alogliptin/pioglitazone (Oseni)

Dosing and uses of Oseni (alogliptin/pioglitazone)

• Adult
• Pediatric

 

Adult dosage forms and strengths

alogliptin/pioglitazone

tablet

• 12.5mg/15mg
• 12.5mg/30mg
• 12.5mg/45mg
• 25mg/15mg
• 25mg/30mg
• 25mg/45mg

 

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

 

Dosage modifications

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

Renal impairment

• 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

 

Dosing Considerations

Assess renal function before initiating alogliptin and periodically thereafter

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Oseni (alogliptin/pioglitazone) adverse (side) effects

>10% (pioglitazone)

Worsening CHF (9.9-13.4%)

Edema when used in combination with sulfonylurea or insulin

 

1-10%

Hypoglycemia (0.8-4.5%)

Nasopharyngitis (4%)

Back pain (4.2%)

Upper respiratory tract infection (4.1%)

 

<1% (alogliptin)

Hypersensitivity (0.6%)

Pancreatitis (0.2%)

 

Postmarketing reports (alogliptin)

Severe and disabling arthralgia

 

Warnings

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

 

Contraindications

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)

 

Cautions

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

Pancreatitis reported

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

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) [JAMA 2015 July 21;314(3):265-277]

 

Pregnancy and lactation

Pregnancy category: C

Lactation: Unknown whether distributed in breast milk

 

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 Oseni (alogliptin/pioglitazone)

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

 

Absorption

Bioavailability: ~100% (alogliptin)

Duration: 24 hr (pioglitazone)

Peak plasma time: 1-2 hr (alogliptin); 2-4 hr (pioglitazone)

 

Distribution

Protein bound: 20% (alogliptin); >99% (pioglitazone)

Vd: 417 L (alogliptin); 0.63 L/kg (pioglitazone)

 

Metabolism

alogliptin

• 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

pioglitazone

• Metabolized to active metabolites by hepatic CYP2C8 and CYP3A4
• Metabolites: metabolite II (hydroxy derivative), metabolite III (keto derivative), metabolite IV (active hydroxy derivative) (active)

 

Elimination

alogliptin

• Half-life: 21 hr
• Renal clearance: 9.6 L/hr
• Total body clearance: 14 L/hr
• Excretion: 76% urine; 13% feces

pioglitazone

• Half-Life: 3-7 hr
• Excretion: 15-30% urine

 

Administration

Instructions

May take with or without food

Swallow whole, do not chew, split, or crush