Dosing and uses of Actos (pioglitazone)
Adult dosage forms and strengths
tablet
- 15mg
- 30mg
- 45mg
Type 2 Diabetes Mellitus
Indicated as monotherapy or with insulin or insulin secretagogues
15-30 mg PO with meal qDay initial; may increase dose by 15 mg with careful monitoring to 45 mg qDay maximum
Monitor ALT at start of treatment, qMonth for 12 months, q3Months thereafter
Dosing Considerations
Coadministration with insulin secretagogue (eg, sulfonylurea): Decrease insulin secretagogue dose
Coadministration with insulin: Decrease insulin dose by 10-25%
Coadministration with strong CYP2C8 inhibitors (eg, gemfibrozil): Limit maximum pioglitazone dose to 15 mg qDay
Pediatric dosage forms and strengths
Not recommended
Actos (pioglitazone) adverse (side) effects
>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
Warnings
Black box warnings
Thiazolidinediones, including pioglitazone and rosiglitazone, cause or exacerbate congestive heart failure in some patients
After initiation of these drugs, as well as after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain; dyspnea; and/or edema); if these signs or symptoms develop, the heart failure should be managed according to the current standards of care; furthermore, discontinuation or dose reduction of these drugs must be considered.
These drugs are not recommended for patients with symptomatic heart failure; initiation of these drugs in patients with established NYHA class III or IV heart failure is contraindicated
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
New onset or exacerbation of existing edema, rapid weight gain, macular edema dyspnea reported
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)
Increased risk of CHF; not recommended in symptomatic heart failure
Cancer risk
- Bladder cancer
- 5-year interim results of a 10-year cohort study suggest that pioglitazone use >12 months increases the relative risk of developing bladder cancer in any given year by 40%, an increase from ~7 cases in 10,000 to ~10 cases in 10,000
- Greatest risk was shown in patients with long-term use and the highest cumulative doses
- FDA recommendations include not prescribing pioglitazone for patients with active bladder cancer and cautious use in patients with a history of bladder cancer
- 7/22/2015: A prospective study found that during ~7 years' follow-up, the rate of incident bladder cancer was higher in patients who had ever used pioglitazone than nonusers (89.8 vs. 75.9 per 100,000 person-years), but the difference was not significant after adjustment for potential confounders [JAMA 2015 July 21;314(3):265-277]
- 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 and lactation
Pregnancy category: C
Lactation: Not known if excreted in breast milk; discontinue drug or do not nurse
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.
Pharmacology of Actos (pioglitazone)
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%)
