CONFIRMED BY
The Order of the Ukrainian Ministry of Public Health 

16.03.2016 р. № 195

The registration certificate

№ UA № UA/14971/01/01

 

 

 

INSTRUCTION
for medical use of the preparation

ANAPIRON

 

Composition:

Active substance: paracetamol;

100 ml of solution contains 1000 mg of paracetamol;

Auxiliary substances: mannitol (E 421); sodium hydrogen phosphate, dihydrate; water for injections.

Dosage form. Solution for infusion.

Main physical and chemical properties: transparent, colorless to pale-yellow solution.

Pharmacotherapeutical group.

Analgesics and antipyretics. ATC code: N02B E01.

Pharmacological properties.

Pharmacodynamics.

Paracetamol has analgesic and antipyretic effect. Paracetamol blocks cyclooxygenase (COX) I and II only in the central nervous system, affecting the centers 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 delay).

Pharmacokinetics.

Maximum plasma concentration is reached in 15 minutes; Maximum concentration - 15-30 mg/ml. The volume of distribution is 1 L/kg. Paracetamol is poorly bound to plasma proteins. It permeates the hematoencephalic barrier.

It is metabolized in the liver to form glucuronides and sulfates. A small portion (4%) metabolized by cytochrome P450 to form an intermediate metabolite (N-acetylbenzoquinoneimine), that, in normal conditions, is quickly neutralized by restored glutathione and excreted in the urine after connection with cysteine and mercaptopurine acid. However, the amount of this toxic metabolite increases when massive poisoning. The half-life in adults – 2.7 hours, in children – 1.5-2 hours, total clearance – 18 L/h. Paracetamol is excreted primarily in the urine; 90% of the dose excreted by the kidneys within 24 hours, mainly as glucuronide (60-80%) and sulphate (20-30%). Less than 5% is excreted in unchanged state. 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 sulfate in patients with severe renal failure is 3 times lower than in healthy volunteers.

In children, pharmacokinetics is not very different from the pharmacokinetics in adults, except for a shorter half-life (1.5-2 hours). Children under 10 years have significantly decreased conjugation with glucuronic acid and a little bit increased conjugation with sulfates in comparison with adults.

In children the pharmacokinetic parameters associated with age (standardized clearance),

*CL_std/F_oral (l.h^-1 70 kg^-1)

Age	Weight (kg)	CLstd/Foral (l.h-1 70 kg-1)
1 year 2 years 5 years 8 years	10 12 20 25	13,6 15,6 16,3 16,3

*CL_std – standardized clearance;

F_oral  ̶  bioavailability at oral intake.

 

Clinical characteristics.

Indication.

Adults: short-term treatment of medium intensity pain syndrome, especially in the postoperative period, or short-term treatment of fever, when it is necessary to introduce the preparation only intravenously.

Short-term treatment of hyperthermia reactions.

Children: symptomatic treatment of pain and postoperative hyperthermia in patients. 

Contraindication.

Hypersensitivity to paracetamol and other ingredients.

Severe hepatocellular insufficiency.

Interaction with other medical preparations and other forms of interaction.

Probenecid reduces the clearance of paracetamol in 2 times by blocking its connection with glucuronic acid, so paracetamol dose should be reduced at combination therapy with probenecid.

Salicylates can increase the half-life of paracetamol from the body.

Inductors of microsomal oxidation in the liver (phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants) can promote the development of severe intoxication even with a small overdose.

Oral anticoagulants. Concomitant use of paracetamol (4 g per day for 4 days) with oral coagulants may lead to small variations of international normalized ratio (INR). The monitoring of INR indicators for concomitant use of medicines, as well as for a week after paracetamol treatment is required.

 

Peculiarities of use.

To avoid the risk of overdose, do not use concomitantly with medicines containing acetaminophen.

Use caution in patients with:

• hepatocellular insufficiency;
• severe renal failure (creatinine clearance is less than 30 mL/min);
• chronic alcoholism;
• alimentary cachexia (decrease of glutathione in the liver reserve);
• dehydration.

During Anapiron treatment, the risk of liver damage increases in patients with alcoholic liver.

Use of Anapiron may adversely effect on the results of laboratory tests at the quantitative determination of content of glucose and uric acid in blood plasma.

During long-term treatment, the monitoring of peripheral blood and functional state of the liver are required.

Excipients. Anapiron contains less than 1 mmol (23 mg) / dose of sodium that is substantially free of sodium.

Use during pregnancy and lactation.

There are no data regarding the negative effect of paracetamol for intravenous use on the development of fetus or regarding fetotoxic effects, but before using the preparation you should carefully evaluate the benefit/risk. The close observation should be installed for a pregnant woman during the period of use.

Paracetamol permeates in small quantities into breast milk. During the treatment the breastfeeding should be discontinued.

Ability to influence on the rate of reaction when driving or operating other mechanisms. 

No effect.

Method of administration and dosage.

Anapiron is used 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 whose weight is 50 kg or more.

The maximum single dose makes 1g of paracetamol that is 1 container (100 ml). The maximum daily dose makes 4 g. For patients with additional risk factor of hepatoxicity the maximum daily dose makes 3 g. Interval between administrations of medicine should be no less than 4 hours. Usually 1 to 4 infusions are used during the first day of pain syndrome (postoperative), if necessary, treatment duration can be increased, but it should not exceed 72 hours (3 days) and the total number of 12 infusions.

Adults and children whose weight is 33 kg to 50 kg.

In 15 mg/kg of paracetamol on administration, that is 1.5 ml/kg. The maximum daily dose – 60 mg/kg of body weight, but no more than 3 g. The minimum interval between doses should be 4 hours. Usually treatment duration makes no more than 4 infusions a day.

Children whose weight is 10 kg to 33 kg.

In 15 mg/kg of paracetamol on administration, that is 1.5 ml/kg. The maximum daily dose – 60 mg/kg of body weight, but no more than 2 g. The minimum interval between doses should be 4 hours. Usually treatment duration makes no more than 4 infusions a day.

Using the preparation for children, before infusion the surplus of the preparation is selected from the container and the volume of solution is left corresponding to a single dose.

In adult patients with renal failure the interval between administrations of medicine should be 6 hours (creatinine clearance £ 30 ml/min). Treatment duration should not exceed 48 hours.

The maximum daily dose should not exceed 3 g for adult patients with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low supply of hepatic glutathione), and dehydration.

Children.

Do not use for children under 1 year and with body weight less than 10 kg.

Use for children from 1 year and with body weight more than 10 kg only for the symptomatic treatment of pain and postoperative hyperthermia.

Overdose.

The risk of toxic effect of the preparation is increased in elderly patients, children and patients with hepatic failure, in the case of chronic alcoholism, presence of alimentary dystrophy and in persons with reduced enzymatic activity. In these cases, overdose can be life-threating for the patients.

The symptoms as nausea, vomiting, anorexia, pallor and abdominal pain occur within the first 24 hours.

In adults the overdose may occur at a single intake in the dose of 7.5 g or more and in children  ̶  140 mg/kg of body weight. There are developments of cytolysis of liver, liver failure, metabolic acidosis, encephalopathy, which can 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.

Treatment: emergency hospitalization. Introduction of donators of SH-groups and precursors of glutathione-methionine synthesis in 8 – 9 hours after the overdose and N-acetylcysteine – in 12 hours. The necessity of conducting the additional therapeutic measures (further introduction of methionine and intravenous introduction of N-acetylcysteine) is established depending on the concentration of paracetamol in the blood, as well as the time elapsed after the intake.

Side effects.

Cardiovascular system: malaise, hypersensitivity reactions, tachycardia.

Liver/biliary system: increase of level of hepatic transaminases.

Blood system: thrombocytopenia, leucopenia, neutropenia.

General: pain and burning in the injection site, malaise, hypersensitivity reactions, rare cases – anaphylactic shock.

There were reported about rare cases of urticaria, or simple skin rash.

Shelf life. 2 years.

Storage conditions.

Keep out of the reach of children in the original package at temperature below 25 C. Unused medical preparation that remains must be eliminated.

Incompatibility.

Anapiron should not be mixed with other medicinal products.

Packaging.

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

Terms of dispensing. On prescription.

Manufacturer.

Eurolife Healthcare Pvt. Ltd.

Manufacturer’s registered address.

Hashra No 520, Bhagwanpur, Ruhr, Haridwar, India.

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, SW6 2PY, London, United Kingdom.

Date of last update.

16.03.2016 .