Apidra - Side Effects insulin glulisine
The following adverse reactions are discussed elsewhere:
- Hypoglycemia [see Warnings and Precautions (5.3)]
- Hypokalemia [see Warnings and Precautions (5.5)]
- Hypersensitivity and Allergic Reactions [see Warnings and Precautions (5.6)]
clinical trials 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 drug reactions during APIDRA clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
|APIDRA, % |
|All Comparators |
Insulin lispro, regular human insulin, insulin aspart
Only severe symptomatic hypoglycemia
|Upper respiratory tract infection||6.6||5.6|
|APIDRA, % |
|Regular Human Insulin, % |
|Upper respiratory tract infection||10.5||7.7|
Table 3 summarizes the adverse reactions occurring with frequency higher than 5% in a clinical study in pediatric patients with type 1 diabetes treated with APIDRA (n=277) or insulin lispro (n=295).
|APIDRA, % |
|Lispro, % |
|Upper respiratory tract infection||8.3||10.8|
Severe Symptomatic Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including APIDRA. 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 APIDRA with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that occur in clinical practice. The rates and incidence of severe symptomatic hypoglycemia, defined as hypoglycemia requiring intervention from a third party are presented in Table 4. In the clinical trials, children and adolescents with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to adults with type 1 diabetes (see Table 4) [see Clinical Studies (14)].
|Type 1 Diabetes |
12 weeks with insulin glargine
|Type 1 Diabetes |
26 weeks with insulin glargine
|Type 2 Diabetes |
26 weeks with NPH human insulin
|Type 1 Diabetes |
| APIDRA |
| APIDRA |
|Regular Human Insulin||APIDRA||Insulin Lispro||APIDRA||Regular Human Insulin||APIDRA||Insulin Lispro|
|Events per month per patient||0.05||0.05||0.13||0.02||0.02||0.00||0.00||0.09||0.08|
|Percent of patients (n/total N)||8.4% |
Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII)
In a 12-week randomized study in patients with type 1 diabetes (n=59), the rates of catheter occlusions and infusion site reactions were similar for APIDRA and insulin aspart–treated patients (see Table 5).
|Insulin Aspart |
|Infusion site reactions||10.3% (3/29)||13.3% (4/30)|
Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including APIDRA. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.
In controlled clinical trials up to 12 months duration, potential systemic allergic reactions were reported in 79 of 1833 patients (4.3%) who received APIDRA and 58 of 1524 patients (3.8%) who received the comparator short-acting insulins. During these trials, treatment with APIDRA was permanently discontinued in 1 of 1833 patients due to a potential systemic allergic reaction.
Injection Site Reactions
As with any insulin therapy, patients taking APIDRA may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks, but in some occasions may require discontinuation of APIDRA. 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.
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 APIDRA, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption [see Dosage and Administration (2.2)].
Insulin, including APIDRA, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
Weight gain can occur with insulin therapy, including APIDRA, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to APIDRA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
In a study in patients with type 1 diabetes (n=333), the concentrations of insulin antibodies that react with both human insulin and insulin glulisine (cross-reactive insulin antibodies) remained near baseline during the first 6 months of the study in the patients treated with APIDRA. A decrease in antibody concentration was observed during the following 6 months of the study. In a study in patients with type 2 diabetes (n=411), a similar increase in cross-reactive insulin antibody concentration was observed in the patients treated with APIDRA and in the patients treated with human insulin during the first 9 months of the study. Thereafter the concentration of antibodies decreased in the APIDRA patients and remained stable in the human insulin patients. There was no correlation between cross-reactive insulin antibody concentration and changes in HbA1c, insulin doses, or incidence of hypoglycemia. APIDRA did not elicit a significant antibody response in a study of children and adolescents with type 1 diabetes.
The following adverse reactions have been identified during postapproval use of APIDRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.
Medication errors have been reported in which other insulins, particularly long-acting insulins, have been accidentally administered instead of APIDRA.