XCLORIZ P

Prescribing Information

For the Use of a Registered Medical Practitioner or a Hospital Or a Laboratory Only

Aceclofenac and Paracetamol tablets

XCLORIZ P

Paracetamol: Box Warning About Its Liver Toxicity

Taking more than daily dose may cause serious liver damage or allergic reactions (e.g., swelling of the face, mouth and throat, difficulty in breathing, itching or rash). The risk of liver injury primarily occurs when patient take multiple products containing paracetamol at one time and exceed the current maximum dose of 4,000 mg within a 24-hour period.

COMPOSITION

Each film coated tablet contains:

Aceclofenac IP 100 mg

Paracetamol IP 325 mg

Excipients q.s.

CLINICAL PHARMACOLOGY

Mechanism of Action:

The mode of action of aceclofenac is largely based on the inhibition of prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclo-oxygenase, which is involved in the production of prostaglandins.

Aceclofenac has been shown to exert effects on a variety of mediators of inflammation. The drug inhibits synthesis of the inflammatory

cytokines interleukin (IL)- and tumour necrosis factor and inhibits prostaglandin E2 (PGE2) production. Effects on cell adhesion molecules from neutrophils have also been noted. In vitro data indicate inhibition of cyclo-oxygenase (COX)-1 and 2 by aceclofenac in whole blood assays, with selectivity for COX-2 being evident.

In contrast to some other NSAIDs, aceclofenac has shown stimulatory effects on cartilage matrix synthesis, that may be linked to the ability of the drug to inhibit IL-1 b data indicate stimulation by activity. In vitro the drug of synthesis of glycosaminoglycan in osteoarthritic cartilage. There is also evidence that aceclofenac stimulates the synthesis of IL-1 receptor antagonist in human articular chondrocytes subjected to inflammatory stimuli and that 4'-hydroxyaceclofenac has chondroprotective properties attributable to suppression of IL-1 mediated promatrix metalloproteinase production and proteoglycan release. In patients with osteoarthritis of the knee, aceclofenac decreases pain, reduces disease severity and improves the functional capacity of the knee. It reduces joint inflammation, pain intensity and the duration of morning stiffness in patients with rheumatoid arthritis. The duration of morning stiffness and pain intensity are reduced and spinal mobility improved, by aceclofenac in patients with ankylosing spondylitis.

PHARMACOKINETIC PROPERTIES

Aceclofenac is well absorbed from gastrointestinal tract and peak plasma concentrations (Cmax) are reached 1-3 hours after an oral dose. The drug is more than 99% bound to plasma proteins and the volume of distribution (Vd) is approximately 25 liters. The presence of food reduced rate of absorption (increased tmax) but not the extent of absorption (Cmax or AUC). In patients with knee pain and synovial fluid effusion, the plasma concentration of Aceclofenac was twice that in synovial fluid after multiple doses of the drug. Aceclofenac is metabolized mainly to 4’ hydroxy-aceclofenac. The drug is eliminated primarily through renal excretion with 70-80% of administered dose found in urine as glucoronides and rest being excreted in faeces. The plasma elimination half life of Aceclofenac is approximately 4 hours.

Paracetamol is rapidly and almost completely absorbed from gastrointestinal tract with peak plasma concentrations (Cmax) occurring about 10 to 60 minutes after oral administration. Plasma protein binding is negligible at usual therapeutic concentration but increases with increasing concentrations. Paracetamol is relatively uniformly distributed throughout most body fluids. The plasma half life (t1/2) 2-3 hours and the effect after oral dose lasts for 3-5 hours. Paracetamol is metabolized predominantly in liver and excreted in the urine mainly as glucuronide and sulfate conjugate. Less than 5% is excreted unchanged.

INDICATIONS

Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, cervical spondylitis, intervertebral disc syndrome, sciatica, non-articular rheumatic conditions, post-operative and traumatic inflammations, painful inflammatory conditions in gynaecology and dentistry and pain and fever associated with inflammation

DOSAGE AND ADMINISTRATION

The recommended dose of Aceclofenac with Paracetamol is 1 tablet twice daily. Generally, no dose adjustment is necessary in elderly patients and those with mild renal impairment. Safety and efficacy has not been established in children.

CONTRAINDICATIONS

The combination should not be administered to:

Patients sensitive to Aceclofenac, Paracetamol or to any of the excipients of the product
Patients in whom aspirin or other NSAIDs, precipitate attacks of bronchospasm, acute rhinitis or urticaria or patients hypersensitive to these drugs
Patients with active or suspected peptic ulcer or gastrointestinal bleeding or bleeding disorders
Patients with severe heart failure, hypertension, hepatic or renal insufficiency
Third trimester of pregnancy

WARNINGS AND PRECAUTIONS

Warnings

Close medical surveillance is imperative in patients with symptoms indicative of gastrointestinal disorders, with a history suggestive of gastrointestinal ulceration, with ulcerative colitis or with Crohn’s disease, bleeding diathesis or haematological abnormalities.

Gastrointestinal bleeding or ulcerative perforation, haematemesis and melaena have in general more serious consequences in the elderly. They can occur at any time during treatment, with or without warning symptoms or previous history. In the rare instances, where gastrointestinal bleeding or ulceration occurs in patients receiving aceclofenac, the drug should be withdrawn.

Close medical surveillance is also imperative in patients suffering from severe impairment of hepatic function.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug.

Precautions

It may cause dizziness. Driving or operating machinery are to be avoided.

Individuals receiving long-term treatment should be regularly monitored for renal function tests, liver function tests and blood counts. It is to be used with caution in hepatic porphyria, coagulation disorders, history of peptic ulcers, ulcerative colitis, Crohn’s disease, SLE, cerebrovascular bleeding, pregnancy and lactation. Caution should be exercised in patients with mild to moderate impairment of cardiac, hepatic or renal function and in elderly patients who are more likely to be suffering from these conditions. Caution is also required in patients on diuretic therapy or otherwise at risk of hypovolemia.

ADVERSE REACTIONS

Most of the adverse events are minor and reversible with treatment discontinuation. The majority of side effects are related to gastrointestinal system (dyspepsia, abdominal pain, nausea and diarrhea), most frequent being dyspepsia, abdominal pain and rise in hepatic enzymes. Other rare side-effects include dizziness, constipation, vomiting, ulcerative stomatitis, rash, dermatitis, headache, fatigue, allergic reactions, anemia, granulocytopenia, thrombocytopenia, neutropenia, oedema, palpitation, leg cramps, flushing, purpura, paraesthesia, tremors, gastrointestinal bleeding, gastrointestinal ulceration, pancreatitis, interstitial nephritis, depression, abnormal dreaming, somnolence, insomnia, vasculitis, hypoglycemia, rise in blood urea, serum creatinine and serum potassium. As with other NSAIDs, severe mucocutaneous skin reactions may occur.

The following adverse events (described as most frequent >5%, occasional < 5% or rare cases < 0.1%) were reported during all clinical trials:

Gastrointestinal disorders: Most frequent: dyspepsia (7.5%), abdominal pain (6.2%), Occasional: nausea (1.5%), diarrhoea (1.5%), flatulence (0.8%), gastritis (0.6%), constipation (0.5%), vomiting (0.5%), ulcerative stomatitis (0.1%). Rare cases: (all <0.1%), pancreatitis, melaena, stomatitis

Central and peripheral nervous system: Occasional: dizziness (1%), vertigo (0.3%). Rare cases: (all<0.1%),

paraesthesia, tremor

Psychiatric: Rare cases: (all<0.1%) depression, abnormal dreaming, somnolence, insomnia

Skin and appendages: Occasional: pruritus (0.9%), rash (0.5%), dermatitis (0.2%). Rare cases: (all<0.1%) eczema

Liver and biliary: Occasional: hepatic enzymes increased (2.5%)

Metabolic: Occasional: BUN increased (0.4%), blood creatinine increased (0.3%). Rare cases (all < 0.1%) alkaline phosphatase increased, hyperkalaemia

Cardiovascular: Rare cases: (all<0.1%) oedema (dependent), palpitation, leg cramps, flushing, purpura

Respiratory: Rare cases: (all<0.1%) anaemia, granulocytopenia, thrombocytopenia

Body as whole, general: Rare cases: (all<0.1%) headache, fatigue, face, oedema, hot flushes, allergic reaction, weight increase

Other: Rare cases: (all<0.1%) abnormal vision, abnormal taste.

DRUG INTERACTIONS

Drug interactions associated with Aceclofenac are similar to those observed with other NSAIDs. Aceclofenac may increase the plasma concentrations of lithium, digoxin and methotrexate. It may increase the activity of anticoagulants, inhibit the activity of diuretics, enhance cyclosporine nehrotoxicity and precipitate convulsions when coadministered with quinolone antibiotics. Coadministration of Aceclofenac with other NSAIDs and corticosteroids are to be avoided due to increased incidence of side-effects.

The risk of Paracetamol toxicity may be increased in patients receiving other potentially heatotoxic drugs or drugs that induce hepatic microsomal enzymes. Coadministration of Paracetamol with rifampicin, isoniazid, chloramphenicol, anti-epileptic drugs and antiviral drugs is to be avoided. Metoclopromide may increase the absorption of Paracetamol whereas excretion and plasma concentration may be altered when coadministered with probenecid. Cholestyramine also reduces the absorption of Paracetamol.

Interaction with other Medicinal Products and other forms of Interaction

Drug interactions associated with aceclofenac are similar to those observed with other NSAIDs.

Aceclofenac may increase plasma concentrations of lithium, digoxin and methotrexate, increase the activity of anticoagulants, inhibit the activity of diuretics, enhance cyclosporin nephrotoxicity and precipitate convulsions when coadministered with quinolone antibiotics.

When concomitant administration with potassium sparing diuretics is employed, serum potassium should be monitored.

Furthermore, hypo or hyperglycaemia may result from the concomitant administration of aceclofenac and antidiabetic drugs, although this is rare. The coadministration of aceclofenac with other NSAIDs or corticosteroids may result in increased frequency of adverse events.

Caution should be exercised if NSAIDs and methotrexate are administered within 2-4 hours of each other, since NSAIDs may increase methotrexate plasma levels, resulting in increased toxicity.

Effects on Ability to Drive and Use

Machines Patients who experience dizziness or other central nervous system disturbances while taking NSAIDs should refrain from driving or operating machinery.

USE IN SPECIAL POPULATIONS

Pregnancy & Lactation

The safety of this medicine for use during pregnancy has not been established. The drug is not recommended in pregnant or breast feeding women.

OVERDOSAGE

Management of acute poisoning with NSAIDs essentially consists of supportive and symptomatic measures.

There are no human data available on the consequences of aceclofenac overdosage. The therapeutic measures to be taken are: absorption should be prevented, as soon as possible after overdosage by means of gastric lavage and treatment with activated charcoal; supportive and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal irritation, and respiratory depression, specific therapies such as forced diuresis, dialysis or haemoperfusion are probably of no help in eliminating NSAIDs due to their high rate of protein binding and extensive metabolism.

INCOMPATIBILITIES :

Not Applicable

STORAGE

Store at a temperature below

25°C. protect from light & moisture.

Keep the medicine out of reach of children.

PRESENTATION

Strip of 10 Tablets

MANUFACTURED BY

Pinnacle Life Science Pvt. Ltd.

(Subsidiary of Aarti Drugs Ltd.)

At D-42, IIE SIDCUL, Selaqui,