Codeterep

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KODETERPH (CODETERPH)

Composition:

Active substances: 1 tablet contains codeine phosphate equivalent to codeine 4 mg, terpin hydrate 0.125 g (125 mg), and sodium bicarbonate 0.125 g (125 mg);

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

Pharmaceutical form. Tablets.

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

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

Pharmacological properties.

Pharmacodynamics.

Codetherp N is a combination medicinal product 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). Guaifenesin exerts an expectorant effect. Sodium bicarbonate reduces the viscosity of sputum by increasing pH.

Pharmacokinetics.

After oral administration, codeine and other components of the medicinal product are well absorbed from the gastrointestinal tract. In the body, due to its lipophilicity, codeine rapidly penetrates the blood-brain barrier; it accumulates in adipose 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. Guaifenesin and sodium bicarbonate are excreted via 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; acute respiratory depression, pulmonary insufficiency, severe obstructive respiratory diseases, bronchial asthma, etc. (opioids should not be used during an asthma attack); pronounced arterial hypotension, arrhythmias, epilepsy, head injuries or conditions accompanied by 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 liver and kidney diseases, postoperative period after surgery on the biliary tract; conditions in which inhibition of peristalsis should be avoided or in which abdominal distension develops; risk of paralytic intestinal obstruction; alcohol intoxication, alcoholism.

The 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;

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 interactions.

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

Codeine should not be used in combination with monoamine oxidase inhibitors (MAOIs) due to the risk of developing CNS excitation or depression; codeine administration may be initiated no earlier than 2 weeks after discontinuation of MAOIs.

Use with caution when co-administering codeine with anticholinergic agents (atropine), antidiarrheal agents (loperamide, kaolin) – increases the risk of acute constipation, which may lead to intestinal obstruction and/or urinary retention; cisapride, metoclopramide, and domperidone – due to possible antagonism of effect; antihypertensive agents – enhanced hypotensive effect; non-narcotic analgesics – enhanced analgesic effect; quinidine – reduced analgesic effect of codeine. Concomitant use of agents that exert a central nervous system depressant effect (anesthetics, sodium oxybate, neuroleptics, tricyclic antidepressants, anxiolytics, sedatives, hypnotics, antihistamines with sedative effect), as well as alcohol, may result in enhanced sedative effect of codeine and increased respiratory depression and/or arterial hypotension. Concomitant use of codeine with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma, or death.

Concomitant use of codeine with opioid antagonists (buprenorphine, naloxone, naltrexone) may cause withdrawal symptoms.

Concomitant use of the drug with bronchodilators and antibacterial agents in the treatment of colds is possible. Chloramphenicol inhibits the biotransformation of codeine in the liver, thereby enhancing its effect. Concomitant use with ciprofloxacin should be avoided, as opioids reduce the plasma concentration of the drug. Administration of ritonavir or cimetidine leads to increased plasma concentration of codeine. When used concomitantly, codeine slows the absorption of mexiletine.

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

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

Special precautions for use

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

The drug should be used with caution 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), prostate hypertrophy, seizure disorders, arterial hypotension, myasthenia gravis, debilitated patients, patients with urethral stricture, as well as patients in shock, pneumonia, respiratory disorders, and history of bronchial asthma, and in patients with drug abuse.

Patients with biliary tract disorders (including cholelithiasis) should avoid using 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 dependence on codeine. In patients who may have physical dependence, discontinuation of treatment should be carried out gradually to avoid precipitating withdrawal symptoms.

The drug should be used with caution in patients who have recently undergone intestinal surgery (due to possible reduction in gastrointestinal motility) or urinary tract surgery (such patients are more prone to urinary retention caused directly by urethral sphincter spasm and constipation due to codeine use). The drug should be used with caution in patients with pheochromocytoma (opioids may stimulate catecholamine release by inducing endogenous histamine release).

The use of meperidine and possibly other opioid analgesics in patients taking monoamine oxidase inhibitors (MAOIs) may result in severe reactions, sometimes fatal. If the use of codeine in patients taking MAOIs is essential, MAOIs should be discontinued at least 2 weeks prior to initiating codeine therapy (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

This medicinal product contains 2.976 mmol (or 68.416 mg) of sodium per dose (2 tablets). Caution should be exercised when prescribing to patients on a sodium-restricted diet.

Metabolism involving CYP2D6

Codeine is converted in the liver to its active metabolite – morphine – by the enzyme CYP2D6. If a patient has a deficiency or complete absence of this enzyme, adequate therapeutic effect may not be achieved. It has been established that up to 7% of Caucasian individuals 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 with usual doses. In such patients, rapid conversion of codeine to morphine leads to higher serum morphine concentrations than expected.

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.

Sleep-related breathing disorders

Opioids may cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent manner. For patients with CSA, consider reducing the total opioid dose.

Severe cutaneous adverse reactions (SCARs)

Cases of life-threatening or fatal acute generalized exanthematous pustulosis (AGEP) have been reported in association with morphine use. Most of these reactions occurred within the first 10 days of treatment. Patients should be informed about the signs and symptoms of AGEP and advised to seek immediate medical attention if such symptoms occur.

If signs or symptoms suggestive of these skin reactions appear, the drug should be discontinued and alternative therapy considered.

Postoperative use in children

There have been reports of life-threatening adverse events, including fatalities, following codeine administration in children after tonsillectomy and/or adenoidectomy for prevention of obstructive sleep apnea (see section "Contraindications"). All children received codeine doses within the recommended range. However, evidence suggests 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 major surgical procedures. These factors may exacerbate symptoms of morphine toxicity.

Hepatobiliary disorders

Codeine may cause dysfunction and spasm of the sphincter of Oddi, thereby increasing intraluminal pressure and increasing the risk of symptoms related to biliary tract disorders and pancreatitis. Therefore, codeine should be used with caution in patients with pancreatitis or biliary tract disease.

Disorders related to opioid use (abuse and dependence)

Tolerance, physical and/or psychological dependence may develop after repeated use of opioids. Repeated use may lead to opioid use disorders (OUD). The risk of developing OUD increases with higher doses and longer duration of opioid treatment. Misuse or intentional inappropriate use of the medicinal product may lead to overdose and death.

The risk of developing OUD is increased in patients with a personal or family history (in parents or siblings) of substance use disorders (including alcohol use disorders), in current tobacco users, or in patients with other psychiatric disorders (e.g., major depression, anxiety, and personality disorders).

Prior to initiating and during treatment, the goals of therapy and a plan for discontinuation should be discussed with the patient. Patients should be informed about the risks and signs of OUD before and during treatment. Patients should be advised to contact their physician if such signs occur.

Patients should be monitored for signs of addictive behavior (e.g., early requests for additional doses). This includes monitoring concomitant use of opioids and psychoactive medicinal products (e.g., benzodiazepines). Patients exhibiting signs and symptoms of OUD should be referred for consultation with an addiction specialist.

Opioids reduce salivary secretion, which may contribute 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 malformations in infants and codeine use during the first trimester of pregnancy. Regular use of codeine during pregnancy may result in physical dependence in the fetus, leading to neonatal opioid withdrawal syndrome. 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.

At usual therapeutic doses, codeine and its active metabolite may be present in breast milk at very low concentrations, making it unlikely to have adverse effects 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.

Patients should refrain from driving or operating machinery during treatment due to possible 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 medicinal product should be administered orally. For adults and children aged 12 years and older, the recommended dose is 2 tablets 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 to morphine in patients of this age group.

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

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 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 clinical triad of opioid overdose includes coma, pinpoint pupils, and acute respiratory center depression, which may lead to cyanosis followed by pupil dilation as hypoxia develops. Other symptoms of opioid overdose include hypothermia, impaired (slowed or labored) breathing, seizures (especially in children), severe dizziness, impaired ocular coordination, headache, pronounced drowsiness, marked weakness, nervousness or restlessness, emotional agitation, sedation, hallucinations, confusion, cardiac rhythm disturbances, arrhythmia; arterial hypotension and tachycardia (less likely), 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. 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.

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

Treatment: gastric lavage, administration of activated charcoal, and general symptomatic and supportive measures, including respiratory support and monitoring of vital signs until stabilization.

Administration of activated charcoal is advisable within the first hour following ingestion of more than 350 mg of codeine in adults or more than 5 mg/kg body weight in children. Subsequently, symptomatic therapy should be continued. An important additional procedure in management includes urinary catheterization and, if necessary, administration of antibiotics. In cases of severe poisoning, hospitalization is required. 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 preparation has been used.

Side effects.

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

Psychiatric disorders: depression, hallucinations, nightmares, restlessness, confusion, sudden mood changes, 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, visual acuity disturbances, photophobia, visual disturbances (particularly blurred vision, double vision).

Ear and labyrinth disorders: vertigo.

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

Respiratory system disorders: dyspnea, respiratory depression (with high doses), bronchospasm, central sleep apnea syndrome.

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, pancreatitis, sphincter of Oddi spasm.

Endocrine 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, acute generalized exanthematous pustulosis.

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, fatigue, hypothermia.

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

Repeated administration of the drug may lead to drug dependence, even when therapeutic doses are used. The risk of developing drug dependence may vary depending on individual patient risk factors, dosage, and duration of opioid treatment (see section "Special instructions").

Regular long-term use of codeine leads to development of dependence and tolerance, as well as 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, piloerection, fever, mydriasis, tremor, muscle spasms, increased heart rate, respiratory rate, and elevated blood pressure.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister; 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

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

Manufacturer's address and location of business activity.

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