Consumer medicine information

Paracetamol Kabi

Paracetamol

BRAND INFORMATION

Brand name

Paracetamol Kabi

Active ingredient

Paracetamol

Schedule

What is in this leaflet

This leaflet answers some common questions about Paracetamol Kabi.

It does not contain all the available information. It 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 you taking Paracetamol Kabi against the benefits they expect it will have for you.

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

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

What Paracetamol Kabi is used for

Paracetamol Kabi is used to relieve pain and reduce fever following surgery.

This medicine belongs to a group of medicines called analgesics.

Ask your doctor if you have any concerns about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you are given Paracetamol Kabi

When you must not be given it

You must not be given Paracetamol Kabi if you have an allergy to paracetamol or to any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to Paracetamol Kabi 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

You must not be given Paracetamol Kabi if you have the following medical conditions.

liver failure
severe liver disease.

If you are not sure whether you should be given Paracetamol Kabi, talk to your doctor or pharmacist.

Before you start to take it

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

Tell your doctor or pharmacist if you have or have had any medical conditions:

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

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above tell him/her before you are given Paracetamol Kabi.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines including:

all prescription medicines
all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from a pharmacy, supermarket, naturopath or health food shop.

Some medicines may be affected by Paracetamol Kabi or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

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

Tell your doctor or your pharmacist if you are taking any of the following:

Pro-Cid (probenecid) – a medicine used to treat gout or given with antibiotics
Anticonvulsants – medicines used to treat epilepsy or fits, such as Dilantin® (phenytoin), Tegretol® or Teril® (carbamazepine)
Other forms of paracetamol, such as tablets, liquid preparations or capsules
Myleran® or Busulfex® (busulfan) a cancer drug
Dolobid (diflunisal) an anti-inflammatory drug
Barbiturates (such as amytal sodium or phenobarbitone)
Retrovir® (zidovudine) – a HIV drug or other drugs containing zidovudine
Anticoagulants which are used to stop blood from clotting (including warafin)
Isoniazid® (isoniazid) a tuberculosis drug
Antibiotics containing amoxicillin plus clavulanic acid (such as Clamoxyl®) or flucloxacillin.

Your doctor and pharmacist have more information on medicines to be careful to avoid while receiving Paracetamol Kabi.

How Paracetamol Kabi is given

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

How much is given

Your doctor will decide what dose you will be given, and for how long you will be given Paracetamol Kabi. Tell your doctor if you have been taking other forms of paracetamol (tablets, capsules, liquid preparations) and the quantity that you have been taking.

How Paracetamol Kabi is given

Paracetamol Kabi is given as a slow infusion (drip) into a vein. Paracetamol Kabi must only be given by a doctor or nurse.

If you take too much (Overdose)

Your doctor has information on how to recognise and treat an overdose. Ask your doctor or nurse if you have any concerns.

Adults: keep to the recommended dose. Don’t take this medicine for longer than a few days at a time unless advised to by a doctor.

Children and adolescents: keep to the recommended dose. Do not give this medicine for longer than 48 hours at a time unless advised to by a doctor.

If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 131 126; New Zealand 0800 764 766) or go to a hospital straightaway even if you feel well because of risk of delayed, serious liver damage and abnormal pigment levels.

Do not take with other products containing paracetamol, unless advised to do so by a doctor or pharmacist.

While you are being given Paracetamol Kabi

Things you must do

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given Paracetamol Kabi.

Tell any other doctors, dentists, and pharmacists who are treating you that you are being given Paracetamol Kabi.

Tell your doctor immediately if you develop a rash or other symptoms of an allergic reaction.

These symptoms 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

Side effects

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

It can be difficult to tell whether side effects are the result of being given Paracetamol Kabi, effects of your condition or side effects from other medicines you may be taking. For this reason, it is important to tell your doctor of any change in your condition.

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

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

Tell your doctor if…

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

The above list includes rare side effects of your medicine. They are usually mild.

Tell your doctor as soon as possible if…

Tell your doctor as soon as possible if you notice any of the following:

Allergic reaction – 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

The above list contains serious side effects that may require medical attention.

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

After being given Paracetamol Kabi

Storage

Paracetamol Kabi will be stored in the pharmacy or on a hospital ward. The injection should be kept in a dry cool place where the temperature stays below 25°C for the freeflex® bags and below 25°C for the vials.

What it looks like

Paracetamol Kabi solution for infusion 10 mg/mL is clear and slightly yellowish solution.

Paracetamol Kabi is available in glass vials containing 50 mL or 100 mL, or in plastic bags (freeflex®) containing 50 mL or 100 mL.

Ingredients

Active ingredient: paracetamol 10 mg/mL

50 mL vial: AUST R 203625 contains 500 mg paracetamol

100 mL vial: AUST R 203624 contains 1 g of paracetamol.

50 mL freeflex® bag: AUST R 218687 contains 500 mg paracetamol

100 mL freeflex® bag: AUST R 218688 contains 1 g paracetamol

Other ingredients: mannitol, cysteine hydrochloride, nitrogen (as protective gas), water for injections.

Supplier

Paracetamol Kabi is supplied in Australia by:

Fresenius Kabi Australia Pty Limited
Level 2, 2 Woodland Way
Mount Kuring-gai NSW 2080
Australia
Telephone: (02) 9391 5555

Paracetamol Kabi is supplied in New Zealand by:

Fresenius Kabi New Zealand Limited
60 Pavilion Drive
Airport Oaks, Auckland 2022
New Zealand
Freecall: 0800 144 892

® = Registered Trademark

This leaflet was prepared:
26 February 2020

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Paracetamol Kabi

Active ingredient

Paracetamol

Schedule

1 Name of Medicine

Paracetamol.

2 Qualitative and Quantitative Composition

Paracetamol Kabi solution for infusion contains 10 mg/mL of paracetamol (50 mL vial/bag contains 500 mg of paracetamol, 100 mL vial/bag contains 1 g of paracetamol).
Paracetamol Kabi solution for infusion contains the excipients mannitol, cysteine hydrochloride, nitrogen (as protective gas), water for injections. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Paracetamol solution for infusion 10 mg/mL is a clear to slightly yellowish solution. Paracetamol is a white crystalline solid or powder chemically described as 4-acetamidophenol. 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Paracetamol 10 mg/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 suitable oral analgesic treatment be substituted for paracetamol solution for infusion as soon as the patient can be treated by the oral route (see Section 4.3 Contraindications).

Intravenous route.

Paracetamol solution for infusion 10 mg/mL should not be mixed with other medicinal products.
Use of the 100 mL vial/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 hepatocellular insufficiency.
Gilbert's syndrome (familial hyperbilirubinaemia).
Chronic alcoholism.
Chronic malnutrition (low reserves of hepatic glutathione).
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.

Compatibility.

Paracetamol Kabi 10 mg/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).

Instructions for use/handling.

Before administration, the product should be visually inspected for any particulate matter and discolouration.
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 the administration route. This monitoring at the end of the perfusion applies particularly for central route infusion, in order to avoid air embolism.
It is recommended that for the administration of paracetamol solution for infusion 10 mg/mL, a syringe or giving set with a diameter equal to or below 0.8 mm should be used for solution sampling. In addition, it is recommended that the bung is pierced at the location designed for needle introduction (where the thickness of the bung is the lowest). If these recommendations are not adhered to the likelihood of bung fragmentation or the bung being forced into the vial is increased.

Paediatric patients.

Paracetamol Kabi 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 Kabi (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.
For paediatric dosing, the 50 mL vial/bag of Paracetamol Kabi can be diluted using either a 0.9% sodium chloride solution or a 5% glucose solution up to one-tenth dilution (one volume paracetamol injection into nine volumes diluent). The diluted solution must be used within one hour following its preparation (infusion time included).

4.3 Contraindications

Paracetamol 10 mg/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 solution for infusion should be used with caution in cases of:
hepatic insufficiency (see Use in hepatic impairment);
renal insufficiency (see Use in renal impairment);
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.)
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 non-prescription, oral or PR forms of the drug to this total daily paracetamol dose prior to administering paracetamol solution for infusion. 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.

High anion gap metabolic acidosis.

Caution is advised when paracetamol is administered concomitantly with flucloxacillin due to the increased risk of high anion gap metabolic acidosis (HAGMA). Patients at high risk for HAGMA are in particular those with severe renal impairment, sepsis or malnutrition especially if the maximum daily doses of paracetamol are used.
After co-administration of flucloxacillin and paracetamol, close monitoring is recommended in order to detect the appearance of acid-base disorders, namely HAGMA, including testing of urinary 5-oxoproline.

Use in hepatic impairment.

Patients with hepatic insufficiency, chronic alcoholism, chronic malnutrition or dehydration may be at a higher risk of liver damage following administration of paracetamol solution for infusion.
Paracetamol solution for infusion should be used with caution in cases of hepatocellular insufficiency, including Gilbert's syndrome (familial hyperbilirubinaemia).
See Section 4.3 Contraindications.

Use in renal impairment.

Paracetamol solution for infusion should be used with caution in cases of severe renal insufficiency (creatinine clearance ≤ 30 mL/min).

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties.

Paediatric use.

The safety and efficacy of paracetamol solution for infusion in premature neonates has not been established. There is limited data on the use of paracetamol solution for infusion in neonates and infants < 6 months of age (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration.)

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.
Concomitant use of paracetamol (4 g per day for at least 4 days) with oral 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.
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 risk factors.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

IV 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 pro-drug, 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.
Premature constriction/closure of the fetal ductus arteriosus has been reported following in utero exposure to paracetamol. In most of these reports, exposure to paracetamol occurred during the third trimester of pregnancy.
Nevertheless, paracetamol solution for infusion 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 solution for infusion may be used in breast-feeding 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 patients treated with IV paracetamol 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 events for propacetamol/paracetamol.

The following adverse events have also been reported during postmarketing surveillance, but 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/safety/reporting-problems.

4.9 Overdose

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 body weight 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 (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.
The Rumack-Matthews nomogram relates plasma levels of paracetamol and the time after oral ingestion to the predicted severity of liver injury. The relation of parenteral 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 solution for infusion overdose.
Methaemoglobinaemia has been reported in cases of paracetamol overdose.

Emergency measures.

Immediate hospitalisation.
Before beginning treatment, take blood for plasma paracetamol assay, as soon as possible after the overdose.
Treatment of paracetamol overdose may include the antidote N-acetylcysteine (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 solution for infusion.
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.

Adults.

Keep to the recommended dose. Do not take this medicine for longer than a few days at a time unless advised by a doctor.

Children and adolescents.

Keep to the recommended dose.
If an overdose is taken or suspected, go to a hospital straight away even if you feel well because of the risk of delayed, serious liver damage.
Do not take with other products containing paracetamol, unless advised to do so by a doctor or pharmacist.
For information on the management of overdose, contact the Poison 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 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 10 mg/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 solution for infusion and propacetamol. Propacetamol 2 g is equivalent to paracetamol solution for infusion 1 g. See Section 4.2 Dose and Method of Administration for the correct dosing instructions for Paracetamol Kabi.
Analgesia - adults. Two Phase III studies were conducted to compare the safety and analgesic efficacy of intravenous (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 solution for infusion 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%) of 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 solution for infusion 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) and patients global evaluation (PGA)). The secondary measured efficacy endpoint parameter was paracetamol solution for infusion 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 solution for infusion 1 g and 50 patients 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 solution for infusion 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 solution for infusion 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 15 mg/kg solution for infusion. 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 and changes from baseline in HR, SBP and DBP.
An overview of results is shown in Tables 9 and 10.

Antipyrexia. Propacetamol is a different formulation than paracetamol solution for infusion 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 IV 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 solution for infusion) 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 re-medication (with calculation of time at which 50% of children require re-medication) over the T₀-T₆ period, number and percentage of children requiring rescue medication over the T₀-T₆ period and safety vital signs and adverse events.
An overview of the results are shown in Tables 11 and 12.

5.2 Pharmacokinetic Properties

Absorption.

Adults.

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 as and from 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 bioavailability of paracetamol following infusion of 500 mg of paracetamol 10 mg/mL, solution is similar to that observed following infusion of 1 g propacetamol (containing 500 mg paracetamol). The maximum plasma concentration (C_max) of paracetamol observed at the end of 15 minutes intravenous infusion of 500 mg of paracetamol 10 mg/mL, is about 15 microgram/mL.
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.

Pharmacokinetics in special populations.

Neonates and infants < 6 months of age.

Clinical trials examining the pharmacokinetics of paracetamol solution for infusion in neonates and infants < 6 months of age are limited. The safety and efficacy of paracetamol solution for infusion in premature neonates has not been established. In a trial of twelve children between 1 and 232 days of age, which included five (5) children less than 10 days of age, the pharmacokinetic results for paracetamol solution for infusion are shown in 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 hours) than in adults.

Elderly (> 65 years).

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.

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).

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 impairment may decrease the clearance of paracetamol or increase the probability of hepatic toxicity.

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

Mannitol, cysteine hydrochloride, nitrogen (as protective gas), water for injections.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned, see Section 4.2 Dose and Method of Administration.

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.

6.4 Special Precautions for Storage

Vials.

Store below 25°C.

Freeflex bags.

Store below 25°C.
Do not refrigerate or freeze.

6.5 Nature and Contents of Container

Paracetamol 10 mg/mL solution for infusion is available in clear glass vials of 50 mL or 100 mL.
Paracetamol 10 mg/mL solution for infusion is available in 50 mL and 100 mL freeflex bags. Freeflex bags consist of a primary bag made of polyolefine, and an overpouch as a secondary protective bag. An oxygen absorber is placed between the inner bag and overpouch. The ports are made of polypropylene.
50 mL vials are available in packs of 10.
100 mL vials are available in packs of 10, 12 and 20.
50 mL freeflex bags are available in cartons of 20, 50 and 60 bags.
100 mL freeflex bags are available in cartons of 20, 50 and 60 bags.
*Not all pack sizes may be marketed.

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 Name: N-(4-hydroxyphenyl) acetamide.

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