ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
- Hypoglycemia [See Warnings and Precautions]
- Hypokalemia [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 drug reactions during APIDRA clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
Table 1: Treatment –emergent adverse events in pooled studies of adults with type 1 diabetes (adverse events with frequency ≥ 5%) | | APIDRA, %
(n=950) | All comparatorsInsulin lispro, regular human insulin, insulin aspart, %
(n=641) |
|---|
| Nasopharyngitis | 10.6 | 12.9 |
| HypoglycemiaOnly severe symptomatic hypoglycemia | 6.8 | 6.7 |
| Upper respiratory tract infection | 6.6 | 5.6 |
| Influenza | 4.0 | 5.0 |
Table 2: Treatment –emergent adverse events in pooled studies of adults with type 2 diabetes (adverse events with frequency ≥ 5%) | | APIDRA, %
(n=883) | Regular human insulin, %
(n=883) |
|---|
| Upper respiratory tract infection | 10.5 | 7.7 |
| Nasopharyngitis | 7.6 | 8.2 |
| Edema peripheral | 7.5 | 7.8 |
| Influenza | 6.2 | 4.2 |
| Arthralgia | 5.9 | 6.3 |
| Hypertension | 3.9 | 5.3 |
Table 3 summarizes the adverse reactions occurring with frequency higher than 5% in a clinical study in children and adolescents with type 1 diabetes treated with APIDRA (n=277) or insulin lispro (n=295).
Table 3: Treatment –emergent adverse events in children and adolescents with type 1 diabetes (adverse reactions with frequency ≥ 5%) | | APIDRA, %
(n=277) | Lispro, %
(n=295) |
|---|
| Nasopharyngitis | 9.0 | 9.5 |
| Upper respiratory tract infection | 8.3 | 10.8 |
| Headache | 6.9 | 11.2 |
| Hypoglycemic seizure | 6.1 | 4.7 |
- Severe symptomatic hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including APIDRA [See Warnings and Precautions]. The rates and incidence of severe symptomatic hypoglycemia, defined as hypoglycemia requiring intervention from a third party, were comparable for all treatment regimens (see Table 4). In the phase 3 clinical trial, 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].
Table 4: Severe Symptomatic HypoglycemiaSevere symptomatic hypoglycemia defined as a hypoglycemic event requiring the assistance of another person that met one of the following criteria:
the event was associated with a whole blood referenced blood glucose <36mg/dL or the event was associated with prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. | Type 1 Diabetes
Adults
12 weeks
with insulin glargine | Type 1 Diabetes Adults
26 weeks
with insulin glargine | Type 2 Diabetes
Adults
26 weeks
with NPH human insulin | Type 1 Diabetes Pediatrics
26 weeks |
|---|
| APIDRA
Pre-meal | APIDRA
Post-meal | 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% (24/286) | 8.4% (25/296) | 10.1% (28/278) | 4.8%
(16/339) | 4.0%
(13/333) | 1.4%
(6/416) | 1.2%
(5/420) | 16.2%
(45/277) | 19.3%
(57/295) |
- 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. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy. [See Dosage and Administration (2.2, 2.3) ].
Weight gain can occur with insulin therapy, including APIDRA, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.
Insulin, including APIDRA, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
- 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 (Table 5).
Table 5: Catheter Occlusions and Infusion Site Reactions. | APIDRA
(n=29) | insulin aspart
(n=30) |
|---|
| Catheter occlusions/month | 0.08 | 0.15 |
| Infusion site reactions | 10.3% (3/29) | 13.3% (4/30) |
Local Allergy
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.
Systemic Allergy
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.
Localized reactions and generalized myalgias have been reported with the use of metacresol, which is an excipient of APIDRA.
Antibody Production
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. The clinical significance of these antibodies is not known.
APIDRA did not elicit a significant antibody response in a study of children and adolescents with type 1 diabetes.
Postmarketing experience
The following adverse reactions have been identified during post-approval 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 [See Patient Counseling Information].
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