PARACIP Injection (Paracetamol )

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1 Published on: 22 Sep 2014 PARACIP Injection (Paracetamol ) Black Box Warning: For Medication Error And Hepatotoxicity Vigilance is advised when prescribing and administering I.V. paracetamol 10 mg/ml solution for infusion to ensure that the correct dose is given. For all patients, dose requirement is based on weight as outlined below. Paracetamol has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of paracetamol at doses that exceed the recommended maximum daily limits, and often involve more than one paracetamol-containing product. Composition PARACIP Solution for Infusion Each 100 ml contains: Paracetamol, IP...1,000 mg Water for Injection, IP...q.s. Dosage Form Solution for I.V. infusion Pharmacology Pharmacodynamics Paracetamol is a non-opiate, para-aminophenol derivative that exhibits analgesic and antipyretic activity. The precise mechanism of the analgesic and antipyretic properties of paracetamol has yet to be established; it may involve central and peripheral actions. Paracetamol I.V. 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 I.V. reduces fever within 30 minutes after the start of administration, with duration of the antipyretic effect lasting for at least 6 hours. Pharmacokinetics Absorption Paracetamol I.V. pharmacokinetics is linear up to 2 g after single administration and after repeated administration during 24 hours. The bioavailability following the infusion of 1 g paracetamol 10mg/mL is similar to that observed following the infusion of 2 g propacetamol (containing 1 g paracetamol). The peak plasma concentration is obtained as and from the end of infusion. The maximal plasma concentration (C max ) of paracetamol observed followingi.v. infusion of 1 g of paracetamol

2 I.V. is about 30 μg/ml and about 15minutes is required to obtain the maximal concentration (T max ). Distribution The volume of distribution of paracetamoli.v. is approximately 1 L/kg.Paracetamolis not extensively bound to plasma proteins. Following infusion of 1 g paracetamoli.v., significant concentrations of paracetamol (about 1.5 μg/ml) were observed in the cerebrospinal fluid 20 minutes following infusion. Metabolism Paracetamol is metabolized 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 metabolized by cytochrome (CY) 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 overdosing, the quantity of this toxic metabolite is increased. At the therapeutic doses, CYP3A4, the major isoform of P450 in the human liver, contributes to the production of the cytotoxic metabolite. For very high, supratherapeutic plasma concentration (1,500mg/L) of paracetamol, the 2E1 and 1A2 isoforms may also be involved. Elimination The metabolites of paracetamoli.v. are mainly excreted in the urine. Of the dose administered,90%is excreted within 24 hours, mainly as glucuronide (60 to 80%) and sulphate (20 to 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 I.V. in neonates and infants <6 months of age are limited. The safety and efficacy of paracetamol in premature neonates has not been established. In a trial of 12 children between 1 and 232 days of age, which included 5 children <10 days of age, the pharmacokinetic results for paracetamol were as follows: Pharmacokinetic parameters of all children and of children aged <10 days and >10 days Total <10 days >10 days P t 1/2, h 2.7 (1.0) 3.5 (0.5) 2.1 (0.9) <0.05 AUC, μg/l/h 41.3 ((25.9) 64.0 (23.7) 25.0 (10.9) <0.01 CL,L/kg/h (0.2) (0.067) (0.219) <0.05 V, L/kg 0.8 (0.2) 0.7 (0.2) 0.9 (0.1) NS Results are expressed as means, with SD in parentheses. T 1/2 = Elimination halflife; AUC = area under the curve; CL = total body clearance of drug from the plasma; V = volume of distribution. The infants in the study were aged between 1 and 232 days(mean, 88 ± 95 days). In the neonates aged <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

3 ± kg (1 to 3.8); birth weight was ± kg (1 to kg). The mean administered dose was 15.3 ± 2 mg/kg (13.40 to 20mg/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. Indications PARACIP is indicated for the short-term treatment of moderate pain, especially following surgery; and, short-term treatment of fever When administration by the I.V. route is clinically justified by an urgent need to treat pain or hyperthermia and/or when other routes of administration are not possible. Dosage And Administration Dosage PARACIP may be given as a single or repeated dose for the treatment of acute pain or fever. No dose adjustment is required in adults and adolescents who weigh 50 kg and above. The calculated maximum daily dose of paracetamol is based on all routes of administration (i.e. I.V., oral, and rectal) and all products containing paracetamol. Exceeding the maximum mg/kg daily dose of paracetamol as described in the tables belowmay result in hepatic injury, including the risk of liver failure and death. To avoid the risk of overdose, ensure that the total amount of paracetamol from all routes and from all sources does not exceed the maximum recommended dose. Adults and Adolescents Adults and adolescents weighing 50 kg and over: the recommended dosage of PARACIP is 1,000 mg every 6 hours or 650 mg every 4 hours, with a maximum single dose of PARACIP of 1,000 mg, a minimum dosing interval of 4 hours, and a maximum daily dose of paracetamol of 4,000 mg per day (includes all routes of administration and all paracetamolcontaining products, including combination products). Adults and Adolescents Weighing Under 50 kg: The recommended dosage of PARACIP is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours, with a maximum single dose of PARACIP of 15 mg/kg, a minimum dosing interval of 4 hours, and a maximum daily dose of paracetamol of 75 mg/kg per day (includes all routes of administration and all paracetamol-containing products including combination products). Dosing for Adults and Adolescents

4 Age group Dose given every 4 hours Dose given every 6 hours Maximum single dose Maximum total daily dose of paracetamol (by all routes) Adults and adolescents (13 years and older) weighing 50 kg 650 mg 1,000 mg 1,000 mg 4,000 mg in 24 hours Adults and adolescents (13 years and older) weighing 12.5 mg/kg 15 mg/kg 15 mg/kg (up to 750 mg) 75 mg/kg in 24 hours (up to 3,750 mg) Children Children 2 to 12 Years of Age: The recommended dosage of PARACIP is 15mg/kg every 6 hours or 12.5 mg/kg every 4 hours, with a maximum single dose of PARACIP of 15 mg/kg, a minimum dosing interval of 4 hours, and a maximum daily dose of paracetamol of 75 mg/kg per day. Dosing for Children Age group Dose given every 4 hours Dose given every 6 hours Maximum single dose Maximum total daily dose of paracetamol (by all routes) Children, 2 to 12 years of age 12.5 mg/kg 15 mg/kg 15 mg/kg (up to 750 mg) 75 mg/kg in 24 hours (up to 3,750 mg) PARACIP should not be mixed with other medicinal products. Paracetamol 1g per administration, i.e. one 100 ml vial, up to four times a day. The minimum interval between each administration must be 4 hours in patients without hepatic impairment.the maximum daily dose from all sources of paracetamol must not exceed 4 g. The paracetamol solution is administered as a 15-minute I.V. infusion; it contains no antimicrobial agent, and is for single use in one patient only. Dosage for Renal and Hepatic Impairment In patients with renal and/or hepatic impairment, the minimum interval between doses must not be less than 6 hours.

5 Contraindications PARACIP 10mg/ml is contraindicated In patients with a hypersensitivity to paracetamol or to propacetamol hydrochloride (prodrug of paracetamol) or to any of the excipients; In cases of severe hepatocellular insufficiency; and, In patients with hepatic failure or decompensated active liver disease. Warnings And Precautions General Hepatic Injury Administration of paracetamol in doses higher than recommended may result in hepatic injury, including the risk of liver failure and death. Do not exceed the maximum recommended daily dose of paracetamol. The maximum recommended daily dose of paracetamol includes all routes of paracetamol administration and all paracetamol-containing products administered, including combination products. Use caution when administering paracetamol in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolaemia (e.g. due to dehydration or blood loss), or severe renal impairment (creatinine clearance 30 ml/min). Serious Skin Reactions Rarely, paracetamol may cause serious skin reactions such as acute generalized exanthematouspustulosis (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. Risk of Medication Errors Take care when prescribing and administering paracetamol I.V.in order to avoid dosing errors, which could result in accidental overdose and death. In particular, be careful to ensure that the dose in milligrams (mg) and millilitres (ml) is not confused; the dosing is based on weight for patients under 50 kg; and, the total daily dose of paracetamol from all sources does not exceed the maximum daily limits. The total dose of paracetamol should not exceed 4g per day. It is important to consider the contribution of all paracetamol-containing medications, including non-prescription, oral or Prescription forms of the drug, to thetotal daily paracetamol dose prior to administering paracetamol I.V. If the daily dose of paracetamol from all sources exceeds the maximum recommended dose, severe hepatic injury may occur. Clinical signs and symptoms of liver damage are not usually seen until 2days, and up to a maximum of 4 to 6 days, after administration. Treatment with an antidote should be given as soon as possible. Allergy and Hypersensitivity There have been postmarketing reports of hypersensitivity and anaphylaxis associated with the use of paracetamol. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, and pruritus. There were infrequent reports of life-threatening anaphylaxis requiring emergent medical attention. Discontinue immediately if symptoms associated with allergy or hypersensitivity occurs. It is recommended that a suitable analgesic oral treatment be used as soon as this route of administration is possible. Paracetamol should be used with caution in cases of hepatocellular insufficiency;

6 severe renal insufficiency (creatinine clearance 30 ml/min); chronic alcoholism; chronic malnutrition (low reserves of hepatic glutathione); and, dehydration. Drug Interactions Probenecid causes an almost 2-fold reduction in the clearance of paracetamol by inhibiting its conjugation with glucuronic acid. A reduction in the paracetamol dose should be considered if it is to be used concomitantly with probenecid. Salicylamide may prolong the elimination t 1/2 of paracetamol. Caution should be taken with the conconmitantintake of enzyme-inducing substances such as certain barbiturates, isoniazid, anticoagulants, zidovudine, amoxicillin + clavulanic acid, carbamazepine and ethanol. Induction of the 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 may lead to slight variations of the international normalized ratio (INR) values. In this case, increased monitoring of the INR values should be conducted during the period of concomitant use as well as for 1 week after paracetamol treatment has been discontinued. Phenytoin administered concomitantly may result in decreased paracetamol effectiveness andan 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 is eliminated from the body via conjugation with glutathione. Concomitant use with paracetamol may result in reduced busulfan clearance. 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. Therefore, when giving paracetamol to patients with severe renal impairment (creatinine clearance 30 ml/min), the daily dose of paracetamol should be minimized and the minimum interval between each administration should be increased to 6 hours. Hepatic Impairment Paracetamol is contraindicated in patients with severe hepatic impairment or severe active liver disease and should be used with caution in patients with hepatic impairment or active liver disease. A reduced total daily dose of paracetamol may be warranted. Pregnancy Pregnancy Category C There are no studies of paracetamol I.V.in pregnant women; however, epidemiological data on oral paracetamol use in pregnant women show no increased risk of major congenital malformations. Animal reproduction studies have not been conducted with paracetamoli.v., and it is not known whether paracetamol I.V.can cause foetal harm when administered to a pregnant woman. Paracetamol I.V.should be given to a pregnant woman only if clearly needed. Lactation After oral administration, paracetamol is excreted into breast milk in small quantities. No undesirable effects on nursing infants have been reported. Consequently, paracetamoli.v. may be used in breastfeeding women; caution should be

7 used when administering paracetamoli.v. to women who are breastfeeding. Paediatric Use The safety and effectiveness of paracetamol I.V.for the treatment of acute pain and fever in paediatric patients aged 2 years is supported by evidence from adequate and well-controlled studies of paracetamol I.V. in adults. The effectiveness of paracetamol I.V.for the treatment of acute pain and fever has not been studied in paediatric patients <2 years of age. Geriatric Use There was a significant increase in the AUC and a reduction in the clearance of paracetamol and its metabolites in elderly subjects. However, these statistically significant differences were not likely to be clinically relevant during shortterm infusions. Hence, no dose adjustment is required in this population. Undesirable Effects The overall incidence of adverse events in paracetamol I.V.-treated patients compared withplacebo within the clinical trial set is given below: Adverse Events in Adults-Greater Than 1% Neurological: Dizziness, headache, dystonia Gastrointestinal: Vomiting, dry mouth, diarrhoea, constipation, nausea, dyspepsia, enlarged abdomen, gastrointestinal disorder NOS Haematological: Anaemia, post-operative haemorrhage Hepatobiliary: Increase in gamma GT, increase in SGPT Psychiatric: Insomnia Skin and Appendage: Injection site pain, injection site reaction, post-operative site reaction, pruritus Respiratory: Alveolitis, coughing Endocrine/Metabolic: Hyperglycaemia, hypokalaemia General: Fatigue, fever, oedema peripheral, chest pain Adverse Events in Children-Greater Than 1% (observed in the clinical trial set) Skin and Appendage: Injection site pain, injection site reaction Neurological: Hypotonia Gastrointestinal: Nausea, vomiting, abdominal pain, eructation Body as a Whole: Fever Other Adverse Events As with all paracetamol products, adverse drug reactions are rare (>1/10,000, <1/1,000) or very rare (<1/10,000), andare described below: General Disorders and Administration Site Conditions Rare: Malaise Very rare: Hypersensitivity reaction Cardiac Disorders Rare: Hypotension Very rare: Shock Hepatobiliary Disorders Rare: Increased levels of hepatic transaminases Blood and the Lymphatic System Disorders

8 Rare: Agranulocytosis, neutropenia Isolated reports: Thrombocytopenia Neurological Very rare: Neurological disorders Isolated reports: Coma Renal/Genitourinary Very rare: Acute renal failure Skin and Subcutaneous Tissue Disorders Rare: Macular rash, injection site reaction Very rare:maculo-papular rash, pemphigoid reaction, pustular rash Isolated cases: Lyell'ssyndrome Postmarketing Adverse Events for Propacetamol/ Paracetamol The following adverse events have also been reported during postmarketing surveillance, but the incidence rate (frequency) is not known. Organ system Blood and the lymphatic system disorders Cardiac disorders Gastrointestinal disorders General disorders and administration site conditions Hepatobiliary disorders Adverse event - Thrombocytopenia - Tachycardia - Nausea - Vomiting - Administration site reaction - Fulminant hepatitis - Hepatic necrosis - Hepatic failure - Hepatic enzymes increased

9 Immune system disorders Skin and subcutaneous tissue disorders - Angioneurotic (Quincke's) oedema - Anaphylactic shock - Anaphylaxis - Hypersensitivity reactions (ranging from simple skin rash or urticaria to anaphylactic shock) have been reported and require the discontinuation of treatment - Erythema - Flushing - Pruritus - Rash - Urticaria Overdosage 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. Overdosing 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 comprisenausea, vomiting, anorexia, pallor, and abdominal pain. An overdose of 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 hepatic cytolysis likely to induce complete and irreversible necrosis, resulting in 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. Emergency Measures Immediate hospitalization. Before beginning treatment, a blood sample for a plasma paracetamol assay must be taken as soon as possible after the overdose. The treatment includes administration of the antidote, N-acetylcysteine (NAC) by the I.V. or oral route, if possible before the tenthhour. NAC can, however, give some degree of protection even after 10 hours, but, in these cases, prolonged treatment is given. The optimal time for administration of NAC and the necessary duration of therapy have not been established for an overdose of paracetamol I.V. 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 1to 2weeks with full return of normal liver function. In very severe cases, however, liver transplantation may be necessary.

10 Incompatibility Paracetamol I.V. should not be mixed with other medicinal products. Storage And Handling Instructions Store in a cool, dry and dark place. Do not freeze Packaging Information PARACIP Solution for Infusion: Bottle of 100 ml Last reviewed: December 2013 Last updated: December 2013 PARACIP Injection Source URL: