Paracetamol Fresenius 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. See section 4.2

DO NOT EXCEED THE RECOMMENDED DOSE

The prescribed dose must be based on the patientu2019s weight. For single use only. 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 4.8)

For Paediatric use: Restricted to children weighing more than 10 kg (approximately 1 year of age) but less than 33 kg (approximately 11 years old).

Recommended dosage in adult patients: The recommended dose in adult patients weighing more than 50 kg is: PARACETAMOL FRESENIUS 10 mg/ml per administration (i.e., one 100 ml vial) 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.

The recommended dose in adult patients weighing less than 50 kg and more than 33 kg (approximately 11 years old) is: PARACETAMOL FRESENIUS 10 mg/ml : 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. For these adult underweight patients, the maximum daily dose must not exceed 60 mg/kg and must not exceed 3 g in 24 hours.

ADULT PATIENTS: DOSING IS BASED ON PATIENT WEIGHT 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 vial) 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

* The maximum daily dose takes into account all the medicines containing paracetamol.

The dosage should be calculated on non-oedematous weight.

Recommended dosage in paediatric and adolescent patients The 100 ml vial is restricted to adults, adolescents, and children weighing more than 33 kg.

PAEDIATRIC AND ADOLESCENT PATIENTS: DOSING IS BASED ON PATIENT WEIGHT 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 > 10 kg and u2264 33 kg 15 mg/kg (ie. 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

Patients with severe renal insufficiency: It is recommended to leave a minimum interval time of 6 hours in patients with severe renal impairment (creatinine clearance of u2264 30 ml/min).

Patients with 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
• Gilbertu2019s syndrome (familial hyperbilirubinaemia)
• chronic alcoholism
• chronic malnutrition (low reserves of hepatic glutathione)
• dehydration

Method of administration General For all patients, PARACETAMOL FRESENIUS 10 mg/ml is to be administered as a 15-minute intravenous infusion. Before administration, the product should be visually inspected for any particulate matter and discolouration. It is intended for single use only. Once opened, the vial should be used immediately. As PARACETAMOL FRESENIUS 10 mg/ml is presented in glass vials, close monitoring to avoid air embolism is needed, notably at the end of the infusion, regardless of the route of administration but especially if a central venous catheter is used for the infusion. Any unused solution should be discarded. PARACETAMOL FRESENIUS 10 mg/ml should not be mixed with other medicines. PARACETAMOL FRESENIUS 10 mg/ml may be diluted up to one-tenth (one volume PARACETAMOL FRESENIUS 10 mg/ml into nine volumes diluent) in 0,9 % sodium chloride solution or a 5 % glucose solution. The volume of the diluted solutions should take into account the total volume of fluid to be administered to the patient as well as the medical condition of the patient. When PARACETAMOL FRESENIUS 10 mg/ml (50 ml vial) is diluted as recommended, the total volume of diluted solution to be administered must be infused within one hour of its preparation (infusion time included).

PARACETAMOL FRESENIUS 10 mg/ml should not be used in:

• Patients that are hypersensitive to paracetamol, pro-paracetamol hydrochloride (pro-drug of paracetamol), or any of the excipients of PARACETAMOL FRESENIUS 10 mg/ml.
• Patients with severe hepatocellular insufficiency, or active liver disease including alcoholic hepatitis.

Warnings 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. See section 4.9

PARACETAMOL FRESENIUS 10 mg/ml can cause serious skin reactions such as acute generalized 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 medicine should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

PARACETAMOL FRESENIUS 10 mg/ml 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 should be contacted immediately.

Patients recovering from liver damage should not be given high doses of PARACETAMOL FRESENIUS 10 mg/ml. PARACETAMOL FRESENIUS 10 mg/ml should be used with caution in patients with renal damage of disease.

Special precautions: PARACETAMOL FRESENIUS 10 mg/ml 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 10 mg/ml should also be used with caution in the following cases:

• Patients with renal damage or disease
• Patients with severe renal insufficiency (creatinine clearance u2264 30 ml/min) see section 4.9 and
• Hepatocellular insufficiency, including Gilbertu2019s syndrome (familial hyperbilirubinaemia) See sections 4.2 and section 5
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency which may lead to haemolytic anaemia.
• Chronic alcoholism, 3 or more alcoholic drinks every day.
• Chronic malnutrition, anorexia, bulimia, cachexia (low reserves of hepatic glutathione).
• Dehydration, hypovolaemia.

u201cPARACETAMOL FRESENIUS 10 mg/ml contains mannitol and may have a laxative effect.u201d

u2022 Phenytoin administered concomitantly with PARACETAMOL FRESENIUS 10 mg/ml may result in decreased paracetamol efficacy and an increased risk of hepatotoxicity. Patients receiving phenytoin should avoid large and/or chronic doses of paracetamol. Patients should be monitored for evidence of hepatotoxicity.

u2022 Probenecid causes a significant decrease in the clearance of paracetamol by inhibiting its conjugation with glucuronic acid. A reduction of the PARACETAMOL FRESENIUS 10 mg/ml dose should be considered when administered concomitantly with probenecid.

u2022 Salicylamide may prolong the elimination half-life of PARACETAMOL FRESENIUS 10 mg/ml.

u2022 Concomitant intake of PARACETAMOL FRESENIUS 10 mg/ml with 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, anticoagulants, zidovudine and chronic use of alcohol See section 4.9

u2022 Flucloxacillin: Caution is advised when paracetamol is administered concomitantly with flucloxacillin due to the increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with a risk factor for glutathione deficiency such as severe renal impairment, sepsis, malnutrition and chronic alcoholism. Close monitoring is recommended in order to detect the appearance of acid base disorders, namely HAGMA, including the search of urinary 5-oxoproline.

Effect of PARACETAMOL FRESENIUS 10 mg/ml on other medicines:

u2022 PARACETAMOL FRESENIUS 10 mg/ml may increase the chance of unwanted effects when administered with other medicines.

u2022 Anticoagulants: Concomitant use of PARACETAMOL FRESENIUS 10 mg/ml (4 g per day for at least 4 days) with coumarins including warfarin may lead to 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 10 mg/ml treatment has been discontinued.

Pregnancy: Clinical experience of intravenous administration of PARACETAMOL FRESENIUS 10 mg/ml 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. 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 foetotoxic effects. Nevertheless, PARACETAMOL FRESENIUS 10 mg/ml 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 10 mg/ml to woman who are breastfeeding.

PARACETAMOL FRESENIUS 10 mg/ml has no influence on the ability to drive and use machines.

Blood and the lymphatic system disorders Less frequent: Thrombocytopenia, agranulocytosis, leukopenia, pancytopenia, neutropenia, anaemia.

Immune system disorders Less frequent: Hypersensitivity, anaphylactic shock, angioedema.

Cardiac disorders Frequency unknown: Tachycardia, Hypotension

Vascular disorders Less frequent: Hypotension, flushing.

Gastrointestinal disorders Less frequent: Nausea, vomiting, pancreatitis.

Hepato-biliary disorders Less frequent: Increased levels of hepatic transaminases, hepatitis, hepatic necrosis, hepatic failure.

Frequency unknown: Fulminant hepatitis, pancreatitis

Skin and subcutaneous tissue disorders Less frequent: Dermatitis, skin rash, urticaria, erythema, pruritus.

Acute generalised exanthematous pustulosis, Toxic epidermal necrolysis Stevens-Johnson syndrome Frequency unknown: Flushing

Renal and urinary disorders Less frequent: Renal colic, renal failure and sterile pyuria.

General disorders and administrative site conditions Less frequent: Malaise, administration site reactions, hypersensitivity.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

See sections 4.4 and 4.8 Overdosage with paracetamol (including PARACETAMOL FRESENIUS 10 mg/ml) 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 10 mg/ml 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. 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 to 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, 11 th 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.