Metformin FAQs

 

 

a. Is liquid metformin permitted?

Yes, any formulation of metformin is permitted providing one of the dose schedules stated it the STAMPEDE protocol are followed. All patients should aim to receive the target dose of 850mg BD. Please refer to protocol section 6.2.6 for further details.

 

b. What steps should be taken if patient develops a macrocytic anaemia whilst on metformin?

Vitamin B12 deficiency which can cause macrocytic anaemia is a recognised side-effect of metformin.

• Test vitamin B12 serum levels if deficiency is suspected (for example, in patients presenting with megaloblastic anaemia) and follow current clinical guidelines on investigation and management of vitamin B12 deficiency.
• Consider periodic vitamin B12 monitoring in patients with risk factors for vitamin B12 deficiency (See below).
• Administer corrective treatment for vitamin B12 deficiency in line with current clinical guidelines; continue metformin therapy for as long as it is tolerated and not contraindicated.
• Report adverse events as per the protocol. 
• Additionally, information and guidance on the management of B12 deficiency is also available on the NICE website:

 

https://cks.nice.org.uk/topics/anaemia-b12-folate-deficiency/

 

c. What risk factors could increase risk of vitamin B12 deficiency in those taking metformin?

• Baseline vitamin B12 levels at the lower end of the normal range.
• Longer metformin treatment duration or higher treatment dose.
• Conditions associated with reduced vitamin B12 absorption including:
• Old age 
• Gastrointestinal disorders such as total or partial gastrectomy, Crohn’s disease and other bowel inflammatory disorders, or autoimmune conditions
• Diets with reduced sources of vitamin B12 (such as strict vegan and some vegetarian diets).
• Concomitant medication known to impair vitamin B12 absorption including proton pump inhibitors or colchicine.
• Genetic predisposition to vitamin B12 deficiency, such as intrinsic factor receptor deficiency (Imerslund-Gräsbeck syndrome) and transcobalamin II deficiency.

 

d. Is dose escalation allowed post 4 weeks?

Yes, all patients should attempt a dose escalation to the target dose of 850mg BD providing the starting dose is reasonably well tolerated. Dose escalation should be attempted around 4-6 weeks post treatment starting but can be attempted at any time point. If a dose escalation is not attempted the reason why should be clearly documented.

 

e. What is the advice on alcohol consumption and metformin?

The reference safety information for metformin advises against metformin use in individuals with excessive alcohol intake as this is a risk factor for lactic acidosis. Reasonable alcohol intake is safe. Metformin should not be given in individuals with alcohol dependency.

 

f. When should patients stop taking metformin?

Patients with metastatic disease at trial entry should continue on metformin whilst on ADT and post progression i.e. lifelong providing it is judged to be in the patients’ best interest.

Patients with non-metastatic disease should continue also continue metformin whilst on ADT. If ADT is stopped after the minimum of 2 years, metformin should continue for a further 12 months i.e. 3 years. If metformin is stopped 12 months after last administration of LHRH, it should not be re-started in the event of relapse.

 

g. How to label metformin bottles prescribed to patients allocated to arm K?

All Arm K stock will require additional trial-specific labelling by the site pharmacist before dispensing. Pharmacies are required to have a written SOP in place for trial-specific labelling procedures. Template labels are available on the STAMPEDE website, further information may be added to the labels but nothing should be omitted.

 

h. How to document accountability and destruction of metformin tablets?

No template destruction or accountability logs are provided. Pharmacies must use local templates for Arm K supplies.

 

i. Can metformin be couriered to a patient?

For accountability reasons, STAMPEDE related treatment drugs cannot be posted to patients.

 

j. Should pharmacies inform the STAMPEDE unit each time their brand of metformin changes?

No, this is not necessary as long as the batch number is appropriately recorded for each dispensed visit and is able to be traced to the brand of metformin that was dispensed.

 

k. A patient has progressed and is starting second line treatment, should metformin stop?

No, metformin should continue for as long at the patient is receiving ADT. Metformin can be safely given with all treatments given for disease progression.

 

l. A patient is being considered for a second line CTIMP in castrate resistant prostate cancer, should being on continued metformin affect his participation?

It is not usually permitted for patients to receive two IMPs at once. If the treating medical team believe it would be in the best interest of the patient to join a second line trial, metformin should be stopped.

 

m. A patient is attending hospital for a CT scan, does metformin need to be paused?

If the GFR is <60 ml/min/1.73m² metformin should be paused for 24 hours prior to receiving contrast and re-started 48 hours post‑administration.

 

n. What drugs are contra-indicated for patients receiving metformin?

Caution is needed when starting any medications that may be potentially nephrotoxic due to the risk of reduced metformin clearance. This includes non-steroidal anti-inflammatories such as naproxen, diclofenac and ibuprofen, anti-hypertensives such as ACE inhibitors, diuretics and certain intravenous antibiotics. Metformin can be safely given with all prostate cancer treatments that may be given after disease progression and should continue where possible.

 

o. A patient has been admitted for a procedure and has worsening urinary outcome and renal function, should metformin be permanently stopped?

Metformin should be paused in any scenario where there is a risk of deteriorating renal function. If the eGFR falls to less than 30 ml/min/1.73m² and does not recover metformin must be permanently stopped.

 

p. A patient has developed diabetes after being randomised to Arm K, how should this be managed?

Diabetes should be managed according to the treating clinician and any changes to the metformin dose should be documented on the metformin treatment log. The patient can remain on STAMPEDE follow-up as per normal.

 

q. Is there further information available about metformin NDMA contamination?

Yes, the MHRA published a press statement about this, please review it here.

 

r. Are the drugs listed on Table 25 of the protocol a contraindication to metformin?

None of the drugs listed on this table are interactions with metformin. Metformin is contraindicated in poor/significantly impaired renal function and the drugs listed on Table 25 fall into two classes:

 

1.  Those that could damage kidney function (NSAIDs)
2.  Those that can increase creatinine levels but which are actually indicated for, among other reasons, limiting renal damage in conditions which might impair renal function (ACE e.g. Ramipril)

Using Metformin Safely in Patients with Renal Impairment

Metformin is not metabolised and is entirely cleared by renal excretion. Studies have indicated that plasma levels of metformin below 5 mg/L are not associated with lactic acidosis.

Since metformin metabolism is entirely dependent on renal function a dose reduction is required in patients with stable renal impairment. The new advice on metformin doses in renal impairment is derived from a population pharmacokinetic study. This study included patients with varying levels of renal impairment (Table 1).

 

Table 1: Maximum recommended doses of metformin

Renal function (creatinine clearance )	Maximum daily metformin dose
15-30 mL/min	500 mg
30-60 mL/min	1000 mg
60¬-120 mL/min	2000 mg

 

Have another question or looking for more information? why not check out the STAMPEDE Training Suite for the training slides detailing information on STAMPEDE.