Generic Name: Pioglitazone Hydrochloride
Class: Thiazolidinediones
ATC Class: A10BG03
VA Class: HS502
Chemical Name: (±)-5-[p-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione monohydrochloride
Molecular Formula: C19H20N2O3S•ClH
CAS Number: 112529-15-4

Warning(s)

  • CHF
  • Thiazolidinediones, including pioglitazone, cause or exacerbate CHF in some patients.1 27 28 Monitor for signs and symptoms of CHF (e.g., dyspnea, rapid and excessive weight gain, edema) after initiation of therapy and dosage titration.1 27 28 If CHF develops, manage disorder according to current standards of care; consider discontinuance or reduction in dosage of pioglitazone.1 27 28

  • Not recommended in patients with symptomatic CHF.1 27 28

  • Initiation of pioglitazone contraindicated in patients with NYHA class III or IV CHF.1 27 28 (See CHF under Cautions.)

REMS:

FDA approved a REMS for pioglitazone to ensure that the benefits outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antidiabetic agent; thiazolidinedione (glitazone).1 8 9 12

Uses for Actos

Diabetes Mellitus

Used alone or in combination with a sulfonylurea, metformin, or insulin as an adjunct to diet and exercise to improve glycemic control in patients with type 2 (noninsulin-dependent) diabetes mellitus (NIDDM).1 2 14 27 28 Should be added to, not substituted for, other antidiabetic agents in patients whose NIDDM is not adequately controlled by these agents.13

Slideshow: Can Prescription Drugs Lead to Weight Gain?

May be added to glyburide/metformin fixed combination therapy if hyperglycemia is not adequately controlled with the fixed combination.14 May be used in combination with repaglinide if hyperglycemia is not adequately controlled with diet, exercise, and monotherapy with another oral antidiabetic agent.17

Not effective as sole therapy for type 1 diabetes mellitus or diabetic ketoacidosis.1

Actos Dosage and Administration

Administration

Oral Administration

Administer pioglitazone once daily without regard to meals.1

Administer fixed combination of pioglitazone and immediate-release metformin hydrochloride (ActoPlus Met) once or twice daily with meals to reduce the GI effects of metformin component.27

Administer fixed combination of pioglitazone and extended-release metformin hydrochloride (ActoPlus Met XR) once daily with the evening meal to reduce GI effects of metformin component.27

Administer fixed combination of pioglitazone and glimepiride (Duetact) once daily with the first main meal.28

Dosage

Available as pioglitazone hydrochloride; dosage expressed in terms of pioglitazone.1

Initiation or discontinuance of a CYP2C8 inducer during pioglitazone therapy may necessitate changes in antidiabetic therapy.1 (See Interactions.)

If a potent CYP2C8 inhibitor is used concomitantly, reduction of the maximum daily pioglitazone dosage is recommended.1 (See Interactions.)

Adults

Diabetes Mellitus
Monotherapy
Oral

Initially, 15 or 30 mg once daily.1 If response inadequate, increase dosage gradually up to maximum of 45 mg daily.1

Allow sufficient time (8–12 weeks) to evaluate adequacy of response as determined by HbA1c unless glycemic control based on fasting plasma glucose deteriorates.27

Pioglitazone/Immediate-release Metformin Hydrochloride Fixed-combination Therapy (ActoPlus Met)
Oral

Base initial dosage of fixed combination on patient's current dosage of pioglitazone and/or immediate-release metformin hydrochloride and on usual initial dosages of these drugs.27

Initially, 15 mg of pioglitazone and 500 or 850 mg of immediate-release metformin hydrochloride once or twice daily.27

Gradually titrate dosage based on adequacy of therapeutic response.27 Allow sufficient time (8–12 weeks) to evaluate adequacy of response as determined by HbA1c unless glycemic control based on fasting plasma glucose deteriorates.27

Pioglitazone/Extended-release Metformin Hydrochloride Fixed-combination Therapy (ActoPlus Met XR)
Oral

Base initial dosage of fixed combination on patient's current dosage of pioglitazone and/or extended-release metformin hydrochloride and on usual initial dosages of these drugs.27

Initially, 15 or 30 mg of pioglitazone and 1 g of extended-release metformin hydrochloride once daily.1

Gradually titrate dosage based on adequacy of therapeutic response.27 Allow sufficient time (8–12 weeks) to evaluate adequacy of response as determined by HbA1c unless glycemic control based on fasting plasma glucose deteriorates.27

Pioglitazone/Glimepiride Fixed-combination Therapy (Duetact)
Oral

Base initial dosage of fixed combination on patient's current dosage of pioglitazone and/or sulfonylurea (e.g., glimepiride).28

Patients currently receiving glimepiride monotherapy: Initially, 30 mg of pioglitazone and 2 or 4 mg of glimepiride once daily.28

Patients currently receiving pioglitazone monotherapy: Initially, 30 mg of pioglitazone and 2 mg of glimepiride once daily.28

Patients switching from combined therapy with separate pioglitazone and glimepiride preparations: Usual initial dosage of the fixed combination is the same as the patient's existing dosage of the individual drugs.28 When switching to the fixed combination, carefully monitor patients with inadequate glycemic control on pioglitazone 15 mg daily in combination with glimepiride.28

Patients switching from monotherapy with a sulfonylurea other than glimepiride (e.g., glyburide, glipizide, chlorpropamide, tolbutamide, acetohexamide) or from combined therapy with pioglitazone plus a sulfonylurea other than glimepiride: Initially, 30 mg of pioglitazone and 2 mg of glimepiride once daily; no exact dosage relationship exists between glimepiride and other sulfonylureas.28

Gradually titrate dosage based on adequacy of therapeutic response.28 Allow sufficient time (8–12 weeks) to evaluate adequacy of response as determined by HbA1c unless glycemic control based on fasting plasma glucose deteriorates.28

Prescribing Limits

Adults

Maximum 45 mg daily (as monotherapy or in combination with a sulfonylurea, metformin, or insulin).1 27 28

Special Populations

Hepatic Impairment

Monotherapy

No dosage adjustment necessary.1

Pioglitazone/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Do not initiate in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).27

Pioglitazone/Glimepiride Fixed-combination Therapy

Initially, glimepiride 1 mg daily as monotherapy, followed by conservative initial and maintenance dosages of the fixed combination; individuals with hepatic impairment may be particularly sensitive to the hypoglycemic effects of glimepiride.28

Do not initiate in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).28

Renal Impairment

Monotherapy

No dosage adjustment necessary.1

Pioglitazone/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Do not use in patients with renal impairment.27

Pioglitazone/Glimepiride Fixed-combination Therapy

Initially, glimepiride 1 mg daily as monotherapy, followed by conservative initial and maintenance dosages of the fixed combination; individuals with renal impairment may be particularly sensitive to the hypoglycemic effects of glimepiride.28

Geriatric Patients

Monotherapy

No dosage adjustment necessary.1

Pioglitazone/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Conservative initial and maintenance dosages recommended; geriatric individuals are particularly sensitive to hypoglycemic effects.27 Generally, do not titrate to maximum recommended dosage.27

Pioglitazone/Glimepiride Fixed-combination Therapy

Initially, glimepiride 1 mg daily as monotherapy, followed by conservative initial and maintenance dosages of the fixed combination; geriatric individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.28

Patients with CHF

NYHA class III or IV: Use contraindicated.1 27 28

Monotherapy

NYHA class I or II: Initially, 15 mg once daily.1 Increase dosage gradually, if needed, up to maximum of 45 mg daily based on HbA1c concentrations.1 Monitor carefully for weight gain, edema, or other manifestations of CHF exacerbation following initiation and dosage increase.1

Pioglitazone/Glimepiride Fixed-combination Therapy

Systolic dysfunction: Initially, pioglitazone 15 mg once daily as monotherapy; safely titrate dosage to 30 mg once daily as monotherapy before initiating the fixed combination of glimepiride 2 mg and pioglitazone 30 mg.28 If subsequent dosage adjustment is necessary with the fixed-combination preparation, monitor closely for weight gain, edema, or other manifestations of CHF exacerbation.28

Debilitated or Malnourished Patients

Pioglitazone/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Generally, do not titrate to maximum recommended dosage; these individuals are particularly susceptible to hypoglycemic effects.27

Pioglitazone/Glimepiride Fixed-combination Therapy

Initially, glimepiride 1 mg daily as monotherapy, followed by conservative initial and maintenance dosages of the fixed combination; these individuals are particularly susceptible to hypoglycemic effects.28

Patients with Adrenal or Pituitary Insufficiency

Pioglitazone/Glimepiride Fixed-combination Therapy

Initially, glimepiride 1 mg daily as monotherapy, followed by conservative initial and maintenance dosages of the fixed combination; these individuals are particularly susceptible to hypoglycemic effects.28

Cautions for Actos

Contraindications

  • Initiation of therapy in patients with NYHA class III or IV CHF.1 27 28 (See Boxed Warning.)

  • Known serious1 hypersensitivity to pioglitazone or any ingredient in the formulation.1 27 28

Warnings/Precautions

Warnings

CHF

Fluid retention associated with use of pioglitazone, alone or in combination with other antidiabetic agents, may lead to or exacerbate CHF.1 19 27 28 30 31 37 38 40 41 (See Boxed Warning.) Use in combination with insulin or in patients with NYHA class I or II heart failure may increase the risk.1

Monitor for signs and symptoms of heart failure (e.g., dyspnea, rapid weight gain, edema, unexplained cough or fatigue), especially during initiation of therapy and dosage titration.1 19 27 28 37 40

If heart failure develops, manage according to current standards of care.1 19 27 28 37 40 Consider dosage reduction or discontinuance of pioglitazone.1 19 27 28 37 40

Do not initiate thiazolidinedione therapy in hospitalized patients with diabetes mellitus because of delayed onset of action and potential for increased vascular volume and CHF.34

Edema

Fluid retention reported; may lead to or exacerbate heart failure.1 13

Use with caution in patients with edema and in those at risk for CHF.1 27 Observe for manifestations of heart failure (e.g., dyspnea, rapid weight gain, edema).1 (See CHF under Cautions.)

Weight Gain

Reported; may involve fluid retention and fat accumulation.1 (See Boxed Warning.)

Other Warnings/Precautions

Hepatic Effects

No evidence of hepatotoxicity in clinical studies to date.1 12 13 However, hepatitis, elevations in hepatic enzymes, mixed hepatocellular-cholestatic liver injury,15 and, very rarely, hepatic failure associated with fatalities reported during postmarketing experience.1

Monitor liver function tests prior to initiation of therapy, then periodically thereafter according to clinician judgment.1 12 Monitor more frequently if used in patients with mild hepatic impairment (ALT 1–2.5 times the upper limit of normal [ULN]).1 (See Hepatic Impairment under Cautions.)

Recheck liver function if ALT increases to >3 times the ULN or if manifestations suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine) occur.1 Discontinue therapy if ALT remains elevated at >3 times the ULN or if jaundice develops.1

Musculoskeletal Effects

Risk of bone loss and fractures in women, and possibly in men, receiving thiazolidinedione therapy.1 29 35 36 39 47 50

Fractures reported more frequently in women receiving pioglitazone (5.1%) than in women receiving placebo (2.5%) in long-term study (mean 34.5 months follow-up).1 27 28 30 32 33 Effects noted after first year of treatment and persisted throughout treatment.1 27 28 30 32 33 Most fractures were nonvertebral, occurring in a distal limb (forearm, hand, wrist, foot, ankle, fibula, tibia).1 27 28 29

In an observational study, use of pioglitazone or rosiglitazone for approximately 12–18 months associated with twofold to threefold increase in fractures, particularly of hip and wrist.50 Overall risk of fracture similar among men and women.50

Consider risk of fracture, particularly in female patients.1 29 35 Assess and maintain bone health according to current standards of care.1 28 29 30 32 33 35

Risk of Bladder Cancer

Increased risk of bladder cancer.1 27 28 Do not use in patients with active bladder cancer; use with caution in patients with history of bladder cancer, weighing benefits of glycemic control against unknown risks of cancer recurrence.1 27 28 80

Hypoglycemia

Concomitant use of insulin or other antidiabetic drugs (e.g., insulin secretagogues) increases risk for hypoglycemia.1 27 28 May need to reduce dosage of concomitant antidiabetic agent to decrease risk of hypoglycemia.1 27 28 (See Dosage under Dosage and Administration.)

Ocular Effects

New-onset or worsening (diabetic) macular edema with decreased visual acuity reported rarely; concurrent peripheral edema reported frequently.1 27 28 32 33 Symptoms improved in some patients following discontinuance of pioglitazone.1 27 28 32 33

Regular eye examinations by ophthalmologist advised.1 27 28 32 33 34 Promptly refer patients reporting visual symptoms to ophthalmologist, regardless of other concurrent therapy or physical findings.1 27 28 32 33

Ovulatory Effects

May cause ovulation in premenopausal anovulatory women; risk of pregnancy unless adequate contraceptive measures initiated.1

Macrovascular Outcomes

Evidence of macrovascular risk reduction with pioglitazone or any other antidiabetic agent has not been conclusively demonstrated in controlled clinical trials.1

Laboratory Abnormalities

Possible dose-related decreases in hemoglobin and hematocrit; usually evident within 4–12 weeks of therapy.1 May be related to plasma volume expansion.1 Rarely associated with clinically important hematologic manifestations.1

Isolated elevations in serum CK >10 times ULN noted rarely during clinical trials.1 Resolved in most patients without apparent sequelae despite continued therapy with the drug; any relationship to pioglitazone therapy unknown.1

Use of Fixed Combinations

When used in fixed combination with metformin hydrochloride or glimepiride, consider the cautions, precautions, and contraindications associated with the concomitant agent.27 28

Specific Populations

Pregnancy

Category C.1 Most clinicians recommend that insulin be used during pregnancy in women with diabetes mellitus.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use not recommended.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age; use not recommended.1 13

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1

Hepatic Impairment

Use with caution in patients with mild hepatic impairment (ALT 1–2.5 times the ULN).1 12 Use not recommended in patients with active hepatic disease, ALT >2.5 times the ULN, or troglitazone-associated jaundice (troglitazone no longer commercially available in US).1 12

Common Adverse Effects

Upper respiratory tract infection, headache, sinusitis, myalgia, pharyngitis, edema.1

Interactions for Actos

Metabolized principally by CYP2C8 and, to a lesser extent, by CYP3A4 and other isoenzymes (e.g., CYP1A1).1 Weak inducer of CYP3A4.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP2C8 inhibitors: Increased pioglitazone AUC and half-life; do not exceed maximum pioglitazone dosage of 15 mg once daily.1

CYP2C8 inducers: Decreased pioglitazone AUC.1 Initiation or discontinuance of a CYP2C8 inducer during pioglitazone therapy may necessitate changes in antidiabetic therapy; however, do not exceed maximum recommended pioglitazone dosage of 45 mg daily.1

Specific Drugs

Drug

Interaction

Comments

Antidiabetic agents

Additive effects; possible hypoglycemia1

May need to reduce dosage of other antidiabetic agents1

Atorvastatin

Decreased plasma concentrations and AUC for atorvastatin and pioglitazone1

Digoxin

Pharmacokinetic interaction unlikely1

Fexofenadine

Pharmacokinetic interaction unlikely1

Gemfibrozil

Increased pioglitazone AUC and half-life1 27

Do not exceed maximum pioglitazone dosage of 15 mg once daily

Ketoconazole

Increased serum concentrations and AUC for pioglitazone1 13 27

Midazolam

Decreased midazolam AUC and peak plasma concentrations1

Nifedipine, extended-release

Decreased peak plasma nifedipine concentrations and AUC1

Clinical importance unknown1

Oral contraceptives, hormonal (ethinyl estradiol/norethindrone)

Small decreases in peak plasma ethinyl estradiol concentrations and AUC1

Clinical importance unknown1

Ranitidine

Pharmacokinetic interaction unlikely1

Rifampin

Decreased pioglitazone AUC1 27

May require change in antidiabetic therapy if rifampin initiated or discontinued during pioglitazone therapy, but do not exceed maximum pioglitazone dosage of 45 mg daily1 27

Theophylline

Pharmacokinetic interaction unlikely1

Warfarin

Pharmacokinetic or pharmacologic interaction (e.g., effect on PT) unlikely1

Actos Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations attained within 2 hours.1

Absolute bioavailability is 83%.81

Food

Food delays time to peak serum concentration to 3–4 hours but does not affect extent of absorption.1

Special Populations

In patients with hepatic impairment (Child-Pugh class B or C), peak pioglitazone concentration is decreased by 45%.1

In geriatric patients, AUC of pioglitazone is increased; not clinically relevant.1

In females, peak serum concentration and AUC are increased by 20–60%.1

Distribution

Extent

Distributed into milk in rats.1 Not known whether the drug distributes into human milk.1

Plasma Protein Binding

>99% (mainly albumin).1

Elimination

Metabolism

Extensively metabolized, principally by CYP2C8 and, to a lesser extent, by CYP3A4 and other isoenzymes (e.g., CYP1A1).1

Elimination Route

Excreted in urine (15–30%) and in feces, primarily as metabolites.1

Half-life

3–7 hours (for pioglitazone) or 16–24 hours (for pioglitazone and metabolites).1

Special Populations

In geriatric patients, terminal half-life is prolonged; not clinically relevant.1

Stability

Storage

Oral

Tablets

Tight containers at 25°C (may be exposed to 15–30°C).1 Protect from moisture and humidity.1

Actions

  • Structurally and pharmacologically related to rosiglitazone and troglitazone (no longer commercially available in the US);1 8 9 1 12 unrelated to other antidiabetic agents (e.g., sulfonylureas, biguanides, α-glucosidase inhibitors).1 12

  • A peroxisome proliferator-activated receptorγ (PPARγ) agonist; increases transcription of insulin-responsive genes.1

  • Increases insulin sensitivity in target tissues and decreases hepatic gluconeogenesis.1 Ameliorates insulin resistance associated with type 2 diabetes mellitus without increasing insulin secretion from pancreatic β cells.1 Does not lower glucose concentrations below euglycemia.1

  • Ineffective in absence of insulin.1

Advice to Patients

  • Importance of reading medication guide provided by manufacturer before starting pioglitazone and each time prescription is refilled.1

  • Importance of informing patients of potential risks and advantages of therapy and of alternative therapies.28

  • Discuss potential for alterations in dosage requirements during periods of stress (e.g., fever, trauma, infection, surgery); importance of contacting a clinician promptly.1 27

  • Importance of informing patients that pioglitazone must not be used in patients with severe heart failure (NYHA class III or IV).1 Importance of immediately informing clinician if potential manifestations of heart failure (e.g., rapid weight gain, edema, unusual fatigue, trouble breathing, shortness of breath) occur.1 27 28

  • Importance of informing patients that liver function tests will be performed prior to initiation of therapy and periodically thereafter.1 (See Hepatic Effects under Cautions.) Advise patients to inform clinician if potential manifestations of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine, yellowing of skin or whites of eyes) occur.1 27 28

  • Increased risk of bladder cancer.1 27 28 Importance of patient not taking pioglitazone if receiving treatment for bladder cancer.1 27 28 Importance of patient reporting any sign of macroscopic hematuria or symptoms such as dysuria or urinary urgency that develop or increase during pioglitazone treatment.1 27 28

  • Importance of taking exactly as prescribed.1 27 28 If a dose is missed on one day, take the next dose as prescribed unless otherwise instructed by clinician; do not double the dose to make up for the missed dose.1 27 28 Importance of changing dosage with caution and only under medical supervision.27 28 Importance of immediately contacting a clinician or going to the nearest hospital emergency department if accidental overdosage occurs.1

  • Importance of advising patient not to chew, cut, or crush the combination preparation containing pioglitazone and extended-release metformin hydrochloride (ActoPlus Met XR); must swallow this dosage form whole.27 Advise patients that biologically inert components of the extended-release combination tablet may occasionally be eliminated in feces as a soft mass that may resemble original tablet.27

  • Risk of hypoglycemia in patients receiving concomitant insulin or other antidiabetic therapy.1 Provide instructions regarding management of hypoglycemia, including recognition of symptoms, predisposing conditions, and treatment.1

  • Risk of pregnancy in premenopausal anovulatory women.1 27 28 Advise patients to utilize effective contraception during therapy.1 27 28

  • Importance of adhering to diet and exercise regimen.1 Importance of regular monitoring (preferably self-monitoring) of blood glucose and of HbA1c.1 27

  • Risk of fractures (e.g., hand, upper arm, foot) in women.1 50

  • Importance of regular eye examinations.1 Importance of reporting changes in vision.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 27

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 27 28

  • Importance of informing patients of other important precautionary information.1 27 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Pioglitazone Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

15 mg (of pioglitazone)

Actos

Takeda

30 mg (of pioglitazone)

Actos

Takeda

45 mg (of pioglitazone)

Actos

Takeda

Pioglitazone Hydrochloride Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

15 mg (of pioglitazone) with Metformin Hydrochloride 500 mg

Actoplus Met

Takeda

15 mg (of pioglitazone) with Metformin Hydrochloride 850 mg

Actoplus Met

Takeda

30 mg (of pioglitazone) with Glimepiride 2 mg

Duetact

Takeda

30 mg (of pioglitazone) with Glimepiride 4 mg

Duetact

Takeda

Oral

Tablets, extended-release (metformin hydrochloride core)

15 mg (of pioglitazone) with Metformin Hydrochloride 1 g

Actoplus Met XR

Takeda

30 mg (of pioglitazone) with Metformin Hydrochloride 1 g

Actoplus Met XR

Takeda

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Actoplus Met 15-500MG Tablets (TAKEDA PHARMACEUTICALS): 30/$142.99 or 90/$405.97

Actoplus Met 15-850MG Tablets (TAKEDA PHARMACEUTICALS): 30/$142.99 or 90/$409.99

Actoplus met XR 15-1000MG 24-hr Tablets (TAKEDA PHARMACEUTICALS): 30/$158.99 or 90/$456.96

Actoplus met XR 30-1000MG 24-hr Tablets (TAKEDA PHARMACEUTICALS): 30/$309.99 or 90/$906.96

Actos 15MG Tablets (TAKEDA PHARMACEUTICALS): 30/$193.48 or 90/$554.66

Actos 30MG Tablets (TAKEDA PHARMACEUTICALS): 30/$289.98 or 90/$859.99

Actos 45MG Tablets (TAKEDA PHARMACEUTICALS): 30/$310.00 or 90/$907.00

Duetact 30-2MG Tablets (TAKEDA PHARMACEUTICALS): 30/$294.86 or 90/$856.64

Duetact 30-4MG Tablets (TAKEDA PHARMACEUTICALS): 30/$289.98 or 90/$849.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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2. Kawamori R, Matsuhisa M, Kinoshita J et al. Pioglitazone enhances splanchnic glucose uptake as well as peripheral glucose uptake in non-insulin-dependent diabetes mellitus. AD-4833 Clamp-OGL Study Group. Diabetes Res Clin Pract. 1998 Jul;41(1):35-43.

3. Berger J, Bailey P, Biswas C et al. Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-γ: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology. 1996; 137:4189-95. [PubMed 8828476]

8. Young PW, Buckle DR, Cantello BC et al. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma. J Pharmacol Exp Ther. 1998; 284:751-9. [PubMed 9454824]

9. Arakawa K, Inamasu M, Matsumoto M et al. Novel benzoxazol 2,4-thiazolidinediones as potent hypoglycemic agents. Chem Pharm Bull. 1997; 45:1984-93. [PubMed 9433768]

10. Matsuhisa M, Shiz Q, Wan C et al. The effect of pioglitazone on hepatic glucose uptake measured with indirect and direct methods in alloxan-induced diabetic dogs. Diabetes. 1997; 46:224-31. [PubMed 9000698]

12. Anon. Rosiglitazone for type 2 diabetes mellitus. Med Lett Drugs Ther. 1999; 41:71-3. [PubMed 10603986]

13. Takeda Pharmaceuticals North America, Indianapolis, IN: Personal communication.

14. Bristol-Myers-Squibb Company. Glucovance (glyburide and metformin hydrochloride) tablets prescribing information. Princeton, NJ; 2001 Mar.

15. May LD, Lefkowitch JH, Kram MT et al. Mixed hepatocellular-cholestatic liver injury after pioglitazone therapy. Ann Intern Med. 2002; 136:449-52. [IDIS 480334] [PubMed 11900497]

16. American Diabetes Association. Type 2 diabetes in children and adolescents. Pediatrics. 2000; 105:671-80. [IDIS 443594] [PubMed 10699131]

17. Novo Nordisk. Prandin (repaglinide) tablets prescribing information. Princeton, NJ; 2002 Oct.

19. Nesto RW, Bell D, Bonow RO et al for the American Heart Association and American Diabetes Association. AHA/ADA consensus statement: thiazolidinedione use, fluid retention, and congestive heart failure. Circulation. 2003; 108:2941-48. [IDIS 511519] [PubMed 14662691]

20. Kidd RS, Straughn AB, Meyer MC et al. Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics. 1999; 9:71-80. [IDIS 424517] [PubMed 10208645]

21. Bottorf M, Hansen P. Long-term safety of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors: the role of metabolism. Arch Intern Med. 2000; 160:2273-80. [IDIS 453535] [PubMed 10927723]

22. Nowak SN, Edwards DJ, Clarke A et al. Pioglitazone: effect on CYP3A4 activity. J Clin Pharmacol. 2002; 42:1299-1302. [IDIS 492542] [PubMed 12463723]

23. Yeates RA, Scharpf F, Laufen H et al. Screening for cytochrome P450 3a in man: studies with midazolam and nifedipine. J Pharm Pharmacol. 1996; 48:933-4. [IDIS 376297] [PubMed 8910856]

24. Ma JD, Nafziger AN, Kashuba ADM et al. Limited sampling strategy of S-warfarin concentrations, but not warfarin S/R ratios accurately predicts S-warfarin AUC during baseline and inhibition in CYP2C9 extensive metabolizers. J Clin Pharmacol. 2004; 44:570-6. [IDIS 516320] [PubMed 15145963]

25. Martinez C, Albet C, Agundez JAG et al. Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2Dg, and CYP3A4 by H2-receptor antagonists. Clin Pharmacol Ther. 1999; 65:369-76. [PubMed 10223772]

27. Takeda Pharmaceuticals America. Actoplus Met (pioglitazone hydrochloride and metformin hydrochloride) and Actoplus Met XR (pioglitazone hydrochloride and metformin hydrochloride extended-release) tablets prescribing information. Deerfield, IL; 2011 Jul.

28. Takeda Pharmaceuticals America. Duetact (pioglitazone hydrochloride and glimepiride) tablets prescribing information. Deerfield, IL; 2011 Jul.

29. Spanheimer R. Dear healthcare provider letter: Observation of an increased incidence of fractures in female patients who received long-term treatment with Actos (pioglitazone hydrochloride) tablets for type 2 diabetes mellitus. Takeda Pharmaceuticals North America, Inc.; 2007 Mar.

30. GlaxoSmithKline. Avandia (rosiglitazone maleate) tablets prescribing information. Research Triangle Park, NC; 2009 Feb.

31. Dormandy JA, Charbonnel B, Eckland DJ et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005; 366:1279-89. [PubMed 16214598]

32. GlaxoSmithKline. Avandaryl (rosiglitazone maleate and glimepiride) tablets prescribing information. Research Triangle Park, NC; 2008 Dec.

33. GlaxoSmithKline. Avandamet (rosiglitazone maleate and metformin hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2008 Dec.

34. American Diabetes Association. Standards of medical care in diabetes--2009. Diabetes Care. 2009; 32 Suppl 1:S13-61.

35. Cobitz AR. Dear health care provider letter: Clinical trial observation of an increased incidence of fractures in female patients who received long-term treatment with Avandia (rosiglitazone maleate) tablets for type 2 diabetes mellitus. GlaxoSmithKline; 2007 Feb.

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