Paracetamol Fresenius Infusion solution 1g / 100ml 10 vials х 100 ml

composition

active ingredients

Paracetamol

excipients

Mannitolum, Antiox.: Cysteinum, Nitrogenium qs, Aqua ad iniectabile qs

dosage form and amount of active ingredient per unit

Infusion solution with 10 mg/ml paracetamol.

One 100 ml vial or 100 ml bag contains 1 g paracetamol.

Indications/Application possibilities

For the short-term treatment of mild to moderate pain when oral administration is not possible (e.g. immediately post-operatively, where non-steroidal anti-inflammatory drugs are often contraindicated).

For the short-term treatment of fever.

Dosage/Application

The use of the preparation Paracetamol Fresenius 1 g is restricted to patients who weigh more than 33 kg.

To avoid the risk of overdose, make sure that other medicines you are taking (prescription and non-prescription) do not contain paracetamol.

Application

Paracetamol Fresenius 1 g is a ready-to-use solution. It is administered as a 15-minute IV infusion. The efficacy and safety of a slower or faster administration have not been studied. For patients weighing less than 50 kg, the volume of the infusion solution is 1.5 ml/kg per administration.

As with all infusion solutions in glass vials, it should be remembered that the infusion must be closely monitored, regardless of the infusion route, particularly towards the end of the infusion. Monitoring at the end of the infusion is particularly important with central venous infusion to avoid air embolism.

dosage

The dosage is based on the patient’s weight.

patients >50 kg

1 g paracetamol per administration, up to 4 times daily. The minimum time interval between two administrations must be 4 hours and the maximum daily dose must not exceed 4 g.

Adults and children weighing more than 33 kg and less than 50 kg

15 mg paracetamol per kg body weight per administration, up to 4 times daily. The minimum time interval between two administrations must be 4 hours and the maximum daily dose must not exceed 60 mg/kg.

Special patient groups

In cases of severe renal insufficiency (creatinine clearance 10–30 ml/min), the minimum time interval between two administrations should be extended to 6 hours (see “Kinetics in special patient groups”).

In patients weighing more than 33 kg and with chronic or compensated active liver disease, particularly with mild to moderate hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione) or dehydration, as well as in adult cachectic patients, the dose must be reduced or the dosing interval prolonged and the daily dose of 2 g paracetamol must not be exceeded (see “Kinetics in special patient groups”).

Maximum therapy duration

Duration of treatment in adults and children: max. 2 days.

contraindications

Hypersensitivity reactions to paracetamol, propacetamol (prodrug of paracetamol) or to any of the excipients listed in the list of ingredients (see “Composition”).

Glucose-6-phosphate dehydrogenase deficiency (can lead to hemolytic anemia).

Hereditary constitutional hyperbilirubinemia (Meulengracht disease).

Severe hepatocellular insufficiency or decompensated, active liver disease.

Very severe renal impairment (creatinine clearance <10 ml/min).

Warnings and Precautions

Paracetamol should be used with caution in:

• hepatocellular insufficiency,
• severe renal insufficiency (creatinine clearance ≤30 ml/min; see “Pharmacokinetics”),
• Caution is advised when paracetamol is administered with flucloxacillin as there is an increased risk of increased anion gap metabolic acidosis (HAGMA). Patients at increased risk of increased anion gap metabolic acidosis include those with severe renal impairment, sepsis or malnutrition, particularly when maximum daily doses of paracetamol are used.
  Close monitoring is recommended following concomitant administration of paracetamol and flucloxacillin to detect the occurrence of acid-base imbalances, particularly increased anion gap metabolic acidosis. A urine test for 5-oxoproline should also be performed.
  If flucloxacillin is continued after paracetamol is discontinued, it is advisable to ensure that there are no signs of increased anion gap metabolic acidosis, as there is a possibility that flucloxacillin may maintain the clinical picture of increased anion gap metabolic acidosis (see section 'Interactions').
• chronic alcoholism,
• concomitant administration of potentially hepatotoxic drugs, liver enzyme inducers or excessive alcohol consumption; in these cases the benefit/risk ratio must be carefully reviewed, taking into account therapeutic alternatives,
• Anorexia, bulimia or cachexia; chronic malnutrition (low reserves of hepatic glutathione) (see «Dosage/Administration»),
• Dehydration, hypovolemia.

In patients with depleted glutathione status, such as in sepsis, the use of paracetamol may increase the risk of metabolic acidosis.

Caution is advised when consuming excessive amounts of alcohol. Alcohol can increase the hepatotoxicity of paracetamol, particularly when fasting. In such cases, even a therapeutic dose of paracetamol can cause liver damage.

Doses higher than recommended carry the risk of very serious liver damage. Clinical signs of liver damage can usually be seen within 1 to 2 days after a paracetamol overdose and usually reach their maximum after 3 to 4 days. Treatment with an antidote should be started as soon as possible.

Paracetamol can cause severe skin reactions such as acute generalized pustular exanthema (AGEP), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed of the symptoms of severe skin reactions and the use of the drug should be discontinued at the first appearance of skin reactions or other signs of hypersensitivity.

interactions

The simultaneous use of Paracetamol Fresenius 1 g with other medicines may increase the likelihood of undesirable effects.

Phenytoin: Co-medication with phenytoin can lead to a reduced effectiveness of paracetamol and an increased risk of hepatotoxicity due to the increase in toxic paracetamol metabolites. Patients on phenytoin therapy should therefore avoid the use of high and/or chronic doses of paracetamol. Patients should be monitored for signs of hepatotoxicity.

The dose-dependent potential hepatotoxicity of paracetamol may be increased by concomitant administration of inducers of the cytochrome P450 system (such as isoniazid, rifampicin, anticonvulsants, barbiturates, zidovudine, anticoagulants, amoxicillin/clavulanic acid and alcohol).

Hepatotoxicity may also be increased by salicylamide because it prolongs the elimination half-life of paracetamol.

Chlorzoxazone: When paracetamol and chlorzoxazone are administered simultaneously, the hepatotoxicity of both substances increases.

Paracetamol prolongs the elimination half-life of chloramphenicol by 5-fold.

The simultaneous use of zidovudine and paracetamol increases the tendency to neutropenia.

Probenecid inhibits the conjugation of paracetamol with glucuronic acid and thus reduces the clearance of paracetamol by about half. If probenecid is administered at the same time, the dose of paracetamol should therefore be reduced.

Anticoagulants: The simultaneous use of paracetamol with coumarins can lead to an increase in the INR value. More intensive monitoring of the INR value should therefore be carried out during simultaneous use and for one week after discontinuation of paracetamol treatment. There are no data available on the interaction of paracetamol with the newer oral anticoagulants (dabigatran, rivaroxaban, apixaban).

Flucloxacillin: Caution is advised when paracetamol is administered concomitantly with flucloxacillin as there is an increased risk of increased anion gap metabolic acidosis (HAGMA), particularly in patients with risk factors for glutathione deficiency such as severe renal impairment, sepsis, malnutrition and chronic alcoholism. Close monitoring, including urinary 5-oxoproline testing, is recommended to detect the occurrence of acid-base disturbances, namely HAGMA.

pregnancy/breastfeeding

pregnancy

Epidemiological studies on the neurodevelopment of children exposed to paracetamol in utero have not produced any clear results. The risk of functional and organ damage, malformations and adaptation disorders when paracetamol is used during pregnancy in the correct dosage is currently considered to be low. There are no controlled studies in pregnant women. Animal studies have shown no reproductive toxicity (see "Preclinical data").

Paracetamol can be used during pregnancy if clinically needed, but it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

breastfeeding

Paracetamol passes into breast milk. The concentration in breast milk is similar to the current concentration in the mother's plasma. Skin rashes have been reported in breastfed infants. However, no permanent adverse effects on the infant are known. Although the use of paracetamol is considered compatible with breastfeeding, caution should be exercised when using Paracetamol Fresenius 1 g during breastfeeding.

fertility

Clinical data on fertility are not available. Animal studies with paracetamol have shown an effect on fertility (see “Preclinical data”).

Effects on ability to drive and operate machinery

No relevant studies have been conducted.

Undesirable effects

Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000).

diseases of the blood and lymphatic system

Rare: allergic thrombocytopenia, hemolysis, leukopenia, pancytopenia, neutropenia, agranulocytosis.

diseases of the immune system

Very rare: allergic reactions such as Quincke's edema, breathing difficulties, bronchospasm, sweating, nausea, drop in blood pressure up to anaphylactic shock.

A small proportion (5-10%) of patients with acetylsalicylic acid-induced asthma or other manifestations of so-called acetylsalicylic acid intolerance may react in a similar manner to paracetamol (analgesic asthma).

vascular diseases

Rare: hypotension.

liver and gallbladder diseases

See “Warnings and precautions” and “Overdose”.

Rare: increased liver transaminase levels.

In case of overdose, hepatic necrosis may occur.

diseases of the skin and subcutaneous tissue

Occasionally: skin rashes (redness or urticaria).

Rare: exfoliation, toxic epidermal necrolysis (TEN, Lyell syndrome), Stevens-Johnson syndrome (SJS).

Diseases of the kidneys and urinary tract

In case of overdose, nephrotoxicity may occur.

General disorders and administration site conditions

Rare: malaise.

post-marketing experience

The following adverse reactions were also reported during the post-marketing surveillance period (frequency not known):

diseases of the blood and lymphatic system

Hemolytic anemia (especially in patients with G-6-PD deficiency).

heart disease

tachycardia.

diseases of the gastrointestinal tract

Vomiting, pancreatitis.

liver and gallbladder diseases

Cholestasis, jaundice, fulminant hepatitis, liver necrosis, liver failure, increased liver enzymes.

diseases of the skin and subcutaneous tissue

Itching, flushing, acute generalized pustular exanthema (AGEP).

General disorders and administration site conditions

Reaction at the injection site (erythema, itching).

Reporting suspected side effects after authorisation is very important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are requested to report any suspected new or serious side effects via the ElViS (Electronic Vigilance System) online portal. Information on this can be found at www.swissmedic.ch.

overdose

There is a particular risk of poisoning in the elderly, in small children, in patients with liver disease, in chronic alcoholism, in chronically malnourished patients and in patients receiving enzyme inducers. In these cases, poisoning can be fatal.

An overdose, 7.5 g paracetamol or more in a single dose in adults or 140 mg/kg body weight in a single dose in children, causes cytolytic hepatitis, which can induce complete and irreversible hepatic necrosis. This can lead to acute or fulminant liver failure, liver insufficiency, metabolic acidosis and encephalopathy, which can result in coma and death. At the same time, increased plasma levels of liver transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed 12-48 hours after administration, together with a decreased prothrombin level. Clinical symptoms of liver damage usually first appear after 2 days and reach their peak after 3-4 days.

There are no specific early symptoms during the first 24 hours. Anorexia, nausea, vomiting and malaise, pallor and abdominal pain may occur and persist. Hepatic damage may occur 24 hours to 5 days after administration.

The occurrence of a massive overdose, the main risk of paracetamol (especially with tablets), seems unlikely with Paracetamol Fresenius 1 g (iv administration in hospital).

emergency measures

Regardless of the suspected amount of paracetamol administered, N-acetylcysteine ​​(NAC) must be administered intravenously or orally as quickly as possible (preferably within 10 hours of the overdose). NAC can still provide some protection after 10 hours, but in these cases longer treatment is required. The paracetamol concentration in the plasma must be determined as quickly as possible (at least 3 hours after the overdose). However, the result does not have to be available before treatment with NAC is started.

Plasma concentrations of >200 µg/ml after 4 hours, >100 µg/ml after 8 hours, >50 µg/ml after 12 hours and >30 µg/ml after 15 hours can cause liver damage and even hepatic coma with a fatal outcome. Hepatotoxicity is directly dependent on the plasma concentration.

Liver tests should be performed from the beginning and repeated every 24 hours. An increase in liver enzymes (ALT and AST) is usually observed, which returns to normal after one to two weeks. Additional symptomatic treatment (after N-acetylcysteine ​​iv or orally) should be determined based on paracetamol blood levels and the time since the paracetamol overdose.

properties/effects

ATC code

N02BE01

Mechanism of action

Paracetamol Fresenius 1 g with the active ingredient paracetamol is an analgesic and antipyretic that does not contain salicylic acid or opioids. The analgesic effect of paracetamol is more dependent on the inhibition of prostaglandin synthesis at the central level than at the peripheral level. The antipyretic effect is based on the inhibition of the effect of endogenous pyrogens on the hypothalamic temperature regulation center. Paracetamol does not have a pronounced anti-inflammatory effect and has no effect on hemostasis or the gastric mucosa.

pharmacodynamics

With an iv infusion of paracetamol over 15 minutes, the maximum analgesic effect is achieved in 1 hour; the analgesic effect generally lasts 4 to 6 hours.

With an iv infusion of paracetamol over 15 minutes, fever reduction begins within 30 minutes of the start of administration and the antipyretic effect lasts for at least 6 hours.

Clinical efficacy

Not specified.

pharmacokinetics

absorption

The pharmacokinetics of paracetamol in adults are linear up to a dose of 2 g, administered as a single dose and after repeated administration over 24 hours.

The maximum plasma concentration (C max ) at the end of a 15-minute intravenous infusion of 500 mg paracetamol is approximately 15 µg/ml and after infusion of 1 g paracetamol approximately 30 µg/ml.

distribution

The distribution volume of paracetamol in adults is approximately 1 l/kg. Plasma protein binding is less than 20%, but up to 50% in the event of an overdose.

metabolism

Paracetamol is metabolized in the liver in adults via two main pathways: glucuronidation (60–80%) and sulfoconjugation (20–40%). The latter pathway can be saturated very quickly at doses above the therapeutic range. A small portion (less than 4%) is metabolized by cytochrome P450 to a reactive intermediate (N-acetylbenzoquinone imine), which, under normal use, is rapidly detoxified by reduced glutathione and excreted in the urine after conjugation with cysteine ​​and acetylcysteine ​​(mercapturic acid). However, the amount of toxic metabolites is increased after massive overdose.

elimination

Excretion occurs mainly via the kidneys. 90% of the administered dose is excreted in the urine within 24 hours, as glucuronides (60–80%), as sulfoconjugates (20–30%) and less than 5% in unchanged form.

The plasma half-life is on average 2.7 hours and the total body clearance is approximately 18 l/h.

Paracetamol does not pass into the bile. It crosses the placenta and passes into breast milk.

The distribution of paracetamol into the cerebrospinal fluid was studied after a short infusion (1 g paracetamol) in 43 patients hospitalized for lumbosacral nerve root compression pain. Significant paracetamol concentrations (approximately 1.5 µg/ml) were detected in the cerebrospinal fluid 20 minutes after the infusion. The maximum paracetamol concentrations in the cerebrospinal fluid were measured between the 2nd and 4th hours and were greater than the plasma concentrations between the 4th and 12th hours.

kinetics of special patient groups

renal insufficiency

In the case of severe renal insufficiency (creatinine clearance 10-30 ml/min), paracetamol elimination is slightly slowed, the elimination half-life is between 2 and 5.3 hours. The elimination rate of glucuronides and sulphoconjugates is 3 times slower in patients with severe renal insufficiency than in healthy subjects. However, no dose adjustment is necessary in this population, as these glucuronides and sulphoconjugates are not toxic. However, it is recommended that the minimum interval between individual applications be extended to 6 hours when paracetamol is used in patients with severe renal insufficiency (creatinine clearance ≤30 ml/min) (see “Dosage/Administration”). If creatinine clearance is less than 10 ml/min, paracetamol should not be administered intravenously, as no data are available. The use of paracetamol intravenously in patients on dialysis has not been studied and is not recommended.

liver failure

The plasma half-life is largely unchanged in patients with mild hepatic insufficiency. However, it is considerably prolonged in patients with severe hepatic insufficiency.

In clinical studies with oral paracetamol, moderately impaired paracetamol metabolism was demonstrated in patients with chronic liver disease, including patients with alcohol-induced liver cirrhosis, based on increased paracetamol plasma concentrations and prolonged elimination half-life. However, no significant paracetamol accumulation was observed. The increased paracetamol plasma half-life was associated with reduced synthetic capacity of the liver. For this reason, paracetamol should be used with caution in patients with liver disease and the maximum daily dose should be reduced or the dosing interval should be prolonged (see “Dosage/Administration”). Paracetamol is contraindicated in the presence of decompensated active liver disease, particularly hepatitis caused by excessive alcohol consumption (due to CYP2E1 induction, which leads to increased formation of hepatotoxic metabolites of paracetamol).

Older patients

The pharmacokinetics and metabolism of paracetamol are unchanged in elderly patients. Therefore, no dose adjustment is necessary in this population.

Newborns, infants and children

The observed pharmacokinetic parameters of paracetamol in infants and children are similar to those in adults, with the exception of the plasma half-life, which is slightly shorter (1.5 to 2 hours). In newborns, the plasma half-life is longer than in infants, i.e. approximately 3.5 hours. Newborns, infants and children up to 10 years of age eliminate significantly less glucuronides and more sulfoconjugates than adults. The total excretion of paracetamol and its metabolites is independent of age.

Preclinical data

toxicity

Very high acute doses of paracetamol are hepatotoxic.

mutagenicity/carcinogenicity

A genotoxic potential has been identified in various studies. However, this must be viewed in perspective, as it is dose-dependent. Based on the presumed mechanisms that trigger these effects, it can be assumed that no genotoxic effects occur at doses below certain limits, although lower thresholds are possible if the glutathione reserve is reduced.

However, the threshold values ​​at which a genotoxic effect could be demonstrated in animal experiments are clearly in the toxic dose range, which causes liver and bone marrow damage. In addition, non-hepatotoxic doses (up to 300 mg/kg in rats and 1,000 mg/kg in mice) are not carcinogenic. It can therefore be practically ruled out that therapeutic doses have a genotoxic or carcinogenic effect.

reproductive toxicity

No conventional studies are available using currently accepted standards for the assessment of reproductive and developmental toxicity.

However, animal studies with paracetamol showed no effects on reproduction and no teratogenic effects.

Repeated administration of high doses of paracetamol resulted in testicular atrophy in mice and rats. Repeated administration of very high doses of paracetamol (≥500 mg/kg) to male rats resulted in reduced fertility (impairment of libido and sexual performance as well as sperm motility).

Additional data

Studies on the local tolerance of paracetamol in rats and rabbits showed good tolerability.

Studies on guinea pigs showed no delayed contact allergy.

Other information

incompatibilities

It is recommended not to mix Paracetamol Fresenius 1 g with other medicines without first checking compatibility.

influencing diagnostic methods

Paracetamol can distort the results of blood uric acid determination using the phosphotungstate reduction method and blood sugar measurement using the glucose oxidase method.

durability

This medicine should only be used until the date stated on the carton with “EXP”.

Shelf life after opening

The infusion solution contains no preservatives and, for microbiological reasons, must be used immediately after opening. Any remaining solution must be destroyed.

Stability studies show that Paracetamol Fresenius 1 g can be diluted up to 10 times with 0.9% sodium chloride solution or 5% glucose solution. After such dilution, the solution should be inspected visually and must not be used if cloudiness, particles or precipitates are visible. In addition, the diluted solution should also be used immediately, but no more than one hour (including the infusion time) after dilution.

Special storage instructions

Store at 15-25 °C. Do not refrigerate or freeze.

Keep out of reach of children.

Instructions for handling

Before use, Paracetamol Fresenius 1 g should be checked for particles and discoloration. The solution should be clear and colorless.

registration number

61442 (Swissmedic).

marketing authorization holder

Fresenius Kabi (Switzerland) AG, 6010 Kriens.