Farxiga and Acetaminophen Interaction: Safety, Risks, and Clinical Guidance

Does the Farxiga label list acetaminophen as an interaction?

No. The label's table of clinically relevant interactions covers insulin and insulin secretagogues such as sulfonylureas, lithium, positive urine glucose tests and interference with the 1,5-anhydroglucitol assay [1]. Acetaminophen is not in it.

The label also reports the drugs it was tested against: metformin 1,000 mg, pioglitazone 45 mg, sitagliptin 100 mg, glimepiride 4 mg, voglibose, hydrochlorothiazide 25 mg, bumetanide 1 mg, valsartan 320 mg, simvastatin 40 mg, digoxin 0.25 mg, warfarin 25 mg, rifampin 600 mg once daily and mefenamic acid [1]. Acetaminophen is not among them [1]. Two of those tested drugs do move dapagliflozin exposure: rifampin 600 mg daily for 6 days lowered dapagliflozin AUC by 22%, and mefenamic acid raised it by 51%. The label says no dapagliflozin dose adjustment is recommended for the drugs in its tables [1].

How the two drugs are metabolized

Dapagliflozin reaches peak plasma levels within about 2 hours, has 78% oral bioavailability and is about 91% protein bound; it is metabolized mainly by UGT1A9 to an inactive glucuronide and has a half-life of about 12.9 hours. About 75% of a dose appears in urine and 21% in feces, with under 2% of the urine fraction being unchanged drug [1].

Acetaminophen is cleared in the liver by glucuronidation, sulfation and CYP2E1 oxidation. CYP2E1 produces a reactive metabolite, NAPQI, that is normally cleared by conjugation with glutathione, and substances that induce or regulate CYP2E1 may change acetaminophen metabolism and its liver toxicity [4].

The label's in vitro work covered CYP enzymes and transporters: dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6 or 3A4 nor induced CYP 1A2, 2B6 or 3A4; dapagliflozin is a weak P-glycoprotein substrate, its glucuronide is an OAT3 substrate, and neither meaningfully inhibited P-gp, OCT2, OAT1 or OAT3 [1].

What acetaminophen does to the liver

Acetaminophen overdose can cause liver toxicity [2]. The injury is dose-related [5].

In a prospective study of 662 patients with acute liver failure at 22 US centers, 275 cases (42%) were attributed to acetaminophen, at a median ingested dose of 24 g. Unintentional overdose accounted for 131 of those 275 cases (48%), and within the unintentional group 38% had taken two or more acetaminophen preparations and 63% had used narcotic-containing products [3].

Does Farxiga cause liver problems?

The Farxiga label carries no hepatotoxicity warning and no boxed warning. Its warnings cover ketoacidosis, volume depletion and acute kidney injury, genitourinary infections including necrotizing fasciitis of the perineum (Fournier's gangrene), and hypoglycemia when used with insulin or insulin secretagogues [1]. The label also states that no new adverse reactions were identified in the DAPA-HF, DELIVER or DAPA-CKD trials [1].

Farxiga's own warnings

Ketoacidosis: blood glucose at presentation may be below 250 mg/dL, and the label lists acute febrile illness, reduced caloric intake, a ketogenic diet, surgery, volume depletion, alcohol abuse, and missed or reduced insulin doses among precipitating conditions. Signs and symptoms include nausea, vomiting, abdominal pain, generalized malaise and shortness of breath [1].

Volume depletion: the label names impaired renal function (eGFR <60 mL/min/1.73 m2), older age and loop diuretics as risk factors, and postmarketing reports describe acute kidney injury, some requiring dialysis [1]. In the DECLARE trial's loop-diuretic subgroup, volume-depletion events occurred in 6.6% of patients on dapagliflozin versus 6.1% on placebo [1].

Genitourinary infection: the label says patients with pain, tenderness, erythema or swelling in the genital or perineal area along with fever or malaise should be evaluated immediately for necrotizing fasciitis [1].

Practical points

Dapagliflozin is taken once daily with or without food. A high-fat meal can lower peak levels by up to 50% without changing total exposure. For a missed dose, the label says to take it as soon as possible and not to double the next one [1].