Parafast

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT P ARAFAST (PARAFAST)

Composition:

Active substance: paracetamol;

1 soft capsule contains 500 mg of paracetamol;

Excipients: macrogol 400 (polyethylene glycol 400); propylene glycol; colloidal anhydrous silicon dioxide; purified water;

Capsule shell: gelatin 180 Bloom; partially dehydrated sorbitol solution (Polysorb® 85/70/00); titanium dioxide; purified water.

Pharmaceutical form. Soft capsules.

Main physicochemical characteristics: opaque white, oval-shaped soft gelatin capsule containing a suspension ranging from almost white to beige-pinkish color.

Pharmacotherapeutic group. Analgesics and antipyretics. Anilides. Paracetamol.

ATC code N02B E01.

Pharmacological properties.

Pharmacodynamics.

ParaFast capsules contain paracetamol – an analgesic and antipyretic (pain-relieving and fever-reducing agent). The effect is based on inhibition of prostaglandin synthesis in the central nervous system.

Pharmacokinetics.

Paracetamol is rapidly and almost completely absorbed in the gastrointestinal tract and distributed into most body tissues. Plasma protein binding of paracetamol is minimal when administered at therapeutic doses.

Paracetamol is primarily metabolized in the liver and excreted in the urine as metabolites. The mean elimination half-life of paracetamol in plasma after oral administration is approximately 2.3 hours.

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, marked anemia, leukopenia. Age under 10 years.

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.

The anticoagulant effect of warfarin and other coumarins, with an increased risk of bleeding, may be enhanced during prolonged concomitant use of paracetamol. Occasional use does not have 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. Concurrent use of paracetamol with hepatotoxic agents increases the hepatotoxic effects of the drugs. Probenecid reduces paracetamol clearance by half by blocking its conjugation with glucuronic acid; therefore, in combined therapy with probenecid, the dose of paracetamol should be reduced.

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

Concomitant use of high doses of paracetamol with isoniazid increases the risk of developing hepatotoxic syndrome.

Paracetamol reduces the effectiveness of diuretics. Do not use concurrently with alcohol.

When paracetamol is used concomitantly with flucloxacillin, caution is required, as concomitant 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").

Special precautions for use

Do not exceed the recommended doses. The medicine contains paracetamol; therefore, it should not be used together with other medicinal products containing paracetamol, such as those used for fever reduction, pain relief, flu and cold symptoms, or insomnia. Concurrent use with other paracetamol-containing medicines may result in overdose. Paracetamol overdose can cause liver failure, which may require liver transplantation or lead to death.

Patients with liver or kidney disease should consult a physician before using this medicine.

It should be noted that patients with non-cirrhotic alcoholic liver disease have an increased risk of hepatotoxic effects of paracetamol.

Cases of impaired liver function/liver failure have been reported in patients with reduced glutathione levels, for example, in cases of severe malnutrition, anorexia, low body mass index, chronic alcoholism, or sepsis.

Consult a physician regarding the possibility of using the medicine:

• in patients with impaired kidney or liver function;
• in patients taking warfarin or similar anticoagulant medicines;
• in patients using analgesics for mild forms of arthritis;
• if headaches become persistent.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic acid) accumulation have been reported in patients with severe underlying conditions, such as severe renal impairment, sepsis, malnutrition, or other sources of glutathione deficiency (e.g., chronic alcoholism), who received prolonged treatment with paracetamol at therapeutic doses 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 urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

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. Immediate medical attention should be sought if these symptoms occur.

If symptoms persist, consult a physician. Prolonged use without medical supervision may be dangerous.

The medicine should be used only when clearly necessary.

Keep the medicine out of sight and reach of children.

Use during pregnancy or breastfeeding

As with other medicinal products, consult a physician before using paracetamol during pregnancy. Extensive data from pregnant women do not indicate any malformative or fetal/neonatal toxicity. Epidemiological studies on nervous system development in children exposed to paracetamol in utero have not provided conclusive evidence. Paracetamol may be used during pregnancy if clinically necessary, but should be administered at the lowest effective dose, for the shortest duration, and with the lowest possible frequency.

Paracetamol is excreted in breast milk, but in clinically insignificant amounts when used at recommended doses. Available published data do not contraindicate the use of the medicine during breastfeeding.

Effect on ability to drive or operate machinery

No effect.

Method of Administration and Dosage

The product is intended for oral administration.

Do not exceed the recommended dose. The lowest effective dose required to achieve the therapeutic goal should be used.

Adults and children aged 16 years and older: 2 capsules, to be taken every 4–6 hours as needed. Do not take more than 4 doses (8 capsules) within 24 hours.

Children aged 10 to 15 years: 1 capsule, to be taken every 4–6 hours as needed. Do not take more than 4 doses (4 capsules) within 24 hours.

The dose should not be taken more frequently than every 4 hours. Do not use the product for more than 3 days unless directed by a physician.

Children.

Not recommended for children under 10 years of age unless prescribed by a physician.

Overdose.

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

There is an increased risk of paracetamol poisoning, particularly in elderly patients, children, patients with liver disease, chronic alcoholism, or chronic malnutrition.

Symptoms of overdose within the first 24 hours: pallor, nausea, vomiting, loss of appetite, and abdominal pain; however, overdose may also be asymptomatic.

Acute paracetamol overdose in adults or children after a single ingestion may cause reversible or irreversible hepatocellular necrosis, leading to disturbances in glucose metabolism, metabolic acidosis, hepatocellular insufficiency, encephalopathy, hemorrhage, hypoglycemia, coma, and potentially death. Elevated levels of liver transaminases (AST, ALT), lactate dehydrogenase, bilirubin, and prolonged prothrombin time may be observed 12–48 hours after paracetamol ingestion. Liver damage is likely in adults who have ingested more than the recommended amount of paracetamol. It is believed that an increased amount of a paracetamol metabolite (normally detoxified by glutathione when standard doses are used) binds irreversibly to liver tissue.

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 acute pancreatitis have also been reported, usually accompanied by liver function abnormalities and hepatotoxicity.

With prolonged use of the drug in high doses, hematological side effects may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. High doses may affect the central nervous system, causing dizziness, psychomotor agitation, and disorientation. Effects on the urinary system may include nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).

Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage.

Risk factors for paracetamol overdose include:

• Long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, and other drugs that induce hepatic enzyme synthesis;
• Chronic alcohol abuse;
• Reduced glutathione levels, e.g., due to malnutrition, fasting, cachexia, cystic fibrosis, or HIV.

In case of overdose, prompt medical attention is required. Treatment for overdose, or even suspected overdose, must be initiated immediately by transporting the patient to a hospital, even if early symptoms are absent, as liver damage may not develop immediately. Plasma paracetamol concentration should be measured at least 4 hours or later after ingestion (earlier measurements are unreliable).

Treatment with activated charcoal should be considered if a paracetamol dose exceeding 150 mg/kg has been ingested within 1 hour. Treatment with N-acetylcysteine or methionine should also be considered. Symptomatic treatment is also necessary.

Adverse reactions.

The frequency of adverse reactions is defined according to the following criteria: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), not known (cannot be estimated from the available data). Information on the adverse reactions listed below was obtained from post-marketing surveillance.

Blood and lymphatic system disorders: very rare – thrombocytopenia, agranulocytosis.

Immune system disorders: very rare – anaphylaxis, skin hypersensitivity reactions including skin rash, angioedema.

Skin and subcutaneous tissue disorders: very rare – Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, fixed drug eruption.

Respiratory, thoracic and mediastinal disorders: very rare – bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.

Hepatobiliary disorders: very rare – liver function abnormalities.

Also, following administration of medicinal products containing paracetamol, the following adverse reactions may occur: pruritus, erythema multiforme, nausea, epigastric pain, hypoglycemia up to hypoglycemic coma, agranulocytosis, anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruising or bleeding, increased liver enzyme activity, usually without development of jaundice.

Metabolism and nutrition disorders: not known – metabolic acidosis with high anion gap.

Description of selected adverse reactions

Metabolic acidosis with high anion gap

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

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging. 10 capsules in a blister; 1 or 2 blisters in a cardboard box.

Prescription status. Over-the-counter.

Manufacturer. Oliv Healthcare.

Manufacturer's address and place of business.

Unit-II, Plot No. 163/2, Mahatma Gandhi Udhyog Nagar, Dabhel Village, Nani Daman, Daman - 396 210, India.