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The following adverse reactions are discussed elsewhere:

• Hypoglycemia [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity and allergic reactions [see WARNINGS AND PRECAUTIONS]

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 the LEVEMIR add-on to liraglutide+metformin trial, all patients received liraglutide 1.8 mg + metformin during a 12-week run-in period. During the run-in period, 167 patients (17% of enrolled total) withdrew from the trial: 76 (46% of withdrawals) of these patients doing so because of gastrointestinal adverse reactions and 15 (9% of withdrawals) doing so due to other adverse events. Only those patients who completed the run-in period with inadequate glycemic control were randomized to 26 weeks of add-on therapy with LEVEMIR or continued, unchanged treatment with liraglutide 1.8 mg + metformin. During this randomized 26-week period, diarrhea was the only adverse reaction reported in ≥5% of patients treated with liraglutide 1.8 mg + metformin (11.7%) and greater than in patients treated with liraglutide 1.8 mg and metformin alone (6.9%).

Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and 24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart + LEVEMIR to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and 24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)

Table 4: Adverse reactions (excluding hypoglycemia) in a 26-week clinical trial of children and adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Pregnancy

A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1 diabetes. [see Use in Specific Populations]

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LEVEMIR [see WARNINGS AND PRECAUTIONS].

Tables 5 and 6 summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR clinical trials. 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. 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.

The rates of hypoglycemia in the LEVEMIR clinical trials (see Section 14 for a description of the study designs) were comparable between LEVEMIR-treated patients and non-LEVEMIR-treated patients (see Tables 5 and 6).

Table 5: Hypoglycemia in Patients with Type 1 Diabetes

Table 6: Symptomatic Hypoglycemia in Patients with Type 2 Diabetes

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 adsorption. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy [see DOSAGE AND ADMINISTRATION].
• 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 [see Clinical Studies].
• Peripheral Edema
  Insulin, including LEVEMIR, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Allergic Reactions

Local Allergy

As with any insulin therapy, patients taking LEVEMIR may experience injection site reactions, including localized erythema, pain, pruritis, urticaria, edema, and inflammation. In clinical studies in adults, three patients treated with LEVEMIR reported injection site pain (0.25%) compared to one patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in discontinuation of therapy.

Rotation of the injection site within a given area from one injection to the next may help to reduce or prevent these reactions. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin usually resolve in a few days to a few weeks.

Systemic Allergy

Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR, and may be life-threatening [see WARNINGS AND PRECAUTIONS].

• Antibody Production
  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 phase 3 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 during post-approval use of LEVEMIR in which other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered instead of LEVEMIR [see PATIENT INFORMATION]. To avoid medication errors between LEVEMIR and other insulins, patients should be instructed always to verify the insulin label before each injection.

A number of medications affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.

The following are examples of medications that may increase the blood-glucose-lowering effect of insulins including LEVEMIR and, therefore, increase the susceptibility to hypoglycemia: oral antidiabetic medications, pramlintide acetate, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, pentoxifylline, salicylates, somatostatin analogs, and sulfonamide antibiotics.

The following are examples of medications that may reduce the blood-glucose-lowering effect of insulins including LEVEMIR: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors and atypical antipsychotic medications (e.g. olanzapine and clozapine).

Beta-blockers, clonidine, lithium salts, and alcohol may either increase or decrease the blood-glucoselowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.

Last reviewed on RxList: 5/14/2012
This monograph has been modified to include the generic and brand name in many instances.