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
Brands: Actos
Special Alerts:
[Posted 09/17/2010] ISSUE: FDA notified healthcare professionals and patients that the Agency is reviewing data from an ongoing, ten-year epidemiological study designed to evaluate whether pioglitazone (Actos) is associated with an increased risk of bladder cancer. Findings from studies in animals and humans suggest this is a potential safety risk that needs further study. At this time, FDA has not concluded that pioglitazone increases the risk of bladder cancer. Its review is ongoing, and the Agency will update the public when it has additional information.
BACKGROUND: The drug manufacturer, Takeda, conducted a planned analysis of the study data at the five-year mark, and submitted their results to FDA. Overall, there was no statistically significant association between pioglitazone exposure and bladder cancer risk. However, further analyses were also performed looking at how long patients were on pioglitazone and the total amount of the drug they received during that time. An increased risk of bladder cancer was observed among patients with the longest exposure to pioglitazone, as well as in those exposed to the highest cumulative dose of pioglitazone.
RECOMMENDATIONS: Healthcare professionals should continue to follow the recommendations in the drug label when prescribing pioglitazone. Patients should continue taking pioglitazone unless told otherwise by their healthcare professional. Patients who are concerned about the possible risks associated with using pioglitazone should talk to their healthcare professional.
Additional Information for Patients, Information for Healthcare Professionals, and a Data Summary are provided in the Drug Safety Communication. For more information visit the FDA website at: and .
[Posted 08/14/2007] After a review of postmarketing adverse event reports, FDA determined that an updated label with a boxed warning on the risks of heart failure was needed for the entire thiazolidinedione class of antidiabetic drugs. These drugs are used in conjunction with diet and exercise to improve blood sugar control in adults with type 2 (non-insulin-dependent) diabetes. Manufacturers of certain drugs have agreed to the upgraded warning.
The strengthened warning advises healthcare professionals to observe patients carefully for the signs and symptoms of heart failure, including excessive, rapid weight gain, shortness of breath, and edema after starting drug therapy. Patients with these symptoms who then develop heart failure should receive appropriate management of the heart failure and use of the drug should be reconsidered. People who have questions should contact their healthcare providers to discuss alternative treatments. For more information visit the FDA website at: , , and .
[Posted 03/09/2007] Takeda and FDA notified healthcare professionals of recent safety data concerning pioglitazone-containing products. The results of an analysis of the manufacturer’s clinical trial database of pioglitazone showed more reports of fractures in female patients taking pioglitazone than those taking a comparator (either placebo or active). The majority of fractures observed in female patients were in the distal upper limb (forearm, hand and wrist) or distal lower limb (foot, ankle, fibula and tibia). There were more than 8100 patients in the pioglitazone-treated groups and over 7400 patients in the comparator-treated groups. The duration of pioglitazone treatment was up to 3.5 years. Healthcare professionals should consider the risk of fracture when initiating or treating female patients with type 2 diabetes mellitus with pioglitazone-containing products. For more information visit the FDA website at: and .
REMS:
FDA approved a REMS for pioglitazone to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of pioglitazone and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().
Introduction
Antidiabetic agent; thiazolidinedione (glitazone).1 8 9 12
Uses for Pioglitazone Hydrochloride
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Diabetes Mellitus
Used alone or in combination with a sulfonylurea, metformin, or insulin as an adjunct to diet and exercise for the management of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM).1 2 Should be added to, not substituted for, other antidiabetic agents in patients whose NIDDM is not adequately controlled by these agents.13
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; insulin is necessary.1
Pioglitazone Hydrochloride Dosage and Administration
Administration
Oral Administration
Administer orally once daily without regard to meals.1
Dosage
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Available as pioglitazone hydrochloride; dosage expressed in terms of pioglitazone.1
Adults
Diabetes Mellitus
Monotherapy
Oral
Initially, 15 or 30 mg once daily.1 If response is inadequate, increase dosage in increments, up to a maximum dosage of 45 mg daily.1 If response is inadequate with monotherapy, consider combination therapy.1
Combination with Other Antidiabetic Agents
Oral
May continue current dosage of the sulfonylurea, metformin, or insulin upon initiation of pioglitazone.1
Combination therapy with a sulfonylurea: Initially, 15 or 30 mg once daily.1 If hypoglycemia occurs, reduce sulfonylurea dosage.1
Combination therapy with metformin: Initially, 15 or 30 mg once daily.1 Adjustment of metformin dosage unlikely.1
Combination therapy with insulin: Initially, 15 or 30 mg once daily.1 If hypoglycemia occurs or if fasting plasma glucose (FPG) concentrations decrease to <100 mg/dL, decrease insulin dosage by 10–25%.1 Further adjustments should be individualized based on therapeutic response.1
Prescribing Limits
Adults
Maximum 45 mg daily (as monotherapy or in combination with a sulfonylurea, metformin, or insulin).1
Special Populations
Renal Impairment
No dosage adjustment necessary.1
Geriatric Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
No dosage adjustment necessary.1
CHF
Should be initiated at the lowest approved dosage in patients with type 2 diabetes and systolic CHF (NYHA class II).1 If subsequent dosage escalation is necessary, increase dosage gradually only after several months of treatment.1 Monitor carefully for weight gain, edema, or other manifestations of CHF exacerbation.1 Use not recommended in patients with more severe CHF (NYHA class III or IV).1
Cautions for Pioglitazone Hydrochloride
Contraindications
Known hypersensitivity to pioglitazone or any ingredient in the formulation.1
Warnings/Precautions
Warnings
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Effects on Fluid Balance
Risk of fluid retention; may cause or exacerbate heart failure.1 13 Weight gain reported, possibly associated with fluid retention and fat accumulation.1
Use with caution in patients with edema.1 Observe for manifestations of heart failure (e.g., dyspnea, rapid weight gain, edema) and discontinue therapy if any deterioration in cardiac status occurs.1 Use not recommended in patients with New York Heart Association (NYHA) class III or IV heart failure.1
General Precautions
Ovulatory Effects
Possible ovulation in premenopausal anovulatory women; risk of pregnancy unless contraceptive measures initiated.1
Hematologic Effects
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
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
Specific Populations
Pregnancy
Category C.1 Most clinicians recommend that insulin be used during pregnancy.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.1 12
Common Adverse Effects
Upper respiratory tract infection, headache, sinusitis, myalgia, tooth disorder, aggravation of diabetes mellitus, pharyngitis, edema.1
Interactions for Pioglitazone Hydrochloride
Metabolized principally by CYP2C8 and, to a lesser extent, by CYP3A4 and other isoenzymes (e.g., CYP1A1).1 Weak inducer of CYP3A4.1
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 | |
Ketoconazole | Increased serum concentrations and AUC for pioglitazone13 | |
Midazolam | Decreased midazolam concentrations1 | |
Nifedipine, extended-release | Decreased peak nifedipine concentrations and AUC1 | Clinical importance unknown1 |
Oral contraceptives, hormonal (ethinyl estradiol and norethindrone) | Decreased ethinyl estradiol concentrations1 | Clinical importance unknown1 |
Ranitidine | Pharmacokinetic interaction unlikely1 | |
Theophylline | Pharmacokinetic interaction unlikely1 | |
Warfarin | Pharmacokinetic or pharmacologic interaction (e.g., effect on PT) unlikely1 |
Pioglitazone Hydrochloride Pharmacokinetics
Absorption
Bioavailability
Peak serum concentrations attained within 2 hours.1
Absolute bioavailability is 83%.a
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
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Importance of adhering to diet and exercise regimen.1 Importance of regular monitoring (preferably self-monitoring) of blood glucose and HbA1c.1
Importance of immediately informing clinician if potential manifestations of heart failure (e.g., rapid weight gain, edema, shortness of breath) occur.1
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) occur.1
Risk of hypoglycemia in patients receiving concomitant antidiabetic agent 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 Advise patients to utilize effective contraception during therapy.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 15 mg | Actos | Takeda |
30 mg | Actos | Takeda | ||
45 mg | Actos | Takeda |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. 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/$135.99 or 90/$385.98
Actoplus Met 15-850MG Tablets (TAKEDA PHARMACEUTICALS): 30/$135.99 or 90/$385.98
Actoplus met XR 15-1000MG 24-hr Tablets (TAKEDA PHARMACEUTICALS): 30/$145.45 or 90/$415.57
Actoplus met XR 30-1000MG 24-hr Tablets (TAKEDA PHARMACEUTICALS): 30/$280.99 or 90/$800.00
Actos 15MG Tablets (TAKEDA PHARMACEUTICALS): 30/$179.98 or 90/$515.96
Actos 30MG Tablets (TAKEDA PHARMACEUTICALS): 30/$273.98 or 90/$799.99
Actos 45MG Tablets (TAKEDA PHARMACEUTICALS): 30/$289.99 or 90/$849.97
Duetact 30-2MG Tablets (TAKEDA PHARMACEUTICALS): 30/$274.29 or 90/$796.86
Duetact 30-4MG Tablets (TAKEDA PHARMACEUTICALS): 30/$255.58 or 90/$712.75
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
1. Takeda Pharmaceuticals America. Actos (pioglitazone hydrochloride) tablets prescribing information. Lincolnshire, IL; 2004 July.
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]
4. Parke-Davis. Rezulin (troglitazone) tablets prescribing information. Morris Plains, NJ; 1998 Jul.
5. Parke-Davis. Rezulin (troglitazone) tablets prescribing information. Morris Plains, NJ; 1999 Jun.
6. Sigmund WR II. Dear health professional letter regarding important prescribing information for Rezulin. Morris Plains: Parke-Davis. (undated)
7. Anon. New labeling and use changes for Rezulin. FDA Talk Paper. Rackville, MD: Food and Drug Administration; 1999 Jun 16.
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 peroxisonal 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]
11. Tanis SP, Parker TT, Colca JR et al. Synthesis and biological activity of metabolites of the antidiabetic, antihyperglycemic agent pioglitazone. J Med Chem. 1996; 39:5053-63. [PubMed 8978836]
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.
18. Kipnes MS, Krosnick A, Rendell MS et al. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med. 2001; 111:10-7. [IDIS 467740] [PubMed 11448655]
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 rations accurately predicts S-warfarin AUC during basline 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 vitor and in vivo inhibition of cytochrome P450 CYP1A2, CYP2Dg, and CYP3A4 by H2-receptor antagonists. Clin Pharmacol Ther. 1999; 65:369-76. [PubMed 10223772]
26. Bachmann K, White D, Jauregui L et al. An evaluation of the dose-dependent inhibition of CYP1A2 by rofecoxib using theophylline as a CYP1A2 probe. J Clin Pharmacol. 2003; 43:1082-90. [IDIS 505406] [PubMed 14517190]
a. Hanefeld M. Pharmcokinetics and clinical efficacy of pioglitazone. Int J Clin Pract Suppl. 2001; 121:19-25. [PubMed 11594240]
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- Pioglitazone Hydrochloride Drug Interactions
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