INSTRUCTION

for medical use of the medicinal product

 

ANAPIRON

 

Composition:

active substance: paracetamol;

100 ml of solution contains 1000 mg of paracetamol;

excipients: mannitol (E 421); sodium hydrogen phosphate, dihydrate; water for injection.

 

Dosage form. Solution for infusion.

Basic physical and chemical properties: a clear, colourless to pale-yellow solution.

 

Pharmacotherapeutic group.

Analgesics and antipyretics. ATC code N02B E01.

 

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The precise mechanism of the analgesic and antipyretic properties of paracetamol has yet to be established; it may involve central and peripheral actions.

Pharmacodynamic effects

Anapiron provides onset of pain relief within 5 to 10 minutes after the start of administration. The peak analgesic effect is obtained in 1 hour and the duration of this effect is usually 4 to 6 hours.

Anapiron reduces fever within 30 minutes after the start of administration with a duration of the antipyretic effect of at least 6 hours.

Pharmacokinetics.

Adults

Absorption

Paracetamol pharmacokinetics is linear up to 2 g after single administration and after repeated administration during 24 hours.

The bioavailability of paracetamol following infusion of 500 mg and 1 g of paracetamol is similar to that observed following infusion of 1 g and 2 g propacetamol (corresponding to 500 mg and 1 g paracetamol respectively). The maximal plasma concentration (C_max) of paracetamol observed at the end of 15-minutes intravenous infusion of 500 mg and 1 g of paracetamol is about 15 mcg/mL and 30 mcg/mL respectively.

Distribution

The volume of distribution of paracetamol is approximately 1 L/kg. Paracetamol is not extensively bound to plasma proteins. Following infusion of 1 g paracetamol, significant concentrations of paracetamol (about 1.5 mcg/mL) were observed in the cerebrospinal fluid in 20 minutes following infusion.

Metabolism

Paracetamol is metabolised mainly in the liver following two major hepatic pathways: glucuronic acid conjugation and sulphuric acid conjugation. The latter route is rapidly saturable at doses that exceed the therapeutic doses. A small fraction (less than 4%) is metabolised by cytochrome P450 to a reactive intermediate (N-acetyl benzoquinone imine) which, under normal conditions of use, is rapidly detoxified by reduced 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.

Elimination

The metabolites of paracetamol are mainly excreted in the urine. 90% of the dose administered is excreted in 24 hours, mainly as glucuronide (60-80%) and sulphate (20-30%) conjugates. Less than 5% is eliminated unchanged. Plasma half-life is 2.7 hours and total body clearance is 18 L/h.

Neonates, infants and children

The pharmacokinetic parameters of paracetamol observed in infants and 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. In neonates, the plasma half-life is longer than in infants i.e. around 3.5 hours. Neonates, infants and children up to 10 years excrete significantly less glucuronide and more sulphate conjugates than adults.

Age related pharmacokinetic values (standardized clearance, *CL_std/F_oral (l.h^-1 70 kg^-1) are presented below.

Age	Weight (kg)	CLstd/Foral (l.h-1 70 kg-1)
40 weeks PCA 3 months PNA 6 months PNA 1 year PNA 2 years PNA 5 years PNA 8 years PNA	3.3 6 7.5 10 12 20 25	5.9 8.8 11.1 13.6 15.6 16.3 16.3

*CL_std – is the population estimate for CL.

Special populations

Renal impairment

In cases of severe renal impairment (creatinine clearance 10-30 mL/min), the elimination of paracetamol is slightly delayed, the elimination half-life ranging from 2 to 5.3 hours. For the glucuronide and sulphate conjugates, the elimination rate is 3 times slower in subjects with severe renal impairment than in healthy subjects. Therefore, it is recommended, when giving paracetamol to patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), to increase the minimum interval between each administration to 6 hours

Elderly

The pharmacokinetics and the metabolism of paracetamol are not modified in elderly subjects. No dose adjustment is required in this population.

 

Clinical particulars.

Indications.

Anapiron is indicated for the 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 to treat pain or hyperthermia and/or when other routes of administration are not possible.

 

Contraindications.

Hypersensitivity to paracetamol or to any of the excipients or to propacetamol hydrochloride (prodrug of paracetamol). In cases of severe hepatocellular insufficiency.

 

Special precautions.

Caution should be taken when prescribing and using Anapiron to avoid dosing errors due to confusion between milligram (mg) and milliliter (mL), which could result in accidental overdose and death. When prescribing, it is necessary to indicate the total dose in milligrams and the volume of the total dose in milliliters.

In order to avoid the risk of overdose, check that other medicines administered do not contain paracetamol.

 

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 of the paracetamol dose should be considered for concomitant treatment with probenecid.

Salicylamide may prolong the elimination t1/2 of paracetamol.

Inducers of microsomal oxidation in the liver (phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants) can cause 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.

Caution should be exercised when paracetamol is co-administered with flucloxacillin, as co-administration has been associated with metabolic acidosis with an increased anion gap, particularly in patients with risk factors (see section “Precautions for use”).

 

Precautions for use.

Take care to avoid dosing errors due to confusion between milligram (mg) and milliliter (mL), which could result in accidental overdose and death. It is recommended to use a suitable analgesic oral treatment as soon as this administration route is possible.

In order to avoid the risk of overdose, check that other medicines administered do not contain either paracetamol or propacetamol.

Doses higher than the recommended entails risk for very serious liver damage. Clinical symptoms and signs of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) are usually first seen after two days of drug administration with a peak seen usually after 4 - 6 days. Treatment with antidote should be given as soon as possible (see section “Overdose”).

Paracetamol can cause serious skin reactions. Patients should be informed about the signs of serious skin reactions and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Caution is advised when paracetamol is co-administered with flucloxacillin due to the high risk of metabolic acidosis with a high anion gap, particularly in patients with severe renal insufficiency, sepsis, malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism), as well as those taking maximum daily doses of paracetamol. Careful monitoring, including measurement of urinary 5-oxoproline, is recommended.

Paracetamol should be used with caution in cases of:

hepatocellular insufficiency, Gilbert's syndrome; severe renal impairment (creatinine clearance is less than 30 mL/min); chronic alcoholism; chronic malnutrition (low reserves of hepatic glutathione); dehydration; glucose-6-phosphatase dehydrogenase deficiency (can lead to hemolytic anaemia).

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.

Pregnancy

Clinical experience of intravenous administration of paracetamol is limited. A large amount of data for oral use in on pregnant women indicates neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Breast feeding

After oral administration, paracetamol is excreted into breast milk in small quantities. No undesirable effects on nursing infants have been reported. Consequently, paracetamol may be used in breast-feeding women.

 

Effects on ability to drive and use machines.

Does not affect.

 

Method of administration and dosage.

Intravenous use.

Dosing based on patient weight (please see the dosing table here below).

 

Patient weight	Dose per administration	Volume per administration	Maximum volume of Anapiron (10 mg/mL) per administration based on upper weight limits of group (mL)*	Maximum daily dose**
>10 kg to ≤33 kg	15 mg/kg	1.5 mL/kg	49.5 mL	60 mg/kg not exceeding 2 g
>33 kg to ≤50 kg	15 mg/kg	1.5 mL/kg	75 mL	60 mg/kg not exceeding 3 g
>50 kg with additional risk factors for hepatotoxicity	1 g	100 mL	100 mL	3 g
> 50 kg and no additional risk factors for hepatotoxicity	1 g	100 mL	100 mL	4 g

* Patients weighing less will require smaller volumes.

The minimum interval between each administration must be at least 4 hours. No more than 4 doses to be given in 24 hours.

The minimum interval between each administration in patients with severe renal impairment must be at least 6 hours.

** Maximum daily dose: The maximum daily dose as presented in the table above is for patients that are not receiving other paracetamol containing products and should be adjusted accordingly taking such products into account.

Patients with severe renal failure

When prescribing paracetamol to patients with severe renal insufficiency (creatinine clearance ≤30 ml/min), it is recommended to increase the minimum interval between doses to 6 hours.

Patients with hepatocellular insufficiency, chronic alcoholism, patients with chronic malnutrition (low liver glutathione stores), patients with dehydration, Gilbert's syndrome, with a body weight of less than 50 kg

The maximum daily dose should not exceed 3 g (see section "Precautions of use").

Elderly

No dose adjustment is usually required in elderly.

To avoid dosing errors due to confusion between milligram (mg) and milliliter (mL), it is necessary to carefully adjust the doses when prescribing and administering Anapiron. Such confusion can result in accidental overdose and even death. When prescribing Anapiron, the total dose in milligram (mg) and the volume of the total dose in milliliter (ml) should be specified.

The paracetamol solution is administered as a 15-minute intravenous infusion.

 

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.

There is a risk of liver injury (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis), particularly in elderly subjects, in young children, in patients with liver disease, in cases of chronic alcoholism, in patients with chronic malnutrition and in patients receiving enzyme inducers. Overdosing may be fatal in these cases.

Symptoms generally appear within the first 24 hours and comprise: nausea, vomiting, anorexia, pallor, abdominal pain.

Overdose, 7.5 g or more of paracetamol in a single administration in adults and 140 mg/kg of body weight in a single administration in children, causes hepatic cytolysis likely to induce complete and irreversible necrosis, resulting in hepatocellular insufficiency, metabolic acidosis and encephalopathy which may lead to coma and death. Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed together with decreased prothrombin levels that may appear 12 to 48 hours after administration. Clinical symptoms of liver damage are usually evident initially after two days and reach a maximum after 4 to 6 days.

Emergency measures:

• - immediate hospitalisation;
• - before beginning treatment, take a tube of blood for plasma paracetamol assay, as soon as possible after the overdose;
• - the treatment includes administration of the antidote, N-acetylcysteine (NAC), by the intravenous or oral route, if possible before the 10th hour. NAC can, however, give some degree protection even after 10 hours, but in these cases prolonged treatment is given;
• - symptomatic treatment.

Hepatic tests must be carried out at the beginning of treatment and repeated every 24 hours. In most cases hepatic transaminases return to normal in one to two weeks with full restitution of liver function. In very severe cases, however, liver transplantation may be necessary.

 

Adverse reactions.

As all paracetamol products, adverse drug reactions, presented below, are divided into common (≥ 1/100 − < 1/10), uncommon (> 1/10000 − < 1/1000), rare (< 1/10000) not known (cannot be estimated from available data):

 

Organ system	Common	Uncommon	Rare	Not known
Immune system disorders			hypersensitivity reactions *, anaphylactic shock*
Cardiovascular disorders		arterial hypotension		tachycardia
Hepatobiliary system disorders		increased levels of hepatic transaminases
Blood and lymphatic system disorders			thrombocytopenia, leukopenia, neutropenia
Skin and subcutaneous tissue disorders			rash *, urticaria*, serious skin reactions***
General disorders and administration site conditions	injection site reactions (pain and burning sensation)	malaise		erythema, hot flashes, itching
Metabolism disorders			metabolic acidosis with a large anion gap (HAGMA) **

* Very rare cases of hypersensitivity reactions ranging from simple skin rash or urticaria to anaphylactic shock have been reported and require discontinuation of treatment.

** In the post-registration period, with the concomitant use of paracetamol with flucloxacillin, usually in the presence of risk factors.

*** Very rare cases of serious skin reactions requiring discontinuation of treatment have been reported.

 

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national pharmacovigilance system.

 

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 vial. 1 vial in a carton.

 

Terms of dispensing.

On prescription.

 

 

Date of last update.

11.03.2024