Bofalgan   – Solution for IV Infusion
(1 gm/ 100ml Infusion)

(Paracetamol B.P.) (Product Specs.: Bosch)

COMPOSITION
Each 100mL vial contains 1g Paracetamol B.P.

CLINICAL PHARMACOLOGY
Pharmacodynamics
Pharmacotherapeutic group: OTHER ANALGESICS AND ANTIPYRETICS, ATC
code: N02BE01
BOFALGAN 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.
BOFALGAN reduces fever within 30 minutes after the start of administration
with a duration of the antipyretic effect of at least 6 hours.

Mechanism of Action
The precise mechanism of the analgesic and antipyretic properties of paracetamol has yet to be established; it may involve central and peripheral actions.

Pharmacokinetics
Absorption:
BOFALGAN (Paracetamol) IV Infusion pharmacokinetics is linear up to 2g after single administration and after repeated administration during 24 hours. The maximal plasma concentration (Cmax) of paracetamol IV infusion observed at the end of 15-minutes intravenous infusion of 1g BOFALGAN is about 30μg/mL respectively.

Distribution:
The volume of distribution of paracetamol IV infusion is approximately 1L/kg. Paracetamol IV is not extensively bound to plasma proteins. Following infusion of 1g of BOFALGAN (Paracetamol) IV Infusion, significant concentrations of paracetamol (about 1.5μg/mL) were observed in the cerebrospinal fluid at and after the 20th minute following infusion.

Metabolism:
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 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 half-life is 2.7 hours and total body clearance is 18L/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.

SPECIAL 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, when giving paracetamol to patients with severe renal impairment (creatinine clearance<_ 30mL/min), the minimum interval, between each administration should be increased to 6 hours.

Elderly patients:
The pharmacokinetics and the metabolism of paracetamol are not modified in elderly subjects. No dose adjustment is required in this population.

INDICATIONS:
BOFALGAN (Paracetamol) IV Infusion is indicated for the short-term treatment of moderate pain, especially following surgery, and for the short-term treatment of fever, when administered 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:
The BOFALGAN (Paracetamol) IV Infusion contains 100mL solution and is restricted to adults, adolescents and children weighing more than 33kg (approximately 11 years old).

Adolescents and adults weighing more than 50kg:
BOFALGAN (Paracetamol) IV Infusion 1g per administration, i.e., one 100 mL vial, 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 33kg (approximately 11years old), adolescents
and adults weighing less than 50kg:
Paracetamol 15 mg/kg per administration, i.e., 1.5mL solution/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 3g).

Children weighing more than 10kg (approximately 1 year old) and weighing
less than 33kg:
Paracetamol 15mg/kg per administration, i.e., 1.5mL 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 60mg/kg (without exceeding 2g).

Children weighing less than 10kg:
Paracetamol 7.5mg/kg per administration, i.e. 0.75mL 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 30mg/kg.

Severe renal insufficiency:
It is recommended, when giving paracetamol to patients with severe renal impairment (creatinine clearance<_ 30mL/min), that the minimum interval between each administration be increased to 6 hours.
In adults with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition
(low reserves of hepatic glutathione), dehydration.

METHOD OF ADMINISTRATION:
The paracetamol solution is administered as a 15-minute intravenous infusion.

For 100ml Vial
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 perfusion applies particularly for central route infusion, in order to avoid air embolism.

Patients weighing ≤ 10 kg:

• The glass vial of Bofalgan should not be hung as an infusion due to the small volume of the medicinal product to be administered in this population
• The volume to be administered should be withdrawn from the vial and could be administered undiluted or diluted (from one to nine volumes diluent) in a 0.9% sodium chloride solution or 5% glucose solution and administered in 15-minute.
• Use the diluted solution within the hour following its preparation (infusion time included).
• 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 7.5ml per dose

CONTRAINDICATIONS:

• In patients with hypersensitivity to paracetamol or to propacetamol hydrochloride (prodrug of paracetamol) or to any of the excipients.
• In cases of severe hepatocellular insufficiency.

WARNINGS:
Ensure the proper dose is communicated and dispensed to minimize risk of medication errors due to confusion between milligram (mg) and milliliter (mL), which could result in accidental overdose and death.
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, check that no other medicines administered contain paracetamol. Doses higher than those recommended entail the risk of very serious liver damage. Clinical signs and symptoms of liver damage 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.

PRECAUTIONS:
Paracetamol should be used with caution in cases of:

• Hepatocellular insufficiency
• Severe renal insufficiency (creatinine clearance<_30mL / min)
• Chronic alcoholism
• Chronic malnutrition (low reserves of hepatic glutathione)
• Dehydration
• 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.

DRUG 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 t½ of paracetamol.
• Caution should be taken with the concomitant intake of enzyme-inducing substances.

PREGNANCY:
BOFALGAN should only be used during pregnancy after a careful benefit-risk assessment. In this case, the recommended dosage 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, BOFALGAN may be used in breast-feeding women.

ADVERSE EFFECTS:
As with all paracetamol products, adverse drug reactions are rare >1/10000, <1/1000) or very rare (<1/10000). They are described below:

OVERDOSAGE:
There is a risk of poisoning, 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 are nausea, vomiting, anorexia, pallor and abdominal pain.

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 return of normal liver function. In very severe cases, however, liver transplantation may be necessary.

INCOMPATIBILITIES:
BOFALGAN should not be mixed with other medicinal products. INSTRUCTION FOR USE,

HANDLING AND DISPOSAL:
Before administration, the product should be visually inspected for any particulate matter and discolouration. It is for single use only. Any unused solution should be discarded.

PRESENTATION:
BOFALGAN IV 1g/100mL in glass vial.

STORAGE AND DIRECTION:

• Shelf life of BOFALGAN IV Infusion vial is of 2 years.
• Protect from heat & sunlight,
• Store below 25°C.
• Do not refrigerate or freeze.
• The expiration date refer to the product correctly stored at the required condition.
• Do not use if solution contains undissolved particle.
• Do not use in case of colour change.
• Keep out of the reach of children.
• Patients and healthcare professionals can also report suspected adverse drug reaction at ade@bosch-pharma.com.
• To be sold on prescription of a registered medical practitioner only.