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Oseni

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Congestive Heart Failure

Pioglitazone

Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone must be considered [see BOXED WARNING, CONTRAINDICATIONS, and ADVERSE REACTIONS].

Pancreatitis

There have been postmarketing reports of acute pancreatitis in patients taking alogliptin. After initiation of OSENI, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, OSENI should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using OSENI.

Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin. These reactions include anaphylaxis, angioedema, and severe cutaneous adverse reactions including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue OSENI, assess for other potential causes for the event, and institute alternative treatment for diabetes [see ADVERSE REACTIONS]. Use caution in patients with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with OSENI.

Hepatic Effects

There have been postmarketing reports of fatal and non-fatal hepatic events in patients taking pioglitazone or alogliptin, although the reports contain insufficient information necessary to establish the probable cause [see ADVERSE REACTIONS]. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date [see ADVERSE REACTIONS]. In randomized controlled studies of alogliptin, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were observed: 1.3% in alogliptin-treated patients and 1.5% in all comparator-treated patients.

Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (ALT, aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating OSENI therapy. In patients with abnormal liver tests, OSENI should be initiated with caution.

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), OSENI treatment should be interrupted and an investigation done to establish the probable cause. OSENI should not be restarted in these patients without another explanation for the liver test abnormalities.

Edema

Pioglitazone

In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose related [see ADVERSE REACTIONS]. In postmarketing experience, reports of new onset or worsening of edema have been received. OSENI should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, OSENI should be used with caution in patients at risk for congestive heart failure. Patients treated with OSENI should be monitored for signs and symptoms of congestive heart failure [see BOXED WARNING and PATIENT INFORMATION].

Fractures

Pioglitazone

In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 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. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.

Urinary Bladder Tumors

Pioglitazone

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology]. In two 3-year trials in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) cases on placebo.

A five-year interim report of an ongoing 10-year observational cohort study found a nonsignificant increase in the risk for bladder cancer in subjects ever exposed to pioglitazone, compared to subjects never exposed to pioglitazone (HR 1.2 [95% CI 0.91.5]). Compared to never exposure, a duration of pioglitazone therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9-2.1]), which reached statistical significance after more than 24 months of pioglitazone use (HR 1.4 [95% CI 1.03-2.0]). Interim results from this study suggested that taking pioglitazone longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of 3 cases in 10,000 (from approximately 7 in 10,000 [without pioglitazone] to approximately 10 in 10,000 [with pioglitazone]).

There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, pioglitazone should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone should be considered in patients with a prior history of bladder cancer.

Use with Medications Known to Cause Hypoglycemia

Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with OSENI.

Macular Edema

Pioglitazone

Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.

Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione.

Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings [see ADVERSE REACTIONS].

Ovulation

Pioglitazone

Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking OSENI [see Use In Specific Populations]. This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with OSENI is recommended.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with OSENI or any other antidiabetic drug.

Patient Counseling Information

See FDA-Approved Patient Labeling (Medication Guide).

Instructions

Inform patients of the potential risks and benefits of OSENI.

Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on OSENI should immediately report these symptoms to their physician.

Patients should be informed that acute pancreatitis has been reported during use of alogliptin. Patients should be informed that persistent, severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue OSENI and contact their physician if persistent severe abdominal pain occurs.

Patients should be informed that allergic reactions have been reported during use of alogliptin and pioglitazone. If symptoms of allergic reactions (including skin rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients should be instructed to discontinue OSENI and seek medical advice promptly.

Patients should be informed that postmarketing reports of liver injury, sometimes fatal, have been reported during use of alogliptin and pioglitazone. If signs or symptoms of liver injury occur (e.g. unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine), patients should be instructed to discontinue OSENI and seek medical advice promptly.

Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.

Inform patients that hypoglycemia can occur, particularly when an insulin secretagogue or insulin is used in combination with OSENI. Explain the risks, symptoms, and appropriate management of hypoglycemia.

Therapy with thiazolidinediones, including pioglitazone which is one of the active components of OSENI, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking OSENI. Therefore, adequate contraception should be recommended for all premenopausal women who are prescribed OSENI.

Instruct patients to take OSENI only as prescribed daily. OSENI can be taken with or without meals. If a dose is missed, advise patients not to double their next dose.

Patients should be informed that the tablets must never be split.

Instruct patients to read the Medication Guide before starting OSENI therapy and to reread each time the prescription is refilled. Instruct patients to inform their healthcare provider if an unusual symptom develops or if a symptom persists or worsens.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Alogliptin and Pioglitazone

No carcinogenicity, mutagenicity, or impairment of fertility studies have been conducted with OSENI. The following data are based on findings in studies performed with alogliptin or pioglitazone individually.

Alogliptin

Rats were administered oral doses of 75, 400, and 800 mg/kg alogliptin for 2 years. No drug-related tumors were observed up to 75 mg/kg or approximately 32 times the maximum recommended clinical dose of 25 mg, based on AUC exposure. At higher doses (approximately 308 times the maximum recommended clinical dose of 25 mg), a combination of thyroid C-cell adenomas and carcinomas increased in male but not female rats. No drug-related tumors were observed in mice after administration of 50, 150, or 300 mg/kg alogliptin for 2 years, or up to approximately 51-times the maximum recommended clinical dose of 25 mg, based on AUC exposure.

Alogliptin was not mutagenic or clastogenic, with and without metabolic activation, in the Ames test with S. typhimurium and E. coli or the cytogenetic assay in mouse lymphoma cells. Alogliptin was negative in the in vivo mouse micronucleus study.

In a fertility study in rats, alogliptin had no adverse effects on early embryonic development, mating, or fertility, at doses up to 500 mg/kg, or approximately 172-times the clinical dose based on plasma drug exposure (AUC).

Pioglitazone

A two year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the MRHD of 45 mg based on mg/m²). Druginduced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg and above (approximately equal to the MRHD based on mg/m²). A two year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg (approximately 11 times the MRHD based on mg/m²). No drug-induced tumors were observed in any organ.

Pioglitazone was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.

No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone daily prior to and throughout mating and gestation (approximately 9 times the MRHD based on mg/m²).

Use In Specific Populations

Pregnancy

Pregnancy Category C

Alogliptin and Pioglitazone

There are no adequate and well-controlled studies in pregnant women with OSENI or its individual components. Based on animal data, the likelihood that OSENI increases the risk of developmental abnormalities is predicted to be low. OSENI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When administered to rats during organogenesis the combination treatment with alogliptin and pioglitazone (100 mg/kg alogliptin plus 40 mg/kg pioglitazone) slightly augmented pioglitazone-related fetal effects of delayed development and reduced fetal weights, but did not result in embryo-fetal mortality or teratogenicity.

Alogliptin

Alogliptin administered to pregnant rabbits and rats during the period of organogenesis was not teratogenic at doses of up to 200 and 500 mg/kg, or 149-times and 180-times, respectively, the clinical dose based on plasma drug exposure (AUC).

Doses of alogliptin up to 250 mg/kg (approximately 95-times clinical exposure based on AUC) given to pregnant rats from gestation day 6 to lactation day 20 did not harm the developing embryo or adversely affect growth and development of offspring.

Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats.

Pioglitazone

In animal reproductive studies, pregnant rats and rabbits received pioglitazone at doses up to approximately 17 (rat) and 40 (rabbit) times the MRHD based on body surface area (mg/m²); no teratogenicity was observed. Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more times the MRHD (mg/m² basis). No functional or behavioral toxicity was observed in rat offspring. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses approximately 2 or more times the MRHD (mg/m² basis). In rabbits, embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m² basis).

Nursing Mothers

No studies have been conducted with the combined components of OSENI. In studies performed with the individual components, both alogliptin and pioglitazone are secreted in the milk of lactating rats. It is not known whether alogliptin and/or pioglitazone are secreted in human milk. Because many drugs are excreted in human milk, and because of the potential for OSENI to cause serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue OSENI, taking into account the importance of OSENI to the mother.

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 [see WARNINGS AND PRECAUTIONS].

Geriatric Use

Alogliptin and Pioglitazone

Of the total number of patients (N=1533) in clinical safety and efficacy studies treated with alogliptin and pioglitazone, 248 (16.2%) patients were 65 years and older and 15 (1%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. While this and other reported clinical experiences have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be excluded.

Alogliptin

Of the total number of patients (N=8507) in clinical safety and efficacy studies treated with alogliptin, 2064 (24.3%) patients were 65 years and older and 341 (4%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients.

Pioglitazone

A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16- to 26-week double-blind, placebo-controlled, monotherapy, trials were ≥ 65 years old and 2 patients (0.3%) were ≥ 75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥ 65 years old and 19 (1.8%) were ≥ 75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥ 65 years old and 19 (1.9%) were ≥ 75 years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥ 65 years old and 22 (2.1%) were ≥ 75 years old.

In PROactive, 1068 patients (41%) treated with pioglitazone were ≥ 65 years old and 42 (1.6%) were ≥ 75 years old.

In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients. These clinical experiences have not identified differences in effectiveness and safety between the elderly ( ≥ 65 years) and younger patients although small sample sizes for patients ≥ 75 years old limit conclusions [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

Alogliptin

No dose adjustments are required in patients with mild to moderate hepatic impairment (Child-Pugh Grade A and B) based on insignificant change in systemic exposures (e.g., AUC) compared to subjects with normal hepatic function in a pharmacokinetic study. Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh Grade C). Use caution when administering alogliptin to patients with liver disease [see WARNINGS AND PRECAUTIONS].

Pioglitazone

No dose adjustments are required in patients with hepatic impairment (Child-Pugh Grade B/C) based on insignificant change in systemic exposures (e.g., AUC) compared to subjects with normal hepatic function in a pharmacokinetic study. However, use with caution in patients with liver disease [see WARNINGS AND PRECAUTIONS].

Last reviewed on RxList: 2/11/2013
This monograph has been modified to include the generic and brand name in many instances.

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