observed. Cases of rhabdomyolysis progressing to renal failure have been reported following opioid overdose.

Overdose effects are potentiated by concomitant intake of alcohol and psychotropic agents.

Treatment: general symptomatic and supportive measures, including measures to support 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 adults at doses exceeding 350 mg or in children at doses exceeding 5 mg/kg body weight. Subsequently, symptomatic therapy should be continued. An important additional procedure in management includes catheterization of the urinary bladder and, if necessary, administration of antibiotics. In cases of severe poisoning, the patient should be hospitalized. 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 required 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 preparation has been 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, convulsions (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 vision, double vision).

Ear and labyrinth disorders: vertigo.

Cardiovascular system disorders: tachycardia, bradycardia, palpitations, orthostatic hypotension, facial flushing, arterial hypotension (with high doses).

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

Gastrointestinal disorders: dry mouth, dyspepsia, nausea, vomiting, constipation, stomach spasms, pancreatitis, abdominal pain.

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

Endocrine system 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 high doses).

Renal and urinary disorders: bladder sphincter spasm, ureteral 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—typically develop during prolonged use of codeine.

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

Withdrawal syndrome: sudden discontinuation of codeine therapy 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, piloerection, fever, mydriasis, tremor, muscle spasms, increased heart rate, respiratory rate, and elevated blood pressure.

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister; 1 blister per carton.

10 tablets in a blister.

Prescription category. Prescription only.

Manufacturer.

Limited liability company "INTERKHIM".

Manufacturer's address and place of business.

40-A, 21st km, Starokyivska Road, Odesa, 65025, Ukraine.