Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activities. The mechanism of action of Etodolac, like that of other NSAIDs related to prostaglandin synthesis inhibition.
Paracetamol is a fast acting and safe analgesic with marked antipyretic property. It is especially suitable for patients who, for any reason, cannot tolerate aspirin or other analgesics.The presence of Etodolac increases the effectiveness of Paracetamol.

Indications & Usage:
Combination of Etodolac and Paracetamol used to treat:
● Mild to moderate pain e.g. headaches, muscle aches, backache, toothache, or symptoms of cold.
● It is also used for the treatment of Rheumatoid arthritis, gout and osteoarthritis.
● Control fever (high temperature, also known as pyrexia), e.g. when someone has flu (influenza).

Mechanism of Action:

Etodolac:
Etodolac belongs to a class of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs are used for the management of mild to moderate pain, fever, and inflammation. They work by reducing the levels of prostaglandins, which are chemicals that are responsible for pain and the fever and tenderness that occur with inflammation. Etodolac blocks the enzyme that makes prostaglandins (cyclooxygenase), resulting in lower concentrations of prostaglandins. As a consequence, inflammation, pain and fever are reduced.

Paracetamol:
Paracetamol is thought to act primarily in the CNS, increasing the pain threshold by inhibiting cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin (PG) synthesis. Paracetamol indirectly blocks COX, and that this blockade is ineffective in the presence of peroxides. Paracetamol is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides. The antipyretic properties of paracetamol are likely due to direct effects on the heat-regulating centres of the hypothalamus resulting in peripheral vasodilation, sweating and hence heat dissipation.

Drug Interactions:

Etodolac:
Etodolac is known to interact with other drugs like alcohol, cyclosporin A, nateglinide, phenylbutazone, phenytoin (Na), warfarin (Na), zidovudine.

Paracetamol:
Paracetamol is known to interact with other drugs like alcohol, ascorbic acid, azilisartan medoxomil, busulphan, carbamazepine, chloramphenicol, cimetidine (HCl), diflunisal, interferon alpha, isoniazid, itopride (HCl), metoclopramide (HCl).
Always consult your physician for the change of dose regimen or an alternative drug of choice that may strictly be required.

Pharmacokinetics:

Etodolac:
Absorption: Etodolac is well absorbed and has a systemic availability of at least 80%. It does not undergo significant first-pass metabolism following oral administration. Mean (± 1 SD) peak plasma concentrations (Cmax) range from approximately 14 ± 4 to 37 ± 9 µg/mL after single dose and are reached in 80 ± 30 minutes. The dose-proportionality based on the area under the plasma concentration-time curve (AUC) is linear every 12 hours. The extent of absorption of etodolac is not affected when administered after a meal. Food intake, however, reduces the peak concentration reached by approximately one-half and increases the time to peak concentration by 1.4 to 3.8 hours.
Distribution: The mean apparent volume of distribution (Vd/F) of etodolac is approximately 390 mL/kg. Etodolac is more than 99% bound to plasma proteins, primarily to albumin. The free fraction is less than 1% and is independent of etodolac total concentration over the dose range studied. It is not known whether it is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected.
Metabolism: Etodolac is extensively metabolized in the liver. Several etodolac metabolites have been identified in human plasma and urine. After a single dose, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated-etodolac metabolite does not accumulate in the plasma of patients with normal renal function. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces.
Excretion: The mean oral clearance of etodolac following oral dosing is 49 (± 16) mL/h/kg. Approximately 1% dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite. Fecal excretion accounted for 16% of the dose.

Paracetamol:
Absorption: Paracetamol is well absorbed in the gastrointestinal tract. Oral bioavailability is dose dependant: with larger doses, the hepatic first pass effect is reduced due to overwhelming of the liver enzymatic capacity; and therefore, bioavailability is increased. Rectal administration of paracetamol is also feasible. In this case, bioavailability is inconsistent and in overall reduced, due to incomplete dissolution of the suppository in the rectum. The absorption rate through this route of administration is elongated.
Distribution: Paracetamol is distributed throughout the body fluids in a homogeneous way. The analgesic activity is attributable to the small fraction that penetrates into the brain. Paracetamol given at therapeutic doses binds to plasma proteins at less than 20%. In case of intoxication, this proportion may increase to up to 50%.
Metabolism: Paracetamol is essentially metabolized in the liver by conjugation with glucuronic acid (55%) and sulfuric acid (35%). Hepatotoxic metabolites are produced in small amounts by the cytochrome P450 (isoenzyme CYP2E1). In the therapeutic plasma concentration range, this metabolite is detoxified by conjugation with glutathione.
Elimination: Metabolites are excreted through the kidneys in the urine. Only 2-5% of the dose is excreted in an unchanged form in the urine. As a consequence of its short elimination half-life (1-3h), 24 hours after the ingestion of a single dose of paracetamol, 98% of the dose is eliminated.

Warning & Precautions:
Etodolac should be given with caution in patients with severe hepatic reactions, pre-existing asthma, fluid retention, hypertension or heart failure. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash etc.), it should be discontinued.
Pregnancy & Lactation: There are no adequate and well-controlled studies in pregnant and lactating women. It should be used, only if the potential benefit justifies the potential risk to the fetus.
Paracetamol should be given cautiously in the following cases: In patients with hepatic or renal failure, in patients taking other hepatotoxic medication.
Pregnancy & Lactation: Pregnant mothers should consult with doctors before taking Paracetamol. It can be taken whilst breast feeding.

Side Effects:
The common side effects of Etodolac involve abdominal pain, constipation, diarrhea, dyspepsia, flatulence, heartburn, nausea, GI ulcers, vomiting.
Side effects of Paracetamol are usually mild, though haematological reactions including thrombocytopenia, leukopenia, pancytopenia, neutropenia, and agranulocytosis have been reported.

Contraindications:
Etodolac is contraindicated in patients with known hypersensitivity to Etodolac. Etodolac should not be given to patients who have experienced asthma, urticaria or other allergic-type reactions after taking Aspirin or other NSAIDs. Paracetamol is contraindicated in patients with severe renal function impairment and hepatic disease (Viral Hepatitis). It is also contraindicated if there is known hypersensitivity to paracetamol.

Overdose:

Etodolac:
Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain which are generally reversible with supportive care.

Paracetamol:
Symptoms of Paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 40 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur.

Storage:
Store at room temperature.
Keep away from moisture.