Drugs List

Therapeutic Indications

Uses

Combination treatment of Type 2 diabetes with insulin
Oral combination treatment of type 2 diabetes

For the treatment of adult patients with type 2 diabetes mellitus.

For the treatment of type 2 diabetes as an adjunct to diet and exercise to improve glycaemic control in adult patients inadequately controlled on their maximal tolerated dose of metformin alone, or those already being treated with the combination of linagliptin and metformin.

For the treatment of type 2 diabetes in combination with a sulfonylurea as an adjunct to diet and exercise in adult patients inadequately controlled on their maximal tolerated dose of metformin and a sulfonylurea.

For the treatment of type 2 diabetes in combination with insulin as an adjunct to diet and exercise in adult patients inadequately controlled on their maximal tolerated dose of metformin and insulin.

Contraindications

Acute alcohol intoxication
Children under 18 years
Severe infection
Shock
Alcoholism
Breastfeeding
Decompensated cardiac failure
Dehydration
Diabetic pre-coma
Hepatic impairment
Pregnancy
Recent myocardial infarction
Renal impairment - glomerular filtration rate below 30ml/minute
Respiratory failure

Precautions and Warnings

Patients over 80 years
History of pancreatitis
Renal impairment - glomerular filtration rate 30 to 59 ml/minute

Reduce dose in patients with moderate renal impairment
Advise patient to take precautions to avoid hypoglycaemia whilst driving
Caution when adding a drug likely to impair renal function (NSAID,diuretic)
Test vit B12 levels if deficiency is suspected or risk factors are present
Monitor renal function prior to initiating treatment
Monitor for development of lactic acidosis
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
Advise patient to report symptoms of low vitamin B12 levels
Advise patient to report unexplained nausea,vomiting,abdominal pain
Advise patients to report symptoms of acute pancreatitis immediately
Discontinue if pemphigus-type reactions develop
Discontinue 48 hours before elective surgery with general anaesthesia
Discontinue if lactic acidosis is suspected
Discontinue if pancreatitis occurs
Pregnancy confirmed: Change patient to insulin treatment
Advise patient not to take St John's wort concurrently
Advise patient to avoid alcohol during treatment
Dietary restrictions should be maintained
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 metformin and hospitalise the patient immediately.
Risk factors for lactic acidosis include:
Poorly controlled diabetes
Ketosis
Prolonged fasting
Excessive alcohol intake
Hepatic impairment
Any condition associated with hypoxia

Treatment should be discontinued 48 hours prior to elective surgery with general, spinal or epidural anaesthesia. Treatment should not usually be resumed earlier than 48 hours after surgery and only after renal function has been re-evaluated and found to be normal.

Pregnancy and Lactation

Pregnancy

Linagliptin with metformin tablets are contraindicated in pregnancy.

There is no adequate data from the use of linagliptin during pregnancy. Animal studies have not shown direct or indirect harmful effects.

Metformin does cross the placenta, although it has not been shown to be teratogenic in the majority of studies. Animal data generally does not indicate harmful effects on pregnancy, embryonic or foetal development, parturition or postnatal development. Data suggests that metformin is low risk in pregnancy.

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/ng3

When diet alone is not successful, insulin is the treatment of choice for both Type 1 and Type 2 diabetes during pregnancy. Hyperglycaemia in the mother, particularly in the early stages of gestation, is associated with a number of foetal and maternal adverse effects, including foetal structural abnormalities. Carefully prescribed insulin therapy will provide better control of the mother's blood glucose thereby preventing the foetal and neonatal complications that occur with the disease (Briggs, 2011).

If the patient plans to become pregnant, or if pregnancy occurs, treatment should be switched to insulin treatment as soon as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.

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

Linagliptin with metformin tablets are contraindicated in breastfeeding.

It is unknown whether linagliptin is excreted in human breast milk. Animal studies have shown excretion of linagliptin and/or metabolite in milk, a risk to the nursing infant cannot be excluded.

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, as a single agent, appears in breast milk at low concentrations and that it is considered compatible for use in breastfeeding mothers.

Insulin therapy should be considered for diabetic patients who wish to breastfeed.

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
Abnormal liver function tests
Angioedema
Bronchial hyperreactivity
Bullous pemphigoid
Constipation
Cough
Decreased appetite
Decreased vitamin-B12 absorption
Diarrhoea
Elevated amylase levels
Elevated serum lipase
Erythema
Hepatitis
Hypersensitivity reactions
Hypoglycaemia
Lactic acidosis
Megaloblastic anaemia
Nasopharyngitis
Nausea
Pancreatitis
Pruritus
Rash
Taste disturbances
Urticaria
Vomiting

Presentation

Tablets containing linagliptin and metformin hydrochloride

Drugs List

Therapeutic Indications

Uses

Combination treatment of Type 2 diabetes with insulin
Oral combination treatment of type 2 diabetes

For the treatment of adult patients with type 2 diabetes mellitus.

For the treatment of type 2 diabetes as an adjunct to diet and exercise to improve glycaemic control in adult patients inadequately controlled on their maximal tolerated dose of metformin alone, or those already being treated with the combination of linagliptin and metformin.

For the treatment of type 2 diabetes in combination with a sulfonylurea as an adjunct to diet and exercise in adult patients inadequately controlled on their maximal tolerated dose of metformin and a sulfonylurea.

For the treatment of type 2 diabetes in combination with insulin as an adjunct to diet and exercise in adult patients inadequately controlled on their maximal tolerated dose of metformin and insulin.

Dosage

Adults

Patients with Renal Impairment

Additional Dosage Information

Contraindications

Acute alcohol intoxication
Children under 18 years
Severe infection
Shock
Alcoholism
Breastfeeding
Decompensated cardiac failure
Dehydration
Diabetic pre-coma
Hepatic impairment
Pregnancy
Recent myocardial infarction
Renal impairment - glomerular filtration rate below 30ml/minute
Respiratory failure

Precautions and Warnings

Patients over 80 years
History of pancreatitis
Renal impairment - glomerular filtration rate 30 to 59 ml/minute

Reduce dose in patients with moderate renal impairment
Advise patient to take precautions to avoid hypoglycaemia whilst driving
Caution when adding a drug likely to impair renal function (NSAID,diuretic)
Test vit B12 levels if deficiency is suspected or risk factors are present
Monitor renal function prior to initiating treatment
Monitor for development of lactic acidosis
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
Advise patient to report symptoms of low vitamin B12 levels
Advise patient to report unexplained nausea,vomiting,abdominal pain
Advise patients to report symptoms of acute pancreatitis immediately
Discontinue if pemphigus-type reactions develop
Discontinue 48 hours before elective surgery with general anaesthesia
Discontinue if lactic acidosis is suspected
Discontinue if pancreatitis occurs
Pregnancy confirmed: Change patient to insulin treatment
Advise patient not to take St John's wort concurrently
Advise patient to avoid alcohol during treatment
Dietary restrictions should be maintained
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 metformin and hospitalise the patient immediately.
Risk factors for lactic acidosis include:
Poorly controlled diabetes
Ketosis
Prolonged fasting
Excessive alcohol intake
Hepatic impairment
Any condition associated with hypoxia

Treatment should be discontinued 48 hours prior to elective surgery with general, spinal or epidural anaesthesia. Treatment should not usually be resumed earlier than 48 hours after surgery and only after renal function has been re-evaluated and found to be normal.

Pregnancy and Lactation

Pregnancy

Linagliptin with metformin tablets are contraindicated in pregnancy.

There is no adequate data from the use of linagliptin during pregnancy. Animal studies have not shown direct or indirect harmful effects.

Metformin does cross the placenta, although it has not been shown to be teratogenic in the majority of studies. Animal data generally does not indicate harmful effects on pregnancy, embryonic or foetal development, parturition or postnatal development. Data suggests that metformin is low risk in pregnancy.

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/ng3

When diet alone is not successful, insulin is the treatment of choice for both Type 1 and Type 2 diabetes during pregnancy. Hyperglycaemia in the mother, particularly in the early stages of gestation, is associated with a number of foetal and maternal adverse effects, including foetal structural abnormalities. Carefully prescribed insulin therapy will provide better control of the mother's blood glucose thereby preventing the foetal and neonatal complications that occur with the disease (Briggs, 2011).

If the patient plans to become pregnant, or if pregnancy occurs, treatment should be switched to insulin treatment as soon as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.

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

Linagliptin with metformin tablets are contraindicated in breastfeeding.

It is unknown whether linagliptin is excreted in human breast milk. Animal studies have shown excretion of linagliptin and/or metabolite in milk, a risk to the nursing infant cannot be excluded.

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, as a single agent, appears in breast milk at low concentrations and that it is considered compatible for use in breastfeeding mothers.

Insulin therapy should be considered for diabetic patients who wish to breastfeed.

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 patients to report severe, persistent abdominal pain.

Advise patient to report symptoms of low vitamin B12 levels.

Advise patient to avoid consumption of alcohol and alcohol containing medications.

Advise patients that they should not self-medicate with St John's Wort while taking linagliptin with metformin.

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

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
Abnormal liver function tests
Angioedema
Bronchial hyperreactivity
Bullous pemphigoid
Constipation
Cough
Decreased appetite
Decreased vitamin-B12 absorption
Diarrhoea
Elevated amylase levels
Elevated serum lipase
Erythema
Hepatitis
Hypersensitivity reactions
Hypoglycaemia
Lactic acidosis
Megaloblastic anaemia
Nasopharyngitis
Nausea
Pancreatitis
Pruritus
Rash
Taste disturbances
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: July 2015

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 01 July 2015.

Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.

Summary of Product Characteristics. Jentadueto 2.5 mg/850 mg and 2.5 mg/1,000 mg film-coated tablets. Boehringer Ingelheim International GmbH. Revised March 2017.

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: 10 March 2015
Last accessed: 01 July 2015

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
Linagliptin. Last revised: 10 March 2015
Last accessed: 01 July 2015

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