Solpalgine

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

Composition:

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

Excipients: maize starch, magnesium stearate, hypromellose;

Capsule shell composition: titanium dioxide (E 171), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules with white or almost white opaque body and cap, with hemispherical ends. The capsule contents – white or almost white powder.

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

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 produces analgesic and antitussive effects.

Pharmacokinetics.

Paracetamol is well 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 in 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 within approximately 1 hour and ranges between 100–300 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 codeine metabolism to morphine is increased, potentially leading to opioid toxicity. Approximately 86% of an oral dose of codeine and its metabolites are 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 and joint pain, musculoskeletal pain, sciatica; dental pain, post-extraction and post-dental procedure pain; pain associated with sinusitis, sore throat; menstrual pain; pain associated with fever.

Contraindications.

Hypersensitivity to opioid analgesics or to any component of the drug. Ultra-rapid metabolism via CYP2D6 increases the risk of opioid toxicity symptoms even when the drug is used at normally recommended doses.

Severe impairment of liver and/or kidney function, bronchial asthma, 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 excitability; sleep disorders, severe arterial hypertension, organic cardiovascular diseases (including atherosclerosis), decompensated heart failure, cardiac conduction disorders, ischemic heart disease, glaucoma, epilepsy, hyperthyroidism, severe atherosclerosis, predisposition to vascular spasm, thrombosis, thrombophlebitis; acute pancreatitis, prostatic hyperplasia. 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.

Interaction with other medicinal products and other forms of interactions.

Caused by the presence of paracetamol: the absorption rate of paracetamol may be increased when used concomitantly with metoclopramide and domperidone, and decreased when used with cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by long-term 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 conversion of the drug into hepatotoxic metabolites. Concomitant use of high-dose paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Paracetamol reduces the efficacy of diuretics. Do not use concomitantly with alcohol. Caution is advised when using paracetamol concomitantly with flucloxacillin, as such concomitant use has been associated with metabolic acidosis with a high anion gapas a result of pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions for use").

Caused by the presence of codeine: codeine may reduce the effect of metoclopramide and domperidone on gastrointestinal motility. Codeine enhances the effects of central nervous system depressants (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 presence of caffeine: caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents, potentiates the effects of xanthine derivatives and psychostimulants. Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; acts as an antagonist to anesthetic agents and other drugs that depress the CNS; is a competitive antagonist of adenosine and ATP preparations. When used concomitantly with ergotamine, caffeine improves gastrointestinal absorption of ergotamine; with thyrotropic agents – increases thyroid effect. Caffeine reduces blood lithium concentration.

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

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. Do not take other medicines containing paracetamol or codeine simultaneously. Concurrent use with other paracetamol-containing medicines may lead to overdose. Paracetamol overdose can cause liver failure, which may require liver transplantation or result in death.

If symptoms persist or worsen, consult a doctor.

The risk of overdose is higher in patients with non-cirrhotic alcoholic liver disease.

Patients with impaired liver or kidney function should consult a doctor before using this medicine. Liver disease increases the risk of liver damage caused by paracetamol. It should be noted that patients with alcoholic liver disease have an increased risk of hepatotoxic effects of paracetamol.

Cases of impaired liver function or liver failure have been observed in patients with reduced glutathione levels who were malnourished, suffering from anorexia, had low body mass index, or chronically consumed alcohol.

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 cases of malnutrition and other causes 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 and close monitoring are recommended. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Seek immediate medical attention if these symptoms occur.

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

The medicine may affect laboratory test results for blood uric acid levels.

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

Codeine is metabolized in the liver to morphine by the enzyme CYP2D6. If a patient has a deficiency or complete absence of this enzyme, adequate analgesic effect will not be achieved. However, if a patient is a "rapid" or "ultra-rapid" metabolizer of codeine, there is an increased risk of opioid toxicity, even when the medicine is used at standard doses. In these 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 occasionally fatal.

Prolonged or excessive use of codeine may lead to dependence. The medicine should be prescribed with caution in conditions that may be worsened by opioid use, such as depression or 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.

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

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

Inform your doctor before taking medicines containing codeine, as well as metoclopramide or domperidone, and other medicines used to treat nausea and vomiting.

Before taking this medicine, inform your doctor if you are taking sedatives, hypnotics, tricyclic antidepressants, neuroleptics, or alcohol.

Use during pregnancy or breastfeeding.

Do not use during pregnancy. This particularly applies to use by women during childbirth due to the possible occurrence 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 consumption.

Do not use the medicine during breastfeeding. In breastfeeding women who are ultra-rapid metabolizers of codeine, elevated levels of morphine may occur in blood and breast milk. Morphine toxicity may cause excessive drowsiness, hypotension, breathing difficulties, and feeding problems in infants. In severe cases, respiratory depression may develop, potentially leading to death.

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

Ability to affect reaction speed when driving or operating machinery.

Given that adverse reactions (such as drowsiness, dizziness, or excitation) may occur during treatment with this medicine, patients should refrain from driving or operating machinery or performing other tasks requiring concentration during treatment.

Dosage and Administration

The medicine is intended for oral use.

Adults: 1-2 capsules every 4-6 hours as needed, but no more frequently than every 4 hours. Do not exceed 8 capsules within 24 hours. Do not use for more than 3 days without consulting a physician.

Children

Do not administer this medicine to children.

Overdose

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

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

Overdose of codeine may contribute to the toxic effects of excessive paracetamol doses on the liver. In case of overdose, seek immediate medical attention even if symptoms are not present.

Paracetamol overdose symptoms: Paracetamol overdose can lead to liver failure, which may necessitate liver transplantation or result in death. Liver damage is possible in adults who have ingested 10 g or more of paracetamol, and in children who have ingested 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 (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. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, liver failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and death. Acute kidney failure with acute tubular necrosis may present as severe flank pain, hematuria, proteinuria, and may develop even without severe kidney damage. Cardiac arrhythmias and pancreatitis have also been reported.

Immediate medical assistance is required in case of overdose. The patient should be taken to hospital immediately, even if early symptoms 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 should be considered if an 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 48 hours. The efficacy of the antidote decreases sharply after this time. Intravenous N-acetylcysteine should be administered according to established dosing guidelines if needed. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Codeine overdose symptoms: Codeine overdose initially presents with nausea and vomiting. Acute respiratory center depression may cause cyanosis, slowed breathing, drowsiness, ataxia, and less commonly, pulmonary edema. Respiratory arrest, dyspnea, arterial hypotension, tachycardia, miosis, seizures, circulatory collapse, and urinary retention may occur. Signs of histamine release may also be observed.

Treatment for codeine overdose includes general symptomatic and supportive measures, including ensuring fresh air access. Gastric lavage and bowel cleansing are indicated. Vital functions should be monitored. Activated charcoal is recommended within the first hour after ingestion of more than 350 mg of codeine in adults or more than 5 mg/kg body weight in children. In cases of coma or respiratory depression, administer the specific antidote naloxone and observe the patient for at least 4 hours after administration, or at least 8 hours if prolonged-release naloxone is used. Severe CNS depression 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, anxiety, excitement, restlessness, anxiety, hyperreflexia syndrome, 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 for caffeine overdose: gastric lavage is required; diazepam should be administered in case of seizures. Symptomatic therapy and oxygen therapy are indicated. There is no specific antidote for caffeine overdose; however, as supportive measures, beta-adrenergic receptor antagonists should be prescribed to counteract cardiotoxic effects.

Adverse reactions.

Adverse reactions depend on the dose and individual metabolism of the patient.

Blood and lymphatic system disorders: agranulocytosis, anemia, sulfhemoglobinemia, and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruising or bleeding, leukopenia, neutropenia, pancytopenia.

Discontinue the drug and immediately inform a physician if unexplained bruising or bleeding occurs.

Immune system disorders: toxic epidermal necrolysis (Lyell’s syndrome), anaphylactic shock, skin and mucous membrane rashes (usually generalized, erythematous rash, urticaria), angioneurotic edema, multiform exudative erythema (including Stevens-Johnson syndrome).

Skin and subcutaneous tissue disorders: purpura, allergic dermatitis, pruritus, erythroderma, hemorrhages, oral mucosal ulcers, sweating.

Hepatobiliary disorders: liver function disturbances, increased liver enzyme activity, hepatonecrosis, liver failure, jaundice.

Central and peripheral nervous system disorders: paresthesia, restlessness, anxiety, insomnia, weakness, irritability, tachycardia, psychomotor agitation and disorientation, apprehension, nervous excitement, fear, sleep disturbances, confusion, euphoria, dysphoria, depression, hallucinations, anxiety, sedative effect.

Gastrointestinal disorders: abdominal discomfort and pain, heartburn, digestive disturbances.

Cardiovascular system disorders: increased blood pressure, palpitations, chest pain, bradycardia, arrhythmia, arterial hypotension.

Renal and urinary system disorders: urinary retention, renal colic.

Eye disorders: miosis.

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

Adverse effects according to clinical trial data are infrequent and occur in a small number of patients. Information based on post-marketing experience at therapeutic doses is provided below by system organ classes; adverse effects were assessed according to spontaneous reports and are considered very rare.

Paracetamol

*Cases of metabolic acidosis with a high anion gap resulting from pyroglutamic acidosis have been observed in patients with risk factors who were administered paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur as a result of low glutathione levels in these patients.

Caffeine

When using paracetamol-caffeine-codeine in combination with caffeine consumption, an increased concentration of caffeine and enhanced side effects are possible, such as insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and rapid heartbeat.

Codeine

Adverse reactions identified from post-marketing experience are listed below. The frequency of these reactions is unknown.

Shelf life. 2 years.

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

Packaging. 10 capsules per blister, 1 blister per carton.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's location and address of its business activities.

Ukraine, 61002, Kharkiv region, city of Kharkiv, street Kulikivska, 41.