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.

HUMULIN R KWIKPEN (BLA-018780)

(INSULIN HUMAN)

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

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06/27/2022 (SUPPL-180)

Approved Drug Label (PDF)

6 Adverse Reactions

Additions and/or revisions underlined:

…

Hypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4)]

…

Peripheral Edema

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

Weight Gain

Weight gain can occur with insulins, including HUMULIN R, and has been attributed to the anabolic effects of insulin.

Immunogenicity

As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The incidence of antibody formation with HUMULIN R is unknown.

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

PATIENT INFORMATION

Additions and/or revisions underlined:

Humulin® (HU-mu-lin) R (insulin human) injection, for subcutaneous or intravenous use U-100 (100 units/mL)
…
Humulin R may cause serious side effects that can lead to death, including:

low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include:
- dizziness or lightheadedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood changes, hunger.
- Your healthcare provider may prescribe a glucagon product for emergency use so that others can give you an injection if your blood sugar becomes too low (hypoglycemic) and you are unable to take sugar by mouth.

…

Inactive ingredients: glycerin, metacresol, and Water for Injection as inactive ingredients. Sodium hydroxide and hydrochloric acid may be added to adjust the pH.

…

11/15/2019 (SUPPL-176)

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 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 medications may be needed.

6 Adverse Reactions

(Additions and/or revisions are underlined)

…

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.

Medication Errors

Medication errors in which other insulins have been accidentally substituted for HUMULIN R have been identified during postapproval use.

Peripheral Edema

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

Weight Gain

Weight gain can occur with insulin therapy, including HUMULIN R, and has been attributed to the anabolic effects of insulin.

Immunogenicity

As with all therapeutic peptides, insulin administration may cause anti-insulin antibodies to form. The incidence of antibody formation with HUMULIN R is unknown.

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 Needles or Syringes between Patients

Advise patients using HUMULIN R 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. Instruct patients on self- management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of HUMULIN R 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.

Medication Errors

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

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions have occurred with HUMULIN R. Inform patients on the symptoms of hypersensitivity reactions and to seek medical attention if they occur.

PATIENT INFORMATION

(Extensive changes; please refer to labeling)

08/22/2019 (SUPPL-172)

Approved Drug Label (PDF)

8 Use in Specific Populations

For U-500: PLLR conversion; as below:

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from published studies over decades have not established an association with human insulin use during pregnancy and 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. Animal reproduction studies were not performed.

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

While available studies cannot definitively establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. All available studies have methodological limitations, including lack of blinding, unclear methods or randomization, and small sample size.

8.2 Lactation

Risk Summary

Available data from published literature suggests that exogenous human insulin products, including HUMULIN R, 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 HUMULIN R on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HUMULIN R and any potential adverse effects on the breastfed child from HUMULIN R or from the underlying maternal condition.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Inspect HUMULIN R U-500 visually for particulate matter and discoloration. Only use HUMULIN R U-500 if the solution appears clear and colorless.