Acenocoumarol is an oral anticoagulant used to prevent and treat blood clots (venous thrombosis, pulmonary embolism) and to prevent stroke in people with atrial fibrillation. It works by reducing the liver production of vitamin K-dependent clotting factors.
Also known as: Acenocumarol, Sintrom, Sinthrome
Acenocoumarol + amiodarone: amiodarone increases the anticoagulant effect of acenocoumarol, with bleeding risk — monitor INR when starting or stopping amiodarone.
QUADRO 2 of Annex 7 (Warfarin) lists amiodarone among drugs that increase the anticoagulant effect with bleeding risk; acenocoumarol refers to warfarin ("Acenocoumarol: see Warfarin"), sharing the coumarin interaction profile. Amiodarone inhibits coumarin metabolism (CYP2C9) and displaces them from plasma proteins, and the effect persists for weeks after discontinuation due to amiodarone's long half-life.
Monitor INR 3-7 days after starting, adjusting or stopping amiodarone, and periodically thereafter.
Markedly elevated INR, bleeding or spontaneous bruising after starting amiodarone.
When starting amiodarone in a patient stabilized on acenocoumarol, reduce the anticoagulant dose (typically 30-50%) and titrate by INR; when stopping amiodarone, reassess the dose.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin; Amiodarone)
Acenocoumarol + diclofenac: diclofenac increases the hypoprothrombinemic response and irritates the gastric mucosa — increased bleeding risk.
QUADRO 2 (Warfarin) records that "some agents increase the hypoprothrombinemic response (diclofenac, ibuprofen, ketorolac)". Diclofenac combines a pharmacodynamic effect on coagulation with the gastrotoxic risk of NSAIDs, potentiating the bleeding risk of coumarins.
Monitor INR and signs of gastrointestinal bleeding during co-administration.
Haematochezia, melaena, elevated INR or falling haemoglobin with concomitant use.
Prefer alternative analgesics (paracetamol at controlled dose) when possible; if diclofenac is unavoidable, use the lowest dose and shortest duration, with gastric protection.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin)
Acenocoumarol + cimetidine: cimetidine inhibits coumarin metabolism and increases INR — bleeding risk; monitor when starting, adjusting or stopping.
QUADRO 2 (Warfarin) lists cimetidine among drugs that increase the anticoagulant effect with bleeding risk. Cimetidine inhibits the CYP enzymes (including CYP2C9 and CYP3A4) responsible for coumarin metabolism, raising concentrations and anticoagulant effect.
Monitor INR in the first days after starting or stopping cimetidine.
Elevated INR or bleeding after starting cimetidine.
Consider an alternative H2 antagonist (e.g. famotidine) that does not inhibit CYP; if cimetidine is kept, watch INR and reduce the anticoagulant dose if needed.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin; Cimetidine)
Acenocoumarol + clopidogrel: additive bleeding from dual haemostasis inhibition — avoid unless formally indicated (e.g. stent) with tight monitoring.
QUADRO 2 (Warfarin) lists clopidogrel among drugs that increase the anticoagulant effect with bleeding risk. Combining a coumarin with an antiplatelet agent inhibits two haemostatic pathways (coagulation and platelets), with significant additive bleeding risk.
Close clinical monitoring of bleeding signs and more frequent INR.
Major bleeding, intracranial or gastrointestinal haemorrhage with the combination.
Avoid the combination whenever possible; when essential (acute coronary syndrome with stent in a patient with anticoagulation indication), use the shortest duration of dual therapy and INR-titrated doses.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin; Clopidogrel)
Acenocoumarol + paracetamol: high doses or prolonged paracetamol use may potentiate the anticoagulant effect — limit the dose and watch INR.
QUADRO 2 (Warfarin) records that paracetamol "prevents the synthesis of coagulation factors", potentiating the anticoagulant effect. The interaction is dose-dependent, becoming clinically relevant mainly with high doses (e.g. >2 g/day) or chronic use.
Watch INR in patients using paracetamol daily at high doses.
Unexplained elevated INR in a patient with daily paracetamol use.
Use the lowest effective paracetamol dose for the shortest time; with chronic use, monitor INR.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin; Paracetamol)
Acenocoumarol + aspirin: additive bleeding (platelet inhibition + hypoprothrombinemic effect at high doses) — avoid unless formally indicated for cardiovascular disease.
QUADRO 2 (Warfarin) records: "Salicylates: platelet inhibition with acetylsalicylic acid... at high doses they have a hypoprothrombinemic effect". Aspirin adds irreversible platelet inhibition to anticoagulation, with additive bleeding risk, especially gastrointestinal.
Monitor for signs of gastrointestinal bleeding and more frequent INR during the combination.
Melaena, haematochezia, haematemesis or very high INR with the combination.
Avoid the combination; if low-dose aspirin is clinically essential (e.g. coronary disease), add gastric protection and closely watch INR and bleeding signs.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin; Salicylates)
Acenocoumarol + cotrimoxazole: sulfamethoxazole-trimethoprim inhibits coumarin metabolism and displaces it from proteins — marked INR increase and bleeding risk.
QUADRO 2 (Warfarin) records: "Sulfamethoxazole + Trimethoprim: inhibit warfarin metabolism and displace it from the transport protein". Cotrimoxazole combines enzyme inhibition with protein displacement, causing a rapid and sometimes marked increase in the anticoagulant effect.
Monitor INR 2-4 days after starting cotrimoxazole and after stopping it.
Very high INR, bleeding or extensive bruising during or after the antibiotic.
Avoid cotrimoxazole in patients on coumarins when an alternative exists; if unavoidable, preventively reduce the anticoagulant dose and monitor INR closely.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin; Sulfamethoxazole + Trimethoprim)
Acenocoumarol + levothyroxine: thyroxine accelerates coagulation factor catabolism and may reduce the anticoagulant effect — watch INR when the thyroxine dose changes.
QUADRO 2 (Warfarin) records: "Thyroxine: accelerates the catabolism of coagulation factors". Increased catabolism of vitamin K-dependent factors reduces the anticoagulant effect; conversely, stopping or reducing thyroxine may increase it.
Monitor INR whenever the levothyroxine dose changes.
Suddenly low INR after starting thyroxine or high INR after reducing it.
When starting, adjusting or stopping levothyroxine, monitor INR and adjust the anticoagulant dose accordingly.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin; Thyroxine)
Acenocoumarol + propafenone: propafenone probably reduces anticoagulant metabolism — may increase INR; watch when starting or stopping.
QUADRO 2 (Warfarin) records that propafenone "probably reduces the metabolism of the anticoagulant". Propafenone's enzyme inhibition may raise coumarin concentrations and potentiate the anticoagulant effect.
Monitor INR in the first days after starting or stopping propafenone.
Elevated INR or bleeding after starting propafenone.
When starting propafenone, preventively reduce the anticoagulant dose and titrate by INR; reassess when stopping.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin; Propafenone)
Acenocoumarol + allopurinol: allopurinol may potentiate the anticoagulant effect of coumarins — watch INR when starting allopurinol.
QUADRO 2 (Warfarin) explicitly refers "See also: Alcohol, Allopurinol", recognising the potential interaction of allopurinol with coumarin anticoagulants (increased anticoagulant effect, possibly via metabolic inhibition).
Monitor INR after starting or changing the allopurinol dose.
Elevated INR or bleeding after starting allopurinol.
When starting allopurinol, monitor INR and adjust the anticoagulant dose if needed.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin; Allopurinol)
Acenocoumarol, like other coumarins, is a vitamin K antagonist; foods rich in vitamin K (broccoli, leafy greens, spinach, liver) counteract its effect and shift the INR as dietary intake varies (Prontuário QUADRO 2: "Acenocoumarol: see Warfarin").
Keep dietary vitamin K intake stable and consistent; monitor INR after significant dietary changes.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin)
The QUADRO 2 entry for warfarin refers "See also: Alcohol"; acute heavy alcohol intake may inhibit coumarin metabolism and raise INR, while chronic heavy intake may induce it and reduce the anticoagulant effect.
Advise against heavy or binge drinking; moderate intake is acceptable if consistent, with INR monitoring if drinking habits change.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin)
Prontuário 4.3.1.2: coumarins are contraindicated during the first trimester (teratogenic) and in the last weeks of pregnancy (risk of fetal or placental haemorrhage).
Contraindicated in pregnancy; use heparin when anticoagulation is needed.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — 4.3.1.2
EMC-UK (Sinthrome 4.3) and Prontuário 4.3.1.2: contraindicated in conditions where the bleeding risk is greater than the clinical benefit — haemorrhagic diathesis or haemorrhagic blood dyscrasia, peptic ulcer or gastrointestinal, urogenital or respiratory tract haemorrhage, cerebrovascular haemorrhages, acute pericarditis and infective endocarditis.
Contraindicated in patients at high bleeding risk (active peptic ulcer, recent haemorrhage, haemorrhagic diathesis).
EMC-UK — Sinthrome SmPC 4.3: https://www.medicines.org.uk/emc/product/2058
The coumarins (acenocoumarol and warfarin) are contraindicated during the first trimester (teratogenic) and in the last weeks of pregnancy (risk of fetal or placental haemorrhage) (Prontuário 4.3.1.2).
Contraindicated in the 1st trimester (teratogenic) and in the last weeks (fetal/placental haemorrhage); alternative: heparin (does not cross the placenta).
No specific Prontuário data on breastfeeding; the coumarin class requires case-by-case evaluation.
Weigh the pregnancy risk before therapy in women of childbearing potential (contraception recommended).
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Oral anticoagulants, 4.3.1.2 ; EMC-UK Sinthrome 4.6
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Indirect anticoagulant: reduces the hepatic synthesis of coagulation factors II, VII, IX and X by antagonising vitamin K; no in vitro anticoagulant effect. Effect apparent only after plasma depletion of the factors (2-3 days); monitored by INR (Prontuário 4.3.1.2).
Antagonism of vitamin K (phytonadione) — inhibition of gamma-carboxylation of vitamin K-dependent clotting factors.
Oral coumarin derivative; complete oral bioavailability. The effect depends on hepatic function (factor synthesis) and vitamin K availability (diet).
Interactions arise from altered metabolism (increase, e.g. carbamazepine; decrease, e.g. cimetidine), increased bleeding risk from antiplatelet action (e.g. acetylsalicylic acid) or potentiation of the anticoagulant action (NSAIDs, antihormones, antiarrhythmics and others) (Prontuário 4.3.1.2). EMC-UK records inhibition or induction of CYP2C9 as the main interaction mechanism.
Shorter half-life than warfarin (daily regimen); EMC-UK refers to frequent INR monitoring (twice weekly when starting or withdrawing a concomitant drug).
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
