Drug Dossier- Paracip

Introduction

Pain management has become an increasingly complex topic and as the complexity of managing patients' pain syndromes has increased, so too have the drugs used to treat pain.

The World Health Organization (WHO), American Pain Society (APS), and the American College of Rheumatology (ACR) all recommend combination therapy for pain management. Also several published studies have pointed to the benefits of using medication regimens that take a Multimodal Approach-those that contain a combination of drugs using different metabolic pathways or different mechanisms of action in such a way as to have complimentary, additive or synergistic effects.

In addition, using a multimodal approach involves using lower amounts of each individual medication, thus reducing dose-limiting side effects or toxicity of an individual drug while still providing analgesia that is at least as effective (if not more so) than the individual medication. However, when administering analgesics, especially in combination, clinicians must account for the metabolic pathway(s) of the medications as well as any metabolites that are formed.

Balanced analgesia is also a validated concept in the postoperative period and is recommended by guidelines and publications as combination of analgesic drugs is expected to improve pain relief and limit the incidence and severity of the side effects of each drug.

Multimodal approach to pain

IV Paracetamol, a centrally acting inhibitor of cyclooxygenase, has less gastrointestinal and platelet-inhibiting side effects and is clinically better tolerated than NSAIDs. Therefore, it could be ideally suited for use as multimodal approach to pain.

I.V. Paracetamol (Paracip)

Composition

Each 100ml contains
Paracetamol IP.............1000mg
Water for Injection IP........qs

Dosage Form

Solution for infusion

Pharmacology

Pharmacodynamics

Paracetamol is a non-opiate para-aminophenol derivative that exhibits analgesic and antipyretic activity.

The precise mechanism of the analgesic and antipyretic properties of paracetamol has yet to be established; it may involve central and peripheral actions. Paracetamol IV 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 IV reduces fever within 30 minutes after the start of administration with duration of the antipyretic effect of at least 6 hours.

Pharmacokinetics

Absorption:
Paracetamol IV pharmacokinetics is linear up to 2g after single administration and after repeated administration during 24 hours. The peak plasma concentration is obtained as and from the end of infusion. The maximal plasma concentration (C_max) of paracetamol observed following intravenous infusion of 1g of Paracetamol IV is about 30 ?g/ml and a time of about 15 minutes is required to obtain the maximal concentration (T_max)

Distribution:

The volume of distribution of paracetamol IV is approximately 1 L/kg. Paracetamol IV is not extensively bound to plasma proteins. Following infusion of 1 g paracetamol IV, significant concentrations of paracetamol (about 1.5 pg/mL) were observed in the cerebrospinal fluid at and after the 20th minute following infusion.

Metabolism:
Paracetamol IV 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.

At the therapeutic doses, CYP3A4, the major isoform of P450 in human liver, contributes to the production of the cytotoxic metabolite. For very high, supratherapeutic plasma concentration (1500mg/L) of paracetamol, the 2E1 and 1A2 isoforms may also be involved.

Elimination:
The metabolites of paracetamol IV 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.

Indications

PARACIP solution for infusion is indicated for

short-term treatment of moderate pain, especially following surgery
short-term treatment of fever when administration by intravenous route is clinically justified by an urgent need to treat pain or hyperthermia and/or when other routes of administration are not possible.

Dosage and Administration

Intravenous Use

PARACIP solution for infusion should not be mixed with other medicinal products.

Paracetamol 1g per administration, i.e. one 100 ml vial, up to four times a day.The minimum interval between each administration must be 4 hours in patient swithout hepatic impairment.

The maximum daily dose from all sources of paracetamol must not exceed 4g. The paracetamol solution is administered as a 15-minute intravenous infusion, it contains no antimicrobial agent, and is for single use in one patient only.

Dosage for Renal and Hepaic Impairment

In patients with renal and/or hepatic impairment the minimum interval between closes must not be less than 6 hours.

Contraindications

PARACIP 10mg/ml, solution for infusion is contraindicated:

In patients with hypersensitivity to paracetamol or to propacetamol hydrochloride (prodrug of paracetamol) or to any of the excipients
In cases of severe hepatocellular insufficiency
In patients with hepatic failure

Warnings and Precautions

It is recommended that a suitable analgesic oral treatment 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 paracetamol. Doses higher than those recommended entail the risk of very serious liver damage. Clinical signs and symptoms of liver damage are not usually seen until two days, and up to a maximum of 4-6 days, after administration. Treatment with antidote should be given as soon as possible (See section on Overdosage)

Precautions for Use

Paracetamol should be used with caution in cases of:

Hepatocellular insufficiency,
Severe renal insufficiency (creatinine clearance ≤30 mL/min) (see section on Dosage and method of administration and Pharmacokinetic properties),
Chronic alcoholism,
Chronic malnutrition (low reserves of hepatic glutathione),
Dehydration.

The total dose of paracetamol should not exceed 4g per day. It is important to consider the contribution of all paracetamol containing medications, including non-prescription, oral or PR forms of the drug to this total daily paracetamol dose prior to administering paracetamol IV. If the daily dose of paracetamol from all sources exceeds the maximum, severe hepatic injury may occur (see section on Overdosage)

Drug Interactions

Probenecid causes an almost 2-fold reduction in clearance of paracetamol by inhibiting its conjugation with glucuronic acid. A reduction in the parac etamol dose should be considered if it is to be used concomitantly with probenecid.
Salicylamide may prolong the elimination t_1/2 of paracetamol.
Caution should be taken with the conconmitant intake of enzyme-inducing substances such as certain anticonvulsants (barbiturates, carbamazepines, phenytoin) (see section on Overdosage).
Concomitant use of paracetamol (4 g 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.

Renal Impairement

Paracetamol should be administered with caution to patients with renal impairment. 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 (see section on dosage and method of administration).

Hepatic Imairment

Paracetamol should be administered with caution to patients with hepatic impairment. Hepatic impairment may decrease the clearance of paracetamol or increase the probability of hepatic toxicity.

Pregnancy

Pregnancy Category A

Paracetamol has been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.

Clinical experience of the intravenous administration of paracetamol is limited. However, epidemiological data from the use of oral therapeutic doses of paracetamol indicate no undesirable effects in pregnancy or on the health of the foetus / newborn infant.

Prospective data on pregnancies exposed to overdoses did not show any increase in the risk of malformation.

No reproductive studies with the intravenous form of paracetamol have been performed in animals. However, studies with the oral route did not show any malformation or foetotoxic effects.

Nevertheless, paracetamol IV should only be used during pregnancy after a careful benefit-risk assessment. In this case, the recommended posology and duration must be strictly observed.

Lactation

After oral administration, paracetamol is excreted into breast milk in small quantities. No undesirable effects on nursing infants have been reported. Consequently, paracetamol IV may be used in breast-feeding women; caution should be used when administering paracetamol IV to women who are breastfeeding.

Geriatric Use

There was a significant increase in AUC and reduction in clearance of paracetamol and its metabolites in elderly subjects. However, these statistically significant differences were not likely to be clinically relevant during short-term infusions. Hence, no dose adjustment is required in this population.

Undesirable Effects

As with all paracetamol products, adverse drug reactions are rare (>1/10000, <1/1000) or very rare (1<1/10000). The overall incidence of adverse events in paracetamol IV treated patients compared to placebo within the clinical trial set is given below: Adverse events in adults - greater than 1% Neurological: dizziness, headache, dystonia Gastrointestinal: vomiting, dry mouth, diarrhoea, constipation, nausea, dyspepsia, enlarged abdomen, gastrointestinal disorder NOS Haematological: anaemia, post operative haemorrhage Hepatobiliary: increase in gamma GT, increase in SGPT Psychiatric: insomnia Skin and appendage: injection site pain, injection site reaction, post-operative site reaction, pruritis Respiratory: alveolitis, coughing Endocrine/Metabolic: hyperglycemia, hypokalemia General: fatigue, fever, oedema- peripheral, chest pain

Post Market Adverse Events for Propacetamol/Paracetamol

As with all paracetamol products, adverse drug reactions are rare (1/10000, 1/1000) or very rare (1/10000), they are described below:

Very rare cases of hypersensitivity reactions ranging from simple skin rash or urticaria to anaphylactic shock have been reported and require discontinuation of treatment.
Isolated reports of thrombocytopenia have been observed.

Overdosage

There is a risk of poisoning, 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. Acute overdose with paracetamol may also lead to acute renal tubular necrosis.

Symptoms generally appear within the first 24 hours and comprise: nausea, vomiting, anorexia, pallor and abdominal pain.

Overdose of 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.

Emergency Measures

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 I.V. 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. The optimal time for administration of NAC and necessary duration of therapy have not been established for over dose of paracetamol IV.
Symptomatic treatment.
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 return of normal liver function. In very severe cases, however, liver transplantation may be necessary.

Incompatibility

Paracetamol IV should not be mixed with other medicinal products.

Shelf-Life

2 years
From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Storage and Handling Instructions

Store in a cool, dry & dark place. Do not freeze.

Presentation

PARACIP: bottle of 100ml

Paracip (Paracetamol I.V.) Drug Dossier