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 70/30 (BLA-019717)

(INSULIN RECOMBINANT HUMAN; INSULIN SUSP ISOPHANE RECOMBINANT HUMAN)

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

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06/27/2022 (SUPPL-174)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Hypoglycemia Due to Medication Errors

Newly added subsection:

Accidental mix-ups between insulin products have been reported. To avoid medication errors between HUMULIN 70/30 and other insulins, instruct patients to always check the insulin label before each injection.

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)]

7 Drug Interactions

Addition of Table 1, please refer to label

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of HUMULIN 70/30 in pediatric patients have not been established.

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

PATIENT INFORMATION

Additions and/or revisions underlined:

HUMULIN® (HU-mu-lin) 70/30 (insulin isophane human and insulin human) injectable suspension, for subcutaneous use

…

Inactive Ingredients: dibasic sodium phosphate, glycerin, metacresol, phenol, protamine sulfate, zinc oxide, and Water for Injection as inactive ingredients. Sodium hydroxide and/or hydrochloric acid may be added to adjust the pH.

…

Other

Revisions throughout labeling: “an individual” revised to read “the patient”, “individual” revised to read “patient”, “nerve disease” revised to read “neuropathy”, “insulin preparations” revised to read “insulin”, “co-administered medication” revised to read “concomitant drugs”, and “some insulin therapies” revised to read “insulins”

11/15/2019 (SUPPL-169)

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

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.

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 Use HUMULIN 70/30?

Use HUMULIN 70/30 exactly as your healthcare provider tells you to. HUMULIN 70/30 is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms. 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.

08/22/2019 (SUPPL-165)

Approved Drug Label (PDF)

8 Use in Specific Populations

PLLR conversion for below 2 subsections; as below:

8.1 Pregnancy

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 (see Data). 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 70/30, 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 70/30 on milk

production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HUMULIN 70/30 and any potential adverse effects on the breastfed child from HUMULIN 70/30 or from the underlying maternal condition.

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

PATIENT INFORMATION

Before using HUMULIN 70/30, tell your healthcare provider about all your medical conditions including, if you:

Additions and/or revisions underlined:

are pregnant, planning to become pregnant. Talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.
are breast-feeding or plan to breastfeed. HUMULIN 70/30 may pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while using HUMULIN 70/30.