Solpadeine

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

Composition:

Active substances: paracetamol, caffeine, codeine phosphate hemihydrate;

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

Excipients: maize starch, pregelatinized starch, potassium sorbate, povidone, talc, magnesium stearate, microcrystalline cellulose, stearic acid.

Pharmaceutical form. Tablets.

Main physicochemical properties: White, capsule-shaped tablets, 8.4 × 15.8 mm in size, embossed with "S" on one side, smooth on the other side.

Pharmacotherapeutic group. Analgesics and antipyretics. ATC code N02B E51.

Pharmacological Properties.

Pharmacodynamics.

Paracetamol exerts analgesic and antipyretic effects through selective inhibition of prostaglandin synthesis in the central nervous system (CNS). Therefore, paracetamol is suitable for patients in whom peripheral inhibition of prostaglandins is undesirable, for example, those with a history of gastrointestinal bleeding, or elderly patients. Caffeine enhances the analgesic efficacy of paracetamol. Codeine is a centrally-acting opioid analgesic. After metabolism by the hepatic enzyme CYP2D6, it exerts analgesic, antitussive, and decongestant 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, and 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 in about 1 hour and ranges from 100–300 ng/mL when administered in 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. Individuals 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; musculoskeletal pain; sciatica; dental pain; pain following tooth extraction and dental procedures; pain associated with sinusitis; sore throat; menstrual pain; pain associated with fever.

Contraindications.

Severe impairment of liver and/or kidney function, acute hepatitis, bronchial asthma, respiratory depression, head injury, increased intracranial pressure, postoperative period after biliary tract surgery, congenital hyperbilirubinemia, glucose-6-phosphate dehydrogenase deficiency, alcoholism, blood disorders, severe anemia, leukopenia, states of increased excitability, sleep disorders, severe arterial hypertension, organic cardiovascular diseases (including atherosclerosis), decompensated heart failure, conduction disorders of the heart, ischemic heart disease, glaucoma, epilepsy, hyperthyroidism, severe atherosclerosis, predisposition to vascular spasm, thrombosis, thrombophlebitis, acute pancreatitis; benign prostatic hyperplasia, diabetes mellitus, concomitant use with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of MAOIs, hypersensitivity to opioid analgesics or to any component of the drug.

Ultrarapid metabolism via CYP2D6 increases the risk of opioid toxicity even when the drug is used at normally recommended doses. Common 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 develop, which can be life-threatening and in rare cases lead to fatal outcomes.

Elderly age.

Contraindicated in patients taking tricyclic antidepressants or beta-blockers.

Interaction with other medicinal products and other forms of interaction.

Caused by the content of paracetamol. 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 elimination and plasma concentration of paracetamol. Paracetamol may reduce the bioavailability of lamotrigine, potentially reducing its efficacy due to possible induction of its hepatic metabolism. Concomitant use of paracetamol and zidovudine increases the risk of neutropenia. Concurrent use of high doses of 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"). Paracetamol reduces the effectiveness of diuretics. Do not use concomitantly with alcohol.

Caused by the content of codeine. Codeine may inhibit the effects 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 monoamine oxidase inhibitors (MAOIs), potentially causing serotonin syndrome.

Caused by the content of caffeine. 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 of anesthetic agents and other drugs that depress the CNS, and as a competitive antagonist of adenosine and ATP preparations. When used concomitantly with ergotamine, caffeine improves gastrointestinal absorption of ergotamine; when used with thyroid-stimulating agents, it enhances the thyroid effect. Caffeine reduces blood lithium concentration. Cimetidine, hormonal contraceptives, and isoniazid enhance the effect of caffeine.

Special precautions for use.

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

The drug contains paracetamol. Do not use other medications containing paracetamol or codeine simultaneously. Concurrent use with other paracetamol-containing drugs 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, enzyme inducers, or other hepatotoxic drugs. Paracetamol overdose may cause liver failure, potentially requiring liver transplantation or resulting in death.

If symptoms persist or worsen, consult a physician.

Patients with impaired liver or kidney function should consult a physician before using the medication. Liver disease increases the risk of hepatotoxicity from paracetamol. Particular caution is advised in patients with alcohol-induced liver damage, as this increases the risk of paracetamol-induced hepatotoxicity.

Cases of liver dysfunction/liver failure have been reported in patients with reduced glutathione levels, particularly in malnourished patients, those with anorexia, low body mass index, or chronic alcohol abuse.

Do not use the medication for longer than 3 days unless otherwise directed by a physician.

The drug may interfere with laboratory tests for blood glucose and uric acid levels.

In patients with conditions associated with reduced glutathione levels, such as sepsis, the risk of metabolic acidosis may increase during paracetamol use. 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 therapeutic doses of paracetamol over a prolonged period or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and close monitoring of the patient are recommended. 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.

Patients with obstructive gastrointestinal disorders or acute abdominal conditions should consult a physician before using the medication. Patients with a history of cholecystectomy should consult a physician prior to use due to the risk of acute pancreatitis.

Codeine is metabolized in the liver to morphine by the CYP2D6 enzyme. In individuals with deficiency or complete absence of this enzyme, adequate analgesic effect may not be achieved. Conversely, in patients who are "rapid" or "ultrarapid" metabolizers of codeine, there is an increased risk of opioid toxicity, even at standard therapeutic doses (see section "Contraindications").

Prolonged or excessive use of codeine may lead to dependence. Exercise caution when prescribing the drug to patients with conditions that may be exacerbated by opioids, such as depression or respiratory disorders.

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

Inform your physician about concomitant use of codeine-containing medications, as well as metoclopramide or domperidone, drugs used to treat nausea and vomiting.

Inform your physician before using the medication if you are taking sedatives, hypnotics, neuroleptics, or consuming alcohol.

The drug contains carmoisine (E 122), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

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

The safety of the drug in pregnant women with regard to 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 drug during breastfeeding. In women who are ultrarapid metabolizers of codeine, elevated levels of morphine may occur in blood and breast milk. Morphine toxicity may result in excessive drowsiness, hypotension, respiratory and feeding difficulties in infants. In severe cases, respiratory failure, including fatal outcomes, may occur.

There are no data on the effect of the drug on fertility.

Effect on ability to drive or operate machinery.

Given that adverse reactions (drowsiness, dizziness, excitation) may occur during treatment, patients should refrain from driving or operating machinery and avoid other activities requiring concentration during therapy.

Dosage and Administration.

The product is intended for oral use.

Adults (patients aged 18 years and older): 1–2 tablets 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 more than 3 days without consulting a physician. The lowest effective dose should be used to achieve the desired effect.

Children

Do not administer the product to children (under 18 years of age), as unpredictable codeine metabolism in children increases the risk of opioid toxicity.

Overdose.

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

In case of overdose, excessive sweating, psychomotor stimulation or CNS depression, drowsiness, disturbances of consciousness, cardiac arrhythmias, tachycardia, tremor, hyperreflexia, and seizures may occur.

Paracetamol overdose symptoms. Paracetamol overdose may lead to liver failure, which may require liver transplantation or result in death. Liver damage may occur in adults who ingest 8–15 g of paracetamol, depending on body weight, and in children who ingest more than 150 mg/kg body weight. 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 (due to malnutrition, cystic fibrosis, HIV infection, fasting, cachexia)), ingestion of 5 g or more of paracetamol may cause 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. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, liver failure may progress to encephalopathy, hemorrhage, hypoglycemia, 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.

Prolonged use of high doses may cause hematopoietic system disorders: aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. High doses may also cause CNS disturbances (dizziness, psychomotor excitation, disorientation) and urinary system disorders – nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

In case of overdose, immediate medical assistance is required. The patient should be taken to hospital immediately, 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. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). The use of activated charcoal to reduce paracetamol absorption in the gastrointestinal tract is controversial. The specific antidote, N-acetylcysteine, should be administered within 8–15 hours after paracetamol overdose, although a beneficial effect has been observed even with later administration. If necessary, N-acetylcysteine should be administered intravenously according to established dosing guidelines. In the absence of vomiting, methionine may be used orally as an alternative in remote areas outside hospitals.

Codeine overdose symptoms. Codeine overdose in the initial phase is characterized by nausea and vomiting. Acute respiratory center depression may lead to cyanosis, slow breathing, drowsiness, ataxia, and less frequently, pulmonary edema. Respiratory depression, 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 and monitoring vital functions. Gastric lavage and bowel cleansing are indicated. If more than 350 mg of codeine is ingested by adults or more than 5 mg/kg body weight by children, activated charcoal is recommended 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 naloxone administration or at least 8 hours until complete elimination of the drug. Severe depression of central nervous system function requires oxygen therapy and mechanical ventilation.

Overdose of codeine may result in complications that 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 of overdose are absent.

Caffeine overdose. Caffeine overdose may cause epigastric pain, vomiting, diuresis, rapid breathing, flushing, tachycardia or cardiac arrhythmia, gastrointestinal disturbances, and central nervous system stimulation (insomnia, restlessness, excitement, anxiety, hyperirritability syndrome, tremor, seizures, dizziness, irritability, emotional lability, disorganized thinking and speech, psychomotor agitation, or periods of hyperactivity). Clinically significant symptoms of caffeine overdose may also be associated with liver damage due to paracetamol.

Treatment of caffeine overdose: gastric lavage and oxygen therapy are required. There is no specific antidote for caffeine overdose; however, beta-adrenergic receptor antagonists may be used as supportive treatment to counteract cardiotoxic effects, and diazepam may be administered in case of seizures. Symptomatic therapy.

Adverse Reactions

Adverse reactions depend on the dose and individual patient metabolism.

The following rare adverse reactions (frequency of occurrence – <1/10,000) or adverse reactions with unknown frequency have been observed during post-marketing surveillance:

Disorders of the blood and lymphatic system: 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, hemorrhages, sweating, oral mucosal ulcers, purpura.

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

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

Central nervous system disorders: increased excitability, dizziness, tremor, paresthesia, restlessness, anxiety, headache exacerbation with prolonged use of the drug, somnolence, insomnia, irritability, tachycardia.

Psychiatric disorders: psychomotor agitation and disorientation, fear, confusion, euphoria, dysphoria, depression, hallucinations, sedative state; prolonged use at high doses may lead to dependence.

Gastrointestinal disorders: abdominal discomfort and pain, heartburn, constipation, nausea, vomiting, dyspepsia, dry mouth, acute pancreatitis in patients with a 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 (cannot be estimated from available data).

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 who used 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 caffeine-containing products may result in increased caffeine intake, which may enhance possible caffeine-related adverse effects such as insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and tachycardia.

Shelf life

5 years.

Storage conditions

Store at temperatures not exceeding 25°C, in a place inaccessible to children.

Packaging

12 tablets per blister pack, 1 blister pack per cardboard box.

Prescription status

Prescription only.

Manufacturer

GlaxoSmithKline Dungarvan Limited, Ireland.

Manufacturer's address and place of business

Knockbrack, Dungarvan, Co. Waterford, Ireland.