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University Of Nairobi
Aceclofenac is an orally administered phenyl acetic acid derivatives with effects on a variety of inflammatory mediators.
Aceclofenac contains not less than 99.0% and not more than the equivalent of 101.0 percent of 2-[[2-[2-[(2, 6-dichlorophenyl) amino] phenyl] acetyl] oxy] acetic acid.
It is a white or almost white crystalline powder. It is an effective analgesic and anti-inflammatory agent with a good tolerability profile. Through its analgesic and anti-inflammatory properties, Aceclofenac provides symptomatic relief in a variety of painful conditions. A reduction in the stimulated generation of reactive oxygen species (O2), which may play a role in joint damage, was observed after 15 days in these patients, but after 180 days. At day 180, O2 release was similar to that seen in a group of 41 healthy untreated individuals.
The mode of action of Aceclofenac is largely based on the inhibition of prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclooxygenase, which is involved in the production of prostaglandins.
The Drugs inhibits synthesis of the inflammatory cytokines interleukin (IL)-1 and tumor necrosis factor and prostaglandin E2 (PGE2) production. Effects on cell adhesion molecular from neurophils have also been noted. In vitro data indicate inhibition of cyclooxygenase (Cox)-1 and 2 by Aceclofenac in whole blood assays, with selectivity for Cox-2 being evident.
Aceclofenac has shown stimulatory effects on cartilage matrix synthesis that may be linked to the ability of the drug to inhibit IL-1 activity. In vitro data indicate stimulation by 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'-hydroxyacelofenac has chondroprotective properties attributable to suppression of IL-1 mediated promatrix metalloproteinase production and proteoglycan release.
In patients with osteoarthritis of the knee, Aceclofenac decrease 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.
Aceclofenac is rapidly and completely absorbed after oral administration, peak plasma concentrations are reached 1 to 3 hours after an oral dose. The drug is highly protein bound (79.9%). The presence of food does alter the extent of absorption of Aceclofenac but the absorption rate is reduced. The plasma concentration of Aceclofenac was approximately twice that in synovial fluid after multiple doses of the drug in-patient with knee pain and synovial fluid effusion. Aceclofenac is metabolized to a major metabolite, 4'-hydroxyAceclofenac and to a number of other metabolites including 5-hydroxyAceclofenac, 4'-hydroxydiclofenac, diclofenac and 5-hydroxydiclofenac. Renal excretion is the main route of elimination of Aceclofenac with 70 to 80% of an administered dose found in the urine, mainly as the glucuronides of Aceclofenac and its metabolites of each dose of Aceclofenac, 20% is excreted in the faeces. The plasma elimination half-life of the drug is approximately 4 hours.
Aceclofenac may increase plasma concentrations of lithium, digoxin and methotrexate, increase the activity of anticoagulant, inhibits the activity of diuretics, enhance cyclosporin nephrotoxicity and precipitate convulsions when co-administered with quinolone antibiotics. Furthermore, hypo or hyperglycaemia may result from the concomitant administration of Aceclofenac and antidiabetic drugs, although this is rare. The co administration of Aceclofenac with other NSAIDS of corticosteroids may results in increased frequency of adverse event.
Adverse Drug Reaction
Aceclofenac is well tolerated, with most adverse events being minor and reversible and affecting mainly the GI system. Most common events include dyspepsia (7.5%), abdominal pain (6.2%), nausea (1.5%), diarrhea (1.5%), flatulence (0.8%), gastritis (0.6%), constipation (0.5%), vomiting (0.5%), ulcerative stomatitis (0.1%), pancreatitis (0.1%).
Although the incidence of gastro intestinal adverse events with Aceclofenac was similar to those of comparator NSAIDS in individual clinical trials, withdrawal rates due to these events were significantly lower Aceclofenac than with ketoprofen and tenoxicam.
Other adverse effect, which is not common such as dizziness (1%), vertigo (0.3%), and rare cases: par aesthesia and tremor.
Dosage and Administration
The usual dose of Aceclofenac is 100 mg given twice daily by mouth, one tablet in the morning and one in the evening. 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.
Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 10 to 60 minutes after oral administration. Paracetamol is distributed into most body tissues. Plasma protein binding is negligible at usual therapeutic doses but increases with increasing doses. The elimination half-life varies from about 1 to 3 hours.
Paracetamol is metabolised extensively in the liver and excreted in the urine mainly as inactive glucuronide and sulfate conjugates. Less than 5% is excreted unchanged. The metabolites of paracetamol include a minor hydroxylated intermediate which has hepatotoxic activity. This intermediate metabolite is detoxified by conjugation with glutathione, however, it can accumulate following paracetamoloverdosage (more than 150mg/kg or 10g total paracetamol ingested) and if left untreated can cause irreversible liver damage.
Paracetamol is metabolised differently by premature infants, newborns, infants and young children compared to adults, the sulfate conjugate being predominant.
Pharmacodynamics/Mechanism of action:
Paracetamol is a p-aminophenol derivative that exhibits analgesic and antipyretic activity. It does not possess anti-inflammatory activity. Paracetamol is thought to produce analgesia through a central inhibition of prostaglandin synthesis.
This section must contain the indications of the product as specified in the ARTG. If the indications are not specified in the ARTG (e.g. for a non-validated grandfathered product), the indications must be as specified on the product label.
Paracetamol is contraindicated for use in patients with known hypersensitivity or idiosyncratic reaction to paracetamol (or any of the other ingredients in the product)
Paracetamol should be used with caution in patients with:
• impaired hepatic function
• impaired renal function
Use in pregnancy
Category A: Paracetamol has been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.
Paracetamol is excreted in small amounts (< 0.2%) in breast milk. Maternal ingestion of paracetamol in usual analgesic doses does not appear to present a risk to the breastfed infants.
Interaction with other medicines
The following interactions with paracetamol have been noted:
• Anticoagulant drugs (warfarin) - dosage may require reduction if paracetamol and anticoagulants are taken for a prolonged period of time
• Paracetamol absorption is increased by substances that increase gastric emptying, e.g. metoclopramide
• Paracetamol absorption is decreased by substances that decrease gastric emptying, e.g. propantheline, antidepressants with anticholinergic properties, and narcotic analgesics
• Paracetamol may increase chloramphenicol concentrations
• The risk of paracetamol toxicity may be increased in patients receiving other potentially hepatotoxic drugs or drugs that induce liver microsomal enzymes such as alcohol and anticonvulsant agents
• Paracetamol excretion may be affected and plasma concentrations altered when given with probenecid
• Colestyramine reduces the absorption of paracetamol if given within 1 hour of paracetamol.
Side effects of paracetamol are rare and usually mild, although haematological reactions have been reported. Skin rashes and hypersensitivity reactions occur occasionally. Overdosage with paracetamol if left untreated can result in severe, sometimes fatal liver damage and rarely, acute renal tubular necrosis.
Symptomatic treatment of muscle spasm and pain associated with acute musculoskeletal conditions
Use - Dental:
Treatment of muscle spasm and pain associated with acute temporomandibular joint pain
Pregnancy Risk Factor: C
Excretion in breast milk unknown/not recommended
Hypersensitivity to chlorzoxazone or any component of the formulation; impaired liver function
Frequency not defined.
Central nervous system: Dizziness, drowsiness lightheadedness, paradoxical stimulation, malaise
Dermatologic: Rash, petechiae, ecchymoses (rare), angioneurotic edema
Gastrointestinal: Nausea, vomiting, stomach cramps
Genitourinary: Urine discoloration
Hepatic: Liver dysfunction
Miscellaneous: Anaphylaxis (very rare)
Symptoms of overdose include nausea, vomiting, diarrhea, drowsiness, dizziness, headache, absent tendon reflexes, and hypotension. Treatment is supportive following attempts to enhance drug elimination. Dialysis, hemoperfusion, and osmotic diuresis have all been useful in reducing serum drug concentrations. The patient should be observed for possible relapses due to incomplete gastric emptying.
Substrate of CYP1A2 (minor), 2A6 (minor), 2D6 (minor), 2E1 (major), 3A4 (minor); Inhibits CYP2E1 (weak), 3A4 (weak)
CNS depressants: Effects may be increased by chlorzoxazone.
CYP2E1 inhibitors: May increase the levels/effects of chlorzoxazone. Example inhibitors include disulfiram, isoniazid, and miconazole.
Disulfiram: May increase chlorzoxazone concentration; monitor.
Isoniazid: May increase chlorzoxazone concentration; monitor.
Ethanol: Avoid ethanol (may increase CNS depression).
Mechanism of Action:
Acts on the spinal cord and subcortical levels by depressing polysynaptic reflexes
Onset of action: ~1 hour
Duration: 6-12 hours
Absorption: Readily absorbed
Metabolism: Extensively hepatic via glucuronidation
Excretion: Urine (as conjugates)
Children: 20 mg/kg/day or 600 mg/m2/day in 2-4 divided doses
Adults: 500 mg 2-4 times/day up to 750 mg 2-4 times/day
Periodic liver functions tests
Dental Health: Effects on Dental Treatment:
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions:
No information available to require special precaution
Mental Health: Effects on Mental Status:
Drowsiness is common; may produce depression or paradoxical stimulation
Mental Health: Effects on Psychiatric Treatment
May produce aplastic anemia and leukopenia; use caution with clozapine and carbamazepine
Zyrtal MR dosage 1 tablet twice a day.