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.

HUMALOG MIX 50/50 KWIKPEN (BLA-021018)

(INSULIN LISPRO PROTAMINE RECOMBINANT; INSULIN LISPRO RECOMBINANT)

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

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07/21/2023 (SUPPL-132)

Approved Drug Label (PDF)

6 Adverse Reactions

ADVERSE REACTIONS

Addition of the following to the bulleted line listing:

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

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Changes to table 1 and table 2; please refer to label

…

Common adverse reactions, excluding hypoglycemia, were defined as events that occurred in ?5% of patients treated with insulin lispro or regular human insulin. The frequencies of adverse reactions during HUMALOG clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.

…

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including HUMALOG.

…

In a randomized, 16-week, open-label, parallel design study of pediatric patients with type 1 diabetes, adverse reactions related to infusion-site reactions were similar for insulin lispro and insulin aspart (21% of 100 patients versus 17% of 198 patients, respectively). In both groups, the most frequently reported infusion site reactions were infusion site erythema and infusion site reaction.

…

7 Drug Interactions

Extensive changes; please refer to label

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Available data from published literature suggests 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 insulin, any potential adverse effects on the breastfed child from HUMALOG or from the underlying maternal condition.

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of HUMALOG to improve glycemic control have been established in pediatric patients with diabetes mellitus. Use of HUMALOG for this indication is supported by evidence from adequate and well-controlled studies in 831 pediatric patients with type 1 diabetes mellitus aged 3 years and older and from studies in adults with diabetes mellitus [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

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

MEDICATION GUIDE

Additions and/or revisions underlined:
…

What are the ingredients in HUMALOG?

Active ingredient: insulin lispro

Inactive ingredients: dibasic sodium phosphate, glycerin, hydrochloric acid, metacresol, trace amounts of phenol, sodium hydroxide, zinc oxide (zinc ion), and Water for Injection, USP.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Hypoglycemia due to Medication Errors

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

Inform patients that HUMALOG U-200 contains 2 times as much insulin per mL as HUMALOG U-100. The HUMALOG U-200 KwikPen dose window shows the number of units of HUMALOG U-200 to be injected so no dose conversion is required [see Dosage and Administration (2.1)].

Instruct patients to NOT transfer HUMALOG U-200 from the HUMALOG U-200 KwikPen to a syringe. The markings on the syringe will not measure the dose correctly and this can result in overdosage and severe hypoglycemia. [see Warnings and Precautions (5.4)].

…

Instructions For Patients Using Continuous Subcutaneous Insulin Pumps

Do not use HUMALOG U-200 in a subcutaneous insulin pump.
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 HUMALOG 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; infusion sets and infusion set insertion sites should be changed in accordance with the manufacturers’ user manual. By following this schedule, patients avoid insulin degradation, infusion set occlusion, and loss of the insulin preservative.
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-129)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hyperglycemia and Hypoglycemia with Changes in Insulin Regimen

Additions and/or revisions 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, dosage adjustments of concomitant anti-diabetic products may be needed.

6 Adverse Reactions

Adverse Reactions from Clinical Studies or Postmarketing Reports

Newly added information:

Localized cutaneous amyloidosis

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.

8 Use in Specific Populations

8.1 Pregnancy

Data

Animal Data

Additions and/or revisions underlined:

Animal reproduction studies have not been performed with HUMALOG Mix75/25. However, subcutaneous reproduction and teratology studies have been conducted with insulin lispro (a component of HUMALOG Mix75/25). In a combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and 3 times the human subcutaneous dose of 1unit insulin lispro/kg/day, based on units/body surface area, respectively) from 2 weeks prior to cohabitation through Gestation Day 19 …

… In an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.2 times the human subcutaneous dose of 1unit insulin lispro/kg/day, based on units/body surface area, respectively)

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Hyperglycemia or Hypoglycemia

Newly added to end of titled section:

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.

PATIENT INFORMATION

Additions and/or revisions underlined:
How should I take HUMALOG Mix50/50?

Inject HUMALOG Mix50/50 under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs or upper arms. Do not inject HUMALOG Mix50/50 into your vein
Change (rotate) your injection sites within the area you choose 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.

09/26/2018 (SUPPL-70)

Approved Drug Label (PDF)

6 Adverse Reactions

Addition of edema to this section; please refer to label for complete information.

09/26/2018 (SUPPL-74)

Approved Drug Label (PDF)

Other

PLR conversion; extensive changes to all sections; please refer to label.