Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

OSENI (NDA-022426)

(ALOGLIPTIN BENZOATE; PIOGLITAZONE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

Download Data

Expand all

06/28/2024 (SUPPL-16)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

OSENI is contraindicated in patients with:

• Established NYHA Class III or IV heart failure at the time of OSENI initiation [see Boxed Warning].

• 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 [see Warnings and Precautions (5.3), Adverse reactions (6.2)].

5 Warnings and Precautions

Additions and/or revisions underlined:

…

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 clinically significant liver enzyme elevations (serum ALT greater than three times the ULN) and if abnormal liver tests persist or worsen, OSENI 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.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

•     Edema [see Warnings and Precautions (5.5)]

•     Fractures [see Warnings and Precautions (5.6)]

•     Urinary Bladder Tumors [see Warnings and Precautions (5.7)]

•     Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.8)]

•     Macular Edema [see Warnings and Precautions (5.9)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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

7 Drug Interactions

7.1 Insulin Secretagogues and Insulin

Newly added subsection:

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 [see Warnings and Precautions (5.8)].

7.2 Strong CYP2C8 Inhibitors

Additions and/or revisions underlined:

An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the concentration-time curve [AUC]) 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 [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

7.3 CYP2C8 Inducers

Additions and/or revisions underlined:

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) [see Clinical Pharmacology (12.3)].

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There is no information regarding the presence of pioglitazone or alogliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone and alogliptin are present in rat milk; however, due to species-specific differences in lactation physiology, animal lactation data may not reliably predict drug levels in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OSENI and any potential adverse effects on the breastfed infant from OSENI or from the underlying maternal condition.

8.5 Geriatric Use

Additions and/or revisions underlined:

Alogliptin and Pioglitazone

Of the total number of patients (N=1,533) 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 patients 65 years of age and older and younger adult patients.

Alogliptin

Of the total number of patients (N=9,052) in clinical safety and efficacy studies treated with alogliptin, 2,257 (24.9%) patients were greater than or equal to 65 years old and 386 (4.3%) patients were  greater than or equal to 75 years old. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients.

…

8.6 Renal Impairment

Additions and/or revisions underlined:

Alogliptin

A total of 602 patients with moderate renal impairment (eGFR greater than or equal to 30 and <60 mL/min/1.73 m2) and four patients with severe renal impairment/end-stage renal disease (eGFR <30 mL/min/1.73 m2 or

<15 mL/min/1.73 m2, respectively) at baseline were treated with alogliptin in clinical trials in patients with type 2 diabetes mellitus.

In the EXAMINE trial of high CV risk type 2 diabetes mellitus patients, 694 patients had moderate renal impairment and 78 patients had severe renal impairment or end-stage renal disease at baseline. The recommended dosage of OSENI for patients with moderate renal impairment (CrCl  greater than or equal to 30 to <60 mL/min) is 12.5 mg of alogliptin and 30 mg of pioglitazone once daily. OSENI is not recommended for patients with severe renal impairment (CrCl greater than or equal to 15 to <30 mL/min) or ESRD (CrCl < 15 mL/min or requiring hemodialysis) [see Dosage and Administration (2.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

• Bladder tumors. There may be an increased chance of having bladder cancer when you take OSENI. You should not take OSENI if you are receiving treatment for bladder cancer. Tell your healthcare provider right away if you have any of the following symptoms of bladder cancer:

  • blood or a red color in your urine  

  • an increased need to urinate  

  • pain while you urinate

…

What are the ingredients in OSENI?

Active Ingredients: alogliptin and pioglitazone

Inactive Ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose; the tablets are film-coated with ferric oxide (yellow and/or red), hypromellose, polyethylene glycol, talc, titanium dioxide, and are marked with printing ink (Red A1 or Gray F1).

…

PATIENT COUNSELING INFORMATION

Extensive changes; please refer to label

03/11/2022 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues

Subsection title revised

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and revisions underlined:

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Extensive changes; please refer to label

Patient Counseling Information

Extensive changes; please refer to label

07/01/2019 (SUPPL-12)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

(addition underlined)

…

Acute pancreatitis, hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic enzyme elevations, fulminant hepatic failure, severe and disabling arthralgia and bullous pemphigoid , rhabdomyolysis, diarrhea, constipation, nausea and ileus.

…

12/21/2017 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

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.

7 Drug Interactions

7.3 Topiramate

(Newly added subsection)

Pioglitazone

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.

12/12/2016 (SUPPL-6)

5 Warnings and Precautions

5.7 Urinary Bladder Tumors

(additions underlined)

Pioglitazone

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In addition, 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]).

Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone, while others did.

A large prospective10 year observational cohort study conducted in the United States found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to pioglitazone, compared to those never exposed to pioglitazone (HR =1.06 [95% CI 0.89–1.26]).

A retrospective cohort study conducted with data from the United Kingdom found a statistically significant association between ever exposure to pioglitazone and bladder cancer (HR: 1.63; [95% CI: 1.22–2.19]).

 

Associations between cumulative dose or cumulative duration of expo sure to pioglitazone and bladder cancer were not detected in some studies including the 10 year observational study in the U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies preclude conclusive interpretations of the observational data.po

Pioglitazone may be associated with an increase in the risk of urinary bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors.

Consequently, OSENI should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with OSENI should be considered in patients with a prior history of bladder cancer.

6 Adverse Reactions

 (addition underlined)

•         Severe and Disabling Arthralgia

6.1 Clinical Trials Experience

(additions underlined)

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)

6.3 Postmarketing Experience

(additions underlined)

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.

Acute pancreatitis, hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic enzyme elevations, fulminant hepatic failure, severe and disabling arthralgia diarrhea, constipation, nausea and ileus.

8 Use in Specific Populations

8.1 Pregnancy

 (PLLR conversion)

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.

 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 3

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, still birth 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 and45 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

logliptin 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 of10 mg/kg and above or ?2 times the 45 mg clinical dose, by body surface area.

8.2 Lactation

Risk Summary

There is no information regarding the presence of pioglitazone or alogliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone and alogliptin are present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OSENI and any potential adverse effects on the breastfed infant from OSENI or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

(PLLR Conversion)

Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some anovulatory women.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(additions underlined)

Inform female patients that treatment with pioglitazone, like other thiazolidinediones, may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation.

Medication Guide

(additions underlined)

What should I tell my doctor before and during treatment with OSENI?

·       are a premenopausal woman who does not have periods regularly or at all. OSENI may increase your chance of becoming pregnant. Talk to your doctor about birth control choices while taking OSENI. Tell your doctor right away if you become pregnant while taking OSENI.

·       are breastfeeding or plan to breastfeed. It is not known whether OSENI passes into your breast milk and if it can harm your baby. Talk with your doctor about the best way to control your blood glucose levels while breastfeeding.

12/12/2016 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Bullous Pemphigoid

 (New subsection added)

 

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving OSENI. If bullous pemphigoid is suspected, OSENI should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

6 Adverse Reactions

(addition underlined)

•         Bullous Pemphigoid

6.3 Postmarketing Experience

(addition underlined)

Acute pancreatitis, hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic enzyme elevations, fulminant hepatic failure, severe and disabling arthralgia and bullous pemphigoid , diarrhea, constipation, nausea and ileus.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

 (addition underlined)

Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur.

MEDICATION GUIDE

(addition underlined)

OSENI can cause serious side effects, including:

• Skin reaction. Some people who take medicines called DPP-4 inhibitors, one of the medicines in OSENI, may develop a skin reaction called bullous pemphigoid that can require treatment in a hospital. Tell your doctor right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your doctor may tell you to stop taking OSENI.