Aceclofenac and Paracetamol Tablets IP 100mg/325mg (Acetaj P) Taj Pharma

Aceclofenac and Paracetamol Tablets IP 100mg/325mg (Acetaj P) Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT:

Aceclofenac and Paracetamol Tablets IP 100mg/325mg (Acetaj P) Taj Pharma

Aceclofenac and Paracetamol Tablets IP 100mg/500mg (Acetaj P) Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION:

a) Each film-coated tablet contains:
Aceclofenac IP                                   100mg
Paracetamol IP                                   325mg
Excipients                                                q.s.
Colour: Titanium Dioxide IP

b) Each film-coated tablet contains:
Aceclofenac IP                                 100mg
Paracetamol IP                                 500mg
Excipients                                             q.s.
Colour: Titanium Dioxide IP

3. PHARMACEUTICAL FORM:

Film-Coated Tablet

Description:

ACETAJ P is a fixed dose combination of Aceclofenac 100mg and Paracetamol 325mg. This combination offers the advantage of peripheral effects of Aceclofenac and Central effect of paracetamol for pain management.

Aceclofenac is an orally administered phenylacetic acid derivative with effects on a variety of inflammatory mediators. Through its analgesic and anti-inflammatory properties, aceclofenac provides symptomatic relief in a variety of painful conditions. Due to its preferential cox-2 blockade, it has better safety than conventional NSAIDs with respect to adverse effects on gastrointestinal and        cardiovascular system.

Paracetamol acts predominantly by inhibiting prostaglandin synthesis in the central nervous system and to lesser extent, through a peripheral action by blocking pain impulse generation. Paracetamol is one of the effective mild analgesics, suitable for treating mild to moderate pain.

4. CLINICAL PARTICULARS:

4.1 Therapeutic indications:

ACETAJ P is indicated for relief from severe pain and inflammation in Osteoarthritis, Rheumatoid arthritis, Ankylosing spondylitis, Low back pain, Dental pain, Gynaecological pain and painful & Inflammatory conditions of ear, nose & throat.

4.2 Dosage and administration:

ACETAJ P tablets are supplied for oral administration in adults and should be swallowed whole with sufficient amount of liquid. It should be taken preferably with or after food.

The maximum recommended dose of ACETAJ P is two tablets daily, taken as one tablet in the morning and one in the evening.

4.3 Contraindications:

ACETAJ P is contraindicated in the following situations:

• Patients sensitive to Aceclofenac, Paracetamol or to any of the excipients of the product.
• Patients with active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
• Patients who have previously shown hypersensitivity reactions (eg. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.
• Patients with severe heart failure, hypertension, hepatic or renal insufficiency should not be prescribed.
• During pregnancy, especially during the last trimester of pregnancy, unless there are compelling reasons for doing so. The lowest effective dosage should be used.

4.4 Warnings and Precautions:

General

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. Concomitant use with NSAIDs including cyclooxygenase- 2 selective inhibitors should be avoided. It should not be combined with other analgesic medications that contain paracetamol and should be given with care to patients with impaired kidney or liver function.

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients

Respiratory Disorders
Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Hepatic Toxicity

Paracetamol may cause liver damage if taken more than the recommended dose. Allergic reactions like swelling of the face, mouth and throat, difficulty in breathing, itching or rash may occur due to high doses of paracetamol. Severe liver damage may occur if:

• Adult takes more than 4000 mg in 24 hours, which is the maximum daily amount
• Child takes more than 5 doses in 24 hours
• Taken with other drugs containing paracetamol
• Adult has 3 or more alcoholic drinks every day while using this product.

Cardiovascular and Cerebrovascular Effects
Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for aceclofenac.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal Bleeding, Ulceration and Perforation
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

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

The risk of GI bleeding, ulceration or  perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk.

Patients with a history of GI toxicity,   particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or antiplatelet agents such as aspirin. When GI bleeding or ulceration occurs the treatment should be withdrawn.

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated.

SLE and Mixed Connective Tissue Disease
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Dermatological
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment.  Discontinuation should be done at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Doses higher than those recommended involve a risk of very severe liver damage. If liver damage is suspected then liver function tests should be performed.

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

Haematological
May cause reversibly inhibit platelet aggregation.

Long-term treatment
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, 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.

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

4.5 Drug Interactions:

Aceclofenac
Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects.

Anti-hypertensives: Reduced anti-hypertensive effect.

Diuretics: Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. Although it was not shown to affect blood pressure control when co-administered with bendrofluazide, interactions with other diuretics cannot be ruled out. When concomitant administration with potassium-sparing diuretics is employed, serum potassium should be monitored.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR (glomerular filtration rate) and increase plasma glycoside levels.

Lithium: Decreased elimination of lithium.

Methotrexate: Decreased elimination of methotrexate. Caution should be exercised if NSAIDs and methotrexate are administered within 24 hours of each other, since NSAIDs may increase plasma levels, resulting in increased toxicity.

Ciclosporin: Increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding.

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin. Close monitoring of patients on combined anti-coagulants and Aceclofenac therapy should be undertaken.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Antidiabetic agents: Clinical studies have shown that diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However, there have been isolated reports of hypoglycaemic and hyperglycaemic effects. Thus with Aceclofenac, consideration should be given to adjustment of the dosage of hypoglycaemic agents.

Other NSAIDs: Concomitant therapy with aspirin or other NSAIDs may increase the frequency of adverse reactions, including the risk of GI bleeding.

Paracetamol
Drugs which induce hepatic microsomal enzymes such as alcohol, barbiturates and other anticonvulsants, may increase the hepatotoxicity of paracetamol, particularly after overdosage.

The anti-coagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding. The effect appears to increase as the dose of paracetamol is increased, but can occur with doses as low as 1.5 – 2 g paracetamol per day for at least 5 – 7 days. Occasional doses have no significant effect.

Probenicid inhibits the glucuronidation of paracetamol which can affect the clearance of paracetamol. This should be considered when these medicines are administered concomitantly.

Paracetamol may affect the pharmacokinetics of chloramphenicol. This interaction should be considered when these medications are administered concomitantly, especially in malnourished patients.

Enzyme-inducing medicines, such as some antiepileptic drugs (phenytoin, phenobarbital, carbamazepine) have been shown in pharmacokinetic studies to reduce the plasma AUC of paracetamol to approx. 60 %. Other substances with enzyme inducing properties, e.g. rifampicin and St. John’s wort (hypericum) are also suspected of causing lowered concentrations of paracetamol. In addition, the risk of liver damage during treatment with maximum recommended doses of paracetamol will be higher in patients being treated with enzyme-inducing agents.

4.6 Pregnancy, lactation and others:

Renal impairment

It should be avoided in patients with moderate and severe renal impairment. The importance of prostaglandins in maintaining renal blood flow should be taken into account in patients with impaired cardiac or renal function, those being treated with diuretics or recovering from major surgery. Effects on renal function are usually reversible on withdrawal.

Hepatic impairment

In patients with hepatic impairment, dosage reductions are recommended. If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), it should be discontinued. Close medical surveillance is necessary in patients suffering from mild to moderate impairment of hepatic function. Hepatitis may occur without prodromal symptoms. Use in patients with hepatic porphyria may trigger an attack.

Pregnancy

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus) and on the possible risk of persistent pulmonary hypertension of the new born, use in the last trimester of pregnancy is contraindicated. The regular use of NSAIDs during the last trimester of pregnancy may decrease uterine tone and contraction. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus. The drug in not recommended in pregnant  women.

Lactation

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

The use of Aceclofenac should therefore be avoided in pregnancy and lactation unless the potential benefits to the other outweigh the possible risks to the foetus. The drug in not recommended in breast-feeding women.

Geriatric

As with other NSAIDs and combinations, caution is advised in elderly patients who are more likely to have concomitant renal, hepatic or cardiovascular impairment or receiving concurrent medication. The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

4.7 Undesirable effects:

Gastrointestinal: The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular: Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Vasculitis has been reported rarely.

Other Adverse reactions Reported Less Commonly

Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephritic syndrome and renal failure.

Hepatic: abnormal liver function, hepatitis and jaundice.

Neurological and special senses: Visual disturbances, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation, depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.

Haematological: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Dermatological: Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity.

Within the system organ classes, undesirable effects are listed under headings of frequency, using the following categories: very common ( 1/10); common ( 1/100 to <1/10); uncommon ( 1/1,000 to <1/100); rare ( 1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Most of the adverse events are minor and reversible with treatment discontinuation. As with other NSAIDs, severe mucocutaneous skin reactions may also occur.

4.8 Overdosage:

Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of 5 g or more of paracetamol may lead to liver damage if the patient has risk factors.

Risk factors

If the patient

• is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John’s wort or other drugs that induce liver enzymes, or
• is likely to be glutathione depleted e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Immediate treatment is essential in the management of overdose. Despite a lack of significant early symptoms, patients should be referred to a hospital urgently for immediate medical attention.

Symptoms include headache, pallor, nausea, vomiting, epigastric pain, gastrointestinal irritation, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, hypotension, respiratory depression, fainting, occasionally convulsions, anorexia and abdominal pain. In cases of significant poisoning, acute renal failure and liver damage are possible. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. Administration of oral methionine or intravenous N-acetylcysteine which may have a beneficial effect up to at least 48 hours after the overdose may be required. General supportive measures must be available.

Specific therapies such as dialysis or haemoperfusion are probably of no help in eliminating NSAIDs due to their high rate of protein binding and extensive metabolism. Good urine output should be ensured.

Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. In case of frequent or prolonged convulsions, patients should be treated with intravenous diazepam.

Other measures may be indicated by the patient’s clinical condition. Management of acute poisoning with NSAIDs essentially consists of supportive and symptomatic measures. Management of acute poisoning with NSAIDs essentially consists of supportive and symptomatic measures.

5. PHARMACOLOGICAL PROPERTIES:

5.1 Pharmacodynamic properties:

Aceclofenac
Aceclofenac is a non-steroidal agent with marked anti-inflammatory and analgesic properties. The mode of action of aceclofenac is largely based on the inhibition to prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclo-oxygenase, which is involved in the production of prostaglandins.

Aceclofenac relieves pain and inflammation through a variety of mechanisms and in addition exerts stimulatory effects on cartilage matrix synthesis.

Anti-inflammatory activity: The anti-inflammatory effects of Aceclofenac have been shown in both acute and chronic inflammation. It inhibits various mediators of pain and inflammation including:

• PGE2 via cyclooxygenase inhibition(COX-1 & COX-2) after intracellular metabolism to 4-hydroxyaceclofenac and diclofenac in human rheumatoid synovial cells and other inflammatory cells.
• IL-1β, IL-6 and tumor necrosis factorin human osteoarthritic synovial cells and human articular chondrocytes.
• Reactive oxygen species(which plays a role in joint damage) has also been observed in patients with osteoarthritis of knee.
• Expression of cell adhesion molecules(which is implicated in cell migration and inflammation) has also been shown in human neutrophils.

Stimulatory effects on cartilage matrix synthesis: Aceclofenac stimulates glycosaminoglycan synthesis in human osteoarthritic cartilage by inhibition of IL-1 and suppresses cartilage degeneration by inhibiting IL-1 mediated promatrix metalloproteinase production and proteoglycan release.

Paracetamol
Paracetamol is an aniline derivative with analgesic and antipyretic actions similar to those of aspirin but with no demonstrable anti-inflammatory activity. Paracetamol is less irritant to the stomach than aspirin. It does not affect thrombocyte aggregation or bleeding time. Paracetamol is generally well tolerated by patients hypersensitive to acetylsalicylic acid.

Analgesic action: The central analgesic action of Paracetamol resembles that of aspirin. It produces analgesia by raising pain threshold.

Antipyretic effect: The antipyretic effect of Paracetamol is attributed to its ability to inhibit COX in the brain where peroxide tone is low. Recent evidence suggests inhibition of COX-3 (believed to be splice variant product of the COX-1 gene) could represent a primary central mechanism by which Paracetamol decreases pain and possibly fever.

5.2 Pharmacokinetic properties:

Aceclofenac
Absorption
After oral administration, aceclofenac is rapidly and completely absorbed as unchanged drug. Peak plasma concentrations are reached approximately 1.25 to 3.00 hours following ingestion.

Distribution
Aceclofenac penetrates into the synovial fluid, where the concentrations reach approximately 57% of those in plasma. The volume of distribution is approximately 25 L. Aceclofenac is highly protein- bound (>99%). Aceclofenac circulates mainly as unchanged drug.

Metabolism
4’hydroxyaceclofenac is the main metabolite detected in plasma.

Elimination
The mean plasma elimination half-life is around 4 hours. Approximately two- thirds of the administered dose is excreted via the urine, mainly as hydroxymetabolites.

Paracetamol
Absorption
Paracetamol is well absorbed by oral route. The plasma half-life is about 2 hours.

Distribution
Plasma protein binding is negligible at usual therapeutic concentration but increases with increasing concentrations. Acetaminophen is relatively uniformly distributed throughout most body fluids. The plasma half-life is (t1/2) 2-3 hours and the effect after oral dose lasts for 3-5 hours.

Metabolism
Paracetamol is primarily metabolised in the liver by conjugation to glucuronide and sulphate. A small amount (about 3-10% of a therapeutic dose) is metabolised by oxidation and the reactive intermediate metabolite thus formed is bound preferentially to the liver glutathione and excreted as cysteine and mercapturic acid conjugates.

Elimination
Excretion occurs via the kidneys. 2-3% of a therapeutic dose is excreted unchanged; 80-90% as glucuronide and sulphate and a smaller amount as cystein and mercapturic acid derivatives.

6. PHARMACEUTICAL PARTICULARS:

6.1 Incomaptibilities:
None stated.

6.2 Shelf life:
3 years

6.3 Storage and handling instructions:
Store in a cool dry place. Protect from light.

6.4 Packaging information:
ACETAJ P is available in a strip of 10 tablets.

6.5 Special precautions for disposal and other handling:
N/A

7. Manufactured in India by:
TAJ PHARMACEUTICALS LIMITED
At Plot No.: 220, Mahagujarat Industrial Estate,
At & Post: Moraiya, Tal – Sanand, Dist. Ahmedabad, Gujarat, INDIA.