Solpadeine

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SOLPADEINE (SOLPADEINE)

Composition:

Active substances: 1 tablet contains 500 mg of paracetamol, 30 mg of caffeine, 8 mg of codeine phosphate hemihydrate;

Excipients: sodium hydrogencarbonate, sorbitol (E 420), sodium saccharin, sodium lauryl sulfate, anhydrous citric acid, anhydrous sodium carbonate, povidone, dimethicone.

Pharmaceutical form. Soluble tablets.

Main physicochemical properties: flat, white tablets with bevelled edges, smooth on one side, with a break line on the other side.

Pharmacotherapeutic group. Agents acting on the nervous system; analgesics; other analgesics and antipyretics; anilides; combinations with paracetamol. ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics.

Paracetamol exerts analgesic and antipyretic effects due to selective inhibition of prostaglandin synthesis in the central nervous system (CNS).

Caffeine enhances the analgesic effect of paracetamol.

Codeine is a centrally-acting opioid analgesic. After metabolism by the hepatic enzyme CYP2D6, it exerts analgesic and antitussive effects.

Pharmacokinetics.

Paracetamol is rapidly absorbed from the gastrointestinal tract (GI tract) and distributed into body tissues. Protein binding is minimal. It is metabolized in the liver and excreted by the kidneys predominantly as metabolites. The elimination half-life from plasma is approximately 2.3 hours.

Caffeine is rapidly absorbed from the gastrointestinal tract (GI tract) and distributed throughout the body. It is almost completely metabolized in the liver; metabolites are excreted by the kidneys. The elimination half-life from plasma is approximately 4.9 hours.

Maximum plasma concentration of codeine after oral administration is reached approximately within 1 hour and ranges from 100 to 300 ng/mL when administered at therapeutic doses. The elimination half-life from plasma is approximately 3–4 hours. Codeine is metabolized by the hepatic enzyme CYP2D6 to morphine and norcodeine, as well as other metabolites. Patients who are heterozygous for the CYP2D6*2A allele are classified as ultra-rapid metabolizers of codeine, in whom the rate of conversion of codeine to morphine is increased, potentially leading to opioid toxicity. Approximately 86% of an oral dose of codeine and its metabolites is excreted in urine within 24 hours.

The combination of active substances in the medicinal product does not affect the bioavailability of paracetamol.

Clinical characteristics.

Indications.

Headache, migraine, back pain, neuralgia, muscle pain, joint pain, musculoskeletal pain, dental pain, pain following tooth extraction and dental procedures, pain associated with sinusitis, sore throat, menstrual pain, pain associated with fever.

Contraindications.

Hypersensitivity to opioid analgesics and to any component of the drug. Ultra-rapid metabolizers via CYP2D6 enzyme have an increased risk of developing symptoms of opioid poisoning even when using the drug at normally recommended doses. Common symptoms of opioid poisoning include confusion, drowsiness, shallow breathing, pinpoint pupils, nausea, vomiting, constipation, and loss of appetite. In severe cases, symptoms of circulatory and respiratory insufficiency may develop, which can be life-threatening and in isolated cases lead to fatal outcomes.

Severe impairment of liver and/or kidney function, acute hepatitis, bronchial asthma, respiratory depression, head injury, increased intracranial pressure, postoperative period following biliary tract surgery, congenital hyperbilirubinemia, glucose-6-phosphate dehydrogenase deficiency, alcoholism, blood disorders, severe anemia, leukopenia, states of increased excitation; sleep disorders; severe arterial hypertension; organic cardiovascular diseases (including atherosclerosis); decompensated heart failure, conduction disorders, ischemic heart disease, glaucoma; epilepsy, hyperthyroidism, severe atherosclerosis, tendency to vascular spasm, thrombosis, thrombophlebitis; acute pancreatitis; prostate hyperplasia; diabetes mellitus. Contraindicated in patients taking tricyclic antidepressants or beta-blockers.

Concomitant use with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of MAOIs.

Elderly age.

Age under 18 years (due to the risk of opioid toxicity caused by variability and unpredictability of codeine metabolism into morphine).

Interaction with other medicinal products and other forms of interaction.

Caused by paracetamol content. The absorption rate of paracetamol may be increased when used concomitantly with metoclopramide and domperidone, and decreased when used with cholestyramine. Paracetamol increases plasma levels of acetylsalicylic acid and chloramphenicol. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol, increasing the risk of bleeding. Occasional use does not produce a significant effect. Barbiturates reduce the antipyretic effect of paracetamol. Anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol due to increased formation of hepatotoxic metabolites. Probenecid affects the excretion and plasma concentration of paracetamol. Paracetamol may reduce the bioavailability of lamotrigine, potentially decreasing its efficacy, possibly due to induction of its hepatic metabolism. Concurrent use of paracetamol and zidovudine increases the risk of neutropenia. Concomitant use of high-dose paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Paracetamol should be used with caution when administered concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions for use"). Paracetamol reduces the effectiveness of diuretics. Do not use concomitantly with alcohol.

Caused by codeine content. Codeine may inhibit the effect of metoclopramide and domperidone on gastrointestinal motility. Codeine enhances the effects of agents that depress the central nervous system (including alcohol, anesthetics, hypnotics, sedatives, tricyclic antidepressants, phenothiazine tranquilizers). Opioid analgesics may interact with MAO inhibitors, potentially causing serotonin syndrome.

Caused by caffeine content. Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents and potentiates the effects of xanthine derivatives and psychostimulants. Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; it acts as an antagonist to anesthetic agents and other drugs that depress the CNS, and as a competitive antagonist to adenosine and ATP preparations. When used concomitantly with ergotamine, caffeine improves ergotamine absorption in the gastrointestinal tract; when used with thyroid-stimulating agents, it enhances thyroid effects. Caffeine reduces lithium blood concentration (caffeine may accelerate lithium elimination from the body; concomitant use is not recommended).

Cimetidine, hormonal contraceptives, and isoniazid enhance the effect of caffeine.

Cases of serotonin syndrome (including altered mental status, autonomic dysfunction, and neuromuscular disturbances) have been reported with concomitant use of opioids, serotonergic agents (SSRIs, SNRIs), and MAOIs.

Special precautions for use.

Before using the medicine, consult a doctor. Do not exceed the recommended dose. In case of overdose, seek immediate medical attention.

The medicine contains paracetamol and codeine. Do not take other medicines containing paracetamol or codeine at the same time. Concurrent use with other paracetamol-containing medicines may lead to overdose. Paracetamol may be hepatotoxic at doses exceeding 6–8 g per day. Liver damage may occur even at significantly lower doses when combined with alcohol, hepatic enzyme inducers, or other hepatotoxic medicinal products. Paracetamol overdose may result in liver failure, which may necessitate liver transplantation or lead to death.

If symptoms persist or worsen, consult a doctor.

Patients with impaired liver or kidney function should consult a doctor before using the medicine. Liver disease increases the risk of liver injury from paracetamol. Note that patients with alcoholic liver disease have an increased risk of hepatotoxic effects of paracetamol.

Cases of liver function disorders / liver failure have been reported in debilitated patients with reduced glutathione levels, patients with anorexia, fasting patients, patients with low body mass index, chronic alcohol users, and patients with sepsis.

Do not use the medicine for longer than 3 days unless otherwise recommended by a doctor.

The medicine may interfere with blood glucose and uric acid level test results.

In patients with conditions such as sepsis, which are associated with reduced glutathione levels, the use of paracetamol may increase the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Seek immediate medical attention if these symptoms occur.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring of the patient. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Consider the overall risk-benefit balance before administering this medicine to patients with the following conditions:

• Impaired liver function (primary liver diseases increase the risk of paracetamol-associated liver injury);
• Impaired kidney function;
• Conditions associated with reduced glutathione levels (paracetamol use may increase the risk of metabolic acidosis).

Patients with obstructive gastrointestinal disorders or acute abdominal conditions should consult a doctor before using the medicine. Patients with a history of cholecystectomy should consult a doctor before use, as there is a risk of developing acute pancreatitis.

Codeine is metabolized in the liver to morphine by the CYP2D6 enzyme. If a patient has a deficiency or complete absence of this enzyme, adequate analgesic effect may not be achieved. However, if a patient is a rapid or ultrarapid metabolizer of codeine, there is an increased risk of opioid toxicity, even when the medicine is used at standard doses. In such patients, codeine is rapidly converted to morphine, leading to a sharp increase in serum morphine levels. Common symptoms of opioid poisoning include confusion, drowsiness, shallow breathing, pinpoint pupils, nausea, vomiting, constipation, and loss of appetite. In severe cases, circulatory and respiratory depression may develop, which can be life-threatening and in rare cases lead to death.

Prolonged or excessive use of codeine may lead to dependence. Exercise caution when prescribing the medicine to patients with conditions that may be worsened by opioid use, including depression and respiratory disorders.

During treatment with this medicine, avoid excessive consumption of beverages containing caffeine (e.g., coffee, tea), as this may intensify caffeine-related side effects such as dizziness, increased excitability, insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and tachycardia.

The medicine should be taken at the lowest effective dose and for the shortest duration necessary to relieve symptoms.

Each soluble tablet contains 427 mg of sodium, equivalent to 21.4% of the WHO recommended maximum daily sodium intake (2 g) for adults. This should be considered by patients on a sodium-controlled diet.

Each tablet contains 50 mg of sorbitol (E 420). Patients with rare hereditary fructose intolerance should not take this medicine.

If headache becomes persistent, consult a doctor. If symptoms do not resolve, worsen, or persist for more than 3 days, seek medical advice.

Inform your doctor before taking medicines containing codeine, as well as medications such as metoclopramide or domperidone, and medicines used for nausea and vomiting.

Inform your doctor before taking the medicine if you are using sedatives, hypnotics, tricyclic antidepressants, neuroleptics, or alcohol.

Cases of serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular disturbances) have been reported in patients taking opioids, particularly when used concomitantly with other serotonergic agents (including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants). If concomitant opioid therapy is clinically justified, appropriate medical monitoring of the patient is recommended.

Use during pregnancy or breastfeeding.

Do not use during pregnancy. This particularly applies to use by women during labor due to the potential risk of respiratory depression in the newborn.

The safety of this medicine during pregnancy with regard to its effects on fetal development has not been established, and its use should be avoided due to the potential increased risk of spontaneous abortion associated with caffeine intake.

Do not use the medicine during breastfeeding. In women who are ultrarapid metabolizers of codeine and who are breastfeeding, morphine levels in blood and breast milk may increase. The toxic effects of morphine may cause excessive drowsiness, arterial hypotension, breathing and feeding difficulties in infants. In severe cases, respiratory depression, including fatal outcomes, may occur.

Data on the effect of the medicine on fertility are lacking.

Ability to affect reaction speed when driving or operating machinery.

Due to the possibility of adverse reactions (such as drowsiness, dizziness, and excitation) during treatment, patients should refrain from driving vehicles or performing other tasks requiring concentration during therapy.

Dosage and Administration.

The medication is intended for oral use.

Adults: 1-2 tablets dissolved in half a glass of water every 4-6 hours as needed, but no more frequently than every 4 hours. Do not exceed 8 tablets per day. Do not use for longer than 3 days without consulting a physician. The minimum effective dose required to achieve the desired effect should be used.

Children

Do not administer this medication to children.

Overdose.

Prolonged use of high doses of the medication may lead to aplastic anemia, thrombocytopenia, pancytopenia, agranulocytosis, neutropenia, and leukopenia. High doses may also cause central nervous system (CNS) disturbances (dizziness, psychomotor agitation, disorientation, attention disturbances, insomnia, tremor, nervousness, restlessness), and urinary system toxicity – nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

In case of overdose, symptoms may include increased sweating, psychomotor stimulation or CNS depression, drowsiness, impaired consciousness, cardiac arrhythmias, tachycardia, extrasystoles, hyperreflexia, and seizures.

The consequences of codeine overdose may be part of the toxic effects of excessive paracetamol doses on the liver. In case of overdose, immediate medical attention is required, even if symptoms are not present.

Paracetamol overdose symptoms. Paracetamol overdose may lead to hepatic failure, which may necessitate liver transplantation or result in death. 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. Acute pancreatitis has been observed, typically in association with impaired liver function and signs of hepatotoxicity. In patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; chronic excessive alcohol consumption; glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia)), ingestion of 5 g or more of paracetamol may lead to liver damage.

Symptoms within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become evident 12–48 hours after overdose and peak at 4–6 days. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, cerebral edema, coma, and death. Acute renal failure with acute tubular necrosis may present as severe flank 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 the medication in high doses, hematological disorders may develop, including aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. High doses may also cause CNS disturbances such as dizziness, psychomotor agitation, and disorientation; and urinary system toxicity – nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

In case of overdose, prompt medical assistance is required. The patient should be immediately transported to a hospital, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose or risk of organ damage. Activated charcoal treatment should be considered if the excessive paracetamol dose was ingested within the past hour. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine can be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours after ingestion. The efficacy of the antidote decreases significantly after this time. If necessary, N-acetylcysteine should be administered intravenously according to established dosing recommendations. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside of hospital settings.

Codeine overdose symptoms. Codeine overdose in the initial phase is characterized by nausea and vomiting. Acute respiratory center depression may cause cyanosis, slowed breathing, drowsiness, ataxia, and less frequently, pulmonary edema. Respiratory arrest, dyspnea, arterial hypotension, tachycardia, miosis, seizures, collapse, and urinary retention may occur. Signs of histamine release may also be observed.

Treatment of codeine overdose includes general symptomatic and supportive measures, including ensuring access to fresh air. Gastric lavage and intestinal decontamination are indicated. Vital functions should be monitored. If more than 350 mg of codeine has been ingested by an adult or more than 5 mg/kg body weight by a child, administration of activated charcoal is advisable within the first hour. In cases of coma or respiratory depression, the specific antidote naloxone should be administered, and the patient should be observed for at least 4 hours after administration or for at least 8 hours until complete elimination of the drug. Naloxone is a competitive antagonist with a short half-life; therefore, in severe poisoning, large and repeated doses may be required. Severe depression of central nervous system function requires oxygen therapy and mechanical ventilation.

Caffeine overdose symptoms. Caffeine overdose may cause epigastric pain, vomiting, diuresis, rapid breathing, flushing, tachycardia or cardiac arrhythmia, gastrointestinal disturbances, and central nervous system stimulation (nervousness, insomnia, restlessness, excitement, anxiety, syndrome of increased neuromuscular excitability, tremor, seizures, extrasystoles, dizziness, irritability, affective state, incoherent thoughts and speech, psychomotor agitation, or periods of hyperactivity). Clinically significant symptoms of caffeine overdose may also be associated with liver damage caused by paracetamol.

Treatment of caffeine overdose: gastric lavage is required; diazepam should be administered in case of seizures. Symptomatic therapy and oxygen therapy are indicated. Administration of activated charcoal may be beneficial if given within one hour after overdose, but may be considered up to four hours after overdose. There is no specific antidote for caffeine overdose; however, beta-adrenergic receptor antagonists should be administered as a supportive measure to counteract cardiotoxic effects.

Sodium bicarbonate. High doses of sodium bicarbonate may provoke gastrointestinal symptoms such as belching and nausea. Additionally, high doses of sodium bicarbonate may cause hypernatremia; therefore, electrolyte balance should be monitored and appropriate corrective measures provided if necessary.

Adverse Reactions

Adverse reactions depend on the dose and individual patient metabolism.

Blood and lymphatic system disorders: thrombocytopenia, agranulocytosis, anemia, sulfhemoglobinemia and methemoglobinemia, cyanosis, dyspnea, hypoglycemic coma, hemolytic anemia, leukopenia, neutropenia, pancytopenia. Discontinue the drug and immediately inform a physician if unexplained bruising or bleeding occurs.

Immune system disorders: anaphylaxis, anaphylactic shock, erythema multiforme, toxic epidermal necrolysis (Lyell's syndrome), skin hypersensitivity reactions including rash, angioedema, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis.

Skin and subcutaneous tissue disorders: erythematous rash, urticaria, pruritus, diaphoresis, hemorrhages, oral mucosal ulcers, purpura.

Respiratory, thoracic and mediastinal disorders: bronchospasm in patients sensitive to aspirin and other NSAIDs.

Hepatobiliary disorders: liver function abnormalities (including increased liver enzyme activity, hepatonecrosis, liver failure, jaundice).

Central nervous system disorders: increased excitability, dizziness, tremor, paresthesia, restlessness, anxiety, worsening of headache with prolonged use, drowsiness, insomnia, irritability, tachycardia.

Psychiatric disorders: psychomotor agitation and disorientation, fear, confusion, euphoria, dysphoria, depression, hallucinations, sedative state with prolonged use of high doses, potential for dependence development.

Gastrointestinal disorders: gastrointestinal disturbances, abdominal discomfort and pain, heartburn, constipation, nausea, vomiting, dyspepsia, dry mouth, acute pancreatitis in patients with history of cholecystectomy.

Cardiac disorders: increased blood pressure, palpitations, chest pain, bradycardia, tachycardia, arrhythmia, arterial hypotension.

Renal and urinary disorders: urinary retention, renal colic.

Metabolism and nutrition disorders: metabolic acidosis with high anion gap (frequency unknown).

Other: general weakness, miosis, hypoglycemia.

Description of selected adverse reactions

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap as a result of pyroglutamic acidosis have been observed in patients with risk factors taking paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Concomitant use of the drug at recommended doses with products containing caffeine may lead to increased caffeine intake, which may enhance possible caffeine-related adverse effects such as insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and tachycardia.

Shelf life

4 years.

Storage conditions

Store out of reach of children at a temperature below 25°C.

Packaging

2 tablets in a strip, 6 strips in a cardboard box.

Prescription category

Prescription only.

Manufacturer

GlaxoSmithKline Dungarvan Limited, Ireland.

Manufacturer's address

Knockbrack, Dungarvan, Co. Waterford, Ireland.