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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.
APIDRA (BLA-021629)
(INSULIN GLULISINE RECOMBINANT)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
11/30/2022 (SUPPL-42)
4 Contraindications
Additions and/or revisions underlined:
APIDRA is contraindicated:
during episodes of hypoglycemia
in patients with known hypersensitivity to insulin glulisine or to any of the excipients in APIDRA; systemic allergic reactions have occurred with APIDRA [see Adverse Reactions (6.1)].
5 Warnings and Precautions
5.3 Hypoglycemia
5.5 Hypokalemia
‘insulins’ replaces ‘insulin therapies’
‘the patient’ replaces ‘an individual’
‘neuropathy’ replaces ‘nerve disease’
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
Because clinical trials are conducted under widely
varying designs, the adverse reaction rates reported in one clinical trial may
not be easily compared to those rates reported in another clinical trial and
may not reflect the rates actually observed in clinical practice.
The data in Table 1 reflect the exposure of 1591 patients with type 1 diabetes to APIDRA or comparators [see Clinical Studies (14.1)]. The type 1 diabetes population had the following characteristics: Mean age was 39.74 years. 54.5 % were male, 95.5% were Caucasian, 1.5% were Black or African American.
The data in Table 2 reflect the exposure of 1766 patients with type 2 diabetes to APIDRA or comparators [see Clinical Studies (14.2)]. The type 2 diabetes population had the following characteristics: Mean age was 59.08 years. 51.2% were male, 88.5% were Caucasian, 7.2% were Black or African American …
6.2 Immunogenicity
Additions and/or revisions underlined:
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to APIDRA in the studies described below with the incidence of antibodies in other studies or to other insulin products may be misleading …
… There was no correlation between cross-reactive insulin antibody concentration and changes in HbA1c, insulin doses, or incidence of hypoglycemia. APIDRA did not elicit a significant antibody response in a study of pediatric patients with type 1 diabetes.
8 Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
… 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 …
8.4 Pediatric Use
Additions and/or revisions underlined:
The safety and effectiveness of APIDRA to improve glycemic control have been established in pediatric patients. Use of APIDRA for this indication is supported by evidence from an active-controlled non-inferiority study in pediatric patients 4 years of age and older with type 1 diabetes mellitus treated with APIDRA (n=271) and from studies in adults with diabetes mellitus [see Clinical Pharmacology (12.3), and Clinical Studies (14)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or revisions underlined:
Instructions For Patients Using Continuous Subcutaneous Insulin Pumps
Train patients in intensive insulin therapy with multiple injections and in the function of their pump and pump accessories.
Instruct patients to follow healthcare provider recommendations when setting pump basal rates and bolus settings.
Refer to the continuous subcutaneous infusion pump user manual to see if APIDRA can be used with the pump. See recommended reservoir and infusion sets in the insulin pump user manual.
Instruct patients to replace APIDRA in the reservoir at least every 48 hours, or according to the pump user manual, whichever is shorter. By following this schedule, patients avoid insulin degradation, infusion set occlusion, and loss of the insulin preservative.
Instruct patients that infusion sets and infusion set insertion sites should be changed according to the manufacturer’s user manual.
Instruct patients to discard insulin exposed to temperatures higher than 98.6°F (37°C). The temperature of the insulin may exceed ambient temperature when the pump housing, cover, tubing, or sport case is exposed to sunlight or radiant heat.
Instruct patients to inform healthcare provider and select a new site for infusion if infusion site becomes erythematous, pruritic, or thickened.
Instruct patients on the risk of rapid hyperglycemia and ketosis due to pump malfunction; infusion set occlusion, leakage, disconnection, or kinking; and degraded insulin. Instruct patients on the risk of hypoglycemia from pump malfunction. If these problems cannot be promptly corrected, instruct patients to resume therapy with subcutaneous insulin injection and contact their healthcare provider [see Warnings and Precautions (5) and How Supplied/Storage and Handling (16.2)].
11/15/2019 (SUPPL-40)
5 Warnings and Precautions
5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin RegimenAdditions and/or revisions underlined:
Changes in an insulin regimen (e.g., insulin, 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; a sudden change in the injection site (to 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, dosage adjustments in concomitant oral antidiabetic treatment may be needed.
6 Adverse Reactions
6.3 Postmarketing ExperienceNewly added information to the end of the subsection:
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 INFORMATIONAdditions and/or revisions underlined:
Hyperglycemia or Hypoglycemia
Inform patients that hypoglycemia is the most common adverse reaction with insulin … 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.
Additions and/or revisions underlined:
How should I use APIDRA?
APIDRA comes in a SoloStar single-patient-use prefilled pen or in a vial.
APIDRA is injected under the skin (subcutaneously) of your upper arms, thighs, buttock, or stomach area (abdomen), or by continuous infusion under the skin (subcutaneously) through an insulin pump into an area of your body recommended in the instructions that come with your insulin pump
Change (rotate) injection sites within the area you chose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites:
Do not use the exact same spot for each injection.
Do not inject where the skin has pits, is thickened, or has lumps.
Do not inject where the skin is tender, bruised, scaly, or hard, or into scars or damaged skin.
12/20/2018 (SUPPL-37)
4 Contraindications
(Additions and/or revisions are underlined)
APIDRA is contraindicated:
- in patients with known hypersensitivity to APIDRA or to any of its excipients; systemic allergic reactions have occurred with APIDRA.
5 Warnings and Precautions
5.2 Never Share an APIDRA SoloStar Pen or Syringe or Needle between Patients(Additions and/or revisions are underlined)
Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen
Changes in insulin, insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia. These changes should be made cautiously and only under close medical supervision and the frequency of blood glucose monitoring should be increased. For patients with type 2 diabetes, dosage adjustments in concomitant oral anti-diabetic treatment may be needed.
(Extensive changes; please refer to labeling)
(Additions and/or revisions are underlined)
Accidental mix-ups between insulin products have been reported. To avoid medication errors between APIDRA and other insulins, instruct patients to always check the insulin label before each injection.
(Additions and/or revisions are underlined)
If hypersensitivity reactions occur, discontinue APIDRA; treat per standard of care and monitor until symptoms and signs resolve. APIDRA is contraindicated in patients who have had a hypersensitivity reaction to it or any of its excipients.
(Additions and/or revisions are underlined)
Malfunction of the insulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with APIDRA may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure.
6 Adverse Reactions
(Additions and/or revisions are underlined)
The following adverse reactions are discussed elsewhere:
Hypersensitivity and Allergic Reactions
(Extensive changes; please refer to labeling)
(Additions and/or revisions are underlined)
As with all therapeutic proteins, there is a potential for immunogenicity. 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 APIDRA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Extensive changes – please refer to labeling)
(Additions and/or revisions are underlined)
Risk Summary
Available data from published literature suggest that human insulin products, including APIDRA, are transferred into human milk. There are no adverse reactions reported in the breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including APIDRA, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for APIDRA and any potential adverse effects on the breastfed infant from APIDRA or from the underlying maternal condition.
(Additions and/or revisions are underlined)
APIDRA is indicated for glycemic control in pediatric patients with type 1 diabetes mellitus. Use of APIDRA for this indication is supported by evidence from a 26-week, randomized, open- label, active-controlled, non-inferiority study in pediatric patients older than 4 years of age with type 1 diabetes mellitus treated with APIDRA (n=271).
In the clinical trials, pediatric patients with type 1 diabetes mellitus had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to adults with type 1 diabetes mellitus.
(Additions and/or revisions are underlined)
Nevertheless, caution should be exercised when APIDRA is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to reduce the risk of hypoglycemia.
(Newly Added Subsection)
Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent APIDRA dose adjustment and more frequent blood glucose monitoring.
(Newly Added Subsection)
Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent APIDRA dose adjustment and more frequent blood glucose monitoring.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Extensive changes; please refer to labeling)
12/20/2018 (SUPPL-38)
4 Contraindications
(Additions and/or revisions are underlined)
APIDRA is contraindicated:
- in patients with known hypersensitivity to APIDRA or to any of its excipients; systemic allergic reactions have occurred with APIDRA.
5 Warnings and Precautions
5.2 Never Share an APIDRA SoloStar Pen or Syringe or Needle between Patients(Additions and/or revisions are underlined)
Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen
Changes in insulin, insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia. These changes should be made cautiously and only under close medical supervision and the frequency of blood glucose monitoring should be increased. For patients with type 2 diabetes, dosage adjustments in concomitant oral anti-diabetic treatment may be needed.
(Extensive changes; please refer to labeling)
(Additions and/or revisions are underlined)
Accidental mix-ups between insulin products have been reported. To avoid medication errors between APIDRA and other insulins, instruct patients to always check the insulin label before each injection.
(Additions and/or revisions are underlined)
If hypersensitivity reactions occur, discontinue APIDRA; treat per standard of care and monitor until symptoms and signs resolve. APIDRA is contraindicated in patients who have had a hypersensitivity reaction to it or any of its excipients.
(Additions and/or revisions are underlined)
Malfunction of the insulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with APIDRA may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure.
6 Adverse Reactions
(Additions and/or revisions are underlined)
The following adverse reactions are discussed elsewhere:
Hypersensitivity and Allergic Reactions
(Extensive changes; please refer to labeling)
(Additions and/or revisions are underlined)
As with all therapeutic proteins, there is a potential for immunogenicity. 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 APIDRA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
8 Use in Specific Populations
8.2 Lactation(Additions and/or revisions are underlined)
Risk Summary
Available data from published literature suggest that human insulin products, including APIDRA, are transferred into human milk. There are no adverse reactions reported in the breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including APIDRA, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for APIDRA and any potential adverse effects on the breastfed infant from APIDRA or from the underlying maternal condition.
(Additions and/or revisions are underlined)
APIDRA is indicated for glycemic control in pediatric patients with type 1 diabetes mellitus. Use of APIDRA for this indication is supported by evidence from a 26-week, randomized, open- label, active-controlled, non-inferiority study in pediatric patients older than 4 years of age with type 1 diabetes mellitus treated with APIDRA (n=271).
(Additions and/or revisions are underlined)
Nevertheless, caution should be exercised when APIDRA is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to reduce the risk of hypoglycemia.
(Newly Added Subsection)
Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent APIDRA dose adjustment and more frequent blood glucose monitoring.
(Newly Added Subsection)
Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent APIDRA dose adjustment and more frequent blood glucose monitoring.17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Extensive changes; please refer to labeling)