Cetagesic Iv Paed 10 mg/mL Solution for Infusion.

CETAGESIC IV PAED is indicated in children 1 year of age and older, for:

• short-term treatment of mild to moderate pain e.g., following minor surgery.
• short-term treatment of fever when the oral route 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 minimum risk factors for hepatotoxicity including hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione), and dehydration (see section 4.4). Restricted to children weighing more than 10 kg (approximately 1 year of age) but less than 33 kg (approximately 11 years old).

Dosage: 15 mg/kg of paracetamol pre-administration (i.e., 1,5 mL solution per kg) of CETAGESIC IV PAED up to four times a day. The minimum interval between each administration must be at least 4 hours. The maximum daily dose must not exceed 60 mg/kg.

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 (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

* The maximum daily dose takes into account all the medicines containing paracetamol. The dosage should be calculated on non-oedematous weight.

Special populations:

Patients with renal impairment It is recommended to leave a minimum interval of 6 hours between each administration in patients with severe renal impairment (creatinine clearance u2264 30 mL/min) (see section 5.2).

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. u2022 Gilbertu2019s syndrome (familial hyperbilirubinaemia) u2022 Chronic alcoholism u2022 Chronic malnutrition (low reserved of hepatic glutathione) and u2022 Dehydration

Method of administration CETAGESIC IV PAED 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 CETAGESIC IV PAED is presented in glass vials, dose 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. CETAGESIC IV PAED should not be mixed with other medicines (see section 6.2).

CETAGESIC IV PAED may be diluted up to one-tenth (one volume CETAGESIC IV PAED into nine volumes diluent) in a 0,9 % sodium chloride solution or a 5 % glucose solution. The volume of the diluted solution 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 CETAGESIC IV PAED 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) (see section 6.6).

CETAGESIC IV PAED is contraindicated in:

• known hypersensitivity to paracetamol or to paracetamol hydrochloride (pro-drug of paracetamol) or to any of the excipients (see section 6.1).
• cases of severe hepatocellular insufficiency or decompensated active liver disease including alcoholic hepatitis (see section 4.4).

This product contains paracetamol which may be fatal in overdose. In the event of overdosage or suspected overdose and notwithstanding the fact that the person may be asymptomatic, the nearest doctor, hospital or Poison Centre must be contacted immediately. Take care to avoid dosing errors due to confusion between milligram (mg) and milliliter (mL), which could result in accidental overdose and death. 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 either paracetamol or propacetamol. Doses higher than the recommended entails risk for very serious liver damage. Clinical symptoms and signs of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) are usually first seen after two days of drug administration with a peak seen usually after 4 - 6 days. Treatment with antidote should be given as soon as possible.

CETAGESIC IV PAED 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 medicine should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

This medicine contains 56.85 mg sodium per 50 mL. CETAGESIC IV PAED is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

CETAGESIC IV PAED contains 8,0 mg propylene glycol in each mL, which is equivalent to 12 mg/kg per 1,5 mL (total daily dose for patients > 10 kg and u2264 33 kg is 48 mg/kg propylene glycol.

CETAGESIC IV PAED should be used with caution in cases of:

• Hepatocellular insufficiency, including Gilbertu2019s syndrome (familial hyperbilirubinaemia).
• Severe renal insufficiency (creatinine clearance u2264 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)

Patients suffering from hepatitis or alcoholism, or recovering from any form of liver disease should not use excessive quantities of CETAGESIC IV PAED. Use with caution in renal disease.

Effects of other medicines on CETAGESIC IV PAED:

• 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,
• Salicylamide may prolong the elimination half-life of paracetamol,
• Caution should be paid to the concomitant use of paracetamol and enzyme-inducing substances as these substances increase the risk of paracetamol induced liver injury. These substances include but are not limited to: barbiturates, isoniazid, anticoagulants, zidovudine, amoxicillin + clavulanic acid, and ethanol,
• Phenytoin administered concomitantly with paracetamol 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.
• 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.

Effects of CETAGESIC IV PAED on other medicines:

• Paracetamol may increase the chance of unwanted effects where administered with other medicines.
• Anticoagulants: Concomitant use of paracetamol (4 g per day for at least 4 days) with concomitants 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 treatment has been discontinued.

Pregnancy Clinical experience of intravenous administration of paracetamol 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/new-born infant. Prospective data on pregnancies exposed to overdoses 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 malformation of foetotoxic effects. Nevertheless, paracetamol should be used with caution during pregnancy. In this case, the recommended dosage and duration must be strictly observed.

Breastfeeding After oral administration, paracetamol is excreted into breastmilk in small quantities. No undesirable effects on nursing infants have been reported. Rash in nursing infants has been reported. Caution should be used when administering paracetamol to women who are breastfeeding.

Not relevant.

The following Adverse Drug Reactions (ADRs) can occur:

Blood and lymphatic system disorders Less frequent: Thrombocytopenia, agranulocytosis, leucopenia, pancytopenia, neutropenia, anaemia

Cardiac disorders Less frequent: Hypotension

Hepatobiliary disorders Less frequent: Increased levels of hepatic transaminases, hepatitis, pancreatitis

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

General disorders and administration site condition Frequent: reactions at injections site (pain and burning sensation) Less frequent: Malaise, hypersensitivity reaction

Post-marketing experience: The following adverse events have also been reported during post-marketing surveillance but the incidence rate (frequency) is not known.

Organ System Adverse event Immune system disorders Anaphylactic shock Anaphylaxis Hypersensitivity reaction Angioedema Blood and lymphatic system disorders Thrombocytopenia Cardiac disorders Tachycardia Gastrointestinal disorders Nausea Vomiting Hepatobiliary disorders Fulminant hepatitis Hepatic necrosis Hepatic failure Increased hepatic enzymes

Skin and subcutaneous tissue disorders Erythema Flushing Pruritus Rash Urticarial Acute generalised exanthematous pustulosis Toxic epidermal necrolysis Stevens-Johnson syndrome General disorders and administration site condition Administration site reaction

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. Healthcare 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

Prompt treatment is essential. In the event of an overdosage, consult a doctor immediately, or take the person directly to a hospital. 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 toxicity is increased in patients who have taken repeated high doses (greater than 5 -10 g/day) of paracetamol for several days, in chronic alcoholism, chronic liver disease, AIDS, malnutrition, and with the use of drugs that induce liver microsomal oxidation such as barbiturates, isoniazid, rifampicin, phenytoin and carbamazepine.

Symptoms of paracetamol overdosage in the first 24 hours include pallor, nausea, vomiting, anorexia and possibly 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 ingestion, initially by elevation of the serum transaminase and lactic dehydrogenase activity, increased serum bilirubin concentration and prolongation of the prothrombin time. Liver damage may lead to encephalopathy, coma and death. 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 arrhythmias have been reported.

Treatment for paracetamol overdosage: Although evidence is limited it is recommended that any adult person who has ingested 5 - 10 grams or more of paracetamol (or a child who has had more than 140 mg/kg) within the preceding four hours, should have the stomach emptied by lavage (emesis may be adequate for children) and a single dose of 50 g activated charcoal given via the lavage tube. Ingestion of amounts of paracetamol smaller than this may require treatment in patients susceptible to paracetamol poisoning (see above). In patients who are stuperose or comatose endotracheal intubation should precede gastric lavage in order to avoid aspiration.

N-acetylcysteine 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 ingestion may still be of benefit, especially if more than 150 mg/kg of paracetamol was taken. An initial dose of 150 mg/kg N-acetylcysteine in 200 mL dextrose injection given intravenously over 15 minutes, followed by an infusion of 50 mg/kg in 500 ml dextrose injection over the next four hours, and then 100 mg/kg in 1 000 ml dextrose injection over the next sixteen hours. 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.

A plasma paracetamol level should be determined four hours after ingestion in all cases of suspected overdosage. Levels done before four hours may be misleading. Patients at risk of liver damage, and hence requiring continued treatment with N-acetylcysteine, can be identified according to their 4-hour plasma paracetamol level. The plasma paracetamol level can be plotted against time since ingestion in the nomogram below. The nomogram should be used only in relation to a single acute ingestion. 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. Prothrombin index correlates best with survival.

For overdose with an extended/modified release preparation the value of the nomogram is unknown. As there is no information on the plasma levels of paracetamol after an overdose of extended/modified release paracetamol preparations, all patients with suspected or known overdose with such preparations should receive N-acetylcysteine. Because of lack of data for extended/modified release formulations, a level below the u201ctreatment lineu201d of the nomogram may not exclude the possibility of toxicity. Monitor all patients with significant ingestion for at least ninety six hours.