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 (BLA-020563)

(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-202)

Approved Drug Label (PDF)

6 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

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-196)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hyper- or Hypoglycemia with Changes in Insulin Regimen

(Additions and/or revisions underlined)

Changes in 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 under close medical supervision and the frequency of blood glucose monitoring should be increased.

11/15/2019 (SUPPL-198)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hyper- or Hypoglycemia with Changes in Insulin Regimen

(Additions and/or revisions underlined)

11/15/2019 (SUPPL-199)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hyper- or Hypoglycemia with Changes in Insulin Regimen

(Additions and/or revisions underlined)

08/13/2019 (SUPPL-195)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

The limited available data with HUMALOG in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Published studies with insulin lispro used during pregnancy have not reported an association between insulin lispro and the induction of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

Pregnant rats and rabbits were exposed to insulin lispro in animal reproduction studies during organogenesis. No adverse effects on embryo/fetal viability or morphology were observed in offspring of rats exposed to insulin lispro at a dose approximately 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day. No adverse effects on embryo/fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.2 times the human subcutaneous dose of 1 unit/kg/day.

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% 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, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Human Data

Published data from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy.

However, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups.

Animal Data

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 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) from 2 weeks prior to cohabitation through Gestation Day 19. There were no adverse effects on female fertility, implantation, or fetal viability and morphology. However, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter.

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 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation days 7 through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose.

8.2 Lactation

Risk Summary

There are no data on the presence of HUMALOG in human milk, the effects on the breastfed infant, or the effect on milk production. One small published study reported that exogenous insulin was present in human milk. However, there is insufficient information to determine the effects of HUMALOG on the breastfed infant and no available information on the effects of HUMALOG 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.

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

PATIENT INFORMATION

Additions and/or revisions underlined:

· Know the type, strength and amount of insulin you take.

· Check your insulin label each time you give your injection to make sure you are taking the correct insulin.

· Inject HUMALOG under your skin (subcutaneously) or by continuous infusion under your skin through an insulin pump.

· Change (rotate) your injection site with each dose.

• Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels.

Keep HUMALOG and all medicines out of the reach of children.

Your healthcare provider may prescribe a glucagon emergency kit so that someone else can give you glucagon if your blood sugar becomes too low (severe hypoglycemia) and you are unable to take sugar by mouth.

Get emergency medical help if you have:

• trouble breathing • sweating

• shortness of breath • extreme drowsiness

• fast heartbeat • dizziness

• swelling of your face, tongue, or throat • confusion

The most common side effects of HUMALOG include:

• low blood sugar (hypoglycemia) • weight gain

• reactions at your injection site • swelling in your hands or feet

• skin thickening or pits at the injection site • itching (lipodystrophy) • rash

This Patient Information leaflet summarizes the most important information about HUMALOG. If you would like more information, talk with your healthcare provider.

11/01/2018 (SUPPL-191)

Approved Drug Label (PDF)

Other

Instructions for Use

(Additions and/or revisions are underlined)

HUMALOG KwikPen®

…

People who are blind or have vision problems should not use the Pen without help from a person trained to use the Pen.

Instructions for Use

(Additions and/or revisions are underlined)

HUMALOG® Junior

…

People who are blind or have vision problems should not use the Pen without help from a person trained to use the Pen.