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Pioglitazone with metformin oral


Tablets containing pioglitazone with metformin

Drugs List

  • COMPETACT film coated tablets
  • pioglitazone 15mg and metformin 850mg tablets
  • Therapeutic Indications


    Oral combination treatment of type 2 diabetes

    Treatment of type 2 diabetes mellitus patients, particularly overweight patients, who have been unsuccessful in maintaining sufficient glycaemic control at their maximally tolerated dose of oral metformin monotherapy.



    The usual starting dose is 30 mg/day pioglitazone and 1700 mg/day metformin hydrochloride (given as one tablet containing 15 mg pioglitazone and 850 mg metformin hydrochloride twice daily).


    The usual starting dose is 30 mg/day pioglitazone and 1700 mg/day metformin hydrochloride (given as one tablet containing 15 mg pioglitazone and 850 mg metformin hydrochloride twice daily).

    Patients with Renal Impairment

    Dose for renally impaired patients is determined by Glomerular Filtration Rate (GFR). 60 to 89 GFR ml/minute Metformin: Maximum daily dose is 3000 mg. Dose reduction may be considered in relation to declining renal function. Pioglitazone: No dose adjustment. Maximum daily dose is 45 mg. 45 to 59 GFR ml/minute Metformin: Maximum daily dose is 2000 mg. The starting dose is at most half of the maximum dose. Pioglitazone: No dose adjustment. Maximum daily dose is 45 mg. 30 to 44 GFR ml/minute Metformin: Maximum daily dose is 1000 mg. The starting dose is at most half of the maximum dose. Pioglitazone: No dose adjustment. Maximum daily dose is 45 mg.

    Additional Dosage Information

    Before initiating combined treatment, consider dose titration with pioglitazone, added to the optimal dose of metformin.

    Where clinically appropriate a direct switch from metformin monotherapy may be considered.

    When used in combination with a sulfonylurea, a lower dose of the sulfonylurea may be required to reduce the risk of hypoglycaemia.


    Acute alcohol intoxication
    Children under 18 years
    Elevated serum transaminases - greater than 2.5 times upper limit of normal
    Hypovolaemic shock
    Severe infection
    Bladder carcinoma
    Cardiac failure
    Diabetic pre-coma
    Hepatic impairment
    History of bladder carcinoma
    History of cardiac failure
    Recent myocardial infarction
    Renal impairment - glomerular filtration rate below 30ml/minute
    Respiratory failure
    Uninvestigated haematuria

    Precautions and Warnings

    Polycystic ovarian syndrome
    Poor cardiac reserve
    Renal impairment - glomerular filtration rate 30 to 59 ml/minute

    Not suitable for treatment of diabetic ketoacidosis
    Reduce dose in patients with moderate renal impairment
    Advise patient to take precautions to avoid hypoglycaemia whilst driving
    Exclude bladder carcinoma before treatment
    No experience with triple combination therapy with other oral antidiabetics
    Test vit B12 levels if deficiency is suspected or risk factors are present
    Assess risk of bladder cancer before treatment
    Exclude pregnancy prior to initiation of treatment
    Monitor renal function prior to initiating treatment
    Perform liver function tests before commencing therapy and during therapy
    If visual disturbances occur, perform ophthalmic evaluation
    Investigate macroscopic haematuria
    Monitor for development of lactic acidosis
    Monitor liver function if fatigue or dark urine occurs
    Monitor patient's weight
    Monitor patients for signs and symptoms of cardiac failure
    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
    Review treatment 3-6 months after initiation
    Treatment is associated with a reduction in haemoglobin levels
    Advise patient to report symptoms of low vitamin B12 levels
    Discontinue if any deterioration in cardiac status occurs
    Increased incidence of fracture during pioglitazone therapy
    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 patient is attempting to conceive
    Pregnancy confirmed: Change patient to insulin treatment
    Advise patient to avoid alcohol during treatment
    Ovulation may resume in patients anovulatory due to insulin resistance
    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 was used in combination with insulin, especially in patients with risk factors for cardiac failure. If this combination is prescribed, patients should be observed for symptoms of heart failure, including weight gain and oedema. Pioglitazone should be discontinued if there is any deterioration in cardiac symptoms.

    Pioglitazone may cause fluid retention which may exacerbate or precipitate cardiac failure. Monitor patients for signs of cardiac failure, particularly those with diminished cardiac reserve. Discontinue if there is any deterioration in cardiac function.

    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. A diagnosis of lactic acidosis should be considered in the presence of non-specific symptoms such as muscle cramps, digestive disorders, abdominal pain or severe asthenia. 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.

    Patients who develop laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis occurs treatment with pioglitazone with metformin must be stopped immediately and other appropriate corrective measures initiated.

    Intravascular administration of iodinated contrast agents can lead to renal failure which has been associated with lactic acidosis in patients receiving metformin. Pioglitazone with metformin therapy should be discontinued prior to, or at the time of the test and not reinstated until 48 hours afterwards and only after renal function has been re-evaluated and found to be normal.

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

    Pregnancy and Lactation


    Pioglitazone with metformin is contraindicated in pregnancy.

    Insufficient information available relating to the use of pioglitazone during human pregnancy. Animal studies have shown foetotoxicity but no teratogenic effects of pioglitazone.

    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

    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 ( ) or if this is unavailable at the backup site ( ).


    Pioglitazone with metformin is contraindicated in breastfeeding.

    In animal studies both pioglitazone and metformin have been detected in the milk of lactating rats.

    At the time of writing, there are no reports of the use of pioglitazone during breastfeeding.

    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


    Taking this product with or shortly after food may help reduce gastrointestinal discomfort associated with oral metformin.

    Remind patients that adherence to a calorie controlled diet is an essential part of their treatment.

    Advise patients with polycystic ovarian syndrome that ovulation may occur as a result of improved insulin action. These patients should be made aware of the risk of pregnancy and advised to use appropriate contraception.

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

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

    Advise patient to report symptoms of low vitamin B12 levels.

    Patients should avoid alcohol.

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

    Advise patient to take precautions to avoid hypoglycaemia when driving.

    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.

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

    Side Effects

    Abdominal pain
    Allergic reaction
    Altered liver function tests
    Bladder cancer
    Blood lipid changes
    Decreased appetite
    Decreased vitamin-B12 absorption
    Erectile dysfunction
    Fluid retention
    Hepatic impairment
    Hypersensitivity reactions
    Increased risk of fractures
    Lactic acidosis
    Macular oedema
    Taste disturbances
    Upper respiratory tract infection
    Visual disturbances
    Weight gain


    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 ( ) or if this is unavailable at the backup site ( ).

    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 10 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: Competact 15 mg/850 mg film-coated tablets. Takeda UK Ltd. Revised December 2016.

    US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
    Available at:
    Pioglitazone. Last revised: 07 September 2013
    Metformin. Last revised: 07 September 2013
    Last accessed: 08 October 2014

    MHRA August 2011
    Last accessed: 10 October 2014

    EMA Safety Update December 2016
    Available at:
    Last accessed: 18 January 2017

    MHRA Drug Safety Update June 2022
    Available at:
    Last accessed: 21 July 2022

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