1. Name Of The Medicinal Product
PERFALGAN 10 mg/ml, solution for infusion.
2. Qualitative And Quantitative Composition
One ml contains 10 mg paracetamol
One 50 ml vial contains 500 mg paracetamol
One 100 ml vial contains 1000 mg paracetamol
One 100 ml bag contains 1000 mg paracetamol
Excipients: Sodium 0.04 mg/ml
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for infusion.
The solution is clear and slightly yellowish.
4. Clinical Particulars
4.1 Therapeutic Indications
Perfalgan 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.
4.2 Posology And Method Of Administration
Intravenous route.
The 100 ml vial or 100 ml bag is restricted to adults, adolescents and children weighing more than 33 kg.
The 50 ml vial is restricted to term newborn infants, infants, toddlers and children weighing less than 33 kg.
Posology:
• Adolescents and adults weighing more than 50 kg:
Paracetamol 1 g per administration, i.e. one 100 ml vial or one 100 ml bag, up to four times a day.
The minimum interval between each administration must be 4 hours.
The maximum daily dose must not exceed 4 g.
• Children weighing more than 33 kg (approximately 11 years old), adolescents and adults weighing less than 50 kg:
Paracetamol 15 mg/kg per administration, i.e. 1.5 ml solution per kg up to four times a day.
The minimum interval between each administration must be 4 hours.
The maximum daily dose must not exceed 60 mg/kg (without exceeding 3 g)
• Children weighing more than 10 kg (approximately 1 year old) and weighing less than 33 kg:
Paracetamol 15 mg/kg per administration, i.e. 1.5 ml solution per kg up to four times a day.
The minimum interval between each administration must be 4 hours.
The maximum daily dose must not exceed 60 mg/kg (without exceeding 2 g)
• Term newborns infants, infants, toddlers and children weighing less than 10 kg (up to approximately 1 year old) :
Paracetamol 7.5 mg/kg per administration, i.e. 0.75 ml solution per kg up to four times a day.
The minimum interval between each administration must be 4 hours.
The maximum daily dose must not exceed 30 mg/kg.
No safety and efficacy data are available for premature neonates (see also 5.2).
Severe renal insufficiency:
It is recommended, when giving paracetamol to patients with severe renal impairment (creatinine clearance
In adults with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione), dehydration:
The maximum daily dose must not exceed 3 g (see section 4.4).
Method of administration:
The paracetamol solution is administered as a 15-minute intravenous infusion.
Text for the 50ml and 100ml vials:
Use a 0.8 mm needle and vertically perforate the stopper at the spot specifically indicated.
Text for the 50ml vial:
Perfalgan of 50ml vial can also be diluted in a 0.9% sodium chloride solution or 5% glucose solution up to one tenth. In this case, use the diluted solution within the hour following its preparation (infusion time included).
Text for the 50ml and 100ml vials:
As for all solutions for infusion presented in glass vials, it should be remembered that close monitoring is needed notably at the end of the infusion, regardless of administration route. This monitoring at the end of the perfusion applies particularly for central route infusion, in order to avoid air embolism.
4.3 Contraindications
PERFALGAN 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.
4.4 Special Warnings And Precautions For Use
Warnings
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 4.9).
This medicinal product contains less than 1 mmol sodium (23mg) per 100ml of Perfalgan, i.e. essentially "sodium free".
Text for the 50ml and 100ml vials:
As for all solutions for infusion presented in glass vials, a close monitoring is needed notably at the end of the infusion (see section 4.2).
Precautions for use
Paracetamol should be used with caution in cases of:
• hepatocellular insufficiency,
• severe renal insufficiency (creatinine clearance
• chronic alcoholism,
• chronic malnutrition (low reserves of hepatic gluthatione),
• dehydration.
4.5 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
• Caution should be paid to the concomitant intake of enzyme-inducing substances (see section 4.9
• 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.
4.6 Pregnancy And Lactation
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, PERFALGAN 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, PERFALGAN may be used in breast-feeding women.
4.7 Effects On Ability To Drive And Use Machines
Not relevant.
4.8 Undesirable Effects
As all paracetamol products, adverse drug reactions are rare (>1/10000, <1/1000) or very rare (<1/10000), they are described below:
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Frequent adverse reactions at injection site have been reported during clinical trials (pain and burning sensation).
Very rare cases of hypersensitivity reactions ranging from simple skin rash or urticaria to anaphylactic shock have been reported and require discontinuation of treatment.
Cases of erythema, flushing, pruritus and tachycardia have been reported.
4.9 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 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: OTHER ANALGESICS AND ANTIPYRETICS, ATC code: N02BE01
The precise mechanism of the analgesic and antipyretic properties of paracetamol has yet to be established; it may involve central and peripheral actions.
PERFALGAN 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.
PERFALGAN reduces fever within 30 minutes after the start of administration with a duration of the antipyretic effect of at least 6 hours.
5.2 Pharmacokinetic Properties
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 PERFALGAN 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 PERFALGAN 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.
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.
Table. Age related pharmacokinetic values (standardized clearance,* CLstd/Foral (l.h-1 70 kg-1), are presented below.
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*CLstd is the population estimate for CL
Special populations:
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 (creatinine clearance
Elderly subjects
The pharmacokinetics and the metabolism of paracetamol are not modified in elderly subjects. No dose adjustment is required in this population.
5.3 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 PERFALGAN in rats and rabbits showed good tolerability. Absence of delayed contact hypersensitivity has been tested in guinea pigs.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Cysteine hydrochloride monohydrate
Disodium phosphate dihydrate
Hydrochloric acid
Mannitol
Sodium hydroxide
Water for injections.
6.2 Incompatibilities
PERFALGAN should not be mixed with other medicinal products.
6.3 Shelf Life
2 years.
From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.
Text for the 50ml vial:
If diluted in 0.9% sodium chloride or 5% glucose, the solution should also be used immediately. However, if the solution is not used immediately, do not store for more than 1 hour (infusion time included).
6.4 Special Precautions For Storage
Do not store above 30°C. Do not refrigerate or freeze.
Text for the 100ml bag:
For the 100 ml bag, store the immediate packaging in the outer, aluminium overpackaging.
Following the opening of the overpackaging, the product must be used immediately.
6.5 Nature And Contents Of Container
Text for the 50ml and 100ml vials:
50 ml and 100 ml Type II clear glass vial with bromobutyl stopper and a aluminium/plastic Flip-Off cap.
Pack size: pack of 12 vials.
Text for the 100ml bag:
The 100 ml bag is a multilayer, plastic bag (PP and polyolefin) packed in an oxygen-proof, aluminium overpackaging.
Pack size: carton of 50 bags
6.6 Special Precautions For Disposal And Other Handling
Text for the 50ml and 100ml vials:
Use a 0.8 mm needle and vertically perforate the stopper at the spot specifically indicated.
Before administration, the product should be visually inspected for any particulate matter and discoloration. For single use only. Any unused solution should be discarded.
The diluted solution should be visually inspected and should not be used in presence of opalescence, visible particulate matters or precipitate.
Text for the 100ml bag:
There is a potential presence of moisture between the bag and the outer packaging as a result of the sterilization process. It does not impact the quality of the solution.
7. Marketing Authorisation Holder
Bristol-Myers Squibb Pharmaceuticals Ltd
BMS House
Uxbridge Business Park
Sanderson Road
Uxbridge
Middlesex UB8 1DH
United Kingdom
8. Marketing Authorisation Number(S)
PL 11184/0094
9. Date Of First Authorisation/Renewal Of The Authorisation
20 November 2002/ 13 December 2006
10. Date Of Revision Of The Text
29 April 2010
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