Paracetamol Kabi - instructions for use, dose, side effects, contraindications

Composition:1 ml of the solution contains: active substance paracetamol 10.0 mg; Excipients: Mannitol 36.7 mg, cysteine 0.1 mg, water for injection q.s. up to 1 ml.

Description:Transparent colorless or slightly yellowish solution.

Pharmacotherapeutic group:Analgesic non-narcotic remedy.

ATX: & nbsp

N.02.B.E Anilides

N.02.B.E.01 Paracetamol

Pharmacodynamics:The exact mechanism of action of paracetamol is not established.
Painful action. Paracetamol blocks cyclooxygenase (COX1 and COX2) mainly in the central nervous system. affecting the centers of pain.
Antipyretic action. Paracetamol selectively blocks TSOTZ in the CNS-centers of thermoregulation (central component).
Absence of anti-inflammatory action. In inflamed tissues, cellular peroxidases neutralize the effect of paracetamol on COX, which explains the almost complete absence of anti-inflammatory effect. The absence of a blocking effect on the synthesis of prostaglandins in peripheral tissues determines the absence of a negative effect on water-salt metabolism (Na + and water retention) and gastrointestinal mucosa (gastrointestinal tract).
Paracetamol Cubi provides the beginning of pain relief within 5-10 minutes after administration. The peak of analgesic effect is observed after 1 hour and is usually maintained for 4-6 hours.
Paracetamol Cabi reduces body temperature within 30 minutes after administration. The antipyretic effect is usually maintained for a minimum of 6 hours.

Pharmacokinetics:Adult patients
Pharmacokinetics of paracetamol is linear after single and repeated administration of the drug for 24 hours in doses up to 2 g.
Bioavailability of paracetamol after infusion of 500 mg and 1 g of paracetamol is similar to bioavailability after infusion of 1 g and 2 g of proparacetamol (corresponding to 500 mg and 1 g of paracetamol), respectively.
The maximum concentration of paracetamol in the blood plasma (C_max) observed at the end of a 15-minute intravenous infusion of 500 mg and 1 g of paracetamol is approximately 15 μg / ml and 30 μg / ml, respectively.
Distribution
The volume of distribution of paracetamol is approximately 1 l / kg. The binding of paracetamol to blood plasma proteins is negligible (about 10%). 20 minutes after the infusion of 1 g of paracetamol, significant concentrations of the drug (about 1.5 μg / ml) in the cerebrospinal fluid are detected.
Biotransformation
Most paracetamol is metabolized in the liver in two main ways: by conjugation with glucuronic or sulfuric acid. In doses exceeding therapeutic, the last way of metabolism is quickly saturated. A small fraction of paracetamol (less than 4%) is metabolized by the cytochrome P450 system to the intermediate metabolite (N-acetyl-benzoquinonimine), which is usually rapidly inactivated by therapeutic doses of the drug by conjugation with reduced glutathione and excreted by the kidneys after conjugation with cysteine and mercapturonic acid . However, after a serious overdose, the amount of this toxic metabolite is increased.
Excretion
Metabolites of paracetamol are mainly excreted by the kidneys.90% of the administered dose of the drug is excreted within 24 hours, mainly in the form of conjugates of glucuronide (60 -80%) and sulfate (20-30%), less than 5% is unchanged. The half-life of plasma is 2.7 hours, the total clearance is 18 l / h.
Newborn babies, children of the first year of life and older children
The pharmacokinetic parameters of paracetamol observed in infants and children are similar to those in adult patients, except for the period of excretion from the blood plasma, which in children is somewhat shorter (from 1.5 to 2 hours). In newborn babies, the half-life of plasma is longer than in infants of the first year of life, that is, about 3.5 hours. In newborn infants, children 1 year of age and children under 10 years of age, significantly fewer glucuronide conjugates and more sulfate conjugates are produced than in adult patients.
Age pharmacokinetic parameters (standardized clearance, * CLstd / Foral (lh^-1 70 kg^-1):

Age	Weight, kg)	CLstd / Foral (lh^-1 70 kg^-1)
40 weeks (gestational age) full-term newborns	3.3	5.9
3 months (postnatal age)	6	8.8
6 months (postnatal age)	7.5	11.1
1 year (postnatal age)	10	13.6
2 years (postnatal age)	12	15.6
5 years (postnatal age)	20	16.3
8 years (postnatal age)	25	16.3

* CLstd - CL calculation by population size
Special patient groups
Impaired renal function
With severe renal dysfunction (creatinine clearance 10-30 ml / min) excretion of paracetamol occurs somewhat more slowly, the half-life period varies from 2 to 5.3 hours. In patients with severe renal dysfunction, the elimination rate of sulfate and glucuronate conjugates is three times lower than in healthy patients. Therefore, when treating patients with severe impairment of renal function with paracetamol (creatinine clearance ≤ 30 mL / min), the minimum interval between each administration of the drug should be increased to 6 hours.
Elderly patients
The pharmacokinetics and metabolism of paracetamol in elderly patients do not change. In the treatment of elderly patients, dosage adjustment of paracetamol is not required.

Indications:The drug is indicated for the removal of pain and febrile syndrome in those cases where the intravenous route of administration is most rational, including if other methods of administration are not possible.
A short course of treatment of pain syndrome of moderate intensity, especially after surgical interventions.
A short course of treatment of febrile syndrome on the background of infectious and inflammatory diseases.

Contraindications:Hypersensitivity to paracetamol or propacetamol hydrochloride (paracetamol prodrug) and to any other component of the drug, severe liver dysfunction (more than 9 on the Child-Pugh scale) or liver disease in the active stage, neonatal period (up to 1 month).

Carefully:WARNING: Use caution when calculating the dose of the drug! An error between dosing in MG or in ML can cause an accidental overdose and death.
In situations where this is possible, it is recommended to use oral medications.
To avoid the risk of overdose, it must be ensured that other medications used in the same period do not contain paracetamol or propacetamol hydrochloride.
The use of doses exceeding the recommended dose is associated with a risk of developing severe liver damage. Clinical signs and symptoms of liver damage (including fulminant hepatitis, hepatic insufficiency, cholestatic hepatitis, cytolytic hepatitis) usually do not appear before 2 days later, and may not be obvious within 4-6 days after drug administration.In this case it is necessary to apply the antidote as soon as possible.
Special care should be taken with paracetamol in patients with the following conditions:
- Dysfunction of the liver (less than ≤9 on the Child-Pugh scale);
- Benign hyperbilirubinemia, incl. Gilbert-Meilengracht syndrome (non-hemolytic family jaundice), viral hepatitis, alcoholic liver damage;
- Severe renal insufficiency (creatinine clearance ≤ 30 ml / min);
- Chronic alcohol dependence;
- Chronic malnutrition (low reserve of glutathione liver), incl. anorexia, bulimia, cachexia;
- Complete parenteral nutrition;
- Deficiency of glucose-6-phosphate dehydrogenase (favism) (development of hemolytic anemia due to reduced release of glutathione after paracetamol administration is possible);
- Hypovolemia, dehydration;
- Elderly age.
Influence on indicators of laboratory research
Paracetamol can distort the results of uric acid analysis when using phosphotungstic acid and influence the results of the analysis of blood glucose concentration using glucose oxidase peroxidase.

Pregnancy and lactation:The clinical experience of paracetamol for intravenous administration in pregnancy is limited. Studies of the use of paracetamol for oral administration at therapeutic doses showed no adverse effects on the course of pregnancy, fetal development and child health.
The use of Paracetamol Cabi in pregnant women is permissible only after a thorough evaluation if the expected benefit to the mother exceeds the potential risk to the fetus or the baby. In this case, the prescribed doses and duration of treatment should be closely monitored.
Ingestion paracetamol in small amounts penetrates into breast milk. No adverse effects on the child have been reported. Paracetamol can be used in the period of breastfeeding, if the expected benefit for the mother exceeds the risk for the child.

Dosing and Administration:Intravenously, once, in the form of infusion for 15 minutes.
100 ml bottle is intended for the treatment of adult patients, adolescents and children weighing more than 33 kg.
Bottle of 50 ml is intended for the treatment of term infants, children of the first year of life and children with a body weight not more than 33 kg.
The drug should not be mixed in one vial for infusions with other medications.
Infusion should be performed immediately after opening the vial, the unused remnant of the drug is destroyed. Before starting the infusion, the vial with the drug should be carefully inspected for lack of visible mechanical particles and discoloration of the solution.
Additional dilution of the preparation with 0.9% sodium chloride solution or 5% dextrose (glucose) solution up to 1/10 of the original volume (1 volume of Paracetamol Cabi and 9 volumes of this solvent) is allowed. The diluted solution should be applied within an hour after preparation, including the infusion time. Before starting the infusion, the vial with diluted drug should be carefully inspected for lack of mechanical particles and discoloration of the solution.
For infusion, use a needle 0.8 mm in diameter, which is injected into the vial in a place marked on the rubber stopper, holding the bottle strictly vertically. As with other infusion solutions supplied in glass containers, special care must be taken to avoid embolism with air bubbles, especially at the end of the infusion,in what vein is injected the drug.
Dosing regimen

The patient's body weight (interval of the weight group)	The dose of paracetamol for a single administration	Volume of solution for a single injection	Maximum volume of solution for infusions Paracetamol Cabi 10 mg / ml for single administration, calculated for the upper limit of the weight group of patients ***	Maximum daily dose**
less than or equal to 10 kg *	7.5 mg / kg	0.75 ml / kg	7.5 ml	30 mg / kg
more than 10 kg and less than or equal to 33 kg	15 mg / kg	1.5 ml / kg	49.5 ml	60 mg / kg (total not more than 2 g)
more than 33 kg and less than or equal to 50 kg	15 mg / kg	1.5 ml / kg	75 ml	60 mg / kg (total not more than 3 g)
more than 50 kg with a risk of developing hepatotoxicity	1 g	100 ml	100 ml	3 grams
more than 50 kg without risk of hepatotoxicity	1 g	100 ml	100 ml	4 grams

* Data on the safety and efficacy of the drug for the treatment of preterm neonatal infants are not available.
** The maximum daily dose is indicated in the table for patients not receiving other paracetamol-containing drugs. Otherwise, the dose should be adjusted accordingly taking into account the intake of all other drugs containing paracetamol or propacetamol.
*** Patients with a lower body weight require less volume of solution administration.
The administration of no more than 4 doses of the drug per day is allowed.
The minimum interval between each use of the drug should be at least 4 hours.
Special instructions for the use of Paracetamol Cabi in patients with body weight less than or equal to 10 kg:
- To avoid errors in the calculation of doses, it is recommended to specify the volume for a single injection in milliliters (ml);
- the volume of the injected drug should not exceed 7.5 ml per infusion;
- You can not use the holder to suspend the bottle due to the introduction of a small amount of the drug;
- the required volume of the drug should be extracted from the vial, diluted in 0.9% solution of sodium chloride or glucose solution 5% to one tenth of the total volume (1 volume of the preparation and 9 volumes of this solvent) and injected for 15 minutes;
- To extract the required volume of the drug from the bottle (depending on the weight of the child and the required dose), use syringes with a volume of 5 or 10 ml.
Severe renal dysfunction
For severe renal impairment (creatinine clearance ≤ 30 ml / min), the interval between administration of the drug should be increased to 6 hours.
With violations of liver function in adult patients and in patients with chronic alcoholism,malnutrition (low reserve glutathione liver) or dehydration, the maximum daily dose should not exceed 3 g.
Dose adjustments in elderly patients are not required.

Side effects:The frequency of adverse reactions listed below is set out in accordance with the following gradation:
Very often? 1/10
Frequently ≥ 1/100, <1/10
Not infrequently ≥ 1/1000, <1/100
Rarely ≥ 1/10000, <1/1000
Very rarely <1/10000
The frequency is unknown (can not be calculated from the available data)
When using medicines containing paracetamol, adverse reactions are rare or very rare:

System-Organic grade	Rarely	Rarely	Unknown
Violations of the blood and lymphatic system		Thrombocytopenia. leukopenia. neutropenia. agranulocytosis
Immune system disorders		Hypersensitivity (from a simple skin rash or hives to anaphylactic shock, requiring immediate withdrawal of treatment), bronchospasm
Heart Disease			Tachycardia
Vascular disorders	Decrease arterial pressures
Disturbances from the skin and subcutaneous tissues		Serious skin reactions	Erythema, hyperemia, itchy skin
General disorders and disorders at the site of administration	General weakness
Laboratory and instrumental data	Increased activity of "liver" transaminases
Local Reactions			Soreness and burning sensation at the site of injection

Overdose:Elderly patients, young children, patients with impaired liver function, patients with chronic alcohol dependence, chronic malnutrition and patients simultaneously receiving enzyme inducing drugs are at increased risk of liver damage (including fulminant hepatitis, liver failure, cholestatic hepatitis, cytolytic hepatitis). In these cases, an overdose of paracetamol can lead to death.
Symptoms of overdose usually occur within 24 hours: nausea, vomiting, decreased appetite, pale skin, pain in the abdomen.
Overdose with a single injection of 7.5 g or more of paracetamol to adult patients or with a single administration of 140 mg / kg of body weight to children leads to necrosis of liver cells,which can cause complete and irreversible necrosis and subsequent liver failure, metabolic acidosis and encephalopathy, which can lead to coma and death. At the same time there is an increase in the activity of "liver" transaminases (ACT, ALT), lactate dehydrogenase and bilirubin in combination with a decrease in prothrombin in 12-48 hours after drug administration. Clinical signs of liver damage become evident after 2 days. and the maximum degree of liver damage - within 4-6 days after an overdose.
Treatment:
- Immediate hospitalization.
- Before the beginning of treatment it is necessary to take a blood sample as soon as possible to determine the content of paracetamol in the blood plasma.
- Introduction of donors of SH-groups and precursors of the synthesis of glutathione-methionine and N-acetylcysteine (NAC) for 10 hours after an overdose. The need for additional therapeutic measures (further introduction of methionine, intravenous injection of acetylcysteine) is determined depending on the concentration of paracetamol in the blood, as well as on the time elapsed after its administration
- Symptomatic treatment.
- It is necessary to perform functional tests to assess liver function at the beginning of treatment and, then, repeat every 24 hours. Usually, liver transaminase activity returns to normal after 1 or 2 weeks with complete restoration of liver function. In very serious cases, liver transplantation may be required.
- Hemodialysis can reduce the content of paracetamol in the blood plasma, however, its effectiveness is limited.

Interaction:The use of probenecid causes approximately a two-fold reduction in paracetamol clearance by inhibiting its binding to glucuronic acid. In case of application, the possibility of reducing the dose of paracetamol should be considered.
Phenytoin decreases the effectiveness of paracetamol and increases the risk of hepatotoxicity. Patients receiving phenytoin, paracetamol should be avoided in high doses and / or for a long time. It is necessary to monitor the condition of such patients for the development of signs of hepatotoxicity.
Inducers of microsomal liver enzymes (eg, ethanol, barbiturates, isoniazid, rifampicin, anticoagulants, zidovudine, amoxicillin + clavulanic acid, phenytoin) increase the production of hydroxylated active metabolites, which causes the possibility of developing severe intoxication with small overdoses.
Ethanol promotes the development of acute pancreatitis.
Inhibitors of microsomal liver enzymes (incl. cimetidine) reduce the risk of hepatotoxic effects.
Long-term use of barbiturates reduces the effectiveness of paracetamol.
Long-term simultaneous use of paracetamol and NSAIDs (non-steroidal anti-inflammatory drugs) increases the risk of developing analgesic nephropathy and renal papillary necrosis, the onset of the terminal stage of renal failure.
Simultaneous long-term use of paracetamol in high doses and salicylates increases the risk of developing kidney or bladder cancer. Salicylamide increases the half-life of paracetamol.
Simultaneous use of paracetamol in the form of infusions (4 g / day, not less than 4 days) and indirect anticoagulants can lead to a slight change in INR (International Normalized Relationship). It should be monitored by INR during treatment and within a week after discontinuation of paracetamol infusions.

Special instructions:Solution Paracetamol Cabi is administered by intravenous infusion for 15 minutes. Only for a single injection. Remains of unused solution must be destroyed.
Use only a transparent solution that does not contain any mechanical inclusions from intact packaging.
The drug can be diluted in a 0.9% solution of sodium chloride or 5% dextrose (glucose) to a ratio of 1:10. The diluted solution should not be used when opalescence is detected, visible suspended particles or sediment.
When working with any solution for intravenous administration, supplied in glass bottles, at the end of the infusion careful monitoring is necessary to avoid embolism.

Effect on the ability to drive transp. cf. and fur:It was not reported on the effect of the drug on the ability to drive and work with machinery.

Form release / dosage:Solution for infusions 10 mg / ml.

Packaging:50 ml or 100 ml in glass bottles (hydrolytic glass of Class II, Heavy Pharm.) With drawing of a risk with or without casting, closed with rubber (halobutyl) stoppers (Hebrew Pharm.), Coated with aluminum caps, with plastic covers for monitoring first autopsy or without.
For 1, 10, 12 or 20 bottles with or without holders, together with instructions for medical use in a cardboard box.

Storage conditions:Store at a temperature of 15 to 25 ° C. Do not chill or freeze.
Keep out of the reach of children.

Shelf life:2 years.
Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003906

Date of registration:17.10.2016

Expiration Date:17.10.2021

The owner of the registration certificate:Fresenius Kabi Deutschland GmbHFresenius Kabi Deutschland GmbH Germany

Manufacturer: & nbsp

FRESENIUS KABI AUSTRIA, GmbH Austria

Representation: & nbspFresenius Kabi, OOOFresenius Kabi, OOORussia

Information update date: & nbsp2016-11-10

Illustrated instructions

Instructions

Paracetamol Cabi (Paracetamol Kabi)