Oseni Drug Information

OSENI is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: OSENI is not recommended for use in patients with type 1 diabetes mellitus.

Important Dosage and Administration Information

Obtain liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) prior to initiating OSENI. Take OSENI orally once daily. Do not split tablets.

OSENI may be taken with or without food. If a dose is missed, do not double the next dose.

Recommended Dosage and Administration Recommended Starting Dosage Based on Current Regimen Individualize the starting dosage of OSENI based on the patient's current regimen and the available strengths of OSENI (see Table 1 ). Table 1: Recommended Starting Dosage Based on the Patient’s Current Regimen Current Regimen Starting Dosage of OSENI (alogliptin/pioglitazone) For dosage recommendations for patients with renal impairment and/or congestive heart failure,. Dosage Titration for Additional Glycemic Control Titrate the OSENI dosage gradually, as needed, after assessing therapeutic response and tolerability, up to a maximum dosage of 25 mg of alogliptin and 45 mg of pioglitazone once daily.

Recommended Dosage for Patients with Renal Impairment

Assess renal function prior to initiation of OSENI and periodically thereafter. The recommended dosage of OSENI in patients with mild renal impairment (creatinine clearance ≥60 mL/min) is the same as the recommended dosage in patients with normal renal function. OSENI is not recommended for patients with severe renal impairment (CrCl ≥15 to <30 mL/min) or ESRD (CrCl <15 mL/min or requiring hemodialysis) because these patients require a lower dosage of alogliptin than what is available in the fixed dose combination product, OSENI.

Recommendations for Congestive Heart Failure Starting Dosage in Patients with NYHA Class I or II Congestive Heart Failure For patients with preexisting NYHA Class I or II congestive heart failure, the recommended starting dosage of OSENI is 25 mg of alogliptin and 15 mg of pioglitazone. Monitoring for Fluid Retention and Dosage Modifications for Congestive Heart Failure After initiation of OSENI or with dosage increase, monitor patients carefully for adverse reactions related to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and symptoms of congestive heart failure). If congestive heart failure develops while taking OSENI, consider discontinuation of OSENI or dosage reduction of pioglitazone in OSENI.

Coadministration with Strong CYP2C8 Inhibitors

The maximum recommended dosage of OSENI is 25 mg of alogliptin and 15 mg of pioglitazone once daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Alogliptin and Pioglitazone Over 1,500 patients with type 2 diabetes mellitus have received alogliptin coadministered with pioglitazone in four large, randomized, double-blind, controlled clinical trials. The mean exposure to alogliptin and pioglitazone was 29 weeks with more than 100 subjects treated for more than one year.

In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions was 65% in patients treated with alogliptin and pioglitazone compared to 57% treated with placebo. Adverse reactions reported in ≥4% of patients treated with alogliptin and pioglitazone and more frequently than in patients who received alogliptin, pioglitazone or placebo are summarized in Table 2. Table 2.

Adverse Reactions Reported in ≥4% of Patients Treated with Alogliptin and Pioglitazone and More Frequently than in Patients Receiving Either Alogliptin, Pioglitazone or Alogliptin Add-On Therapy to a Thiazolidinedione In a 26 week, placebo-controlled, double-blind study, patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea were treated with add-on alogliptin therapy or placebo; the adverse reactions reported in ≥5% of patients and more frequently than in patients who received placebo was influenza (alogliptin, 5.5%; placebo, 4.1%). The ethnic distribution was 30% Hispanic or Latino and 70% was not Hispanic or Latino. The mean exposure to alogliptin was 49 weeks with 3,348 subjects treated for more than one year.

Adverse reactions reported in ≥4% of adult patients treated with alogliptin 25 mg and more frequently than in patients who received placebo are summarized in Table 3. Table 3. Adverse Reactions Reported in ≥4% Adult Patients with Type 2 Diabetes Mellitus Treated with Alogliptin 25 mg and More Frequently Than in Patients Given 101 121 Hypoglycemia Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia.

In the monotherapy trial, the incidence of hypoglycemia was 1.5% in patients treated with alogliptin compared to 1.6% with placebo. The use of alogliptin as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy trial comparing alogliptin to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with alogliptin compared to 26% with glipizide.

In the EXAMINE trial, the incidence of investigator reported hypoglycemia was 6.7% in patients receiving alogliptin and 6.5% in patients receiving placebo. Serious adverse reactions of hypoglycemia were reported in 0.8% of patients treated with alogliptin and in 0.6% of patients treated with placebo. Renal Impairment In glycemic control trials in patients with type 2 diabetes mellitus, 3.4% of patients treated with alogliptin and 1.3% of patients treated with placebo had renal function adverse reactions.

In the EXAMINE trial of high CV risk type 2 diabetes mellitus patients, 23% of patients treated with alogliptin and 21% of patients treated with placebo had an investigator reported renal impairment adverse reaction. Laboratory measures of renal function were also assessed. Estimated glomerular filtration rate decreased by 25% or more in 21.1% of patients treated with alogliptin and 18.7% of patients treated with placebo.

Worsening of chronic kidney disease stage was seen in 16.8% of patients treated with alogliptin and in 15.5% of patients treated with placebo. Pioglitazone Over 8,500 patients with type 2 diabetes mellitus have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2,605 patients with type 2 diabetes mellitus and macrovascular disease treated with pioglitazone in the PROactive clinical trial. In these trials, over 6,000 patients have been treated with pioglitazone for six months or longer, over 4,500 patients have been treated with pioglitazone for one year or longer, and over 3,000 patients have been treated with pioglitazone for at least two years.

Common Adverse Reactions: 16 to 26-Week Monotherapy Trials A summary of the incidence and type of common adverse reactions reported in three pooled 16 to 26 week placebo-controlled monotherapy trials of pioglitazone is provided in Table 4. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse reactions were related to pioglitazone dose.

Table 4. None of the reactions were fatal. Patients with type 2 diabetes mellitus and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either pioglitazone at daily doses of 30 mg to 45 mg (N=262) or glyburide at daily doses of 10 mg to 15 mg (N=256).

A summary of the incidence of adverse reactions related to congestive heart failure reported in this study is provided in Table 5. Table 5. Treatment-Emergent Adverse Reactions of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with Pioglitazone or Glyburide Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 6.

Table 6. Treatment-Emergent Adverse Reactions of Congestive Heart Failure (CHF) in PROactive Trial Cardiovascular Safety In the PROactive trial, 5,238 patients with type 2 diabetes mellitus and a history of macrovascular disease were randomized to pioglitazone (N=2,605), force-titrated up to 45 mg daily or placebo (N=2,633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates).

At baseline, patients had a mean age of 62 years, mean duration of diabetes mellitus of 9.5 years and mean A1C of 8.1%. Mean duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events.

The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle and bypass surgery or revascularization in the leg. Although there was no statistically significant difference between pioglitazone and placebo for the three-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with pioglitazone. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 7.

Table 7. PROactive: Number of First and Total Events for Each Component Within the Cardiovascular Composite Endpoint Weight Gain Dose-related weight gain occurs when pioglitazone is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Edema Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure. Hepatic Effects There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date.

One randomized, double-blind, three-year trial comparing pioglitazone to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. None of the patients treated with pioglitazone in the pioglitazone controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury. Hypoglycemia In the pioglitazone clinical trials, adverse reactions of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with finger stick glucose testing.

In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with pioglitazone 30 mg and 0.5% with placebo. Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving pioglitazone 30 mg (0.9%) in the 24-week add-on to insulin trial.

An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient’s usual activities) that did not require hospitalization. These patients were receiving pioglitazone 45 mg in combination with sulfonylurea (N=2) or pioglitazone 30 mg or 45 mg in combination with insulin (N=12). Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study.

After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and 2 (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. Laboratory Abnormalities Pioglitazone Hematologic Effects Pioglitazone may cause decreases in hemoglobin and hematocrit.

These changes primarily occurred within the first four to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and are not likely to be associated with any clinically significant hematologic effects. Creatine Phosphokinase During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) patients treated with pioglitazone (values of 2,150 to 11,400 IU/L) and in no comparator-treated patients.

Six of these nine patients continued to receive pioglitazone, two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued pioglitazone due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown.

Postmarketing Experience

The following adverse reactions have been identified during the postmarketing use of alogliptin or pioglitazone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Alogliptin Gastrointestinal Disorders: acute pancreatitis, diarrhea, constipation, nausea, ileus Hepatobiliary Disorders: fulminant hepatic failure Immune System Disorders: hypersensitivity reactions including anaphylaxis Investigations: hepatic enzyme elevations Musculoskeletal and Connective Tissue Disorders: severe and disabling arthralgia, rhabdomyolysis Renal and Urinary Disorders: tubulointerstitial nephritis Skin and Subcutaneous Tissue Disorders: angioedema, rash, urticaria and severe cutaneous adverse reactions including Stevens-Johnson syndrome, bullous pemphigoid Pioglitazone Cardiac Disorders: rapid increases in weight, edema, congestive heart failure both with and without previously known heart disease or concomitant insulin administration Eye Disorders: New onset or worsening diabetic macular edema with decreased visual acuity Hepatobiliary Disorders: Fatal and nonfatal hepatic failure

Insulin Secretagogues and Insulin Insulin and insulin secretagogues are known to cause hypoglycemia. Coadministration of OSENI with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue and insulin to reduce the risk of hypoglycemia.

Strong CYP2C8 Inhibitors

An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the concentration-time curve ) and half-life of pioglitazone. Therefore, the maximum recommended dosage of OSENI is 25 mg of alogliptin and 15 mg of pioglitazone once daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors.

CYP2C8 Inducers

An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with OSENI, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of OSENI (25 mg of alogliptin and 45 mg of pioglitazone).

Topiramate

A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate. The clinical relevance of this decrease is unknown; however, when OSENI and topiramate are used concomitantly, monitor patients for adequate glycemic control.

Pregnancy Risk Summary Limited data with OSENI in pregnant women are not sufficient to inform 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. In animal reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5 and 35 times the 45 mg clinical dose, respectively, based on body surface area.

No adverse developmental effects were observed when alogliptin was administered to pregnant rats and rabbits during organogenesis at exposures 180 and 149 times the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC). The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Data Animal Data Alogliptin and Pioglitazone Co-administration of 100 mg/kg alogliptin and 40 mg/kg pioglitazone (39 and 10 times the 25 mg and 45 mg clinical doses, respectively, based on body surface area) to pregnant rats during organogenesis slightly augmented pioglitazone-related fetal effects of delayed development and reduced fetal weights but did not result in embryofetal mortality or teratogenicity. Alogliptin Alogliptin administered to pregnant rabbits and rats during the period of organogenesis did not cause adverse developmental effects at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times, the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC). Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats.

No adverse developmental outcomes were observed in offspring when alogliptin was administered to pregnant rats during gestation and lactation at doses up to 250 mg/kg (~95 times the 25 mg clinical dose, based on AUC). Pioglitazone Pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (~5-times the 45 mg clinical dose), but delayed parturition and reduced embryofetal viability at 40 and 80 mg/kg, or ≥9-times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35-times the 45 mg clinical dose), but reduced embryofetal viability at 160 mg/kg, or ~69-times the 45 mg clinical dose, by body surface area.

When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or ≥2 times the 45 mg clinical dose, by body surface area.

Pediatric Use Safety and effectiveness of OSENI in pediatric patients have not been established. OSENI is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures and urinary bladder tumors.

OSENI is contraindicated in patients with: Established NYHA Class III or IV heart failure at the time of OSENI initiation. A history of serious hypersensitivity reaction to alogliptin, pioglitazone, or any of the excipients in OSENI. Reactions such as anaphylaxis, angioedema and severe cutaneous adverse reactions have been reported.

In the event of an overdose, it is reasonable to institute the necessary clinical monitoring and supportive therapy as dictated by the patient's clinical status. Per clinical judgment, it may be reasonable to initiate removal of unabsorbed material from the gastrointestinal tract. Alogliptin is minimally dialyzable; over a three-hour hemodialysis session, approximately 7% of the drug was removed.

Therefore, hemodialysis is unlikely to be beneficial in an overdose situation. It is not known if alogliptin is dialyzable by peritoneal dialysis. In the event of an overdose, contact the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.