Metformin and Rivaroxaban Interaction: What Patients and Clinicians Need to Know

Why the two drugs are handled differently

Metformin is not metabolized, is negligibly bound to plasma proteins and is cleared by the kidneys [1]. It is excreted unchanged in urine by tubular secretion, with renal clearance about 3.5 times creatinine clearance and a plasma half-life of about 6.2 hours [1]. Its label's interaction table is short and specific: carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide, dichlorphenamide); drugs that reduce metformin clearance through OCT2 and MATE transporters (ranolazine, vandetanib, dolutegravir, cimetidine); alcohol; insulin and insulin secretagogues; and drugs that can raise blood glucose, such as thiazides, corticosteroids, phenytoin, thyroid products and calcium channel blockers [1]. Rivaroxaban is not named in that table [1].

Rivaroxaban is a direct factor Xa inhibitor [4] and a CYP3A4 and P-glycoprotein substrate [2]. It does not inhibit cytochrome P450 enzymes or known drug transporter systems, and because it has several elimination pathways it has no clinically relevant interactions with most commonly prescribed medicines [4].

What does change rivaroxaban levels?

The Xarelto label says to avoid combined P-glycoprotein and strong CYP3A4 inhibitors such as ketoconazole and ritonavir, and combined P-glycoprotein and strong CYP3A4 inducers such as rifampin, carbamazepine, phenytoin and St. John's wort. For clarithromycin, the label says no precautions are needed.

For St John's wort, two human studies exist. Twelve healthy volunteers took a single 20 mg rivaroxaban dose before and after two weeks of a Hypericum perforatum extract; after induction the rivaroxaban AUC ratio was 0.76 (90% CI 0.70 to 0.82), the Cmax ratio 0.86 (0.76 to 0.97) and the factor Xa inhibition area-under-effect ratio 0.80 [6]. A second study in 12 healthy volunteers found rivaroxaban AUC and Cmax both 25% lower after St John's wort, alongside a 272% rise in CYP3A activity [2].

Kidney function is the shared issue

Kidney function matters for both drugs, but that is not an interaction between them.

For metformin, the label calls for an eGFR before starting and at least yearly afterwards, more often in people at risk of kidney decline. Metformin is contraindicated below 30 mL/min/1.73 m2, starting is not recommended at 30 to 45, and the label says to reassess the benefit and risk of continuing if eGFR falls below 45 and to discontinue if it falls below 30 [1]. The label also directs stopping metformin at the time of, or before, an iodinated contrast imaging procedure in patients with eGFR 30 to 60, a history of liver disease, alcoholism or heart failure, or when intra-arterial contrast is used, with eGFR rechecked 48 hours later and metformin restarted only if kidney function is stable [1].

For rivaroxaban, the Xarelto label gives 20 mg once daily with the evening meal for atrial fibrillation when creatinine clearance is above 50 mL/min, and 15 mg once daily when it is 50 or below. It also says to avoid use for DVT or PE treatment when creatinine clearance is below 15 mL/min.

Does metformin add to rivaroxaban bleeding risk?

The bleeding figures below come from rivaroxaban trials and do not measure any effect of metformin.

In ROCKET AF, 14,264 patients with non-valvular atrial fibrillation received rivaroxaban 20 mg daily or dose-adjusted warfarin; major or non-major clinically relevant bleeding occurred at 14.9% per year with rivaroxaban and 14.5% per year with warfarin [7]. A meta-analysis of 43 randomized trials (151,578 patients) of new oral anticoagulants found an odds ratio for gastrointestinal bleeding of 1.48 (95% CI 1.21 to 1.82) for rivaroxaban compared with standard care [5]. In COMPASS, rivaroxaban 2.5 mg twice daily plus aspirin in 27,395 patients with stable atherosclerotic disease produced major bleeding in 3.1% versus 1.9% with aspirin alone (HR 1.70) [8].

What the metformin label warns about

Metformin carries a boxed warning for lactic acidosis, with postmarketing cases that resulted in death, hypothermia, hypotension and resistant bradyarrhythmias. Symptoms are often nonspecific: malaise, myalgias, respiratory distress, somnolence and abdominal pain. Cases were characterized by blood lactate above 5 mmol/L, and metformin plasma levels were generally above 5 mcg/mL. Named risk factors include renal impairment, certain concomitant drugs such as carbonic anhydrase inhibitors, age 65 or older, radiologic studies with contrast, surgery and other procedures, hypoxic states such as acute congestive heart failure, excessive alcohol intake and hepatic impairment [1].

The label also reports subnormal vitamin B12 in about 7% of patients in 29-week trials and directs measuring hematologic parameters annually and vitamin B12 every 2 to 3 years [1]. It says alcohol potentiates metformin's effect on lactate metabolism and warns against excessive intake [1].

Taking both on the same day

Metformin immediate-release is taken with meals [1]. The extended-release tablet is swallowed whole once daily with the evening meal and must not be crushed, cut or chewed [9]. For rivaroxaban, the 15 mg and 20 mg tablets reach 80% to 100% bioavailability when taken with food [4]; the Xarelto label says these strengths must be taken with food, while the 2.5 mg and 10 mg tablets can be taken with or without food.

Surgery, procedures and interrupted doses

In the PAUSE study, 3,007 patients with atrial fibrillation taking apixaban, dabigatran or rivaroxaban stopped the anticoagulant for 1 day before a low-bleeding-risk procedure and 2 days before a high-bleeding-risk procedure; among the 1,082 patients in the rivaroxaban group, major bleeding within 30 days of the procedure occurred in 1.85% [10]. The metformin label says metformin should be temporarily discontinued while patients have restricted food and fluid intake [1].