Paracetamol 10 Mg/50 Ml/100 Ml Solution

Adults and children (1 year and body mass 10 kg) Short-term treatment of mild to moderate pain e.g., after dental procedures and minor orthopaedic surgery and the short-term treatment of fever when the oral route of administration is unsuitable.

Posology
DO NOT EXCEED THE RECOMMENDED DOSE
The prescribed dose must be based on the patientu2019s weight. Unintentional overdose can lead to serious liver damage and death (see section 4.9). 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 4.4).

Adults and adolescents weighing more than 50 kg: PARACETAMOL FRESENIUS 1 g per administration (i.e., one 100 mL bottle/bag) up to 4 times a day. The minimum interval between each administration must be 4 hours. The maximum daily dose must not exceed 4 g in 24 hours.

Adults and adolescents weighing less than 50 kg and children weighing more than 33 kg (approximately 11 years old): PARACETAMOL FRESENIUS: 15 mg/kg per administration (i.e., 1,5 mL solution per kg) up to 4 times per day. The minimum interval between each administration must be 4 hours. The maximum daily dose must not exceed 60 mg/kg and must not exceed 3 g in 24 hours.

DOSING RECOMMENDATIONS ARE PRESENTED IN THE TABLE BELOW.

* The maximum daily dose takes into account all the medicines containing paracetamol. The dosage should be calculated on non-oedematous weight. The 100 mL bottle/bag is restricted to adults, adolescents, and children weighing more than 33 kg. Paediatric use: Restricted to children weighing more than 10 kg (approximately 1 year old).

DOSING RECOMMENDATIONS ARE PRESENTED IN THE TABLE BELOW.

Patient weight (non-oedematous weight) Paracetamol dose (10 mg/mL) per administration Minimum interval between each administration Maximum daily dose*
> 50 kg 1 g (i.e. 100 mL bottle/bag) up to 4 times a day 4 hours Must not exceed 4 g in 24 hours
> 33 kg and u2264 50 kg 15 mg/kg (i.e. 1,5 mL solution per kg) up to 4 times a day 4 hours u2264 60 mg/kg Must not exceed 3 g in 24 hours
> 10 kg and u2264 33 kg 15 mg/kg (i.e. 1,5 mL solution per kg) up to 4 times a day 4 hours u2264 60 mg/kg Must not exceed 2 g in 24 hours

Severe renal insufficiency: It is recommended to leave a minimum interval time of 6 hours between each administration in patients with severe renal impairment (creatinine clearance of u2264 30 mL/min). 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:
u2022 adults weighing less than 50 kg
u2022 chronic or compensated active hepatic disease, especially those with mild to moderate hepatocellular insufficiency
u2022 Gilbertu2019s syndrome (familial hyperbilirubinaemia)
u2022 chronic alcoholism
u2022 chronic malnutrition (low reserves of hepatic glutathione)
u2022 dehydration.

Method of administration
Intravenous infusion. For all patients, PARACETAMOL FRESENIUS is to be administered as a 15-minute intravenous infusion. Close monitoring to avoid air embolism is needed, notably at the end of the infusion, especially if a central venous catheter is used for the infusion. For instructions on dilution of the product before administration, see section 6.6.

PARACETAMOL FRESENIUS should not be used in:
u2022 Patients that are hypersensitive to paracetamol, pro-paracetamol hydrochloride (pro-drug of paracetamol), or any of the excipients of PARACETAMOL FRESENIUS (see section 6.1).
u2022 Patients with severe hepatocellular insufficiency, or active liver disease including alcoholic hepatitis.
u2022 Children weighing less than 10 kg (approximately 1 year old) (see sections 4.1, 4.2).

It is highly recommended to use the oral route of administration as soon as it is available. To avoid the chance of overdose, check that any other medicines also used do not contain paracetamol. Higher doses than recommended can cause severe liver damage. The clinical signs of hepatic damage are usually seen first after 2 days with maximum damage seen after 4 u2013 6 days. Treatment with the antidote should be started as soon as possible as PARACETAMOL FRESENIUS overdose may be fatal (see section 4.9).

Severe cutaneous adverse reactions (SCARs)
Severe cutaneous adverse reactions (SCARs) such as toxic epidermal necrolysis (TEN), Steven-Johnson syndrome (SJS), acute generalised exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) / Drug-induced hypersensitivity syndrome (DIHS) and fixed drug eruptions (FDE) have been reported in patients treated with paracetamol containing medicines. If a patient develops SCAR, treatment with PARACETAMOL FRESENIUS must immediately be discontinued and appropriate treatment instituted.

PARACETAMOL FRESENIUS contains paracetamol, which may be fatal in overdose. In the event of overdosage or suspected overdose and notwithstanding the fact that the patient may be asymptomatic, the nearest doctor, hospital, or Poison Control Centre must be contacted immediately.

PARACETAMOL FRESENIUS should be used with caution in patients with mild to moderate liver impairment and it is contraindicated where there is active disease, particularly in alcoholic hepatitis. PARACETAMOL FRESENIUS should be used with caution in patients with renal damage or disease, as prolonged excessive use of PARACETAMOL FRESENIUS can produce nephropathy. Paracetamol-induced renal function impairment may be sufficiently severe and could result in uraemia, especially with prolonged use of high doses. In patients with renal impairment with a creatinine clearance of 30 mL/minute or less, the elimination of PARACETAMOL FRESENIUS is delayed, therefore a 6 hourly dose interval is recommended (see section 4.2).

PARACETAMOL FRESENIUS should be used with caution in the following cases:
u2022 Patients with renal damage or disease.
u2022 Patients with severe renal insufficiency (creatinine clearance u2264 30 mL/min) (see section 4.2).
u2022 Hepatocellular insufficiency, including Gilbertu2019s syndrome (familial hyperbilirubinaemia) (see sections 4.2, 4.3).
u2022 Glucose-6-phosphate dehydrogenase (G6PD) deficiency which may lead to haemolytic anaemia.
u2022 Chronic alcoholism, excessive alcohol intake (three or more alcoholic drinks every day).
u2022 Anorexia, bulimia or cachexia, chronic malnutrition (low reserves of hepatic glutathione).
u2022 Dehydration, hypovolaemia.

Effect of other medicines on PARACETAMOL FRESENIUS:
u2022 Phenytoin administered concomitantly with PARACETAMOL FRESENIUS may result in decreased paracetamol efficacy and an increased risk of hepatotoxicity. Patients receiving phenytoin should avoid large and/or chronic doses of PARACETAMOL FRESENIUS. Patients should be monitored for evidence of hepatotoxicity.
u2022 Probenecid could increase the plasma concentrations of PARACETAMOL FRESENIUS by almost a 2-fold reduction in the clearance of paracetamol, by inhibiting its conjugation with glucuronic acid. A reduction of the PARACETAMOL FRESENIUS dose should be considered when administered concomitantly with probenecid.
u2022 The absorption of PARACETAMOL FRESENIUS may be accelerated when used together with metoclopramide.
u2022 Salicylamide may prolong the elimination half-life of PARACETAMOL FRESENIUS.
u2022 Salicylates in prolonged treatment together with PARACETAMOL FRESENIUS significantly increase the risk of analgesic nephropathy, renal papillary necrosis, end-stage renal diseases, and cancer of the urinary bladder. The recommended individual doses for PARACETAMOL FRESENIUS and the salicylates should not be exceeded.
u2022 Medicines that induce liver microsomal enzymes such as barbiturates or primidone could decrease the therapeutic effect of PARACETAMOL FRESENIUS.
u2022 Concomitant intake of PARACETAMOL FRESENIUS with hepatic enzyme-inducing substances should be cautioned as these substances increase the risk of paracetamol induced liver injury. These substances include, but are not limited to, barbiturates, rifampicin, isoniazid, phenytoin, carbamazepine, anticoagulants, zidovudine, amoxicillin, clavulanic acid, chronic use of alcohol or hepatotoxic medicines (see section 4.9).
u2022 Flucloxacillin: Caution is advised when PARACETAMOL FRESENIUS is administered concomitantly with flucloxacillin due to the increased risk of high anion gap metabolic acidosis (HAGMA) caused by pyroglutamic acidosis, particularly in patients with a risk factors (see section 4.4).

Effect of PARACETAMOL FRESENIUS on other medicines:
u2022 PARACETAMOL FRESENIUS may increase the chance of unwanted effects when administered with other medicines.
u2022 Anticoagulants: Concomitant use of PARACETAMOL FRESENIUS (4 g per day for at least 4 days) with coumarins, including warfarin, and/or indandione derivatives, may lead to increase in anticoagulant effects and variations in 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 FRESENIUS treatment has been discontinued.

Pregnancy
Clinical experience of intravenous administration of PARACETAMOL FRESENIUS in pregnant women is limited. However, epidemiological data from the use of oral therapeutic doses of paracetamol indicate no undesirable effects on the pregnancy or on the health of the foetus/newborn infant. A large amount of data on pregnant women indicates neither malformative nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. Prospective data on pregnancies exposed to overdose did not show an increase in malformation risk. Reproductive studies with the intravenous form of paracetamol have not been performed in animals. However, studies with the oral route did not show any teratogenic or fetotoxic effects. Nevertheless, PARACETAMOL FRESENIUS should only be used during pregnancy after a careful benefit-risk assessment. In this case, the recommended dosage and duration must be strictly observed.

Breastfeeding
After oral administration paracetamol is excreted into breastmilk in small quantities. Rash in nursing infants has been reported. No undesirable effects on breastfed infants have been reported with frequent use. However, caution should be used when administering PARACETAMOL FRESENIUS to woman who are breastfeeding.

Fertility
No information available.

PARACETAMOL FRESENIUS has no influence on the ability to drive and use machines.

Tabulated list of adverse reactions
System organ class Less frequent Frequency unknown
Blood and lymphatic system disorders Thrombocytopenia Agranulocytosis Leukopenia Pancytopenia Neutropenia Anaemia 0B Immune system disorders Hypersensitivity Anaphylactic shock Angioedema 1B Metabolism and nutrition disorders High anion gap metabolic acidosis* 2B Endocrine disorders Pancreatitis 3B Cardiac disorders Tachycardia Vascular disorders Hypotension 4B Gastrointestinal disorders Nausea
Vomiting 5B Hepatobiliary disorders Increased levels of hepatic transaminases Hepatitis Fulminant hepatitis Hepatic necrosis Hepatic failure 6B Skin and subcutaneous tissue disorders Dermatitis Skin rash Urticaria Erythema Pruritus Acute generalised exanthematous pustulosis Toxic epidermal necrolysis Stevens-Johnson syndrome Flushing Drug-induced hypersensitivity syndrome (DIHS) Fixed drug eruptions (FDE) 7B Renal and urinary disorders Renal colic Renal failure Sterile pyuria 8B General disorders and administration site conditions Malaise Administration site reactions * High anion gap metabolic acidosis: Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol (see section 4.4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

Post-marketing experience
Drug-induced hypersensitivity syndrome (DIHS) and fixed drug eruptions (FDE) have been reported in patients treated with paracetamol containing medicines (see section 4.4).

See sections 4.4 and 4.8. Overdosage with PARACETAMOL FRESENIUS can result in severe liver damage and sometimes acute renal tubular necrosis. Prompt treatment is essential. In the event of an overdosage, consult a doctor immediately, or take the person to a hospital directly. A delay in starting treatment may mean that antidote is given too late to be effective. Evidence of liver damage is often delayed until after the time for effective treatment has lapsed. Susceptibility to PARACETAMOL FRESENIUS toxicity is increased in patients who have taken repeated high doses (greater than 5 u2013 10 g/day) of paracetamol for several days. 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, AIDS and with the use of medicines that induce liver microsomal oxidation such as barbiturates, isoniazid, rifampicin, phenytoin and carbamazepine (see section 4.5). Overdosing may be fatal in these cases.

Symptoms of overdose:
Symptoms generally appear within the first 24 hours and comprise: nausea, vomiting, anorexia, pallor and abdominal pain. Mild symptoms during the first two days of acute poisoning do not reflect the potential seriousness of the overdosage. Liver damage may become apparent 12 to 48 hours or later after administration, initially by elevation of the serum transaminase and lactic dehydrogenase activity, increased serum bilirubin concentration and prolongation of the prothrombin time/increased INR. Liver damage may lead to encephalopathy, coma and death. Overdose with a single administration of 7,5 g or more of paracetamol in adults or 140 mg/kg of body weight 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. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Abnormalities of glucose metabolism and metabolic acidosis may occur. Cardiac dysrhythmias have been reported.

Treatment of PARACETAMOL FRESENIUS 10 mg/mL overdose:
- Immediate hospitalisation.
- Before beginning treatment, take a tube of blood for plasma paracetamol assay, as soon as possible after the overdose.
- N-acetylcysteine (NAC) should be administered in all cases of suspected overdose as soon as possible, preferably within eight hours of overdosage; although treatment up to 36 hours after administration may still be of benefit especially if more than 150 mg/kg of paracetamol was administered. An initial dose of 150 mg/kg N-acetylcysteine in 200 mL dextrose 5 % m/v injection given intravenously over 15 minutes, followed by an infusion of 50 mg/kg in 500 mL dextrose 5 % m/v injection over the next four hours and then 100 mg/kg in 1 000 mL dextrose 5 % m/v injection over the next sixteen hours. Sodium chloride 0,9 % m/v may be used where dextrose 5 % m/v is unsuitable. The volume of intravenous fluid should be modified for children. Although the oral formulation is not the treatment of choice, 140 mg/kg dissolved in water may be administered initially, followed by 70 mg/kg every four hours for seventeen doses. Source: Goodman & Gilmanu2019s The Pharmacological Basis of Therapeutics, 11th ed. Those, whose plasma paracetamol levels are above the u201cnormal treatment lineu201d, should continue N-acetylcysteine treatment with 100 mg/kg IV over sixteen hours repeatedly until recovery. Patients with increased susceptibility to liver damage as identified above, should continue treatment if concentrations are above the u201chigh risk treatment lineu201d. (Refer to the paracetamol nomogram above). Prothrombin index correlates best with survival. Monitor all patients with significant overdose for 96 hours.
- 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.