Drugs List

Therapeutic Indications

Uses

Combination treatment of Type 2 diabetes with insulin
Control of type-2 diabetes if metformin+sulfonylurea therapy is inadequate
Monotherapy for type2 diabetes if overweight and metformin inappropriate
Oral combination treatment of type 2 diabetes

Monotherapy
Treatment of type 2 diabetes mellitus patients (particularly when overweight) inadequately controlled by diet and exercise and for whom metformin is inappropriate due to contraindication or intolerance.

Dual oral therapy
Treatment of type 2 diabetes mellitus in combination with:

metformin, in patients (particularly obese patients) with insufficient glycaemic control despite maximal tolerated dose of oral metformin monotherapy;
sulfonylurea, in patients for whom metformin is contraindicated or who are intolerant to metformin, with insufficient glycaemic control despite maximal tolerated dose of oral sulfonylurea monotherapy.

Triple oral therapy
Treatment of type 2 diabetes mellitus in combination with metformin and a sulfonylurea, in patients (particularly obese patients) with insufficient glycaemic control despite dual oral therapy.

Combination with insulin
Treatment of type 2 diabetes mellitus, in patients with insufficient glycaemic control on insulin alone and who are intolerant of, or contraindicated for metformin.

Contraindications

Children under 18 years
Elevated serum transaminases - greater than 2.5 times upper limit of normal
Acute porphyria
Bladder carcinoma
Breastfeeding
Cardiac failure
Diabetic ketoacidosis
Galactosaemia
Hepatic impairment
History of bladder carcinoma
History of cardiac failure
Pregnancy
Uninvestigated haematuria

Precautions and Warnings

Elderly
Coronary arteriosclerosis
Glucose-galactose malabsorption syndrome
Lactose intolerance
Myocardial infarction
Poor cardiac reserve

Exclude bladder carcinoma before treatment
Contains lactose
Oral anti-diabetics should be omitted on the morning of surgery
Assess risk of bladder cancer before treatment
Perform liver function tests before commencing therapy and during therapy
If hepatic impairment symptoms occur monitor LFT & consider discontinuation
If visual disturbances occur, perform ophthalmic evaluation
Investigate macroscopic haematuria
Monitor liver function if anorexia,nausea,vomiting,abdominal pain develop
Monitor liver function if fatigue or dark urine occurs
Monitor patient's weight
Monitor patients for signs and symptoms of cardiac failure
Review treatment 3-6 months after initiation
Treatment is associated with a reduction in haemoglobin levels
Advise patient to report bloody/cloudy/strong smelling or dark urine
Advise patient to report unexplained nausea,vomiting,abdominal pain
Discontinue if any deterioration in cardiac status occurs
Increased incidence of fracture during pioglitazone therapy
Discontinue at first signs of jaundice
Discontinue if ALT level exceed 3 times the upper limit of normal & persist
Discontinue if patient is attempting to conceive
Pregnancy confirmed: Change patient to insulin treatment
Ovulation may resume in patients anovulatory due to insulin resistance
Advise patients to adhere to a strict calorie-controlled diet
Advise patients to report bloody urine, dysuria or urinary urgency
Patient to inform DVLA if fitness to drive impaired or hypoglycaemic risk

Cases of cardiac failure have been reported when pioglitazone and insulin are used in combination, especially in patients with a high risk of development of cardiac failure. If this combination is used, patients should be observed for symptoms of heart failure, weight gain and oedema.

There is some disagreement between reference sources as to whether pioglitazone is porphyrinogenic. The majority of sources suggest that pioglitazone should not be used in patients with acute porphyria.

Liver enzymes should be monitored at baseline and then periodically based on clinical judgement. If ALT levels are increased to 3 times the upper limit of normal during pioglitazone therapy, liver enzymes should be reassessed as soon as possible. If ALT levels remain greater than 3 times the upper limit of normal, therapy should be discontinued. Patients showing any signs of hepatic dysfunction such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine should have their liver enzymes checked. A decision whether to continue therapy with pioglitazone should be guided by clinical judgement pending laboratory evaluations.

Pregnancy and Lactation

Pregnancy

Pioglitazone is contraindicated in pregnancy.

Foetal growth restriction has been observed in animal studies; however, at the time of writing no reports of pioglitazone use in human pregnancy have been located.

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

When dieting alone is not successful, 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

Pioglitazone is contraindicated in breastfeeding.

At the time of writing, there are no reports of the use of pioglitazone during breastfeeding. It is unknown whether pioglitazone is secreted in human milk, although evidence provided by studies on rats suggest this may be possible.

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

Anaemia
Anaphylaxis
Angioedema
Arthralgia
Back pain
Bladder cancer
Bronchitis
Cardiac failure
Creatine phosphokinase increased
Dizziness
Dyspnoea
Erectile dysfunction
Fatigue
Flatulence
Glycosuria
Haematuria
Headache
Hepatotoxicity
Hypoaesthesia
Hypoglycaemia
Impotence
Increase in HDL cholesterol
Increase in total cholesterol
Increased appetite
Increased risk of fractures
Increases in hepatic enzymes
Insomnia
Macular oedema
Oedema
Proteinuria
Sinusitis
Sweating
Upper respiratory tract infection
Urticaria
Vertigo
Visual disturbances
Weight gain

Presentation

Oral formulations of pioglitazone

Drugs List

Therapeutic Indications

Uses

Combination treatment of Type 2 diabetes with insulin
Control of type-2 diabetes if metformin+sulfonylurea therapy is inadequate
Monotherapy for type2 diabetes if overweight and metformin inappropriate
Oral combination treatment of type 2 diabetes

Monotherapy
Treatment of type 2 diabetes mellitus patients (particularly when overweight) inadequately controlled by diet and exercise and for whom metformin is inappropriate due to contraindication or intolerance.

Dual oral therapy
Treatment of type 2 diabetes mellitus in combination with:

metformin, in patients (particularly obese patients) with insufficient glycaemic control despite maximal tolerated dose of oral metformin monotherapy;
sulfonylurea, in patients for whom metformin is contraindicated or who are intolerant to metformin, with insufficient glycaemic control despite maximal tolerated dose of oral sulfonylurea monotherapy.

Triple oral therapy
Treatment of type 2 diabetes mellitus in combination with metformin and a sulfonylurea, in patients (particularly obese patients) with insufficient glycaemic control despite dual oral therapy.

Combination with insulin
Treatment of type 2 diabetes mellitus, in patients with insufficient glycaemic control on insulin alone and who are intolerant of, or contraindicated for metformin.

Dosage

Treatment should be started with the lowest available dose and then dose can be increased gradually, particularly when pioglitazone is used in combination with insulin.

Adults

Elderly

Contraindications

Children under 18 years
Elevated serum transaminases - greater than 2.5 times upper limit of normal
Acute porphyria
Bladder carcinoma
Breastfeeding
Cardiac failure
Diabetic ketoacidosis
Galactosaemia
Hepatic impairment
History of bladder carcinoma
History of cardiac failure
Pregnancy
Uninvestigated haematuria

Precautions and Warnings

Elderly
Coronary arteriosclerosis
Glucose-galactose malabsorption syndrome
Lactose intolerance
Myocardial infarction
Poor cardiac reserve

Exclude bladder carcinoma before treatment
Contains lactose
Oral anti-diabetics should be omitted on the morning of surgery
Assess risk of bladder cancer before treatment
Perform liver function tests before commencing therapy and during therapy
If hepatic impairment symptoms occur monitor LFT & consider discontinuation
If visual disturbances occur, perform ophthalmic evaluation
Investigate macroscopic haematuria
Monitor liver function if anorexia,nausea,vomiting,abdominal pain develop
Monitor liver function if fatigue or dark urine occurs
Monitor patient's weight
Monitor patients for signs and symptoms of cardiac failure
Review treatment 3-6 months after initiation
Treatment is associated with a reduction in haemoglobin levels
Advise patient to report bloody/cloudy/strong smelling or dark urine
Advise patient to report unexplained nausea,vomiting,abdominal pain
Discontinue if any deterioration in cardiac status occurs
Increased incidence of fracture during pioglitazone therapy
Discontinue at first signs of jaundice
Discontinue if ALT level exceed 3 times the upper limit of normal & persist
Discontinue if patient is attempting to conceive
Pregnancy confirmed: Change patient to insulin treatment
Ovulation may resume in patients anovulatory due to insulin resistance
Advise patients to adhere to a strict calorie-controlled diet
Advise patients to report bloody urine, dysuria or urinary urgency
Patient to inform DVLA if fitness to drive impaired or hypoglycaemic risk

Cases of cardiac failure have been reported when pioglitazone and insulin are used in combination, especially in patients with a high risk of development of cardiac failure. If this combination is used, patients should be observed for symptoms of heart failure, weight gain and oedema.

There is some disagreement between reference sources as to whether pioglitazone is porphyrinogenic. The majority of sources suggest that pioglitazone should not be used in patients with acute porphyria.

Liver enzymes should be monitored at baseline and then periodically based on clinical judgement. If ALT levels are increased to 3 times the upper limit of normal during pioglitazone therapy, liver enzymes should be reassessed as soon as possible. If ALT levels remain greater than 3 times the upper limit of normal, therapy should be discontinued. Patients showing any signs of hepatic dysfunction such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine should have their liver enzymes checked. A decision whether to continue therapy with pioglitazone should be guided by clinical judgement pending laboratory evaluations.

Pregnancy and Lactation

Pregnancy

Pioglitazone is contraindicated in pregnancy.

Foetal growth restriction has been observed in animal studies; however, at the time of writing no reports of pioglitazone use in human pregnancy have been located.

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

When dieting alone is not successful, 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

Pioglitazone is contraindicated in breastfeeding.

At the time of writing, there are no reports of the use of pioglitazone during breastfeeding. It is unknown whether pioglitazone is secreted in human milk, although evidence provided by studies on rats suggest this may be possible.

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 female patients with polycystic ovary syndrome that there is an increased risk of pregnancy with this treatment as ovulation may resume. Adequate contraception should be used and they should seek medical advice if they wish to become pregnant or if pregnancy is suspected.

Patients should be advised to adhere to a strict calorie-controlled diet.

Patients should be advised to report any deterioration in visual acuity to their physician and an appropriate ophthalmic referral should be considered.

Advise patients to report blood in urine, painful urination or urinary urgency to their doctor immediately.

Advise patient to report any unexplained nausea, vomiting or abdominal pain.

No effects on ability to drive or use machinery have been observed. If patients experience any visual disturbances they should avoid driving or operating any machinery.

Inform the patient that he/she needs to inform the Driving and Vehicle Licensing Agency (DVLA) about the medication they are receiving. The Drivers Medical Group at the DVLA will be able to advise the patient on the legal issues surrounding the treatment of diabetes mellitus and driving.

The DVLA can be contacted by post at the following address:

Drivers Medical Group, DVLA, Swansea, SA99 1TU

By phone on 0870 600 0301; or by fax on 0845 850 0095

Detailed guidance on eligibility to drive, and precautions required, is available from the DVLA.

https://www.gov.uk/government/publications/at-a-glance

Further information concerning diabetes and driving may be obtained from the DVLA website at:

https://www.gov.uk/government/organisations/driver-and-vehicle-licensing-agency

Side Effects

Anaemia
Anaphylaxis
Angioedema
Arthralgia
Back pain
Bladder cancer
Bronchitis
Cardiac failure
Creatine phosphokinase increased
Dizziness
Dyspnoea
Erectile dysfunction
Fatigue
Flatulence
Glycosuria
Haematuria
Headache
Hepatotoxicity
Hypoaesthesia
Hypoglycaemia
Impotence
Increase in HDL cholesterol
Increase in total cholesterol
Increased appetite
Increased risk of fractures
Increases in hepatic enzymes
Insomnia
Macular oedema
Oedema
Proteinuria
Sinusitis
Sweating
Upper respiratory tract infection
Urticaria
Vertigo
Visual disturbances
Weight gain

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: March 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 16 March 2015.

Martindale: The Complete Drug Reference (online) London: Brayfield A (ed). Pharmaceutical Press. Accessed on 25 March 2015.

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

Summary of Product Characteristics: Actos tablets. Takeda UK Ltd. Revised June 2014.

Summary of Product Characteristics: Glidipion 15 mg tablets. Actavis UK Ltd. Revised December 2013.
Summary of Product Characteristics: Glidipion 30 mg tablets. Actavis UK Ltd. Revised December 2013.
Summary of Product Characteristics: Glidipion 45 mg tablets. Actavis UK Ltd. Revised December 2013.

Summary of Product Characteristics: Pioglitazone 15 mg tablets. Dr. Reddy's Laboratories (UK) Ltd. Revised August 2014.
Summary of Product Characteristics: Pioglitazone 30 mg tablets. Dr. Reddy's Laboratories (UK) Ltd. Revised August 2014.
Summary of Product Characteristics: Pioglitazone 45 mg tablets. Dr. Reddy's Laboratories (UK) Ltd. Revised August 2014.

The Renal Drug Handbook. Fourth Edition (2014) ed. Ashley, C and Dunleavy, A, Radcliffe Publishing Ltd, London.

MHRA Drug Safety Update August 2011
Available at: https://www.mhra.gov.uk
Last accessed: 18 March 2015

The Welsh Medicines Information Centre (WMIC) - Porphyria Information Service.
Available at: https://www.wmic.wales.nhs.uk/porphyria_info.php
Last revised: April 2014
Last accessed: 26 March 2015

The Norwegian Porphyria Centre (NAPOS).
Available at: https://www.drugs-porphyria.com/languages/UnitedKingdom/s1.php?l=gbr
Last revised: 16 May 2013
Last accessed: 26 March 2015