OSENI SIDE EFFECTS

SIDE EFFECTS

The following serious adverse reactions are described below or elsewhere in the prescribing information:

• Congestive Heart Failure
• Pancreatitis
• Hypersensitivity Reactions
• Hepatic Effects
• Severe and Disabling Arthralgia
• Bullous Pemphigoid

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 1500 patients with type 2 diabetes have received alogliptin coadministered with pioglitazone in four large, randomized, double-blind, controlled clinical trials. The mean exposure to OSENI was 29 weeks with more than 100 subjects treated for more than one year. The studies consisted of two placebo-controlled studies of 16 to 26 weeks in duration and two active-controlled studies of 26 weeks and 52 weeks in duration. In the OSENI arm, the mean duration of diabetes was approximately six years, the mean body mass index (BMI) was 31 kg/m² (54% of patients had a BMI ≥30 kg/m²), and the mean age was 54 years (16% of patients ≥65 years of age).

In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions was 65% in patients treated with OSENI compared to 57% treated with placebo. Overall discontinuation of therapy due to adverse reactions was 2.5% with OSENI compared to 2.0% with placebo, 3.7% with pioglitazone or 1.3% with alogliptin.

Adverse reactions reported in ≥4% of patients treated with OSENI and more frequently than in patients who received alogliptin, pioglitazone or placebo are summarized in Table 1.

Table 1. Adverse Reactions Reported in ≥4% of Patients Treated with OSENI and More Frequently than in Patients Receiving Either Alogliptin, Pioglitazone or Placebo.

Number of Patients (%)
	OSENI*	Alogliptin†	Pioglitazone‡	Placebo
	N=1533	N=446	N=949	N=153
Nasopharyngitis	75 (4.9)	21 (4.7)	37 (3.9)	6 (3.9)
Back Pain	64 (4.2)	9 (2.0)	32 (3.4)	5 (3.3)
Upper Respiratory Tract Infection	63 (4.1)	19 (4.3)	26 (2.7)	5 (3.3)
*OSENI – includes data pooled for patients receiving alogliptin 25 mg and 12.5 mg combined with pioglitazone 15 mg, 30 mg and 45 mg †Alogliptin – includes data pooled for patients receiving alogliptin 25 mg and 12.5 mg ‡Pioglitazone – includes data pooled for patients receiving pioglitazone 15 mg, 30 mg and 45 mg

 

Alogliptin Add-On Therapy To A Thiazolidinedione

In addition, 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%).

Hypoglycemia

In a 26 week, placebo-controlled factorial study with alogliptin in combination with pioglitazone on background therapy with metformin, the incidence of subjects reporting hypoglycemia was 0.8%, 0% and 3.8% for alogliptin 25 mg with pioglitazone 15 mg, 30 mg or 45 mg, respectively; 2.3% for alogliptin 25 mg; 4.7%, 0.8% and 0.8% for pioglitazone 15 mg, 30 mg or 45 mg, respectively; and 0.8% for placebo.

In a 26 week, active-controlled, double-blind study with alogliptin alone, pioglitazone alone or alogliptin coadministered with pioglitazone in patients inadequately controlled on diet and exercise, the incidence of hypoglycemia was 3% on alogliptin 25 mg with pioglitazone 30 mg, 0.6% on alogliptin 25 mg and 1.8% on pioglitazone 30 mg.

In a 52 week, active-controlled, double-blind study of alogliptin as add-on therapy to the combination of pioglitazone 30 mg and metformin compared to the titration of pioglitazone 30 mg to 45 mg and metformin, the incidence of subjects reporting hypoglycemia was 4.5% in the alogliptin 25 mg with pioglitazone 30 mg and metformin group versus 1.5% in the pioglitazone 45 mg and metformin group.

Alogliptin

A total of 14,778 patients with type 2 diabetes participated in 14 randomized, double-blind, controlled clinical trials of whom 9052 subjects were treated with alogliptin, 3469 subjects were treated with placebo and 2257 were treated with an active comparator. The mean duration of diabetes was seven years, the mean body mass index (BMI) was 31 kg/m² (49% of patients had a BMI ≥30 kg/m²) and the mean age was 58 years (26% of patients ≥65 years of age).

The mean exposure to alogliptin was 49 weeks with 3348 subjects treated for more than one year.

In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse reactions was 73% in patients treated with alogliptin 25 mg compared to 75% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse reactions was 6.8% with alogliptin 25 mg compared to 8.4% with placebo or 6.2% with active comparator.

Adverse reactions reported in ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo are summarized in Table 2.

Table 2. Adverse Reactions Reported in ≥4% Patients Treated with Alogliptin 25 mg and More Frequently than in Patients Given Placebo in Pooled Studies

	Number of Patients (%)
	Alogliptin 25 mg	Placebo	Active Comparator
	N=6447	N=3469	N=2257
Nasopharyngitis	309 (4.8)	152 (4.4)	113 (5.0)
Upper Respiratory Tract Infection	287 (4.5)	121 (3.5)	113 (5.0)
Headache	278 (4.3)	101 (2.9)	121 (5.4)

 

Hypoglycemia

Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia.

In the monotherapy study, 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 study 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, 3.4% of patients treated with alogliptin and 1.3% of patients treated with placebo had renal function adverse reactions. The most commonly reported adverse reactions were renal impairment (0.5% for alogliptin and 0.1% for active comparators or placebo), decreased creatinine clearance (1.6% for alogliptin and 0.5% for active comparators or placebo) and increased blood creatinine (0.5% for alogliptin and 0.3% for active comparators or placebo).

In the EXAMINE trial of high CV risk type 2 diabetes patients, 23% of patients treated with alogliptin and 21% of patients treated with placebo had an investigator reported renal impairment adverse reaction. The most commonly reported adverse reactions were renal impairment (7.7% for alogliptin and 6.7% for placebo), decreased glomerular filtration rate (4.9% for alogliptin and 4.3% for placebo) and decreased renal clearance (2.2% for alogliptin and 1.8% for placebo). 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 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with pioglitazone in the PROactive clinical trial. In these trials, over 6000 patients have been treated with pioglitazone for six months or longer, over 4500 patients have been treated with pioglitazone for one year or longer, and over 3000 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 3. 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 3. Three Pooled 16 to 26 Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Reactions Reported at an Incidence >5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo

% of Patients
	Placebo N=259	Pioglitazone N=606
Upper Respiratory Tract Infection	8.5	13.2
Headache	6.9	9.1
Sinusitis	4.6	6.3
Myalgia	2.7	5.4
Pharyngitis	0.8	5.1

 

Congestive Heart Failure

A summary of the incidence of adverse reactions related to congestive heart failure for the 16 to 24 week add-on to sulfonylurea trials, for the 16 to 24 week add-on to insulin trials, and for the 16 to 24 week add-on to metformin trials were (at least one congestive heart failure, 0.2% to 1.7%; hospitalized due to congestive heart failure, 0.2% to 0.9%). None of the reactions were fatal.

Patients with type 2 diabetes 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 4.

Table 4. 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

	Number (%) of Subjects
	Pioglitazone N=262	Glyburide N=256
Death due to cardiovascular causes (adjudicated)	5 (1.9%)	6 (2.3%)
Overnight hospitalization for worsening CHF (adjudicated)	26 (9.9%)	12 (4.7%)
Emergency room visit for CHF (adjudicated)	4 (1.5%)	3 (1.2%)
Patients experiencing CHF progression during study	35 (13.4%)	21 (8.2%)

 

Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 5.

Table 5. Treatment-Emergent Adverse Reactions of Congestive Heart Failure (CHF) in PROactive Trial

	Number (%) of Patients
	Placebo N=2633	Pioglitazone N=2605
At least one hospitalized congestive heart failure event	108 (4.1%)	149 (5.7%)
Fatal	22 (0.8%)	25 (1%)
Hospitalized, nonfatal	86 (3.3%)	124 (4.7%)

 

Cardiovascular Safety

In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) 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 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. A total of 514 (19.7%) patients treated with pioglitazone and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).

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 6.

Table 6. PROactive: Number of First and Total Events for Each Component Within theCardiovascular Composite Endpoint

Cardiovascular Events	Placebo N=2633		Pioglitazone N=2605
	First Events n (%)	Total Events n	First Events n (%)	Total Events n
Any Event	572 (21.7)	900	514 (19.7)	803
All-Cause Mortality	122 (4.6)	186	110 (4.2)	177
Nonfatal Myocardial   Infarction (MI)	122 (4.6)	157	105 (4)	131
Stroke	96 (3.6)	119	76 (2.9)	92
Acute Coronary Syndrome	63 (2.4)	78	42 (1.6)	65
Cardiac Intervention   (CABG/PCI)	101 (3.8)	240	101 (3.9)	195
Major Leg Amputation	15 (0.6)	28	9 (0.3)	28
Leg Revascularization	57 (2.2)	92	71 (2.7)	115
CABG=coronary artery bypass grafting; PCI=percutaneous intervention

 

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. A total of 3/1051 (0.3%) patients treated with pioglitazone and 9/1046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. 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. In the 16 week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with pioglitazone 15 mg, 15.4% with pioglitazone 30 mg and 4.8% with placebo. The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to pioglitazone 30 mg in both the 24 week add-on to sulfonylurea trial (15.7% versus 13.4%) and in the 24 week add-on to insulin trial (47.8% versus 43.5%). 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 . During the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer. 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 two (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. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; 95% CI: 0.59-1.72).

Laboratory Abnormalities

Pioglitazone

Hematologic Effects

Pioglitazone may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. 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 2150 to 11400 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

Alogliptin

The following adverse reactions have been identified during the postmarketing use of alogliptin. 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.

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

The following adverse reactions have been identified during the postmarketing use of 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.

Cardiac disorders: rapid increases in weight and increases in excess of that generally observed in clinical trials, excessive edema, congestive heart failure both with and without previously known heart disease and both with and without concomitant insulin administration

Eye disorders: New onset or worsening diabetic macular edema with decreased visual

Hepatobiliary disorders: Fatal and nonfatal hepatic failure

 

SRC: NLM .