Fevridol 1gm IV

Paracetamol Infusion IP 1.0% w/v

Each 100 ml contains:

Paracetamol IP 1000 mg

Water for Injections IP q.s.

Solution for infusion.

1000mg/100ml

4.1. Therapeutic indications

For short term treatment of moderate pain, especially following surgery and for the short term treatment of fever, when administration by intravenous route is clinically justified.

4.2. Posology and method of administration

Dosing based on patient weight.

* Preterm new-born infants:

No safety and efficacy data are available for premature newborn infants

** 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.

*** 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.

Severe renal insufficiency:

It is recommended, when giving paracetamol to patients with severe renal impairment (creatinine clearance ≤ 30 ml/min), to reduce the dose and increase the minimum interval between each administration to 6 hours.

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

The maximum daily dose must not exceed 3000 mg.

Method of administration

Intravenous use.

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

Take care when prescribing and administering Paracetamol 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. Take care to ensure the dose is measured and administered accurately.

Patients weighing ≤ 10 kg:

● The volume to be administered should be withdrawn and diluted in a sodium chloride (0.9%) solution or glucose (5%) solution up to one tenth (one volume Paracetamol into nine volumes diluent) and administered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 7.5 ml per dose

● The user should be referred to the product information for dosing guidelines. Paracetamol can be diluted in (0.9%) sodium chloride solution or (5%) glucose solution or a combination of both solutions up to one tenth (one volume Paracetamol into nine volumes diluent). In this case, use the diluted solution within the hour following its preparation (infusion time included).

For single use only. Any unused solution should be discarded.

Before administration, the product should be visually inspected for any particulate matter and discolouration. Only to be used if solution is clear, and the container and its closure are undamaged.

As for all solutions for infusion presented in containers with air space inside, 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.

4.3. Contraindications

• Hypersensitivity to paracetamol, or to any of the excipients.
• Cases of severe hepatocellular insufficiency.

4.4.Special warnings and precautions for use

RISK OF MEDICATION ERRORS

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

rolonged or frequent use is discouraged. It is recommended that a suitable analgesic oral treatment will 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. The dose may require adjustment.

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.

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

● patients suffering from a genetically caused G-6-PD deficiency (favism), the occurrence of a haemolytic anaemia is possible due to the reduced allocation of glutathione following the administration of paracetamol.

Caution is advised if paracetamol is administered concomitantly with flucloxacillin due to increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism), as well as those using maximum daily doses of paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.

4.5. Interaction with other medicinal products and other forms of interaction

• Probenecid causes an almost two-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 half-life of paracetamol.
• Caution should be taken with the concomitant intake of enzyme-inducing substances.
• Concomitant use of paracetamol (4000 mg 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.
• Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis, especially in patients with risks factors.

4.6. Fertility, pregnancy and lactation

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 inconclusive 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.

Lactation:

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

4.7.Effects on ability to drive and use machines

Not relevant.

4.8.Undesirable effects

As with all paracetamol products, adverse drug reactions are rare (≥ 1/10 000 to <1/1 000) or very rare (<1/10 000). They are described below:

(1) Very rare cases of hypersensitivity reactions ranging from simple skin rash or urticaria to anaphylactic shock have been reported and require discontinuation of treatment.

(2) Isolated cases

(3) Very rare cases of serious skin reactions have been reported.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: Website: https://www.zuventus.co.in/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9.Overdose

Symptoms

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. Immediate emergency measures are necessary in case of paracetamol overdose, even when no symptoms are present.

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.

Treatment

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 intravenous 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 restitution to normal in one to two weeks with full return of normal liver function. In very severe cases, however, liver transplantation may be necessary.

Pharmacotherapeutic group:

Analgesics; Other analgesics and antipyretics; Anilides

ATC Code: N02BE01

5.1 Mechanism of action

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

5.2 Pharmacodynamic effects

Paracetamol 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 reduces fever within 30 minutes after the start of administration with a duration of the antipyretic effect of at least 6 hours.

5.3 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 500 mg and 1 g of Paracetamol is similar to that observed following infusion of 1 g 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 500 mg and 1 g of Paracetamol is about 15 μ g/ml and 30 μ g/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 µ g/ml) were observed in the cerebrospinal 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 sulphuric 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 is increased.

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 sulphate (20 – 30 %) conjugates. Less than 5 % is eliminated unchanged. Plasma half-life is 2.7 hours and total body clearance is 18 l/h.

Newborn infants, 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 newborn infants, the plasma half-life is longer than in infants i.e. around 3.5 hours. Newborn infants, infants and children up to 10 years excrete significantly less glucuronide and more sulphate conjugates than adults.

Table - Age related pharmacokinetic values

(standardised clearance, *CLstd/Foral (l× h-1× 70 kg-1)

*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 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 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 data reveal no special hazard for humans beyond the information included in other sections of the SmPC.

Studies on local tolerance of paracetamol 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.

Acetaminophen is a non-salicylate antipyretic and non-opioid analgesic agent. Its chemical name is N-acetyl-p-aminophenol.

Acetaminophen has a molecular weight of 151.16.

Its structural formula is:

1. Incompatibilities

Paracetamol must not be mixed with other medicinal products except those mentioned in dosage administration section.

2. Shelf-life

Refer on the pack. After dilution: Chemical and physical in use stability (including infusion time) in the solutions listed in dosage administration section has been demonstrated for 48 hours at 23 ° C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

3. Packaging information

A bottle of 100 ml.

4. Storage and handing instructions

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

Keep out of reach of children.

Before administration, the product should be visually inspected for any particulate matter and discoloration. The product is intended for single use only. The product should be used immediately after opening and any unused solution should be discarded.

• Paracetamol Injection helps in relieving moderate pain and fever for the short-term, especially following surgery. Paracetamol Injection 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.
• Ask patient to inform doctor if also taking other medications containing paracetamol. Inform your doctor if you suffer from liver disease, severe kidney disease, or alcohol abuse.
• Inform your doctor if you experience symptoms such as feeling or being sick, weight loss, pale skin (pallor), or abdominal pain within the first 24 hours as it indicates an overdose.
• Your doctor may regularly monitor your kidney function, liver function and levels of blood components if you are taking this medicine for long-term treatment.

18th Sept. 2024