A Critical Examination of Metformin Package Inserts and Summaries of Product Characteristics

Article 11 of the German Medicinal Products Act stipulates that proprietary medicinal products which are neither destined for clinical testing nor exempt from the requirement for licensing must not be marketed without a package insert. The insert must contain information about the drug in a particular order and in accordance with article 11a, which states that pharmaceutical companies are obliged, on demand, to provide medical personnel with a summary of product characteristics for all proprietary medicinal products that are either subject to the requirement for licensing or exempt from this requirement but authorized only for distribution by pharmacies. The licensees are obliged to ensure that the package inserts and summaries of product characteristics are kept up to date and scientifically accurate (1). This represents a cornerstone of efficient healthcare. At a time of shrinking supply, physicians are having to resort increasingly to generic pharmaceuticals (2). Using the example of the antidiabetic drug metformin, we set out to examine whether different manufacturers supply the same information to users in their package inserts and summaries of product characteristics.

Material and methods

We compared the data provided in the package inserts and summaries of product characteristics for 17 preparations of metformin. Information from all manufacturers who are currently licensed to market metformin and distribute the drug in the dosages 500 mg, 850 mg, and 1000 mg was analyzed. Package inserts and summaries of product characteristics for metformin XR (extended release) were excluded. We evaluated the newest versions of the package inserts and summaries of product characteristics, found either on the respective manufacturer’s website or at https://portal.dimdi.de/amguifree/termsofuse.xhtml, an online database of the German Federal Institute for Drugs and Medical Devices (BfArM). The analysis focused on drug interactions, adverse drug reactions, and use during pregnancy and breastfeeding.

Results

Drug interactions: All of the manufacturers state that consumption of medications such as diuretics, COX inhibitors, ACE inhibitors, and angiotensin-2-receptor antagonists at the same time as metformin can have a deleterious effect on the patient’s kidney function, increasing the danger of lactic acidosis. Sixteen manufacturers recommend more frequent determination of blood sugar levels in patients taking metformin simultaneously with medications that have intrinsic hyperglycemic activity. One manufacturer gives this advice in the package insert, but not in the summary of product characteristics. Drugs with intrinsic hyperglycemic activity include medications such as glucocorticoids, which can disturb glucose tolerance (3). Sixteen manufacturers state that there may be a drug interaction with medications that inhibit or induce organic cation transporters. Two of the 17 manufacturers mention that metformin can lead to attenuation of the action of phenprocoumon. One manufacturer states that levothyroxine may reduce the blood-glucose-lowering effect of metformin (Table 1).

Table 1

Drug interactions

Desired or existing pregnancy and breastfeeding period: With regard to women who are or want to become pregnant, 13 of the 17 manufacturers state in the summary of product characteristics that metformin can be taken, while four advise against it. The package inserts either advise against metformin or recommend consulting a medical professional. All package inserts and summaries of product characteristics advise against taking metformin during the breastfeeding period.

Adverse drug reactions: The information differs with regard to the frequency of reduced concentration of vitamin B₁₂. Eleven manufacturers state that it occurs very rarely (<1/10 000 patients), five that it may be frequent (<1/100 patients). The information from one manufacturer differs between the package insert and the summary of product characteristics (Table 2).

Table 2

Adverse drug reactions

Advice on iodine-containing contrast media and the perioperative setting: All manufacturers advise discontinuation of metformin before contrast-enhanced imaging procedures, but none specify how long before. They also all recommend that metformin should be discontinued in the perioperative period, again without stating exactly when.

In general: No inconsistencies were found between the package inserts and summaries of product characteristics for different dosages from the same manufacturer.

Discussion

With regard to drug interactions, studies have shown that metformin interacts with phenprocoumon and levothyroxine (4, 5). However, this eventuality is mentioned in hardly any of the summaries of product characteristics and package inserts. As for adverse drug reactions, it is unclear from the package inserts and summaries of product characteristics how often vitamin-B₁₂ deficiency may occur. It is difficult to say what is scientifically correct. For instance, data on the frequency of occurrence of adverse drug reactions depend on many factors, e.g., the reporting of suspected cases by the authorities of the different federal states of Germany. Users expect consistency among manufacturers with regard to intake during pregnancy and breastfeeding. The discussion (in German) of metformin on the website www.embrytox.de reveals a positive attitude towards metformin intake by pregnant and nursing women. As for discontinuation of metformin prior to surgery or contrast-enhanced imaging, it would be helpful to be told how long in advance. Our work has shown that the advice on many topics is consistent; however, discrepant or imprecise information can leave users in the dark. One potential approach towards improvement of package inserts and summaries of product characteristics might be for the BfArM to work towards standardization of the content of these documents for all drugs. With the help of the manufacturers and the professional medical associations, the advice could then be continually corrected and updated.

Lara-Renate Rühle, Roland Seifert

Institute for Pharmacology, Hanover Medical School (Rühle, Seifert) [e-mail]

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 20 August 2024, revised version accepted on 31 January 2025.

Translated from the original German by David Roseveare.

Cite this as:
Rühle LR, Seifert R: A critical examination of metformin package inserts and summaries of product characteristics. Dtsch Arztebl Int 2025; 122: 245–6. DOI: 10.3238/arztebl.m2025.0020

References

1. AMG – Gesetz über den Verkehr mit Arzneimitteln. www.gesetze-im-internet.de/amg_1976/BJNR024480976.html (last accessed on 29 November 2024).

2. BfArM – Lieferengpässe. www.bfarm.de/DE/Arzneimittel/Arzneimittelinformationen/Lieferengpaesse/_node.html (last accessed on 29 November 2024).

3. Petri H: Arzneimittelnebenwirkungen: Welche Medikamente diabetogen wirken. Dtsch Arztebl 2016; 113(17): [12] ; DOI: 10.3238/PersDia.2016.04.29.03

4. Amirabadizadeh A, Amouzegar A, Mehran L, Azizi F: The effect of ­metformin therapy on serum thyrotropin and free thyroxine ­concentrations in patients with type 2 diabetes: A meta-analysis. Sci Rep 2023; 13: 18757

5. Stage TB, Pottegård A, Henriksen DP, et al.: Initiation of glucose-­lowering treatment decreases international normalized ratio levels among users of vitamin K antagonists: A self-controlled register study. J Thromb Haemost 2016; 14: 129–33