Metformin Legal & Patent Challenges: FDA Approval, Label History, and Safety Oversight

What metformin's current approval record covers

Metformin is a prescription biguanide. Immediate-release tablets are labeled for adults and children 10 and older with type 2 diabetes; extended-release tablets are labeled for adults only [1][2]. Approval records and labeling sit in Drugs@FDA, which for brand-name drugs typically includes the most recent labeling, regulatory information and FDA staff reviews [4].

What the label warns about

The boxed warning is lactic acidosis. The label describes postmarketing cases that resulted in death, hypothermia, hypotension and resistant bradyarrhythmias, with a subtle onset of malaise, myalgias, respiratory distress, somnolence and abdominal pain, blood lactate above 5 mmol/L and metformin plasma levels generally above 5 mcg/mL [1]. Named risk factors include renal impairment, carbonic anhydrase inhibitors such as topiramate, age 65 or older, contrast studies, surgery, hypoxic states such as acute heart failure, excessive alcohol intake, hepatic impairment and mitochondrial disease [1].

Kidney function drives the label's dosing rules. The label says to check eGFR before starting and at least yearly. It contraindicates metformin below 30 mL/min/1.73 m2, does not recommend starting at 30 to 45, says to reassess benefit and risk if eGFR falls below 45, and says to discontinue below 30 [1]. For iodinated contrast, the label says to stop metformin at the time of or before the procedure in patients with eGFR 30 to 60, a history of liver disease, alcoholism or heart failure, or when intra-arterial contrast is used, and to re-evaluate eGFR 48 hours afterward [1].

The vitamin B12 warning reports subnormal B12 in about 7% of patients in 29-week trials; the label says to measure hematologic parameters annually and vitamin B12 every 2 to 3 years [1]. In the Diabetes Prevention Program Outcomes Study, B12 of 203 pg/mL or less occurred in 4.3% of metformin users versus 2.3% of placebo users at 5 years (7.4% versus 5.4% at 13 years, not a significant difference), and the odds of deficiency rose 13% per year of metformin use [6].

The 2020 and 2021 NDMA recalls

FDA's metformin update page logs voluntary recalls of extended-release products across 2020 and early 2021 [3]. Bayshore Pharmaceuticals recalled two lots in August 2020; Marksans Pharma expanded its recall to 76 additional unexpired lots of 500 mg and 750 mg tablets labeled as Time-Cap Labs; Sun Pharmaceutical recalled one lot of Riomet ER, an extended-release oral suspension; Nostrum Laboratories recalled four lots in November 2020 and one more in January 2021 [3]. The notices said the recalled products contained, or may have contained, NDMA above the acceptable intake limit [3].

FDA said its testing had not shown NDMA in immediate-release metformin, the most commonly prescribed type [3].

Nitrosamine guidance

FDA's final guidance, Control of Nitrosamine Impurities in Human Drugs, recommends steps manufacturers of active ingredients and finished products should take to detect and prevent unacceptable nitrosamine levels, covering root causes, detection, risk assessment, testing and controls; it revises an earlier version issued February 24, 2021 [7].