"Miriam E. Tucker
Medscape Medical News
The U.S. Food and Drug Administration (FDA) will now require a "for single patient use only" warning on all multidose pen devices used for injectable diabetes medications.
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%).
In two pooled trials, a total of 1155 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 (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%)
|Upper respiratory tract infection||26.1||21.4|
A total of 320 adults with type 1 diabetes were exposed to individualized doses of 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 (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 ≥
(n = 159)
|Upper respiratory tract infection||26.7||32.1|
In two pooled trials, a total of 869 adults with type 2 diabetes were exposed to individualized doses of 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 are summarized in Table 3.
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%)
|Upper respiratory tract infection||12.5||11.2|
A total of 347 children and adolescents (6-17 years) 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 4.
Table 4: Adverse reactions (excluding hypoglycemia) in
one 26-week clinical trial of children and adolescents with type 1 diabetes
(adverse reactions with incidence ≥ 5%)
|Upper respiratory tract infection||35.8||42.6|
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1 diabetes. [see Use in Specific Populations]
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.
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 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.
The rates of hypoglycemia in the LEVEMIR® clinical trials (see Clinical Studies) 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
|Severe Hypoglycemia||Non-Severe Hypoglycemia|
|Percent of patients with at least 1 event (n/total N)||Event/ patient/ year||Percent of patients (n/total N)||Event/ patient/ year|
|Study A Type 1 Diabetes Adults 16 weeks In combination with insulin aspart||Twice-Daily LEVEMIR®||8.7 (24/276)||0.52||88.0 (243/276)||26.4|
|Twice-Daily NPH||10.6 (14/132)||0.43||89.4 (118/132)||37.5|
|Study B Type 1 Diabetes Adults 26 weeks In combination with insulin aspart||Twice-Daily LEVEMIR®||5.0 (8/161)||0.13||82.0 (132/161)||20.2|
|Once-Daily Glargine||10.1 (16/159)||0.31||77.4 (123/159)||21.8|
|Study C Type 1 Diabetes Adults 24 weeks In combination with regular insulin||Once-Daily LEVEMIR®||7.5 (37/491)||0.35||88.4 (434/491)||31.1|
|Once-Daily NPH||10.2 (26/256)||0.32||87.9 (225/256)||33.4|
|Study D Type 1 Diabetes Pediatrics 26 weeks In combination with insulin aspart||Once- or Twice Daily LEVEMIR®||159 (37/232)||0.91||931 (216/232)||31.6|
|Once- or Twice Daily NPH||20.0 (23/115)||0.99||95 7 (110/115)||37.0|
|Study I Type 1 Diabetes Pediatrics 52 weeks In combination with insulin aspart||Once- or Twice Daily LEVEMIR®||1.7 (3/177)||0.02||949 (168/177)||56.1|
|Once- or Twice Daily NPH||7.1 (12/170)||0.09||97.6 (166/170)||70.7|
Table 6: Hypoglycemia in Patients with Type 2 Diabetes
|Study E Type 2 Diabetes Adults 24 weeks In combination with oral agents||Study F Type 2 Diabetes Adults 22 weeks In combination with insulin aspart||Study H Type 2 Diabetes Adults 26 weeks in combination with Liraglutide and Metformin|
|Twice-Daily LEVEMIR®||Twice-Daily NPH||Once- or Twice Daily LEVEMIR®||Once- or Twice Daily NPH||Once Daily LEVEMIR® + Liraglutide + Metformin||Liraglutide + Metformin|
|Severe hypoglycemia||Percent of patients with at least 1 event (n/total N)||0.4 (1/237)||2.5 (6/238)||1.5 (3/195)||4.0 (8/199)||0||0|
|Non-severe hypoglycemia||Percent of patients (n/total N)||40.5 (96/237)||64.3 (153/238)||32 3 (63/195)||32.2 (64/199)||9.2 (15/163)||1.3 (2/158*)|
|*One subject is an outlier and was excluded due to 25 hypoglycemic episodes that the patient was able to self-treat. This patient had a history of frequent hypoglycemia prior to the study|
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.
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. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy [see DOSAGE AND ADMINISTRATION].
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].
Insulin, including LEVEMIR®, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
As with any insulin therapy, 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%) 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.
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].
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.
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.
Read the Levemir (insulin detemir) Side Effects Center for a complete guide to possible side effects
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-glucose-lowering 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.
Read the Levemir Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 2/3/2016
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