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The following serious adverse reactions are described below and elsewhere in the labeling:

  • Acute bronchospasm in patients with chronic lung disease [see WARNINGS AND PRECAUTIONS]
  • Hypoglycemia [see WARNINGS AND PRECAUTIONS]
  • Decline in pulmonary function [see WARNINGS AND PRECAUTIONS]
  • Lung cancer [see WARNINGS AND PRECAUTIONS]
  • Diabetic ketoacidosis [see WARNINGS AND PRECAUTIONS]
  • Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying designs, the incidence of adverse reactions reported in one clinical trial may not be easily compared to the incidence reported in another clinical trial, and may not reflect what is observed in clinical practice.

The data described below reflect exposure of 3017 patients to AFREZZA and include 1026 patients with type 1 diabetes and 1991 patients with type 2 diabetes. The mean exposure duration was 8.17 months for the overall population and 8.16 months and 8.18 months for type 1 and 2 diabetes patients, respectively. In the overall population, 1874 were exposed to AFREZZA for 6 months and 724 for greater than one year. 620 and 1254 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for up to 6 months. 238 and 486 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for greater than one year (median exposure = 1.8 years). AFREZZA was studied in placebo and active-controlled trials (n = 3 and n = 10, respectively).

The mean age of the population was 50.2 years and 20 patients were older than 75 years of age. 50.8% of the population were men; 82.6% were White, 1.8% were Asian, and 4.9% were Black or African American. 9.7% were Hispanic. At baseline, the type 1 diabetes population had diabetes for an average of 16.6 years and had a mean HbA1c of 8.3%, and the type 2 diabetes population had diabetes for an average of 10.7 years and had a mean HbA1c of 8.8%. At baseline, 33.4% of the population reported peripheral neuropathy, 32.0% reported retinopathy and 19.6% had a history of cardiovascular disease.

Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of controlled trials in type 2 diabetes patients. These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA.

Table 1: Common Adverse Reactions in Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA

  Placebo*
(n = 290)
AFREZZA
(n = 1991)
Non-placebo comparators
(n=1363)
Cough 19.7% 25.6% 5.4%
Throat pain or irritation 3.8% 4.4% 0.9%
Headache 2.8% 3.1% 1.8%
Diarrhea 1.4% 2.7% 2.2%
Productive cough 1.0% 2.2% 0.9%
Fatigue 0.7% 2.0% 0.6%
Nausea 0.3% 2.0% 1.0%
*Carrier particle without insulin was used as placebo [see DESCRIPTION].

Table 2 shows common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of active-controlled trials in type 1 diabetes patients. These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on comparator, and occurred in at least 2% of patients treated with AFREZZA.

Table 2: Common Adverse Reactions in Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA

  Subcutaneous Insulin
(n = 835)
AFREZZA
(n=1026)
Cough 4.9% 29.4%
Throat pain or irritation 1.9% 5.5%
Headache 2.8% 4.7%
Pulmonary function test decreased 1.0% 2.8%
Bronchitis 2.0% 2.5%
Urinary tract infection 1.9% 2.3%

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including AFREZZA [see WARNINGS AND PRECAUTIONS]. The incidence of severe and non-severe hypoglycemia of AFREZZA versus placebo in patients with type 2 diabetes is shown in Table 3. A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose value consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia.

Table 3: Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled Study of Patients with Type 2 Diabetes

  Placebo
(N=176)
AFREZZA
(N=177)
Severe Hypoglycemia 1.7% 5.1%
Non-Severe Hypoglycemia 30% 67%

Cough

Approximately 27% of patients treated with AFREZZA reported cough, compared to approximately 5.2% of patients treated with comparator. In clinical trials, cough was the most common reason for discontinuation of AFREZZA therapy (2.8% of AFREZZA-treated patients).

Pulmonary Function Decline

In clinical trials lasting up to 2 years, excluding patients with chronic lung disease, patients treated with AFREZZA had a 40 mL (95% CI: -80, -1) greater decline from baseline in forced expiratory volume in one second (FEV1) compared to patients treated with comparator anti-diabetes treatments. The decline occurred during the first 3 months of therapy and persisted over 2 years (Figure 2). A decline in FEV1 of ≥ 15% occurred in 6% of AFREZZA-treated subjects compared to 3% of comparator-treated subjects.

Figure 2: Mean (+/-SE) Change in FEV1 (Liters) from Baseline for Type 1 and Type 2 Diabetes Patients

Mean (+/-SE) Change in FEV1 (Liters) from Baseline for Type 1 and Type 2 Diabetes Patients - Illustration

Weight gain

Weight gain may occur with some insulin therapies, including AFREZZA. Weight gain has been attributed to the anabolic effects of insulin and the decrease in glycosuria. In a clinical trial of patients with type 2 diabetes [see Clinical Studies], there was a mean 0.49 kg weight gain among AFREZZA-treated patients compared with a mean 1.13 kg weight loss among placebo-treated patients.

Antibody Production

Increases in anti-insulin antibody concentrations have been observed in patients treated with AFREZZA. Increases in anti-insulin antibodies are observed more frequently with AFREZZA than with subcutaneously injected mealtime insulins. Presence of antibody did not correlate with reduced efficacy, as measured by HbA1c and fasting plasma glucose, or specific adverse reactions.