Parcetol

Each 1 mL contains: Paracetamol JP 10 mg.

Pharmacology: Pharmacodynamics: The precise mechanism of the analgesic and antipyretic properties of paracetamol has yet to be established; it may involve central and peripheral actions.
Paracetamol 1 g/100 mL solution for IV infusion 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.
Paracetamol 1 g/100 mL solution for IV infusion reduces fever within 30 minutes after the start of administration with a duration of the antipyretic effect of at least 6 hours.
Pharmacokinetics: 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 1 g/100 ml solution for IV infusion 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 (Cmax) of paracetamol observed at the end of 15 minutes intravenous infusion of 500 mg and 1 g of Paracetamol 1 g/100 mL solution for IV infusion 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.
Following infusion of 1 g paracetamol, significant concentrations of paracetamol (about 1.5 μg /mL) were observed in the Cerebro Spinal Fluid as and from the 20th minute 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.
Pediatric: 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.
Elderly: The pharmacokinetics and the metabolism of paracetamol are not modified in elderly subjects. No dose adjustment is required in this population.
Renal insufficiency: 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, to increase the minimum interval between each administration to 6 hours.

Paracetamol 1 g/100 mL solution for IV infusion 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.

Intravenous route. It is restricted to adults, adolescents and children weighing more than 33 kg.
Posology: See Table 1.

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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 insufficiency must be at least 6 hours.
The solution is administered as a 15-minute intravenous infusion.
Severe renal insufficiency: It is recommended, when giving paracetamol to patients with severe renal impairment (creatinine clearance ≤30 mL/min), to reduce the dose and increase the minimum interval between each administration to 6 hours.

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 i.v. 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.

Paracetamol 1 g /100 mL solution for IV infusion is contraindicated: In patients with hypersensitivity to paracetamol or to propacetamol hydrochloride (prodrug of paracetamol) or to one of the excipients.
In cases of severe hepatocellular insufficiency or decompensated active liver disease.

Risk of Medication errors: 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.
Paracetamol can cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. 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.

Paracetamol 1 g/100 mL solution for IV infusion should be used with caution in cases of: Hepatocellular insufficiency; Severe renal insufficiency; Glucose-6-phosphate dehydrogenase deficiency (may lead to haemolytic anemia); Chronic alcoholism excessive alcohol intake (3 or more alcoholic drinks every day); anorexia, bulimia or cachexia; Chronic malnutrition (low reserves of hepatic gluthatione); Dehydration, hypovolemia.

Pregnancy: Clinical experience of intravenous administration of paracetamol is limited. However, epidemiological data from the use of oral therapeutic doses of paracetamol indicate no undesirable effects on the pregnancy or on the health of the foetus / newborn infant. Prospective data on pregnancies exposed to overdoses did not show an increase in malformation risk.
Reproductive studies with the intravenous form of paracetamol have not been performed in animals. However, studies with the oral route did not show any malformation of foetotoxic effects. Nevertheless, Paracetamol 1 g/100 mL solution for IV infusion should only be used during pregnancy after a careful benefit-risk assessment. In this case, the recommended posology and duration must be strictly observed.
Lactation: After oral administration, paracetamol is excreted into breast milk in small quantities. No undesirable effects on nursing infants have been reported. Consequently, Paracetamol 1 g/100 mL solution for IV infusion may be used in breast-feeding women.

As all paracetamol products, adverse drug reactions are rare (>1/10000, <1/1000) or very rare (<1/10000), they are described as follows: See Table 2.

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Post Market Adverse Effects for Propacetamol/Paracetamol: The following adverse events have also been reported during post-marketing surveillance, but incidence rate (frequency) is not known. (See Table 3.)

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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.
Phenytoin administered concomitantly may result in decreased paracetamol effectiveness and an increased risk of hepatotoxicity. Patients receiving phenytoin therapy should avoid large and/or chronic doses of paracetamol. Patients should be monitored for evidence of hepatotoxicity.
Salicylamide may prolong the elimination t1/2 of paracetamol.
Caution should be paid to the concomitant intake of enzyme-inducing substances.
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.

Special Precautions: Paracetamol 1 g/100 mL solution for IV infusion should not be mixed with other medicinal products.
Before administration, the product should be visually inspected for any particulate matter and discoloration.

Store at temperatures not exceeding 30°C.
Do not refrigerate or freeze.
For single use only. Any unused solution should be discarded.
Shelf-Life: 24 months from the manufacturing date.

Analgesics (Non-Opioid) & Antipyretics

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

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