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.

NOVOLIN R (BLA-019938)

(INSULIN RECOMBINANT HUMAN)

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

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11/15/2019 (SUPPL-79)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen

(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, dosage adjustments of concomitant anti-diabetic products may be needed.

6 Adverse Reactions

(Additions and/or revisions are underlined)

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

Hypoglycemia
Medication Errors
Hypersensitivity Reactions

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 NOVOLIN 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, life-threatening, generalized allergy, including anaphylaxis.

Hypoglycemia

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

Hypokalemia

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

Injection site reactions

NOVOLIN R can cause local injection site reactions including redness, swelling, or itching at the site of injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation. Localized reactions and generalized myalgias have been reported with the use of metacresol, which is an excipient in NOVOLIN R.

Lipodystrophy

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

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 NOVOLIN R have been identified during postapproval use.

Peripheral edema

Insulins, including NOVOLIN 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 therapies, including NOVOLIN R, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

Immunogenicity

As with all therapeutic peptides, insulin administration may cause anti-insulin antibodies to form. Increases in titers of anti-insulin antibodies that react with human insulin have been observed in patients treated with NOVOLIN R.

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 a NOVOLIN R FlexPen or Syringe between Patients

Advise patients using NOVOLIN R vials or FlexPen not to share needles, syringes or FlexPen 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 NOVOLIN 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.

Hypoglycemia due to 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 NOVOLIN 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)

06/01/2018 (SUPPL-76)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Hypersensitivity and Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with NOVOLIN.

Generalized allergy to insulin may manifest as a whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. If hypersensitivity reactions occur, discontinue NOVOLIN R; treat per standard of care and monitor until symptoms and signs resolve. NOVOLIN R is contraindicated in patients who have had hypersensitivity reactions to insulin human injection or its excipients.

5.6 Hypokalemia

… 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 …

5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma agonists

Thiazolidinediones (TZDs), which are peroxisome …

Additions and/or revisions underlined:

5.1 Never Share a NOVOLIN R FlexPen or Syringe Between Patients replaces subsection title Administration

NOVOLIN R FlexPen must never be shared between patients, even if the needle is changed. Patients using NOVOLIN 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 newly added subsection

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. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.

5.3 Hypoglycemia

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 NOVOLIN 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 at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

5.4 Hypoglycemia Due to Medication Errors (newly added subsection)

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

6 Adverse Reactions

Additions and/or revisions underlined:

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

Hypoglycemia
Medication Errors
Hypersensitivity Reactions
Hypokalemia

Adverse Reactions from Clinical Studies or Postmarketing Reports

Adverse reactions associated with insulin initiation and glucose control intensification

Intensification or rapid improvement …

Hypersensitivity reactions

Severe, life-threatening, generalized allergy, including anaphylaxis.

Hypokalemia

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

Injection site reactions

Lipodystrophy

Administration of insulin subcutaneously, including NOVOLIN 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 NOVOLIN R have been identified during postapproval use.

Peripheral edema

Insulins, including NOVOLIN R, may cause sodium retention and edema …

Immunogenicity

All tables have been deleted from this section.

7 Drug Interactions

Newly created Table 1: Clinically Significant Drug Interactions with Novolin R; please see label for complete information.

8 Use in Specific Populations

8.6 Renal Impairment

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

8.7 Hepatic Impairment

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

8.1 Pregnancy

Newly added information:

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 (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 greater than 7 and has been reported to be as high as 20-25% in women with a HbA1c greater than 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 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 of randomization, and small sample size.

8.2 Lactation

Newly added information:

Risk Summary

Available data from published literature suggest that exogenous human insulin products, including NOVOLIN R, are transferred into human milk. There are no adverse reactions reported in the breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including NOVOLIN R, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NOVOLIN R and any potential adverse effects on the breastfed infant from NOVOLIN R or from the underlying maternal condition.

8.4 Pediatric Use

Additions and/or revisions underlined:
NOVOLIN R is indicated to improve glycemic control in pediatric patients with diabetes mellitus.

The dosage of NOVOLIN 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

Additions and/or revisions underlined:

… The effect of age on the pharmacokinetics and pharmacodynamics of NOVOLIN R has not been studied.

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

PATIENT COUNSELING INFORMATION

Substantive changes; please refer to label for complete information.