Paracetamol Kabi

Clear colorless to almost colorless solution.
The solution is iso-osmotic, and its pH is between 5.0 and 7.0.
1 ml contains 10 mg paracetamol.
Each 100 ml vial or bag contains 1000 mg paracetamol.
Excipients/Inactive Ingredients: Cysteine, Mannitol (E421), Water for injections.

Pharmacotherapeutic group: Other analgesics and antipyretics, anilides. ATC code: N02BE01.
Pharmacology: Pharmacodynamics: The precise analgesic and antipyretic mode of action of paracetamol has not been established. A central and peripheral effect is likely.
Paracetamol Kabi provides onset of pain relief within 5 to 10 minutes following administration. The peak analgesic effect is obtained within 1 hour and analgesia usually persists 4 to 6 hours.
Paracetamol Kabi reduces fever within 30 minutes following administration. The antipyretic effect persists for at least 6 hours.
Pharmacokinetics: Adults: Absorption: Following single and repeated administration during 24 hours paracetamol pharmacokinetics is linear up to 2 g.
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 a 15-minute intravenous infusion of 500 mg and 1 g of paracetamol is about 15 μg/ml and 30 μg/ml, respectively.
Distribution: The volume of distribution of paracetamol is approximately 1 l/kg. Paracetamol is not extensively bound to plasma proteins (about 10%). Twenty minutes following infusion of 1 g paracetamol, significant concentrations of paracetamol (about 1.5 μg/ml) were observed in the cerebrospinal fluid.
Biotransformation: Paracetamol is mainly metabolised in the liver following two major hepatic pathways: conjugation with glucuronic acid and sulphuric acid. At doses that exceed the therapeutic dose, the latter route is rapidly saturated. A small fraction (less than 4%) is metabolised by cytochrome P450 to a reactive intermediate (N-acetyl benzoquinone imine) which, with normal dosing, is rapidly detoxified by reduced glutathione and eliminated in the urine after conjugation with cysteine and mercapturic acid. However, in the event of massive overdose, 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 within 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.
Newborn infants, 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 hours) than in adults. In newborn infants, the plasma half-life is longer than in infants, i.e. around 3.5 hours. Newborn infants, infants and children up to 10 years excrete significantly less glucuronide and more sulphate conjugates than adults. (See Table 1.)

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Special population: Renal insufficiency: In severe renal impairment (creatinine clearance 10-50 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 lower in subjects with severe renal impairment than in healthy subjects. Therefore, when giving paracetamol to patients with severe renal impairment (creatinine clearance 10-50 ml/min), the minimum interval between each administration should be increased to 6 hours (see Dosage & Administration).
Elderly: The pharmacokinetics and metabolism of paracetamol are not altered in elderly. No dose adjustment is required in this patient population.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans beyond the information included in other sections of the SmPC. Studies on local tolerance of paracetamol solution for infusion in rats and rabbits showed good tolerability. Absence of delayed contact hypersensitivity has been tested in guinea pigs.
Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.
Paracetamol was found to be noncarcinogenic in male rats as well as in male and female mice. Equivocal evidence of carcinogenic activity was noted for female rats based on an increased incidence of mononuclear cell leukemia.
A comparative review of the literature on paracetamol genotoxicity and carcinogenicity showed that genotoxic effects of paracetamol appear only at dosages above the recommended range resulting in severe toxic effects including pronounced liver and bone marrow toxicity. The threshold level for genotoxicity is not reached at therapeutic dosages of paracetamol.

Paracetamol Kabi is indicated for: the short-term treatment of moderate pain, especially following surgery, 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.

Intravenous use.
The 100 ml vial or bag is restricted to adults, adolescents and children weighing more than 33 kg.
Posology: Dosing based on patient weight (see the dosing table as follows): See Table 2.

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Method of administration: Take care when prescribing and administering Paracetamol Kabi 10 mg/ml solution for infusion to avoid dosing errors due to confusion between milligram (mg) and millilitre (mL), which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Take care to ensure the dose is measured and administered accurately.
For single use only. Any unused solution should be discarded.
Before administration, the product should be visually inspected for any particulate matter and discolouration.
The paracetamol solution is administered as a 15-minute intravenous infusion.
Patient weighing ≤10 kg: The glass ampoule, vial or bag of Paracetamol Kabi 10 mg/ml solution for infusion should not be hung as an infusion due to small volume of medicinal product to be administered in this population.
The volume to be administered should be withdrawn from the ampoule, vial or bag and diluted in 0.9% sodium chloride solution or 5% glucose solution up to one tenth (one volume Paracetamol Kabi 10 mg/ml solution for infusion into nine volumes diluent) and administered over 15 minutes.
A 5 or 10 mL syringe should be used to measure the dose as appropriate for the weight of the child and the desired volume. However, this should never exceed 7.5 mL per dose.
The user should be referred to the product information for dosing guidelines.
For dilution of Paracetamol Kabi 10 mg/ml solution for infusion see Special precautions for disposal and other handling under Cautions for Usage.

At particular risk for hepatic damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) are elderly patients, young children, patients with hepatic disorders, chronic alcoholism, chronic malnutrition and patients concurrently receiving medicinal products that lead to enzyme induction. In such cases, overdose may be fatal.
Symptoms of overdose: Symptoms generally appear within the first 24 hours and comprise: nausea, vomiting, anorexia, pallor and abdominal pain.
Overdose with 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 paediatric patients, leads to hepatic cell necrosis, which can cause complete and irreversible necrosis and subsequently hepatocellular insufficiency, metabolic acidosis and encephalopathy. This, in turn, can lead to coma, sometimes with fatal outcome. Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin in combination with decreased prothrombin levels are observed, which may occur 12 to 48 hours after administration.
Clinical symptoms of hepatic damage are usually evident after two days, and reach a maximum after 4 to 6 days.
Treatment of overdose: Immediate hospitalisation.
Before initiating treatment, and as soon as possible following the overdose, a blood sample for determination of plasma paracetamol levels should be taken.
The treatment includes administration of the antidote, N-acetylcysteine (NAC) either by the intravenous or the oral route, if possible during the first 10 hours. N-acetylcysteine can also offer some degree of protection even after 10 hours, but in this case prolonged treatment will be required.
Symptomatic treatment.
Liver function tests must be carried out at the beginning of treatment and repeated every 24 hours. Usually hepatic transaminases return to normal in one to two weeks with full recovery of normal liver function. In very severe cases, however, liver transplantation may be necessary.
Haemodialysis can reduce the plasma paracetamol concentration, but the effects are limited.

Hypersensitivity to the active substance, propacetamol hydrochloride (prodrug of paracetamol) or to any of the excipients.
Severe hepatocellular insufficiency (Child-Pugh >9).

Risk of Medication Errors: Take care to avoid dosing errors due to confusion between milligram (mg) and millilitre (mL), which could result in accidental overdose and death (see Dosage & Administration).

It is recommended to use a suitable analgesic oral treatment as soon as this route of administration is possible.
In order to avoid the risk of overdose, check that no other medicinal products administered do contain paracetamol or propacetamol hydrochloride.
Doses higher than those recommended entail the risk of very serious liver damage. Clinical signs and symptoms of hepatic damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) are not usually seen until two days, and up to a maximum of 4-6 days, after administration. Treatment with antidote should be given as soon as possible (see Overdosage).
Paracetamol can cause serious skin reactions. Patients should be informed about the early signs of serious skin reactions, and the use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin.
If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended.
The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.
If flucloxacillin is continued after cessation of paracetamol, it is advisable to ensure that there are no signals of HAGMA, as there is a possibility of flucloxacillin maintaining the clinical picture of HAGMA (see Interactions).
As for all solutions for infusion presented in vials or bags, close monitoring is needed notably at the end of the infusion to avoid air embolism (see Special precautions for disposal and other handling under Cautions for Usage).
Paracetamol should be used with particular caution under the following circumstances: Abnormal Liver Function and Hepatocellular insufficiency (Child-Pugh ≤9).
Hepatobiliary disorders.
Meulengracht Gilbert Syndrome (familial non-haemolytic jaundice).
Severe renal insufficiency (creatinine clearance ≤30 ml/min), see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions.
Chronic alcohol abuse.
Chronic malnutrition (low reserves of hepatic glutathione).
Total parenteral nutrition (TPN) use.
Use of enzyme inducers.
Use of hepatotoxic agents
In patients suffering from a genetically caused G-6-PD deficiency (favism) the occurrence of a haemolytic anaemia is possible due to the reduced allocation of glutathione following the administration of paracetamol.
Dehydration.
Effects on laboratory tests: Paracetamol can affect tests for uric acid using phosphotungstic acid and blood sugar tests using glucose-oxidase-peroxidase.
Effects on ability to drive and use machines: Paracetamol Kabi has no influence on the ability to drive and use machines.

Pregnancy: Clinical experience of intravenous administration of paracetamol is limited. However, a large amount of data from the use of oral therapeutic doses of paracetamol in pregnant women indicate 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 Kabi may be used in breast-feeding women.

The evaluation of undesirable effects is based on the following definition of frequency: Very common: ≥1/10; Common: ≥1/100 to <1/10; Uncommon: ≥1/1,000 to <1/100; Rare ≥1/10,000 to <1/1,000; Very rare: <1/10,000; Not known: Frequency cannot be estimated from the available data.
As with all paracetamol containing medicinal products, undesirable effects are rare or very rare. They are described in the following table: See Table 3.

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Reporting of suspected adverse reactions: Reporting 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 reporting system.

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 half-life of paracetamol.
The metabolism of paracetamol is impaired in patients taking enzyme-inducing medicinal products such as rifampicin, barbiturates, tricyclic antidepressants, isoniazid and some antiepileptics (carbamazepine, phenytoin, phenobarbital, primidone).
Isolated reports describe unexpected hepatotoxicity in patients taking alcohol or enzyme-inducing medicinal products (see Overdosage).
Concurrent administration of paracetamol and chloramphenicol may prolong the action of chloramphenicol.
Concurrent administration of paracetamol and AZT (zidovudine) enhances the tendency to neutropenia.
Concurrent administration of paracetamol and oral contraceptives may reduce the elimination half-life of paracetamol.
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 taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risk factors (see Precautions).

Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned in Special precautions for disposal and other handling as follows.
Special precautions for disposal and other handling: Handling: As for all solutions for infusion presented in vials or bags, it should be remembered that close monitoring is needed notably at the end of the infusion, regardless of infusion route. This monitoring at the end of the infusion applies particularly for central route infusions, in order to avoid air embolism.
Compatibility: Paracetamol Kabi 10 mg/ml solution for infusion can be diluted in sodium chloride 9 mg/ml (0.9%) solution or 50 mg/ml glucose (5%) solution up to one tenth (one volume Paracetamol Kabi 10 mg/ml solution for infusion into nine volumes diluent).
The diluted solution should be visually inspected and should not be used in the presence of opalescence, visible particulate matter or precipitate.
Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Shelf life: Vial before opening: 24 months.
After first opening: Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours, unless opening and storage have taken place in controlled and validated aseptic conditions.
If diluted in sodium chloride 9 mg/ml (0.9%) solution or 50 mg/ml glucose (5%) solution, the solution should also be used immediately.
However, if the diluted solution is not used immediately, do not store for more than 6 hours (infusion time included).
Special precautions for storage: Do not refrigerate or freeze. Store below 30°C.
For storage conditions of the diluted medicinal product, see as Shelf life previously mentioned.

Analgesics (Non-Opioid) & Antipyretics

N02BE01 - paracetamol ; Belongs to the class of anilide preparations. Used to relieve pain and fever.

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