Drugs List

Therapeutic Indications

Uses

Control of type-2 diabetes (NIDDM) if metformin monotherapy is inadequate

Treatment of type 2 diabetes mellitus:

In patients who are unable to achieve adequate glycaemic control at their maximally tolerated dose of metformin monotherapy.

As an alternative for patients already treated with the combination of vildagliptin and metformin as separate tablets.

In combination with a sulfonylurea as an adjunct to diet and exercise in patients inadequately controlled with metformin and a sulfonylurea.

In combination with insulin as an adjunct to diet and exercise to improve glycaemic control in patients when insulin at a stable dose and metformin alone do not provide adequate glycaemic control.

Contraindications

Acute alcohol intoxication
Children under 18 years
Hypovolaemic shock
Severe infection
Alcoholism
Breastfeeding
Cardiac failure
Dehydration
Diabetic pre-coma
Hepatic impairment
Pregnancy
Recent myocardial infarction
Renal impairment - glomerular filtration rate below 30ml/minute
Respiratory failure
Serum transaminases above 3 times upper limit of normal

Precautions and Warnings

Elderly
History of pancreatitis
Renal impairment - glomerular filtration rate 30 to 59 ml/minute

Not suitable for treatment of diabetic ketoacidosis
Not suitable for treatment of Type 1 diabetes mellitus
Reduce dose in patients with moderate renal impairment
Advise patient dizziness may affect ability to drive or operate machinery
Advise patient to take precautions to avoid hypoglycaemia whilst driving
Test vit B12 levels if deficiency is suspected or risk factors are present
Exclude pregnancy prior to initiation of treatment
Monitor renal function prior to initiating treatment
Perform liver function tests before commencing therapy
If hepatic impairment symptoms occur monitor LFT & consider discontinuation
Monitor for development of lactic acidosis
Monitor liver function every 3 months during first year then periodically
Monitor renal function 3 to 6 monthly in elderly patients
Monitor renal function 3- 6 monthly if renal function is borderline normal
Monitor renal function annually in patients with normal renal function
Monitor skin changes
Advise patient to report symptoms of low vitamin B12 levels
Advise patients to report signs of hepatic damage (malaise, jaundice etc.)
Advise patients to report symptoms of acute pancreatitis immediately
Discontinue 48 hours before elective surgery with general anaesthesia
Advise patient to seek advice at first indications of pregnancy
Discontinue at first signs of jaundice
Discontinue if ALT level exceed 3 times the upper limit of normal & persist
Discontinue if lactic acidosis is suspected
Discontinue if pancreatitis occurs
Pregnancy confirmed: Change patient to insulin treatment
Advise patient to avoid alcohol during treatment
Patient to inform DVLA if fitness to drive impaired or hypoglycaemic risk

Lactic acidosis can occur due to metformin accumulation. To reduce the incidence of this occurring, patients should be assessed for risk factors associated with the development of lactic acidosis and monitored regularly.
Symptoms of lactic acidosis include acidotic dyspnoea, abdominal pain, hypothermia and coma. Lactic acidosis is also indicated by decreased blood pH, plasma lactate levels above 5 mmol/L and an increased anion gap and lactate pyruvate ratio.
If lactic acidosis is suspected, discontinue treatment and hospitalise the patient immediately.
Risk factors for lactic acidosis include: poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic impairment and any condition associated with hypoxia.

Treatment with metformin should be discontinued 48 hours prior to elective surgery with general anaesthetic and should not usually be resumed earlier than 48 hours afterwards.

Discontinue treatment prior to, or at the time of administration of iodinated contrast agents due to the possibility of renal failure. Treatment should not be resumed until 48 hours after administration or when renal function has been evaluated and found to be normal.

Pregnancy and Lactation

Pregnancy

Vildagliptin with metformin is contraindicated in pregnancy.

Animal studies have not shown any evidence of teratogenicity, but foetotoxic effects were observed at maternotoxic doses. The potential risk to humans is unknown.

Animal studies for vildagliptin have shown reproductive toxicity at high doses.

Metformin is generally considered to present a low risk when used during pregnancy and animal data generally do not indicate harmful effects on pregnancy, embryonal or foetal development, parturition or postnatal development. Metformin does cross the placenta, although it has been shown to be non-teratogenic in the majority of studies. One reference, however, suggests that metformin may be associated with growth retardation and hyperbilirubinaemia. Rare cases of neural tube defects and malformations of the heart and eye have been seen in animals though studies in pregnant women indicate a low risk to the foetus At the time of writing, current NICE guidelines on the treatment of diabetes during pregnancy recommend that metformin may be used as an adjunct or alternative to insulin in the pre-conception period and during pregnancy where the likely benefits from improved glycaemic control outweigh the potential for harm and informed consent is obtained from the mother. Metformin is not recommended for the treatment of diabetes in pregnancy as it does not provide adequate maternal glycaemic control and insulin therapy is preferred.

Detailed guidance on the treatment of diabetes during pregnancy is available from the National Institute for Health and Clinical Excellence (NICE) at https://www.nice.org.uk/guidance/CG63

Insulin is the treatment of choice for both Type 1 and Type 2 diabetes during pregnancy as it provides better control of maternal blood glucose compared to oral hypoglycaemics. It is believed that human insulin and insulin analogues do not cross the placenta, however there may be endogenous carrier proteins allowing passage of insulin to the embryo during early gestation; animal insulin is believed to cross the human placenta. The foetus produces its own insulin once insulin-secreting cells in the foetal pancreas become differentiated at the end of the first trimester.

Human insulin is considered safe to use during pregnancy and extensive experience with human insulin during pregnancy does not indicate any embryotoxic potential. Human insulin is often the first line treatment for diabetes and the benchmark used when comparing the safety of other insulins during pregnancy.

Infants of diabetic mothers are at an increased risk of congenital abnormalities, the rate of which appears to be related to maternal glycaemic control during the first trimester. Careful control of maternal blood glucose is required throughout pregnancy. Good maternal glycaemic control during labour and birth is important in preventing adverse neonatal outcomes including neonatal hypoglycaemia and respiratory stress.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Vildagliptin with metformin contraindicated in breastfeeding.

Animal studies have shown that vildagliptin is excreted in breast milk. It is not known whether vildagliptin is excreted in human breast milk.

Metformin is excreted in breast milk although data indicates that infant exposure is low. Metformin has occasionally been detected in low-levels in the serum of breastfed infants although studies have found no adverse effects in infants breastfed by women taking metformin. LactMed (via ToxNet) recommends that caution be used in mothers with newborn and premature infants, and infants with renal impairment. Briggs and Schaefer both agree that metformin appears in breast milk at low concentrations and that it is considered compatible for use in breastfeeding mothers. LactMed (via ToxNet) states that maternal metformin levels are reasonably constant and therefore timing of breastfeeding with respect to dose is of little benefit. Current NICE guidelines state that women with pre-existing type 2 diabetes who are breastfeeding can resume or continue to take metformin immediately following birth. The manufacturer, however, recommends that the use of metformin should be avoided during breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Angioedema
Arthralgia
Asthenia
Chills
Constipation
Decreased appetite
Decreased blood glucose
Decreased vitamin-B12 absorption
Diarrhoea
Dizziness
Erythema
Fatigue
Flatulence
Gastroesophageal reflux disease
Headache
Hepatic impairment
Hepatitis
Hyperhidrosis
Hypoglycaemia
Increase in serum transaminases
Lactic acidosis
Metallic taste
Nasopharyngitis
Nausea
Pancreatitis
Peripheral oedema
Pruritus
Skin lesions
Tremor
Upper respiratory tract infection
Urticaria
Vomiting

Presentation

Tablets containing vildagliptin with metformin

Drugs List

Therapeutic Indications

Uses

Control of type-2 diabetes (NIDDM) if metformin monotherapy is inadequate

Treatment of type 2 diabetes mellitus:

In patients who are unable to achieve adequate glycaemic control at their maximally tolerated dose of metformin monotherapy.

As an alternative for patients already treated with the combination of vildagliptin and metformin as separate tablets.

In combination with a sulfonylurea as an adjunct to diet and exercise in patients inadequately controlled with metformin and a sulfonylurea.

In combination with insulin as an adjunct to diet and exercise to improve glycaemic control in patients when insulin at a stable dose and metformin alone do not provide adequate glycaemic control.

Dosage

Adults

Elderly

Patients with Renal Impairment

Additional Dosage Information

Contraindications

Acute alcohol intoxication
Children under 18 years
Hypovolaemic shock
Severe infection
Alcoholism
Breastfeeding
Cardiac failure
Dehydration
Diabetic pre-coma
Hepatic impairment
Pregnancy
Recent myocardial infarction
Renal impairment - glomerular filtration rate below 30ml/minute
Respiratory failure
Serum transaminases above 3 times upper limit of normal

Precautions and Warnings

Elderly
History of pancreatitis
Renal impairment - glomerular filtration rate 30 to 59 ml/minute

Not suitable for treatment of diabetic ketoacidosis
Not suitable for treatment of Type 1 diabetes mellitus
Reduce dose in patients with moderate renal impairment
Advise patient dizziness may affect ability to drive or operate machinery
Advise patient to take precautions to avoid hypoglycaemia whilst driving
Test vit B12 levels if deficiency is suspected or risk factors are present
Exclude pregnancy prior to initiation of treatment
Monitor renal function prior to initiating treatment
Perform liver function tests before commencing therapy
If hepatic impairment symptoms occur monitor LFT & consider discontinuation
Monitor for development of lactic acidosis
Monitor liver function every 3 months during first year then periodically
Monitor renal function 3 to 6 monthly in elderly patients
Monitor renal function 3- 6 monthly if renal function is borderline normal
Monitor renal function annually in patients with normal renal function
Monitor skin changes
Advise patient to report symptoms of low vitamin B12 levels
Advise patients to report signs of hepatic damage (malaise, jaundice etc.)
Advise patients to report symptoms of acute pancreatitis immediately
Discontinue 48 hours before elective surgery with general anaesthesia
Advise patient to seek advice at first indications of pregnancy
Discontinue at first signs of jaundice
Discontinue if ALT level exceed 3 times the upper limit of normal & persist
Discontinue if lactic acidosis is suspected
Discontinue if pancreatitis occurs
Pregnancy confirmed: Change patient to insulin treatment
Advise patient to avoid alcohol during treatment
Patient to inform DVLA if fitness to drive impaired or hypoglycaemic risk

Lactic acidosis can occur due to metformin accumulation. To reduce the incidence of this occurring, patients should be assessed for risk factors associated with the development of lactic acidosis and monitored regularly.
Symptoms of lactic acidosis include acidotic dyspnoea, abdominal pain, hypothermia and coma. Lactic acidosis is also indicated by decreased blood pH, plasma lactate levels above 5 mmol/L and an increased anion gap and lactate pyruvate ratio.
If lactic acidosis is suspected, discontinue treatment and hospitalise the patient immediately.
Risk factors for lactic acidosis include: poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic impairment and any condition associated with hypoxia.

Treatment with metformin should be discontinued 48 hours prior to elective surgery with general anaesthetic and should not usually be resumed earlier than 48 hours afterwards.

Discontinue treatment prior to, or at the time of administration of iodinated contrast agents due to the possibility of renal failure. Treatment should not be resumed until 48 hours after administration or when renal function has been evaluated and found to be normal.

Pregnancy and Lactation

Pregnancy

Vildagliptin with metformin is contraindicated in pregnancy.

Animal studies have not shown any evidence of teratogenicity, but foetotoxic effects were observed at maternotoxic doses. The potential risk to humans is unknown.

Animal studies for vildagliptin have shown reproductive toxicity at high doses.

Metformin is generally considered to present a low risk when used during pregnancy and animal data generally do not indicate harmful effects on pregnancy, embryonal or foetal development, parturition or postnatal development. Metformin does cross the placenta, although it has been shown to be non-teratogenic in the majority of studies. One reference, however, suggests that metformin may be associated with growth retardation and hyperbilirubinaemia. Rare cases of neural tube defects and malformations of the heart and eye have been seen in animals though studies in pregnant women indicate a low risk to the foetus At the time of writing, current NICE guidelines on the treatment of diabetes during pregnancy recommend that metformin may be used as an adjunct or alternative to insulin in the pre-conception period and during pregnancy where the likely benefits from improved glycaemic control outweigh the potential for harm and informed consent is obtained from the mother. Metformin is not recommended for the treatment of diabetes in pregnancy as it does not provide adequate maternal glycaemic control and insulin therapy is preferred.

Detailed guidance on the treatment of diabetes during pregnancy is available from the National Institute for Health and Clinical Excellence (NICE) at https://www.nice.org.uk/guidance/CG63

Insulin is the treatment of choice for both Type 1 and Type 2 diabetes during pregnancy as it provides better control of maternal blood glucose compared to oral hypoglycaemics. It is believed that human insulin and insulin analogues do not cross the placenta, however there may be endogenous carrier proteins allowing passage of insulin to the embryo during early gestation; animal insulin is believed to cross the human placenta. The foetus produces its own insulin once insulin-secreting cells in the foetal pancreas become differentiated at the end of the first trimester.

Human insulin is considered safe to use during pregnancy and extensive experience with human insulin during pregnancy does not indicate any embryotoxic potential. Human insulin is often the first line treatment for diabetes and the benchmark used when comparing the safety of other insulins during pregnancy.

Infants of diabetic mothers are at an increased risk of congenital abnormalities, the rate of which appears to be related to maternal glycaemic control during the first trimester. Careful control of maternal blood glucose is required throughout pregnancy. Good maternal glycaemic control during labour and birth is important in preventing adverse neonatal outcomes including neonatal hypoglycaemia and respiratory stress.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Vildagliptin with metformin contraindicated in breastfeeding.

Animal studies have shown that vildagliptin is excreted in breast milk. It is not known whether vildagliptin is excreted in human breast milk.

Metformin is excreted in breast milk although data indicates that infant exposure is low. Metformin has occasionally been detected in low-levels in the serum of breastfed infants although studies have found no adverse effects in infants breastfed by women taking metformin. LactMed (via ToxNet) recommends that caution be used in mothers with newborn and premature infants, and infants with renal impairment. Briggs and Schaefer both agree that metformin appears in breast milk at low concentrations and that it is considered compatible for use in breastfeeding mothers. LactMed (via ToxNet) states that maternal metformin levels are reasonably constant and therefore timing of breastfeeding with respect to dose is of little benefit. Current NICE guidelines state that women with pre-existing type 2 diabetes who are breastfeeding can resume or continue to take metformin immediately following birth. The manufacturer, however, recommends that the use of metformin should be avoided during breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Counselling

Advise patient to avoid alcohol and alcohol containing medications.

Advise patient to seek medical attention if they experience signs of hepatic dysfunction (nausea, vomiting, abdominal pain, fatigue or dark urine) or of pancreatitis (severe, persistent abdominal pain).

Advise patient to report symptoms of low vitamin B12 levels.

Advise patient to seek advice at the first indications of pregnancy.

Advise patients that their ability to drive or operate machinery may be impaired.

Advise patient to take precautions to avoid hypoglycaemia when driving.

Advise patient to report to DVLA if there is a risk of hypoglycaemia, or if fitness to drive may be impaired due to diabetes complications. Guidance can be found by accessing Gov.uk website.

Side Effects

Abdominal pain
Angioedema
Arthralgia
Asthenia
Chills
Constipation
Decreased appetite
Decreased blood glucose
Decreased vitamin-B12 absorption
Diarrhoea
Dizziness
Erythema
Fatigue
Flatulence
Gastroesophageal reflux disease
Headache
Hepatic impairment
Hepatitis
Hyperhidrosis
Hypoglycaemia
Increase in serum transaminases
Lactic acidosis
Metallic taste
Nasopharyngitis
Nausea
Pancreatitis
Peripheral oedema
Pruritus
Skin lesions
Tremor
Upper respiratory tract infection
Urticaria
Vomiting

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: October 2014

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. Accessed on 08 October 2014.

Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.

NICE Clinical Guideline 63. Diabetes in Pregnancy: Management of Diabetes and its Complications from Pre-conception to the Postnatal Period. Issue Date: March 2008 (reissued July 2008).

Summary of Product Characteristics: Eucreas 50 mg/850 mg & 50 mg/1000 mg tablets. Novartis Europharm Ltd. Revised December 2016.

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Metformin. Last revised: 07 September 2013
Last accessed: 08 October 2014

EMA Safety Update December 2016
Available at: https://www.ema.europa.eu/ema/
Last accessed: 18 January 2017

MHRA Drug Safety Update June 2022
Available at: https://www.mhra.gov.uk
Last accessed: 21 July 2022