Drug Safety-related Labeling Changes (SrLC)

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HUMULIN R (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.

05/25/2018 (SUPPL-134)

5 Warnings and Precautions

5.1 Never Share Needles or Syringes between Patients

(Physician Labeling Rule (PLR) Conversion; Additions and/or revisions are underlined)

Patients using HUMULIN R vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.

5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen

(Physician Labeling Rule (PLR) Conversion; Additions and/or revisions are underlined)

Changes in insulin, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia. These changes should be made cautiously and only under medical supervision and the frequency of blood glucose monitoring should be increased. For patients with type 2 diabetes, adjustments in concomitant anti-diabetic medications may be needed.

5.3 Hypoglycemia

(Physician Labeling Rule (PLR) Conversion; Additions and/or revisions are underlined)

Hypoglycemia is the most common adverse reaction of all insulins, including HUMULIN R. Severe hypoglycemia can cause seizures, may lead to unconsciousness, may be life threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).

Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers), or in patients who experience recurrent hypoglycemia.

Risk Factors for Hypoglycemia

The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of HUMULIN R may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature.

Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.

Risk Mitigation Strategies for Hypoglycemia

Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

5.4 Hypoglycemia Due to Medication Errors

(Physician Labeling Rule (PLR) Conversion; Additions and/or revisions are underlined)

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

5.6 Hypokalemia

(Physician Labeling Rule (PLR) Conversion; Additions and/or revisions are underlined)

All insulin products, including HUMULIN R, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).

6 Adverse Reactions

(Physician Labeling Rule (PLR) Conversion; Additions and/or revisions are underlined)

The following adverse reactions are also discussed elsewhere in the labeling:

• Hypoglycemia

• Medication Errors

• Hypersensitivity

• Hypokalemia

Adverse Reactions from Clinical Studies or Postmarketing Reports

The following additional adverse reactions have been identified during clinical studies or from postmarketing reports with use of HUMULIN R. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.

Adverse reactions associated with insulin initiation and glucose control intensification

Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. Over the long-term, improved glycemic control decreases the risk of diabetic retinopathy and neuropathy.

Hypersensitivity Reactions

Severe allergic reactions may include anaphylaxis, generalized skin reactions, rash, angioedema, bronchospasm, hypotension, and shock.

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in HUMULIN R.

Hypokalemia

HUMULIN R can cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia.

Injection Site Reactions

Injection site reactions may include injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass.

Lipodystrophy

Administration of insulin subcutaneously, including HUMULIN R, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients.

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.

7 Drug Interactions

(Physician Labeling Rule (PLR) Conversion; Newly added table - please refer to labeling)

Table 1: Clinically Significant Drug Interactions with HUMULIN R

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

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, stillbirth, 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

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

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.

8.4 Pediatric Use

(Newly Added Subsection)

HUMULIN R is indicated to improve glycemic control in pediatric patients with diabetes mellitus. The dosage of HUMULIN R must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose to reduce the risk of hypoglycemia.

8.5 Geriatric Use

(Newly Added Subsection)

The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN R has not been studied. Elderly patients using HUMULIN R may be at increased risk of hypoglycemia due to co-morbid disease.

8.6 Renal Impairment

(Newly Added Subsection)

The effect of renal impairment on the pharmacokinetics and pharmacodynamics of HUMULIN R has not been studied. Patients with renal impairment are at increased risk of hypoglycemia and may require more frequent HUMULIN R dose adjustment and more frequent blood glucose monitoring.

8.7 Hepatic Impairment

(Newly Added Subsection)

The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of HUMULIN R has not been studied. Patients with hepatic impairment are at increased risk of hypoglycemia and may require more frequent HUMULIN R dose adjustment and more frequent blood glucose monitoring.

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

17 PATIENT COUNSELING INFORMATION

(Newly added section; please refer to labeling)

Patient Information Humulin® (HU-mu-lin) R insulin human injection (100 units per mL)

(Extensive changes; please refer to labeling)

07/08/2016 (SUPPL-153)

Approved Drug Label (PDF)

5 Warnings and Precautions

Hyperglycemia, Hypoglycemia or Death due to Dosing Errors with the Vial Presentation

Dispensing Errors (new information is added below)

• The HUMULIN R U-500 vial, which contains 20 mL, has a band of aqua coloring, a 500 units/mL concentration statement consisting of white lettering on a green rectangular background, and a green “U-500” statement prominently displayed next to the trade name. Additionally, the vial has a green flip top and a red warning on the front panel describing the highly concentrated dose and a statement advising use with only U-500 insulin syringes.

Prescribing Errors (new information is added below)

• Dosing errors have occurred when the HUMULIN R U-500 dose was administered with syringes other than a U-500 insulin syringe. Patients should be prescribed U-500 syringes for use with the HUMULIN R U-500 vials. The prescribed dose of HUMULIN R U-500 should always be expressed in units of insulin.

Administration Errors

• Use only a U-500 insulin syringe with HUMULIN R U-500 to avoid administration errors. Do not use any other type of syringe to administer Humulin R U-500. Adhere to administration instructions replaces A majority of the medication errors with HUMULIN R U-500 vial presentation occurred due to dosing confusion when the HUMULIN R U-500 dose was prescribed in units or volume corresponding to a U-100 syringe or tuberculin syringe markings, respectively, or the prescribed dose was administered without recognizing that the markings on the syringe used do not directly correspond to U-500 dose. Adhere to administration and conversion instructions.

Never Share a HUMULIN R U-500 KwikPen or U-500 Insulin Syringe Between Patients (subheading updated to include U-500 insulin syringe)

• Patients using HUMULIN R U-500 vials should never share needles or U-500 insulin syringes with another person. (addition of U-500 insuling syringes).

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

PI

• Do not share your Humulin R U-500 KwikPen or U-500 insulin syringes… (addition of U-500 insulin syringes)

PI - How should I use Humulin R U-500?

• When using the Humulin R U-500 vial: There is a special U-500 insulin syringe to measure Humulin R U-500.
• Use only a U-500 insulin syringe to draw up and inject your Humulin R U-500 replaces There are no special syringes to measure Humulin R U-500. Use a U-100 insulin syringe or tuberculin syringe as instructed by your healthcare provider.

PI - What is Humulin R U-500?

Addition of the following bullets:

• It is not known if Humulin R U-500 is safe and effective when used in combination with other insulins.
• It is not known if Humulin R U-500 is safe and effective when given by continuous subcutaneous infusion.