PARACIP Injection (Paracetamol )

Table of Content

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

 Qualitative and Quantitative Composition

PARACIP IV

Each 100ml contains

Paracetamol IP…….1000mg

Water for injections IP…… q.s

Excipients: Mannitol IP, Di-Sodium

Hydrogen Phosphate Dihydrate BP,

Hydrochloric Acid IP

Dosage Form and Strength

Solution for infusion

Clinical Particulars

Therapeutic Indications

Paracetamol 10 mg/ml Solution for Infusion is indicated for the short-term treatment of moderate pain, especially following surgeryand for the short-term treatment of fever, when administration by intravenous route is clinically justified by an urgent need to treat pain or hyperthermia and/or when other routes of administration are not possible.

Posology and Method of Administration

Intravenous use.

The 50 ml vial is adapted to term newborn infants, infants, toddlers and children weighing less than 33kg.

The 100 ml vial is restricted to adults, adolescentsand children weighing more than 33 kg.

Posology

Dosing based on patient weight (please see the dosing table here below)

Patient weight

Dose per

administration

Volume

per

administration

Maximum volume of paracetamol, solution

for infusion (10 mg/

mL) peradministration

based on upper weightlimits of group (mL)**

Maximum

Daily Dose

***

≤10kg *

7.5mg/kg

0.75mL/kg

7.5mL

30mg/kg

> 10kg to

≤33kg

15mg/kg

1.5mL/kg

49.5mL

60mg/kg not

exceeding 2g

> 33kg to

≤50kg

15mg/kg

1.5mL/kg

75mL

60mg/kg not

exceeding 3g

>50kg with

additional

risk factors for

hepatotoxicity

1g

100ml

100mL

3g

> 50kg and

no additional

risk factors for

hepatotoxicity

1g

100ml

100mL

4g

* Pre-term newborn infants: No safety and efficacy data are available for pre-term new-born infants.

**Patients weighing less will require smaller volumes.

The minimum interval between each administration must be at least 4 hours. No more than 4 doses to be given in 24 hours.

The minimum interval between each administration in patients with severe renal insufficiency must be at least 6 hours.

***Maximum daily dose: The maximum daily dose as presented in the table above is for patients that are not receiving other paracetamol containing products and should be adjusted accordingly taking such products into account.

Severe renal insufficiency: It is recommended, when giving paracetamol to patients with severe renal impairment (creatinine clearance ≤30 mL/min), to increase the minimum interval between each administration to 6 hours.

In adults with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione), dehydration:

The maximum daily dose must not exceed 3 g.

Method of administration

Take care when prescribing and administering paracetamol, solution for infusion, to avoid dosing errors due to confusion between milligram (mg) and millilitre (ml), which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume.

The paracetamol solution is administered as a 15-minute intravenous infusion.

Patients weighing ≤ 10 kg:

• The glass vial/bag of paracetamol, solution for infusion, should not be hung as an infusion due to the small volume of the medicinal product to be administered in this population

• The volume to be administered should be withdrawn from the vial/bag and diluted in a 0.9% sodium chloride solution or 5% glucose solution up to one tenth (one volume paracetamol, solution for infusion, into nine volumes diluent) and administered over 15 minutes

• A 5 or 10 ml syringe should be used to measure the dose as appropriate for the weight of the child and the desired volume. However, this should never exceed 7.5ml per dose

• The user should be referred to the product information for dosing guidelines.

To remove solution, use a 0.8 mm needle (21 gauge needle) and vertically perforate the stopper at the spot specifically indicated.

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 administration route. This monitoring at the end of the infusion applies particularly for central route infusions, in order to avoid air embolism

Contraindications

Hypersensitivity to the active substance or to propacetamol hydrochloride (prodrug of paracetamol) or to any of the excipients listed.

In cases of severe hepatocellular insufficiency.

Special Warnings and Precautions for Use

Warnings

RISK OF MEDICATION ERRORS

Take care to avoid dosing errors due to confusion between milligram (mg) and millilitre (ml), which could result in accidental overdose and death.

 

RISK OF MEDICATION ERRORS

Take care to avoid dosing errors due to confusion between milligram (mg) and millilitre (ml), which could result in accidental overdose and death.

It is recommended that a suitable analgesic oral treatment be used as soon as this route of administration 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 those recommended entail the risk of very serious liver damage. Clinical signs and symptoms 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.

Text for the 50ml and 100ml vials:

As for all solutions for infusion presented in glass vials, a close monitoring is needed notably at the end of the infusion.

Precautions for use

Paracetamol should be used with caution in cases of:

• hepatocellular insufficiency,

• severe renal insufficiency (creatinine clearance ≤30 mL/min),

• chronic alcoholism,

• chronic malnutrition (low reserves of hepatic glutathione),

• dehydration.

This medicine contains less than 1 mmol sodium (23 mg) per 50ml vial and 100ml vial, that is to say essentially 'sodiumfree'.

Drug Interactions

• Probenecid causes an almost 2-fold reduction in 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 t½ of paracetamol.

• Caution should be taken with the concomitant intake of enzyme-inducing substances. Concomitant use of paracetamol (4 g per day for at least 4 days) with oral anticoagulants 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 1 week after paracetamol treatment has been discontinued.

Use in Special Populations

Pregnancy

A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show in conclusive results. If clinically needed,paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Breast-feeding

After oral administration, paracetamol is excreted into breast milk in small quantities. No undesirable effects on nursing infants have been reported. Consequently, Paracetamol 10 mg/ml Solution for Infusion may be used in breast-feeding women.

Effects on Ability to Drive and Use Machines

Not relevant.

Undesirable Effects

The frequency of adverse events listed below is defined using the following convention:

very common (≥ 1/10); common (≥ 1/100 to 1/10); uncommon (≥ 1/1,000 to 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Organ System

 

Rare

 

Very rare

General

 

 

Malaise

Hypersensitivity reaction

Cardiovascular

Hypotension

 

Liver

 

Increased levels of hepatic transaminases

 

Platelet/blood

 

 

Thrombocytopenia

Leucopenia, Neutropenia

Frequent adverse reactions at injection site have been reported during clinical trials (pain and burning sensation).

Very rare cases of hypersensitivity reactions ranging from simple skin rash or urticaria to anaphylactic shock have beenreported and require discontinuation of treatment.Cases of erythema, flushing, pruritus and tachycardia have been reported.

If you experience any sideeffects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 18002677779 (Cipla number) or you can report to PvPI on 1800 180 3024. By reporting sideeffects, you can help provide more information on the safety of this product.

Overdose

There is a risk of liver injury (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis), 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.

Symptoms generally appear within the first 24 hours and comprise: 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 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 hospitalisation.

Before beginning treatment, take a blood sample for plasma paracetamol assay, 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 10th hour. NAC can, however, give some degree of protection even after 10 hours, but in these cases prolonged treatment is given.

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 return of normal liver function. In very severe cases, however, liver transplantation may be necessary.

Pharmacological Properties

Pharmacodynamic Properties

The precise mechanism of the analgesic and antipyretic properties of paracetamol has yet to be established; it may involve central and peripheral actions.

Paracetamol 10 mg/ml 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.

Pharmacokinetic Properties

Adults

Absorption

Paracetamol pharmacokinetics is linear up to 2 g after single administration and after repeated administration during 24 hours.

The bioavailability of paracetamol following infusion of 500mg and 1 g of Paracetamol 10 mg/ml Solution for Infusion is similar to that observed following infusion of 1g and 2 g propacetamol (containing 500mg and 1 g paracetamol respectively). The maximal plasma concentration (Cmax) of paracetamol observed at the end of 15-minutes intravenous infusion of 500mg and 1 g of Paracetamol 10 mg/ml Solution for Infusion is about 15μg/ml and 30 μg/ml respectively.

Distribution

The volume of distribution of paracetamol is approximately 1 L/kg.

Paracetamol is not extensively bound to plasma proteins.

Following infusion of 1 g paracetamol, significant concentrations of paracetamol (about 1.5 μg/mL) were observed in thecerebrospinal fluid at and after the 20th minute following infusion.

Biotransformation

Paracetamol is metabolised mainly in the liver following two major hepatic pathways: glucuronic acid conjugation and sulfuric 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 overdosing, the quantity of this toxic metabolite isincreased.

Elimination

The metabolites of paracetamol are mainly excreted in the urine. 90% of the dose administered is excreted within 24 hours, mainly as glucuronide (60-80%) and sulfate (20-30%) conjugates. Less than 5% is eliminated unchanged. Plasma half-life is 2.7 hours and total body clearance is 18 L/h.

Neonates, infants and children

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 h) than in adults. In neonates, the plasma half-life is longer than in infants i.e. around 3.5 hours. Neonates, infants and children up to 10 years excrete significantly less glucuronide and more sulfate conjugates than adults.

Table - Age related pharmacokinetic values (standardised clearance, *CLstd/Foral (L.h-1 70kg-1)

Age

Weight (kg)

CLstd /Foral (L.h-1 70kg-1 )

40 weeks PCA

3.3

5.9

3 months PNA

6

8.8

6 months PNA

7.5

11.1

1 year PNA

10

13.6

2 years PNA

12

15.6

5 years PNA

20

16.3

8 years PNA

25

16.3

*CLstd is the population estimate for CL

Special populations

Renal insufficiency

In cases of severe renal impairment (creatinine clearance 10-30 mL/min), the elimination of paracetamol is slightly delayed, the elimination half-life ranging from 2 to 5.3 hours. For the glucuronide and sulfate 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 minimum interval between each administration should be increased to 6 hours.

Elderly subjects

The pharmacokinetics and the metabolism of paracetamol are not modified in elderly subjects. No dose adjustment is required in this population.

Non-Clinical Properties

Studies on local tolerance of Paracetamol 10 mg/ml Solution for Infusion in rats and rabbits showed good tolerability. Absence of delayed contact hypersensitivity has been tested in guinea pigs.

Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

Description

Paracetamol is a non-salicylate antipyretic and non-opioid analgesic agent. Its chemical name is N-acetyl-p-aminophenol. Paracetamol has a molecular weight of 151.16.

PARACIP IV is a sterile, clear, colourless, nonpyrogenic, isotonic formulation of paracetamol intended for intravenous infusion. It has a pH of approximately 5.5 and an osmolality of approximately 290 mOsm/kg. Each 100 mL contains 1000 mg paracetamol, USP, 3850 mg mannitol, USP, 25 mg cysteine hydrochloride, monohydrate, USP, and 10.4 mg dibasic sodium phosphate, USP. pH is adjusted with hydrochloric acid and/or sodium hydroxide.

Pharmaceutical Particulars

Incompatibilities

This medicinal product must not be mixed with other medicinal products except for dilution with 0.9% sodium chloride or 5% glucose solution

Shelf-Life

See on pack

Packaging Information

Bottle of 100 ml

Storage and Handling Instructions

Store below 30C. Protect from light & moisture. Do not freeze.

Keep out of reach of children.

Patient Counselling Information

What Paracetamol 10mg/ml Solution for Infusion is and what it is used for

Paracetamol 10mg/ml Solution for Infusion is an analgesic (it relieves pain) and an antipyretic (it lowers fever).

• The 100 ml vial is restricted to adults, adolescents and children weighing more than 33 kg.

• The 50 ml vial is adapted to term newborn infants, infants, toddlers and children weighing less than 33 kg.

It is indicated for the short-term treatment of moderate pain, especially following surgery, and for the short-term treatment of fever.

What you need to know before you use Paracetamol 10mg/ml Solution for Infusion

Do not use Paracetamol 10mg/ml Solution for Infusion if you:

• are allergic to paracetamol or any of the other ingredients of this medicine. An allergic reaction may include a rash, itching, difficulty breathing or swelling of the face, lips, throat or tongue.

• are allergic to propacetamol (another analgesic similar to paracetamol).

• suffer from severe liver disease.

Warnings and precautions

Talk to your doctor or pharmacist before using Paracetamol 10mg/ml Solution for Infusion

• Use a suitable oral pain killer as soon as this administration route is possible

• If you suffer from a liver or kidney disease, or from alcohol abuse

• If you are taking other medicines containing paracetamol

• In cases of nutrition problems (malnutrition) or dehydration

Inform your doctor before treatment if any of the above mentioned conditions apply to you.

Other medicines and Paracetamol 10mg/ml Solution for Infusion

Tell your doctor, nurse or pharmacist if you are taking, have recently taken or might take any other medicines.

Take particular care if you are taking the following medicines while under treatment with Paracetamol 10mg/ml Solution for Infusion:

• other paracetamol-containing products, in order not to exceed the recommended daily dose.

• probenecid.

• salicylamide.

• oral anticoagulants. More check-ups to look at the effect of the anticoagulant might be needed.

Pregnancy and breast-feeding

Inform your doctor or nurse if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby.

If necessary, Paracetamol 10mg/ml Solution for Infusion can be used during pregnancy. Your doctor should use the lowest possible dose that reduces your pain and/or your fever and use it for the shortest time possible. Contact your doctor or midwife if the pain and/or fever are not reduced or if you need to receive the medicine more often.

Ask your doctor, nurse or pharmacist for advice before taking any medicine.

Important information about some of the ingredients of Paracetamol 10mg/ml Solution for Infusion

This medicine contains less than 1 mmol sodium (23 mg) per 50ml vial and 100ml vial, that is to say essentially ‘sodium-free’.

How to use Paracetamol 10mg/ml Solution for Infusion

For intravenous use (injection into a vein).

• The 50ml vial is adapted to term newborn infants, infants, toddlers and children weighing less than 33kg.

• The 100ml vial is restricted to adults, adolescents and children weighing more than 33kg.

Dosage

Do not take anything else containing paracetamol while using this medicine.

The dose you will be given will be decided by the doctor and will depend on your weight, liver and kidney function.

Patient weight

Dose per

administration

Volume

per

administration

Maximum volume of

paracetamol, solution

for infusion (10 mg/

mL) per administration

based on upper weight

limits of group (mL)**

Maximum

Daily Dose

***

≤10kg *

7.5mg/kg

0.75mL/kg

7.5mL

30mg/kg

> 10kg to

≤33kg

15mg/kg

1.5mL/kg

49.5mL

60mg/kg not

exceeding 2g

> 33kg to

≤50kg

15mg/kg

1.5mL/kg

75mL

60mg/kg not

exceeding 3g

>50kg with

additional

risk factors for

hepatotoxicity

1g

100ml

100mL

3g

> 50kg and

no additional

risk factors for

hepatotoxicity

1g

100ml

100mL

4g

* Pre-term newborn infants: No safety and efficacy data are available for pre-term newborn infants.

**Patients weighing less will require smaller volumes.

The minimum interval between each administration must be at least 4 hours.

The minimum interval between each administration in patients with severe renal insufficiency must be at least 6 hours.

No more than 4 doses to be given in 24 hours.

***Maximum daily dose: The maximum daily dose as presented in the table above is for patients that are not receiving other paracetamol containing products and should be adjusted accordingly taking such products into account.

In patients weighing 50kg or less or with risk factors, you will be given a maximum dose of 3g per day.

The paracetamol solution is administered in intravenous infusion over 15 minutes.

If you have the impression that the effect of Paracetamol 10mg/ml Solution for Infusion is too strong or too weak, talk to your doctor.

If you are given more Paracetamol 10mg/ml Solution for Infusion than you should

Talk to a doctor at once if you are given too much of this medicine even if you feel well. This is because too much paracetamol can cause delayed, serious liver damage.

In overdose cases, symptoms generally appear within the first 24 hours and comprise: nausea, vomiting, anorexia, pallor, abdominal pain and a risk of liver injury.

If you have any further questions on the use of this medicine, ask your doctor, nurse or pharmacist.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Contact your doctor or nurse and stop treatment immediately if you experience an allergic reaction with symptoms such as swelling of the face, lips, tongue and throat, difficulty breathing or swallowing or a skin rash.

Tell your doctor or nurse if you experience the following side effects:

Rare (may affect up to 1 in 1,000 people)

• a general feeling of being unwell (malaise)

• a drop in blood pressure

• changes in liver enzymes found during blood checks. Should this occur, inform your doctor as regular blood checks may be required later.

Very rare (may affect up to 1 in 10,000 people)

• other changes in laboratory test results which may result in regular blood checks: abnormally low levels of some types of blood cells (platelets, white cells) can occur, possibly leading to bleeding from the nose or gums.

Not Known (frequency cannot be estimated from the available data)

• Cases of redness of the skin, flushing, itching and abnormally rapid beating of the heart have been reported.

• Cases of pain and burning sensation at injection site have been reported.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 267 7779 (Cipla number) or you can report to PvPI on 1800 180 3024. By reporting side effects, you can help provide more information on the safety of this product.

How to store Paracetamol 10mg/ml Solution for Infusion

Keep out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month.

Store below 30ºC. Protect from light. Store in the original package. Do not refrigerate or freeze.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Contents of the pack and other information

What Paracetamol 10mg/ml Solution for Infusion contains

• The active substance is paracetamol.

• One ml contains 10mg paracetamol.

• Each 50ml vial contains 500mg paracetamol

• Each 100ml vial contains 1000mg paracetamol in 100ml.

• The other ingredients are: cysteine hydrochloride monohydrate, disodium phosphate dihydrate, hydrochloric acid (1M) (for pH-adjustment), sodium hydroxide (1M) (for pH-adjustment), mannitol, water for injections.

What Paracetamol 10mg/ml Solution for Infusion looks like and contents of the pack

Vials 50ml and 100ml

Paracetamol 10mg/ml Solution for Infusion is a clear solution.

Details of The Manufacturer

Akums Drugs & Pharmaceuticals Ltd.

2, 3, 4 &5,Sector-6B, I.I.E, SIDCUL,

Haridwar-249 403, India

Marketed by CIPLA LTD.

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg, Lower Parel,

Mumbai-400 013 India.

Details of Permission or Licence Number with Date

1/UA/SC/P(LVP)/2008 on Dated 10.07.2018

Date of Revision

06/03/2020