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Special Alerts
Pioglitazone (Actos®): Ongoing Safety Review: Potential Increased Risk of Bladder Cancer (Update)
June 2011
The U.S. Food and Drug Administration (FDA) has notified healthcare professionals and patients that it is reviewing data from an ongoing, 10-year epidemiological study evaluating if pioglitazone (Actos®) is associated with an increased risk of bladder cancer. In a five-year interim analysis, patients taking pioglitazone for more than one year appeared to be at an increased risk of bladder cancer. The overall risk of bladder cancer was not increased in pioglitazone users, but an increased risk of bladder cancer was associated with patients who had the highest cumulative pioglitazone dose or the longest pioglitazone exposure. The FDA is also aware of an epidemiological study conducted in France which suggests an increased risk of bladder cancer associated with pioglitazone use. The FDA recommends not using pioglitazone in patients who have active bladder cancer and to use caution in patients with a prior history of bladder cancer since the risk of recurrence induced by pioglitazone is unknown.
The FDA will continue to evaluate data from the ongoing, 10-year epidemiological study as well as review findings from the French epidemiologic study. The Agency will update the public when it has additional information.
Any adverse events involving pioglitazone should be reported to the FDA MedWatch program (http://www.fda.gov/MedWatch/report.htm).
For additional information, refer to http://www.fda.gov/Drugs/DrugSafety/ucm259150.htm.
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(pye oh GLI ta zone)
Generic Available (U.S.)
No
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021073s037lbl.pdf, must be dispensed with this medication.
REMS Components
Medication Guide
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Type 2 diabetes mellitus (noninsulin dependent, NIDDM), monotherapy: Adjunct to diet and exercise, to improve glycemic control
Type 2 diabetes mellitus (noninsulin dependent, NIDDM), combination therapy with sulfonylurea, metformin, or insulin: When diet, exercise, and a single agent alone does not result in adequate glycemic control
Pregnancy Risk Factor
C
Pregnancy Considerations
Pioglitazone is classified as pregnancy category C due to adverse effects observed in animal studies. The use of pioglitazone in pregnant women is limited to very few case reports where pregnancy occurred during treatment for polycystic ovarian syndrome (PCOS); details concerning fetal outcomes are limited. Thiazolidinediones may cause ovulation in anovulatory premenopausal women, increasing the risk of pregnancy; adequate contraception in premenopausal women is recommended. Maternal hyperglycemia can be associated with adverse effects in the fetus, including macrosomia, neonatal hyperglycemia, and hyperbilirubinemia; the risk of congenital malformations is increased when the Hb A1c is above the normal range. Diabetes can also be associated with adverse effects in the mother. Poorly-treated diabetes may cause end-organ damage that may in turn negatively affect obstetric outcomes. Physiologic glucose levels should be maintained prior to and during pregnancy to decrease the risk of adverse events in the mother and the fetus. Until additional safety and efficacy data are obtained, the use of oral agents is generally not recommended as routine management of GDM or type 2 diabetes mellitus during pregnancy. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
It is not known if pioglitazone is excreted in breast milk. Breast-feeding is not recommended by the manufacturer.
Contraindications
Hypersensitivity to pioglitazone or any component of the formulation; NYHA Class III/IV heart failure (initiation of therapy)
Canadian labeling: Additional contraindications (not is U.S. labeling): Any stage of heart failure (eg, NYHA Class I, II, III, IV); serious hepatic impairment; pregnancy
Warnings/Precautions
Boxed warnings:
• Heart failure/cardiac effects: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Fractures: Increased incidence of bone fractures in females treated with pioglitazone; majority of fractures occurred in the lower limb and distal upper limb. Consider risk of fracture prior to initiation and during use.
• Heart failure/cardiac effects: [U.S. Boxed Warning]: Thiazolidinediones, including pioglitazone, may cause or exacerbate heart failure; closely monitor for signs and symptoms of heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases. Not recommended for use in any patient with symptomatic heart failure. In the U.S., initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure; if used in patients with NYHA class II (systolic) heart failure, initiate at lowest dosage and monitor closely. In Canada, use is contraindicated in patients with any stage of heart failure (NYHA I, II, III, IV). Use with caution in patients with edema; may increase plasma volume and/or cause fluid retention. Dose reduction or discontinuation is recommended if heart failure suspected.
• Hematologic effects: May decrease hemoglobin/hematocrit; effects may be related to increased plasma volume. Use with caution in patients with anemia.
• Weight gain: Dose-related weight gain observed with use; mechanism unknown but likely associated with fluid retention and fat accumulation.
Disease-related concerns:
• Diabetes, type 1: Mechanism requires the presence of insulin; therefore, use in type 1 diabetes (insulin dependent, IDDM) or diabetic ketoacidosis is not recommended.
• Hepatic impairment: Use with caution in patients with elevated transaminases (AST or ALT); do not initiate in patients with active liver disease of ALT >2.5 times the upper limit of normal at baseline. During therapy, if ALT >3 times the upper limit of normal, reevaluate levels promptly and discontinue if elevation persists or if jaundice occurs at any time during use. Idiosyncratic hepatotoxicity has been reported with another thiazolidinedione agent (troglitazone); avoid use in patients who previously experienced jaundice during troglitazone therapy.
• Macular edema/diabetic retinopathy: Use with caution in patients with pre-existing macular edema or diabetic retinopathy; postmarketing events of new-onset or worsening diabetic macular edema with decreased visual acuity have been reported.
Concurrent drug therapy issues:
• Insulin (Canadian labeling; not in U.S. labeling): Concomitant use with insulin is not indicated.
• Metformin/sulfonylureas (Canadian labeling; not in U.S. labeling): Pioglitazone may be added to metformin or a sulfonylurea (if metformin is contraindicated or not tolerated) if glycemic control is inadequate. The use of triple therapy (pioglitazone in combination with metformin and a sulfonylurea) is not indicated due to increased risks of congestive heart failure and fluid retention.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
• Premenopausal/anovulatory females: Use with caution in premenopausal, anovulatory women; may result in a resumption of ovulation, increasing the risk of pregnancy.
Adverse Reactions
>10%:
Cardiovascular: Edema (5%; in combination trials with sulfonlyureas or insulin, the incidence of edema was as high as 15%)
Respiratory: Upper respiratory tract infection (13%)
1% to 10%:
Cardiovascular: Heart failure (requiring hospitalization; up to 6% in patients with prior macrovascular disease)
Central nervous system: Headache (9%), fatigue (4%)
Hematologic: Anemia (≤2%)
Neuromuscular & skeletal: Myalgia (5%)
Respiratory: Sinusitis (6%), pharyngitis (5%)
<1%: CPK increased, transaminases increased
Frequency not defined: HDL-cholesterol increased, hematocrit/hemoglobin decreased, hypoglycemia (in combination trials with sulfonylureas or insulin), serum triglycerides decreased, weight gain/loss
Postmarketing and/or case reports: Bladder cancer, blurred vision, dyspnea (associated with weight gain and/or edema), fractures (females; usually in distal upper limbs or distal lower limbs), hepatic failure (very rare), hepatitis, macular edema (new onset or worsening), pulmonary edema, rhabdomyolysis, visual acuity decreased
Metabolism/Transport Effects
Substrate of CYP2C8 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C19 (weak), CYP2C8 (moderate), CYP2C9 (weak); Induces CYP3A4 (weak/moderate)
Drug Interactions
ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double aripiprazole dose when initiating concomitant therapy with a CYP3A4 inducer (e.g., carbamazepine). Monitor response and adjust aripiprazole dose as clinically indicated. If CYP3A4 inducer is discontinued, reduce aripiprazole dose to 10-15 mg/day. Risk D: Consider therapy modification
Axitinib: CYP3A4 Inducers (Weakly to Moderately Effective) may decrease the serum concentration of Axitinib. Risk X: Avoid combination
Bile Acid Sequestrants: May decrease the absorption of Antidiabetic Agents (Thiazolidinedione). Risk D: Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
Corticosteroids (Systemic): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
CYP2C8 Inducers (Strong): May increase the metabolism of CYP2C8 Substrates. Risk C: Monitor therapy
CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates. Risk C: Monitor therapy
CYP2C8 Inhibitors (Strong): May decrease the metabolism of CYP2C8 Substrates. Risk D: Consider therapy modification
CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Risk C: Monitor therapy
Deferasirox: May increase the serum concentration of CYP2C8 Substrates. Risk C: Monitor therapy
Gemfibrozil: May decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Risk C: Monitor therapy
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemic Agents. Risk C: Monitor therapy
Hypoglycemic Agents: May enhance the adverse/toxic effect of other Hypoglycemic Agents. Risk C: Monitor therapy
Insulin: May enhance the fluid-retaining effect of Antidiabetic Agents (Thiazolidinedione). Risk C: Monitor therapy
Luteinizing Hormone-Releasing Hormone Analogs: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Pregabalin: May enhance the fluid-retaining effect of Antidiabetic Agents (Thiazolidinedione). Risk C: Monitor therapy
Rifampin: May increase the metabolism of Antidiabetic Agents (Thiazolidinedione). Risk C: Monitor therapy
Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Risk C: Monitor therapy
Somatropin: May diminish the hypoglycemic effect of Antidiabetic Agents. Risk D: Consider therapy modification
Thiazide Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Trimethoprim: May decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Caution with ethanol (may cause hypoglycemia).
Food: Peak concentrations are delayed when administered with food, but the extent of absorption is not affected. Pioglitazone may be taken without regard to meals.
Herb/Nutraceutical: Caution with alfalfa, aloe, bilberry, bitter melon, burdock, celery, damiana, fenugreek, garcinia, garlic, ginger, ginseng (American), gymnema, marshmallow, and stinging nettle (may cause hypoglycemia).
Mechanism of Action
Thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a mechanism of action that is dependent on the presence of insulin for activity. Pioglitazone is a potent and selective agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of nuclear PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism. PPARgamma is abundant in the cells within the renal collecting tubules; fluid retention results from stimulation by thiazolidinediones which increases sodium reabsorption.
Pharmacodynamics/Kinetics
Onset of action: Delayed
Peak effect: Glucose control: Several weeks
Distribution: Vss (apparent): 0.63 L/kg
Protein binding: Pioglitazone >99% and active metabolites >98%; primarily to albumin
Metabolism: Hepatic (99%) via CYP2C8 and 3A4 to both active and inactive metabolites
Half-life elimination: Parent drug: 3-7 hours; Total: 16-24 hours
Time to peak: ~2 hours; delayed with food
Excretion: Urine (15% to 30%) and feces as metabolites
Dosage
Oral:
Adults:
Monotherapy: Initial: 15-30 mg once daily; if response is inadequate, the dosage may be increased in increments up to 45 mg once daily; maximum recommended dose: 45 mg once daily
Combination therapy: Maximum recommended dose: 45 mg/day
With sulfonylureas: Initial: 15-30 mg once daily; dose of sulfonylurea should be reduced if the patient reports hypoglycemia
With metformin: Initial: 15-30 mg once daily; it is unlikely that the dose of metformin will need to be reduced due to hypoglycemia
With insulin: Initial: 15-30 mg once daily; dose of insulin should be reduced by 10% to 25% if the patient reports hypoglycemia or if the plasma glucose falls to <100 mg/dL.
Dosage adjustment in patients with CHF (NYHA Class II) in mono- or combination therapy: Initial: 15 mg once daily; may be increased after several months of treatment, with close attention to heart failure symptoms
Elderly: No dosage adjustment is recommended in elderly patients.
Dosage adjustment in renal impairment: No dosage adjustment is required.
Dosage adjustment in hepatic impairment: Clearance is significantly lower in hepatic impairment (Child-Pugh Grade B/C). Therapy should not be initiated if the patient exhibits active liver disease or increased transaminases (>2.5 times ULN) at baseline. During treatment if ALT levels elevate >3 times ULN, the test should be repeated as soon as possible. If ALT levels remain >3 times ULN or if the patient is jaundiced, therapy should be discontinued.
Administration: Oral
May be administered without regard to meals.
Monitoring Parameters
Hemoglobin A1c, serum glucose; signs and symptoms of heart failure; liver enzymes prior to initiation and periodically during treatment (per clinician judgment). If the ALT is increased to >2.5 times the upper limit of normal, liver function testing should be performed more frequently until the levels return to normal or pretreatment values. Patients with an elevation in ALT >3 times the upper limit of normal should be rechecked as soon as possible. If the ALT levels remain >3 times the upper limit of normal, therapy with pioglitazone should be discontinued. Routine ophthalmic exams are recommended; patients reporting visual deterioration should have a prompt referral to an ophthalmologist and consideration should be given to discontinuing pioglitazone.
Reference Range
Recommendations for glycemic control in adults with diabetes:
Hb A1c: <7%
Preprandial capillary plasma glucose: 70-130 mg/dL
Peak postprandial capillary blood glucose: <180 mg/dL
Dietary Considerations
Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) should include diet control. May be taken without regard to meals.
Patient Education
May be taken without regard to meals. Avoid or use caution with alcohol while taking this medication. If dose is missed, take as soon as possible. If dose is missed completely one day, do not double dose the next day. Follow dietary, exercise, and glucose monitoring instructions of prescriber (more frequent monitoring may be advised in periods of stress, trauma, surgery, increased exercise). Report respiratory infection, unusual weight gain, aggravation of hyper-/hypoglycemic condition, unusual swelling of extremities, shortness of breath, fatigue, yellowing of skin or eyes, dark urine, pale stool, nausea/vomiting, abdominal pain, or muscle pain.
Geriatric Considerations
Intensive glucose control (HbA1c <6.5%) has been linked to increased all-cause and cardiovascular mortality, hypoglycemia requiring assistance, and weight gain in adult type 2 diabetes. How "tightly" to control a geriatric patient's blood glucose needs to be individualized. Such a decision should be based on several factors, including the patient's functional and cognitive status, how well he/she recognizes hypoglycemic or hyperglycemic symptoms, and how to respond to them and other disease states. An HbA1c <7.5% is an acceptable endpoint for a healthy older adult, while <8% is acceptable for frail elderly patients, those with a duration of illness >10 years, or those with comorbid conditions and requiring combination diabetes medications. Patients who are unable to accurately draw up their dose will need assistance, such as prefilled syringes. Initial doses may require considerations for renal function in the elderly with dosing adjusted subsequently based on blood glucose monitoring. For elderly patients with diabetes who are relatively healthy, attaining target goals for aspirin use, blood pressure, lipids, smoking cessation, and diet and exercise may be more important than normalized glycemic control.
Cardiovascular Considerations
The thiazolidinediones are peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists used to treat type 2 diabetes. Their actions ameliorate insulin resistance. Pioglitazone, in clinical trials, has not been shown to negatively affect cardiovascular risk.
The PROACTIVE study is a randomized, double-blind, placebo-controlled study of type 2 diabetes with macrovascular disease (Dormandy, 2005). Patients received either placebo or pioglitazone (45 mg/day). The primary endpoint included all-cause mortality, nonfatal MI, stroke, ACS, and a variety of CV interventions. The secondary endpoint was all-cause mortality, nonfatal MI, and stroke. Over 5000 patients were enrolled and followed for a mean of 2.8 years. The secondary endpoint was achieved in 301 (12.3%) of pioglitazone patients and 358 (14.4%) of placebo patients. Pioglitazone significantly reduced (p = 0.02; CI 0.72-0.98) the incidence of all-cause mortality, nonfatal MI, and stroke in this population. The incidence of edema without heart failure (HF), HF, and weight gain were increased in the pioglitazone group. Confirmation of this trial is necessary.
In general, clinicians should not use thiazolidinediones with an expectation to reduce ischemic heart disease events. No data exists to support one thiazolidinedione over another. In addition, thiazolidinediones should not be initiated in patients with class III/IV HF due to an increased risk of HF exacerbation (Kaul, 2010).
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Tooth disorder. Pioglitazone-dependent diabetics should be appointed for dental treatment in morning in order to minimize chance of stress-induced hypoglycemia.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause fatigue
Mental Health: Effects on Psychiatric Treatment
Weight gain is common; caution with atypical antipsychotics; nefazodone and other CYP3A4 inhibitors may decrease the metabolism of pioglitazone; glucose may need to be checked more frequently
Nursing: Physical Assessment/Monitoring
Monitor for signs of heart failure (weight gain, edema, dyspnea). Teach risks of hyperglycemia. Refer patient to a diabetic educator, if available.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral:
Actos®: 15 mg, 30 mg, 45 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Actos)
15 mg (30): $193.48
30 mg (30): $289.98
45 mg (30): $310.00
References
American Diabetes Association, “Standards of Medical Care in Diabetes Mellitus -- 2012,” Diabetes Care, 2012, 35(Suppl ):11-63.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, "Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada," Can J Diabetes, 20078, 32(suppl 1):1-201.
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(9493):1279-89.
Glueck CJ, Moreira A, Goldenberg N, et al, “Pioglitazone and Metformin in Obese Women With Polycystic Ovary Syndrome Not Optimally Responsive to Metformin,” Hum Reprod, 2003, 18(8):1618-25
Handelsman Y, Mechanick JI, Blonde L, et al, “American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for Developing a Diabetes Mellitus Comprehensive Care Plan,” Endocr Pract, 2011, 17(Suppl 2):1-53.
Kaul S, Bolger AF, Herrington D, et al, "Thiazolidinedione Drugs and Cardiovascular Risks: A Science Advisory From the American Heart Association and American College of Cardiology Foundation," Circulation, 2010, 121(16):1868-77.
Lago RM, Singh PP, and Nesto RW, “Congestive Heart Failure and Cardiovascular Death in Patients with Prediabetes and Type 2 Diabetes Given Thiazolidinediones: A Meta-Analysis of Randomised Clinical Trials,” Lancet, 2007, 370 (9593):1129-36.
Lincoff AM, Wolski K, Nicholls SJ, et al, “Pioglitazone an Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus,” JAMA, 2007, 298(10):1180-8.
Nathan DM, Buse JB, Davidson MB, et al, “Medical Management of Hyperglycemia In Type 2 Diabetes: A Consensus Algorithm For The Initiation And Adjustment of Therapy,” Diabetes Care, 2009, 32(1):193-203.
Rodbard HW, Jellinger PS, Davidson JA, et al, “Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel on Type 2 Diabetes Mellitus: An Algorithm for Glycemic Control,” Endocr Pract, 2009, 15(6):540-59.
Romualdi D, Guido M, Ciampelli M, et al, “Selective Effects of Pioglitazone on Insulin and Androgen Abnormalities in Normo- and Hyperinsulinaemic Obese Patients With Polycystic Ovary Syndrome,” Hum Reprod, 2003, 18(6):1210-8.
Ryden L, Thrainsdottir I, and Swedberg K, “Adjudication of Serious Heart Failure in Patients From PROactive,” Lancet, 2007, 369(9557):189-90.
Schwartz AV, Sellmeyer DE, Vittinghoff E, et al, “Thiazolidinedione Use and Bone Loss in Older Diabetic Adults,” J Clin Endocrin Metab, 2006, 91(9):3349-54.
Yaturu S, Bryant B, Jain SK, “Thiazolidinedione Treatment Decreases Bone Mineral Density in Type 2 Diabetic Men,” Diabetes Care, 2007, 30(6):1574-76.
International Brand Names
Lexi-Comp.com
Last full review/revision February 2012
Content last modified February 2012
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