LEVEMIR SIDE EFFECTS

SIDE EFFECTS

The following adverse reactions are discussed elsewhere:

• Hypoglycemia
• Hypoglycemia Due to Medication errors
• Hypersensitivity Reactions
• Hypokalemia

Clinical Trial Experience

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 frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Tables 1 4 below. See Tables 5 and 6 for the hypoglycemia findings.

In two pooled trials, adults with type 1 diabetes were exposed to individualized doses of LEVEMIR (n=767) or NPH (n=388). The mean duration of exposure to LEVEMIR was 153 days, and the total exposure to LEVEMIR was 321 patient years. The most common adverse reactions are summarized in Table 1.

Table 1: Adverse Reactions Occurring in ≥ 5% of LEVEMIR Treated Adult Patients with Type 1 Diabetes Mellitus in Two Trials of 16 Weeks and 24 Weeks Duration

Adults with type 1 diabetes were exposed to LEVEMIR (n=161) or insulin glargine (n=159). The mean duration of exposure to LEVEMIR was 176 days, and the total exposure to LEVEMIR was 78 patient years. The most common adverse reactions are summarized in Table 2.

Table 2: Adverse Reactions Occurring in ≥ 5% of LEVEMIR Treated Adult Patients with Type 1 Diabetes Mellitus in a 26 week Trial

In two pooled trials, adults with type 2 diabetes were exposed to LEVEMIR (n=432) or NPH (n=437). The mean duration of exposure to LEVEMIR was 157 days, and the total exposure to LEVEMIR was 186 patient years. The most common adverse reactions were comparable to that observed in adult patients with type 1 diabetes mellitus; see Table 1.

Pediatric patients with type 1 diabetes were exposed to individualized doses of LEVEMIR (n=232) or NPH (n=115). The mean duration of exposure to LEVEMIR was 180 days, and the total exposure to LEVEMIR was 114 patient years. The most common adverse reactions are summarized in Table 3.

Table 3: Adverse Reactions Occurring in ≥ 5% of LEVEMIR Treated Pediatric Patients with Type 1 Diabetes Mellitus in a 26 week Trial

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.

For the adult trials and one of the pediatric trials (Study D), severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring assistance of another person and associated with either a plasma glucose value below 56 mg/dL (blood glucose below 50 mg/dL) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration.

For the other pediatric trial (Study I), severe hypoglycemia was defined as an event with semi consciousness, unconsciousness, coma and/or convulsions in a patient who could not assist in the treatment and who may have required glucagon or intravenous glucose. For the adult trials and pediatric trial (Study D), non severe hypoglycemia was defined as an asymptomatic or symptomatic plasma glucose <56 mg/dL (or equivalently blood glucose <50 mg/dL as used in Study A and C) that was self treated by the patient. For pediatric Study I, non severe hypoglycemia included asymptomatic events with plasma glucose <65 mg/dL as well as symptomatic events that the patient could self treat or treat by taking oral therapy provided by the caregiver.

Table 4: Hypoglycemia in Patients with Type 1 Diabetes

Table 5: Hypoglycemia in Patients with Type 2 Diabetes

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.

Insulin Initiation And Intensification Of Glucose Control

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. However, long term glycemic control decreases the risk of diabetic retinopathy and neuropathy.

Lipodystrophy

Long term use of insulin, including LEVEMIR, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption.

Weight Gain

Weight gain can occur with insulin therapy, including LEVEMIR, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. In the clinical program, the mean change in body weight from baseline in adult patients with type 1 diabetes (Study A, B, and C) treated with LEVEMIR ranged from 0.3 kg to 0.5 kg. The mean change in body weight from baseline in adult patients with type 2 diabetes (Study E, F, and H) treated with LEVEMIR ranged from 0.5 kg to 1.2 kg.

Peripheral Edema

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

Injection Site Reactions

Patients taking LEVEMIR may experience injection site reactions, including localized erythema, pain, pruritus, urticaria, edema, and inflammation. In clinical studies in adults, three patients treated with LEVEMIR reported injection site pain (0.25%).

Immunogenicity

All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In clinical trials of LEVEMIR, antibody development has been observed with no apparent impact on glycemic control.

Postmarketing Experience

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.

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.

SRC: NLM .