Apixaban

Mechanism

Apixaban inhibits factor Xa; dabigatran inhibits thrombin. Additive anticoagulation with no therapeutic benefit and high risk of major bleeding.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.

Management

The combination is not prescribed. When switching DOACs, stop the first and start the second at the next scheduled dose. Overlap is only acceptable via a parenteral anticoagulant when bridging is needed.

Mechanism

Apixaban and rivaroxaban are both direct factor Xa inhibitors. Their effects are additive without therapeutic gain. Risk of major bleeding rises sharply.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.

Management

The combination is not prescribed. When switching between DOACs, stop the first agent and start the second at the time of the next scheduled dose, with no overlap. If a patient inadvertently takes both, observe in hospital for at least 24 hours with haemoglobin and creatinine monitoring.

Mechanism

Warfarin blocks vitamin K-dependent clotting factor synthesis (II, VII, IX, X); apixaban directly inhibits factor Xa. The two different mechanisms add up.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.

Management

The combination is not prescribed. Switching from warfarin to apixaban: stop warfarin, wait for INR below 2.0, then start apixaban. Switching from apixaban to warfarin: overlap with INR monitoring, stop apixaban once INR exceeds 2.0.

Mechanism

Aspirin irreversibly blocks platelet cyclooxygenase; apixaban directly inhibits factor Xa. Dual antithrombotic action roughly doubles major bleeding risk versus apixaban alone.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Combine only for strict indications: after coronary stenting or in acute coronary syndrome. Limit aspirin to 75–100 mg/day, and dual therapy to 1–6 months. PPI cover with pantoprazole is mandatory.

Mechanism

Carbamazepine is a strong inducer of CYP3A4 and P-glycoprotein. Apixaban exposure falls by about half (by 54% with rifampicin), weakening protection against stroke in atrial fibrillation and against recurrent venous thromboembolism. The FDA recommends avoiding the combination.

Symptoms

No overdose symptoms – the danger is undertreatment: ischemic stroke, recurrent DVT or PE despite ongoing anticoagulant.

Management

Avoid the combination. The AEMPS label splits by indication: apixaban is not used with carbamazepine to treat deep vein thrombosis or pulmonary embolism, and is used with caution in atrial fibrillation and to prevent recurrent thrombosis. Alternative anticoagulant when carbamazepine is needed: warfarin, whose effect is tracked by INR, so the induction can be offset by dose. Alternative anticonvulsant: levetiracetam or lacosamide, neither induces CYP3A4.

Mechanism

Apixaban directly inhibits factor Xa; clopidogrel blocks the platelet P2Y12 receptor. The two antithrombotic mechanisms add up.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Dual therapy is used after acute coronary syndrome or stenting in atrial fibrillation, generally for no more than 1–6 months. Apixaban dose is selected according to age, weight, and renal function. PPI cover with pantoprazole is mandatory.

Mechanism

Dexamethasone is a CYP3A4 and P-glycoprotein inducer. It reduces apixaban (a substrate of both) levels by 30–50%, raising thrombotic event risk.

Symptoms

The patient feels no symptoms. Stroke risk in atrial fibrillation rises, as do deep vein thrombosis and pulmonary embolism risks.

Management

For prolonged systemic dexamethasone, do not increase apixaban (no titration data); switch to warfarin with INR monitoring instead. For short dexamethasone pulse therapy (1–3 days), no clinically significant effect.

Mechanism

Apixaban inhibits factor Xa; diclofenac injures the gastric mucosa and reduces platelet aggregation. Diclofenac additionally raises cardiovascular event risk, which matters in atrial fibrillation patients.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Avoid where possible. If diclofenac is needed for a short course, use the minimum effective dose for no more than 5–7 days under pantoprazole cover. For chronic analgesia, choose paracetamol, celecoxib, or topical NSAIDs.

Mechanism

Efavirenz induces CYP3A4 and P-gp. Apixaban falls 50% – stroke risk in AF.

Symptoms

Ischemic stroke or recurrent VTE.

Management

Alternative ARV – dolutegravir, or alternative anticoagulant – warfarin with INR 2.5-3.5.

Mechanism

Escitalopram (SSRI) depletes the platelet serotonin pool, impairing primary haemostasis. Apixaban inhibits factor Xa. Combined, GI bleeding risk rises 1.5- to 2-fold.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black tarry stools, blood in urine. Severe cases include gastrointestinal or intracranial haemorrhage.

Management

The combination is acceptable. PPI cover with pantoprazole is mandatory. Alternative antidepressants with minimal platelet effect: mirtazapine or agomelatine.

Mechanism

Apixaban inhibits factor Xa while ginkgo acts on platelet function: bleeding risk adds up at two separate levels of haemostasis. The European monograph places anticoagulants among the treatments that require consultation before taking ginkgo. Unlike warfarin, there is no INR to warn you here: apixaban is not routinely monitored, so the first warning may be the bleed itself.

Symptoms

Gastrointestinal bleeding (black stools, coffee-ground vomit), haematuria, extensive bruising, nosebleeds that do not stop with pressure. Any of these needs urgent attention.

Management

Do not start this combination on your own. Anyone already taking ginkgo with apixaban should raise it at the next appointment; withdrawing the supplement is the first option considered, because the anticoagulant has an indication and ginkgo rarely has one of the same strength. Before surgery or dental extraction, stop ginkgo two weeks ahead.

Mechanism

Apixaban inhibits factor Xa; ibuprofen (NSAID) injures the gastric mucosa and transiently inhibits platelet aggregation. The GI bleeding risk is additive.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Avoid where possible. If a short ibuprofen course is needed, use the minimum effective dose for no more than 5–7 days under pantoprazole cover. For chronic analgesia, choose paracetamol, a selective COX-2 inhibitor (celecoxib), or topical NSAIDs.

Mechanism

Ketoconazole strongly inhibits both CYP3A4 and P-glycoprotein, the two clearance routes of apixaban. In the apixaban SmPC, ketoconazole 400 mg once daily doubled apixaban AUC and raised Cmax 1.6-fold. No label lists the pair as a contraindication: the EMA texts for both drugs advise against it, and the FDA label asks for a dose cut or avoidance.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.

Management

The combination is not recommended. In the EU oral ketoconazole is authorised only for endogenous Cushing's syndrome, and ketoconazole cream gives no measurable plasma levels in adults according to its SmPC, so it does not form this pair. If oral ketoconazole is needed, apixaban is replaced for the course by a parenteral anticoagulant such as a low-molecular-weight heparin. The FDA label allows another route: an apixaban dose of 5 or 10 mg twice daily is halved, and at 2.5 mg twice daily the combination is avoided. With either plan the patient is told the signs of bleeding: black stools, blood in the urine, bruising without injury.

Mechanism

Ketorolac inhibits platelet aggregation, prolongs bleeding time and damages the gastric mucosa; according to its SmPC it causes serious gastrointestinal toxicity more often than equivalent doses of other NSAIDs. Apixaban is a direct factor Xa inhibitor, and its SmPC notes that NSAIDs usually increase bleeding risk, so the risks add up.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Spanish ketorolac SmPCs list anticoagulants among combinations that are not recommended, and for patients on full (therapeutic) doses of anticoagulants the interaction section calls the combination contraindicated (ketorolac 10 mg and 30 mg/ml SmPCs). Ketorolac is therefore not given to patients on a therapeutic dose of apixaban. At any anticoagulant dose, the FDA allows the combination only after weighing benefits against risks, with extreme caution and close monitoring (US ketorolac label). The apixaban SmPC asks for caution when it is combined with NSAIDs (apixaban SmPC, EMA), and the US apixaban label asks doctors to explain the signs of blood loss and to tell patients to report them at once (US apixaban label). In older patients and those at high risk of gastrointestinal complications, start ketorolac at the lowest dose and consider gastroprotection with misoprostol or a proton pump inhibitor; oral treatment lasts no more than 7 days (ketorolac 10 mg SmPC). Stop ketorolac at once if bleeding is suspected (ketorolac SmPCs).

Mechanism

Apixaban is a direct factor Xa inhibitor; meloxicam blocks platelet function and injures the GI mucosa. Additive GI bleeding risk increases 2- to 3-fold.

Symptoms

Black or tarry stools (melena), vomiting blood or coffee-ground material, epigastric pain. Risk multiplies in older patients and with prior peptic ulcer disease.

Management

Avoid prolonged combination. If meloxicam is needed for a short course, use the minimum effective dose for 5–7 days with pantoprazole cover. For chronic analgesia: paracetamol or celecoxib.

Mechanism

This pair has two mechanisms. The first is additive bleeding risk. Naproxen inhibits platelet aggregation, prolongs bleeding time and can cause ulcers and bleeding in the stomach and gut (naproxen SmPC), while apixaban blocks clotting factor Xa. Together they raise the bleeding risk (apixaban SmPC of the European Medicines Agency, EMA). The second is pharmacokinetic: naproxen inhibits the P-glycoprotein transporter that clears apixaban. A single 500 mg dose of naproxen raised the apixaban area under the curve (AUC) 1.5-fold and peak concentration 1.6-fold. Bleeding time did not change in a clinically relevant way in that study, and this kinetic effect needs no apixaban dose change (apixaban SmPC, EMA).

Symptoms

Black, tarry stools (melena), vomiting blood or coffee-ground material, upper abdominal pain. Other bleeding can occur: bruising without trauma, nosebleeds, blood in the urine. Risk is higher in older patients, after a previous ulcer and at higher naproxen doses (naproxen SmPC).

Management

Avoid non-steroidal anti-inflammatory drugs (NSAIDs) in a patient on an anticoagulant when they are not needed: the European Society of Cardiology (ESC) advises offering other pain relief or disease-modifying treatment (ESC 2024). If naproxen is still needed, use the lowest effective dose for the shortest time (naproxen SmPC) and give apixaban with caution during that period (apixaban SmPC of the European Medicines Agency, EMA). For older patients and those with a previous ulcer, the naproxen SmPC recommends gastroprotection with misoprostol or a proton pump inhibitor, and suggests considering it when other drugs raise the risk of gastrointestinal bleeding (naproxen SmPC). The ESC advises a proton pump inhibitor when gastrointestinal bleeding risk is high (ESC 2024). Apixaban is contraindicated with an active or recent gastrointestinal ulcer (apixaban SmPC, EMA). Naproxen is contraindicated with active or recurrent peptic ulcer or bleeding and after previous NSAID-related bleeding, and is not recommended with creatinine clearance below 30 mL/min (naproxen SmPC). During NSAID use, the European Heart Rhythm Association (EHRA) suggests an extra blood test: haemoglobin, kidney and liver function (EHRA 2021). Stop naproxen at once if gastrointestinal bleeding or an ulcer occurs (naproxen SmPC), and also stop apixaban in severe bleeding (apixaban SmPC, EMA).

Mechanism

Phenytoin is a strong inducer of the CYP3A4 enzyme and the P-glycoprotein transporter, and apixaban is cleared through both routes. Strong inducers can lower the apixaban area under the curve (AUC) by about 50%; with rifampicin the fall was 54% (apixaban SmPC of the European Medicines Agency, EMA). Protection against stroke and thrombosis weakens. In a study of patients with atrial fibrillation, apixaban given with strong inducers showed lower efficacy and a higher bleeding risk (apixaban SmPC, EMA).

Symptoms

Signs of thrombosis from weaker anticoagulation: sudden weakness or numbness of an arm, a leg or one side of the face, speech problems (stroke), leg swelling and pain (deep vein thrombosis), sudden breathlessness and chest pain (pulmonary embolism). Bleeding can also occur: bruising without trauma, nosebleeds, blood in the urine, black stools.

Management

The US Food and Drug Administration (FDA) advises avoiding the combination (FDA apixaban label), and the European Society of Cardiology (ESC) advises avoiding it where possible (ESC 2024). Do not use apixaban to treat deep vein thrombosis or pulmonary embolism in a patient on phenytoin, because efficacy may be reduced (apixaban SmPC of the European Medicines Agency, EMA). For stroke prevention in atrial fibrillation, prevention of thrombosis after elective hip or knee surgery and prevention of recurrent thrombosis, the EMA SmPC allows the combination with caution and without changing the apixaban dose (apixaban SmPC, EMA). The European Heart Rhythm Association (EHRA) also asks for caution, especially when the patient takes several drugs that lower anticoagulant levels (EHRA 2021). If the combination continues, watch for signs of thrombosis, stroke and bleeding: these are the outcomes the SmPC describes in atrial fibrillation patients on strong inducers (apixaban SmPC, EMA).

Mechanism

Rifabutin is a moderate CYP3A4 + P-gp inducer (2-3 fold weaker than rifampicin). Apixaban falls 30-40%. Lower risk than with rifampicin but still significant.

Symptoms

Reduced anticoagulation, thrombosis risk.

Management

If possible – warfarin to INR 2.0-3.0.

Mechanism

Rifampicin is the strongest clinical inducer of CYP3A4 and P-glycoprotein. Apixaban levels fall by 54%, anticoagulation lost. FDA recommends avoiding the combination.

Symptoms

Ischemic stroke or recurrent VTE on apparently active apixaban. Lab: low anti-Xa level.

Management

The combination is avoided. In a patient on rifampicin, the apixaban SmPC does not recommend apixaban for treating deep vein thrombosis or pulmonary embolism, because efficacy may be compromised. For stroke prevention in atrial fibrillation it allows use with caution, while the FDA label says to avoid the pair for any indication. Apixaban is usually replaced for the rifampicin course by a parenteral anticoagulant such as a low-molecular-weight heparin. Warfarin is awkward here: per the rifampicin SmPC, S-warfarin exposure falls by 74%. The warfarin dose is then titrated under frequent INR checks and reduced again after rifampicin stops.

Mechanism

Ritonavir strongly inhibits CYP3A4 and P-glycoprotein, which is why it is used as a pharmacokinetic booster in HIV regimens. Apixaban is cleared through both routes. According to the apixaban SmPC, strong CYP3A4 and P-gp inhibitors may double apixaban exposure, or raise it further in severe renal impairment. No label lists the pair as a contraindication: the EMA advises against it, and the FDA asks for a dose cut or avoidance.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.

Management

The combination is not recommended. If a person with HIV on ritonavir needs anticoagulation, a drug without this interaction is chosen: a low-molecular-weight heparin for short courses, or warfarin. With warfarin, the FDA ritonavir label recommends frequent INR checks at the start of co-administration, because ritonavir can shift warfarin levels either way. The FDA also allows apixaban: a dose of 5 or 10 mg twice daily is halved, and at 2.5 mg twice daily the combination is avoided. The patient is told the signs of bleeding: black stools, blood in the urine, bruising without injury.

Mechanism

Sertraline (SSRI) depletes the platelet serotonin pool and impairs primary haemostasis. Combined with apixaban, upper GI bleeding risk roughly doubles.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

The combination is acceptable when antidepressant therapy is needed. PPI cover with pantoprazole is advisable. Alternative antidepressants with minimal platelet effect: mirtazapine or agomelatine.

Mechanism

Amiodarone and its metabolite inhibit the CYP3A4 enzyme and the P-glycoprotein transporter (amiodarone SmPC), and apixaban is cleared through both routes. Apixaban blood levels may rise, and with them the bleeding risk. There are no direct pharmacokinetic data for this pair (practical guide of the European Heart Rhythm Association, EHRA 2021). The apixaban SmPC of the European Medicines Agency (EMA) lists amiodarone among inhibitors expected to raise apixaban levels to a lesser degree than strong inhibitors. Because amiodarone is cleared slowly, interactions can persist for several months after it is stopped (amiodarone SmPC).

Symptoms

Gum bleeding, nosebleeds, bruising without trauma, blood in the urine or stool, heavy periods. Severe cases include gastrointestinal or intracranial bleeding. Risk is higher in older patients, with body weight 60 kg or less and with impaired kidney function (apixaban SmPC of the European Medicines Agency, EMA).

Management

The combination is allowed with caution. Do not change the apixaban dose because of amiodarone: the apixaban SmPC of the European Medicines Agency (EMA) requires no dose adjustment with inhibitors that are not strong and names amiodarone among them (apixaban SmPC, EMA). In atrial fibrillation, reduce apixaban to 2.5 mg twice daily only by its own criteria: two of three (age 80 years or older, body weight 60 kg or less, serum creatinine 133 µmol/L or higher) or creatinine clearance 15–29 mL/min (apixaban SmPC, EMA). The European Heart Rhythm Association (EHRA) advises caution, especially with polypharmacy. If at least one more risk factor is present (age 75 years or older, body weight 60 kg or less, chronic kidney disease, antiplatelet drugs, non-steroidal anti-inflammatory drugs, systemic steroids, previous bleeding, anaemia or low platelets, frailty or falls), EHRA suggests considering an anticoagulant with fewer interactions or replacing the other drug (EHRA 2021). The effect of amiodarone on other drugs lasts for several months after it is stopped, so caution is needed during that period too (amiodarone SmPC).

Mechanism

Apixaban is a direct factor Xa inhibitor, and NSAIDs, including celecoxib, usually increase bleeding risk (apixaban SmPC). Celecoxib has no antiplatelet effect of its own, but it can cause upper gastrointestinal ulcers and bleeding, sometimes fatal (celecoxib SmPC). With an anticoagulant the risks add up.

Symptoms

Gum bleeding, nosebleeds, bruising without injury, black or tarry stools, blood in the urine. Gastrointestinal complications are more likely in older patients, with a history of ulcer or gastrointestinal bleeding, with alcohol use and with glucocorticoids (celecoxib SmPC).

Management

The combination is allowed with caution: both the apixaban SmPC (EMA) and the Spanish celecoxib SmPC, which names apixaban directly, require it (apixaban SmPC, EMA; celecoxib SmPC). Give celecoxib at the lowest effective daily dose for the shortest possible time and review the need for it regularly (celecoxib SmPC). Take particular care in older patients, in those with a history of ulcer or gastrointestinal bleeding, and in those who drink alcohol or take glucocorticoids or antiplatelet drugs (celecoxib SmPC). The US apixaban label asks doctors to explain the signs of blood loss and to tell patients to report them at once; apixaban is stopped in active pathological bleeding (US apixaban label).

Mechanism

Ciprofloxacin weakly affects CYP3A4 and P-glycoprotein — the main clearance routes of apixaban. It also suppresses vitamin K-producing gut flora. Additive bleeding risk.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

For short ciprofloxacin courses (5–7 days), do not change the apixaban dose but monitor for bleeding signs. In patients over 75 or with creatinine clearance below 50 mL/min, choose an alternative antibiotic without P-glycoprotein effect — ceftriaxone, cefixime, amoxicillin-clavulanate.

Mechanism

Citalopram, like other SSRIs, impairs primary haemostasis by inhibiting platelet serotonin reuptake. Additively with apixaban, bleeding risk rises, mainly GI.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

The combination is acceptable. In patients over 65 or with prior peptic ulcer: pantoprazole 20 mg/day. Citalopram also prolongs QT, so cap older patients at 20 mg/day.

Mechanism

Apixaban is cleared partly through the CYP3A4 enzyme and the P-glycoprotein (P-gp) transporter, and clarithromycin inhibits both. The European Medicines Agency (EMA) does not class clarithromycin as a strong inhibitor of both pathways at once: at 500 mg twice daily it raised the apixaban area under the curve 1.6-fold and peak concentration 1.3-fold, compared with 2-fold and 1.6-fold for ketoconazole (apixaban SmPC, EMA). Higher apixaban levels mean a higher risk of bleeding.

Symptoms

Bleeding gums, nosebleeds, bruising without injury, blood in the urine or stool, heavy periods. In severe cases, gastrointestinal or intracranial bleeding. The risk is higher in patients aged 75 or over, with chronic kidney disease, previous bleeding or anaemia, and with concomitant antiplatelet drugs, non-steroidal anti-inflammatory drugs or systemic corticosteroids.

Management

The combination can be used with caution. The European Medicines Agency (EMA) requires no apixaban dose change with inhibitors that do not strongly block both of its elimination pathways and names clarithromycin among them (apixaban SmPC, EMA). The US Food and Drug Administration (FDA) also requires no dose adjustment with clarithromycin (apixaban FDA label). Caution matters most in patients at high risk of bleeding (clarithromycin SmPC). The European Heart Rhythm Association (EHRA) advises particular caution with polypharmacy and when two or more risk factors are present, such as age 75 or over, chronic kidney disease, antiplatelet drugs, non-steroidal anti-inflammatory drugs, systemic corticosteroids or previous bleeding (EHRA 2021). In that case, first consider whether another anticoagulant or antibiotic with fewer interactions is suitable (EHRA 2021). Watch the patient for signs of bleeding and stop apixaban if severe bleeding occurs (apixaban SmPC, EMA).

Mechanism

Diltiazem is a moderate inhibitor of the CYP3A4 enzyme and a weak inhibitor of the P-glycoprotein transporter (diltiazem and apixaban SmPCs), and apixaban is cleared through both routes. Diltiazem 360 mg once daily raised the apixaban area under the curve (AUC) 1.4-fold and peak concentration 1.3-fold (apixaban SmPC of the European Medicines Agency, EMA). Higher apixaban levels mean a higher bleeding risk.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

The combination is allowed with caution. Do not change the apixaban dose because of diltiazem: the apixaban SmPC of the European Medicines Agency (EMA) requires no dose adjustment with inhibitors that are not strong and names diltiazem among them (apixaban SmPC, EMA). The diltiazem SmPC asks for caution and monitoring with direct oral anticoagulants, especially in patients at high bleeding risk (diltiazem SmPC). In atrial fibrillation, reduce apixaban to 2.5 mg twice daily only by its own criteria: two of three (age 80 years or older, body weight 60 kg or less, serum creatinine 133 µmol/L or higher) or creatinine clearance 15–29 mL/min (apixaban SmPC, EMA). The European Heart Rhythm Association (EHRA) advises caution, especially with polypharmacy. If at least one more risk factor is present (age 75 years or older, body weight 60 kg or less, chronic kidney disease, antiplatelet drugs, non-steroidal anti-inflammatory drugs, systemic steroids, previous bleeding, anaemia or low platelets, frailty or falls), EHRA suggests considering an anticoagulant with fewer interactions or replacing the other drug (EHRA 2021).

Mechanism

Dronedarone is a moderate inhibitor of the CYP3A4 enzyme and a strong inhibitor of the P-glycoprotein transporter, and apixaban is cleared through both routes. Dronedarone can therefore raise apixaban blood levels and the bleeding risk. The dronedarone SmPC does not class it as a strong inhibitor of both routes together, and the labels give no figures for the rise in apixaban levels (dronedarone SmPC of the European Medicines Agency, EMA).

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black stools, blood in urine. Severe cases include gastrointestinal or intracranial haemorrhage.

Management

The combination is allowed with caution. Do not change the apixaban dose because of dronedarone: the dronedarone SmPC of the European Medicines Agency (EMA) says so directly, and the apixaban SmPC requires no dose adjustment with inhibitors that are not strong (dronedarone and apixaban SmPCs, EMA). The dronedarone SmPC requires monitoring of co-administered anticoagulants (dronedarone SmPC, EMA). In atrial fibrillation, reduce apixaban to 2.5 mg twice daily if two of three criteria are present: age 80 years or older, body weight 60 kg or less, serum creatinine 133 µmol/L or higher (apixaban SmPC, EMA). Dronedarone itself raises serum creatinine, on average by 10 µmol/L, usually within the first week. Measure creatinine before starting dronedarone and after 7 days, take the stable value as the new baseline, and then check kidney function regularly (dronedarone SmPC, EMA). Dronedarone is contraindicated with creatinine clearance below 30 mL/min (dronedarone SmPC, EMA). The European Heart Rhythm Association (EHRA) advises caution, especially with polypharmacy. If at least one more risk factor is present (age 75 years or older, body weight 60 kg or less, chronic kidney disease, antiplatelet drugs, non-steroidal anti-inflammatory drugs, systemic steroids, previous bleeding, anaemia or low platelets, frailty or falls), EHRA suggests considering an anticoagulant with fewer interactions or replacing the other drug (EHRA 2021).

Mechanism

Duloxetine (SNRI) moderately impairs primary haemostasis by inhibiting platelet serotonin reuptake. Additively with apixaban, GI bleeding risk rises.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

The combination is acceptable. In patients over 65 or with prior peptic ulcer: pantoprazole 20 mg/day. For long-term therapy, alternative antidepressants without platelet effect: mirtazapine, agomelatine.

Mechanism

Fluoxetine, like other SSRIs, impairs primary haemostasis by inhibiting platelet serotonin reuptake. Additively with apixaban, GI bleeding risk rises.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

The combination is acceptable. In patients over 65 or with prior peptic ulcer: pantoprazole 20 mg/day. The long half-life of fluoxetine and its active metabolite norfluoxetine (4–6 days) prolongs bleeding risk for another 4–6 weeks after discontinuation.

Mechanism

Fluvoxamine impairs primary haemostasis by inhibiting platelet serotonin reuptake. Additively with the direct factor Xa inhibitor apixaban, GI bleeding risk rises by 30–50%.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

The combination is acceptable for short courses. If long-term SSRI is needed, in patients over 65 or with prior peptic ulcer add gastroprotection (pantoprazole 20 mg/day). Antidepressant alternatives without platelet effect: mirtazapine, agomelatine, trazodone.

Mechanism

No direct pharmacokinetic interaction. In chronic kidney disease, spironolactone causes hyperkalaemia and apixaban exposure rises (partly renally cleared). Cumulative adverse event risk in reduced renal function.

Symptoms

Weakness, fatigue, arrhythmia (from hyperkalaemia), bleeding and bruising without trauma (from apixaban). Symptoms are more pronounced with creatinine clearance below 50 mL/min.

Management

With normal renal function, no dose change needed. At creatinine clearance 30–50 mL/min, check potassium and creatinine every 2–4 weeks. In severe CKD (clearance below 30 mL/min), stop spironolactone or switch to eplerenone with careful potassium monitoring.

Mechanism

Tacrolimus is a weak CYP3A4 inhibitor and P-glycoprotein substrate. P-glycoprotein competition may slightly raise apixaban levels; clinical effect is minimal.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

No dose adjustment needed. In post-transplant patients with chronic kidney disease, watch for any bleeding signs and check creatinine clearance every 4 weeks — if it falls below 50 mL/min, reduce apixaban to 2.5 mg twice daily.

Mechanism

Venlafaxine (SNRI) moderately impairs primary haemostasis by inhibiting platelet serotonin reuptake. Additively with apixaban, GI bleeding risk rises.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

The combination is acceptable. In patients over 65 or with prior peptic ulcer: pantoprazole 20 mg/day. Venlafaxine also raises blood pressure at doses above 150 mg/day — consider alternatives in arterial hypertension.

Mechanism

Verapamil inhibits the CYP3A4 enzyme and the P-glycoprotein transporter (verapamil SmPC), and apixaban is cleared through both routes. Apixaban blood levels may therefore rise, and with them the bleeding risk. The size of the effect is unknown: there are no pharmacokinetic data for this pair (practical guide of the European Heart Rhythm Association, EHRA 2021). The apixaban SmPC of the European Medicines Agency (EMA) lists verapamil among inhibitors expected to raise apixaban levels to a lesser degree than strong inhibitors.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

The combination is allowed with caution. The apixaban SmPC of the European Medicines Agency (EMA) requires no dose adjustment with inhibitors that are not strong and names verapamil among them (apixaban SmPC, EMA). The verapamil SmPC notes a possible rise in bleeding risk with direct oral anticoagulants, especially in patients with risk factors, and advises reducing the anticoagulant dose if needed, following its own SmPC (verapamil SmPC). In atrial fibrillation, reduce apixaban to 2.5 mg twice daily only by its own criteria: two of three (age 80 years or older, body weight 60 kg or less, serum creatinine 133 µmol/L or higher) or creatinine clearance 15–29 mL/min (apixaban SmPC, EMA). The European Heart Rhythm Association (EHRA) advises caution, especially with polypharmacy. If at least one more risk factor is present (age 75 years or older, body weight 60 kg or less, chronic kidney disease, antiplatelet drugs, non-steroidal anti-inflammatory drugs, systemic steroids, previous bleeding, anaemia or low platelets, frailty or falls), EHRA suggests considering an anticoagulant with fewer interactions or replacing the other drug (EHRA 2021).

Mechanism

No clinically significant direct interaction. Amlodipine has minimal effect on CYP3A4 and P-glycoprotein — the main routes of apixaban clearance.

Symptoms

The combination usually causes no specific symptoms. Each drug's individual side effects remain.

Management

No dose adjustment needed. In atrial fibrillation with hypertension, the combination is standard.

Mechanism

Fluconazole is a moderate inhibitor of the CYP3A4 enzyme (fluconazole SmPC), and apixaban is partly cleared through this enzyme. The apixaban SmPC of the European Medicines Agency (EMA) lists fluconazole among inhibitors expected to raise apixaban levels to a lesser degree than strong inhibitors. There are no figures for this pair: the European Heart Rhythm Association (EHRA) reports no data yet (EHRA 2021). Fluconazole keeps inhibiting the enzyme for 4–5 days after the last dose (fluconazole SmPC).

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

Do not change the apixaban dose during a fluconazole course. The apixaban SmPC of the European Medicines Agency (EMA) requires no dose adjustment with inhibitors that are not strong and names fluconazole among them (apixaban SmPC, EMA). Choose the apixaban dose by its usual rules: in atrial fibrillation, use 2.5 mg twice daily if two of three criteria are present (age 80 years or older, body weight 60 kg or less, serum creatinine 133 µmol/L or higher) or if creatinine clearance is 15–29 mL/min (apixaban SmPC, EMA). Tell the patient about signs of bleeding, and stop apixaban in severe bleeding (apixaban SmPC, EMA).