Paracetamol 10 Mg/Ml Solution For Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Paracetamol 10 mg/ml Solution for Infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml contains 10 mg paracetamol
One 100 ml vial contains 1000 mg paracetamol.
Excipient with known effect: Sodium 0.076 mg/ml For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for infusion.
The solution is clear, slightly yellowish. pH 5.5
Osmolarity 295 mOsm/litre
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
- short-term treatment of moderate pain, especially following surgery
- 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
The 100 ml vial is restricted to adults, adolescents and children weighing more than 33 kg
Posology:
Dosing based on patient weight (please see the dosing table here below
|
Patient weight |
Dose per administration |
Volume per administration |
Maximum volume of Paracetamol (10 mg/mL) per administration based on upper weight limits of group (mL)*** |
Maximum Daily Dose ** |
|
> 33 kg to <50kg |
15 mg/kg |
1.5mL/kg |
75 mL |
60mg/kg not exceeding 3g |
|
>50kg with additional risk factors for hepatotoxicity |
1g |
100mL |
100mL |
3g |
|
> 50 kg and no additional risk factors for hepatotoxicity |
1 g |
100mL |
100mL |
4g |
**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 weighing less will require smaller volumes.
The minimum interval between each administration must be at least 4 hours.
The minimum interval between each administration in patients with severe renal insufficiency must be at least 6 hours.
No more than 4 doses to be given in 24 hours.
Elderly patients:
Dose adjustment is not required in the elderly (see section 5.2).
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 (see section 5.2).
In adults with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione), and dehydration:
The maximum daily dose must not exceed 3000 mg (see section 4.4).
Method of administration:
Take care when prescribing and administering Paracetamol to avoid dosing errors due to confusion between milligram (mg) and milliliter (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.
The paracetamol solution is administered as a 15-minute intravenous infusion.
To remove solution, use a 0.8 mm needle (21 gauge needle) and vertically perforate the stopper at the spot specifically indicated.
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 infusion applies particularly for central route infusions, in order to avoid air embolism.
Before administration, the product should be visually inspected for any particulate matter and discoloration.
For single use only.
Any unused solution should be discarded.
For instruction on special precautions for disposal of the product, see section 6.6.
4.3 Contraindications
-Hypersensitivity to paracetamol or to propacetamol hydrochloride (prodrug of paracetamol) or to any of the excipients listed in section 6.1.
-in cases of severe hepatocellular insufficiency
4.4 Special warnings and precautions for use
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 (see section 4.2). Prolonged or frequent use is discouraged. It is recommended that a suitable analgesic oral treatment be used as soon as this route of administration is possible.
In order to avoid the risk of overdose, it should be checked that no other medicines administered contain either paracetamol or propacetamol.
Doses higher than those recommended entail the risk of very serious liver damage. Clinical signs and symptoms of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, and 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 section 4.9).
Paracetamol should be used with caution in cases of:
• hepatocellular insufficiency
• severe renal insufficiency (creatinine clearance < 30 ml/min) (see sections 4.2 and 5.2)
• chronic alcoholism
• chronic malnutrition (low reserves of hepatic glutathione)
• dehydration.
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).
This medicinal product contains less than 1 mmol sodium (23 mg) per 100ml, i.e. essentially 'sodium free'.
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 in the paracetamol dose should be considered if it is to be used concomitantly with probenecid.
• Salicylamide may prolong the elimination t% of paracetamol.
• Caution should be taken with 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 Fertility, pregnancy and lactation
Pregnancy:
Clinical experience of the intravenous administration of paracetamol is limited. However, epidemiological data from the use of oral therapeutic doses of paracetamol indicate no undesirable effects in pregnancy or on the health of the foetus / newborn infant.
Prospective data on pregnancies exposed to overdoses did not show any increase in the risk of malformation.
No reproductive studies with the intravenous form of paracetamol have been performed in animals. However, studies with the oral route did not show any malformation or foetotoxic effects.
Nevertheless, Paracetamol 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 may be used in breast-feeding women.
4.7 Effects on ability to drive and use machines
Paracetamol has no influence on the ability to drive and use machines.
4.8 Undesirable effects
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. As with all paracetamol products, adverse reactions are rare (>1/10,000 to <1/1,000) or very rare (<1/10,000). They are described below:
|
System organ class |
Frequency |
Adverse reaction |
|
Blood and lymphatic system disorders |
Very rare |
Thrombocytopenia, Leucopenia, Neutropenia. |
|
Cardiac disorders |
Rare |
Hypotension |
|
Hepatobiliary disorders |
Rare |
Increased levels of hepatic transaminases |
|
General disorders and administration site conditions |
Rare Very rare |
Malaise Hypersensitivity reaction |
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 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 of: nausea, vomiting, anorexia, pallor and abdominal pain. Immediate emergency measures are necessary in case of paracetamol overdose, even when no symptoms are present.
Overdose (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 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 blood sample 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 of 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: Analgesics; other analgesics and antipyretics; anilides
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.
Paracetamol 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 reduces fever within 30 minutes after the start of administration with 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 is similar to that observed following infusion of 1 g and 2 g propacetamol (containing 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 is about 15 pg/ml and 30 pg/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 pg/ml) were observed in the cerebrospinal fluid at and after the 20 th 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 within 24 hours, mainly as glucuronide (60-80%) and sulphate (20-30%) conjugates. Less than 5% is eliminated unchanged. Plasma halflife is 2.7 hours and total body clearance is 18 l/h.
New-born 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 new-born infants, the plasma half-life is longer than in infants i.e. around 3.5 hours. New-born infants, infants and children up to 10 years excrete significantly less glucuronide and more sulphate conjugates than adults.
Table - Age related pharmacokinetic values (standardised clearance, *CLstd/Foral (l.h-1 70kg-1)
|
Age |
Weight (kg) |
CLstd /Foral (l.h-1 70kg-1) |
|
40 weeks PCA |
3.3 |
5.9 |
|
3 months PNA |
6 |
8.8 |
|
6 months PNA |
7.5 |
11.1 |
|
1 year PNA |
10 |
13.6 |
|
2 years PNA |
12 |
15.6 |
|
5 years PNA |
20 |
16.3 |
8 years PNA_ 25_
16.3
*CLstd is the population estimate for CL
Special populations:
Renal insufficiency:
In cases of severe renal impairment (creatinine clearance < 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 (see section 4.2).
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 paracetamol 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, 37% (for pH-adjustment)
Mannitol
Sodium hydroxide 4% (for pH-adjustment)
Water for Injections
Incompatibilities
6.2
This medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
2 years.
Shelf life after first opening of the container Use immediately after opening
6.4 Special precautions for storage
Do not store above 30°C. Keep the vial in the original carton in order to protect from light. Do not refrigerate or freeze.
6.5 Nature and contents of container
Colourless type II glass vial, closed with a bromobutyl rubber stopper and sealed with an aluminium flip-off cap.
Pack sizes: 1 vial, 10 (10 x 1) vials
Not all pack sizes may be marketed
6.6 Special precautions for disposal
Any unused solution should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Sandoz Limited Frimley Business Park,
Frimley,
Camberley,
Surrey,
GU16 7SR
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04416/1388
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/01/2014
10 DATE OF REVISION OF THE TEXT
20/01/2014