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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
TRADJENTA (NDA-201280)
(LINAGLIPTIN)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
06/20/2023 (SUPPL-27)
6 Adverse Reactions
6.2 Postmarketing ExperienceAdditions and revisions underlined:
Additional adverse reactions have been identified during postapproval use of TRADJENTA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal Disorders: Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1)], mouth ulceration, stomatitis
Immune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, severe and disabling arthralgia
Skin and Subcutaneous Tissue Disorders: Bullous pemphigoid, rash
7 Drug Interactions
7.2 Insulin Secretagogues or InsulinNewly added information:
Insulin and insulin secretagogues are known to cause hypoglycemia.
8 Use in Specific Populations
8.4 Pediatric UseAdditions and revisions underlined:
The safety and effectiveness of TRADJENTA have not been established in pediatric patients.
Effectiveness of TRADJENTA was not demonstrated in a 26-week randomized, double-blind, placebo-controlled trial (NCT03429543) in 157 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus.
04/15/2022 (SUPPL-25)
5 Warnings and Precautions
5.2 Hypoglycemia with Concomitant Use with Insulin and Insulin SecretagoguesSection title revised
Additions and revisions underlined:
Insulin secretagogues and insulin are known to cause hypoglycemia. The risk of hypoglycemia is increased when TRADJENTA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin [see Adverse Reactions (6.1)].
6 Adverse Reactions
Additions and revisions underlined:
The following serious adverse reactions are described below or elsewhere in the prescribing information:
Pancreatitis [see Warnings and Precautions (5.1)]
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.2)]
Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
Severe and Disabling Arthralgia [see Warnings and Precautions (5.4)]
Bullous Pemphigoid [see Warnings and Precautions (5.5)]
Heart Failure [see Warnings and Precautions (5.6)]
7 Drug Interactions
7.2 Insulin Secretagogues or InsulinAdditions and revisions underlined:
The risk of hypoglycemia is increased when linagliptin is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Coadministration of TRADJENTA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.2)].
8 Use in Specific Populations
8.1 PregnancyAdditions and revisions underlined:
Data
Animal Data
No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent approximately 943-times (rats) and 1943-times (rabbits) the 5 mg maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49-times the maximum recommended human dose, based on exposure.
Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.
Additions and revisions underlined:
Safety and effectiveness of TRADJENTA have not been established in pediatric patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Counseling InformationAdditions and revisions underlined:
Hypoglycemia
Inform patients that the incidence of hypoglycemia is increased when TRADJENTA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin, and that a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia [see Warnings and Precautions (5.2)].
Missed Dose
Instruct patients to take TRADJENTA only as prescribed. If a dose is missed, it should be taken as soon as the patient remembers. Advise patients not to double their next dose.
03/30/2020 (SUPPL-20)
6 Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions underlined)
Hypoglycemia
Table 2 summarizes the incidence of hypoglycemia in placebo-controlled studies of TRADJENTA. The incidence of hypoglycemia increased when TRADJENTA was administered with sulfonylurea or insulin.
Table 2: Incidence (%) of Hypoglycemia in Placebo-Controlled Clinical Studies of TRADJENTA in Patients with Type 2 Diabetes Mellitus
*Hypoglycemia requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
In an active-controlled (glimepiride) cardiovascular safety study with TRADJENTA (CAROLINA) with median time on treatment of 5.9 years, the incidence of severe hypoglycemia was 0.3% in the TRADJENTA group (N=3014) and 2.2% in glimepiride group (N=3000).
Increase in Lipase: In a placebo-controlled clinical trial with TRADJENTA in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the TRADJENTA arm compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the TRADJENTA and placebo arms, respectively.
Increase in Amylase: In a cardiovascular safety study comparing TRADJENTA versus glimepiride in patients with type 2 diabetes mellitus, amylase levels above 3 times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the TRADJENTA and glimepiride arms, respectively.
The clinical significance of elevations in lipase and amylase with TRADJENTA is unknown in the absence of potential signs and symptoms of pancreatitis.
8 Use in Specific Populations
8.4 Geriatric Use
(Additions and/or revisions underlined)
In the 15 type 2 diabetes studies with linagliptin, 1085 linagliptin-treated patients were 65 years of age and older (including 131 were linagliptin-treated patients 75 years of age and older). Of these 15 studies, 12 were double-blind placebo-controlled. In these 12 studies, 591 linagliptin-treated patients were 65 years of age and older (including 82 linagliptin-treated patients 75 years of age and older). In these linagliptin studies, no overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients.
07/03/2019 (SUPPL-18)
4 Contraindications
(Additions and/or revisions are underlined)
TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity.
5 Warnings and Precautions
5.7 Macrovascular Outcomes(Newly Added Subsection)
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Advise the patient to read the FDA-approved patient labeling (Medication Guide).)
Medication Guide
Instruct patients to read the Medication Guide before starting TRADJENTA therapy and to reread it each time the prescription is renewed. Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
Inform patients of the potential risks and benefits of TRADJENTA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change.
Pancreatitis
Inform patients that acute pancreatitis has been reported during postmarketing use of TRADJENTA.
Bullous Pemphigoid
Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur.
Missed Dose
Instruct patients to take TRADJENTA only as prescribed. If a dose is missed, advise patients not to double their next dose.
Blood Glucose and A1C Monitoring
Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C levels, with a goal of decreasing these levels toward the normal range. A1C monitoring is especially useful for evaluating long-term glycemic control.
(Extensive changes; please refer to labeling)
07/01/2019 (SUPPL-21)
6 Adverse Reactions
6.2 Postmarketing Experience(addition underlined)
…
Rhabdomyolysis
08/10/2017 (SUPPL-16)
5 Warnings and Precautions
5.2 Heart Failure(Newly added subsection)
An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.
Consider the risks and benefits of TRADJENTA prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of TRADJENTA.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Additions and/or revisions are underlined)
What is the most important information I should know about TRADJENTA?
Serious side effects can happen to people taking TRADJENTA, including:
- Heart failure. Heart failure means your heart does not pump blood well enough. Before you start taking TRADJENTA, tell your doctor if you have ever had heart failure or have problems with your kidneys. Contact your doctor right away if you have any of the following symptoms:
- increasing shortness of breath or trouble breathing, especially when you lie down
- swelling or fluid retention, especially in the feet, ankles or legs
- an unusually fast increase in weight
- unusual tiredness
These may be symptoms of heart failure.
(Additions and/or revisions are underlined)
Heart Failure
Inform patients of the signs and symptoms of heart failure. Before initiating TRADJENTA, patients should be asked about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their healthcare provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet.
03/14/2017 (SUPPL-14)
6 Adverse Reactions
6.1 Clinical Trials Experience(Additions and/or revisions are underlined)
Laboratory Tests
Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the TRADJENTA group and greater than or equal to 1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group).
Increase in Lipase: In a placebo-controlled clinical trial with TRADJENTA in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the TRADJENTA arm compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the TRADJENTA and placebo arms, respectively.
Vital Signs
No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) conversion-additions and/or revisions are underlined)
Risk Summary
The limited data with TRADJENTA use in pregnant women are not sufficient to inform of drug-associated risk for major birth defects and 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 linagliptin was administered to pregnant rats during the period of organogenesis at doses similar to the maximum recommended clinical dose, based on exposure.
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 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 to 4% and 15 to 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, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.
Data
Animal Data
No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively. These doses represent approximately 943 times (rats) and 1943 times (rabbits) the 5 mg clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49 times the 5 mg clinical dose, based on exposure.(Pregnancy and Lactation Labeling Rule (PLLR) conversion -Newly added subsection)
Risk Summary
There is no information regarding the presence of linagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. However, linagliptin is present in rat milk. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRADJENTA and any potential adverse effects on the breastfed child from TRADJENTA or from the underlying maternal condition.
12/23/2016 (SUPPL-15)
5 Warnings and Precautions
5.5 Bullous Pemphigoid(Newly added subsection)
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 TRADJENTA. If bullous pemphigoid is suspected, TRADJENTA should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
6 Adverse Reactions
6.2 Postmarketing Experience(Additions and/or revisions are underlined)
- Bullous pemphigoid
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Bullous Pemphigoid
Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur.
(Additions and/or revisions are underlined)
What are the possible side effects of TRADJENTA? TRADJENTA may cause serious side effects, including:
- Skin reaction. Some people who take medicines called DPP-4 inhibitors like TRADJENTA, 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 TRADJENTA.