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Guide
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.
NOVOLOG MIX 70/30 (BLA-021172)
(INSULIN ASPART PROTAMINE RECOMBINANT; INSULIN ASPART RECOMBINANT)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
04/28/2021 (SUPPL-74)
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)]
Hypersensitivity reactions[see Warnings and Precautions (5.5)]
Hypokalemia [see Warnings and Precautions (5.6)]
11/15/2019 (SUPPL-71)
5 Warnings and Precautions
5.2 Hyperglycemia or 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.
(Newly Added Subsection)
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
6.1 Clinical Trial Experience(Extensive changes; please refer to labeling)
(Extensive changes; please refer to labeling)
(Additions and/or revisions underlined)
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.
8 Use in Specific Populations
8.4 Pediatric Use(Additions and/or revisions underlined)
NOVOLOG is approved for use in children for subcutaneous daily injections and for subcutaneous continuous infusion by external insulin pump. NOVOLOG has not been studied in pediatric patients younger than 2 years of age. NOVOLOG has not been studied in pediatric patients with type 2 diabetes.
(Additions and/or revisions underlined)
Of the total number of patients (n=1,375) treated with NOVOLOG in 3 controlled clinical studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes (18/1285) and the other half had type 2 diabetes (18/90). The HbA1c response to NOVOLOG, as compared to regular human insulin, did not differ by age.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Extensive changes; please refer to labeling)
11/15/2019 (SUPPL-72)
5 Warnings and Precautions
5.2 Hyperglycemia or 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.
(Newly Added Subsection)
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
6.1 Clinical Trial Experience(Extensive changes; please refer to labeling)
(Extensive changes; please refer to labeling)
(Additions and/or revisions underlined)
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.
8 Use in Specific Populations
8.4 Pediatric Use(Additions and/or revisions underlined)
NOVOLOG is approved for use in children for subcutaneous daily injections and for subcutaneous continuous infusion by external insulin pump. NOVOLOG has not been studied in pediatric patients younger than 2 years of age. NOVOLOG has not been studied in pediatric patients with type 2 diabetes.
(Additions and/or revisions underlined)
Of the total number of patients (n=1,375) treated with NOVOLOG in 3 controlled clinical studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes (18/1285) and the other half had type 2 diabetes (18/90). The HbA1c response to NOVOLOG, as compared to regular human insulin, did not differ by age.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Extensive changes; please refer to labeling)
(Extensive changes; please refer to labeling)
12/20/2018 (SUPPL-68)
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Extensive changes – please refer to labeling)
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
There are no data on the presence of NOVOLOG MIX 70/30 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 MIX 70/30, and any potential adverse effects on the breastfed infant from NOVOLOG MIX 70/30, or from the underlying maternal condition.
05/08/2017 (SUPPL-62)
5 Warnings and Precautions
5.1 Never Share NOVOLOG MIX 70/30 FlexPen Between Patients(Additions and/or revisions are underlined)
NOVOLOG MIX 70/30 FlexPen should never be shared between patients, even if the needle is changed. Patients using NOVOLOG MIX 70/30 vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.
(Revised subsection title; Additions and/or revisions are 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.
(Additions and/or revisions are underlined)
Hypoglycemia is the most common adverse effect of all insulin therapies, including NOVOLOG MIX 70/30. 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 MIX 70/30 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; increased frequency of blood glucose monitoring is recommended. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia; increased frequency of blood glucose monitoring is recommended.
(Newly added subsection)
Accidental mix-ups between NOVOLOG MIX 70/30 and other insulin products have been reported. To avoid medication errors between NOVOLOG MIX 70/30 and other insulins, instruct patients to always check the insulin label before each injection.
(Additions and/or revisions are underlined)
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including NOVOLOG MIX 70/30. If hypersensitivity reactions occur, discontinue NOVOLOG MIX 70/30; treat per standard of care and monitor until symptoms and signs resolve. NOVOLOG MIX 70/30 is contraindicated in patients who have had hypersensitivity reactions to insulin aspart or one of the excipients.
(Additions and/or revisions are underlined)
…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).
6 Adverse Reactions
(Additions and/or revisions are underlined)
The following adverse reactions are also discussed elsewhere:
- Hypoglycemia
- Hypersensitivity and allergic reactions
- Hypokalemia
(Additions and/or revisions are underlined)
…The data in Table 1 reflect the exposure of 55 patients with type 1 diabetes to NOVOLOG MIX 70/30 with a mean exposure duration of three months. The mean age was 43.2 years. Sixty-four percent were male and 100% were Caucasian. The mean body mass index (BMI) was 26.1 kg/m2. The mean duration of diabetes was 14.9 years.
The data in Table 2 reflect the exposure of 85 patients with type 2 diabetes to NOVOLOG MIX
70/30 with a mean exposure duration of three months. The mean age was 62.7 years. Fifty-four percent were male and 100% were Caucasian. The mean body mass index (BMI) was 28.1 kg/m2. The mean duration of diabetes was 15.0 years.
Common adverse reactions were defined as events occurring in greater than or equal to 5%, excluding hypoglycemia, of the population studied. Common adverse events occurring at the same rate or greater for NOVOLOG MIX 70/30-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. The trial was a three-month, open-label trial in patients with type 1 or type 2 diabetes who were treated twice daily (before breakfast and before supper) with NOVOLOG MIX 70/30.
Table 1: Adverse Reactions Occurring in Greater than or Equal to 5% of Type 1 Diabetes Mellitus Adult Patients treated with NOVOLOG MIX 70/30 and at the same rate or greater on NOVOLOG MIX 70/30 than on comparator (Table title has been revised)
Table 2: Adverse reactions Occurring in Greater than or Equal to 5% of Type 2 Diabetes Mellitus Adult Patients treated with NOVOLOG MIX 70/30and at the same rate or greater on NOVOLOG MIX 70/30 than on comparator (Table title has been revised)
Severe Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including NOVOLOG MIX 70/30. 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 MIX 70/30 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.
…
The incidence of severe hypoglycemia in adult patients receiving subcutaneous NOVOLOG MIX 70/30 was 16% and 4 % for type 1 and type 2 diabetes patients respectively at 12 weeks.
Allergic Reactions
Patients have experienced reactions such as erythema, edema or pruritus at the site of NOVOLOG MIX 70/30 injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, have required discontinuation of NOVOLOG MIX 70/30.
Severe cases of generalized allergy (anaphylaxis) have been reported.
Peripheral Edema
Insulin products, including NOVOLOG MIX 70/30, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
(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 MIX 70/30 in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
In a 3-month study with an extension in adult subjects with type 2 diabetes, 100% of patients who received NOVOLOG MIX 70/30 were positive for anti-insulin antibodies (AIA) at least once during the first 12 months of the study including 91.4% that were positive at baseline. A total of 91.4% of patients who received NOVOLOG MIX 70/30 were positive for anti-drug antibodies (ADA) at least once during the first 12 months of the study, including 62.1% that were positive at baseline.
In a phase 3 type 2 diabetes clinical trial of NOVOLOG MIX 70/30, initial increase in titers of antibodies to insulin followed by a decrease approaching to baseline values was observed in NOVOLOG MIX 70/30 and Novolin 70/30 treatment groups with similar incidences. These antibodies did not cause deterioration in glycemic control or necessitate increases in insulin dose.
(Additions and/or revisions are underlined)
The following adverse reactions have been identified during post-approval use of NOVOLOG MIX 70/30. Because 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 in which other insulins have been accidentally substituted for NOVOLOG MIX 70/30 have been reported.
7 Drug Interactions
(Additions and/or revisions are underlined)
Table 3: Clinically Significant Drug Interactions with NOVOLOG MIX 70/30 (Table has been added; please refer to label)
8 Use in Specific Populations
8.5 Geriatric Use(Additions and/or revisions are underlined)
…In elderly patients with diabetes, the initial dosing, dose increments should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly.
(Additions and/or revisions are underlined)
The effect of renal impairment on the pharmacokinetics of NOVOLOG MIX 70/30 has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent NOVOLOG MIX 70/30 dose adjustment and more frequent blood glucose monitoring.
(Additions and/or revisions are underlined)
The effect of hepatic impairment on the pharmacokinetics of NOVOLOG MIX 70/30 has not been studied. Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent NOVOLOG MIX 70/30 dose adjustment and more frequent blood glucose monitoring.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 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 NOVOLOG MIX 70/30 FlexPen between Patients
Advise patients that they must never share NOVOLOG MIX 70/30 FlexPen device with another person even if the needle is changed. Advise patients using NOVOLOG MIX 70/30 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 MIX 70/30 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 MIX 70/30. 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
- Advise patients to inspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Instruct them to not use it if it looks clear or contains solid particles.
- NOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.
- Instruct patients when using the vial, to roll the vial gently in their hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. The patient should use immediately after resuspension.
- Instruct patients when using the FlexPen, to roll the FlexPen gently between their hands in a horizontal position 10 times. Then, to turn the FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy. The patient should use immediately after resuspension.
- Instruct patients to administer NOVOLOG MIX 70/30 by subcutaneous injection in the abdominal region, buttocks, thigh, or upper arm and to rotate injection sites within the same region to reduce the risk of lipodystrophy.