Paracetamol Infusion IP 10 mg/ml (For IV Infusion only)
COMPOSITION
Each ml contains:
Paracetamol IP 10 mg
Water for Injections BP q.s.
DESCRIPTION
A clear, colorless to almost colorless solution.
PHARMACODYNAMIC
Pharmacotherapeutic group: Analgesics; Other analgesics and antipyretics; Anilides.
ATC Code: N02BE01
Mechanism of action
The precise mechanism of the analgesic and antipyretic properties of paracetamol has still to be established; it may involve central and peripheral actions.
Pharmacodynamic effects
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 a duration of the antipyretic effect of at least 6 hours.
PHARMACOKINETICS
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 Paracetamol is similar to that observed following infusion of 1 g and 2 g propacetamol (containing 500mg 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 is about 15 μ g/ml and 30 μ g/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 µ g/ml) were observed in the cerebrospinal fluid at and after the 20th minute following infusion.
Biotransformation
Paracetamol is metabolized 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 metabolized 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.
Excretion
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 h) 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.
Table-Age related pharmacokinetic values (standardized clearance, *CLstd/Foral (l× h-1×70kg-1)
| Age | Weight (Kg) | CLstd /Foral (l x h-1 x 70 Kg-1) |
| 40 weeks post-conception | 3.3 | 5.9 |
| 3 months postnatal | 6 | 8.8 |
| 6 months postnatal | 7.5 | 11.1 |
| 1 year postnatal | 10 | 13.6 |
| 2 years postnatal | 12 | 15.6 |
| 5 years postnatal | 20 | 16.3 |
| 8 years postnatal | 25 | 16.3 |
*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, when giving paracetamol to patients with severe renal impairment (creatinine clearance ≤ 30 ml/min), the minimum interval between each administration should be increased to 6 hours.
Elderly subjects:
The pharmacokinetics and the metabolism of paracetamol are not modified in elderly subjects. No dose adjustment is required in this population.
THERAPEUTIC INDICATION
Paracetamol is indicated for:
- 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.
DOSAGE AND ADMINISTRATION
The 100 ml bottle is restricted to adults, adolescents and children weighing more than 33 kg.
| Patient Weight | Dose (per administration) | Volume per administration | Maximum volume of paracetamol B. Braun (10mg/ml) per administration based on upper weight limits of group (ml)*** | Maximum daily dose ** |
| > 33 kg to ≤ 50 kg | 15 mg/kg | 1.5 ml/kg | 75 ml | 60 mg/kg not exceeding 3 g |
| > 50 kg with additional risk factors for hepatotoxicity | 1 g | 100 ml | 100 ml | 3 g |
| > 50 kg and no additional risk factors for hepatotoxicity | 1 g | 100 ml | 100 ml | 4 g |
** 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.
Method of administration: Intravenous injection.
OVERDOSE
Symptoms
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 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.
Treatment
Immediate hospitalization.
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 intravenous 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 restitution to normal in one to two weeks with full return of normal liver function. In very severe cases, however, liver transplantation may be necessary.
CONTRAINDICATION
- Hypersensitivity to paracetamol, propacetamol hydrochloride (prodrug of paracetamol) or to any of the excipients.
- Cases of severe hepatocellular insufficiency.
WARNING AND PRECAUTIONS
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.
Prolonged or frequent use is discouraged. It is recommended that a suitable analgesic oral treatment will be used as soon as this route of administration is possible.
In order to avoid the risk of overdose, check that other medicines administered do not contain either paracetamol or propacetamol. The dose may require adjustment.
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, 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 should be used with caution in cases of:
- hepatocellular insufficiency
- severe renal insufficiency (creatinine clearance ≤ 30 ml/min)
- chronic alcoholism
- chronic malnutrition (low reserves of hepatic glutathione)
- dehydration
- 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.
Caution is advised if paracetamol is administered concomitantly with flucloxacillin due to increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism), as well as those using maximum daily doses of paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.
This medicinal product contains less than 1 mmol sodium (23 mg) per container, i.e. essentially ‘sodium- free’.
PREGNANCY AND LACTATION
Pregnancy:
A large amount of data on pregnant women indicates neither malformities, 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.
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.
DRUG INTERACTION
- Probenecid causes an almost two-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.
- Caution should be taken with the concomitant intake of enzyme-inducing substances.
- Concomitant use of paracetamol (4 000 mg 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, especially in patients with risks factors.
ADVERSE EFFECTS
As with all paracetamol products, adverse drug reactions are rare (≥ 1/10 000 to <1/1 000) or very rare (<1/10 000) & Not Known (cannot be estimated from the available data). They are described below:
| System Organ Class | Rare (≥ 1/10 000 to <1/1 000) | Very rare (<1/10 000) | Not known (cannot be estimated from the available data) |
| Blood and lymphatic system disorders | — | Thrombocytopenia, Leucopenia, Neutropenia | — |
| Immune system disorders | — | Hypersensitivity reaction (1, 3) | — |
| Cardiac disorders | — | — | Tachycardia (2) |
| Vascular disorders | Hypotension | — | Flushing (2) |
| Hepatobiliary disorders | Increased levels of hepatic transaminases | — | — |
| Skin and subcutaneous tissue disorders | — | serious skin reactions (3) | Pruritus (2),
Erythema (2) |
| General disorders and administration site conditions | Malaise | — | — |
(1) Very rare cases of hypersensitivity reactions ranging from simple skin rash or urticaria to anaphylactic shock have been reported and require discontinuation of treatment.
(2) Isolated cases
(3) Very rare cases of serious skin reactions have been reported.
Frequent adverse reactions at injection site have been reported during clinical trials (pain and burning sensation).
PRESENTATION
PARACARE Infusions are supplied in 100 ml Flint, ISO Type II, Moulded infusion vial.
STORAGE AND OTHER INFORMATION
Store in a cool and dry place. Protect from light.
Store at below 30°C temperature.
Caution: Not to be used if container is found leaking or solution is hazy or contain any visible solid particles. Keep this medicine out of the sight and reach of children.
