Drug Safety-related Labeling Changes (SrLC)

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NOVOLOG (BLA-020986)

(INSULIN ASPART RECOMBINANT)

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

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02/28/2023 (SUPPL-96)

Approved Drug Label (PDF)

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

Patient Counseling Information

Additions and revisions underlined:

. . .

• This NOVOLOG product can be used with continuous subcutaneous insulin infusion pumps labeled for use with NOVOLOG (insulin aspart) - refer to the insulin pump user manual to see if NOVOLOG can be used. See recommended infusion sets in the insulin pump user manual.

. . .

03/23/2021 (SUPPL-93)

Approved Drug Label (PDF)

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are also discussed elsewhere:

• Hypoglycemia [see Warnings and Precautions (5.3)]

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

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of NOVOLOG to improve glycemic control have been established in pediatric patients. Use of NOVOLOG for this indication is supported by evidence from an adequate and well-controlled study in 283 pediatric patients with type 1 diabetes mellitus aged 6 to 18 years and from studies in adults with diabetes mellitus [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

11/15/2019 (SUPPL-90)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hyperglycemia 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 only 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.

11/15/2019 (SUPPL-91)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hyperglycemia 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 only 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.

12/20/2018 (SUPPL-87)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Extensive changes – please refer to labeling)

8.2 Lactation

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

Risk Summary

There are no data on the presence of NOVOLOG in human milk, the effects on the breastfed infant, or the effect on milk production. One small published study reported that exogenous insulin, including insulin aspart, was present in human milk. However, there is insufficient information to determine the effects of insulin aspart on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NOVOLOG, and any potential adverse effects on the breastfed infant from NOVOLOG, or from the underlying maternal condition.

03/16/2017 (SUPPL-79)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Never Share NOVOLOG FlexPen, NOVOLOG FlexTouch, PenFill Cartridge or PenFill Cartridge Device Between Patients

Additions and/or revisions underlined:

NOVOLOG FlexPen, NOVOLOG FlexTouch, PenFill cartridge, and PenFill cartridge devices should never be shared between patients, even if the needle if changed. Patients using NOVOLOG 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 only 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

Additions and/or revisions underlined:

Hypoglycemia is the most common adverse effect of all insulin therapies, including NOVOLOG.

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 NOVOLOG may vary in different individuals or at different times in the same individual and depends on may 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, increased frequency of blood glucose monitoring is recommended. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, and increased frequency of blood glucose monitoring is recommended.

5.4 Hypoglycemia Due to Medication Errors

Newly added subsection:

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

5.5 Hypersensitivity and Allergic Reactions

Newly added subsection:

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including NOVOLOG. If hypersensitivity reactions occur, discontinue NOVOLOG; treat per standard of care and monitor until symptoms and signs resolve.  NOVOLOG is contraindicated in patients who have had hypersensitivity reactions to insulin aspart or one of the excipients.

5.6 Hypokalemia

Additions and/or revisions underlined:

All insulin products, including NOVOLOG, can 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 concentration).

5.7 Fluid Retention and Heart Failure With Concomitant Use of PPAR-gamma Agonists

 

5.8 Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction

Additions and/or revisions underlined:

Malfunction of the insulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with NOVOLOG may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure.

6 Adverse Reactions

The following adverse reactions are also discussed elsewhere:

•     Hypoglycemia

•     Hypersensitivity and allergic reactions

•     Hypokalemia

6.1 Clinical Trial Experience

Additions and/or revisions underlined:

Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The safety of NOVOLOG was evaluated in two treat-to-target trials of 6 months duration, conducted in subjects with type 1 diabetes or type 2 diabetes.

The data in Table 1 reflect the exposure of 596 patients with type 1 diabetes to NOVOLOG in one clincal trial with a mean exposure duration to NOVOLOG of 24 weeks. The mean age was 38.9 years. Fifty-one percent were male, 94% were Caucasian, 2% were Black and 4% were other races. The mean body mass index (BMI) was 25.6 kg/m2. The mean duration of diabetes was 15.7 years and the mean HbA1c at baseline was 7.9%.

The data in Table 2 reflect the exposure of 91 patients with type 2 diabetes to NOVOLOG in one clincal trial with a mean exposure duration to NOVOLOG of 24 weeks. The mean age was 56.6 years. Sixty-three percent were male, 76% were Caucasian, 9% were Black and 15% were other races. The mean BMI was 29.7 kg/m2. The mean duration of diabetes was 12.7 years and the mean HbA1c at baseline was 8.1%.

Common adverse reactions were defined as events occurring in ?5%, excluding hypoglycemia, of the population studied. Common adverse events occurring at the same rate or greater for NOVOLOG-treated subjects than on comparator-treated subjects during clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus (other than hypoglycemia) are listed in Table 1 and Table 2, respectively.

Table 1: Adverse reactions occurring in ? 5% of Type 1 Diabetes Mellitus Adult Patients treated with NOVOLOG and at the same rate or greater on NOVOLOG than on comparator Please refer to label for table.

Table 2: Adverse reactions occurring in ? 5% of Type 2 Diabetes Mellitus Adult Patients treated with NOVOLOG and at the same rate or greater on NOVOLOG than on comparator Please refer to label for table.

Severe hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including NOVOLOG. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for NOVOLOG with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.

Severe hypoglycemia was defined as hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization.

The incidence of severe hypoglycemia in adult and pediatric patients receiving subcutaneous NOVOLOG with type 1 diabetes mellitus was 17% at 24 weeks and 6% at 24 weeks, respectively.

The incidence of severe hypoglycemia in adult patients receiving subcutaneous NOVOLOG with type 2 diabetes mellitus was 10% at 24 weeks.

The incidence of severe hypoglycemia in adult and pediatric patients with type 1 diabetes mellitus, receiving NOVOLOG via continuous subcutaneous insulin infusion by external pump was 2% at 16 weeks and 10% at 16 weeks respectively.

No severe hypoglycemic episodes were reported in adult patients with type 2 diabetes mellitus receiving NOVOLOG via continuous subcutanuous insulin infusion by external pump at 16 weeks.

Allergic Reactions

Some patients taking insulin therapy, including NOVOLOG have experienced erythema, local edema, and pruritus at the site of injection. These conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been reported.

Insulin initiation and glucose control intensification

Intensification …

Lipodystrophy

Administration of insulin, including NOVOLOG,  subcutaneously and via subcutaneous insulin infusion by external pump, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients.

Peripheral Edema

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

Weight gain

Weight gain has occurred with some insulin …

6.2 Immunogenicity

Newly added subsection:

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to NOVOLOG in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In a 6-month study with a 6 month extension in adult subjects with type 1 diabetes, 99.8% of patients who received NOVOLOG were positive for anti-insulin antibodies (AIA) at least once during the study, including 97.2% that were positive at baseline. A total of 92.1% of patients who received NOVOLOG were positive for anti-drug antibodies (ADA) at least once during the study, including 64.6% that were positive at baseline.

In a phase 3 type 1 diabetes clinical trial of NOVOLOG, initial increase in titers of antibodies to insulin, followed by a decrease to baseline values, was observed in regular human insulin and insulin aspart treatment groups with similar incidences. These antibodies did not cause deterioration in glycemic control or necessitate increases in insulin dose.

6.3 Post Marketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post-approval use of NOVOLOG.

ecause these adverse reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported in which other insulins have been accidentally substituted for NOVOLOG.

8 Use in Specific Populations

8.3 Nursing Mothers

Additions and/or revisions underlined:

Endogenous insulin is present in human milk; it is unknown whether insulin aspart is excreted in human milk. Because many drugs, including human insulin, are excreted in human milk, caution should be exercised when NOVOLOG is administered to a nursing woman. Use of NOVOLOG is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.

8.6 Renal Impairment

Additions and/or revisions underlined:

Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent NOVOLOG dose adjustment and more frequent blood glucose monitoring.

8.7 Hepatic Impairment

Additions and/or revisions underlined:

Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent NOVOLOG dose adjustment and more frequent blood glucose monitoring.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

Never Share a NOVOLOG FlexPen or a NOVOLOG Flex Touch, PenFill Cartridge or PenFill Cartridge Device Between Patients

Advise patients that they must never share NOVOLOG FlexPen, NOVOLOG Flex Touch, PenFill cartridge or PenFill cartridge devices with another person even if the needle is changed, because doing so carries a risk for trasmission of blood-borne pathogens. Advise patients using NOVOLOG vials not to share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.

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 NOVOLOG 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.

Hypoglycemia with 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 NOVOLOG. Inform patients of the symptoms of hypersensitivity reactions.

Women of Reproductive Potential

Advise patients to inform their health care professional if they are pregnant or are contemplating pregnancy.

Administration

NOVOLOG must only be used if the solution is clear and colorless with no particles visible. Instruct patients that when injecting NOVOLOG, they must press and hold down the dose button until the dose counter shows 0 and then keep the needle in the skin and count slowly to 6 as the prescribed dose is not completely delivered until 6 seconds later. If the needle is removed earlier, the full dose  may not be delivered (a possible under-dose may occur by as much as 20%). Inform the patient to increase the frequency of checking their blood glucose and that possible additional insulin administration may be necessary.

Patients Using Continuous Subcutaneous Insulin Pumps

• Train patients in both intensive insulin therapy with multiple injections and in the function of their pump and pump accessories.

• Instruct patients to replace insulin in the reservoir at least every 6 days; infusion sets and infusion set insertion sites should be changed at least every 3 days. By following this schedule, patients avoid insulin degradation, infusion set occlusion, and loss of the insulin preservative.  NOVOLOG is recommended for use in any reservoir and infusion sets that are compatible with insulin and the specific pump. Please see recommended reservoir and infusion sets in the pump manual.

• Instruct patients to discard insulin exposed to temperatures higher than 37°C (98.6°F).

• Instruct patients to inform physician and select a new site for infusion if infusion site becomes erythematous, pruritic, or thickened.

• Instruct patients of the risk of rapid hyperglycemia and ketosis due to pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. If these problems cannot be promptly corrected, instruct patients to resume therapy with subcutaneous insulin injection and contact their physician.

• Instruct patients of 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 physician.