Drug Safety-related Labeling Changes (SrLC)

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LEVEMIR (BLA-021536)

(INSULIN DETEMIR RECOMBINANT)

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

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12/08/2022 (SUPPL-62)

Approved Drug Label (PDF)

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

PATIENT INFORMATION

Additions and or revisions underlined:

…

Who should not take LEVEMIR?

Do not take LEVEMIR if you:

• are having an episode of low blood sugar (hypoglycemia).

• have an allergy to LEVEMIR or any of the ingredients in LEVEMIR. See the end of this Patient Information leaflet for a complete list of ingredients in LEVEMIR.

Before taking LEVEMIR, tell your healthcare provider about all your medical conditions including, if you:

• take any other medicines, especially medicines commonly called TZDs (thiazolidinediones).

• are pregnant, planning to become pregnant, or are breastfeeding.

  …

  What are the possible side effects of LEVEMIR?

  LEVEMIR may cause serious side effects that can lead to death, including:

  …

   

• low potassium in your blood (hypokalemia).

• heart failure. Taking certain diabetes pills called TZDs (thiazolidinediones) with LEVEMIR may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure, it may get worse while you take TZDs with LEVEMIR. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:

• shortness of breath    

• swelling of ankles or feet

• sudden weight gain

Treatment with TZDs and LEVEMIR may need to be changed or stopped by your healthcare provider if you have new or worse heart failure.

…

07/01/2022 (SUPPL-60)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

LEVEMIR is contraindicated:

• During episodes of hypoglycemia [see Warnings and Precautions (5.3)]

• In patients with hypersensitivity to insulin detemir or any of the excipients in LEVEMIR. Reactions have included anaphylaxis [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

5 Warnings and Precautions

5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen

Newly added subsection

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 [see Warnings and Precautions (5.4)] 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 [see Adverse Reactions (6)].

5.3 Hypoglycemia

Additions and/or revisions underlined:

Hypoglycemia is the most common adverse reaction of insulin, including LEVEMIR [see Adverse Reactions (6.1)]. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). LEVEMIR, or any insulin, should not be used during episodes of hypoglycemia [see Contraindications (4)].

Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, using drug that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or who experience recurrent hypoglycemia.

Risk Factors for Hypoglycemia

The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia after an injection is related to the duration of action of the insulin [see Clinical Pharmacology (12.2)] and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins, the glucose lowering effect time course of LEVEMIR may vary among different patients or at different times in the same patient 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 concomitant drugs [see Drug Interactions (7)]. When a GLP-1 receptor agonist is used in combination with LEVEMIR, the LEVEMIR dose may need to be lowered or more conservatively titrated to minimize the risk of hypoglycemia [see Adverse Reactions (6.1)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].

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)]

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Hypoglycemia

Hypoglycemia was the most commonly observed adverse reaction in patients treated with LEVEMIR. 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 LEVEMIR 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.

…

Table 4 (type 1 diabetes) and Table 5 (type 2 diabetes) summarize the incidence of severe and non- severe hypoglycemia in the LEVEMIR clinical trials.

…

Hypersensitivity Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occurred with insulin, including LEVEMIR, and may be life-threatening.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post approval use of LEVEMIR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported in which rapid-acting or short-acting insulins and other insulins, have been accidentally administered instead of LEVEMIR.

7 Drug Interactions

Additions and/or revisions underlined:

Table 6 includes clinically significant drug interactions with LEVEMIR.

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

Available data from published studies and postmarketing case reports with LEVEMIR use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In a randomized, parallel-group, open-label clinical trial that included 152 pregnant women with type 1 diabetes who were administered LEVEMIR once or twice daily, beginning in gestational weeks 8 to 12 or prior to conception, no clear evidence of maternal or fetal risk associated with LEVEMIR was observed (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Animal reproduction studies were conducted in non-diabetic pregnant rats and rabbits with insulin detemir administration at 3 and 135 times the human dose of 0.5 units/kg/day, respectively, throughout pregnancy. Overall, the effects of insulin detemir did not generally differ from those observed with regular human insulin (see Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA1c>10. The estimated background risk of miscarriage for the indicated population is unknown.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre- gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, 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

In an open-label clinical trial, pregnant females with type 1 diabetes (n=310) were treated with LEVEMIR (once or twice daily) or NPH insulin (once, twice, or thrice daily); both groups also received preprandial insulin aspart. Approximately half of the study participants in each arm were randomized as pregnant and were exposed to NPH or to other insulins prior to conception and in the first 8 weeks of gestation. The rates of preeclampsia observed in the study were within expected rates for pregnancy complicated by diabetes. No differences in pregnancy outcomes or the health of the fetus and newborn were seen between the two groups. In this study, the proportion of subjects with severe hypoglycemia and non-severe hypoglycemia was similar between the two treatment arms; for the definitions of severe hypoglycemia and non-severe hypoglycemia [see Adverse Reactions (6.1)].

In about a quarter of infants, LEVEMIR was detected in the infant cord blood at levels above the lower level of quantification (<25 pmol/L).

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of LEVEMIR to improve glycemic control in pediatric patients with diabetes mellitus have been established. The use of LEVEMIR for this indication is supported by evidence from adequate and well-controlled trials (Studies D and I) in 694 pediatric patients aged 2 to 17 years with type 1 diabetes mellitus [see Clinical Studies (14.2)] and from other studies in pediatric patients and adults with diabetes mellitus [see Clinical Pharmacology (12.3), Clinical Studies (14.4)].

8.5 Geriatric Use

Additions and/or revisions underlined:

In clinical trials of LEVEMIR, 64 of 1624 patients (4%) in the type 1 diabetes trials and 309 of 1082 patients (29%) in the type 2 diabetes trials were 65 years or older. A total of 52 (7 type 1 and 45 type 2) patients (2%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but small sample sizes limits conclusions. Greater sensitivity of some older individuals cannot be ruled out. In geriatric patients, the initial dosing, dosage increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to recognize in the geriatric patients.

8.6 Renal Impairment

Additions and/or revisions underlined:

No difference was observed in the pharmacokinetics of LEVEMIR between non-diabetic patients with kidney impairment and healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with kidney impairment. Careful glucose monitoring and dose adjustments of LEVEMIR, may be necessary in patients with kidney impairment [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Additions and/or revisions underlined:

Non-diabetic patients with severe hepatic impairment had lower systemic exposures to insulin detemir compared to healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with liver impairment. Careful glucose monitoring and dosage adjustments of LEVEMIR, may be necessary in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

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

17 PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

See FDA-Approved Patient Labeling (Patient Information and Instructions for Use). There are separate Instructions for Use for the Vials and LEVEMIR FlexTouch Pen.

Never Share a LEVEMIR FlexTouch Pen or Insulin Syringe between Patients

Advise patients that they must never share a LEVEMIR FlexTouch pen with another person, even if the needle is changed. Advise patients using LEVEMIR vials not to share needles or insulin syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].

Hyperglycemia or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia (e.g., impaired ability to concentrate and react ). This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.2)].

Hypoglycemia Due to Medication Errors

Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions (5.4)].

12/27/2019 (SUPPL-56)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

LEVEMIR is contraindicated:

·       During episodes of hypoglycemia [see Warnings and Precautions (5.3)]

5 Warnings and Precautions

Never Share a LEVEMIR FlexTouch Pen, Needle, or Syringe Between Patients

(Section title revised)

(Additions and/or revisions underlined)

LEVEMIR FlexTouch prefilled pens must never be shared between patients, even if the needle is changed. Patients using LEVEMIR vials should never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.

Hypoglycemia

(Extensive changes; please refer to label)

Hypoglycemia Due to Medication Errors

(Newly added subsection)

Hypersensitivity and Allergic Reactions

(Additions and/or revisions underlined)

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LEVEMIR. If hypersensitivity reactions occur, discontinue LEVEMIR; treat per standard of care and monitor until symptoms and signs resolve. LEVEMIR is contraindicated in patients who have had hypersensitivity reactions to insulin detemir or any of the excipients [see Contraindications (4)].

Hypokalemia

(Newly added subsection)

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are discussed elsewhere:

·       Hypoglycemia [see Warnings and Precautions (5.3)]

·       Medication errors [see Warnings and Precautions (5.4)]

·       Hypersensitivity and allergic reactions [see Warnings and Precautions (5.5)]

·       Hypokalemia [see Warnings and Precautions (5.6)]

Clinical Trial Experience

(Extensive changes to tables; please refer to label)

(Extensive changes; please refer to label)

Postmarketing Experience

(Newly added information)

Medication errors have been reported in which other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered instead of LEVEMIR.

7 Drug Interactions

(Newly added table; please refer to label)

8 Use in Specific Populations

Pregnancy

(PLLR conversion. Please refer to label for complete information.)

Lactation

(PLLR conversion. Please refer to label for complete information.)

Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of LEVEMIR to improve glycemic control in type 1 and type 2 diabetes mellitus have been established in pediatric patients.

The use of LEVEMIR for this indication is supported by evidence from an adequate and well-controlled study in 694 pediatric patients aged 2 to 17 years with type 1 diabetes mellitus [see Clinical Studies (14.2)] and from other studies in pediatric patients and adults with diabetes mellitus [see Clinical Pharmacology (12.3), Clinical Studies (14.4)].

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise patients using LEVEMIR vials not to share needles or syringes with another person. . .

Hypoglycemia

Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of LEVEMIR 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 [see Warnings and Precautions (5.3)].

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions have occurred with LEVEMIR. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)].

Medication Errors

Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions (5.4)].

11/15/2019 (SUPPL-58)

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, dosage adjustments of concomitant antidiabetic products may be needed.

As with all insulin preparations, the time course of action for LEVEMIR may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the local blood supply, local temperature, and physical activity.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following adverse reactions have been identified during post approval use of LEVEMIR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported during post-approval use of LEVEMIR in which other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered instead of LEVEMIR. To avoid medication errors between LEVEMIR and other insulins, patients should be instructed always to verify the insulin label before each injection.

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

...

17.2     Instructions for Patients

(Additions and/or revisions are underlined)

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.  Patients should be informed about the potential side effects of insulin therapy, including hypoglycemia, weight gain, lipodystrophy and localized cutaneous amyloidosis (and the need to rotate injection sites within the same body region), and allergic reactions. Patients should be informed that the ability to concentrate and react may be impaired as a result of hypoglycemia.  This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.  Patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use caution when driving or operating machinery.

Accidental mix-ups between LEVEMIR and other insulins, particularly short-acting insulins, have been reported. To avoid medication errors between LEVEMIR and other insulins, patients should be instructed to always check the insulin label before each injection.

LEVEMIR must only be used if the solution is clear and colorless with no particles visible. Patients must be advised that LEVEMIR must NOT be diluted or mixed with any other insulin or solution.

Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia. Patients should be instructed 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.

Patients should receive proper training on how to use LEVEMIR. Instruct patients that when injecting LEVEMIR, 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. When the dose counter returns to 0, the prescribed dose is not completely delivered until 6 seconds later. If the needle is removed earlier, they may see a stream of insulin coming from the needle tip. If so, the full dose will not be delivered (a possible under-dose may occur by as much as 20%), and they should increase the frequency of checking their blood glucose levels and possible additional insulin administration may be necessary.

• If 0 does not appear in the dose counter after continuously pressing the dose button, the patient may have used a blocked needle. In this case they would not have received any insulin – even though the dose counter has moved from the original dose that was set.

• If the patient did have a blocked needle, instruct them to change the needle as described in Section 5 of the Instructions for Use and repeat all steps in the IFU starting with Section 1: Prepare your pen with a new needle. Make sure the patient selects the full dose needed.

  Patients with diabetes should be advised to inform their healthcare professional if they are pregnant or are contemplating pregnancy. Refer patients to the LEVEMIR "Patient Information" for additional information.

PATIENT INFORMATION

(Extensive changes; please refer to labeling)