Aceclofenac + Paracetamol

Aceclofenac + Paracetamol is a an Non-Opioid Analgesic & Antipyretic agent belonging to pharmacological class of Non-steroidal anti-inflammatory drugs

Aceclofenac + Paracetamol is approved for the treatment of Joint pains and trauma, Pelvic inflammatory disease, Oedema and swelling ,Deep Epiosiotomy , Caesearian cases , Dental pain, Post-operative pain.

Aceclofenac is rapidly and completely absorbed as an unmodified medication after oral administration. Peak plasma concentrations are attained between 1.25 and 3 hours after intake. Aceclofenac penetrates the synovial fluid, where concentrations are about 57% higher than in plasma.The distribution's volume is roughly 25 L. Around 4 hours is the half-life on average for plasma elimination. Over 99% of aceclofenac is linked to proteins. Aceclofenac is typically found in unmodified form in circulation. The primary metabolite found in plasma is 4'-hydroxyaceclofenac. The supplied dose is eliminated in the urine in around 15 to 2/3 of its total amount, primarily as hydroxymetabolites. The elderly show no variations in the pharmacokinetics of aceclofenac.

Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. Paracetamol appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9L/kg. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.

The common side effects associated with Aceclofenac + Paracetamol include Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease

Aceclofenac + Paracetamol is available in the form of tablets and suspension

The molecule is available in India, USA, Japan, Germany

Aceclofenac + Paracetamol, belonging to the pharmacological class of Non-steroidal anti-inflammatory drugs acts as Non-Opioid Analgesic & Antipyretic agent.

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.

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.

The Onset of action was within 30 minutes.

The Cmax of Aceclofenac + Paracetamol is about 1-3 hours.

Aceclofenac + Paracetamol is available in tablets, oral suspension

Aceclofenac + Paracetamol tablets and suspension to be swallowed whole with water/liquid.

Aceclofenac + Paracetamol can be used in the treatment of Joint pains and trauma, Pelvic inflammatory disease, Oedema and swelling ,Deep Epiosiotomy , Caesearian cases , Dental pain, Post-operative pain.

It is a pain reliever and works effectively in arthritis, osteoarthritis and ankylosing spondylitis. It also reduces back pain, throat pain, etc.

Aceclofenac + Paracetamol is approved for use in the following clinical indications

• Joint pains and trauma
• Pelvic inflammatory disease
• Oedema and swelling
• Deep Epiosiotomy
• Caesearian cases
• Dental pain
• Post-operative pain

Pain and inflammation

Adult: Aceclofenac 100 mg and paracetamol 500 mg are included in each tablet, which ought to be taken once in the morning and once in the evening. Two tablets maximum daily.

(Aceclofenac + Paracetamol can be administered orally before/ after meals. The dosage and duration of treatment should be as per the clinical judgement of the treating physician)

(The dosage and duration of treatment should be as per the clinical judgement of the treating physician)

Tablets: 100 mg + 325 mg; 100 mg+ 500 mg

Suspension: 60 ml.

Tablets and Suspension.

Aceclofenac + Paracetamol should be used in the treatment of Joint pains and trauma, Pelvic inflammatory disease, Oedema and swelling,Deep Epiosiotomy , Caesearian cases , Dental pain, Post-operative pain. Along with appropriate dietary restrictions

The dietary restriction should be individualized as per patient requirements.

(Aceclofenac + Paracetamol may be contraindicated in the following conditions:-

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

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Unwanted side effects can be reduced by taking the lowest effective dose for the shortest time necessary to control symptoms. It is best to avoid taking with other NSAIDs, such as cyclooxygenase-2 selective inhibitors.

Aceclofenac

• Elderly: The elderly are more likely to have severe reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which can be fatal.
• Respiratory Disorders: Caution is advised when administering NSAIDs to patients suffering from or with a history of bronchial asthma, as NSAIDs have been proven to trigger bronchospasm in such patients.
• Cardiovascular, renal, and hepatic impairment: The use of an NSAID may result in a dose-dependent decrease in prostaglandin production, precipitating renal failure. Patients with poor renal function, cardiac impairment, liver failure, diuretics, and the elderly are most at risk of this response. Renal function in these patients should be monitored.
• Renal: The role of prostaglandins in maintaining renal blood flow should be considered in individuals with decreased cardiac or renal function, those using diuretics, or those recovering from severe surgery.When aceclofenac is stopped, the effects on renal function are usually reversible.
• Hepatic: Aceclofenac should be discontinued if abnormal liver function tests persist or worsen, clinical signs or symptoms compatible with liver disease emerge, or if additional manifestations (eosinophilia, rash) occur. Close medical supervision is required in patients with mild to moderate hepatic function impairment. Hepatitis can occur without any warning signs. Aceclofenac use in patients with hepatic porphyria may precipitate an episode.
• Fluid retention and oedema have been documented in conjunction with NSAID medication. Appropriate monitoring and guidance are required for individuals with a history of hypertension and/or mild to moderate congestive heart failure.
• Clinical trial and epidemiological data suggest that using some NSAIDs (especially at high dosages and for long periods of time) may be related with a slight increase in the risk of arterial thrombotic events (such as myocardial infarction or stroke). There is inadequate evidence to rule out such risks for aceclofenac.
• Fluid retention and oedema have been reported in the presence of NSAID treatment. Individuals with a history of hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and guidance.
• According to clinical trial and epidemiological evidence, taking certain NSAIDs (particularly in high doses and for long periods of time) may be associated with a slight rise in the risk of arterial thrombotic events (such as myocardial infarction or stroke). There is insufficient data to rule out such dangers associated with aceclofenac.
• Patients having symptoms suggestive of gastro-intestinal diseases, a history suggestive of gastrointestinal ulcers, ulcerative colitis or Crohn's disease, bleeding diathesis or haematological abnormalities require close medical supervision.
• With increased NSAID doses, the risk of GI bleeding, ulceration, or perforation increases, as does the risk in individuals with a history of ulcer, especially if worsened by haemorrhage or perforation, and in the elderly. These patients should begin treatment at the lowest available dose. Combination therapy with protective medications (e.g., misoprostol or proton pump inhibitors) should be considered for these individuals, as well as those who need low-dose aspirin or other drugs that may increase gastrointestinal risk.
• Patients with a history of GI toxicity, especially the elderly, should report any unusual abdominal symptoms (especially GI bleeding) early in treatment.
• Patients receiving concomitant drugs that may 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, should exercise caution.
• Aceclofenac should be discontinued in patients that experience GI bleeding or ulceration.
• Patients having a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) should be administered NSAIDs with caution, as these conditions may be aggravated.
• SLE and Mixed Connective Tissue Disease: Aseptic meningitis may be more common in persons with systemic lupus erythematosus (SLE) and mixed connective tissue disorders.
• Dermatological: Serious skin responses, some deadly, have been described in conjunction with the use of NSAIDs, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Patients appear to be more at risk for these events early in the course of medication, with the majority of cases start occurring within the first month of treatment. Aceclofenac should be discontinued as soon as a skin rash, mucosal sores, or any other evidence of hypersensitivity emerges.
• Impaired Female Fertility: Aceclofenac use may affect female fertility and is not suggested in women wanting to conceive. Aceclofenac discontinuation should be considered in women who are having difficulty conceiving or are being investigated for infertility.
• Hypersensitivity reactions: As with other NSAIDs, allergic responses, including anaphylactic/anaphylactoid reactions, can occur without prior contact to the medication.

Aceclofenac may suppress platelet aggregation reversibly.

Paracetamol:

Hepatotoxicity: Paracetamol has been linked to cases of acute liver failure, which has resulted in liver transplantation and death. The majority of occurrences of liver injury are linked to the use of paracetamol at dosages greater than 4,000 milligrams per day, and they frequently involve more than one paracetamol-containing product. Excessive paracetamol consumption may be intentional in order to induce self-harm, or it may be unintended as patients strive to acquire greater pain relief or unknowingly use other paracetamol-containing drugs.

Individuals with underlying liver disease and those who consume alcohol while taking paracetamol are at an increased risk of acute liver failure.

Long-term Treatment

As a precaution, all patients receiving NSAIDs should be evaluated for renal failure, hepatic function (elevation of liver enzymes may occur), and blood counts.

There is no sufficient scientific evidence traceable regarding use and safety of Aceclofenac + Paracetamol in concurrent use with alcohol.

There is no sufficient scientific evidence traceable regarding use and safety of Aceclofenac + Paracetamol in breast feeding.

There is no sufficient scientific evidence traceable regarding use and safety of Aceclofenac + Paracetamol in pregnancy.

There is no sufficient scientific evidence traceable regarding use and safety of Aceclofenac + Paracetamol in concurrent use with any particular food.

The adverse reactions related to Aceclofenac + Paracetamol can be categorized as

• Common Adverse effects: Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melaena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease

• Less Common Adverse effects: abnormal liver function, hepatitis and jaundice, disorientation, depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.

• Rare Adverse effects: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anemia and haemolytic anemia.

The clinically relevant drug interactions of Aceclofenac + Paracetamol is briefly summarized here

Aceclofenac

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.

Diuretics: Reduced diuretic action. Diuretics may increase the risk of NSAID nephrotoxicity. Although it was not demonstrated to alter blood pressure control when co-administered with bendrofluazide, interactions with other diuretics cannot be excluded out. When used with potassium-sparing diuretics, serum potassium should be monitored.

Cardiac glycosides: NSAIDs may worsen heart failure, diminish GFR (glomerular filtration rate), and raise plasma glycoside levels.

Antidiabetic agents: Clinical studies have shown that diclofenac can be given together with oral antidiabetic agents with 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.

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

Paracetamol:

Metoclopramide and Domperidone: The absorption of paracetamol is increased by metoclopramide and domperidone. However, concurrent use need not be avoided.

Cholestyramine: The speed of absorption of paracetamol is reduced by cholestyramine. Therefore, the cholestyramine should not be taken within one hour if maximal analgesia is required.

Chloramphenicol: Increased plasma concentration of chloramphenicol.

The common side of Aceclofenac + Paracetamol include the following

Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease.

The use of Aceclofenac + Paracetamol should be prudent in the following group of special populations

Geriatric Use

The elderly, who are more likely to have compromised renal, cardiovascular, or hepatic function and to be taking concurrent medication, are at a higher risk of major adverse events. If an NSAID is regarded required, the lowest effective dose and the shortest possible time should be utilised. During NSAID therapy, the patient should be examined for GI bleeding on a frequent basis.

Hepatic insufficiency

There is some evidence that the dose of aceclofenac should be reduced in patients with hepatic impairment and it is suggested that an initial daily dose of 100 mg be used.

Renal insufficiency

There is no evidence that the dosage of aceclofenac needs to be modified in patients with mild renal impairment, but as with other NSAIDs caution should be exercised.

Lactation

it should not be ingested during breast feeding. Aceclofenac: In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding. Paracetamol : Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding by women using single ingredient medicinal products containing only paracetamol

Pregnancy

it should not be used during pregnancy. Aceclofenac: 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 12 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. Paracetamol: Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosages.

Symptoms:

Headache, nausea, vomiting, epigastric pain, gastrointestinal irritation, gastrointestinal bleeding, seldom diarrhea, disorientation, excitement, coma, drowsiness, dizziness, tinnitus, hypotension, respiratory depression, fainting, and convulsions are some of the symptoms. Acute renal failure and liver damage are likely in cases of severe intoxication.

Therapeutic measure

Patients should be treated symptomatically as needed. Activated charcoal should be evaluated within one hour of ingesting a potentially hazardous dose. Alternatively, in adults, gastric lavage should be explored within one hour of administration of a potentially life-threatening overdose. Due to their high rate of protein binding and extensive metabolism, specific therapies such as dialysis or haemoperfusion are unlikely to aid in the elimination of NSAIDs. A good production of urine should be ensured. Renal and liver function should be continuously monitored. Patients should be monitored for at least four hours after ingesting potentially dangerous doses. Patients with frequent or persistent convulsions should be treated with intravenous diazepam. Other measurements may be indicated by the patient's clinical condition.

Paracetamol:

Symptoms:

Anorexia, nausea, vomiting, malaise, pallor, and diaphoresis are the first symptoms reported within the first 24 hours after a paracetamol overdose. The most significant adverse effect of paracetamol overdosage is dose-dependent, potentially deadly liver necrosis. Renal tubular necrosis, hypoglycemia coma, and coagulation abnormalities are all possible complications. Nausea, vomiting, diaphoresis, and general malaise are common early symptoms of a potentially hepatotoxic overdose. Hepatic toxicity may not be evident clinically or in the laboratory until 48 to 72 hours after intake.

When diagnosing paracetamol overdose, activated charcoal gastric decontamination should be given soon before N-acetylcysteine (NAC) administration to reduce systemic absorption if paracetamol ingestion is known or suspected to have taken place a few hours prior to presentation. In order to assess the possibility of hepatotoxicity, serum paracetamol levels drawn less than 4 hours after administration may be deceptive. Serum paracetamol levels should be obtained as soon as the patient appears 4 hours or more after ingestion. NAC should be given as soon as feasible when there is a suspicion of a developing or impending liver injury in order to achieve the optimum results. When oral administration of NAC is not an option, intravenous NAC may be used.

Pharmacodynamics:

Aceclofenac:

A non-steroidal treatment having notable analgesic and anti-inflammatory qualities is aceclofenac. Aceclofenac's primary mechanism of action is the suppression of prostaglandin production. The enzyme cyclo-oxygenase, which is necessary for the generation of prostaglandins, is severely inhibited by aceclofenac.

Paracetamol:

Analgesic 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.

Pharmacokinetics:

Aceclofenac

Absorption: Aceclofenac is well absorbed from gastrointestinal tract and peak plasma concentrations (Cmax) are reached 1-3 hours after an oral dose

Distribution: 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.

Metabolism and Excretion: 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:

Absorption: Paracetamol is rapidly and almost completely absorbed from gastrointestinal tract with peak plasma Concentrations (Cmax) occurring about! 0 to 60 minutes after oral administration.

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

Metabolism and Excretion: Paracetamol is metabolized predominantly in liver and excreted in the urine mainly as glucuronide and sulfate conjugate. Less than 5% is excreted unchanged.

Therapeutic Benefits of Aceclofenac+ Paracetamol

It works by inhibiting the COX (Cyclo oxygenase) enzymes which further blocks prostaglandin secretion. Prostaglandins are accountable for producing inflammatory signs and inhibition of prostaglandin aids in providing relief from the symptoms. Paracetamol selectively inhibits the COX enzymes in the brain which aids for its analgesic and antipyretic property.

1. https://media.panaceabiotec.com/documents/2019/7/27/ProductMonograph-Willgo-Aceclefenac-Paracetamol-Thiocolchicosidemonograph.pdf
2. https://fdaghana.gov.gh/img/pils/Alfenac-P Tablet (Aceclofenac and Paracetamol).pdf
3. https://media.panaceabiotec.com/documents/2019/7/27/ProductMonograph-Willgo-Aceclefenac-Paracetamol-Thiocolchicosidemonograph.pdf
4. https://www.nafdac.gov.ng/wp-content/uploads/Files/SMPC/November_2022_Revised/Acel-Plus-Tablets.pdf
5. https://cashkaro.com/blog/how-to-take-aceclofenac-paracetamol-uses-dosage-side-effects-and-more/25027