Paracetamol + Tramadol

FORMULATION
Each film-coated tablet contains:
Paracetamol                                       ………………            325 mg
Tramadol Hydrochloride BP               ………………            37.5 mg

PHARMACOLOGY
Tramadol Hydrochloride is a centrally acting analgesic. It is a non-selective pure agonist at mu, delta and kappa opioid receptors with a higher affinity for the mu receptor. Other mechanisms which may contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release.

Paracetamol: The mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent, through a peripheral action by blocking pain- impulse generation. The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation. Paracetamol probably produces antipyretic by acting centrally on the hypothalamic heat-regulation centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.

PHARMACOKINETICS
Tramadol is readily absorbed after oral doses but is subject to some first-pass metabolism. Mean absolute bioavailability is about 70 to 75% after oral use and 100% after intramuscular injection. Plasma protein binding is about 20%. Tramadol is metabolized by N- and O-demethylation via the cytochrome P450 isoenzymes CYP3A4 and CYP2D6 and glucuronidation or sulfation in the liver. The metabolite O-desmethyltramadol is pharmacologically active. Tramadol is excreted mainly in the urine, predominantly as metabolites. Tramadol is widely distributed, crosses the placenta, and appears in small amounts in breast milk. The elimination half-life is about 6 hours.

Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 10 to 60 minutes after oral doses. Paracetamol is distributed into most body tissues. It crosses the placenta and is present in breast milk. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with
increasing concentrations. The elimination half-life of Paracetamol varies from about 1 to 3 hours.

Paracetamol is metabolized mainly in the liver and excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged Paracetamol. A minor hydroxylated metabolite (N-acetyl-p-benzoquinoneimine), is usually produced in very small amounts by cytochrome P450 isoenzymes (mainly CYP2E1 and CYP3A4) in the liver and kidney. It is usually detoxified by conjugation with glutathione but may accumulatez after Paracetamol overdosage and cause tissue damage.

INDICATION
For the symptomatic treatment of moderate to severe pain. Paracetamol is mild to moderate pain and for fever, Tramadol is used for moderate to severe pain.

DOSAGE AND ADMINISTRATION
Adult:
An initial dose of two tablets is recommended.
Additional doses can be taken as needed, not exceeding 8 tablets per day. The dosing interval should not be less than six hours.
Children:
The effective and safe use has not been established in children below the age of 12 years.
Treatment is therefore not recommended in this population. Or as prescribed by the physician.

CONTRAINDICATION
Hypersensitivity to the active substance or to any of the excipients.

PRECAUTIONS
Tramadol should be used with caution in patients with renal or hepatic impairment and should be avoided if renal impairment is severe. Removal by haemodialysis is reported to be minimal at 7%. Tramadol should be used with care in patients with a history of epilepsy or those susceptible to seizures. Paracetamol should be given with care to patients with impaired kidney or liver function. It should also be given with care to patients with alcohol dependence.

Pregnancy
It should not be used during pregnancy.

Lactation
It is a fixed combination of active ingredients including tramadol, it should not be ingested during breast feeding. Tramadol and its metabolites are found in small amounts in human breast milk. An infant could ingest about O. I % of the dose given to the mother.

ADVERSE EFFECTS
Tramadol may produce fewer typical opioid adverse effects such as respiratory depression and constipation. In addition to hypotension, hypertension has occasionally occurred. Adverse effects of Paracetamol are rare and usually mild, although haematological reactions including thrombocytopenia, leukopenia, pancytopenia, neutropenia, and agranulocytosis has been reported. Skin rashes and other hypersensitivity reactions occur occasionally.

DRUG INTERACTIONS
Carbamazepine is reported to diminish the analgesic activity of Tramadol by reducing serum concentrations. The risk of seizures is increased if Tramadol is used with other drugs that have the potential to lower the seizure threshold. Tramadol inhibits reuptake of noradrenaline and serotonin and enhances serotonin release and there is the possibility that it may interact with other drugs that enhance monoaminergic neurotransmission including lithium, tricyclic antidepressants, and SSRls; it should not be given to patients receiving MAOIs or within 14 days of their discontinuation. Metabolism of Tramadol is mediated by the cytochrome P450 isoenzyme CYP2D6. Use with specific inhibitors of this enzyme, such as Quinidine, may increase concentrations of Tramadol and lower concentrations of its active metabolite but the clinical consequences of this effect are unclear.

The risk of Paracetamol toxicity may be increased in patients receiving other potentially hepatotoxic drugs or drugs that induce liver microsomal enzymes. The absorption of Paracetamol may be accelerated by drugs such as Metoclopramide. Excretion may be affected and plasma concentrations altered when given with Probenecid. Cholestyramine reduces the absorption of Paracetamol if given within I hour of Paracetamol.

CAUTION
Foods, Drugs, Devices, and Cosmetics Act prohibits dispensing without prescription.

KEEP ALL MEDICINES OUT OF REACH OF CHILDREN.

“For suspected adverse drug reaction, report to the FDA: www.fda.gov.ph”

STORAGE CONDITION
Store at temperatures not exceeding 300C.

AVAILABILITY
Alu/Alu Blister Pack 10’s (Box of 10’s)