Paracod ic®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARACOD IC

Composition:

Active substances: 1 tablet contains 500 mg (0.500 g) of paracetamol and 8 mg (0.008 g) of codeine phosphate hemihydrate;

Excipients: maize starch, microcrystalline cellulose, povidone, magnesium stearate, sodium metabisulfite (E 223).

Pharmaceutical form. Tablets.

Main physicochemical properties: white-colored, flat cylindrical tablets with a bevel and a score line; the company trademark is printed on one side of the tablet.

Pharmacotherapeutic group.

Analgesics. Other analgesics and antipyretics. Anilides. Paracetamol, combinations without psychotropic agents. ATC code N02BE51.

Pharmacological Properties.

Pharmacodynamics.

Paracetamol is an analgesic and antipyretic (pain-relieving and fever-reducing agent).

Codeine is an analgesic agent with effects similar to those of morphine, but with significantly weaker analgesic activity and a milder sedative effect. Codeine is a weak centrally-acting analgesic. Codeine exerts its effects by interacting with μ-opioid receptors, although it has low affinity for these receptors; the analgesic effect of codeine is due to its conversion into morphine. Codeine is also used as an antitussive and antidiarrheal agent.

Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in the treatment of acute nociceptive pain.

Pharmacokinetics of paracetamol and codeine phosphate is not altered when these components are administered simultaneously.

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration. Maximum plasma concentration of paracetamol is reached within 45–75 minutes after oral administration. Paracetamol is metabolized in the liver to form inactive compounds with glucuronic acid and sulfates. A small amount (less than 4%) is metabolized via oxidation to form cysteine and mercapturic acid (mediated by cytochrome P450). It is excreted in urine, mainly as metabolites. Approximately 5% of the administered dose is excreted unchanged. The elimination half-life is approximately 3 hours.

Paracetamol metabolism is not altered in elderly patients or in patients with hepatic insufficiency.

Codeine phosphate is rapidly absorbed from the gastrointestinal tract after oral administration and widely distributed in tissues and organs. Maximum plasma concentration is reached within 60 minutes. The elimination half-life from plasma is 3–4 hours. It is metabolized by O- and N-demethylation in the liver to form morphine and norcodeine. Codeine and its metabolites are excreted by the kidneys, primarily 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.

In elderly patients, metabolism and elimination of codeine may be slower.

Codeine and its salts cross the placental barrier and are also excreted in breast milk.

Clinical characteristics.

Indications.

For short-term treatment of acute moderate pain not relieved by paracetamol, ibuprofen, or acetylsalicylic acid (headache, migraine, menstrual pain, toothache, neuralgia, rheumatic and muscular pain, back pain).

Contraindications.

Hypersensitivity to codeine or other opioid analgesics, or to any component of the drug. Liver disease, severe hepatic or renal dysfunction, acute respiratory depression, obstructive respiratory tract disorders, bronchial asthma (opioids should not be used during an asthma attack), respiratory insufficiency, congenital hyperbilirubinemia (including Gilbert’s syndrome), glucose-6-phosphate dehydrogenase deficiency, blood disorders (including severe anemia, leukopenia), 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), alcohol intoxication; conditions where inhibition of peristalsis should be avoided or that involve abdominal distension; risk of paralytic intestinal obstruction.

The drug is contraindicated in the following patient groups:

• children under 12 years of age;

• children aged 12 to 18 years undergoing tonsillectomy and/or adenoidectomy to prevent development of obstructive sleep apnea;

• children aged 12 to 18 years with compromised respiratory function;

• pregnant or breastfeeding women;

• patients of any age who are ultra-rapid/extensive metabolizers via CYP2D6.

Interaction with other medicinal products or other types of interactions.

The absorption rate of paracetamol may be increased when co-administered with metoclopramide or domperidone, and decreased with cholestyramine. Barbiturates reduce the antipyretic effect of paracetamol. Anticonvulsants (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effects of paracetamol due to increased formation of hepatotoxic metabolites. Concurrent 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. The anticoagulant effect of warfarin and other coumarins may be enhanced, increasing the risk of bleeding, during long-term, regular daily use of paracetamol; occasional use does not show significant effects. Paracetamol reduces the efficacy of diuretics. Paracetamol should be used with caution in combination with flucloxacillin, as this combination has been associated with metabolic acidosis with a high anion gap, particularly in patients with risk factors (see section "Special precautions for use"). Do not use concurrently with alcohol.

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 central nervous system (CNS) excitation or depression (including arterial hypertension or hypotension). Although such an interaction has not been documented with codeine, a similar interaction cannot be ruled out. Therefore, codeine should not be used concurrently with MAOIs or within 2 weeks of discontinuing MAOI therapy.

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

Antihistamines: concurrent use of codeine and antihistamines with sedative properties may lead to enhanced CNS depression and/or respiratory depression and/or arterial hypotension.

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

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

Neuroleptics: enhanced sedative and hypotensive effects.

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 slows the absorption of mexiletine. Concurrent use of codeine and quinidine may significantly reduce the analgesic effect of codeine due to quinidine's negative effect on its metabolism.

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

Antidiarrheal agents: increased risk of severe constipation.

Opioid antagonists (e.g., buprenorphine, naltrexone, naloxone): possible precipitation of withdrawal syndrome. Do not use concurrently with nalbuphine and/or pentazocine.

Cyprofloxacin: avoid premedication with opioids, as they may reduce plasma concentrations of cyprofloxacin.

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

Mexiletine: co-administration with codeine slows the absorption of mexiletine.

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

Effect on diagnostic tests: 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 sphincter of Oddi constriction and increased pressure in the biliary tract.

Special precautions for use.

In patients with liver or kidney disease, consult a physician before using the medication. It should be noted that in patients with non-cirrhotic alcoholic liver disease, the risk of hepatotoxic effects of paracetamol and the danger of overdose are increased. Patients with mild forms of arthritis who take analgesics daily, and patients taking warfarin or similar drugs with anticoagulant effects, should consult a physician before using Paracod ISO.

In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, the use of paracetamol increases the risk of developing metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Medical attention should be sought immediately if these symptoms occur.

Concomitant use of paracetamol with flucloxacillin is recommended with caution due to an increased risk of high anion gap metabolic acidosis, particularly in patients with sepsis, malnutrition, and other conditions associated with glutathione deficiency, as well as in patients receiving the maximum daily dose of paracetamol. Close monitoring of patients is advised, including measurement of urinary 5-oxoproline levels.

Paracetamol may affect laboratory test results for blood glucose and uric acid levels.

The drug is not recommended for use in patients with acute asthma. Codeine should be used with caution or at a reduced dose in the treatment of asthma or reduced respiratory reserve. Codeine use should be avoided during acute asthma attacks (see section "Contraindications"). The drug should be used with caution in patients with impaired kidney or liver function, gallbladder disorders (particularly gallstone disease), history of drug abuse, respiratory function disorders, or history of asthma. Dose reduction is recommended in elderly patients, debilitated patients, patients with arterial hypotension, hypothyroidism, prostatic hypertrophy, adrenal insufficiency (e.g., Addison's disease), inflammatory or obstructive gastrointestinal disorders (codeine reduces intestinal peristalsis, increases intestinal tone and segmentation, and may increase colonic pressure), urethral stricture, seizure disorders, myasthenia gravis, and in patients in shock. The drug should be used cautiously in patients who have recently undergone gastrointestinal surgery (due to possible reduced 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). Codeine should be used with caution in patients with pheochromocytoma (opioids may stimulate catecholamine release by inducing endogenous histamine release). Discontinuation of treatment should be gradual in patients who may have physical dependence, to avoid precipitating withdrawal symptoms.

CYP2D6 metabolism

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 lacks CYP2D6 entirely, adequate analgesic effect will not be achieved. Estimates suggest that up to 7% of the Caucasian population may have this CYP2D6 metabolic trait. However, if a patient is an ultra-rapid or extensive metabolizer via CYP2D6, there is an increased risk of adverse effects—symptoms of opioid toxicity—even when standard doses are used. In such patients, the conversion of codeine to morphine rapidly leads to higher serum morphine levels than expected.

General symptoms of opioid toxicity include confusion, drowsiness, constricted pupils, shallow breathing, nausea, vomiting, constipation, and 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:

Population	Prevalence, %
Africans/Ethiopians	29
African Americans	3.4–6.5
Mongoloids	1.2–2
Caucasians	3.6–6.5
Greeks	6
Hungarians	1.9
North Europeans	1–2

Postoperative use in children

Published literature contains 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. 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 not recommended for use in children whose respiratory function may be compromised by neuromuscular disorders, severe cardiac or respiratory diseases, upper respiratory tract infections or pulmonary infections, multiple trauma, or major surgical procedures. These factors may exacerbate symptoms of morphine toxicity.

Opioid analgesics should be avoided or used with caution in patients with biliary tract disorders, or should be administered in combination with spasmolytics.

The use of meperidine and possibly other opioid analgesics in patients taking MAO inhibitors may be associated with severe reactions, sometimes resulting in fatal outcomes. If the use of codeine in patients taking MAO inhibitors is essential, codeine should be administered with extreme caution or MAO inhibitors should be discontinued 14 days prior to initiating codeine therapy (see section "Interaction with other medicinal products and other forms of interaction").

Alcohol consumption should be avoided during treatment with codeine.

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

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

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

Prolonged use of the drug without medical consultation may be hazardous.

In case of overdose, immediate medical attention should be sought due to the risk of liver damage, even if the patient feels well.

The medicinal product contains sodium metabisulfite (E 223), which rarely may cause hypersensitivity reactions and bronchospasm.

Use during pregnancy or breastfeeding.

The use of the drug during pregnancy is contraindicated.

Possible associations between congenital respiratory and cardiac malformations in infants and codeine use during the first trimester of pregnancy have been reported. 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 cause respiratory depression in the newborn. Opioid analgesics may cause gastric stasis during labor, increasing the risk of aspiration pneumonia in the mother.

If use of the drug is necessary, breastfeeding should be discontinued.

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 affect reaction speed when driving or operating machinery.

During treatment with this drug, 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.

Tablets should be taken orally with water.

Adults

1–2 tablets depending on the intensity of pain symptoms every 4–6 hours as needed, but not more than 8 tablets per day. The interval between repeated doses should be at least 4 hours; however, an interval of 6 hours is more optimal. Maximum daily dose – 8 tablets.

Children aged 12 to 18 years

1–2 tablets depending on the intensity of pain symptoms every 6 hours as needed, but not more than 8 tablets per day. Maximum daily dose – 8 tablets.

Codeine must not be used in children aged 12 to 18 years undergoing tonsillectomy and/or adenoidectomy to prevent the occurrence of obstructive sleep apnea (see sections "Contraindications", "Special Warnings and Precautions for Use", "Children").

Codeine must not be used in children aged 12 to 18 years with compromised respiratory function (see sections "Contraindications", "Special Warnings and Precautions for Use", "Children").

Children under 12 years of age

Do not use (see sections "Contraindications", "Children").

In cases of severe renal impairment, the interval between doses should be at least 8 hours (see section "Contraindications").

Do not exceed the recommended dose.

The duration of treatment should be determined by a physician. The medicinal product should not be used for more than 3 consecutive days without consulting a physician. If symptoms persist (in particular, if headache becomes persistent), medical advice should be sought.

Do not take together with other medicinal products containing paracetamol.

Children.

The medicinal product is indicated for children aged 12 to 18 years for the treatment of acute moderate pain not relieved by other analgesics such as paracetamol or ibuprofen (as monotherapies).

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

Codeine must not be used in children aged 12 to 18 years undergoing tonsillectomy and/or adenoidectomy to prevent the occurrence of obstructive sleep apnea, due to the risk of serious and life-threatening adverse reactions (see sections "Contraindications", "Special Warnings and Precautions for Use").

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", "Special Warnings and Precautions for Use").

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

Overdose.

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

Symptoms related to paracetamol use.

If a patient has taken a dose exceeding the recommended dose, immediate medical attention is required due to the risk of hepatotoxicity. Liver damage may occur in adults who have ingested 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight. Ingestion of 5 g or more of paracetamol may lead to hepatotoxicity in patients with risk factors (chronic use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs inducing liver enzymes; chronic excessive alcohol consumption; glutathione system deficiency, e.g. eating disorders, HIV infection, fasting, cystic fibrosis, cachexia).

Symptoms within the first 24 hours: pallor, nausea, vomiting, loss of appetite, and abdominal pain. Liver damage may become evident 12–48 hours after overdose. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and death. Acute renal failure with acute tubular necrosis may present as severe lumbar 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 high-dose paracetamol, blood dyscrasias such as aplastic anemia, pancytopenia, agranulocytosis, leukopenia (including neutropenia), and thrombocytopenia may develop. High doses may also cause central nervous system effects such as dizziness, psychomotor agitation, and disorientation. Renal toxicity (renal colic, interstitial nephritis, papillary necrosis) may occur in the urinary system.

Treatment: immediate medical assistance is required. The patient should be taken to hospital immediately, even if no early symptoms of overdose are present. Symptoms such as nausea and vomiting may be mild and not reflect the severity of overdose or risk of organ damage. Administration of activated charcoal should be considered within 1 hour of ingestion of an excessive paracetamol dose. 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 of paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours of ingestion. The efficacy of the antidote decreases sharply after this time. Intravenous N-acetylcysteine should be administered as needed, according to current guidelines. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Symptoms related to codeine use: central nervous system depression, including respiratory depression, particularly when used concomitantly with other sedative agents (e.g. alcohol) or in cases of overdose. Marked miosis, dry mouth, increased sweating, facial flushing, nausea, and vomiting are common. Arterial hypotension and tachycardia are possible but unlikely. High doses of codeine may cause sedation or emotional excitation; in children, seizures may occur.

Treatment: general symptomatic and supportive measures, including measures to support 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 and in children at doses exceeding 5 mg/kg body weight. 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 in cases where a prolonged-release naloxone formulation has been used.

Side effects.

When used correctly at recommended doses, adverse reactions occur very rarely and depend on the dose and duration of treatment.

The drug should be discontinued and immediate medical advice sought if any adverse reactions occur.

Associated with paracetamol:

Immune system disorders: anaphylaxis, hypersensitivity reactions including skin itching, rash on the skin and mucous membranes (usually generalized rash, erythematous, urticaria), angioedema, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome);

Gastrointestinal disorders: nausea, epigastric pain;

Hepatobiliary disorders: liver function abnormalities, increased liver enzyme activity, usually without development of jaundice;

Endocrine disorders: hypoglycemia, potentially leading to hypoglycemic coma;

Blood and lymphatic system disorders: thrombocytopenia, agranulocytosis, anemia (including hemolytic anemia), sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), bleeding, bruising;

Respiratory system disorders: bronchospasm in patients sensitive to acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs);

Urinary system disorders: aseptic pyuria.

Associated with codeine:

Immune system disorders: maculopapular rash considered as a symptom of hypersensitivity syndrome related to oral administration of codeine; fever, splenomegaly and 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;

Eye disorders: constricted pupils, blurred vision, photophobia, miosis, visual disturbances (including blurred or double vision);

Ear and labyrinth disorders: dizziness;

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

Respiratory disorders: dyspnea, respiratory depression (with large doses);

Gastrointestinal disorders: nausea, vomiting, constipation, dry mouth, stomach spasms, pancreatitis;

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, itching, increased sweating, facial swelling;

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

Urinary system disorders: urinary tract spasm, difficulty in urination, urinary retention, dysuria, antidiuretic effect;

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

General disorders: malaise, increased fatigue, hypothermia.

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

Long-term regular use of codeine is known to lead to dependence, tolerance, and symptoms of restlessness and irritability after discontinuation of treatment. It should be remembered that tolerance decreases rapidly after stopping codeine, so re-administration of a previously tolerated dose may be fatal.

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

Prolonged use of the drug for headache treatment may lead to worsening of headaches.

Shelf life. 3 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 status. Prescription only.

Manufacturer.

Limited liability company "INTERKHIM".

Manufacturer's address and location of business operations.

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