The Medicines and Healthcare products Regulatory Agency of the United Kingdom (MHRA) has published a warning regarding the use of medicinal products containing metformin due to the risk of vitamin B12 deficiency.
Reduced vitamin B12 levels or vitamin B12 deficiency is currently considered a common adverse reaction in patients treated with metformin, especially in those taking higher doses or receiving longer treatment, as well as in patients with existing risk factors. Therefore, we recommend checking serum vitamin B12 levels in patients treated with metformin who have symptoms indicating its deficiency. We also recommend considering periodic monitoring of patients with risk factors for vitamin B12 deficiency.
Advice for healthcare professionals
- metformin can usually reduce vitamin B12 levels, which may lead to its deficiency;
- the risk of low vitamin B12 levels increases with increasing metformin dose, longer duration of treatment and in patients with risk factors for vitamin B12 deficiency;
- check serum vitamin B12 levels when a deficiency is suspected (for example, in patients with megaloblastic anemia or recently developed neuropathy) and follow current clinical recommendations on investigation and treatment of vitamin B12 deficiency;
- conduct periodic monitoring of vitamin B12 levels in patients with risk factors for its deficiency (see the list of risk factors in the article);
- carry out corrective treatment of vitamin B12 deficiency in accordance with current clinical recommendations; continue metformin therapy for as long as it is well tolerated and not contraindicated;
- report suspected adverse reactions associated with the use of metformin.
Advice for healthcare professionals to give to patients, parents, and caregivers
- if you are taking metformin, seek medical attention if the following symptoms appear or worsen: severe fatigue, inflamed and swollen tongue, tingling in the limbs, pale or yellow skin – these may be signs of low vitamin B12 levels;
- you may need a blood test to find out the cause of such symptoms; these symptoms may also be caused by diabetes mellitus or by other problems unrelated to health;
- you can continue taking metformin while your vitamin B12 level is being corrected;
- do not stop treatment without first consulting your doctor.
About metformin and vitamin B12 deficiency
Metformin is a medicinal product authorized for the treatment of type 2 diabetes mellitus and for the prevention of type 2 diabetes mellitus in patients at high risk of developing it. Metformin is available as immediate-release and modified-release tablets, and as an oral solution.
Vitamin B12 (cobalamin) is a substance that helps maintain the health of nerve cells and blood cells. It is found in foods of animal origin, including milk, cheese, yogurt, and eggs. It is also added to some fortified foods, such as breakfast cereals. Common causes of vitamin B12 deficiency are infections, malabsorption, medical conditions (Crohn's disease, pernicious anemia), gastric resection, and inadequate nutrition.
Vitamin B12 deficiency may be asymptomatic, or symptoms of megaloblastic anemia and/or neuropathy may occur. Other symptoms of low vitamin B12 levels may include mental disorders (depression, irritability, cognitive impairment), glossitis (swollen and inflamed tongue), mouth ulcers, as well as visual and motor disorders. For patients with anemia or neuropathy caused by vitamin B12 deficiency, it is important to establish a diagnosis and prescribe treatment as soon as possible.
A decrease in vitamin B12 levels is a known consequence of long-term treatment with metformin. It is currently believed that the mechanism of this phenomenon is multifactorial: altered intestinal motility, bacterial overgrowth and reduced absorption of vitamin B12 in the small intestine (or a combination of these factors).
Update of the package leaflet
A known adverse reaction associated with vitamin B12 deficiency was recently reviewed for the originator of metformin in Europe with the participation of the MHRA. Following this review, we agreed that the instructions for medical use of medicinal products containing metformin should be updated.
Current data indicate that the frequency of this adverse reaction is higher than previously thought – it may develop in 1 out of 10 people taking metformin. The package insert will be updated accordingly.
The instructions for medical use have also been updated to state that the risk of this adverse reaction increases with increasing metformin dose and treatment duration, as well as in patients with risk factors known to cause vitamin B12 deficiency.
The updated instructions for medical use also contain new recommendations for health care professionals on monitoring vitamin B12 levels in patients with anemia or neuropathy, as well as on the need for periodic monitoring of vitamin B12 levels in patients with risk factors for its deficiency. The instructions for medical use of other medicinal products containing metformin will also be updated, including fixed-dose combination medicinal products.
Risk factors for vitamin B12 deficiency
Risk factors for vitamin B12 deficiency are wide-ranging. They include:
- baseline vitamin B12 level at the lower limit of the normal range;
- conditions associated with reduced absorption of vitamin B12 (for example, elderly people and people with gastrointestinal disorders such as total or partial gastrectomy, Crohn's disease and other inflammatory bowel disorders, or autoimmune conditions);
- diets with reduced vitamin B12 content (for example, strict vegan and some vegetarian diets);
- concomitant use of medicinal products known to impair the absorption of vitamin B12 (including proton pump inhibitors or colchicine);
- genetic predisposition to vitamin B12 deficiency, for example, Imerslund-Gräsbeck syndrome and transcobalamin II deficiency.
The original text is available at the link https://www.gov.uk/drug-safety-update/metformin-and-reduced-vitamin-b12-levels-new-advice-for-monitoring-patients-at-risk
