pioglitazone (Rx)

>10%

Edema when used in combination with sulfonylurea or insulin (<27%)

Hypoglycemia (<27%)

Upper respiratory infection (13%)

1-10%

Headache (9%)

Heart failure (up to 8%)

Sinusitis (6%)

Fracture of bone (5%)

Pharyngitis (5%)

Myalgia (5%)

Frequency Not Defined

Aggravated diabetes

Diabetic macular edema

Hepatic failure (rare)

Increased cholesterol

Decreased serum triglycerides

Hematocrit/hemoglobin

Bladder cancer

Decreased visual acuity

Dyspnea

Increased transaminases

Pharyngitis

Sinusitis

Weight gain

Contraindications

Hypersensitivity to pioglitazone

Diabetic ketoacidosis

Moderate-severe hepatic impairment (ALT >2.5x ULN)

CHF (NYHA class III, IV)

Cautions

Do initiate treatment in patients with active liver disease who have ALT levels >2.5 times the upper limit of normal (ULN); if ALT >3 times the ULN, stop treatment; if ALT is 1.5-3 times the ULN, retest qWeek until normal or until it reaches 3 times the ULN and treatment must be discontinued

Not recommended for patients with symptomatic heart failure; may cause or exacerbate congestive heart failure in some patients; monitor patients carefully after initiating therapy; observe for signs and symptoms of heart failure; if signs and symptoms develop, manage heart failure according to current standards of care; consider discontinuing therapy or reducing the dose

New onset or exacerbation of existing edema and dyspnea reported

Macular edema reported; patients should be seen by an ophthalmologist if any visual symptoms arise during therapy; all diabetic patients should have regular eye exams

Delayed related weight gain reported with use; likely associated with fluid retention and fat accumulation

Thiazolidinediones, which are peroxisome proliferator-activated receptor (PPAR) gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin

Risk of hypoglycemia, in combination with insulin or other oral agents

May result in ovulation in some premenopausal, anovulatory women; ensure adequate contraception

May decrease hemoglobin/hematocrit

Increased fracture risk in females

Use with caution in premenopausal/anovulatory females (patient may resume ovulation and increase the risk of pregnancy)

Discuss potential for unintended pregnancy with premenopausal women as therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some anovulatory women

Increased risk of CHF; not recommended in symptomatic heart failure

Cancer risk

• Bladder cancer

  • Pioglitazone may be linked to an increased risk of bladder cancer
  • Do not prescribe for patients with active bladder cancer
  • Consider benefit:risk ratio before prescribing in patients with a history of bladder cancer
  • Instruct patients to contact their physician if signs of bladder cancer observed after initiating therapy (eg, blood or red colored urine, new or worsening urinary urgency, pain on urination)

• Prostate cancer

  • 7/22/2015: Compared with nonuse, pioglitazone use was associated with increased risk for prostate cancer (453.3 vs. 449.3 per 100,000 person-years) [JAMA 2015 July 21;314(3):265-277]

• Pancreatic cancer

  • 7/22/2015: Compared with nonuse, pioglitazone use was associated with increased risk for pancreatic cancer (81.1 vs. 48.4 per 100,000 person-years)

Pregnancy: Limited data with pioglitazone in pregnant women are not sufficient to determine a drug- associated risk for major birth defects or miscarriage; there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy; poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications; poorly controlled diabetes increases fetal risk for major birth defects, still birth, and macrosomia related morbidity

Lactation: There is no information regarding the presence of pioglitazone in human milk, the effects on the breastfed infant, or the effects on milk production; the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pioglitazone and any potential adverse effects on the breastfed infant from pioglitazone or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Improves target-cell response to insulin; decreases hepatic gluconeogenesis; depends on the presence of insulin for activity

Absorption

Onset: Initial effect (delayed), max effect (several weeks)

Duration: 24 hr

Peak plasma time: 2-4 hr (delayed by food)

Distribution

Protein bound: >99%

Vd: 0.63 L/kg

Metabolism

Metabolized by hepatic CYP2C8 and CYP3A4 into active metabolites

Active metabolites: Metabolite II (hydroxy derivative), metabolite III (keto derivative), metabolite IV (active hydroxy derivative)

Elimination

Half-life: 3-7 hr

Excretion: Urine (15-30%)