China-Made Metformin XR Tablets Match German Ones in Healthy Adults

A single-center crossover trial in Beijing has shown that extended-release reduced-mass metformin tablets newly manufactured in China are bioequivalent to the same formulation produced in Germany, both when taken on an empty stomach and when taken with a high-fat meal. The study, published in Drugs in R&D, enrolled healthy Chinese adults who each received one 500-mg tablet of each product in a randomized two-period, two-sequence design. The finding matters because a new Chinese manufacturing facility was established to secure supply for the local market, and Chinese regulatory filing requirements demand evidence that the locally made tablets match the German reference product.

Extended-release reduced-mass metformin, sold as Glucophage XR RM, is a newer version of the widely used diabetes drug metformin hydrochloride. Compared with the traditional oblong extended-release tablets, which measure roughly 20 mm along their major axis and weigh about 1000 mg, the reduced-mass tablets are round, 12 mm in diameter, and weigh approximately 720 mg. The smaller size comes from a lower volume of excipients, the inactive ingredients that give a tablet its bulk. Because the tablets are easier to swallow, the reformulation is considered a potential aid to compliance in patients who need long-term therapy. Bioequivalence between the reduced-mass tablets and the original oblong extended-release tablets had already been demonstrated, and a previous study had shown bioequivalence of the older extended-release formulation made in Germany and China. What had never been reported was a direct comparison of the reduced-mass tablets from the two manufacturing sites.

The trial was conducted at Xuanwu Hospital of Capital Medical University between 25 July 2022 and 14 October 2022 and was approved by the hospital’s institutional ethics committee. It was registered as NCT05463094 on ClinicalTrials.gov and CTR20221631 on the Chinese Clinical Trial Register. In total, 177 volunteers were screened and 84 were randomized, 58 to the fasted group and 26 to the fed group. Participants were healthy adults aged at least 18 years, weighing 50 to 90 kg, with a body mass index between 19 and 26 kg/m2, and all were Chinese. More than half, 61.9 percent, were male, the median age was 32.0 years, and the mean BMI was 22.93 kg/m2. Exclusion criteria ruled out anyone with a contraindication to metformin, liver or kidney dysfunction, gastrointestinal surgery that could affect absorption, or recent use of medications, alcohol, or foods such as grapefruit that interfere with drug metabolism.

The study design followed the Chinese technical guidelines for human bioequivalence studies with pharmacokinetic endpoints. Each participant took a single tablet of one product, underwent 48 hours of blood sampling, then waited through a one-week washout before repeating the procedure with the other product. In the fasted group, volunteers abstained from food and drink except water for at least 10 hours before dosing. In the fed group, each dose followed a high-fat breakfast of roughly 800 to 1000 calories, about half of them from fat. After dosing, both groups avoided water for 2 hours and food for 4 hours. Blood samples were drawn before dosing and at 17 time points over 48 hours, and metformin concentrations were measured with a validated liquid chromatography–mass spectrometry method with a lower limit of quantification of 10.0 ng/mL.

The primary endpoints were the maximum observed plasma concentration, Cmax, and the area under the plasma concentration–time curve from time zero to the last quantifiable sampling time, AUC0–t. Under the pre-defined criterion, bioequivalence would be concluded if the 90 percent confidence intervals of the geometric least-squares mean test-to-reference ratios fell within 0.80 to 1.25 for both endpoints. In the fasted group, the geometric mean Cmax was 854 ng/mL for the Chinese-made test product and 821 ng/mL for the German-made reference product, with coefficients of variation of 25.9 percent and 30.1 percent respectively. The geometric mean AUC0–t was 5140 h·ng/mL for the test product and 5020 h·ng/mL for the reference product. The geometric least-squares mean ratios were 1.0362 for Cmax and 1.0191 for AUC0–t, with 90 percent confidence intervals of 0.9750 to 1.1012 and 0.9684 to 1.0725, both comfortably inside the equivalence interval.

The fed group produced the same verdict. There, the geometric mean Cmax was 636 ng/mL for the test product and 604 ng/mL for the reference product, and the geometric mean AUC0–t was 6260 h·ng/mL versus 6130 h·ng/mL. The geometric least-squares mean ratios were 1.0524 for Cmax, 1.0224 for AUC0–t, and 1.0170 for the secondary endpoint AUCinf, all with 90 percent confidence intervals within the 0.80 to 1.25 bounds. Intraparticipant variability was lower in the fed group, with coefficients of variation around 10 percent for the main endpoints compared with roughly 16 to 20 percent in the fasted state. For both tablets, metformin was absorbed slowly, peaking between 3 and 4 hours in fasted participants and at a median of 5 hours in fed participants, and plasma concentrations fell below the quantification limit by 30 hours in the fasted group and 36 hours in the fed group. Secondary parameters including elimination half-life, apparent clearance, and apparent volume of distribution were similar between the two products.

Food changed the pharmacokinetics of both tablets in the same way. Participants in the fed group showed a higher AUC and a lower Cmax than those in the fasted group, a pattern the authors attribute to delayed gastric emptying after a high-fat meal, which postpones and prolongs the drug’s arrival at its absorption site in the intestine. The longer time to peak concentration in the fed state is consistent with previous reports on extended-release metformin. However, the study did not perform a formal statistical comparison between the fasted and fed groups, a limitation the authors acknowledge, so these food effects are descriptive observations rather than tested differences.

Safety results were unremarkable and matched the known profile of metformin. No deaths or serious adverse events occurred, and no hypoglycemia-related events were observed. One participant in the fed group experienced presyncope and withdrew, an event judged unrelated to the study intervention. All treatment-related adverse events were mild and resolved. Product-related treatment-emergent adverse events affected 12 of 58 participants, 20.7 percent, in the fasted group on the test product and 13 of 58, 22.8 percent, on the reference product; in the fed group the figures were 3 of 26, 11.5 percent, on the test product and none on the reference product. Diarrhea was the most common product-related event, occurring in 17.2 percent of fasted participants and 11.5 percent of fed participants, followed by abdominal pain, nausea, and elevated alanine aminotransferase. The authors note that the numerically higher event rates in the fasted group were not statistically analyzed, since safety comparisons fell outside the study objectives.

The trial’s structure deserves a word of explanation, because crossover designs are the standard tool for demonstrating bioequivalence. Giving each volunteer both products in random order means each person serves as their own control, so differences in metabolism, weight, and diet that would otherwise swamp a between-group comparison cancel out. The mixed-effects statistical model accounted for the sequence in which products were taken, the treatment period, and the treatment itself. The prespecified analysis sets followed the National Medical Products Administration bioequivalence guidance, and the primary analysis used all randomized participants with evaluable data rather than only the 57 fasted and 25 fed participants who completed both periods.

The authors conclude that the reduced-mass tablets from the new Chinese facility are bioequivalent to those from Germany and were similarly well tolerated, a result they describe as important both for regulatory approval and for patient adherence when switching between products. Because the smaller, round tablets may be easier to swallow than the traditional oblong ones, the findings could support continuity of care for people with type 2 diabetes who take metformin long term. The study’s scope should be kept in view: it involved a single dose in healthy young Chinese adults at one center, not repeated dosing in patients with diabetes, and the equivalence demonstrated is pharmaceutical, between two manufacturing sites of the same formulation, not between metformin and other glucose-lowering therapies.

Subject of Research: Bioequivalence of China-manufactured and Germany-manufactured extended-release reduced-mass metformin tablets in healthy adults

Article Title: Bioequivalence of China- and Germany-Manufactured Extended-Release Reduced-Mass Metformin (Glucophage® XR RM) Tablets Under Fasted and Fed Conditions in Healthy Participants: An Open-Label, Randomized, Single-Center Crossover Study

Article References: Du, J., Zhang, K., Li, D., Wang, L., Filho, M. N., & Zhang, L. (2026). Bioequivalence of China- and Germany-Manufactured Extended-Release Reduced-Mass Metformin (Glucophage® XR RM) Tablets Under Fasted and Fed Conditions in Healthy Participants: An Open-Label, Randomized, Single-Center Crossover Study. Drugs in R&D. https://doi.org/10.1007/s40268-026-00557-6

Image Credits: AI Generated

DOI: 10.1007/s40268-026-00557-6

Keywords: metformin, bioequivalence, extended-release, pharmacokinetics, type 2 diabetes, crossover trial, drug formulation, healthy volunteers, China, Germany, drug safety, adherence