For short-term treatment of mild to moderately severe pain when oral administration is not possible (e.g. immediately post-operatively, when non-steroidal anti-inflammatory agents are often contraindicated).
For short-term treatment of fever.

Use of the product Paraconica 1000 mg IV is restricted to patients weighing more than 33 kg.
Administration
Paraconica is a ready-to-use solution. It is administered as a 15-minute IV infusion. Efficacy and safety of slower or faster administration have not been investigated. In children, the volume of solution for infusion is 1.5 ml/kg per administration.
As with all solutions for infusion in glass vials, it must be remembered that the infusion must be carefully monitored, regardless of the route of infusion, particularly towards the end of the infusion. Monitoring at the end of the infusion is particularly important in central venous infusions, in order to avoid an air embolism.
Posology
Adults >50 kg
1000 mg paracetamol per administration, up to 4 times daily. The minimum interval between two administrations must be 4 hours and the maximum daily dose must not exceed 4 g.
Adults and children weighing more than 33 kg and less than 50 kg

15 mg paracetamol per kg body weight per administration, up to 4 times daily. The minimum interval between two administrations must be 4 hours and the maximum daily dose must not exceed 60 mg/kg (no more than 3 g).
Special dosage instructions
In severe renal insufficiency (creatinine clearance 10-30 ml/min), the minimum interval between two administrations should be extended to 6 hours (see “Kinetics in special patient groups”).
In patients with chronic or active liver disease, especially with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione) or dehydration, the daily dose must not exceed 3 g paracetamol.
Maximum duration of therapy
Duration of treatment in adults and children: max. 2 days.

Hypersensitivity reactions to paracetamol, propacetamol (prodrug of paracetamol) or any of the excipients in the composition (see the section “Composition”). Glucose-6-phosphate dehydrogenase deficiency (can lead to haemolytic anaemia). Hereditary constitutional hyperbilirubinaemia (Gilbert’s syndrome). Severe hepatocellular insufficiency or severe active liver disease. Severe renal dysfunction (creatinine clearance <10 ml/min).

Paracetamol should be used with caution in cases of:
– hepatocellular insufficiency,
– severe renal insufficiency (creatinine clearance ≤ 30 ml/min; see “Pharmacokinetics”),
– chronic alcoholism,
– concomitant administration of potentially hepatotoxic medicinal products, with liver enzyme inducers or excessive alcohol consumption. In these cases, the benefit/risk ratio should be carefully reviewed, taking therapeutic alternatives into consideration,
– anorexia, bulimia or cachexia; chronic malnutrition (low reserves of hepatic glutathione),
– dehydration, hypovolaemia.

Caution is advised in cases of excessive alcohol consumption. Alcohol can increase the hepatotoxicity of paracetamol, particularly during concomitant fasting. In such cases, even a therapeutic paracetamol dose can lead to liver damage.
To avoid the risk of an overdose, it must be ensured that other administered medicinal products contain no paracetamol.
Higher than recommended dosages carry the risk of very severe liver damage.

The concomitant use of Paraconica with other medicines can increase the likelihood of undesirable effects.
Co-medication with phenytoin can lead to decreased efficacy of paracetamol and, due to the increase in toxic paracetamol metabolites, an increased risk of hepatotoxicity. Patients on phenytoin therapy should therefore avoid the use of high and/or chronic doses of paracetamol. At the same time, the patients should be monitored for signs of hepatotoxicity.
The dose-dependent potential hepatotoxicity of paracetamol may be increased when co-administering cytochrome P450 system inducers (such as isoniazid, rifampicin, anticonvulsants, barbiturates, zidovudine, anticoagulants, amoxicillin/clavulanic acid and alcohol).
Hepatotoxicity can also be increased by salicylamide, as it prolongs the elimination half-life of paracetamol.
Paracetamol prolongs the elimination half-life of chloramphenicol by 5-fold.
The tendency for neutropenia is increased by the concomitant use of zidovudine and paracetamol.
Probenecid inhibits the conjugation of paracetamol with glucuronic acid, thereby reducing paracetamol clearance by about one-half. When co-administering probenecid, the dose of paracetamol should therefore be reduced.
The concomitant use of paracetamol with oral anticoagulants can lead to an increase in the INR value. More intensive monitoring of the INR value should therefore take place during concomitant use and for one week after discontinuation of paracetamol treatment.

Pregnancy: Animal reproductive toxicity studies have not been conducted with the intravenous form of paracetamol. However, studies on oral administration revealed no malformations or foetotoxic effects.
Clinical experience with the intravenous use of paracetamol is limited. However, epidemiological data on the use of oral therapeutic paracetamol doses show no adverse effects on the course of pregnancy or on the health of the foetus/newborn infant.
Prospective data on overdose in pregnancy revealed no increased risk of malformations.
Nevertheless, Paraconica should be used during pregnancy only after careful benefit-risk assessment. The recommended dosage and duration of administration must be strictly observed in this case.
Breast-feeding: In breast-feeding mothers, less than 1% of the administered paracetamol dose is excreted in breast milk. No undesirable effects on breast-fed infants have been reported to date.

No such studies have been performed.

Blood and lymphatic system disorders
Rare: allergy-related thrombocytopenia, haemolysis, leukopenia, pancytopenia, neutropenia, agranulocytosis
Immune system disorders
Very rare: allergic reactions such as angioedema, breathing difficulties, bronchospasm, sweating, nausea, hypotension and even anaphylactic shock
A small proportion (5-10%) of patients with acetylsalicylic acid-induced asthma or other manifestations of so-called acetylsalicylic acid intolerance may also respond in a similar fashion to paracetamol (analgesic asthma).
Vascular disorders
Rare: hypotension
Hepatobiliary disorders
Rare: elevated liver transaminase levels
In the event of an overdose, hepatic necrosis may occur.

Skin and subcutaneous tissue disorders
Uncommon: skin rash (erythema or urticaria)
Rare: exfoliation, toxic epidermal necrolysis, Stevens-Johnson syndrome
Renal and urinary disorders
In the event of an overdose, nephrotoxicity can occur.
General disorders and administration site conditions
Rare: malaise
Post-marketing experience:
During the post-marketing observation phase, the following undesirable effects have also been reported (frequency not known):
Blood and lymphatic system disorders
Haemolytic anaemia (especially in patients with G-6-PD deficiency)
Cardiac disorders
Tachycardia
Gastrointestinal disorders
Vomiting, pancreatitis
Hepatobiliary disorders
Cholestasis, jaundice, fulminant hepatitis, hepatic necrosis, hepatic failure, elevated liver enzyme levels
Skin and subcutaneous tissue disorders
Pruritus, flushing
General disorders and administration site conditions
Injection site reaction (erythema, pruritus)

There is a risk of intoxication especially in elderly subjects, in young children, in patients with liver disease, in cases of chronic alcoholism, in chronically malnourished patients and in patients receiving enzyme inducers. In these cases, intoxication can be fatal.
An overdose, 7.5 g paracetamol or more in a single dose in adults or 140 mg/kg body weight in a single dose in children, causes cytolytic hepatitis, which may induce complete and irreversible hepatic necrosis. This can lead to acute or fulminant liver failure, hepatic insufficiency, metabolic acidosis and encephalopathy, which can result in coma and death.

Simultaneously, elevated plasma levels of liver transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed together with a decreased prothrombin level 12-48 hours after administration. Clinical symptoms of liver damage normally occur for the first time after 2 days and reach their peak after 4-6 days.
During the first 24 hours, there are no specific early symptoms. Anorexia, nausea, vomiting and malaise, pallor and abdominal pain may occur and persist. Hepatic damage can occur 24 hours to 5 days after administration.
Occurrence of a massive overdose, the main risk of paracetamol (especially with tablets), seems unlikely with Paraconica (IV administration in hospital).
Emergency measures
In all cases, regardless of how large the suspected amount of administered paracetamol is, N-acetylcysteine (NAC) must be administered IV or orally as soon as possible (preferably within 10 hours post overdose). NAC may afford some protection even after 10 hours; however, prolonged treatment is required in these cases. The paracetamol concentration in plasma must be determined as soon as possible (no sooner than 3 hours after the overdose). However, the results do not have to be available before starting treatment with NAC.
Plasma concentrations of >200 μg/ml after 4 hours, of >100 μg/ml after 8 hours, of >50 μg/ml after 12 hours and of >30 μg/ml after 15 hours can cause liver damage and even hepatic coma with a fatal outcome. Hepatotoxicity is directly dependent on the plasma concentration.
Liver tests must be performed from the outset and repeated every 24 hours. An increase in liver enzymes (ALT and AST) is usually observed, which normalises after one to two weeks. Supplemental symptomatic treatment (after N-acetylcysteine IV or orally) should be determined on the basis of blood paracetamol levels and the length of time since the Paraconica overdose.

Paraconica, with the active substance paracetamol, is an analgesic and antipyretic which contains no salicylic acid or opioids. Regarding the analgesic action of paracetamol, prostaglandin synthesis inhibition is more predominant on a central level than on a peripheral level. The antipyretic action is based on inhibition of the effect of endogenous pyrogens on the hypothalamic temperature regulation centre. Paracetamol has no pronounced anti-inflammatory effect and has no influence on haemostasis or the gastric mucosa.
Pharmacodynamics
With an IV infusion of paracetamol over 15 minutes, the maximum analgesic effect is achieved in 1 hour; the analgesic action generally lasts 4-6 hours.
With an IV infusion of paracetamol over 15 minutes, defervescence begins within 30 minutes after the start of administration and the antipyretic action lasts for at least 6 hours.

Absorption
The pharmacokinetics of paracetamol in adults is linear up to a dose of 2 g, administered as a single dose and after repeated administration over 24 hours.
The peak plasma concentration (Cmax) is approximately 15 μg/ml at the end of a 15-minute intravenous infusion of 500 mg paracetamol and about 30 μg/ml after infusion of 1000 mg paracetamol.
Distribution
The volume of distribution of paracetamol in adults is about 1 litre/kg. Plasma protein binding is less than 20%, but up to 50% in cases of overdose.
Metabolism
In adults, paracetamol is metabolised in the liver via the following two main metabolic pathways: glucuronide conjugation (60-80%) and sulphate conjugation (20-40%). The latter pathway can become very rapidly saturated at dosages above the therapeutic range. A small fraction (less than 4%) is converted by cytochrome P450 into the two toxic metabolites p-aminophenol and N-acetyl-p-benzoquinone imine, which are rapidly inactivated by conjugation with glutathione and cysteine. In a massive overdose, the amount of these toxic metabolites is increased.
Elimination
Excretion mainly takes place via the kidneys. 90% of the administered dose is excreted within 24 hours in the urine as glucuronide conjugates (60-80%), as sulphate conjugates (20-30%) and less than 5% in unchanged form.
The mean plasma half-life is 2.7 hours and total body clearance is approximately 18 litres/h.

Paracetamol does not pass into bile. It crosses the placenta and is excreted in human milk.
The distribution of paracetamol in cerebrospinal fluid was investigated after a short infusion (1000 mg paracetamol) in 43 patients hospitalised for compression pain of the lumbosacral nerve root. Significant paracetamol concentrations (approximately 1.5 μg/ml) were detected in cerebrospinal fluid 20 minutes after the infusion. Peak paracetamol concentrations in cerebrospinal fluid were measured between 2 and 4 hours and were higher than the plasma concentrations between 4 and 12 hours.
Kinetics in special patient groups
Renal insufficiency: In the case of severe renal insufficiency (creatinine clearance 10–30 ml/min), paracetamol elimination is decelerated slightly; the elimination half-life is between 2 and 5.3 hours. The elimination rate of the glucuronide and sulphate conjugates is 3 times slower in patients with severe renal insufficiency than in healthy persons. However, no dose adjustment is necessary in this population, as these glucuronide and sulphate conjugates are not toxic. However, it is recommended that the minimum interval between the individual administrations be extended to 6 hours when paracetamol is used in patients with severe renal insufficiency (creatinine clearance ≤ 30 ml/min) (see “Posology/Administration”). If creatinine clearance is less than 10 ml/min, paracetamol should not be administered IV, as no relevant data exist.
Hepatic insufficiency: The plasma half-life is largely unaltered in patients with mild hepatic insufficiency. However, it is significantly prolonged in patients with severe hepatic insufficiency.
Elderly patients: The pharmacokinetics and metabolism of paracetamol are not modified in elderly patients. Therefore, no dose adjustment is needed in this population.
Neonates, infants and children: The pharmacokinetic factors of paracetamol observed in infants and children are similar to those in adults, except for the plasma half-life, which is slightly shorter (1.5 to 2 hours). In neonates, the plasma half-life is longer than in infants, i.e. about 3.5 hours. Neonates, infants and children up to 10 years eliminate significantly fewer glucuronide conjugates and more sulphate conjugates than adults. Total excretion of paracetamol and its metabolites is not dependent on age.

Preclinical data indicate no special hazards for humans beyond the information in other sections of this prescribing information.
Local tolerability studies of paracetamol IV in rats and rabbits showed good tolerability.
Studies in guinea pigs showed no delayed contact hypersensitivity.

mannitol, disodium phosphate dihydrate, antioxidant: cysteine hydrochloride monohydrate 25 mg, water for injections q.s.p. 100 ml.

Incompatibilities
It is recommended not to mix Paraconica with other medicinal products without first checking compatibility.

Note the expiry date. The solution for infusion contains no preservatives and should, for microbiological reasons, be used immediately after opening. Any remaining solution must be discarded.

Do not store above 30 ºC. Do not refrigerate or freeze. Keep the vials in the outer carton to protect from light.

Paraconica 1000 mg IV solution for infusion:
10 x 100 ml vials (hospital pack)

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