Paramol

INSTRUCTIONS for medical use of the medicinal product ParaMOL

Composition:

Active ingredient: paracetamol;

100 ml of solution (1 container) contains 1000 mg of paracetamol;

Excipients: mannitol (E 421), disodium phosphate dihydrate, water for injections.

Pharmaceutical form. Solution for infusion.

Main physicochemical properties: clear liquid, colorless to light yellow.

Pharmacotherapeutic group. Analgesics and antipyretics. ATC code N02B E01.

Pharmacological Properties

Pharmacodynamics

Paracetamol exerts analgesic and antipyretic effects. Its mechanism of action involves inhibition of cyclooxygenase (COX) I and II exclusively within the central nervous system, affecting pain and thermoregulatory centers. In activated tissues, cellular peroxidases neutralize the effect of paracetamol on COX, which explains the almost complete lack of anti-inflammatory activity. The absence of influence on prostaglandin synthesis in peripheral tissues accounts for the lack of negative effects on water-electrolyte balance (sodium and water retention) and gastrointestinal mucosa.

Paracetamol provides pain relief within 5–10 minutes after administration. The peak analgesic effect is achieved within 1 hour, and the duration of this effect typically lasts 4–6 hours.

Paracetamol reduces body temperature within 30 minutes after administration, and the antipyretic effect persists for at least 6 hours.

Pharmacokinetics

Adults

Absorption

After single or repeated administration within 24 hours of doses up to 2 g, the pharmacokinetics of paracetamol are linear.

The bioavailability following intravenous infusion of 500 mg or 1 g paracetamol is equivalent to that after administration of 1 g or 2 g propacetamol (containing 500 mg or 1 g paracetamol, respectively). Maximum plasma concentration (C_max) is reached at the end of a 15-minute infusion of 500 mg or 1 g paracetamol, and amounts to 15 µg/mL or 30 µg/mL, respectively.

Distribution

The volume of distribution of paracetamol is approximately 1 L/kg. Paracetamol is weakly bound to plasma proteins. A significant concentration (approximately 1.5 µg/mL) was detected in cerebrospinal fluid 20 minutes after infusion of 1 g paracetamol.

Metabolism

Paracetamol is extensively metabolized in the liver via two major pathways: conjugation with glucuronic acid and conjugation with sulfuric acid. The latter pathway becomes rapidly saturated at doses exceeding therapeutic levels. A small fraction (less than 4%) is metabolized by cytochrome P450 to form a reactive intermediate metabolite (N-acetylbenzoquinoneimine), which under normal conditions is rapidly detoxified by reduced glutathione and excreted in urine after conjugation with cysteine and mercapturic acid. However, in cases of massive overdose, the amount of this toxic metabolite increases.

Excretion

Paracetamol metabolites are primarily excreted in urine. Within 24 hours, approximately 90% of the administered dose is eliminated by the kidneys, mainly as glucuronide conjugate (60–80%) and sulfate conjugate (20–30%). Less than 5% is excreted unchanged. The elimination half-life is 2.7 hours, and total clearance is 18 L/hour.

Neonates, Infants, and Children

The pharmacokinetics of paracetamol in children is almost similar to that in adults, except for a shorter plasma elimination half-life (1.5–2 hours). In neonates, the elimination half-life is longer than in infants—approximately 3.5 hours. Compared to adults, children under 10 years of age have significantly reduced glucuronidation and increased sulfation.

Table 1

Pharmacokinetic parameters by age group (standardized clearance, * CL_std/F_oral (L·h⁻¹·70 kg⁻¹))

*CLstd - estimate of the patient group regarding CL (clearance).

Special patient groups.

Patients with renal impairment.

In patients with severe renal impairment (creatinine clearance 10−30 mL/min), elimination of paracetamol is slightly prolonged, and the elimination half-life ranges from 2 to 5.3 hours. The rate of elimination of glucuronide and sulfate metabolites in patients with severe renal impairment is three times slower than in healthy volunteers. Therefore, in patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), the minimum dosing interval should be increased to 6 hours.

Elderly patients.

The pharmacokinetics and metabolism of paracetamol in elderly patients are not altered. Dose adjustment is not required.

Clinical characteristics.

Indications.

Short-term treatment of moderate-intensity pain, particularly in the postoperative period, and short-term treatment of hyperthermic reactions, when intravenous administration is clinically justified or other routes of administration are not acceptable.

Contraindications.

• Hypersensitivity to paracetamol or to propacetamol hydrochloride (a prodrug of paracetamol), or to any of the excipients.
• Severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Probenecid reduces paracetamol clearance by half by inhibiting its conjugation with glucuronic acid; therefore, when used concomitantly with probenecid, the dose of paracetamol should be reduced.

Salicylamide may increase the elimination half-life of paracetamol.

Inducers of hepatic microsomal oxidation (phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants) may enhance the risk of developing severe hepatic disorders even with minor overdosage (see section "Overdose").

Concomitant use of paracetamol (4 g daily for at least 4 days) with oral anticoagulants may result in minor changes in the international normalized ratio (INR). Therefore, INR should be monitored during concomitant therapy and for one week after discontinuation of paracetamol treatment.

Paracetamol should be used with caution when administered concomitantly with floxacillin, as co-administration has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions for use").

Special precautions for use.

WARNING! Risk of medication error

Due to potential confusion between milligrams (mg) and milliliters (ml), there is a risk of dosing errors that may lead to accidental overdose and fatal outcomes (see section "Method of administration and dosage").

Therefore, Paramol, 1000 mg/100 ml infusion solution, must be used with caution, and prescriptions must clearly state both the total dose in milligrams (mg) and the total volume in milliliters (ml).

To avoid overdose, ensure that other prescribed medicinal products do not contain paracetamol or propacetamol.

It is recommended to switch to an appropriate oral analgesic as soon as this route of administration becomes feasible.

The risk of hepatotoxicity during paracetamol treatment is increased in patients with alcoholic hepatopathy.

Paracetamol may interfere with laboratory test results, particularly quantitative determination of plasma glucose and uric acid levels.

During prolonged treatment, monitoring of peripheral blood count and liver function is required.

As soon as possible, continued treatment with oral analgesic formulations should be initiated.

To avoid the risk of overdose, it is essential to confirm that other prescribed medicinal products do not contain paracetamol or propacetamol.

The risk of liver injury increases when paracetamol is used at doses exceeding the recommended ones. Clinical signs of liver damage (including liver failure, hepatitis, including fulminant, cholestatic, cytolytic forms) typically first appear on day 2 after initiation of treatment and peak on days 4–6. The antidote should be administered as soon as possible (see section "Overdose").

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported. Caution is recommended when paracetamol is used concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe conditions such as severe renal impairment and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism) who have been treated with paracetamol at therapeutic doses for a prolonged period or with a combination of paracetamol and flucloxacillin, as well as in those receiving maximum daily doses of paracetamol. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring, including measurement of urinary 5-oxoproline levels. Measurement of urinary 5-oxoproline may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Paracetamol may cause serious skin reactions. Patients should be informed about the early signs of serious skin reactions, and treatment should be discontinued at the first appearance of rash or other signs of hypersensitivity.

The drug should be used with caution in the following conditions:

• Hepatocellular insufficiency;
• Severe renal impairment (creatinine clearance less than 30 ml/min);
• Chronic alcoholism;
• Chronic malnutrition (reduced hepatic glutathione stores);
• Dehydration.

Paramol, infusion solution 1000 mg/100 ml, contains less than 1 mmol (23 mg) of sodium per 100 ml of solution, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

Clinical experience with intravenous administration of paracetamol is limited. However, epidemiological data on the use of therapeutic doses of oral paracetamol indicate no adverse effects on pregnancy or fetal/neonatal health.

Prospective data on overdose during pregnancy do not indicate an increased risk of fetal malformations.

Reproductive toxicity studies of intravenous paracetamol in animals have not been conducted. Oral administration studies in animals did not demonstrate fetotoxic effects.

Nevertheless, paracetamol should be used during pregnancy only after careful assessment of the benefit-risk ratio, at the lowest effective dose, for the shortest possible duration, and with the lowest feasible frequency.

Breastfeeding period.

After oral administration, paracetamol is excreted in breast milk in small amounts. No adverse effects have been observed in infants during maternal paracetamol use during breastfeeding. Therefore, paracetamol can be used in breastfeeding women.

Ability to affect reaction speed when driving or operating machinery.

No effect.

Method of administration and dosage.

Paramol, solution for infusion 1000 mg/100 ml, is administered intravenously.

Dosage depends on the patient's body weight.

Dosage for adults, adolescents, and children with body weight over 33 kg (see Table 2).

Table 2

* Patients with lower body weight require smaller volumes.

The minimum interval between administrations should be at least 4 hours. The treatment course usually does not exceed 4 infusions within 24 hours.

The minimum interval between administrations in patients with severe renal impairment should be at least 6 hours.

** Maximum daily dose: the maximum daily dose is intended for patients who are not receiving other medicinal products containing paracetamol and should be appropriately adjusted if such products are used.

Patients with severe renal impairment.

When administering paracetamol to patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), it is recommended to increase the minimum interval between doses to 6 hours.

Patients who are chronically undernourished (have low hepatic glutathione stores), dehydrated, or have hepatocellular insufficiency, chronic alcoholism: the maximum daily dose should not exceed 3 g.

WARNING! To avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL) when prescribing and administering PARAMOL infusion solution, doses must be carefully calculated. Such confusion may lead to accidental overdose and even fatal outcomes. Prescriptions should specify the total dose both in mg and in mL.

Paracetamol solution should be administered by intravenous infusion over 15 minutes.

The product should be used immediately after opening the packaging.

Any unused infusion solution should be discarded.

Do not use if the container seal is broken or if the solution is cloudy.

Children.

PARAMOL infusion solution is indicated for children with body weight greater than 33 kg.

Overdose.

The risk of liver damage (including fulminant hepatitis, cholestatic hepatitis, cytolytic hepatitis, and liver failure) increases in elderly patients, young children, patients with liver disease, chronic alcoholics, chronically undernourished patients, and individuals with reduced enzymatic activity. In these cases, overdose may be fatal.

Symptoms usually appear within the first 24 hours and include nausea, vomiting, anorexia, pallor, and abdominal pain. Overdose in adults may occur with a single dose of 7.5 g or more, and in children with a dose of 140 mg/kg body weight. This leads to hepatic cytolysis, liver failure, metabolic acidosis, and encephalopathy, which may progress to coma and death. Within 12–48 hours, levels of liver transaminases (alanine aminotransferase, aspartate aminotransferase), lactate dehydrogenase, and bilirubin increase, while prothrombin levels decrease.

Clinical signs of liver damage appear after two days and peak on days 4–6.

Emergency measures:

• Immediate hospitalization;
• As soon as possible, before starting treatment, determine plasma paracetamol concentration after overdose;
• Intravenous or oral administration of the antidote N-acetylcysteine (NAC), preferably within 10 hours of overdose. NAC may still be administered later than 10 hours after overdose, but in such cases treatment will be longer;
• Symptomatic treatment.
• Liver function tests should be performed before starting treatment and repeated every 24 hours. In most cases, liver transaminase levels return to normal within one to two weeks, with complete recovery of liver function. In some cases, liver transplantation may be required.

Adverse Reactions

As with all paracetamol-containing products, adverse reactions to the medicinal product occur rarely (>1/10,000, <1/1,000) or very rarely (<1/10,000), as described below:

General disorders:

Common: malaise.

Cardiovascular system disorders:

Common: arterial hypotension.

Very rare: tachycardia.

Hepatobiliary system disorders:

Common: increased levels of hepatic transaminases.

Blood and lymphatic system disorders:

Very rare: thrombocytopenia, leukopenia, neutropenia.

Immune system disorders:

Very rare: anaphylactic shock, hypersensitivity reactions.

Administration site reactions:

Very rare: pain and burning sensation, erythema, flushing, pruritus.

Skin and subcutaneous tissue disorders:

Very rare: rash*, urticaria*, serious skin reactions**

Note:

*Very rare cases of hypersensitivity reactions such as anaphylactic shock, urticaria, and rash have been reported, requiring discontinuation of treatment.

**Cases of serious skin reactions requiring discontinuation of treatment have been reported.

Metabolism and nutrition disorders:

Unknown (frequency cannot be estimated from available data): metabolic acidosis with high anion gap.

Description of selected adverse reactions.

Metabolic acidosis with high anion gap.

Cases of metabolic acidosis with high anion gap, resulting from pyroglutamic acidosis, have been observed in patients with risk factors receiving paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions

Reporting of adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life.

18 months.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Do not cool. Do not freeze.

Keep out of reach and sight of children.

Packaging.

100 mL of solution in a polypropylene container. One container per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Subsidiary company "Farmatreyd".

Manufacturer's address and location of operations.

85 Sambirska Street, Drohobych, Lviv Oblast, 82111, Ukraine.

Marketing Authorization Holder.

Subsidiary company "Farmatreyd".

Address of the Marketing Authorization Holder.

85 Sambirska Street, Drohobych, Lviv Oblast, 82111, Ukraine.