Intramol 100 ml Solution for Intravenous Infusion

INTRAMOL is indicated for the short-term treatment (not exceeding 24 hours) of mild to moderate pain e.g. after dental procedures and minor orthopaedic procedures, and the short-term treatment of fever, when the oral route is unsuitable.

DO NOT EXCEED THE RECOMMENDED DOSE. The prescribed dose must be based on the patientu2019s weight. Unintentional overdose can lead to serious liver damage and death. Unintentional overdose has a significant reduced survival compared with intentional overdose. The weight-related dose recommendations, individual patient risk factors for hepatotoxicity (see u201cSPECIAL PRECAUTIONSu201d) and pattern of overdose should be taken into account when assessing patients with paracetamol-induced hepatotoxicity. Irrespective of the patientu2019s admission paracetamol concentrations, patients with unintentional overdose should be managed as high-risk cases due to their significant increased mortality (see u201cKNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENTu201d).

Adults and adolescents weighing more than 50 kg: 1 g INTRAMOL per administration, i.e. one 100 ml vial, up to four times a day. The minimum interval between each administration must be 4 hours. The maximum daily dose must not exceed 4 g in 24 hours.

Children weighing more than 33 kg, adolescents and adults weighing less than 50 kg: INTRAMOL: 15 mg/kg per administration, i.e. 1,5 ml solution per kg up to 4 times per day. The minimum interval between each administration must be 4 hours for these patients (underweight adults etc.). The maximum daily dose must not exceed 60 mg/kg and must not exceed 3 g in 24 hours. The dosage should be calculated on non-oedematous weight. The maximum daily dose takes into account all the medicines containing paracetamol.

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

Recommended dosage in patients with severe renal insufficiency: It is recommended to leave a minimum interval of 6 hours between each administration in patients with severe renal impairment (creatinine clearance u2264 30 ml/min) (see u201cWARNINGSu201d and u201cPharmacokinetic propertiesu201d).

Recommended dosage in patients with hepatic impairment: In patients with chronic or compensated active hepatic disease, the maximum daily dose should not exceed 3 g per day. Hepatic failure or decompensated active liver disease should be regarded as a contraindication to INTRAMOL use (see u201cCONTRAINDICATIONSu201d).

Method of administration: INTRAMOL should be administered as a 15-minute intravenous infusion. It is intended for single-use only. Before administration, the product should be visually inspected for any particulate matter and discolouration e.g. yellowing. Once opened, the vial should be used immediately. Careful monitoring to avoid air embolism is needed, notably at the end of the infusion, especially if a central venous catheter is used for the infusion. Any unused solution should be discarded. INTRAMOL should not be mixed with other medicinal products.

INTRAMOL is contraindicated in:

• cases of hypersensitivity to paracetamol or to paracetamol hydrochloride (prodrug of paracetamol) or to any of the excipients of INTRAMOL
• cases of severe hepatocellular insufficiency, decompensated active liver disease including alcoholic hepatitis and hepatic failure
• children weighing less than 33 kg (approximately 11 years old) as safety and efficacy have not been established

Dosages of INTRAMOL in excess of those recommended may cause severe liver damage. Clinical symptoms and signs of liver damage are usually seen first after two days with a maximum usually after 4 to 6 days. Treatment with an antidote should be given as soon as possible (see u201cKNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENTu201d).

In order to avoid the risk of overdose, check that the other medicines administered do not contain paracetamol. INTRAMOL contains paracetamol which may be fatal in overdose. In the event of overdosage or suspected overdose and notwithstanding the fact that the person may be asymptomatic, the nearest doctor, hospital or poison centre must be contacted immediately. It is recommended to use a suitable oral analgesic treatment as soon as this administration route is possible.

Renal impairment: In patients with renal impairment with a creatinine clearance of 30 ml/minute or less, the elimination of paracetamol is delayed, therefore a 6 hourly dose interval is recommended (see u201cDOSAGE AND DIRECTIONS FOR USEu201d). INTRAMOL should be administered with caution in patients suffering from renal disease, prolonged excessive use of INTRAMOL can produce nephropathy. Paracetamol-induced renal function impairment may be severe and could result in uraemia, especially with prolonged use of high doses (see u201cINTERACTIONSu201d).

Hepatotoxicity: The risk of paracetamol toxicity may be increased in patients receiving potentially hepatotoxic medicines or medicines that induce liver microsomal enzymes (see u201cINTERACTIONSu201d). Patients suffering from alcoholism, liver disease or malnutrition are at special risk of hepatic damage and should not be administered excessive quantities of INTRAMOL.

Severe cutaneous adverse reactions (SCARs): Severe cutaneous adverse reactions (SCARs) such as toxic epidermal necrolysis (TEN), Steven-Johnson syndrome (SJS), acute generalised exanthematous pustulosis (AGEP), eosinophilia and systemic (DRESS)/Drug-induced hypersensitivity syndrome (DIHS) and fixed drug eruptions (FDE) have been reported in patients treated with paracetamol containing medicines. If a patient develops SCAR, treatment with INTRAMOL must immediately be discontinued and appropriate treatment instituted.

Alcohol, hepatic enzyme inducers or hepatotoxic medications: Patients have an increased risk of hepatotoxicity with concurrent use of high doses or prolonged use of INTRAMOL concurrently with chronic alcohol abuse, taking hepatic enzyme inducers (such as barbiturates, isoniazid, zidovudine, phenytoin, rifampicin, carbamazepine, primidone) - or hepatotoxic medications.

Warfarin: The anticoagulant effect may be increased when high doses of INTRAMOL are used together with anticoagulants, such as warfarin. Increased monitoring of INR values should be conducted during and one week after concomitant use. This does not apply to occasional use or if chronic use doses are below 2 g INTRAMOL per day.

Non-steroidal anti-inflammatory medicine (NSAIDu2019s), aspirin or other salicylates: Salicylates in prolonged treatments together with INTRAMOL significantly increased the risk of analgesic nephropathy, renal papillary necrosis, end-stage renal diseases, and cancer of the urinary bladder. Do not exceed the recommended individual dosages for salicylates and INTRAMOL. Prolonged use of INTRAMOL and other NSAIDu2019s may increase the risk of adverse renal effects.

Probenecid: Probenecid causes an almost 2-fold reduction in paracetamol clearance and increases its plasma half-life by decreasing the urinary excretion of the sulphate and glucuronide conjugates of paracetamol. A decrease in INTRAMOL dose should be considered when administered concomitantly with probenecid.

Pregnancy: Clinical experience of intravenous administration of INTRAMOL is limited. However, epidemiological data from the use of oral therapeutic doses of paracetamol indicate no undesirable effects of pregnancy or on the health of the foetus/new-born infant. Nevertheless, INTRAMOL should only be used during pregnancy after a careful benefit risk assessment. In this case, the recommended dosage and duration must be strictly observed.

Lactation: After oral administration, paracetamol is excreted into breast milk in small quantities. No undesirable effects on breastfed infants have been reported. However, caution should be used when administering INTRAMOL to women who are breastfeeding their infants.

INTRAMOL should have no influence on the ability to drive and the use of machines. No unwanted effects which could influence the ability to drive and to operate machinery have been reported by patients using INTRAMOL.

Side effects:

Blood and lymphatic system disorders: Less frequent: Agranulocytosis, anaemia, thrombocytopenia, Leukopenia, pancytopenia, neutropenia.

Vascular disorders: Less frequent: Hypotension.

Cardiac disorders: Less frequent: Tachycardia.

Hepato-biliary disorders: Less frequent: Hepatitis, hepatic necrosis, hepatic failure, Pancreatitis, increased levels of hepatic transaminases.

Gastrointestinal disorders: Frequency unknown: Nausea, vomiting.

Skin and subcutaneous tissue disorders: Less frequent: Dermatitis, allergic skin rash, erythema, flushing, pruritus, urticaria.

Renal and urinary disorders: Less frequent: Renal colic, renal failure, sterile pyuria.

Immune system disorders: Less frequent: Hypersensitivity, anaphylactic shock, angioedema.

General disorders and administrative site conditions: Less frequent: Malaise, administration site reaction.

Post-marketing experience: Skin and subcutaneous tissue disorders: Frequency unknown: Acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), Drug-induced hypersensitivity syndrome (DIHS) and fixed drug eruptions (FDE).

Prompt treatment is essential in the event of an overdosage. A delay in starting treatment may mean that antidote is given too late to be effective. Evidence of liver damage is often delayed until after the time for effective treatment has lapsed. Susceptibility to paracetamol toxicity is increased in patients who have taken repeated high doses (greater than 5 to 10 g per day) of paracetamol for several days. There is a risk of poisoning, particularly in chronic alcoholism, chronic liver disease, AIDS, malnutrition, elderly subjects, young children and with the use of medicines that induce liver microsomal oxidation such as barbiturates, isoniazid, rifampicin, phenytoin and carbamazepine. Overdosing may be fatal in these cases.

Symptoms of paracetamol overdosage in the first 24 hours include pallor, nausea, vomiting, anorexia and abdominal pain. Mild symptoms during the first two days of acute poisoning do not reflect the potential seriousness of the overdosage. Liver damage may become apparent 12 to 48 hours, or later after administration of INTRAMOL, initially by elevation of the serum transaminase and lactic dehydrogenase activity, increased serum bilirubin concentration and prolongation of the prothrombin or INR time. These changes may appear only in 12 to 48 hours after administration. Clinical symptoms of liver damage are usually evident initially only after 2 days, and reach a maximum after 4 to 6 days. Liver damage may lead to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Abnormalities of glucose metabolism and metabolic acidosis may occur. Cardiac dysrhythmias have been reported.

Treatment for paracetamol overdosage following IV administration of INTRAMOL: Before beginning treatment, draw blood for a paracetamol plasma assay as soon as possible after the overdose. N-acetylcysteine (NAC) should be administered to all cases of suspected overdose as soon as possible preferably within eight hours of overdosage, although treatment up to 36 hours after the overdose may still be of benefit, especially if more than 150 mg/kg of paracetamol was administered and taken. An initial dose of 150 mg/kg N-acetylcysteine in 200 ml dextrose 5 % w/v injection given intravenously over 15 minutes, followed by an infusion of 50 mg/kg in 500 ml dextrose 5 % w/v injection over the next four hours, and then 100 mg/kg in 1 000 ml dextrose 5 % w/v injection over the next sixteen hours. Sodium chloride 0,9 % w/v may be used where glucose 5 % w/v is unsuitable. The volume of intravenous fluid should be modified for children. Though the oral formulation is not the treatment of choice, 140 mg/kg dissolved in water may be administered initially, followed by 70 mg/kg every four hours for seventeen doses. After an overdosage with an intravenous infusion, the standard nomogram used for determining treatment from paracetamol plasma concentrations following oral ingestion of an overdose of paracetamol, may not be appropriate. Paracetamol plasma concentrations more than 4 hours after intravenous injection may be lower than those predicted for the same oral dose at the same time point after ingestion.

Adapted from the following sources: Martindale, The Complete Drug Reference, 36th Edition, page 109, fig. 1.2 and Goodman and Gilman 11 th Edition, page 694, fig 26.2. Those whose plasma paracetamol levels are above the u201cnormal treatment lineu201d (the top plotted line), should continue N-acetylcysteine treatment with 100 mg/kg IV over sixteen hours repeatedly until recovery. Patients with increased susceptibility to liver damage as identified above, should continue treatment if concentrations are above the u201chigh risk treatment lineu201d (the bottom plotted line). Prothrombin index correlates best with survival. Monitor all patients with significant overdose for at least ninety six hours.

Treatment is symptomatic and supportive. 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 restitution of the liver function. In very severe cases however liver transplantation may be necessary.