Codeterp

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KODETERP (CODETERP)

Composition:

Active substances: 1 tablet contains codeine phosphate equivalent to 8 mg of codeine, 250 mg of terpin hydrate, 250 mg of sodium hydrocarbonate;

Excipients: microcrystalline cellulose, corn starch, colloidal anhydrous silicon dioxide, magnesium stearate, talc.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white or white with creamy shade tablets, flat surface, with bevel and score line.

Pharmacotherapeutic group. Cough and cold preparations. Opioid derivatives and expectorants. ATC code R05F A02.

Pharmacological properties.

Pharmacodynamics.

CodeTerep is a combined preparation with antitussive and expectorant effects. Codeine is an opioid receptor agonist that exerts a central antitussive action (by suppressing the excitability of the cough center).

Terpin hydrate produces an expectorant effect.

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, codeine, due to its lipophilicity, rapidly penetrates the blood-brain barrier; it accumulates in fatty tissue and, to a lesser extent, in the lungs, liver, kidneys, and spleen. Maximum effect occurs within 30–60 minutes and lasts for 2–6 hours. 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 diseases of the bronchi and respiratory tract.

Contraindications.

Hypersensitivity to any component of the medicinal product or to other opioid analgesics; acute respiratory depression, pulmonary insufficiency, obstructive respiratory tract diseases, bronchial asthma (opioids should not be used during an asthma attack), marked arterial hypotension, arrhythmias, epilepsy, cranial trauma 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 during neurological assessment); severe hepatic and renal diseases, postoperative period following biliary tract surgery; conditions where inhibition of peristalsis should be avoided or which involve abdominal distension; risk of paralytic ileus; 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 interaction.

Adsorbents, astringents, and coating agents may reduce the absorption of the drug's components in the gastrointestinal tract.

The use of MAOIs in combination with pethidine has been associated with severe central nervous system (CNS) excitation or depression (including arterial hypertension/hypotension). Although such effects have not been documented with codeine, this interaction cannot be ruled out. Therefore, codeine should not be used in combination with MAOIs; codeine may be initiated no earlier than 2 weeks after discontinuation of MAOI therapy.

Use with caution when administered concomitantly with codeine:

Anticholinergic agents (e.g., atropine) — increased risk of severe constipation, which may lead to paralytic ileus and/or urinary retention.

Antidiarrheal agents (loperamide, kaolin) — increased risk of severe constipation, potentially leading to intestinal obstruction.

Cisapride, metoclopramide, and domperidone — possible antagonism regarding gastrointestinal motility effects.

Non-opioid analgesics — enhanced analgesic effect.

Use of codeine in combination with opioid antagonists (buprenorphine, naloxone, naltrexone) may precipitate withdrawal symptoms.

Tricyclic antidepressants — enhanced CNS depressant effect of opioid analgesics.

Antihypertensive agents — enhanced hypotensive effect.

Anesthetics, sodium oxybate — possible increased CNS depression, respiratory center depression, and/or arterial hypotension.

Neuroleptics — possible enhancement of sedative and hypotensive effects.

Anxiolytics, sedatives, hypnotics — enhanced sedative effect and respiratory center depression.

Antihistamines with sedative effects — enhanced CNS depression, respiratory center depression, and/or arterial hypotension.

Alcohol — possible enhancement of hypotensive and sedative effects of alcohol, as well as enhanced respiratory center depression caused by alcohol.

Antiarrhythmic agents — codeine may slow the absorption of mexiletine when used concomitantly. When codeine is used with quinidine, the effect of codeine is likely to be significantly reduced due to quinidine's negative impact on its metabolism.

When codeine is used in high doses, the action of cardiac glycosides (digoxin and others) may be enhanced.

Chloramphenicol inhibits the biotransformation of codeine in the liver, thereby enhancing its effect.

Concomitant use of ciprofloxacin should be avoided, as opioids reduce the plasma concentration of the drug.

Administration of ritonavir, cimetidine leads to increased plasma concentration of codeine.

Opioid use may interfere with gastric emptying studies, as opioids delay gastric emptying, and 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 with bronchodilators and antibacterial agents is possible during treatment of cold-related respiratory conditions.

Special precautions for use

Alcohol consumption is prohibited during the use of this medicinal product.

Dosage reduction is recommended in inflammatory diseases of the gastrointestinal tract [codeine affects peristalsis, increases intestinal tone and segmentation, and may increase pressure in the colon (see section "Contraindications")], in renal or hepatic impairment, hypothyroidism, adrenal insufficiency (e.g., Addison's disease), benign prostatic hyperplasia, seizure disorders, arterial hypotension, myasthenia gravis, debilitated patients, patients with urethral stricture, and patients in shock.

This medicinal product should be used with caution in patients with pneumonia, respiratory dysfunction, or a history of bronchial asthma, as well as in patients with a history of drug abuse.

Patients with biliary tract disorders (including cholelithiasis) should avoid the use of opioid analgesics or use them in combination with spasmolytics.

In patients with impaired renal function, elimination of codeine is slowed; therefore, prolonged intervals between doses are recommended.

In elderly patients, metabolism and elimination of codeine may be slower, so dose reduction may be appropriate.

This medicinal product should not be used for prolonged periods due to the risk of developing codeine dependence. In patients who may have physical dependence, discontinuation of treatment should be gradual to avoid precipitating withdrawal symptoms.

This 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). This medicinal product should also be used with caution in patients with phaeochromocytoma (opioids may stimulate catecholamine release by inducing endogenous histamine release).

Codeine use requires regular physician assessment of the benefit-risk balance.

Administration of pethidine and possibly other opioid analgesics to patients taking MAO inhibitors may lead to severe, and sometimes fatal, reactions. If codeine use is essential in patients taking MAO inhibitors, MAO inhibitors should be discontinued at least 2 weeks prior to initiating codeine therapy (see sections "Contraindications", "Interaction with other medicinal products and other types of interactions").

This medicinal product contains 68 mg of sodium per tablet. Caution is advised when administering to patients on a sodium-controlled diet.

Metabolism mediated by 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:

Postoperative use in children

There have been reports that the use of codeine in children after tonsillectomy and/or adenoidectomy for prevention of obstructive sleep apnea has rarely led to life-threatening adverse reactions, including fatal outcomes (see section "Contraindications"). All children received codeine doses within the recommended dosage range. However, evidence suggests that these children were either ultra-rapid or extensive metabolizers of codeine.

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 exacerbate symptoms of morphine toxicity.

Opioid analgesics reduce saliva secretion, which may lead to the development of dental caries and oral mucosal candidiasis.

Use during pregnancy or breastfeeding

The medicinal product is contraindicated during pregnancy. There have been reports of a possible association between congenital respiratory and cardiac defects 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 withdrawal symptoms in the newborn. The use of codeine during labor may depress respiration in the newborn. Opioid analgesics may cause gastric stasis during labor, increasing the risk of aspiration pneumonia in the mother.

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.

The medicinal product is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery

During treatment with this medicinal product, 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.

Administration and Dosage

The medicinal product is intended for oral administration. The recommended dose for adults and children aged 12 years and older 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

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 conversion of codeine into morphine in this age group.

Codeine must not be used in children aged 12 to 18 years who are undergoing tonsillectomy and/or adenoidectomy, due to the risk of developing serious and life-threatening adverse reactions, including postoperative obstructive sleep apnea.

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.

Codeine must not be used in children aged 12 to 18 years who are ultra-rapid metabolizers via CYP2D6.

Overdose

Severe central nervous system (CNS) depression, including respiratory depression, may occur when codeine is used concomitantly with other sedative agents (including alcohol) or in case of significant overdose.

Symptoms of codeine overdose: The classic clinical triad of opioid overdose includes coma, pinpoint pupils (miosis), and acute respiratory depression, which may lead to cyanosis. As hypoxia progresses, pupils may dilate. Other symptoms of opioid overdose include hypothermia, impaired (slow or labored) breathing, seizures (particularly in children), severe dizziness, impaired ocular coordination, headache, pronounced drowsiness, marked weakness, nervousness or restlessness, sedation, hallucinations, confusion, cardiac rhythm disturbances, arrhythmia; arterial hypotension and tachycardia (less common), bradycardia, circulatory failure, increased sweating, facial flushing, dry mouth, constipation, urinary bladder atony. Dyspnea, apnea, collapse, and urinary retention may 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 drugs.

Treatment: gastric lavage, administration of activated charcoal, and general symptomatic and supportive measures, including interventions to support the respiratory center and continuous monitoring of vital signs until the patient's condition stabilizes.

In cases of ingestion exceeding 350 mg of codeine in adults or more than 5 mg/kg body weight in children, administration of activated charcoal is advisable within the first hour. Subsequently, symptomatic therapy should be continued. An important additional procedure in management includes urinary catheterization and, if necessary, administration of antibiotics. Hospitalization is required in cases of severe poisoning. The antidote is naloxone. 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 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, seizures (especially in infants and children), headache, increased intracranial pressure, development of tolerance or dependence, sedative effect.

Eye disorders: miosis, visual acuity disturbances, 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, epigastric pain.

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

Endocrine system disorders: hyperglycemia.

Metabolism and nutrition disorders: loss of appetite.

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

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

Renal and urinary system 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—usually develop with prolonged use of codeine.

Regular long-term use of codeine leads to dependence, tolerance, and the emergence of restlessness and irritability after discontinuation. 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, piloerection, fever, mydriasis, tremor, muscle spasms, increased heart rate, respiratory rate, and elevated blood pressure.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister; 1 blister per carton.

Prescription status.

Prescription only.

Manufacturer.

LLC "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's address.

41 Kulikivska Street, Kharkiv, Kharkiv region, 61002, Ukraine.