Composition:
active substance: paracetamol;
100 ml of solution contains 1000 mg of paracetamol;
excipients: mannitol (E 421); sodium hydrogen phosphate, dihydrate; water for injections.

Dosage form. Solution for infusion.
Basic physical and chemical properties: transparent, colourless to pale-yellow solution.

Pharmacotherapeutic group.
Analgesics and antipyretics. ATC code N02B E01.

Pharmacological properties.
Pharmacodynamics.
Paracetamol has analgesic and antipyretic effects. Paracetamol inhibits cyclooxygenase (COX) I and II only in the central nervous system by affecting the centres of pain and thermoregulation. In inflamed tissues the cellular peroxidase neutralizes the effect of paracetamol on COX that explains the almost complete absence of anti-inflammatory effect. The absence of effect on prostaglandin synthesis in peripheral tissues causes a lack of negative effect on the water-salt metabolism (sodium and water retention).
Pharmacokinetics.
The maximal plasma concentration is reached in 15 minutes. The maximal plasma concentration is 15-30 mg/ml. The volume of distribution is 1 L/kg. Paracetamol is not extensively bound to plasma proteins. It permeates the hematoencephalic barrier.
Paracetamol is metabolised mainly in the liver following two major hepatic pathways: glucuronic acid conjugation and sulphuric acid conjugation. A small fraction (4%) is metabolised by cytochrome P450 to a reactive intermediate (N-acetyl benzoquinone imine) which, under normal conditions of use, is rapidly detoxified by restored glutathione and eliminated in the urine after conjugation with cysteine and mercapturic acid. However, during massive overdosing, the quantity of this toxic metabolite is increased. In adults the half-life is 2.7 hours, in children – 1.5-2 hours, and total body clearance is 18 L/h. Paracetamol is mainly excreted in the urine; 90% of the dose administered is excreted within 24 hours, mainly, mainly as glucuronide (60-80%) and sulphate (20-30%) conjugates. Less than 5% is eliminated unchanged. In severe renal failure (creatinine clearance is less than 10-30 ml/min) the excretion of paracetamol slows down a little bit, and the half-life makes 2.5, 3 hours. The rate of excretion of glucuronide and sulphate conjugates in patients with severe renal failure is 3 times lower than in healthy volunteers.
The pharmacokinetic parameters of paracetamol observed in children are similar to those observed in adults, except for the plasma half-life that is slightly shorter (1.5 to 2 h) than in adults. Children under 10 years of age excrete significantly less glucuronide and more sulphate conjugates than adults.
Age related pharmacokinetic values (standardised clearance, *CLstd/Foral (l.h-1 70 kg-1)

*CL_std – standardised clearance;

F_oral  ̶  oral bioavailability.

Clinical characteristics.
Indication.
Adults: Short-term treatment of moderate pain, especially following surgery, and for the short-term treatment of fever, when administration by intravenous route is clinically justified by an urgent need.
Short-term treatment of hyperthermia reactions.
Children: symptomatic treatment of pain and hyperthermia in postoperative patients.

Contraindications.
Hypersensitivity to paracetamol and to any of the excipients of the medicinal product.
Severe hepatocellular insufficiency.

Interaction with other medicinal products and other forms of interaction.
Probenecid causes an almost 2-fold reduction in clearance of paracetamol by inhibiting its conjugation with glucuronic acid. A reduction in the paracetamol dose should be considered if it is to be used concomitantly with probenecid.
Salicylamide may prolong the elimination of paracetamol.
Inductors of microsomal oxidation in the liver (phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants) may promote the development of severe intoxication even with a small overdose.
Oral anticoagulants. Concomitant use of paracetamol (4 g per day for at least 4 days) with oral anticoagulants may lead to slight variations of INR values. In this case, increased monitoring of INR values should be conducted during the period of concomitant use as well as for 1 week after paracetamol treatment has been discontinued.  

Precaution for use.
In order to avoid the risk of overdose, do not use the product concurrently with medicinal products containing paracetamol.
Paracetamol should be used with caution in cases of:
hepatocellular insufficiency; severe renal insufficiency (creatinine clearance is less than 30 mL/min); chronic alcoholism; chronic malnutrition (low reserves of hepatic glutathione); dehydration.
In the course of Anapiron therapy the risk of liver damage is increased in patients with alcoholic hepatosis.
The use of Anapiron may negatively affect the laboratory test results on blood glucose and uric acid concentrations assay.
The monitoring of peripheral blood and functional liver parameters is required in case of long-term treatment.
Excipients. Anapiron contains less than 1 mmol (23 mg)/dose of sodium, i.e. practically free of sodium.
Pregnancy and lactation.
A large bulk of data on pregnant women indicates a lack of foetal malformations or feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children with prenatal paracetamol exposure have shown inconclusive results. When clinically necessary, paracetamol can be used during pregnancy but should be administered at the lowest effective dose for a short time and at the lowest possible frequency.
Paracetamol is excreted into breast milk in small quantities. Breastfeeding must be discontinued in case of paracetamol treatment.
Effects on ability to drive and use machines.
No effect.

Method of administration and dosage.
Anapiron is intended for the rapid elimination of pain and/or hyperthermal syndrome, when it is necessary to introduce the preparation only intravenously.
The duration of intravenous infusion should be 15 minutes.
Adults and children weighing 50 kg or more.
The maximum single dose is 1g of paracetamol that is 1 container (100 ml). The maximum daily dose is 4 g. For patients with additional risk factor of hepatoxicity the maximum daily dose is 3 g. The interval between administrations of the medicinal product must be no less than 4 hours. As a rule 1 to 4 infusions are used during the first day of pain syndrome onset (postoperative). If necessary, the treatment duration may be increased, but it must not exceed 72 hours (3 days) and the total number of 12 infusions.
Adults and children weighing 33 kg to 50 kg.
15 mg/kg of paracetamol for administration that is 1.5 ml/kg. The maximum daily dose is 60 mg/kg of body weight, but no more than 3 g. The minimum interval between doses must be 4 hours. As a rule the treatment duration is no more than 4 infusions a day.
Children weighing 10 kg to 33 kg.
15 mg/kg of paracetamol for administration that is 1.5 ml/kg. The maximum daily dose is 60 mg/kg of body weight, but no more than 2 g. The minimum interval between doses must be 4 hours. As a rule the treatment duration is no more than 4 infusions a day.
Before administering the product to children, remove the surplus of the preparation from the container to make the volume of solution correspond to a single dose.
In adults with renal failure the interval between administrations is 6 hours (creatinine clearance £ 30 ml/min). Treatment duration must not exceed 48 hours.
The maximum daily dose must not exceed 3 g for adults with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione) and dehydration.

Children.
Do not use the product for children under 1 year of age and those with body weight less than 10 kg.
It is recommended for children over 1 year of age and those with body weight more than 10 kg for the symptomatic treatment of pain and hyperthermia in postoperative patients.

Overdose.
The risk of toxic effect increases in elderly patients, children, patients with liver failure and in the case of chronic alcoholism, alimentary dystrophy and in persons with reduced enzymatic activity. Overdosing may be fatal in these cases.
Symptoms generally appear within the first 24 hours and comprise: nausea, vomiting, anorexia, pallor and abdominal pain.
Overdose, 7.5 g or more of paracetamol in a single administration in adults or 140 mg/kg of body weight in a single administration in children, causes hepatic cytolysis, hepatocellular insufficiency, metabolic acidosis and encephalopathy which may lead to coma and death.
During 12 – 48 hours, the levels of hepatic transaminases (AST, ALT), lactate dehydrogenase, and bilirubin are increased and the level of prothrombin is decreased. Clinical symptoms of liver damage occur after two days and reach the maximum after 4 ̶ 6 days.
Emergency measures: Immediate hospitalisation. The introduction of donators of SH-groups and precursors of glutathione-methionine synthesis in 8 – 9 hours and N-acetylcysteine – in 12 hours after overdose should be initiated. The necessity to take additional therapeutic measures (further methionine introduction and N-acetylcysteine intravenous introduction) is established depending on the concentration of paracetamol in blood and the time elapsed after the intake as well.

Adverse reactions.
Cardiovascular system disorders: malaise, hypersensitivity reactions, tachycardia.
Liver/biliary system disorders: increased hepatic transaminases.
Blood system disorders: thrombocytopenia, leukopenia, neutropenia.
General disorders: pain and burning in the injection site, malaise, hypersensitivity reactions, anaphylactic shock in rare cases.
Rare cases of urticaria or skin rash have been reported.

Shelf life.
3 years.

Storage conditions.
Store in the original packaging at a temperature not exceeding 25 C. Keep out of reach of children. Any unused medicinal product must be disposed.

Incompatibility.
Anapiron must not be mixed with other medicinal products.

Packaging. 100 ml of the preparation in a container, 1 container in a carton box.

Terms of dispensing. On prescription. 

Manufacturer.
Eurolife Healthcare Pvt. Ltd.

Manufacturer’s registered address. Khasra № 520, Bhagwanpur, Roorkee, Haridwar, India.

Applicant.  Ananta Medicare Ltd.

Applicant’s registered address. Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

Date of last update. 13.01.2020 р.