Drug Safety-related Labeling Changes (SrLC)

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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.

ADMELOG (BLA-209196)

(INSULIN LISPRO)

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

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08/31/2023 (SUPPL-7)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

ADMELOG is contraindicated:

during episodes of hypoglycemia [see Warnings and Precautions (5.3)].
in patients who are hypersensitive to insulin lispro or to any of the excipients in ADMELOG [see Warnings and Precautions (5.5)].

5 Warnings and Precautions

5.5 Hypersensitivity Reactions

(Additions and/or revisions underlined)

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including ADMELOG. If hypersensitivity reactions occur, discontinue ADMELOG; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6.1)]. ADMELOG is contraindicated in patients who have had hypersensitivity reactions to insulin lispro or any of the excipients in ADMELOG [see Contraindications (4)].

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are discussed elsewhere:

Hypoglycemia [see Warnings and Precautions (5.3)]
Hypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4)]
Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
Hypokalemia [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions with Subcutaneous Injections of ADMELOG

Two clinical trials with ADMELOG were conducted: one in patients with type 1 diabetes and one in patients with type 2 diabetes [see Clinical Studies (14)].

…

Peripheral Edema

Insulins, including ADMELOG, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII) of ADMELOG

In a randomized, open-label crossover study in adult patients with type 1 diabetes treated over two 4-week periods, the incidence of infusion set occlusions (defined as failure to correct hyperglycemia [plasma glucose greater than or equal to 300 mg/dL] by insulin bolus via insulin pump) inADMELOG-treated patients (n=25) was evaluated. Infusion set occlusions were reported by 24% of patients.

In a randomized, 16-week, open-label, parallel design study of pediatric patients with type 1 diabetes, adverse reactions related to infusion site-related reactions for another insulin lispro product, 100 units/mL, occurred in 21% of patients. The most frequently reported infusion site- related reactions were infusion site erythema and infusion site reaction.

Allergic Reactions

Local Allergy

As with any insulin therapy, patients taking ADMELOG may experience redness, swelling, or itching at the site of the injection. These minor reactions usually resolve in a few days to a few weeks, but in some occasions may require discontinuation of ADMELOG. In some instances,

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 ADMELOG in the studies described below with the incidence of antibodies in other studies or to other insulin products may be misleading.

In a 52-week study of ADMELOG in type 1 diabetes patients, 49.4% were positive at baseline and 22.6% had treatment-emergent ADA (i.e., either new ADA, or increase in titer of at least 4-fold).

In a 26-week study of ADMELOG in type 2 diabetes patients, 26.4% were positive at baseline and 18.8% had treatment-emergent ADA (i.e., either new ADA, or increase in titer of at least 4-fold).

8 Use in Specific Populations

8.2 Lactation

(Additions and/or revisions underlined)

Risk Summary

Available data from published literature suggest that exogenous human insulin products, including insulin lispro, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including insulin lispro, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ADMELOG and any potential adverse effects on the breastfed child from ADMELOG or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of ADMELOG to improve glycemic control have been established in pediatric patients with diabetes mellitus. Use of ADMELOG for this indication is supported by evidence from an adequate and well-controlled study with another insulin lispro product, 100 units/ml, in 60 pediatric patients 3 years of age and older with type 1 diabetes mellitus and studies in adult patients with diabetes mellitus [see Clinical Studies (14)].

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

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

(Additions and/or revisions underlined)

Hypoglycemia due to Medication Errors

Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions (5.4)].

…

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 ADMELOG can be used with the pump. See recommended reservoir and infusion sets in the insulin pump user manual.
Instruct patients to replace insulin in the reservoir at least every 7 days, 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-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen

(Subsection title revised; 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 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 of concomitant anti-diabetic products may be needed.

6 Adverse Reactions

6.3 Postmarketing Experience

(Additions and/or revisions are underlined)

The following additional adverse reactions have been identified during postapproval use of another insulin lispro product, 100 units/mL. 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.

Medication errors in which other insulins have been accidentally substituted for another insulin lispro product, 100 units/mL, have been identified during postapproval use.

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 to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Never Share an ADMELOG SoloStar Prefilled Pen or Syringe Between Patients

Advise patients that they must never share an ADMELOG SoloStar pen with another person, even if the needle is changed. Advise patients using ADMELOG vials not to share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.

Hyperglycemia or Hypoglycemia

Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of ADMELOG therapy. Instruct patients on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of hypoglycemia.

Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. 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.

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions have occurred with ADMELOG. Inform patients on the symptoms of hypersensitivity reactions.

Medication Errors

Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products.

Pregnancy

Advise females of reproductive potential with diabetes to inform their doctor if they are pregnant or are contemplating pregnancy.

Instructions for Patients Using Continuous Subcutaneous Insulin Pumps

Appropriately train patients using external pump infusion therapy on proper pump use.

Insulin pumps should be used in accordance with the pump’s instructions for use. Before using ADMELOG in a pump system for continuous subcutaneous insulin infusion, read the pump user manual to make sure that ADMELOG can be used. ADMELOG is recommended for use in any reservoir and infusion sets that are compatible with insulin and the specific pump. Please see recommended reservoir and infusion sets in the pump manual.

Instruct patients to replace insulin in the reservoir at least every 7 days to avoid insulin degradation, infusion set occlusion, loss of preservative efficacy; infusion sets and infusion set insertion sites should be changed at least every 3 days.

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 report infusion sites that are erythematous, pruritic, or thickened, and to select a new site because continued infusion may increase the skin reaction or alter the absorption of ADMELOG.

Inform patients that pump or infusion set malfunctions or insulin degradation can lead to rapid hyperglycemia and ketosis and to promptly identify and correct the cause of hyperglycemia or ketosis. Problems include pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. Less commonly, hypoglycemia from pump malfunction may occur. Instruct patients to resume therapy with subcutaneous insulin injection and contact their healthcare professional if these problems cannot be promptly corrected.

PATIENT INFORMATION

(Extensive changes; please refer to labeling)

11/01/2018 (SUPPL-2)

Approved Drug Label (PDF)

Other

Instructions for Use

(Additions and/or revisions are underlined)

ADMELOG® (ad-mah-log)

(insulin lispro injection) for subcutaneous use

10 mL or 3 mL Vial (100 Units/mL, U-100)

Read these Instructions for Use before you start taking ADMELOG and each time you get a new ADMELOG vial. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

Do not share your ADMELOG syringes with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.

Supplies needed to give your injection

• an ADMELOG 10 mL or 3 mL vial

• a U-100 insulin syringe and needle

• 2 alcohol swabs

• 1 sharps container for throwing away used needles and syringes. See “Disposing of used needles and syringes” at the end of these instructions.

Instructions for Use

(Additions and/or revisions are underlined)

ADMELOG® SoloStar® (ad-mah-log)

(insulin lispro injection) for subcutaneous use

3 mL disposable prefilled pen (100 Units/mL, U-100)

Read this first

Do not share your ADMELOG SoloStar pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.

People who are blind or have vision problems should not use ADMELOG SoloStar prefilled pen without help from a person trained to use ADMELOG SoloStar prefilled pen.