Acemetacin
Indometacin prodrug for inflammatory rheumatic diseases
Acemetacin is a glycolic acid ester of indometacin and acts as a prodrug. After oral intake it is activated to indometacin, the actual active agent. In Germany acemetacin is available under the brand name Rantudil and as generics in 30 or 60 mg capsules. The substance is prescription only and is used for symptomatic treatment of inflammatory rheumatic diseases when classical NSAIDs such as ibuprofen or naproxen are not sufficiently effective.
Acemetacin belongs to the acetic acid derivative class along with indometacin and diclofenac. The prodrug form is intended to improve gastrointestinal tolerability because local gastric irritation is lower than with direct indometacin. Clinical evidence for this advantage is limited; the systemic side effect profile largely corresponds to that of indometacin. In rheumatology acemetacin is mostly used as second line when standard NSAIDs do not give an adequate response.
Mechanism of Action
After absorption from the small intestine acemetacin is hydrolysed by liver and plasma esterases and releases indometacin. Indometacin non selectively inhibits cyclooxygenase 1 and cyclooxygenase 2, and thus the synthesis of prostaglandins, thromboxanes and prostacyclin from arachidonic acid. Inhibition of COX 2 mediates the anti inflammatory, analgesic and antipyretic effect, while COX 1 inhibition is responsible for most gastrointestinal, renal and platelet related side effects.
The analgesic potency of indometacin is particularly pronounced in acutely inflammatory pain such as gout attack, acute pericarditis and acute gouty arthritis. The half life of indometacin is about 4 to 5 hours, that of acemetacin itself is shorter. The extended release formulation prolongs the duration of action and allows twice daily dosing.
A portion of acemetacin is excreted directly as acemetacin without being converted to indometacin. Full bioequivalence with free indometacin is therefore not given. Manufacturers argue that the prodrug form offers better gastric mucosal tolerability, but meta analyses show no significant superiority in the side effect profile compared with indometacin.
Indications
- Activated osteoarthritis with signs of inflammation and pain
- Rheumatoid arthritis for symptomatic therapy in combination with disease modifying agents
- Ankylosing spondylitis (Bechterew's disease)
- Inflammatory soft tissue rheumatic conditions such as tendinitis, bursitis and periarthritis
- Gout attack for rapid anti inflammatory effect
- Postoperative pain after orthopaedic procedures
Dosage and Administration
Standard dose: 60 mg twice daily (morning and evening) with meals, maximum daily dose of 180 mg in exceptional cases. Mild cases: 30 mg twice daily. Gout attack: initially 60 mg every 6 hours for 1 to 2 days, then reduction.
Taking the capsules with meals reduces gastrointestinal side effects. Capsules should be swallowed whole with sufficient liquid. Treatment duration depends on the indication and response; in chronic rheumatic diseases the aim is the lowest effective dose over the shortest necessary time.
Renal impairment: contraindicated in moderate to severe impairment, cautious dosing with monitoring in mild impairment. Hepatic impairment: contraindicated in severe impairment, dose reduction in moderate impairment. Elderly patients: lowest effective dose with gastrointestinal and cardiovascular risk management.
Side Effects
Common: dyspepsia, nausea, abdominal pain, diarrhoea, constipation, headache, dizziness, skin rash, tinnitus, oedema.
Uncommon: gastrointestinal ulcers and bleeding, blood count changes, elevated liver enzymes, hypertension, worsening of heart failure, impaired concentration, fatigue, insomnia, paradoxical excitation.
Rare to very rare: severe skin reactions such as Stevens Johnson syndrome, toxic epidermal necrolysis, acute kidney failure, interstitial nephritis, aseptic meningitis, pancreatitis, severe blood count changes (agranulocytosis, thrombocytopenia), anaphylactic reactions, cardiovascular events (myocardial infarction, stroke).
CNS side effects: indometacin and its derivatives can cause central nervous system side effects such as headache, dizziness, confusion, hallucinations and psychiatric symptoms that are less common with other NSAIDs. This requires particular attention in elderly patients.
Interactions
- Other NSAIDs, acetylsalicylic acid: additive gastrointestinal bleeding risk
- Anticoagulants (warfarin, DOACs, heparins): increased bleeding risk
- SSRIs, SNRIs: increased gastrointestinal bleeding risk
- Corticosteroids: additive ulcer and bleeding risk
- Antihypertensives: attenuated effect
- Lithium, methotrexate, digoxin: elevated plasma levels
- Diuretics: attenuated effect, monitor renal function
- Ciclosporin, tacrolimus: increased nephrotoxicity
- Probenecid: reduced elimination, elevated plasma levels
Special Notes
Contraindications: active peptic ulcer, severe heart failure, ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, severe renal or hepatic impairment, third trimester of pregnancy, children and adolescents under 14 years, known hypersensitivity, analgesic induced asthma, active bleeding.
Gastric protection: with risk factors (age over 60, ulcer history, concomitant corticosteroids, SSRIs or anticoagulants) a proton pump inhibitor is indicated alongside therapy. For short term use without risk factors it can be omitted.
Pregnancy: in the first and second trimesters only if clearly indicated; contraindicated in the third trimester because of the risk of premature closure of the ductus arteriosus and fetal renal damage. Breastfeeding: indometacin metabolites pass into breast milk; breastfeeding during therapy is not recommended.
Monitoring: regular blood count, liver and kidney values, and blood pressure during long term therapy. Patients should be informed about warning signs such as black stools, blood in vomit, severe abdominal pain, shortness of breath, chest pain and skin changes.
Fitness to drive: dizziness, fatigue and impaired concentration can impair the ability to drive, especially during the initial phase and when combined with alcohol.
You may also be interested in
- Indometacin, classical NSAID of the acetic acid derivatives
- Dexketoprofen, NSAID of the propionic acids
- Piroxicam, oxicam NSAID
- Methotrexate, base therapy for rheumatoid arthritis
- Colchicine, alternative therapy for gout attack
Frequently Asked Questions
What is the difference between acemetacin and indometacin?
Acemetacin is a prodrug of indometacin that is converted to indometacin in the body. The prodrug form is intended to reduce local gastric mucosal irritation. Pharmacodynamically the effect in the body is largely identical to indometacin and the side effect profile does not differ significantly.
Is acemetacin better tolerated than ibuprofen?
Not as a general rule. Ibuprofen is better tolerated in many patients, particularly in terms of gastrointestinal and central nervous system side effects. Acemetacin is often used when other NSAIDs such as ibuprofen or diclofenac are not sufficiently effective, especially in rheumatic diseases and gout attack.
Do I need gastric protection?
With risk factors such as age over 60, ulcer history, combination with corticosteroids, SSRIs or anticoagulants, a proton pump inhibitor alongside therapy is recommended. For short term use without risk factors it can be omitted. The prescribing physician makes the decision individually.
Why headaches on acemetacin?
Headaches are among the most common central nervous system side effects of indometacin and its derivatives. The precise mechanism is unclear; prostaglandin mediated effects on cerebral vessels are suspected. With persistent severe headaches a switch to another NSAID such as ibuprofen or naproxen is advisable.
Sources
- EMA, European Medicines Agency
- AWMF, S3 Guideline Rheumatoid Arthritis and Gout
- Gelbe Liste, Acemetacin active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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