Consumer medicine information

Paracetamol BNM

Paracetamol

BRAND INFORMATION

Brand name

Paracetamol BNM

Active ingredient

Paracetamol

Schedule

What is in this leaflet

Please read this leaflet carefully before you are given Paracetamol BNM.

This leaflet answers some common questions about Paracetamol BNM. It does not contain all the available information.

Reading this leaflet does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of giving you Paracetamol BNM against the benefits this medicine is expected to have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may want to read it again.

What Paracetamol BNM is used for

Paracetamol BNM contains paracetamol, an analgesic medicine which relieves pain and reduces fever.

Paracetamol BNM is a sterile solution for infusion which is given by intravenous infusion directly into a vein, and is used to relieve pain or reduce fever following surgery.

Your doctor may have prescribed this medicine for another reason.

Ask your doctor if you have any questions about why it has been prescribed for you.

Paracetamol BNM is available only with a doctor's prescription.

Paracetamol BNM is not addictive.

Before you are given Paracetamol BNM

Paracetamol BNM is not suitable for everyone.

When you must not be given it

You must not be given Paracetamol BNM if:

you are allergic to any medicine containing paracetamol or any of the ingredients listed at the end of this leaflet
you have liver failure or severe liver disease.

Symptoms of an allergic reaction may include:

shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Paracetamol BNM must not be used after the expiry date printed on the pack, or if the packaging is torn or shows signs of tampering. The solution must be clear before use.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any medical conditions, especially the following:

liver disease
kidney disease
alcoholism
malnutrition, including low reserves of glutathione
dehydration
eating disorders (anorexia, bulimia)
cachexia, a wasting syndrome including unexplained weight loss, fatigue and loss of appetite
a metabolic condition called glucose-6-phosphate dehydrogenase deficiency (G6PD)
an inherited condition called Gilbert’s syndrome (also known as familial hyperbilirubinaemia)
hypovolaemia (decreased blood volume).

Tell your doctor or pharmacist if you are pregnant or breast-feeding. Paracetamol BNM may be given to pregnant women and women who are breast-feeding, but your doctor must be told if you are pregnant or breast-feeding.

If you have not told your doctor about any of the above, tell them before you are given Paracetamol BNM.

Using other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop. It is especially important to tell your doctor if you are taking any other medicines, including over the counter or pharmacy medicines, which contain paracetamol (for example, Panadol®). This may affect the dosage of Paracetamol BNM which you should receive.

Tell your doctor if you drink alcohol. Your doctor may advise you to avoid alcohol as it may interfere with Paracetamol BNM.

Tell your doctor or pharmacist if you are taking flucloxacillin (antibiotic), due to a serious risk of blood and fluid abnormality (high anion gap metabolic acidosis) that must have urgent treatment and which may occur particularly in case of severe renal impairment, sepsis (when bacteria and their toxins circulate in the blood leading to organ damage), malnutrition, chronic alcoholism, and if the maximum daily doses of paracetamol are used.

Some medicines and Paracetamol BNM may interfere with each other. These include:

probenecid, a medicine used to treat gout or given with antibiotics
anticonvulsants, medicines used to treat epilepsy or fits, such as phenytoin, carbamazepine, amytal sodium, and phenobarbitone
other forms of paracetamol, such as tablets, capsules or liquid preparations
busulfan, a medicine used in cancer therapy
diflunisal, a non-steroidal anti-inflammatory medicine
barbiturates
zidovudine, a medicine for HIV treatment
anticoagulants, medicines used to stop blood from clotting, such as warfarin
isoniazid, a medicine used to treat tuberculosis
antibiotics containing amoxicillin plus clavulanic acid.

The above medicines may be affected by Paracetamol BNM, or may affect how well it works. You may need different amounts of Paracetamol BNM, or you may need to use different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid whilst being given Paracetamol BNM.

How Paracetamol BNM is given

How it will be given

Paracetamol BNM will be given by slow intravenous infusion (drip) into a vein. This medicine must only be given by a doctor or a nurse.

How much will be given

Your doctor will decide how many infusions you need, and how often you should receive them. The need for more doses will depend on how well your body responds to the treatment.

Tell your doctor if you have been taking other forms of paracetamol (tablets, capsules, liquid preparations) and the quantity that you have been taking.

While you are being given Paracetamol BNM

Things you must do

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are being given Paracetamol BNM. Likewise, tell any other doctors, dentists and pharmacists who are treating you that you are being given this medicine.

Tell your doctor immediately if you develop a rash or other symptoms of an allergic reaction. Paracetamol BNM can cause serious skin reactions.

Symptoms of an allergic reaction may be:

shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

In case of overdose

Your doctor has information on how to recognise and treat an overdose.

Ask your doctor or nurse if you have any concerns.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are being given Paracetamol BNM.

Like all medicines, Paracetamol BNM may occasionally cause side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

feeling unwell
dizziness, light-headedness
bleeding or bruising more easily than normal
vomiting, nausea
constipation
a faster heartbeat
unusual tiredness or weakness, fatigue
redness of the skin.

These side effects are rare and usually mild.

If any of the following happen, tell your doctor or a nurse immediately:

rash, itching or hives on the skin
other symptoms of an allergic reaction such as shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body
yellowing of the skin and/or eyes, also called jaundice.

These are very serious side effects. You may need urgent medical attention.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some patients.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After being given Paracetamol BNM

Storage

Paracetamol BNM will be stored in the pharmacy or on the ward under the recommended storage conditions.

It should be kept in a cool dry place, protected from light, where the temperature stays below 25ºC. Do not refrigerate or freeze.

Disposal

Any Paracetamol BNM which has passed its expiry date, or is left in the container after use, will be disposed of in a safe manner by your doctor, nurse or pharmacist.

Product description

What it looks like

Paracetamol BNM is a clear and slightly brownish sterile solution for infusion.

It is available in 100 mL transparent plastic bags. A box contains 12 bags.

One 100 mL bag contains 1 g of paracetamol.

Ingredients

Active ingredient:

paracetamol

Inactive ingredients:

mannitol
povidone
sodium hydroxide (for pH adjustment)
dibasic sodium phosphate dihydrate
water for injections.

Paracetamol BNM does not contain any preservatives.

Sponsor details

Boucher & Muir Pty Ltd
Level 9, 76 Berry Street
North Sydney NSW 2010

AUST R 201870

Date of preparation

This leaflet was prepared on 6 September 2022

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Paracetamol BNM

Active ingredient

Paracetamol

Schedule

1 Name of Medicine

Paracetamol.

2 Qualitative and Quantitative Composition

Paracetamol BNM (paracetamol) solution for infusion contains 1000 mg/100 mL of paracetamol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Paracetamol BNM solution for infusion is clear to slightly brownish solution.
The pH of the solution is adjusted to remain between 4.5 and 6.5 during the approved shelf life. The solution is isotonic and slightly hypobaric.

4 Clinical Particulars

4.1 Therapeutic Indications

Paracetamol BNM 1000 mg/100 mL solution for infusion is indicated for the relief of mild to moderate pain and the reduction of fever where an intravenous route of administration is considered clinically necessary.

4.2 Dose and Method of Administration

The prescribed dose must be based on the patient's weight.
Unintentional overdose can lead to serious liver damage and death (see Section 4.9 Overdose). Healthcare providers are reminded that it is essential to follow both the weight related dose recommendations and to consider individual patient risk factors for hepatotoxicity including hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione), and dehydration (see Section 4.2 Dose and Method of Administration, Hepatic impairment).
It is recommended that a suitable oral analgesic treatment be substituted for Paracetamol BNM as soon as the patient can be treated by oral route (see Section 4.3 Contraindications).

Intravenous route.

Paracetamol BNM 1000 mg/100 mL solution for infusion should not be mixed with other medicinal products.
Use of the 100 mL bag is restricted to adults, adolescents and children weighing more than 33 kg.

Dosage.

Dosing is based on patient weight. Dosing recommendations are presented in Table 1.

Hepatic impairment.

In patients with impaired hepatic function, the dose must be reduced or the dosing interval prolonged. The maximum daily dose should not exceed 60 mg/kg/day (not exceeding 2 g/day) in the following situations: adults weighing less than 50 kg, chronic or compensated active hepatic disease, especially those with mild to moderate hepatocelluar insufficiency, Gilbert's syndrome (familial hyperbilirubinaemia), chronic malnutrition (low reserves of hepatic glutathione) and dehydration.

Method of administration.

The paracetamol solution is administered as a 15 minute intravenous infusion; it contains no antimicrobial agent, and is for single use in one patient only.
Paracetamol BNM 1000 mg/100 mL solution for infusion can also be diluted in a 0.9% sodium chloride or 5% glucose solution up to one tenth. In this case, use the diluted solution within the hour following its preparation (infusion time included).
As for all solutions for infusion, it should be remembered that close monitoring is needed notably at the end of the infusion, regardless of the administration route. This monitoring at the end of the perfusion applies particularly for central route infusion, in order to avoid air embolism.

Paediatric patients.

Paracetamol BNM should not be hung as an infusion due to the small volume of the product to be administered in the paediatric population.
To avoid dosing errors in neonates and infants (≤ 10 kg) and confusion between milligrams (mg) and millilitres (mL), it is recommended to specify the intended volume for administration in millilitres (mL). The volume of Paracetamol BNM (10 mg/mL) administered should never exceed 7.5 mL per dose in this weight group. In neonates and infants (≤ 10 kg), very small volumes will be required. A 5 mL or 10 mL syringe should be used to measure the dose as appropriate for the weight of the child and the desired volume.

4.3 Contraindications

Paracetamol BNM 1000 mg/100 mL solution for infusion is contraindicated:
In cases of hypersensitivity to paracetamol or to propacetamol hydrochloride (prodrug of paracetamol) or to any of the excipients.
In cases of severe hepatocellular insufficiency.
In patients with hepatic failure or decompensated active liver disease.
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 paracetamol.
Doses higher than the recommended entail a risk of very serious liver damage. Clinical symptoms and signs of liver damage are usually seen first after two days with a maximum usually after 4 to 6 days. Treatment with antidote should be given as soon as possible (see Section 4.2 Dose and Method of Administration).

4.4 Special Warnings and Precautions for Use

Paracetamol BNM should be used with caution in cases of: hepatocellular insufficiency, including Gilbert's syndrome (familial hyperbilirubinaemia); severe renal insufficiency (creatinine clearance ≤ 30 mL/min); glucose-6-phosphate dehydrogenase (G6PD) deficiency (may lead to haemolytic anaemia); chronic alcoholism, excessive alcohol intake (3 or more alcoholic drinks every day); anorexia, bulimia or cachexia; chronic malnutrition (low reserves of hepatic glutathione); dehydration, hypovolaemia.
(See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.)
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.
The total dose of paracetamol should not exceed 4 g per day for patients weighing 50 kg or more, 60 mg/kg for patients weighing 50 kg or less and more than 33 kg (without exceeding 3 g), 60 mg/kg for patients weighing 33 kg or less and more than 10 kg (without exceeding 2 g) and 30 mg/kg for patients weighing 10 kg or less. It is important to consider the contribution of all paracetamol containing medications, including nonprescription, oral or PR forms, to this total daily paracetamol dose prior to administering Paracetamol BNM. If the daily dose of paracetamol from all sources exceeds the maximum, severe hepatic injury may occur (see Section 4.9 Overdose).
Paracetamol can cause serious skin reactions such as acute generalised 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.

Hepatic injury.

Patients with hepatic insufficiency, chronic alcoholism, chronic malnutrition or dehydration may be at a higher risk of liver damage following administration of paracetamol.

Use in hepatic impairment.

Paracetamol should be administered with caution to patients with hepatic impairment (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Hepatic injury). Hepatic impairment may decrease the clearance of paracetamol or increase the probability of hepatic toxicity.

Use in renal impairment.

Paracetamol should be administered with caution to patients with renal impairment. 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. It is recommended that there be an interval of at least 6 hours between administrations in patients with severe renal impairment (creatinine clearance ≤ 30 mL/min) (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

There was a significant increase in AUC and reduction in clearance of paracetamol and its metabolites in elderly subjects. However, these statistically significant differences were not likely to be clinically relevant during short-term infusions. Hence, no dose adjustment is required in this population.

Paediatric use.

See Section 4.2 Dose and Method of Administration, Paediatric patients.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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.
Caution should be paid to the concomitant intake of enzyme inducing agents. These substances include but are not limited to: barbiturates, isoniazid, anticoagulants, zidovudine, amoxicillin + clavulanic acid, carbamazepine and ethanol. Induction of metabolism of paracetamol from enzyme inducers may result in an increased level of hepatotoxic metabolites.
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 (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant use of paracetamol (4 g per day for at least 4 days) with oral coumarin anticoagulants including warfarin 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 one week after paracetamol treatment has been discontinued.
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.

Busulfan.

Busulfan is eliminated from the body via conjugation with glutathione. Concomitant use with paracetamol may result in reduced busulfan clearance.

Diflunisal.

Concomitant diflunisal increases paracetamol plasma concentrations and this may increase hepatotoxicity.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Intravenous paracetamol (administered as propacetamol) had no effect on fertility of rats at systemic exposure levels (based on AUC) greater than twice those anticipated at the maximum clinical dose.
(Category A)
Paracetamol has been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.
The reproductive toxicity of IV paracetamol has not been directly tested in animal studies. IV administration of maternotoxic doses of the prodrug, propacetamol, to pregnant rats and rabbits during organogenesis increased the incidence of extranumerary ribs and sacral vertebrae (normal variations in these species) at 0.7-fold (rabbits; mg/m² basis) and 7-fold (rats; AUC basis) the maximum anticipated clinical exposure to paracetamol. The clinical significance of these findings is not known. No signs of pre/post-natal toxicity were observed in rats treated with IV propacetamol at maternal exposures (based on AUC) greater than 3-fold those anticipated at the maximum clinical dose.
Nevertheless, Paracetamol BNM should only be used during pregnancy after a careful benefit-risk assessment. In pregnant patients, the recommended posology and duration must be strictly observed.
After oral administration, paracetamol is excreted into breast milk in small quantities. Rash in nursing infants has been reported. No signs of toxicity were observed in rat pups of dams that received IV propacetamol postpartum at maternal exposures (based on AUC) greater than twice those anticipated at the maximum clinical dose. Paracetamol BNM 1000 mg/100 mL solution for infusion may be used in breastfeeding women, but caution should be observed.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The overall incidence of adverse events in paracetamol IV treated patients compared to placebo within the clinical trial set, can be observed in Tables 2 and 3.
As with all paracetamol products, adverse drug reactions are rare (≥ 1/10,000, < 1/1000) or very rare (< 1/10,000), they are described in Table 4.

Postmarket adverse effects for propacetamol/ paracetamol.

The following adverse events have also been reported during postmarketing surveillance, but the incidence rate (frequency) is not known. See Table 5.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

For overdose in general, the mainstay of treatment is supportive and symptomatic care.
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. Poisoning may be fatal in these cases. Acute overdose with paracetamol may also lead to acute renal tubular necrosis.
Symptoms generally appear within the first 24 hours and comprise of 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 bodyweight in a single administration in children, causes cytolytic hepatitis likely to induce complete and irreversible hepatic necrosis, resulting in acute or fulminant hepatic failure, hepatocellular insufficiency, metabolic acidosis and encephalopathy which may lead to coma and death.
Simultaneously, increased levels of hepatic transaminases (aspartate aminotransferase (AST), alanine aminotransferase (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.
The Rummack-Matthews nomogram relates plasma levels of paracetamol and the time after oral ingestion to the predicted severity of liver injury. The relation of parental paracetamol levels in overdose to liver toxicity has not been examined. Advice or treatment protocols based on oral paracetamol overdoses may not accurately predict the incidence of liver toxicity or need for antidote therapy in paracetamol overdose.

Emergency measures.

Immediate hospitalisation.
Treatment of paracetamol overdose may include the antidote N-acetyl cysteine (NAC) by the IV or oral route. In overdoses of oral paracetamol NAC is administered, if possible, before 8 hours but may give some degree of protection from liver toxicity even after this time. The optimal time for administration of NAC and necessary duration of therapy have not been established for overdoses of paracetamol.
Take blood for plasma paracetamol assay, as soon as possible after the overdose.
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 the liver function. In very severe cases, however, liver transplantation may be necessary.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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.
Paracetamol BNM 1000 mg/100 mL solution for 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 BNM 1000 mg/100 mL solution for infusion reduces fever within 30 minutes after the start of administration with a duration of the antipyretic effect of at least 6 hours.

Clinical trials.

Clinical trials were performed with two different formulations of paracetamol, paracetamol IV and propacetamol. Propacetamol 2 g is equivalent to paracetamol IV 1 g. See Section 4.2 Dose and Method of Administration for the correct dosing instructions for Paracetamol BNM.
Analgesia - adults. Two phase III studies were conducted to compare the safety and analgesic efficacy of IV paracetamol and propacetamol in 303 adults. Two accepted acute pain models, i.e. orthopaedic surgery pain and oral surgery pain were used to evaluate analgesic efficacy.
All the studies presented were phase III, randomised, double blind, active and/or placebo controlled. The studies were well conducted according to the GCP guidelines with ethics approval. Treatment compliance was good in all the studies.

Efficacy of IV paracetamol for the treatment of postoperative pain following orthopaedic surgery.

One hundred and fifty one patients were included in this study; 49 patients were administered paracetamol IV 1 g and 52 patients placebo. The groups of patients were comparable with regard to demographic and baseline characteristics. One hundred and thirty seven (90.7%) patients received 4 administrations over 24 hours, 2 (1.3%) patients received 3; 2 (1.3%) patients received 2 and 10 (6.6%) patients received only 1 administration.
The primary measured efficacy endpoint parameter of the trial was the evaluation of paracetamol IV 1 g versus placebo after single dose pain relief scores (PID, PRID, maxPR, maxPID, SPID, TOTPAR); time to peak effects and time to first rescue medication; numbers and proportion of patients requiring rescue medication (PCA morphine); patients global evaluation (PGA). The secondary measured efficacy endpoint parameter was paracetamol IV 1 g versus placebo after repeated doses.
An overview of the results are shown in Tables 6 and 7.

Efficacy of IV paracetamol for the treatment of postoperative pain following oral (postdental) surgery.

One hundred and fifty two patients were included in this study; 51 patients were administered paracetamol IV 1 g and 50 patients with placebo. The groups of patients were comparable with regard to demographic and baseline characteristics.
The primary measured efficacy endpoint parameter of the trial was the evaluation of paracetamol IV 1 g versus placebo after single dose pain relief scores (PID, PRID, maxPR, maxPID, SPID, TOTPAR); time to peak effects and time to first rescue medication; numbers and proportion of patients requiring rescue medication (PCA morphine); patients global evaluation (PGA). The secondary measured efficacy endpoint parameter was paracetamol IV 1 g versus placebo after repeated doses.
An overview of the results are shown in Table 8.

Analgesia - children.

Efficacy of IV paracetamol with postoperative pain (hernia repair).

One hundred and eighty three patients were included in this study, of which 95 patients were administered paracetamol IV 15 mg/kg. The groups of patients were comparable with regard to demographic and baseline characteristics.
The primary measured efficacy endpoint parameter of the trial was the evaluation of pain intensity difference (PID) on VAS (investigator rated) at 15, 30 minutes, 1, 2, 3, 4, 5 and 6 hours postdose. The secondary measured efficacy endpoint parameter for the trial was PID on the objective pain scale (OPS), pain relief rated by the investigator, SPID-OPS, SPID-VAS, TOTPAR, number of children with VAS score ≤ 15 mm, investigators global evaluation, time to remedication, changes from baseline in HR, SBP and DBP.
An overview of the results are shown in Tables 9 and 10.

Antipyrexia. Propacetamol is a different formulation than paracetamol IV which delivers 1 g of paracetamol for every 2 g of propacetamol administered.

Antipyretic efficacy and safety of a single administration of 30 mg/kg of intravenous propacetamol in children (age 3 to 12 years) with acute fever of infectious origin.

Forty one children with acute fever (ear temperature between 38.5°C to 41°C) of infectious origin. The groups of patients were comparable with regard to demographic and baseline characteristics.
The primary measured efficacy endpoint parameter of the trial was to evaluate the antipyretic efficacy of a single intravenous dose of 30 mg/kg of propacetamol (equivalent to 15 mg/kg paracetamol IV) in comparison with placebo in children with acute fever of infectious origin (changes in body temperature (BT) from 0.5 hours to 6 hours postdose).
The secondary measured efficacy endpoint parameter was the evaluation of the percentage of body temperature reduction from baseline at each evaluation time, weighted sum of changes in body temperature over the T0-T4 and T0-T6 periods, weighted sum of percentages of body temperature reduction over the T0-T4 and T0-T6 periods. Time to reach body temperature below 38°C over the T0-T6 period. Number and percentage of children with a BT below 38°C over the T0-T6 period. Maximum value of changes in body temperature and time to occurrence after T0. Vital signs (respiratory rate, heart rate, arterial blood pressure): changes over time after dosing. Investigator's global evaluation. Time to remedication (with calculation of time at which 50% of children require remedication) over the T0-T6 period, number and percentage of children requiring rescue medication over the T0-T6 period. Safety: vital signs and adverse events.
An overview of the results are shown in Tables 11 and 12.

5.2 Pharmacokinetic Properties

Adults.

Absorption.

Paracetamol pharmacokinetics are linear after a single administration of up to 2 g and after repeated administration during 24 hours.
The bioavailability of paracetamol following infusion of 1 g of paracetamol 10 mg/mL is similar to that observed following infusion of 2 g propacetamol (containing 1 g paracetamol). For both these products, peak plasma concentration is obtained at the end of infusion. The maximum plasma concentration (C_max) of paracetamol observed following intravenous infusion of 1 g paracetamol 10 mg/mL is about 30 microgram/mL. About 15 minutes is required to obtain the maximal plasma concentration (T_max).
The pharmacokinetics of oral paracetamol (500 mg) and intravenous propacetamol (1 g) were compared in a randomised, double blind, 2 period crossover study in 12 healthy male subjects. As expected, plasma concentrations of intravenous propacetamol were significantly higher and obtained earlier, compared to oral administration, however after the first hour and up to 24 hours the plasma concentrations remained similar (see Figure 1 and Table 13).

Distribution.

The volume of distribution of paracetamol is approximately 1 L/kg. Paracetamol is not extensively bound to plasma proteins.
Following infusion of 2 g propacetamol (equivalent to 1 g of paracetamol), significant concentrations of paracetamol (about 1.5 microgram/mL) were observed in the cerebrospinal fluid 20 minutes after 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 poisoning, the quantity of this toxic metabolite is increased.
At therapeutic doses, CYP3A4, the major isoform of P450 in human liver, contributes to the production of the cytotoxic metabolite. For very high, supratherapeutic plasma concentrations (1500 mg/L) of paracetamol, the 2E1 and 1A2 isoforms may also be involved.

Excretion.

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 and infants < 6 months of age.

Clinical trials examining the pharmacokinetics of paracetamol IV in neonates and infants < 6 months of age are limited. The safety and efficacy of paracetamol IV in premature neonates has not been established. In a trial of 12 children between 1 and 232 days of age, which included 5 children less than 10 days of age the pharmacokinetic results for paracetamol IV were as follows (see Figure 2 and Table 14).

The infants in the study were aged between 1 and 232 days; mean 88 ± 95 days. In the neonates aged less than 10 days, the gestational age was 37.4 ± 3.9 weeks (32 to 41.3 weeks). The weight of the neonates at the time of the study was 2.578 ± 0.959 kg (1 to 3.8); birth weight was 2.578 ± 1.022 kg (1 to 3.920 kg). The mean administered dose was 15.3 ± 2 mg/kg (13.40 to 20 mg/kg).
In neonates, the plasma half-life is longer than in infants i.e. around 3.5 hours. Neonates and, infants excrete significantly less glucuronide and more sulphate conjugates than adults. The potential effect of immaturity in metabolic and elimination pathways of paracetamol should be considered when administering paracetamol to neonates and children < 6 months of age.

Infants and children > 6 months of age.

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.

5.3 Preclinical Safety Data

Genotoxicity.

Paracetamol was not mutagenic in the bacterial mutagenicity assay, but it was clastogenic in mammalian cell assay systems in vitro (mouse TK, human lymphocyte) and in a mouse micronucleus assay in vivo. The clastogenic effect was dose dependent, and the mechanism appears to involve inhibition of replicative DNA synthesis and ribonucleotide reductase at above threshold doses. The clinical significance of clastogenic findings is equivocal as positive findings in vivo only occurred at exposures (ca. 8 times the maximum anticipated clinical exposure, based on C_max) greater than that for hepatotoxicity, and at doses that were associated with significant cytotoxicity.

Carcinogenicity.

No evidence of carcinogenic potential was observed for paracetamol in long-term oral studies in mice (up to 3000 mg/m²/day, similar to human exposure) and male rats (up to 1800 mg/m²/day, 0.7 times human exposure). Equivocal evidence of carcinogenic potential (mononuclear cell leukaemia) was observed only in female rats at 1900 mg/m²/day, or 0.7 times the maximum anticipated clinical exposure on a mg/m² basis.

6 Pharmaceutical Particulars

6.1 List of Excipients

Paracetamol BNM solution for infusion contains mannitol, dibasic sodium phosphate dihydrate, povidone and sodium hydroxide (for pH adjustment) in water for injections. The solution is preservative free.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
If diluted in 0.9% sodium chloride or 5% glucose, the solution should be used immediately. However, if the solution is not used immediately, do not store for more than one hour (infusion time included).

6.4 Special Precautions for Storage

Store below 25°C. Store bags in the original container to protect from light. Do not refrigerate or freeze.
Before administration, the product should be visually inspected for any particulate matter and discoloration.
For single use in one patient only. The product should be used immediately after opening and any unused solution should be discarded.

6.5 Nature and Contents of Container

Paracetamol BNM sterile solution for infusion is available in 100 mL transparent plastic bags.
One box contains 12 bags. One 100 mL bag contains 1 g of paracetamol.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Paracetamol is 4-acetamidophenol. The structural formula is:

Molecular formula: C₈H₉NO₂.
Molecular weight: 151.2.
Paracetamol is a white crystalline solid or powder. It is soluble in water (1 in 70), soluble in alcohol (1 in 7), acetone (1 in 13), glycerol (1 in 40), propylene glycol (1 in 9) and also soluble in solutions of the alkali hydroxides.

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