Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

THIAZOLIDINEDIONE ANTIDIABETIC AGENTS

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pioglitazone and rosiglitazone are thiazolidinedione oral antihyperglycemic agents. These agents are not chemically or functionally related to either the sulfonylureas, biguanides or alpha-glucosidase inhibitors.
    B) Troglitazone another thiazolidinedione oral antihyperglycemic agent was voluntarily removed the market due to worldwide reports of serious hepatic toxicity.

Specific Substances

    A) PIOGLITAZONE
    1) Actos
    2) AD-4833
    3) U-72107
    ROSIGLITAZONE
    1) BRL-49653
    2) Avandia (Smith-Kline, USA)
    TROGLITAZONE
    1) CS-045
    2) Rezulin (Parke-Davis, USA)
    3) CAS 97322-87-7

    1.2.1) MOLECULAR FORMULA
    1) PIOGLITAZONE: C19H20N2O3S.HCl
    2) ROSIGLITAZONE MALEATE: C18H19N3O3S.C4H4O4

Available Forms Sources

    A) FORMS
    1) PIOGLITAZONE: Available in 15 mg, 30 mg and 45 mg tablets (Prod Info ACTOS(R) oral tablets, 2011a).
    2) ROSIGLITAZONE: Available in 2 mg pink, 4 mg orange and 8 mg red/brown pentagonal film coated tablets (Prod Info AVANDIA(R) oral tablets, 2008).
    B) SOURCES
    1) TROGLITAZONE
    a) WITHDRAWAL FROM MARKET: As of March 2000, the US FDA has requested the manufacturer of troglitazone to remove the product from the market following reports of severe hepatotoxicity.
    b) WITHDRAWAL FROM MARKET: As of December 1997, troglitazone has been voluntarily withdrawn from the United Kingdom market by the companies concerned, based on worldwide reported cases of serious hepatic reactions.
    c) In postmarketing experience, the FDA has reported 5 cases of severe hepatic failure resulting in liver transplant following therapeutic use of troglitazone. As of July 1998, the manufacturer has modified the recommendations for liver function monitoring based on several new cases of severe hepatocellular events.
    d) As of June 1999, based on ongoing reports of potentially serious (sometimes fatal) liver toxicity, the manufacturer has recommended the following labelling changes: (1) troglitazone would be limited to patients not adequately controlled by other therapies, (2) no longer used as initial single agent therapy, (3) monthly liver serum studies recommended during the first year of therapy ((ANon, 1999)).
    C) USES
    1) PIOGLITAZONE
    a) Used as an adjunct to diet and exercise to improve the glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings (Prod Info ACTOS(R) oral tablets, 2011a).
    2) ROSIGLITAZONE
    a) Used in the treatment of type 2 diabetes mellitus, similar to pioglitazone(Prod Info AVANDIA oral tablet, 2011).
    3) TROGLITAZONE
    a) VOLUNTARY WITHDRAWAL: Troglitazone was voluntarily removed from the US market by Parke Davis in 2000 due to reports of severe hepatotoxicity.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USE: Oral hypoglycemic agents used to treat type II diabetes mellitus.
    B) PHARMACOLOGY: Decreases hepatic glucose production. Increases insulin sensitivity in the liver, adipose tissue and skeletal muscle and increases glucose uptake into adipose tissue and skeletal muscle.
    C) TOXICOLOGY: These agents are not likely to cause hypoglycemia after an acute overdose, although it has been reported after therapeutic use in patients also taking insulin or insulin secretagogues. Mechanism of fluid retention and hepatotoxicity not elucidated.
    D) EPIDEMIOLOGY: Exposure is common, rarely resulting in toxicity.
    E) WITH THERAPEUTIC USE
    1) THIAZOLIDINEDIONES
    a) COMMON ADVERSE EFFECTS: Nausea, vomiting, diarrhea, weight gain, hypotension, hypertension, macular edema, edema, transaminitis, anemia, loss of bone density and hypersensitivity reactions can occur.
    b) SEVERE ADVERSE EFFECTS: Liver failure, bladder tumors, congestive heart failure, myocardial infarction, stroke, bladder tumors and Stevens-Johnson syndrome can develop.
    2) PIOGLITAZONE
    a) The following have occurred with therapy: edema, hypoglycemia, hepatic enzyme elevations, paresthesia, and elevations of creatine phosphokinase.
    3) ROSIGLITAZONE
    a) Headache, respiratory tract infection, fluid retention, weight gain, anemia, hepatic failure and hepatocellular injury have been reported. Based on previous postmarketing experience, myocardial ischemic events were associated with angina or myocardial infarction. In 2013, the FDA determined that rosiglitazone does not produce an increase risk of myocardial infarction compared to other antidiabetic (ie, metformin and sulfonylurea) agents. Limitations on prescribing and dispensing recommendations have been removed. However, ongoing monitoring of rosiglitazone will continue to assess and evaluate for any increase in myocardial ischemic events.
    4) TROGLITAZONE
    a) As of 2000, troglitazone has been removed from the US market due to reports of severe hepatotoxicity.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited human data, although hypoglycemia has been reported in clinical trials and animal studies.
    2) SEVERE TOXICITY: Minimal human data. Peripheral edema, congestive heart failure and hepatotoxicity have been reported after chronic therapy, but not after acute overdose. Its anticipated that effects may be similar to adverse effects reported during therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Rosiglitazone is classified as FDA pregnancy category C. The combination products of pioglitazone hydrochloride/metformin hydrochloride and alogliptin benzoate/pioglitazone hydrochloride are classified as FDA pregnancy category C. By mid-late gestation, fetal death and growth retardation were observed in both rats and rabbits receiving treatment. Rosiglitazone has been shown to cross the human placenta and was detectable in fetal tissue; however, the potential clinical significance is unknown. Rosiglitazone has also been detected in the milk of rats.
    0.2.21) CARCINOGENICITY
    A) As of 2015, IARC has placed pioglitazone under review and has classified it as Group 2A (probably carcinogenic to humans). In addition, pioglitazone has been associated with urinary bladder tumors in humans; however, data are insufficient to determine whether pioglitazone is a tumor promoter. No significant risk was observed with rosiglitazone therapy.

Laboratory Monitoring

    A) Laboratory studies are not indicated following a minor ingestion.
    B) Monitor serum electrolytes, blood glucose and renal function in a symptomatic patient.
    C) Monitor liver enzymes, cardiac enzymes and CK in symptomatic patients.
    D) Monitor chest radiograph and ECG in patients with respiratory distress or clinical evidence of congestive heart failure.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Symptomatic and supportive care is the mainstay of treatment in patients who present with mild to moderate thiazolidinedione toxicity. If hypoglycemia develops, coingestion of other hypoglycemic agents should be considered. Hypoglycemia with thiazolidinediones is uncommon, but they are often prescribed with other antidiabetic agents that can produce hypoglycemia. A 4 to 6 hour observation period is reasonable.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Early positive pressure ventilation/intubation should be performed if the patient presents with pulmonary edema. Consider diuresis in massive fluid overload. Adequate circulatory support with IV fluids and vasopressors (if needed) should be assured if a patient presents with circulatory collapse.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal may be considered after a large ingestion, if the patient is alert and cooperative and able to protect their airway.
    2) HOSPITAL: Administer activated charcoal if the patient presents early after a large ingestion and the airway is protected. Lavage is of limited benefit.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with severe symptoms who present with respiratory insufficiency, consider positive pressure ventilation if tolerated.
    E) ANTIDOTE
    1) There is no specific antidote. If hypoglycemia occurs, treat with IV dextrose.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is ineffective because of extensive protein binding and large volume of distribution of these agents.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic individuals with acute inadvertent ingestions may be observed at home.
    2) OBSERVATION CRITERIA: A 4 to 6 hour observation period is recommended after a large or deliberate thiazolidinedione overdose. Patients who remain asymptomatic during this period with no hypoglycemia may be discharged home after appropriate psychiatric clearance as indicated.
    3) ADMISSION CRITERIA: Patients with severe liver injury or evidence of fluid overload should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) Failure to recognize hypoglycemia due to coingestion of other hypoglycemic agents.
    I) PHARMACOKINETICS
    1) Agents that are a member of the thiazolidinedione class of antidiabetic agents improve glycemic control by improving insulin sensitivity. Peak plasma concentrations occur after 1 to 2 hours with thiazolidinedione agents. Plasma protein binding (greater than 99%) is extensive. Metabolism is primarily performed by CYP2C8 in the liver. Half-life is approximately 3 to 4 hours for rosiglitazone and 3 to 7 hours for pioglitazone and 16 to 24 hours for its metabolites (M-lll and M-lV). Large volume of distribution (17.6 L/kg rosiglitazone).
    J) PREDISPOSING CONDITIONS
    1) Renal impairment, congestive heart failure, septicemia, liver disease and/or advanced age.
    K) DIFFERENTIAL DIAGNOSIS
    1) Other hypoglycemic agents; acetaminophen or other agents that are toxic to the liver; rhabdomyolysis or congestive heart failure.

Range Of Toxicity

    A) TOXICITY: The minimum toxic dose for thiazolidinediones is not well established. PIOGLITAZONE: An adult denied any clinical symptoms after taking up to 120 mg/day of pioglitazone for 4 days and then 180 mg/day for 7 days. ROSIGLITAZONE: In clinical studies of rosiglitazone, doses of 20 mg have been well tolerated.
    B) THERAPEUTIC DOSE: PIOGLITAZONE: ADULT: Recommended starting dose is 15 or 30 mg orally once daily; maximum dose is 45 mg once daily. ROSIGLITAZONE: ADULT: Starting dose is 4 mg once daily; maximum dose should not exceed 8 mg daily. PEDIATRIC: Safety and effectiveness of these agents in pediatric patients have not been established. TROGLITAZONE: As of March 2000, the US FDA requested the manufacturer of troglitazone to remove the product from the market following reports of severe hepatotoxicity.

Clinical Effects

Summary Of Exposure

    A) USE: Oral hypoglycemic agents used to treat type II diabetes mellitus.
    B) PHARMACOLOGY: Decreases hepatic glucose production. Increases insulin sensitivity in the liver, adipose tissue and skeletal muscle and increases glucose uptake into adipose tissue and skeletal muscle.
    C) TOXICOLOGY: These agents are not likely to cause hypoglycemia after an acute overdose, although it has been reported after therapeutic use in patients also taking insulin or insulin secretagogues. Mechanism of fluid retention and hepatotoxicity not elucidated.
    D) EPIDEMIOLOGY: Exposure is common, rarely resulting in toxicity.
    E) WITH THERAPEUTIC USE
    1) THIAZOLIDINEDIONES
    a) COMMON ADVERSE EFFECTS: Nausea, vomiting, diarrhea, weight gain, hypotension, hypertension, macular edema, edema, transaminitis, anemia, loss of bone density and hypersensitivity reactions can occur.
    b) SEVERE ADVERSE EFFECTS: Liver failure, bladder tumors, congestive heart failure, myocardial infarction, stroke, bladder tumors and Stevens-Johnson syndrome can develop.
    2) PIOGLITAZONE
    a) The following have occurred with therapy: edema, hypoglycemia, hepatic enzyme elevations, paresthesia, and elevations of creatine phosphokinase.
    3) ROSIGLITAZONE
    a) Headache, respiratory tract infection, fluid retention, weight gain, anemia, hepatic failure and hepatocellular injury have been reported. Based on previous postmarketing experience, myocardial ischemic events were associated with angina or myocardial infarction. In 2013, the FDA determined that rosiglitazone does not produce an increase risk of myocardial infarction compared to other antidiabetic (ie, metformin and sulfonylurea) agents. Limitations on prescribing and dispensing recommendations have been removed. However, ongoing monitoring of rosiglitazone will continue to assess and evaluate for any increase in myocardial ischemic events.
    4) TROGLITAZONE
    a) As of 2000, troglitazone has been removed from the US market due to reports of severe hepatotoxicity.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited human data, although hypoglycemia has been reported in clinical trials and animal studies.
    2) SEVERE TOXICITY: Minimal human data. Peripheral edema, congestive heart failure and hepatotoxicity have been reported after chronic therapy, but not after acute overdose. Its anticipated that effects may be similar to adverse effects reported during therapeutic use.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) MACULAR EDEMA: In postmarketing reports, new onset and worsening diabetic macular edema have been reported in patients receiving thiazolidinedione agents (Prod Info AVANDIA(R) oral tablets, 2012; Prod Info ACTOS(R) oral tablets, 2011). Peripheral edema was also reported in the majority of these patients. Following the discontinuation of therapy, macular edema resolved or improved in some patients. In one case, macular edema resolved after the rosiglitazone dose was reduced (Anon, 2006).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) POTENTIAL EFFECTS: Enhancement of insulin sensitivity has been shown to lower systolic and diastolic blood pressure in a small number of obese subjects who had impaired glucose tolerance and in mildly diabetic hypertensive patients (Ogihara et al, 1995; Nolan et al, 1994). Pulse rate remained unchanged.
    b) Other clinical studies and animal data reported no hypotensive effect (Katayama et al, 1994; Kawaguchi et al, 1995; Iwamoto et al, 1996).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Although poorly understood, hyperinsulinemia and insulin resistance may have a role in aggravating hypertension in some patients (Ogihara et al, 1995).
    C) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) PIOGLITAZONE
    1) Pioglitazone use has caused plasma volume expansion and preload induced cardiac hypertrophy. Pioglitazone should not be used in patients with NYHA class III and IV cardiac status (Prod Info ACTOS(R) oral tablets, 2006).
    b) ROSIGLITAZONE
    1) New onset CHF or the exacerbation of preexisting heart failure may result from rosiglitazone induced fluid retention. If deterioration in cardiac status develops, rosiglitazone should be discontinued. Rosiglitazone should be used with caution in patients with a history of heart failure (Prod Info AVANDIA(R) oral tablets, 2008).
    2) During a clinical study with healthy volunteers who received 8 mg of rosiglitazone daily for 8 weeks, a statistically significant increase in median plasma volume was observed as compared to placebo (Prod Info AVANDIA(R) oral tablets, 2008).
    D) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) In 2013, the FDA determined that rosiglitazone does NOT produce an increase risk of myocardial infarction compared to other antidiabetic (ie, metformin and sulfonylurea) agents. Limitations on prescribing and dispensing recommendations have been removed. However, ongoing monitoring of rosiglitazone will continue to assess and evaluate for any increase in myocardial ischemic events (U.S. Food and Drug Administration (FDA), 2013).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOTENSION
    a) A dose-dependent decrease in systolic blood pressure was observed in insulin-resistant obese Zucker rats (Yoshioka et al, 1993).
    2) CARDIOMEGALY
    a) Heart enlargement without microscopic changes was observed in rats at exposures exceeding 14 times the AUC of the 400 mg human dose; however, serial echocardiographic studies in monkeys did not reveal changes in heart size or function (Prod Info Rezulin(R), troglitazone, 1997).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Nausea, flatulence and diarrhea have been reported with therapeutic use of thiazolidinedione agents (Prod Info AVANDIA(R) oral tablets, 2012; Prod Info ACTOS(R) oral tablets, 2011).
    b) Nausea, vomiting, abdominal fullness, epigastric pain and diarrhea occurred in about 6% of patients; the effects did not appear dose-dependent (Kuzuya et al, 1991).
    B) WEIGHT GAIN FINDING
    1) WITH THERAPEUTIC USE
    a) Dose related weight gain has been associated with pioglitazone and rosiglitazone and may be related to a combination of fluid retention and fat accumulation (Prod Info AVANDIA(R) oral tablets, 2012; Prod Info ACTOS(R) oral tablets, 2011). Rapid increases require further evaluation to assess for excessive edema or congestive heart failure (Prod Info AVANDIA(R) oral tablets, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) PIOGLITAZONE
    1) In postmarketing experience, reports of hepatitis and increased hepatic enzymes has been reported. Rarely, hepatic failure with and without fatal outcome have developed; causality has not been determined (Prod Info ACTOS(R) oral tablets, 2011).
    b) ROSIGLITAZONE
    1) In postmarketing experience, reports of increased hepatic enzymes and hepatitis up to 3 or more times the upper limit of normal have occurred; however, causality has not been established (Prod Info AVANDIA(R) oral tablets, 2012).
    2) CASE REPORT: A 47-year-old woman with type 2 diabetes mellitus and no history of liver disease developed an elevated alkaline phosphatase level (5 times the upper limit of normal, 10.93 microkat/L) four months after starting rosiglitazone 4 mg/day. Her alkaline phosphatase levels returned to normal two weeks after rosiglitazone therapy was discontinued (Hachey et al, 2000).
    3) CASE SERIES: Two patients developed hepatocellular injury after 2 weeks of rosiglitazone (4 mg/day) therapy. One patient had a medical history of chronic obstructive pulmonary disease and a remote history of alcoholism. Both patients recovered following discontinuation of rosiglitazone and supportive care (Al-Salman et al, 2000; Ravinuthala & Nori, 2000).
    B) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) SUMMARY
    1) In postmarketing experience, hepatic failure with and without fatal outcomes have been reported with thiazolidinedione therapy; causality has not been established (Prod Info AVANDIA(R) oral tablets, 2012; Prod Info ACTOS(R) oral tablets, 2011).
    b) ROSIGLITAZONE
    1) CASE REPORT: A 69-year-old man with a history of atrial fibrillation, hypertension, coronary artery disease, and New York Heart Association class II congestive heart failure developed hepatic failure after 21 days of rosiglitazone (4 mg/day) therapy. He recovered fully with supportive care (Forman et al, 2000; Freid et al, 2000).
    c) PIOGLITAZONE
    1) CASE REPORT: A 49-year-old diabetic man developed mixed hepatocellular-cholestatic liver injury after 6 months of pioglitazone therapy (30 mg/day). Liver biopsy revealed mild centrilobular cholestasis in hepatocytes and bile canaliculi, accompanied by lymphocytic infiltrates in portal tracts. Liver enzyme levels returned to normal 6 weeks after discontinuation of pioglitazone therapy (May et al, 2002).
    2) CASE REPORT: A 67-year-old man with type 2 diabetes mellitus developed hepatocellular injury after 7 months of pioglitazone therapy (30 mg/day). Liver enzyme levels returned to normal one month after discontinuation of pioglitazone therapy (Maeda, 2001).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) PIOGLITAZONE
    1) Decreases in hemoglobin and hematocrit have been reported with pioglitazone therapy which declined by 2% to 4%. No significant hematologic changes have been reported and the alterations may be associated with an increase in plasma volume (Prod Info ACTOS(R) oral tablets, 2011).
    b) ROSIGLITAZONE
    1) Small decreases in hemoglobin and hematocrit have been reported in clinical trials, and may be related to increased fluid volume often observed during the first few weeks of therapy (Prod Info AVANDIA(R) oral tablets, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, Stevens-Johnson syndrome has been reported with rosiglitazone therapy (Prod Info AVANDIA(R) oral tablets, 2012).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hypoglycemic symptoms have occurred in a small number of insulin-dependent and non-insulin dependent diabetic patients treated with thiazolidinedione agents at therapeutic dose (Iwamoto et al, 1996; Takino et al, 1994).
    b) Hypoglycemia has developed when thiazolidinedione agents have been used in combination with insulin or an insulin secretagogue (Prod Info AVANDIA(R) oral tablets, 2012; Prod Info ACTOS(R) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) At the time of this review, no data were available regarding blood glucose levels following overdose.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, rash, pruritus, urticaria, angioedema, and anaphylactic reaction have been reported with rosiglitazone therapy (Prod Info AVANDIA(R) oral tablets, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Rosiglitazone is classified as FDA pregnancy category C. The combination products of pioglitazone hydrochloride/metformin hydrochloride and alogliptin benzoate/pioglitazone hydrochloride are classified as FDA pregnancy category C. By mid-late gestation, fetal death and growth retardation were observed in both rats and rabbits receiving treatment. Rosiglitazone has been shown to cross the human placenta and was detectable in fetal tissue; however, the potential clinical significance is unknown. Rosiglitazone has also been detected in the milk of rats.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) There are no adequate and well controlled studies of rosiglitazone use in pregnant women (Prod Info AVANDIA(R) oral tablets, 2014).
    B) PREGNANCY CATEGORY
    1) The manufacturer has classified rosiglitazone as FDA pregnancy category C (Prod Info AVANDIA(R) oral tablets, 2014).
    2) The manufacturer has classified the combination products of pioglitazone hydrochloride/metformin hydrochloride and alogliptin benzoate/pioglitazone hydrochloride as FDA pregnancy category C (Prod Info ACTOPLUS MET(R) oral tablets, 2012; Prod Info OSENI oral tablets, 2013; Prod Info ACTOPLUS MET(R) XR oral extended-release tablets, 2009).
    C) CROSSES PLACENTA
    1) Rosiglitazone has been shown to cross the human placenta and was detectable in fetal tissue; however, the potential clinical significance is unknown (Prod Info AVANDIA(R) oral tablets, 2014).
    D) ANIMAL STUDIES
    1) ROSIGLITAZONE
    a) During early pregnancy, no effect on implantation or the embryo was observed in rats treated with rosiglitazone. By mid-late gestation fetal death and growth retardation were observed in both rats and rabbits receiving treatment. Doses of up to 3 mg/kg in rats and 100 mg/kg in rabbits did not produce any teratogenic effects. The no effect dose on the placenta, embryo/fetus, and offspring was 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits (approximately 4 times human AUC at the maximum recommended human daily dose) (Prod Info AVANDIA(R) oral tablets, 2014).
    2) ALOGLIPTIN/PIOGLITAZONE
    a) RATS: There was no evidence of fetal abnormalities following administration in pregnant rats of 100 mg/kg alogliptin plus 40 mg/kg pioglitazone combination during organogenesis. However, the pioglitazone-related effects of delayed development and reduced weights were slightly augmented in the rat fetuses (Prod Info OSENI oral tablets, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) ROSIGLITAZONE
    1) It is unknown whether rosiglitazone is secreted in human milk; it has been detected in the milk of rats (Prod Info AVANDIA(R) oral tablets, 2014).
    B) ALOGLIPTIN/PIOGLITAZONE
    1) Animal studies with the individual components of alogliptin and pioglitazone showed that they are both excreted in the milk of lactating rats (Prod Info OSENI oral tablets, 2013).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) As of 2015, IARC has placed pioglitazone under review and has classified it as Group 2A (probably carcinogenic to humans). In addition, pioglitazone has been associated with urinary bladder tumors in humans; however, data are insufficient to determine whether pioglitazone is a tumor promoter. No significant risk was observed with rosiglitazone therapy.
    3.21.3) HUMAN STUDIES
    A) SUMMARY
    1) As of 2015, IARC has placed pioglitazone under review and has classified it as Group 2A (probably carcinogenic to humans) (International Agency for Research on Cancer, 2015).
    B) THIAZOLIDINEDIONES
    1) SYSTEMATIC REVIEW/META-ANALYSIS: In a systematic review conducted from June 2012 to July 2013 to determine the overall risk of bladder cancer with pioglitazone or rosiglitazone or the potential risk with cumulative dose or duration of drug therapy. A total of 18 studies were included and comprised 5 randomized controlled trials and 13 observational studies. The results showed a significantly higher overall risk of bladder cancer with pioglitazone in RCTs (7878 participants; odds ratio (OR) 2.51, 95% CI 1.09 to 5.80) and observational studies (greater than 2.6 million patients; OR for 'ever' use compared to non-users 1.21, 95% CI 1.09 to 1.35). Whereas, no significant risk was seen with rosiglitazone in RCTs or 'ever' users compared to non-users in observational studies. In addition, the evidence for any relationship between bladder cancer risk and rosiglitazone cumulative duration was limited and inconsistent. However, the risk of bladder cancer increases with both increasing cumulative dose and duration of pioglitazone exposure (Turner et al, 2014).
    C) PIOGLITAZONE
    1) BLADDER TUMORS: The risk of bladder cancer increased with dose and duration of pioglitazone exposure compared with no exposure in diabetic patients in a 5-year interim analysis of a 10-year observational cohort study. While no significant increase in risk of bladder cancer between pioglitazone-exposed and nonexposed patients was observed (hazard ratio (HR), 1.2; 95% confidence interval (CI), 0.9 to 1.5), results suggest that the relative risk of bladder cancer may increase by 40% in patients exposed to pioglitazone for longer than 12 months compared with nonexposed patients (HR, 1.4; 95% CI, 0.9 to 2.1). This translates to an absolute increase of 3 cases in 10,000. The risk of bladder cancer in patients exposed to pioglitazone reached statistical significance after 24 months of therapy (HR, 1.4; 95% CI, 1.03 to 2) (Prod Info ACTOPLUS MET XR(TM) oral extended release tablets, 2013; Prod Info DUETACT(R) oral tablets, 2011).
    2) BLADDER TUMORS: In two 3-year studies, bladder cancer was reported in 0.44% (16 of 3656) of patients treated with pioglitazone compared with 0.14% (5 of 3679) of patients treated with placebo or glyburide. After exclusion of patients with less than one year of exposure to the study drug at the time of diagnosis of bladder cancer, there were 6 (0.16%) cases with pioglitazone and 2 (0.05%) with placebo (Prod Info ACTOPLUS MET XR(TM) oral extended release tablets, 2013; Prod Info DUETACT(R) oral tablets, 2011).
    3.21.4) ANIMAL STUDIES
    A) PIOGLITAZONE
    1) BLADDER TUMORS: Drug-induced urinary bladder tumors were reported in a 2-year study of male and female rats administered oral pioglitazone doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m(2)) (Prod Info ACTOPLUS MET XR(TM) oral extended release tablets, 2013; Prod Info DUETACT(R) oral tablets, 2011).
    2) NEOPLASMS: Benign and/or malignant transitional cell neoplasms were observed in a 2-year study of male rats administered oral pioglitazone doses of 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m(2)) (Prod Info ACTOPLUS MET XR(TM) oral extended release tablets, 2013; Prod Info DUETACT(R) oral tablets, 2011).
    B) ROSIGLITAZONE
    1) ADIPOSE HYPERPLASIA: An increased incidence of adipose hyperplasia was reported in a 2-year study of Charles River CD-1 mice administered rosiglitazone doses of 1.5 and 6 mg/kg/day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose) (Prod Info AVANDIA oral tablets, 2011).
    2) LIPOMAS: A significant increase in the incidence of benign adipose tissue tumors (lipomas) was observed in Sprague-Dawley rats who received rosiglitazone for 2 years by oral gavage at doses of 0.3 and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose for male and female rats, respectively) (Prod Info AVANDIA oral tablets, 2011).
    C) LACK OF EFFECT
    1) PIOGLITAZONE
    a) MICE: No drug-induced tumors were reported in a 2-year study of male and female mice administered oral pioglitazone doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m(2)) (Prod Info ACTOPLUS MET XR(TM) oral extended release tablets, 2013; Prod Info DUETACT(R) oral tablets, 2011).
    2) ROSIGLITAZONE
    a) MICE: No evidence of carcinogenic effects were noted in a 2-year study of Charles River CD-1 mice administered rosiglitazone doses of 0.4, 1.5, and 6 mg/kg/day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose) (Prod Info AVANDIA oral tablets, 2011).

Genotoxicity

    A) PIOGLITAZONE
    1) Pioglitazone was not mutagenic in several genetic toxicology studies, including Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay (Prod Info ACTOPLUS MET XR(TM) oral extended release tablets, 2013; Prod Info DUETACT(R) oral tablets, 2011).
    B) ROSIGLITAZONE
    1) Rosiglitazone was not clastogenic or mutagenic in the in vitro bacterial assays for gene mutation, the in vitro chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay; however, there was an approximately 2-fold increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation (Prod Info AVANDIA oral tablets, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Laboratory studies are not indicated following a minor ingestion.
    B) Monitor serum electrolytes, blood glucose and renal function in a symptomatic patient.
    C) Monitor liver enzymes, cardiac enzymes and CK in symptomatic patients.
    D) Monitor chest radiograph and ECG in patients with respiratory distress or clinical evidence of congestive heart failure.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe liver injury or evidence of fluid overload should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic individuals with acute inadvertent ingestions may be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) A 4 to 6 hour observation period is recommended after a large or deliberate thiazolidinedione overdose. Patients who remain asymptomatic during this period with no hypoglycemia may be discharged home after appropriate psychiatric clearance as indicated.

Monitoring

    A) Laboratory studies are not indicated following a minor ingestion.
    B) Monitor serum electrolytes, blood glucose and renal function in a symptomatic patient.
    C) Monitor liver enzymes, cardiac enzymes and CK in symptomatic patients.
    D) Monitor chest radiograph and ECG in patients with respiratory distress or clinical evidence of congestive heart failure.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Activated charcoal may be considered after a large ingestion, if the patient is alert and cooperative and able to protect their airway.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Administer activated charcoal if the patient presents early after a large ingestion and the airway is protected. Lavage is of limited benefit.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Symptomatic and supportive care is the mainstay of treatment in patients who present with mild to moderate thiazolidinedione toxicity.
    2) If hypoglycemia develops coingestion of other hypoglycemic agents should be considered, hypoglycemia with thiazolidinediones is uncommon but they are often prescribed with other antidiabetic agents that can produce hypoglycemia.
    B) HYPOGLYCEMIA
    1) Monitor blood glucose frequently; hourly in symptomatic patients and/or coadministration with other antihyperglycemic agents. Although infrequently reported, hypoglycemia may occur when using these agents as a monotherapy; likewise, it has enhanced the hypoglycemic effect of insulin when coadministered (Prod Info AVANDIA(R) oral tablets, 2012; Prod Info ACTOS(R) oral tablets, 2011a).
    C) MONITORING OF PATIENT
    1) Obtain a baseline blood glucose level and monitor frequently; especially when coadministered with other antidiabetic agents.
    2) Monitor liver enzymes following a significant overdose.
    3) Monitor vital signs, blood pressure and fluid and electrolyte status as indicated.
    4) Plasma volume expansion has been reported which may exacerbate heart failure. Monitor fluid status in symptomatic patients with significant overdose or comorbidity (e.g., congestive heart failure). In postmarketing experience, CHF or exacerbation of existing CHF has been reported with rosiglitazone therapy.
    D) CONDUCTION DISORDER OF THE HEART
    1) Obtain baseline ECG and monitor cardiac rhythm in symptomatic patients or as indicated.

Enhanced Elimination

    A) EXTRACORPOREAL ELIMINATION
    1) Thiazolidinedione agents have extensive binding (greater than 99%) to serum albumin (Prod Info AVANDIA(R) oral tablets, 2012; Prod Info ACTOS(R) oral tablets, 2011a) and a large volume of distribution (17.6 L/kg rosiglitazone) (Prod Info AVANDIA(R) oral tablets, 2012); therefore, dialysis and hemoperfusion are UNLIKELY to remove significant amounts of drug.

Range Of Toxicity

Summary

    A) TOXICITY: The minimum toxic dose for thiazolidinediones is not well established. PIOGLITAZONE: An adult denied any clinical symptoms after taking up to 120 mg/day of pioglitazone for 4 days and then 180 mg/day for 7 days. ROSIGLITAZONE: In clinical studies of rosiglitazone, doses of 20 mg have been well tolerated.
    B) THERAPEUTIC DOSE: PIOGLITAZONE: ADULT: Recommended starting dose is 15 or 30 mg orally once daily; maximum dose is 45 mg once daily. ROSIGLITAZONE: ADULT: Starting dose is 4 mg once daily; maximum dose should not exceed 8 mg daily. PEDIATRIC: Safety and effectiveness of these agents in pediatric patients have not been established. TROGLITAZONE: As of March 2000, the US FDA requested the manufacturer of troglitazone to remove the product from the market following reports of severe hepatotoxicity.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) PIOGLITAZONE
    a) INITIAL THERAPY: The recommended starting oral dose of pioglitazone is 15 or 30 mg once daily; if inadequately controlled the dose may be increased in increments up to a maximum of 45 mg once daily (Prod Info ACTOS(R) oral tablets, 2006).
    b) COMBINATION THERAPY: Starting dose is 15 mg or 30 mg once daily along with the prescribed sulfonylurea or metformin dose. If hypoglycemia is reported, the current sulfonylurea dose should be decreased. It is not anticipated that hypoglycemia will be reported during combination therapy with metformin (Prod Info ACTOS(R) oral tablets, 2006).
    1) INSULIN: Start pioglitazone at 15 mg or 30 mg once daily along with insulin therapy. The current insulin dose may be continued, or if hypoglycemia occurs the insulin dose may be decreased by 10% to 25% as needed (Prod Info ACTOS(R) oral tablets, 2006).
    2) ALOGLIPTIN BENZOATE/PIOGLITAZONE HYDROCHLORIDE
    a) INITIAL DOSE: alogliptin 25 mg/pioglitazone 15 mg OR alogliptin 25 mg/pioglitazone 30 mg orally once daily (Prod Info OSENI oral tablets, 2013)
    b) PREVIOUSLY RECEIVING PIOGLITAZONE: alogliptin 25 mg/pioglitazone 15 mg OR alogliptin 25 mg/pioglitazone 30 mg OR alogliptin 25 mg/pioglitazone 45 mg orally once daily; initial dose based on current therapy (Prod Info OSENI oral tablets, 2013)
    c) MAINTENANCE DOSE: orally once daily based on glycemic response (HbA1c); MAX: alogliptin 25 mg/pioglitazone 45 mg orally once daily (Prod Info OSENI oral tablets, 2013)
    3) PIOGLITAZONE HYDROCHLORIDE/METFORMIN HYDROCHLORIDE
    a) IMMEDIATE-RELEASE: Recommended dose is pioglitazone 15 mg/metformin 500 mg orally twice daily OR pioglitazone 15 mg/metformin 850 mg orally once daily. MAXIMUM DOSE: Pioglitazone 45 mg/metformin 2550 mg/day in divided doses (Prod Info ACTOPLUS MET(R) oral tablets, 2012).
    b) EXTENDED-RELEASE: Recommended dose is pioglitazone 15 to 30 mg/metformin 850 to 1000 mg orally once daily. MAXIMUM DOSE: Pioglitazone 45 mg/metformin 2000 mg/day (Prod Info ACTOPLUS MET(R) XR oral extended-release tablets, 2009).
    4) ROSIGLITAZONE
    a) INITIAL DOSE: Start at 4 mg orally as a single daily dose or divided and administered in the morning and evening (Prod Info AVANDIA(R) oral tablets, 2006).
    b) COMBINATION THERAPY - Starting dose of rosiglitazone is 4 mg given as a single dose once daily or divided doses twice daily along with sulfonylurea or metformin. If the patient reports hypoglycemia, the sulfonylurea dose should be decreased. It is unlikely that metformin will require adjustment when combined with rosiglitazone (Prod Info AVANDIA(R) oral tablets, 2006).
    1) INSULIN - The starting dose of rosiglitazone is 4 mg daily in combination with the current insulin dose. If hypoglycemia is reported, decrease the insulin dose by 10% to 25% as needed. Individual adjustments may be required (Prod Info AVANDIA(R) oral tablets, 2006).
    5) TROGLITAZONE
    a) As of March 2000, the USFDA has requested the manufacturer of troglitazone to remove the product from the market following reports of severe hepatotoxicity.
    b) The current insulin dose should be continued upon initiation of troglitazone therapy (Prod Info Rezulin(R), troglitazone, 1997).
    c) INITIAL DOSE/ORAL
    1) The recommended starting dose of troglitazone is 200 milligrams once daily in patients on insulin therapy (Prod Info Rezulin(R), troglitazone, 1997).
    2) After 2 to 4 weeks of therapy the dose may be increased (Prod Info Rezulin(R), troglitazone, 1997).
    3) MAINTENANCE DOSE - The usual dose is 400 milligrams daily (Prod Info Rezulin(R), troglitazone, 1997).
    4) MAXIMUM DOSE: Maximum recommended dose is 600 mg daily (Prod Info Rezulin(R), troglitazone, 1997).
    5) ADMINISTRATION: Troglitazone should be taken with meals (Prod Info Rezulin(R), troglitazone, 1997).
    7.2.2) PEDIATRIC
    A) GENERAL/SUMMARY
    1) Safety and effectiveness of pioglitazone and rosiglitazone in pediatric patients have not been established (Prod Info ACTOS(R) oral tablets, 2006; Prod Info AVANDIA(R) oral tablets, 2006; Prod Info ACTOPLUS MET(R) oral tablets, 2012; Prod Info OSENI oral tablets, 2013).

Maximum Tolerated Exposure

    A) PIOGLITAZONE
    1) A male patient denied any clinical symptoms after taking up to 120 mg/day of pioglitazone for 4 days and then 180 mg/day for 7 days; therapeutic dose 15 or 30 mg (Prod Info ACTOS(R) oral tablets, 2011).
    B) ROSIGLITAZONE
    1) In clinical studies, doses of 20 mg have been well tolerated; normal dosing should not exceed 8 mg daily (Prod Info AVANDIA(R) oral tablets, 2012).
    C) TROGLITAZONE
    1) REMOVED FROM MARKET: In postmarketing experience the US FDA has received reports of potentially serious and sometimes fatal cases of liver toxicity following the use of troglitazone ((ANon, 1999)). As of March 2000, the US FDA requested the manufacturer of troglitazone to remove the product from the market following reports of severe hepatotoxicity.
    D) CASE REPORTS
    1) ADULT
    a) SUMMARY: Hepatic failure has been reported following therapeutic use of these agents (Prod Info AVANDIA(R) oral tablets, 2012; Prod Info AVANDIA(R) oral tablets, 2008; Forman et al, 2000; Neuschwander-Tetri et al, 1998).
    b) PIOGLITAZONE: Based on postmarketing experience, hepatic failure, sometimes fatal, has been reported. An exact cause has not been determined (Prod Info ACTOS(R) oral tablets, 2011).
    c) ROSIGLITAZONE: In postmarketing experience, reports of increased hepatic enzymes and hepatitis (up to 3 or more times the upper limit of normal) have also been reported with rosiglitazone use. Hepatic failure with and without fatal outcome has also occurred, but causality has not been established (Prod Info AVANDIA(R) oral tablets, 2008).

Physicochemical

Physical Characteristics

    A) PIOGLITAZONE is an odorless, white, crystalline powder that is soluble in N,N-dimethylformamide; slightly soluble in anhydrous ethanol; very slightly soluble in acetone and acetonitrile; practically insoluble in water; and insoluble in ether (Prod Info ACTOS(R) oral tablets, 2011).
    B) ROSIGLITAZONE MALEATE is a white to off-white solid with a melting point of 122 to 123 degrees C and pKa values of 6.8 and 6.1. It is readily soluble in ethanol and a buffered aqueous solution with pH of 2.3; solubility decreases with increasing pH in the physiological range (Prod Info AVANDIA(R) oral tablets, 2011).

Molecular Weight

    A) PIOGLITAZONE: 392.9 daltons (Prod Info ACTOS(R) oral tablets, 2011)
    B) ROSIGLITAZONE: 357.44 (Prod Info AVANDIA(R) oral tablets, 2011)
    C) ROSIGLITAZONE MALEATE: 473.52 (Prod Info AVANDIA(R) oral tablets, 2011)

References

General Bibliography

    1) Al-Salman J, Arjomand H, & Kemp DG: Hepatocellular injury in a patient receiving rosiglitazone. A case report. Ann Int Med 2000; 132:121-124.
    2) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    3) Anon: New labeling and use changes for rezulin (letter). USFDA medwatch. U.S. Food and Drug Administration. Rockville, MD, USA. 1999. Available from URL: http://www.fda.gov/medwatch/safety/1999/rezuhp.htm.
    4) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    5) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    6) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    7) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    8) Forman LM, Simmons DA, & Diamond RH: Hepatic failure in a patient taking rosiglitazone. Ann Int Med 2000; 132:118-121.
    9) Freid J, Everitt D, & Boscia J: Rosiglitazone and hepatic failure (letter). Ann Int Med 2000; 132:164.
    10) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    11) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    12) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    13) Hachey DM, O'Neil MP, & Force RW: Isolated elevation of alkaline phosphatase level associated with rosiglitazone (letter). Ann Intern Med 2000; 133:752.
    14) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    15) International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. Geneva, Switzerland. 2015. Available from URL: http://monographs.iarc.fr/ENG/Classification/. As accessed 2015-08-06.
    16) Iwamoto Y, Kosaka K, & Kuzuya T: Effect of troglitazone: A new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care 1996; 19:151-156.
    17) Katayama S, Abe M, & Kashiwabara H: Evidence against a role of insulin in hypertension in spontaneously hypertensive rats: CS-045 does not lower blood pressure despite improvement of insulin resistance. Hypertension 1994; 23:1071-1074.
    18) Kawaguchi M, Tanigawa K, & Kato Y: A study of the effect of CS-045: A new antidiabetic drug, on hypertension in spontaneously hypertensive rat. Endocrine J 1995; 42:557-561.
    19) Kuzuya T, Iwamoto Y, & Kosaka K: A pilot clinical trial of a new oral hypoglycemic agent, CS-045, in patients with non-insulin dependent diabetes mellitus. Diab Res & Clin Prac 1991; 11:147-154.
    20) Maeda K: Hepatocellular injury in a patient receiving pioglitazone (letter). Ann Intern Med 2001; 135:306.
    21) May LD, Lefkowitch JH, & Kram MT: Mixed hepatocellular-cholestatic liver injury after pioglitazone therapy. Ann Intern Med 2002; 136:449-452.
    22) MedWatch - The FDA Safety Information and Adverse Event Reporting Program. Food and Drug Administration. MedWatch. . 2006. Available from URL: http://www.fda.gov/medwatch/safety/2006/safety06.htm#Avandia. As accessed 1/5/06.
    23) Neuschwander-Tetri BA, Isley WL, & Oki JC: Troglitazone-induced hepatic failure leading to liver transplantation. Ann Intern Med 1998; 129:38-41.
    24) Nolan JJ, Ludvik B, & Beerdsen P: Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. New Engl J Med 1994; 18:1188-1193.
    25) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    26) Ogihara T, Rakugi H, & Ikegami H: Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives. Am J Hyperten 1995; 8:316-320.
    27) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    28) Product Information: ACTOPLUS MET XR(TM) oral extended release tablets, pioglitazone metformin HCl oral extended release tablets. Takeda Pharmaceuticals America, Inc. (per FDA), Deerfield, IL, 2013.
    29) Product Information: ACTOPLUS MET(R) XR oral extended-release tablets, pioglitazone HCl metformin HCl oral extended-release tablets. Takeda Pharmaceuticals America, Inc., Deerfield, IL, 2009.
    30) Product Information: ACTOPLUS MET(R) oral tablets, pioglitazone HCl metformin HCl oral tablets. Takeda Pharmaceuticals America, Inc. (per FDA), Deerfield, IL, 2012.
    31) Product Information: ACTOS(R) oral tablets, pioglitazone hcl oral tablets. Takeda Pharmaceuticals America,Inc, Indianapolis, IN, 2006.
    32) Product Information: ACTOS(R) oral tablets, pioglitazone HCl oral tablets. Takeda Pharmaceuticals America, Inc.(per FDA), Deerfield, IL, 2011a.
    33) Product Information: ACTOS(R) oral tablets, pioglitazone hydrochloride oral tablets. Takeda Pharmaceuticals America, Inc, Deerfield, IL, 2011.
    34) Product Information: AVANDIA oral tablet, rosiglitazone maleate oral tablet. GlaxoSmithKline, Research Triangle Park, NC, 2011.
    35) Product Information: AVANDIA oral tablets, rosiglitazone maleate oral tablets. GlaxoSmithKline (manufacturer), Research Triangle Park, NC, 2011.
    36) Product Information: AVANDIA(R) oral tablets, rosiglitazone maleate oral tablets. GlaxoSmithKline, Research Triangle Park, NC, 2006.
    37) Product Information: AVANDIA(R) oral tablets, rosiglitazone maleate oral tablets. GlaxoSmithKline (per DailyMed), Research Triangle Park, NC, 2012.
    38) Product Information: AVANDIA(R) oral tablets, rosiglitazone maleate oral tablets. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2014.
    39) Product Information: AVANDIA(R) oral tablets, rosiglitazone maleate oral tablets. GlaxoSmithKline, Research Triangle Park, NC, 2008.
    40) Product Information: AVANDIA(R) oral tablets, rosiglitazone maleate oral tablets. GlaxoSmithKline, Research Triangle Park, NC, 2011.
    41) Product Information: Avandia(R), rosiglitazone. SmithKline Beecham Pharmaceuticals, Philadelphia, PA, 1999.
    42) Product Information: DUETACT(R) oral tablets, pioglitazone HCl and glimepiride oral tablets. Takeda Pharmaceuticals America, Inc.(per FDA), Deerfield, IL, 2011.
    43) Product Information: OSENI oral tablets, alogliptin pioglitazone oral tablets. Takeda Pharmaceuticals America, Inc. (per manufacturer), Deerfield, IL, 2013.
    44) Product Information: Rezulin(R), troglitazone. Parke-Davis, Morris Plains, NJ, 1997.
    45) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    46) Ravinuthala RS & Nori U: Rosiglitzone toxicity (letter). Ann Int Med 2000; 133:658.
    47) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    48) Takino H, Okuno S, & Uotani S: Increased insulin responsiveness after CS-045 treatment in diabetes associated with Werner's syndrome. Diab Res & Clin Prac 1994; 24:167-172.
    49) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    50) Turner RM, Kwok CS, Chen-Turner C, et al: Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis. Br J Clin Pharmacol 2014; 78(2):258-273.
    51) U.S. Food and Drug Administration (FDA): FDA Drug Safety Communication: FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines. U.S.Food and Drug Administration (FDA). Silver Spring, MD. 2013. Available from URL: http://www.fda.gov/Drugs/DrugSafety/ucm376389.htm. As accessed 2014-01-02.