Dolmorix

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

Composition:

Active substance: paracetamol;

One tablet contains 500 mg or 1000 mg of paracetamol;

Excipients: pregelatinized starch, povidone K30 (E 1201), stearic acid (E 570), crospovidone (E 1202), sodium starch glycolate (Type A).

Pharmaceutical form. Tablets.

Main physicochemical properties:

500 mg: white, biconvex, round-shaped tablets with "PA" embossing on one side. Tablet dimensions: 11.0 ± 0.5 mm in diameter.

1000 mg: white, biconvex, oval-shaped tablets with a break line on one side and "PC" embossing on the other side. Tablet dimensions: 21.0 ± 0.5 mm in length.

Pharmacotherapeutic group.

Analgesics and antipyretics. Anilides. Paracetamol. ATC code N02BE01.

Pharmacological properties.

Pharmacodynamics.

Paracetamol is a non-narcotic analgesic. It non-selectively inhibits cyclooxygenase (COX), affecting pain and thermoregulation centers. In inflamed tissues, cellular peroxidases neutralize the effect of paracetamol on COX, which explains its minimal anti-inflammatory effect. There is no effect on prostaglandin synthesis in peripheral tissues, which accounts for the absence of negative impact of paracetamol on water-electrolyte balance (sodium and water retention) and gastrointestinal mucosa. The possibility of methemoglobin and sulfhemoglobin formation is unlikely.

Pharmacokinetics.

Absorption is high, reaching almost 100%. In systemic circulation, 15% of the absorbed drug binds to plasma proteins. Time to reach maximum plasma concentration (T_max) is 20–30 minutes. Therapeutically effective plasma concentrations of paracetamol are achieved at doses of 10–15 mg/kg. Paracetamol penetrates the blood-brain barrier and is excreted into breast milk. The amount of the drug in breast milk is less than 1% of the dose administered to the nursing mother. Metabolism occurs in the liver: 80% undergoes conjugation with glucuronic acid and sulfates, forming inactive metabolites. About 17% of the drug undergoes hydroxylation, producing active metabolites that conjugate with glutathione to form inactive metabolites. In glutathione deficiency, these metabolites may block enzymatic systems of hepatocytes, leading to hepatic necrosis. The elimination half-life (T_1/2) of paracetamol is 2–3 hours. In elderly patients, drug clearance is reduced and T_1/2 is prolonged. Renal excretion occurs, with 3% excreted unchanged.

Clinical characteristics.

Indications.

Short-term treatment of headache, toothache, muscle pain, menstrual pain, moderate pain associated with osteoarthritis, and symptoms of fever and pain due to colds and influenza.

Contraindications.

Hypersensitivity to the components of the drug, severe impairment of liver and/or kidney function, congenital hyperbilirubinemia, glucose-6-phosphate dehydrogenase deficiency, alcoholism, blood disorders, Gilbert's syndrome, severe anemia, leukopenia.

500 mg tablets – children under 10 years of age.

1000 mg tablets – childhood.

Interaction with other medicinal products and other forms of interaction.

The absorption rate of paracetamol may be increased when used with metoclopramide and domperidone, and decreased when used with cholestyramine. Paracetamol should be administered 1 hour before or 4–6 hours after cholestyramine intake.

Since paracetamol is metabolized in the liver, hepatotoxic metabolites may be formed, which can interact with medicinal products that use the same metabolic pathways, for example:

• Oral anticoagulants (acenocoumarol, warfarin): prolonged use of paracetamol at doses exceeding 2 g per day in combination with these agents may enhance the anticoagulant effect, possibly due to reduced hepatic synthesis of clotting factors. Given the lack of clinical significance at doses below 2 g per day, paracetamol should be considered an alternative to salicylates in patients receiving anticoagulant therapy. Occasional use does not have a significant effect.
• Ethanol: increased toxicity of paracetamol due to possible induction of hepatic metabolites formed after biotransformation of paracetamol.
• Loop diuretics: diuretic effect may be reduced, as paracetamol may decrease renal excretion of prostaglandins and plasma renin activity.
• Lamotrigine: reduced area under the concentration–time curve (AUC) (20%) and T1/2 (15%) of lamotrigine, with possible attenuation of its effect due to possible induction of its hepatic metabolism.
• Propranolol: propranolol inhibits the enzyme system responsible for glucuronidation and oxidation of paracetamol. Thus, it may potentiate the effect of paracetamol.
• Rifampicin: increased paracetamol clearance due to possible induction of its hepatic metabolism.
• Ion-exchange resins (cholestyramine): reduced absorption of paracetamol, possibly leading to diminished effect due to intestinal retention of paracetamol.

Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsants (including phenytoin, barbiturates, carbamazepine), which stimulate the activity of hepatic microsomal enzymes, may enhance the hepatotoxic effect of paracetamol due to increased conversion of the drug into hepatotoxic metabolites. Concurrent use of paracetamol with hepatotoxic agents increases the risk of hepatotoxicity. Concurrent use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome.

Probenecid reduces paracetamol clearance by half by blocking its conjugation with glucuronic acid; therefore, when used concomitantly with probenecid, the dose of paracetamol should be reduced.

Paracetamol should be used with caution with chloramphenicol due to prolonged elimination half-life and increased toxicity of the latter.

Paracetamol reduces the effectiveness of diuretics.

Do not use concurrently with alcohol.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as co-administration has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

Special precautions for use.

Paracetamol should be administered with caution, avoiding prolonged treatment in patients with anemia, heart or lung disease, or renal dysfunction (long-term use of high doses of paracetamol may increase the risk of renal adverse effects). Caution is recommended when administering the drug to patients with bronchial asthma who are sensitive to acetylsalicylic acid, as bronchospastic reactions have been reported, including cross-reactivity to paracetamol in these patients, which in some cases may lead to serious reactions, particularly with high-dose administration.

Do not exceed the recommended doses. Do not take this medicinal product with other medicines containing paracetamol, as this may result in overdose. Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic) acidosis have been reported in patients with severe underlying conditions such as severe renal insufficiency 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 over a prolonged period or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring. 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.

Paracetamol overdose may cause liver failure, which may necessitate liver transplantation or lead to fatal outcomes. It should be noted that patients with alcoholic non-cirrhotic liver disease have an increased risk of hepatotoxic effects from paracetamol.

Cases of liver dysfunction or liver failure have been reported in patients with reduced glutathione levels, such as those with severe cachexia, anorexia, low body mass index, chronic alcoholism, or sepsis. Hepatotoxicity has been reported with daily doses below 4 g.

Consult a physician regarding the possibility of using the medicinal product:

• in patients with impaired renal or hepatic function;
• in patients taking warfarin or similar anticoagulant agents;
• in patients using analgesics for mild forms of arthritis;

− if headache becomes persistent.

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

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

Alcoholic beverages must not be consumed during treatment with paracetamol.

Caution is recommended when paracetamol is used concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis, particularly in patients with severe renal insufficiency, sepsis, malnutrition, and other sources of glutathione deficiency (e.g., chronic alcoholism), as well as in those receiving maximum daily doses of paracetamol. Careful monitoring, including measurement of urinary 5-oxoproline, is recommended. If pain persists for more than 5 days or fever lasts more than 3 days or worsens, the patient's treatment should be re-evaluated.

Use during pregnancy or breastfeeding.

Pregnancy. The drug should be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus or child.

As with other medicinal products, consultation with a physician is recommended before using paracetamol during pregnancy. A large amount of data in pregnant women does not indicate any malformative or fetal/neonatal toxicity. Epidemiological studies on neurodevelopmental outcomes in children exposed to paracetamol in utero have not provided conclusive results. Paracetamol may be used during pregnancy if clinically necessary, but it should be used at the lowest effective dose, for the shortest possible duration, and with the least possible frequency.

Breastfeeding period. Paracetamol passes into breast milk, but in clinically insignificant amounts. The elimination half-life into breast milk is 1.35–3.5 hours. Available published data do not contain contraindications to breastfeeding.

Effect on ability to drive or operate machinery.

No effect.

Dosage and Administration

The medicinal product is intended for oral administration.

500 mg tablets:

Adults and children aged 15 years and older: 1–2 tablets 4 times daily. Do not exceed 4000 mg within 24 hours.

Children: It is recommended to follow the dosage based on the child's body weight. The single dose is 15 mg/kg every 6 hours or 10 mg/kg every 4 hours.

• Children with body weight from 33 to 40 kg (aged 10 to 12 years): 1 tablet every 6 hours, but not more than 4 tablets per day.
• Children with body weight from 41 to 50 kg (aged 12 to 15 years): 1 tablet every 4 hours, but not more than 6 tablets per day.

The maximum daily dose of paracetamol is 60 mg/kg/day, divided into 4–6 doses.

1000 mg tablets:

Adults: Take 1 tablet every 6–8 hours. Do not exceed 4000 mg within 24 hours.

Do not exceed the recommended dose.

Do not take together with other medicinal products containing paracetamol.

Patients with renal impairment

In renal insufficiency, the dose should be adjusted according to the glomerular filtration rate:

Patients with hepatic impairment

In patients with hepatic impairment, a maximum dose of 2 g within 24 hours should not be exceeded, with a minimum interval of 8 hours between doses (see section "Special precautions").

Elderly patients

Due to the prolonged elimination half-life of paracetamol in elderly patients, a dose reduction of 25% is recommended for this population.

Children

500 mg tablets are indicated for children aged 10 years and older.

1000 mg tablets are not indicated for use in children.

Overdose

Paracetamol overdose may cause liver failure, which may necessitate liver transplantation or result in death. Clinical signs of liver damage following paracetamol overdose typically appear within 24–48 hours after ingestion and peak at 4–6 days.

The risk of paracetamol poisoning is increased, particularly in elderly patients, children, patients with liver disease, chronic alcoholism, and chronic malnutrition.

Liver damage may occur in adults who ingest 10 g or more of paracetamol and in children who ingest more than 150 mg/kg body weight. In patients with risk factors (chronic use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs inducing hepatic enzymes; alcohol abuse; glutathione deficiency, e.g., due to malnutrition, 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, loss of appetite, and abdominal pain; however, overdose may also be asymptomatic. Acute overdose of paracetamol in adults and children may cause reversible or irreversible hepatocellular necrosis, leading to disturbances in glucose metabolism, metabolic acidosis, hepatocellular failure, encephalopathy, hemorrhage, hypoglycemia, coma, and potentially death. Within 12–48 hours after ingestion, elevated levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, bilirubin, and prolonged prothrombin time may occur. Acute renal failure with acute tubular necrosis may present with 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 high doses, hematological disorders such as aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, 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, capillary necrosis) may occur in the urinary system.

Treatment

In case of overdose, prompt medical intervention is required. The patient should be immediately transported to a hospital, even if no early symptoms of overdose are present, as liver damage may not develop immediately. Symptoms such as nausea and vomiting may be the only early signs and may not reflect the severity of overdose or risk of organ damage. Administration of activated charcoal should be considered if the excessive dose was ingested within the past hour. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier measurements 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 declines sharply after this time. If required, intravenous N-acetylcysteine should be administered according to current guidelines. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Symptomatic treatment should also be provided.

Adverse Reactions

If any adverse reactions occur, discontinue use of the medicinal product immediately and seek medical advice without delay.

All adverse reactions are listed by system organ classes and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data). Adverse reactions reported with paracetamol are very rare (< 1/10,000):

Respiratory system:
Bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.

Gastrointestinal system:
Nausea, epigastric pain.

Hepatobiliary system:
Hepatotoxicity, liver function abnormalities, increased liver enzyme activity, usually without development of jaundice.

Endocrine system:
Hypoglycemia, up to hypoglycemic coma. Frequency not known – metabolic acidosis with high anion gap.

Cardiovascular system:
Arterial hypotension.

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

Immune system:
Anaphylaxis, hypersensitivity reactions including skin pruritus, skin and mucous membrane rashes (usually generalized rash, erythematous rash, urticaria), angioneurotic edema, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).
General disorders: Malaise.

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 were treated with paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.
No special storage conditions required. Keep out of reach and sight of children.

Packaging.
10 tablets in a blister; 1 blister per cardboard box.

Availability.
Over-the-counter (without prescription).

Manufacturer.
SAG MANUFACTURING, S.L.U.

Manufacturer's address and place of business.
Carretera Nacional 1 Km 36, San Agustín del Guadalix, 28750 Madrid, Spain.