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Diabetes & metabolic

Pioglitazone (pioglitazone)

Pioglitazone is a thiazolidinedione (tzd), insulin sensitiser, ppar-gamma agonist from Takeda Pharmaceutical Company (first US approval 1999), marketed originally as Actos; Actoplus Met and Actoplus Met XR. This monograph covers approved indications, mechanism, dosing, side effects and the manufacturer landscape.

Overview

Pioglitazone is an oral thiazolidinedione (TZD) insulin sensitiser and PPAR-gamma agonist from Takeda Pharmaceutical Company, first approved in the United States in 1999. It is marketed as Actos, with Actoplus Met and Actoplus Met XR as the metformin combinations and Duetact as the glimepiride combination. It is used as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes - as monotherapy in patients not adequately controlled by diet and exercise, or in combination with a sulfonylurea, metformin or insulin when diet, exercise and a single agent do not achieve adequate control. It is not for type 1 diabetes or diabetic ketoacidosis and is not recommended in NYHA Class III or IV heart failure. Pioglitazone carries a boxed warning for congestive heart failure, in place since the FDA action of 14 August 2007: thiazolidinediones can cause or exacerbate heart failure, patients must be observed for rapid weight gain, dyspnoea and oedema after initiation and after each dose increase, and the drug is contraindicated in NYHA Class III or IV cardiac status. Dosing starts at 15 mg or 30 mg once daily and may be increased in 15 mg increments to a maximum of 45 mg once daily; in NYHA Class I or II heart failure therapy starts at 15 mg with careful monitoring. Pioglitazone is off patent and widely manufactured.

How it works

Pioglitazone makes the body more sensitive to its own insulin. It activates a receptor in fat and muscle cells that turns on genes involved in handling glucose, so the liver releases less sugar and muscle takes more of it up. Because it needs some insulin to work, it is used in type 2 diabetes rather than type 1.

Thiazolidinedione that acts as an agonist at the peroxisome proliferator-activated receptor gamma (PPAR-gamma, predominantly the PPAR-gamma1 isoform). Activation increases transcription of insulin-responsive genes involved in glucose uptake and lipid metabolism, increases peripheral insulin sensitivity, and reduces hepatic gluconeogenesis, lowering fasting and postprandial glucose and HbA1c. It also shifts fluid balance, which produces dose-related plasma volume expansion and peripheral oedema, and is the reason for the heart failure warning.

Approved indications

  • As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
  • As monotherapy in patients not adequately controlled by diet and exercise
  • In combination with a sulfonylurea, metformin, or insulin when diet, exercise and a single agent do not achieve adequate control
  • Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis
  • Not recommended in patients with NYHA Class III or IV heart failure (not studied pre-approval at these stages)

Dosage & administration

Start 15 mg or 30 mg orally once daily as monotherapy in patients not adequately controlled by diet and exercise, or when adding to an existing regimen where the patient is not controlled on a single agent. The dose may be increased in increments of 15 mg up to a maximum of 45 mg once daily. In patients with congestive heart failure (NYHA Class I or II), start at 15 mg once daily and titrate in increments of 15 mg with careful monitoring for weight gain, oedema or signs of cardiac failure.

Dose adjustment

Renal impairment: no dose adjustment recommended - the serum elimination half-life of pioglitazone and its active metabolites M-III and M-IV is unchanged in moderate (CrCl 30-60 mL/min) to severe (CrCl less than 30 mL/min) renal impairment. Hepatic impairment: use with caution and monitor liver tests; avoid in active liver disease. Heart failure: only for NYHA Class I-II, starting at 15 mg with close monitoring; contraindicated in NYHA Class III-IV. Allow three months of therapy before judging HbA1c response unless glycaemic control deteriorates.

Side effects

Peripheral oedema and fluid retention - dose related, the most characteristic adverse effect · Weight gain · Upper respiratory tract infection · Bronchitis · Anemia (small dose-related fall in haemoglobin/haematocrit) · Hypoglycemia, particularly in combination with insulin or a sulfonylurea · Headache, myalgia

Serious reactions to watch for
  • Congestive heart failure - may cause or worsen CHF (boxed warning)
  • Increased risk of bladder cancer suggested by observational data - warning in the label
  • Increased risk of bone fracture, particularly in women
Boxed warning

Congestive heart failure - thiazolidinediones, including pioglitazone, cause or exacerbate congestive heart failure in some patients. After initiation and after dose increases, observe patients carefully for signs and symptoms of heart failure (excessive, rapid weight gain, dyspnea, and/or edema) and manage heart failure according to current standards of care if these develop. Pioglitazone is not recommended in patients with symptomatic heart failure and is contraindicated in NYHA Class III or IV cardiac status. (Boxed warning in place since the FDA action of 14 August 2007.)

Monitoring

  • Signs and symptoms of heart failure after initiation and after each dose increase - rapid weight gain, dyspnea, oedema
  • Body weight and oedema at each visit; dose reduction or discontinuation if weight gain or oedema develops
  • HbA1c - reassess after about three months of therapy
  • Liver function tests before and during treatment (active liver disease is a reason to avoid the drug)
  • Fasting blood glucose / self-monitored blood glucose
  • Haemoglobin and haematocrit (small expected fall)
  • Symptoms suggesting bladder cancer - haematuria, dysuria, urinary urgency; do not use in active bladder cancer
  • Signs of hypoglycemia when combined with insulin or a secretagogue
  • Bone health and fracture risk, particularly in women

Generic and biosimilar landscape

Actos (Takeda) is the innovator reference product in 15 mg, 30 mg and 45 mg tablets; pioglitazone is off patent and generics are approved in the US, India and Bangladesh. Because TZDs are highly bioequivalent-sensitive with a narrow tolerability profile (fluid retention), generics should be substituted only where the local regulator has approved them as bioequivalent to the reference product. Bangladeshi and Indian products are locally registered (DGDA / CDSCO) rather than FDA or EMA approved; compare the strength, since the local market has far more 15 mg and 30 mg products than 45 mg.

Who makes it

ManufacturerCountryBrandStrengthNotes
UniMed UniHealth Pharmaceuticals Ltd. Bangladesh Actose 15 mg, 30 mg Most commonly listed Bangladeshi pioglitazone brand on MedEx
The IBN SINA Pharmaceutical PLC Bangladesh Glitazon 15 mg Listed on MedEx with the data
Incepta Pharmaceuticals Ltd. Bangladesh Piodar 15 mg Listed on MedEx with the data
ACME Laboratories Ltd. Bangladesh Pidus 15 mg Listed on MedEx with the data
Pacific Pharmaceuticals Ltd. Bangladesh Piglit 15 mg Listed on MedEx with the data
Drug International Ltd. Bangladesh Piozena 15 mg, 30 mg Listed on MedEx with the data
Medimet Pharmaceuticals Ltd. Bangladesh Diapiotab 15 mg, 30 mg Listed on MedEx with the data
United Pharmaceuticals Ltd. Bangladesh Pizzi 15 mg Lowest-the datad Bangladeshi brand found on MedEx
USV Private Limited India Pioz 15 mg, 30 mg, 45 mg Listed on 1mg with the data
Sun Pharmaceutical Industries Ltd. India Pioglit / Pioglar 15 mg, 30 mg Listed on 1mg with the data
Torrent Pharmaceuticals Ltd. India Piopod 15 mg, 30 mg Listed on 1mg with the data
Lupin Ltd. India Path 15 mg, 30 mg, 45 mg Listed on 1mg with the data
Mankind Pharma Ltd. India Piokind 15 mg, 30 mg Listed on 1mg with the data
Ipca Laboratories Ltd. India Piomed 15 mg, 30 mg Listed on 1mg with the data
Eris Lifesciences Ltd. India Glitaris 15 mg, 30 mg, 45 mg Listed on 1mg with the data

Availability in Southeast Asia

CountryStatusNotes
BangladeshAvailable - widespread local manufacturing (17 brand/strength entries found) and no originator Actos listing on MedExLocal tablets expense about -15 each; 15 mg is the dominant strength, with 30 mg available from several companies
IndonesiaApproved and marketed (pioglitazone listed as a generic)MIMS Indonesia carries a pioglitazone generic monograph with dosage, elimination half-life and excretion data
PhilippinesNot verified in this passCheck FDA Philippines registered products before publishing
MalaysiaNot verified in this passCheck NPRA Quest3+ product search
VietnamNot verified in this passCheck DAV registration database
ThailandNot verified in this passCheck Thai FDA registration database

Frequently asked questions

What is pioglitazone used for and how does it work?

Pioglitazone is approved for: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; As monotherapy in patients not adequately controlled by diet and exercise; In combination with a sulfonylurea, metformin, or insulin when diet, exercise and a single agent do not achieve adequate control; Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis; Not recommended in patients with NYHA Class III or IV heart failure (not studied pre-approval at these stages). It is a pioglitazone (Thiazolidinedione), originally marketed as Actos; Actoplus Met and Actoplus Met XR (with metformin) and Duetact (with glimepiride) are the originator combinations by Takeda Pharmaceutical Company (first US approval 1999).

Why does pioglitazone have a boxed warning for heart failure?

Pioglitazone (Thiazolidinedione (TZD), insulin sensitiser, PPAR-gamma agonist, originally Actos; Actoplus Met and Actoplus Met XR (with metformin) and Duetact (with glimepiride) are the originator combinations by Takeda Pharmaceutical Company (first US approval 1999)) Pioglitazone makes the body more sensitive to its own insulin. It activates a receptor in fat and muscle cells that turns on genes involved in handling glucose, so the liver releases less sugar and muscle takes more of it up. Because it needs some insulin to work, it is used in type 2 diabetes rather than type 1. Start 15 mg or 30 mg orally once daily as monotherapy in patients not adequately controlled by diet and exercise, or when adding to an existing regimen where the patient is not controlled on a single agent. The dose may be increased in increments of 15 mg up to a maximum of 45 mg once daily. In patients with congestive heart failure (NYHA Class I or II), start at 15 mg once daily and titrate in in

What is the usual starting dose of pioglitazone and what is the maximum dose?

Standard dosing for pioglitazone: Start 15 mg or 30 mg orally once daily as monotherapy in patients not adequately controlled by diet and exercise, or when adding to an existing regimen where the patient is not controlled on a single agent. The dose may be increased in increments of 15 mg up to a maximum of 45 mg once daily. In patients with congestive heart failure (NYHA Class I or II), start at 15 mg once daily and titrate in increments of 15 mg with careful monitoring for weight gain, oedema or signs of cardiac failure. Dose adjustments: Renal impairment: no dose adjustment recommended - the serum elimination half-life of pioglitazone and its active metabolites M-III and M-IV is unchanged in moderate (CrCl 30-60 mL/min) to severe (CrCl less than 30 mL/min) renal impairment. Hepatic impairment: use with caution and monitor liver tests; avoid in active liver disease. Heart failure: only for NYHA Class I-II, starting at 15 mg with close monitoring; contraindicated in NYHA Class III-IV. Allow three months of therapy before judging HbA1c response unless glycaemic control deteriorates.

Does pioglitazone cause weight gain or swelling?

Pioglitazone (Thiazolidinedione (TZD), insulin sensitiser, PPAR-gamma agonist, originally Actos; Actoplus Met and Actoplus Met XR (with metformin) and Duetact (with glimepiride) are the originator combinations by Takeda Pharmaceutical Company (first US approval 1999)) Pioglitazone makes the body more sensitive to its own insulin. It activates a receptor in fat and muscle cells that turns on genes involved in handling glucose, so the liver releases less sugar and muscle takes more of it up. Because it needs some insulin to work, it is used in type 2 diabetes rather than type 1. Start 15 mg or 30 mg orally once daily as monotherapy in patients not adequately controlled by diet and exercise, or when adding to an existing regimen where the patient is not controlled on a single agent. The dose may be increased in increments of 15 mg up to a maximum of 45 mg once daily. In patients with congestive heart failure (NYHA Class I or II), start at 15 mg once daily and titrate in in

Is pioglitazone linked to bladder cancer?

Pioglitazone (Thiazolidinedione (TZD), insulin sensitiser, PPAR-gamma agonist, originally Actos; Actoplus Met and Actoplus Met XR (with metformin) and Duetact (with glimepiride) are the originator combinations by Takeda Pharmaceutical Company (first US approval 1999)) Pioglitazone makes the body more sensitive to its own insulin. It activates a receptor in fat and muscle cells that turns on genes involved in handling glucose, so the liver releases less sugar and muscle takes more of it up. Because it needs some insulin to work, it is used in type 2 diabetes rather than type 1. Start 15 mg or 30 mg orally once daily as monotherapy in patients not adequately controlled by diet and exercise, or when adding to an existing regimen where the patient is not controlled on a single agent. The dose may be increased in increments of 15 mg up to a maximum of 45 mg once daily. In patients with congestive heart failure (NYHA Class I or II), start at 15 mg once daily and titrate in in

Can pioglitazone be used in patients with kidney disease?

Pioglitazone (Thiazolidinedione (TZD), insulin sensitiser, PPAR-gamma agonist, originally Actos; Actoplus Met and Actoplus Met XR (with metformin) and Duetact (with glimepiride) are the originator combinations by Takeda Pharmaceutical Company (first US approval 1999)) Pioglitazone makes the body more sensitive to its own insulin. It activates a receptor in fat and muscle cells that turns on genes involved in handling glucose, so the liver releases less sugar and muscle takes more of it up. Because it needs some insulin to work, it is used in type 2 diabetes rather than type 1. Start 15 mg or 30 mg orally once daily as monotherapy in patients not adequately controlled by diet and exercise, or when adding to an existing regimen where the patient is not controlled on a single agent. The dose may be increased in increments of 15 mg up to a maximum of 45 mg once daily. In patients with congestive heart failure (NYHA Class I or II), start at 15 mg once daily and titrate in in

How long does pioglitazone take to work?

Pioglitazone makes the body more sensitive to its own insulin. It activates a receptor in fat and muscle cells that turns on genes involved in handling glucose, so the liver releases less sugar and muscle takes more of it up. Because it needs some insulin to work, it is used in type 2 diabetes rather than type 1. Technically: Thiazolidinedione that acts as an agonist at the peroxisome proliferator-activated receptor gamma (PPAR-gamma, predominantly the PPAR-gamma1 isoform). Activation increases transcription of insulin-responsive genes involved in glucose uptake and lipid metabolism, increases peripheral insulin sensitivity, and reduces hepatic gluconeogenesis, lowering fasting and postprandial glucose and HbA1c. It also shifts fluid balance, which produces dose-related plasma volume expansion and peripheral oedema, and is the reason for the heart failure warning.

Is pioglitazone safe to take with insulin or metformin?

Pioglitazone (Thiazolidinedione (TZD), insulin sensitiser, PPAR-gamma agonist, originally Actos; Actoplus Met and Actoplus Met XR (with metformin) and Duetact (with glimepiride) are the originator combinations by Takeda Pharmaceutical Company (first US approval 1999)) Pioglitazone makes the body more sensitive to its own insulin. It activates a receptor in fat and muscle cells that turns on genes involved in handling glucose, so the liver releases less sugar and muscle takes more of it up. Because it needs some insulin to work, it is used in type 2 diabetes rather than type 1. Start 15 mg or 30 mg orally once daily as monotherapy in patients not adequately controlled by diet and exercise, or when adding to an existing regimen where the patient is not controlled on a single agent. The dose may be increased in increments of 15 mg up to a maximum of 45 mg once daily. In patients with congestive heart failure (NYHA Class I or II), start at 15 mg once daily and titrate in in

Is generic pioglitazone as good as Actos?

Actos (Takeda) is the innovator reference product in 15 mg, 30 mg and 45 mg tablets; pioglitazone is off patent and generics are approved in the US, India and Bangladesh. Because TZDs are highly bioequivalent-sensitive with a narrow tolerability profile (fluid retention), generics should be substituted only where the local regulator has approved them as bioequivalent to the reference product. Bangladeshi and Indian products are locally registered (DGDA / CDSCO) rather than FDA or EMA approved; compare the strength, since the local market has far more 15 mg and 30 mg products than 45 mg. Manufacturers supplying pioglitazone generic versions include ACME Laboratories Ltd. , Drug International Ltd. , Eris Lifesciences Ltd. , Incepta Pharmaceuticals Ltd. , Ipca Laboratories Ltd. , Lupin Ltd. , Mankind Pharma Ltd. , Medimet Pharmaceuticals Ltd. . Brands registered in Bangladesh include Actose, Diapiotab, Diatus, Glitazon, Lit, Ogli.

Which patients should not take pioglitazone?

Pioglitazone (Thiazolidinedione (TZD), insulin sensitiser, PPAR-gamma agonist, originally Actos; Actoplus Met and Actoplus Met XR (with metformin) and Duetact (with glimepiride) are the originator combinations by Takeda Pharmaceutical Company (first US approval 1999)) Pioglitazone makes the body more sensitive to its own insulin. It activates a receptor in fat and muscle cells that turns on genes involved in handling glucose, so the liver releases less sugar and muscle takes more of it up. Because it needs some insulin to work, it is used in type 2 diabetes rather than type 1. Start 15 mg or 30 mg orally once daily as monotherapy in patients not adequately controlled by diet and exercise, or when adding to an existing regimen where the patient is not controlled on a single agent. The dose may be increased in increments of 15 mg up to a maximum of 45 mg once daily. In patients with congestive heart failure (NYHA Class I or II), start at 15 mg once daily and titrate in in

Sources

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021073s034lbl.pdf
  2. https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21073lbl.pdf
  3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21073s024lbl.pdf
  4. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2ddc491-88a9-4063-9150-443b4fa4330c
  5. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/021073orig1s043s044-021842orig1s014s015-022024orig1s008s007-021925orig1s010s011ltr.pdf
  6. https://www.patientcareonline.com/view/boxed-heart-failure-warning-added-two-diabetes-drugs
  7. https://www.takeda.com/newsroom/newsreleases/2014/takeda-announces-completion-of-the-post-marketing-commitment-to-submit-data-to-the-fda-the-ema-and-the-pmda-for-pioglitazone-containing-medicines-including-actos
  8. https://medex.com.bd/generics/888/pioglitazone/brand-names
  9. https://www.1mg.com/generics/pioglitazone-211310
  10. https://www.mims.com/indonesia/drug/info/pioglitazone?mtype=generic
  11. https://my.clevelandclinic.org/health/drugs/19069-pioglitazone-tablets
  12. https://www.drugwatch.com/actos
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