Dosing & Uses
Dosage Forms & Strengths
Diabetes Mellitus Type 2
Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
Starting dose based on patient’s current regimen
Limit initial dose of pioglitazone to 15 mg/day with NYHA Class 1 or II heart failure
Coadministration with strong CYP2C8 inhibitors (eg, gemfibrozil): Do not exceed 15 mg/day pioglitazone
- Moderate (CrCl >30 to <60 mL/min): Not to exceed 12.5 mg/day alogliptin
- Severe (CrCl <30 mL/min or ESRD): Not recommended; coadministration of pioglitazone and alogliptin 6.25 mg qDay may be considered
Assess renal function before initiating alogliptin and periodically thereafter
Safety and efficacy not established
Serious - Use Alternative
Significant - Monitor Closely
Worsening CHF (9.9-13.4%)
Edema when used in combination with sulfonylurea or insulin
Back pain (4.2%)
Upper respiratory tract infection (4.1%)
Postmarketing reports (alogliptin)
Severe and disabling arthralgia
Black Box Warnings
Thiazolidinediones (eg, pioglitazone) can cause or exacerbate congestive heart failure in some patients
After initiation and 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
Discontinuation or dose reduction of thiazolidinedione must be considered
Thiazolidinediones not recommended with symptomatic heart failure; initiation in patients with established NYHA class III or IV heart failure is contraindicated
Hypersensitivity to alogliptin or pioglitazone, including anaphylaxis, angioedema, or severe cutaneous adverse reactions including Stevens-Johnson syndrome
Do not initiate pioglitazone in patients with NYHA Class III or IV heart failure (see Black Box Warnings)
Pioglitazone can cause dose-related fluid retention that may lead to or exacerbate CHF (see Black Box Warnings)
Edema; thiazolidinediones, which are peroxisome proliferator-activated receptor (PPAR) gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin
Caution with sensitivity to another DPP-4 inhibitor; discontinue if serious hypersensitivity reaction suspected (see Contraindications)
Fatal and nonfatal hepatic failure reported; type 2 DM is also known to cause fatty liver disease and liver enzyme elevation; monitor carefully and interrupt alogliptin/pioglitazone treatment if LFTs elevated, do not restart alogliptin/pioglitazone without another explanation for the liver test abnormalities
Insulin secretagogues (eg, sulfonylureas) are known to cause hypoglycemia; therefore, a lower dose may be needed to minimize hypoglycemia risk
Increased fracture risk in females
Macular edema reported with thiazolidinediones (eg, pioglitazone)
Pioglitazone may result in ovulation in premenopausal anovulatory women
Severe and disabling arthralgia reported in patients taking DPP-4 inhibitors; consider as a possible cause for severe joint pain and discontinue drug if appropriate
Congestive heart failure (CHF) risk
- Also see Black Box Warnings regarding CHF risk of pioglitazone
- The EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial enrolled 5,380 patients with type 2 diabetes and recent acute coronary syndrome
- Hospitalization for CHF was observed in 106 (3.9%) patients treated with alogliptin and 89 (3.3%) patients treated with placebo; although the difference was not statistically significant (hazard ratio, 1.19), heart failure was not an end point of the study
- Health care professionals should consider discontinuing medications containing alogliptin in patients who develop heart failure and monitor their diabetes control
- Lancet. 2015 May 23;385(9982):2067-76
- 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) [JAMA 2015 July 21;314(3):265-277]
Pregnancy & Lactation
Pregnancy Category: C
Lactation: Unknown whether distributed in breast milk
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
Alogliptin: Selective dipeptidyl peptidase-4 (DPP-4) inhibitor; slows inactivation of incretin hormones (eg, GLP-1, GIP), thereby reducing fasting and postprandial glucose concentrations in a glucose-dependent manner
Pioglitazone: Thiazolidinedione; improves target cell response to insulin; decreases hepatic gluconeogenesis
Bioavailability: ~100% (alogliptin)
Duration: 24 hr (pioglitazone)
Peak plasma time: 1-2 hr (alogliptin); 2-4 hr (pioglitazone)
Protein bound: 20% (alogliptin); >99% (pioglitazone)
Vd: 417 L (alogliptin); 0.63 L/kg (pioglitazone)
- Does not undergo extensive metabolism and 60-71% of the dose is excreted unchanged in the urine
- Active metabolite: N-demethylated (<1% of parent compound)
- Inactive metabolite: N-acetylated alogliptin (<6% of parent compound)
- Minor substrate of CYP3A4 and CYP2D6
- Metabolized to active metabolites by hepatic CYP2C8 and CYP3A4
- Metabolites: metabolite II (hydroxy derivative), metabolite III (keto derivative), metabolite IV (active hydroxy derivative) (active)
- Half-life: 21 hr
- Renal clearance: 9.6 L/hr
- Total body clearance: 14 L/hr
- Excretion: 76% urine; 13% feces
- Half-Life: 3-7 hr
- Excretion: 15-30% urine
May take with or without food
Swallow whole, do not chew, split, or crush
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The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.
|1||This drug is available at the lowest co-pay. Most commonly, these are generic drugs.|
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|3||This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.|
|4||This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.|
|5||This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.|
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