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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.
TRESIBA (BLA-203314)
(INSULIN DEGLUDEC)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
07/01/2022 (SUPPL-18)
4 Contraindications
Additions and/or revisions underlined:
TRESIBA is contraindicated:
During episodes of hypoglycemia [see Warnings and Precautions (5.3)].
In patients with hypersensitivity to insulin degludec or any of the excipients in TRESIBA [see Warnings and Precautions (5.5)].
5 Warnings and Precautions
5.3 Hypoglycemia
Additions and/or revisions underlined:
Hypoglycemia is the most common adverse reaction of insulin, including TRESIBA [see Adverse Reactions (6.1)]. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). TRESIBA, or any insulin, should not be used during episodes of hypoglycemia [see Contraindications (4)].
Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, using drugs that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or who experience recurrent hypoglycemia.
The long-acting effect of TRESIBA may delay recovery from hypoglycemia compared to shorter-acting insulins.
Risk Factors for Hypoglycemia
The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia after an injection is related to the duration of action of the insulin [see Clinical Pharmacology (12.2)] and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins the glucose lowering effect time course of TRESIBA may vary among different patients or at different times in the same patients and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature.
Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitant drugs [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].
5.5 Hypersensitivity Reactions
Additions and/or revisions underlined:
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including TRESIBA [see Adverse Reactions (6.1)]. If hypersensitivity reactions occur, discontinue TRESIBA; treat per standard of care and monitor until symptoms and signs resolve. TRESIBA is contraindicated in patients who have had hypersensitivity reactions to insulin degludec or any of the excipients.
5.6 Hypokalemia
Additions and/or revisions underlined:
All insulins, including TRESIBA, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).
6 Adverse Reactions
Additions and/or revisions underlined:
The following adverse reactions are also discussed elsewhere:
Hypoglycemia [see Warnings and Precautions (5.3)]
Hypoglycemia due to Medication errors [see Warnings and Precautions (5.4)]
6.1 Clinical Trial Experience
Additions and/or revisions underlined:
…
The data in Table 1 reflect the exposure of 1102 adults with type 1 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 34 weeks in three open-label trials.; Study A, B and C [see Clinical Studies (14.1)]. The mean age was 43 years and 1% were older than 75 years. Fifty-seven percent were male, 81% were White, 2% were Black or African American and 4% were Hispanic. The mean body mass index (BMI) was 26 kg/m2. The mean duration of diabetes was 18 years and the mean HbA1c at baseline was 7.8%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported in 11%, 16%, 7% and 0.5% respectively. The mean eGFR at baseline was 87 mL/min/1.73 m2 and 7% of the patients had an eGFR less than 60 mL/min/1.73 m2.
The data in Table 2 reflect the exposure of 2713 adults with type 2 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 36 weeks in six open-label trials.; Study D, E, F, G, H and I [see Clinical Studies (14.3)]…
Hypoglycemia
Hypoglycemia was the most commonly observed adverse reaction in patients treated with TRESIBA. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for TRESIBA with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.
…
Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occurred with insulin, including TRESIBA and may be life threatening. Hypersensitivity (manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching) and urticaria were reported in 0.9% of patients treated with TRESIBA.
6.2 Immunogenicity
Additions and/or revisions underlined:
As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to TRESIBA with the incidence of antibodies in other studies or to other products may be misleading.
In a 52-week trial of adult insulin-experienced type 1 diabetes patients, 68.9% of patients who received TRESIBA were positive at baseline for anti-insulin degludec antibodies and 12.3% of the patients developed anti-insulin degludec antibodies at least once during the trial. In a 52-week trial of pediatric insulin- experienced type 1 diabetes patients, 84.1% of patients who received TRESIBA were positive at baseline for anti-insulin degludec antibodies and 5.8% of patients developed anti-insulin degludec antibodies at least once during the trial. In a 52-week trial of adult insulin-naïve type 2 diabetes patients, 1.7% of patients who received TRESIBA were positive at baseline for anti-insulin degludec antibodies and 6.2% of patients developed anti-insulin degludec antibodies at least once during the trial. In these trials, between 96.7% and 99.7% of patients who were positive for anti-insulin degludec antibodies were also positive for anti-human insulin antibodies.
8 Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Risk Summary
Available data from one unpublished trial and the published literature with TRESIBA use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In a randomized, parallel-group, open-label actively controlled clinical trial that included 91 pregnant women with type 1 diabetes who were administered TRESIBA once daily and insulin aspart, beginning in gestational weeks 8 to 13 or prior to conception, no clear evidence of maternal or fetal risk associated with TRESIBA use was observed (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).
Rats and rabbits were exposed to insulin degludec in animal reproduction studies during organogenesis. Pre- and post-implantation losses and visceral/skeletal abnormalities were observed in rats at doses 5 times (rat) and at 10 times (rabbit) the human exposure at a dose of 0.75 U/kg/day. These effects were similar to those observed in rats administered human insulin (NPH) [(see Data].).
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. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/fetal Risk
Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. 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
Human Data
In an open-label clinical trial, 185 pregnant females with type 1 diabetes were treated with either TRESIBA (once daily) or insulin detemir (once or twice daily); both groups received insulin aspart 2 to 4 times daily with meals. There were no significant drug-associated differences in pregnancy outcomes or the health of the fetus and newborn between the two groups. In this study, the proportion of subjects with severe hypoglycemia and hypoglycemia was similar between the two treatment arms; for the definitions of severe hypoglycemia and hypoglycemia [see Adverse Reactions (6.1)]. Poor glucose control during pregnancy in both groups and small sample size were limitations of the study.
In about two thirds of infants, insulin degludec was detected in the infant cord blood at levels above the lower level of quantification of the assay.
8.4 Pediatric Use
Additions and/or revisions underlined:
The safety and effectiveness of TRESIBA to improve glycemic control in pediatric patients 1 year of age and older with diabetes mellitus have been established. The use of TRESIBA for this indication is supported by evidence from an adequate and well-controlled trial and a pharmacokinetic study (trials included pediatric patients 1 year of age and older with type 1 diabetes mellitus) [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. The use of TRESIBA in pediatric patients 1 year of age and older with type 2 diabetes mellitus is also supported by evidence from adequate and well-controlled trials in adults with type 2 diabetes mellitus [see Clinical Studies (14.3)].
In pediatric patients 1 year of age and older already on insulin therapy, start TRESIBA at a reduced dose to minimize the risk of hypoglycemia [see Dosage and Administration (2.4)].
The safety and effectiveness of TRESIBA have not been established in pediatric patients less than 1-year-old.
8.5 Geriatric Use
Additions and/or revisions underlined:
In controlled clinical trials [see Clinical Studies (14)] a total of 77 (7%) of the 1102 TRESIBA-treated patients with type 1 diabetes were 65 years or older and 9 (1%) were 75 years or older. A total of 670 (25%) of the 2713 TRESIBA-treated patients with type 2 diabetes were 65 years or older and 80 (3%) were 75 years or older. Differences in safety or effectiveness were not suggested in subgroup analyses comparing subjects older than 65 years to younger subjects.
…
Nevertheless, greater caution should be exercised when TRESIBA is administered to geriatric patients since greater sensitivity of some older individuals to the effects of TRESIBA cannot be ruled out. The initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be more difficult to recognize in the geriatric patients.
8.6 Renal Impairment
Additions and/or revisions underlined:
In clinical trials [see Clinical Studies (14)] a total of 75 (7%) of the 1102 TRESIBA-treated patients with type 1 diabetes had an eGFR less than 60 mL/min/1.73 m2 and 1 (0.1%) had an eGFR less than 30 mL/min/1.73 m2. A total of 250 (9%) of the 2713 TRESIBA-treated patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2 and no subjects had an eGFR less than 30 mL/min/1.73 m2.
In the safety outcomes trial (DEVOTE), a total of 1429 (37.4%) of the 3818 TRESIBA-treated patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2, and 108 (2.8%) subjects had an eGFR less than 30 mL/min/1.73 m2. Differences in safety or effectiveness were not observed in the subgroup analyses.
No clinically relevant difference in the pharmacokinetics of TRESIBA was identified in a study comparing healthy subjects and subjects with kidney impairment including subjects with end stage kidney disease [see Clinical Pharmacology (12.3)]. However, as with all insulin products, glucose monitoring should be intensified and the TRESIBA dosage adjusted on an individual basis in patients with kidney impairment.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use). There are separate Instructions for Use for the Vials and FlexTouch Pens.
Never Share a TRESIBA FlexTouch Pen, Needle, or Insulin Syringe Between Patients
Advise patients that they should never share a TRESIBA FlexTouch pen device with another person, even if the needle is changed. Advise patients using TRESIBA vials not to share needles or insulin syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].
Hyperglycemia or Hypoglycemia
Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia(e.g., impaired ability to concentrate and react . This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery. [see Warnings and Precautions (5.3)]
Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.2)].
Hypoglycemia Due to Medication Errors
Inform patients to always check the insulin label before each injection to reduce the risk of medication error [see Warnings and Precautions (5.4)]. Inform patients that the dose counter of TRESIBA FlexTouch pen shows the number of units of TRESIBA to be injected. NO dose re-calculation is required [see Dosage and Administration (2.2)]. Instruct patients to never use a syringe to remove TRESIBA from the FlexTouch disposable insulin prefilled pen.
Hypersensitivity Reactions
Advise patients that hypersensitivity reactions have occurred with TRESIBA. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)].
07/01/2022 (SUPPL-20)
4 Contraindications
Additions and/or revisions underlined:
TRESIBA is contraindicated:
During episodes of hypoglycemia [see Warnings and Precautions (5.3)].
In patients with hypersensitivity to insulin degludec or any of the excipients in TRESIBA [see Warnings and Precautions (5.5)].
5 Warnings and Precautions
5.3 Hypoglycemia
Additions and/or revisions underlined:
Hypoglycemia is the most common adverse reaction of insulin, including TRESIBA [see Adverse Reactions (6.1)]. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). TRESIBA, or any insulin, should not be used during episodes of hypoglycemia [see Contraindications (4)].
Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, using drugs that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or who experience recurrent hypoglycemia.
The long-acting effect of TRESIBA may delay recovery from hypoglycemia compared to shorter-acting insulins.
Risk Factors for Hypoglycemia
The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia after an injection is related to the duration of action of the insulin [see Clinical Pharmacology (12.2)] and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins the glucose lowering effect time course of TRESIBA may vary among different patients or at different times in the same patients and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature.
Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitant drugs [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].
5.5 Hypersensitivity Reactions
Additions and/or revisions underlined:
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including TRESIBA [see Adverse Reactions (6.1)]. If hypersensitivity reactions occur, discontinue TRESIBA; treat per standard of care and monitor until symptoms and signs resolve. TRESIBA is contraindicated in patients who have had hypersensitivity reactions to insulin degludec or any of the excipients.
5.6 Hypokalemia
Additions and/or revisions underlined:
All insulins, including TRESIBA, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).
6 Adverse Reactions
Additions and/or revisions underlined:
The following adverse reactions are also discussed elsewhere:
Hypoglycemia [see Warnings and Precautions (5.3)]
Hypoglycemia due to Medication errors [see Warnings and Precautions (5.4)]
6.1 Clinical Trial Experience
Additions and/or revisions underlined:
…
The data in Table 1 reflect the exposure of 1102 adults with type 1 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 34 weeks in three open-label trials.; Study A, B and C [see Clinical Studies (14.1)]. The mean age was 43 years and 1% were older than 75 years. Fifty-seven percent were male, 81% were White, 2% were Black or African American and 4% were Hispanic. The mean body mass index (BMI) was 26 kg/m2. The mean duration of diabetes was 18 years and the mean HbA1c at baseline was 7.8%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported in 11%, 16%, 7% and 0.5% respectively. The mean eGFR at baseline was 87 mL/min/1.73 m2 and 7% of the patients had an eGFR less than 60 mL/min/1.73 m2.
The data in Table 2 reflect the exposure of 2713 adults with type 2 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 36 weeks in six open-label trials.; Study D, E, F, G, H and I [see Clinical Studies (14.3)]…
Hypoglycemia
Hypoglycemia was the most commonly observed adverse reaction in patients treated with TRESIBA. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for TRESIBA with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.
…
Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occurred with insulin, including TRESIBA and may be life threatening. Hypersensitivity (manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching) and urticaria were reported in 0.9% of patients treated with TRESIBA.
6.2 Immunogenicity
Additions and/or revisions underlined:
As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to TRESIBA with the incidence of antibodies in other studies or to other products may be misleading.
In a 52-week trial of adult insulin-experienced type 1 diabetes patients, 68.9% of patients who received TRESIBA were positive at baseline for anti-insulin degludec antibodies and 12.3% of the patients developed anti-insulin degludec antibodies at least once during the trial. In a 52-week trial of pediatric insulin- experienced type 1 diabetes patients, 84.1% of patients who received TRESIBA were positive at baseline for anti-insulin degludec antibodies and 5.8% of patients developed anti-insulin degludec antibodies at least once during the trial. In a 52-week trial of adult insulin-naïve type 2 diabetes patients, 1.7% of patients who received TRESIBA were positive at baseline for anti-insulin degludec antibodies and 6.2% of patients developed anti-insulin degludec antibodies at least once during the trial. In these trials, between 96.7% and 99.7% of patients who were positive for anti-insulin degludec antibodies were also positive for anti-human insulin antibodies.
8 Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Risk Summary
Available data from one unpublished trial and the published literature with TRESIBA use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In a randomized, parallel-group, open-label actively controlled clinical trial that included 91 pregnant women with type 1 diabetes who were administered TRESIBA once daily and insulin aspart, beginning in gestational weeks 8 to 13 or prior to conception, no clear evidence of maternal or fetal risk associated with TRESIBA use was observed (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).
Rats and rabbits were exposed to insulin degludec in animal reproduction studies during organogenesis. Pre- and post-implantation losses and visceral/skeletal abnormalities were observed in rats at doses 5 times (rat) and at 10 times (rabbit) the human exposure at a dose of 0.75 U/kg/day. These effects were similar to those observed in rats administered human insulin (NPH) [(see Data].).
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. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/fetal Risk
Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. 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
Human Data
In an open-label clinical trial, 185 pregnant females with type 1 diabetes were treated with either TRESIBA (once daily) or insulin detemir (once or twice daily); both groups received insulin aspart 2 to 4 times daily with meals. There were no significant drug-associated differences in pregnancy outcomes or the health of the fetus and newborn between the two groups. In this study, the proportion of subjects with severe hypoglycemia and hypoglycemia was similar between the two treatment arms; for the definitions of severe hypoglycemia and hypoglycemia [see Adverse Reactions (6.1)]. Poor glucose control during pregnancy in both groups and small sample size were limitations of the study.
In about two thirds of infants, insulin degludec was detected in the infant cord blood at levels above the lower level of quantification of the assay.
8.4 Pediatric Use
Additions and/or revisions underlined:
The safety and effectiveness of TRESIBA to improve glycemic control in pediatric patients 1 year of age and older with diabetes mellitus have been established. The use of TRESIBA for this indication is supported by evidence from an adequate and well-controlled trial and a pharmacokinetic study (trials included pediatric patients 1 year of age and older with type 1 diabetes mellitus) [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. The use of TRESIBA in pediatric patients 1 year of age and older with type 2 diabetes mellitus is also supported by evidence from adequate and well-controlled trials in adults with type 2 diabetes mellitus [see Clinical Studies (14.3)].
In pediatric patients 1 year of age and older already on insulin therapy, start TRESIBA at a reduced dose to minimize the risk of hypoglycemia [see Dosage and Administration (2.4)].
The safety and effectiveness of TRESIBA have not been established in pediatric patients less than 1-year-old.
8.5 Geriatric Use
Additions and/or revisions underlined:
In controlled clinical trials [see Clinical Studies (14)] a total of 77 (7%) of the 1102 TRESIBA-treated patients with type 1 diabetes were 65 years or older and 9 (1%) were 75 years or older. A total of 670 (25%) of the 2713 TRESIBA-treated patients with type 2 diabetes were 65 years or older and 80 (3%) were 75 years or older. Differences in safety or effectiveness were not suggested in subgroup analyses comparing subjects older than 65 years to younger subjects.
…
Nevertheless, greater caution should be exercised when TRESIBA is administered to geriatric patients since greater sensitivity of some older individuals to the effects of TRESIBA cannot be ruled out. The initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be more difficult to recognize in the geriatric patients.
8.6 Renal Impairment
Additions and/or revisions underlined:
In clinical trials [see Clinical Studies (14)] a total of 75 (7%) of the 1102 TRESIBA-treated patients with type 1 diabetes had an eGFR less than 60 mL/min/1.73 m2 and 1 (0.1%) had an eGFR less than 30 mL/min/1.73 m2. A total of 250 (9%) of the 2713 TRESIBA-treated patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2 and no subjects had an eGFR less than 30 mL/min/1.73 m2.
In the safety outcomes trial (DEVOTE), a total of 1429 (37.4%) of the 3818 TRESIBA-treated patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2, and 108 (2.8%) subjects had an eGFR less than 30 mL/min/1.73 m2. Differences in safety or effectiveness were not observed in the subgroup analyses.
No clinically relevant difference in the pharmacokinetics of TRESIBA was identified in a study comparing healthy subjects and subjects with kidney impairment including subjects with end stage kidney disease [see Clinical Pharmacology (12.3)]. However, as with all insulin products, glucose monitoring should be intensified and the TRESIBA dosage adjusted on an individual basis in patients with kidney impairment.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use). There are separate Instructions for Use for the Vials and FlexTouch Pens.
Never Share a TRESIBA FlexTouch Pen, Needle, or Insulin Syringe Between Patients
Advise patients that they should never share a TRESIBA FlexTouch pen device with another person, even if the needle is changed. Advise patients using TRESIBA vials not to share needles or insulin syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].
Hyperglycemia or Hypoglycemia
Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia(e.g., impaired ability to concentrate and react . This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery. [see Warnings and Precautions (5.3)]
Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.2)].
Hypoglycemia Due to Medication Errors
Inform patients to always check the insulin label before each injection to reduce the risk of medication error [see Warnings and Precautions (5.4)]. Inform patients that the dose counter of TRESIBA FlexTouch pen shows the number of units of TRESIBA to be injected. NO dose re-calculation is required [see Dosage and Administration (2.2)]. Instruct patients to never use a syringe to remove TRESIBA from the FlexTouch disposable insulin prefilled pen.
Hypersensitivity Reactions
Advise patients that hypersensitivity reactions have occurred with TRESIBA. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)].11/15/2019 (SUPPL-16)
5 Warnings and Precautions
5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen(Additions and/or revisions are underlined)
Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia.
Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, adjustments in concomitant anti-diabetic treatment may be needed. When converting from other insulin therapies to TRESIBA follow dosing recommendations.
6 Adverse Reactions
6.3 Postmarketing Experience(Newly added subsection)
The following additional adverse reactions have been identified during post-approval use of TRESIBA. 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.
Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Never Share a TRESIBA FlexTouch Pen, Needle, or Syringe Between Patients
Advise patients that they should never share a TRESIBA FlexTouch pen device with another person, even if the needle is changed. Advise patients using TRESIBA vials not to share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.
Hyperglycemia or Hypoglycemia
Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia. Inform patients that the ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.
Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision.
Medication Errors
Inform patients to always check the insulin label before each injection. Inform patients that the dose counter of TRESIBA FlexTouch pen shows the number of units of TRESIBA to be injected. NO dose re-calculation is required. Instruct patients to never use a syringe to remove TRESIBA from the FlexTouch disposable insulin prefilled pen.
(Extensive changes; please refer to labeling)
11/21/2018 (SUPPL-10)
5 Warnings and Precautions
5.1 Never Share a TRESIBA FlexTouch Pen, Needle, or Syringe Between Patients(Additions and revisions are underlined)
TRESIBA FlexTouch disposable prefilled pens should never be shared between patients, even if the needle is changed. Patients using TRESIBA vials should never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.
(Additions and revisions are underlined)
To avoid dosing errors and potential overdose, never use a syringe to remove TRESIBA from the TRESIBA FlexTouch disposable insulin prefilled pen.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and revisions are underlined)
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Never Share a TRESIBA FlexTouch Pen, Needle, or Syringe Between Patients
Advise patients that they should never share a TRESIBA FlexTouch pen device with another person, even if the needle is changed. Advise patients using TRESIBA vials not to share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.
08/09/2018 (SUPPL-9)
6 Adverse Reactions
6.2 Immunogenicity(Additions and/or revisions are underlined)
As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to TRESIBA with the incidence of antibodies in other studies or to other products may be misleading.
In a 52-week study of adult insulin-experienced type 1 diabetes patients, 68.9% of patients who received TRESIBA were positive at baseline for anti-insulin degludec antibodies and 12.3% of the patients developed anti-insulin degludec antibodies at least once during the study. In a 52-week study of pediatric insulin- experienced type 1 diabetes patients, 84.1% of patients who received TRESIBA were positive at baseline for anti-insulin degludec antibodies and 5.8% of patients developed anti-insulin degludec antibodies at least once during the thatstudy. In a 52-week study of adult insulin-naïve type 2 diabetes patients, 1.7% of patients who received TRESIBA were positive at baseline for anti-insulin degludec antibodies and 6.2% of patients developed anti-insulin degludec antibodies at least once during the study. In these trials, between 96.7% and 99.7% of patients who were positive for anti-insulin degludec antibodies were also positive for anti-human insulin antibodies.
03/26/2018 (SUPPL-8)
5 Warnings and Precautions
5.4 Hypoglycemia Due to Medication Errors(Additions and/or revisions are underlined)
To avoid dosing errors and potential overdose, never use a syringe to remove TRESIBA from the TRESIBA pen into a syringe.
6 Adverse Reactions
(Additions and/or revisions are underlined)
The following adverse reactions are also discussed elsewhere:
Medication errors
(Additions and/or revisions are underlined)
The safety of TRESIBA in subjects with type 1 diabetes or type 2 diabetes was evaluated in nine trials of 6-12 month duration in adults and in one trial of 12-month duration in pediatric patients 1 year of age and older with type 1 diabetes. The cardiovascular safety of TRESIBA was evaluated in one double-blinded, event-driven trial of 2-year median duration in patients with type 2 diabetes at high risk of cardiovascular events .
The data in Table 1 reflect the exposure of 1102 adults with type 1 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 34 weeks in three open-label trials…
The data in Table 2 reflect the exposure of 2713 adults with type 2 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 36 weeks. in six open-label trials…
Hypoglycemia
In the open-label adult clinical trials of patients with type 1 and type 2 diabetes, and in the open- label pediatric clinical trial of patients with type 1 diabetes, percentages of adult and pediatric patients with type 1 diabetes randomized to TRESIBA who experienced at least one episode of hypoglycemia in clinical trials and adults with type 2 diabetes are shown in Tables 3 and 4, respectively.
Severe hypoglycemia in the open-label trials with adult patients was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions…
8 Use in Specific Populations
8.5 Geriatric Use(Additions and/or revisions are underlined)
In the safety outcomes trial (DEVOTE), a total of 1983 (52%) of the 3818 TRESIBA-treated patients with type 2 diabetes were 65 years or older and 381 (10%) were 75 years or older. Differences in safety or effectiveness were not observed in these subgroup analyses.
(Additions and/or revisions are underlined)
In the safety outcomes trial (DEVOTE), a total of 1429 (37.4%) of the 3818 TRESIBA-treated patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2, and 108 (2.8%) subjects had an eGFR less than 30 mL/min/1.73 m2. Differences in safety or effectiveness were not observed in the subgroup analyses.
12/16/2016 (SUPPL-3)
6 Adverse Reactions
6.1 Clinical Trial Experience(Extensive changes, please refer to label)
8 Use in Specific Populations
(PLLR conversion)
Risk Summary
There are no available data with TRESIBA or insulin degludec in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].
Rats and rabbits were exposed to insulin degludec in animal reproduction studies during organogenesis. Pre-and post-implantation losses and visceral/skeletal abnormalities were observed in rats at doses 5 times (rat) and at 10 times (rabbit) the human exposure at a dose of
0.75 U/kg/day. These effects were similar to those observed in rats administered human insulin
(NPH) [see Data].
The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c greater than 7 and has been reported to be as high as 20-25% in women with a HbA1c greater than10. 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, stillbirth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.
Data
Animal Data
Insulin degludec was investigated in studies covering fertility, embryo-fetal development and pre- and post-natal development in rats and during the period of embryofetal development in rabbits. Human insulin (NPH insulin) was included as comparator. In these studies insulin degludec caused pre- and post-implantation losses and visceral/skeletal abnormalities when given subcutaneously at up to 21 U/kg/day in rats and 3.3 U/kg/day in rabbits, resulting in 5 times (rat) and 10 times (rabbit) the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day. Overall, the effects of insulin degludec were similar to those observed with human insulin, which were probably secondary to maternal hypoglycemia.
(PLLR conversion)
Risk Summary
There are no data on the presence of insulin degludec in human milk, the effects on the breastfed infant, or the effects on milk production. Insulin degludec is present in rat milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRESIBA and any potential adverse effects on the breastfed infant from TRESIBA or from the underlying maternal condition.
Data
In lactating rats, insulin degludec was present in milk at a concentration lower than that in plasma.
(subsection revised)
The safety and effectiveness of TRESIBA to improve glycemic control in type 1 and type 2 diabetes mellitus have been established in pediatric patients 1 year of age and older. The safety and effectiveness of TRESIBA have not been established in pediatric patients less than 1 year old.
The use of TRESIBA in pediatric patients 1 year of age and older with type 1 and type 2 diabetes mellitus is supported by evidence from an adequate and well-controlled study and a pharmacokinetic study (studies included pediatric patients 1 year of age and older with type 1 diabetes mellitus) . The use of TRESIBA in pediatric patients 1 year of age and older with type 2 diabetes mellitus is also supported by evidence from adequate and well-controlled studies in adults with type 2 diabetes mellitus.
In pediatric patients 1 year of age and older already on insulin therapy, start TRESIBA at a reduced dose to minimize the risk of hypoglycemia.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 Patient Counceling Information(Additions underlined)
Do not share your TRESIBA FlexTouch insulin delivery device with other people, even if the needle has changed. You may give other people a serious infection, or get a serious infection from them.
What is TRESIBA?
• TRESIBA is a man-made insulin that is used to control high blood sugar in adults and children who are 1 year of age and older with diabetes mellitus.
• TRESIBA is not for people with diabetic ketoacidosis (increased ketones in the blood or urine).
• TRESIBA is not for children who need less than 5 units of TRESIBA each day.
Before you start taking TRESIBA, talk to your healthcare provider about low blood sugar and how to manage it.
How should I take TRESIBA?
· Adults: If you miss or are delayed in taking your dose of TRESIBA:
o Take your dose as soon as you remember then continue with your regular dosing schedule.
o Make sure there are at least 8 hours between your doses.
· If children miss a dose of TRESIBA:
o Call the healthcare provider for information and instructions about checking blood sugar levels more often until the next scheduled dose of TRESIBA.