Exubera (Insulin Inhalation) - Description and Clinical Pharmacology

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DESCRIPTION

EXUBERA^® consists of blisters containing human insulin inhalation powder, which are administered using the EXUBERA^® Inhaler. EXUBERA blisters contain human insulin produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Chemically, human insulin has the empirical formula C₂₅₇H₃₈₃N₆₅O₇₇S₆ and a molecular weight of 5808. Human insulin has the following primary amino acid sequence:

EXUBERA (insulin human [rDNA origin]) Inhalation Powder is a white to off-white powder in a unit dose blister (fill mass, see Table 1). Each unit dose blister of EXUBERA contains a 1 mg or 3 mg dose of insulin (see Table 1) in a homogeneous powder formulation containing sodium citrate (dihydrate), mannitol, glycine, and sodium hydroxide. After an EXUBERA blister is inserted into the inhaler, the patient pumps the handle of the inhaler and then presses a button, causing the blister to be pierced. The insulin inhalation powder is then dispersed into the chamber, allowing the patient to inhale the aerosolized powder.

Under standardized in vitro test conditions, EXUBERA delivers a specific emitted dose of insulin from the mouthpiece of the inhaler (see Table 1). A fraction of the total particle mass is emitted as fine particles capable of reaching the deep lung. Up to 45% of the 1 mg blister contents, and up to 25% of the 3 mg blister contents, may be retained in the blister.

Table 1: Dose Nomenclature and Information

Fill Mass
(mg powder) Nominal Dose
(mg insulin) Emitted DoseFlow rate of 30 L/min for 2.5 seconds^, ¹
(mg insulin) Fine Particle DoseFlow rate of 28.3 L/min for 3 seconds^,
(mg insulin)

1.7 1.0 0.53 0.4

5.1 3.0 2.03 1.0

¹ Emitted dose and fine particle dose information are not intended to predict actual pharmacodynamic response.

The actual amount of insulin delivered to the lung will depend on individual patient factors, such as inspiratory flow profile. In vitro, emitted aerosol metrics are unaffected at flow rates above 10 L/min.

CLINICAL PHARMACOLOGY

Mechanism of Action

The primary activity of insulin is regulation of glucose metabolism. Insulin lowers blood glucose concentrations by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.

Pharmacokinetics

Absorption

EXUBERA delivers insulin by oral inhalation. The insulin is absorbed as quickly as subcutaneously administered rapid-acting insulin analogs and more quickly than subcutaneously administered regular human insulin in healthy subjects and in patients with type 1 or type 2 diabetes (see Figure 1).

Figure 1: Mean Changes in Free Insulin Serum Concentrations (µU/mL) in Patients with Type 2 Diabetes Following Administration of Single Doses of Inhaled Insulin from EXUBERA (6 mg) and Subcutaneous Regular Human Insulin (18U)

In clinical studies in patients with type 1 and type 2 diabetes, after inhalation of EXUBERA, serum insulin reached peak concentration more quickly than after subcutaneous injection of regular human insulin, 49 minutes (range 30 to 90 minutes) compared to 105 minutes (range 60 to 240 minutes), respectively.

In clinical studies, the absorption of subcutaneous regular human insulin declined with increasing patient body mass index (BMI). However, the absorption of insulin following inhalation of EXUBERA was independent of BMI.

In a study in healthy subjects, systemic insulin exposure (AUC and C_max) following administration of EXUBERA increased with dose over a range of 1 to 6 mg when administered as combinations of 1 and 3 mg blisters.

In a study where the dosage form of three 1 mg blisters was compared with one 3 mg blister, C_max and AUC after administration of three 1 mg blisters were approximately 30% and 40% greater, respectively, than that after administration of one 3 mg blister (see DOSAGE AND ADMINISTRATION).

Distribution and Elimination

Because recombinant human insulin is identical to endogenous insulin, the systemic distribution and elimination are expected to be the same. However, this has not been confirmed for EXUBERA.

Pharmacodynamics

EXUBERA, like subcutaneously administered rapid-acting insulin analogs, has a more rapid onset of glucose-lowering activity than subcutaneously administered regular human insulin. In healthy volunteers, the duration of glucose-lowering activity for EXUBERA was comparable to subcutaneously administered regular human insulin and longer than subcutaneously administered rapid-acting insulin analogs (see Figure 2).

Figure 2. Mean Glucose Infusion Rate (GIR) Normalized to GIR_max for Each Subject Treatment Versus Time in Healthy Volunteers

*Determined as amount of glucose infused to maintain constant plasma glucose concentrations, normalized to maximum values (percent of maximum values); indicative of insulin activity.

When EXUBERA is inhaled, the onset of glucose-lowering activity in healthy volunteers occurs within 10–20 minutes. The maximum effect on glucose lowering is exerted approximately 2 hours after inhalation. The duration of glucose-lowering activity is approximately 6 hours.

In patients with type 1 or type 2 diabetes, EXUBERA has a greater glucose-lowering effect within the first two hours after dosing when compared with subcutaneously administered regular human insulin.

The intra-subject variability of glucose-lowering activity of EXUBERA is generally comparable to that of subcutaneously administered regular human insulin in patients with type 1 and 2 diabetes.

Special Populations

Pediatric Patients

In children (6–11 years) and adolescents (12–17 years) with type 1 diabetes, time to peak insulin concentration for EXUBERA was achieved faster than for subcutaneous regular human insulin, which is consistent with observations in adult patients with type 1 diabetes.

Geriatric Patients

There are no apparent differences in the pharmacokinetic properties of EXUBERA when comparing patients over the age of 65 years and younger adult patients.

Gender

In subjects with and without diabetes, no apparent differences in the pharmacokinetic properties of EXUBERA were observed between men and women.

Race

A study was performed in 25 healthy Caucasian and Japanese non-diabetic subjects to compare the pharmacokinetic and pharmacodynamic properties of EXUBERA, versus subcutaneous injection of regular human insulin. The pharmacokinetic and pharmacodynamic properties of EXUBERA were comparable between the two populations.

Obesity

The absorption of EXUBERA is independent of patient BMI.

Renal Impairment

The effect of renal impairment on the pharmacokinetics of EXUBERA has not been studied. Careful glucose monitoring and dose adjustments of insulin may be necessary in patients with renal dysfunction (see PRECAUTIONS, Renal Impairment).

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of EXUBERA has not been studied. Careful glucose monitoring and dose adjustments of insulin may be necessary in patients with hepatic dysfunction (see PRECAUTIONS, Hepatic Impairment).

Pregnancy

The absorption of EXUBERA in pregnant patients with gestational and pre-gestational type 2 diabetes was consistent with that in non-pregnant patients with type 2 diabetes (see PRECAUTIONS, Pregnancy).

Smoking

In smokers, the systemic insulin exposure for EXUBERA is expected to be 2 to 5 fold higher than in non-smokers. EXUBERA is contraindicated in patients who smoke or who have discontinued smoking less than 6 months prior to starting EXUBERA therapy. If a patient starts or resumes smoking, EXUBERA must be discontinued immediately due to the increased risk of hypoglycemia, and an alternative treatment must be utilized (see CONTRAINDICATIONS).

In clinical studies of EXUBERA in 123 patients (69 of whom were smokers), smokers experienced a more rapid onset of glucose-lowering action, greater maximum effect, and a greater total glucose-lowering effect (particularly during the first 2–3 hours after dosing), compared to non-smokers.

Passive Cigarette Smoke

In contrast to the increase in insulin exposure following active smoking, when EXUBERA was administered to 30 healthy non-smoking volunteers following 2 hours of exposure to passive cigarette smoke in a controlled experimental setting, insulin AUC and Cmax were reduced by approximately 20% and 30%, respectively. The pharmacokinetics of EXUBERA have not been studied in nonsmokers who are chronically exposed to passive cigarette smoke.

Patients with Underlying Lung Diseases

The use of EXUBERA in patients with underlying lung disease, such as asthma or COPD, is not recommended because the safety and efficacy of EXUBERA in this population have not been established (see WARNINGS). The use of EXUBERA is contraindicated in patients with unstable or poorly controlled lung disease, because of wide variations in lung function that could affect the absorption of EXUBERA and increase the risk of hypoglycemia or hyperglycemia (see CONTRAINDICATIONS).

In a pharmacokinetic study in 24 non-diabetic subjects with mild asthma, the absorption of insulin following administration of EXUBERA, in the absence of treatment with a bronchodilator, was approximately 20% lower than the absorption seen in subjects without asthma. However, in a study in 24 non-diabetic subjects with Chronic Obstructive Pulmonary Disease (COPD), the systemic exposure following administration of EXUBERA was approximately two-fold higher than that in normal subjects without COPD (see PRECAUTIONS, Underlying Lung Disease).

Administration of albuterol 30 minutes prior to administration of EXUBERA in non-diabetic subjects with both mild asthma (n=36) and moderate asthma (n=31) resulted in a mean increase in insulin AUC and C_max of between 25 and 50% compared to when EXUBERA was administered alone (see PRECAUTIONS, Drug Interactions).

CLINICAL STUDIES

The safety and efficacy of EXUBERA has been studied in approximately 2500 adult patients with type 1 and type 2 diabetes. The primary efficacy parameter for most studies was glycemic control, as measured by the reduction from baseline in hemoglobin A1c (HbA_1c).

Type 1 Diabetes

A 24-week, randomized, open-label, active-control study (Study A) was conducted in patients with type 1 diabetes to assess the safety and efficacy of EXUBERA administered pre-meal three times daily (TID) with a single nighttime injection of Humulin^® U Ultralente^® (human insulin extended zinc suspension) (n = 136). The comparator treatment was subcutaneous regular human insulin administered twice daily (BID) (pre-breakfast and pre-dinner) with BID injection of NPH human insulin (human insulin isophane suspension) (n = 132). In this study, the mean age was 38.2 years (range: 20–64) and 52% of the subjects were male.

A second 24-week, randomized, open-label, active-control study (Study B) was conducted in patients with type 1 diabetes to assess the safety and efficacy of EXUBERA (n = 103) compared to subcutaneous regular human insulin (n = 103) when administered TID prior to meals. In both treatment arms, NPH human insulin was administered BID (in the morning and at bedtime) as the basal insulin. In this study, the mean age was 38.4 years (range: 19–65) and 54% of the subjects were male.

In each study, the reduction in HbA_1c and the rates of hypoglycemia were comparable for the two treatment groups. EXUBERA-treated patients had a greater reduction in fasting plasma glucose than patients in the comparator group. The percentage of patients reaching an HbA_1c level of <8% (per American Diabetes Association treatment Action Level at the time of study conduct) and an HbA_1c level of <7% was comparable between the two treatment groups. The results for Studies A and B are shown in Table 2.

Table 2: Results of Two 24-Week, Active-Control, Open-Label Trials in Patients With Type 1 Diabetes (Studies A and B)

Study A Study B

EXUBERA (TID) + UL (QD) SC R (BID) + NPH (BID) EXUBERA (TID) + NPH (BID) SC R (TID) + NPH (BID)

Sample Size 136 132 103 103

UL = Humulin^® U Ultralente^®; SC R = subcutaneous regular human insulin

HbA_1c (%)

  Baseline mean 7.9 8.0 7.8 7.8

  Adj. mean change from baseline -0.2 -0.4 -0.3 -0.2

    EXUBERA minus SC RA negative treatment difference favors EXUBERA 0.14 -0.11

    95% CI for treatment difference (-0.03, 0.32) (-0.30, 0.08)

Fasting Plasma Glucose (mg/dL)

  Baseline mean 191 198 178 191

  Adj. mean change from baseline -32 -6 -23 13

    EXUBERA minus SC R -27 -35

    95% CI for treatment difference (-47, -6) (-58, -13)

2-hr Post-Prandial Glucose Concentration (mg/dL)

  Baseline mean 283 305 273 293

  Adj. mean change from baseline -21 14 -1 -3

    EXUBERA minus SC R -35 2

    95% CI for treatment difference (-61, -8) (-29, 32)

Patients with end-of-study HbA_1c < 8%American Diabetes Association treatment Action Level at the time of study conduct 64.0% 68.2% 74.8% 66.0%

Patients with end-of-study HbA_1c < 7% 16.9% 19.7% 28.2% 30.1%

Body Weight

  Baseline mean (kg) 77.4 76.4 76.0 76.9

  Adj. mean change from baseline (kg) 0.4 1.1 0.4 0.6

    EXUBERA minus SC R -0.72 -0.24

    95% CI for treatment difference (-1.48, 0.04) (-1.07, 0.59)

End of study daily insulin dose

  Short-acting insulin 13.4 mg ¹ 18.3 IU 10.9 mg 25.7 IU

  Long-acting insulin 26.4 IU 37.1 IU 31.5 IU 31.9 IU

¹ 1 mg inhaled insulin from Exubera is approximately equivalent to 3 IU of subcutaneously injected regular human insulin (See DOSAGE AND ADMINISTRATION)

Type 2 Diabetes

Monotherapy in Patients Not Optimally Controlled With Diet and Exercise Treatment

A 12-week, randomized, open-label, active-control study (Study C) was conducted in patients with type 2 diabetes not optimally controlled with diet and exercise, assessing the safety and efficacy of pre-meal TID EXUBERA (n = 75) compared to an insulin-sensitizing agent. In this study, the mean age was 53.7 years (range: 28–80), 55% of the subjects were male and the mean body mass index was 32.3 kg/m².

At 12 weeks, HbA_1c levels in patients treated with EXUBERA decreased 2.2% (SD = 1.0) from a baseline of 9.5% (SD = 1.1). The proportion of patients treated with EXUBERA reaching an end-of-study HbA_1c level of <8% increased to 82.7%. The proportion of patients treated with EXUBERA reaching an end-of-study HbA_1c level of <7 % was 44.6%. Fasting plasma glucose levels in patients treated with EXUBERA decreased 60 mg/dl from a baseline of 208 mg/dl. Patients treated with EXUBERA experienced a mean increase in body weight of 2 kg. The rate of hypoglycemia was higher in the Exubera group than the group receiving an insulin-sensitizing agent.

Monotherapy and Add-On Therapy in Patients Previously Treated With Oral Agent Therapy

A 12-week, randomized, open-label, active-control study (Study D) was conducted in patients with type 2 diabetes who were currently receiving treatment, but were poorly controlled, with two oral agents (OA). Baseline OAs included an insulin secretagogue, and either metformin or a thiazolidinedione. Patients were randomized to one of three arms: continuing OA therapy alone (n = 96), switching to pre-meal TID EXUBERA monotherapy (n = 102) or adding pre-meal TID EXUBERA to continued OA therapy (n = 100). In this study, the mean age was 57.4 years (range: 33–80), 66% of the subjects were male and the mean body mass index was 30 kg/m².

EXUBERA monotherapy and EXUBERA in combination with OA therapy were superior to OA therapy alone in reducing HbA_1c levels from baseline. The rates of hypoglycemia for the two EXUBERA treatment groups were slightly higher than in the OA therapy alone group. Compared to OA therapy alone, the percentage of patients reaching an HbA_1c level of <8% (per American Diabetes Association treatment Action Level at time of study conduct) and an HbA_1c level of <7% was greater for patients treated with EXUBERA monotherapy and EXUBERA in combination with OA therapy. Patients in both EXUBERA treatment groups had greater reductions in fasting plasma glucose than patients treated with OA therapy alone. The results for Study D are shown in Table 3.

Table 3: Results of a 12-Week, Active-Control, Open-Label Trial in Patients With Type 2 Diabetes Not Optimally Controlled With Dual Oral Agent Therapy (Study D)

Study D EXUBERA monotherapy OAsOAs = treatment with two oral agents (an insulin secretagogue in addition to metformin or a thiazolidinedione) EXUBERA + OAs

Sample Size 102 96 100

HbA_1c (%)

  Baseline mean 9.3 9.3 9.2

  Adj. mean change from baseline -1.4 -0.2 -1.9

    EXUBERA group minus OAs ¹ -1.18^, ² ^, ³      -1.67^, ⁴ ^,

    95% CI for treatment difference (-1.41, -0.95) (-1.90, -1.44)

Fasting Plasma Glucose (mg/dL)

  Baseline mean 203 203 195

  Adj. mean change from baseline -23 1 -53

    EXUBERA group minus OAs -24         -53

    95% CI for treatment difference (-36, -11) (-66, -41)

Patients with end-of-study HbA_1c < 8%American Diabetes Association treatment Action Level at the time of study conduct 55.9% 18.8% 86.0%

Patients with end-of-study HbA_1c < 7% 16.7% 1.0% 32.0%

Body Weight

  Baseline mean (kg) 89.5 88.0 88.6

  Adj. mean change from baseline (kg) 2.8 0.0 2.7

    EXUBERA group minus OAs 2.80         2.75

    95% CI for treatment difference (1.94, 3.65) (1.89, 3.61)

¹ A negative treatment difference favors EXUBERA
² Comparison of EXUBERA monotherapy to combination oral agent therapy alone
³ p < 0.0001
⁴ Comparison of EXUBERA plus oral agents to combination oral agent therapy alone

A 24-week, randomized, open-label, active-control study (Study E) was conducted in patients with type 2 diabetes, currently receiving sulfonylurea therapy. This study was designed to assess the safety and efficacy of the addition of pre-meal EXUBERA to continued sulfonylurea therapy (n = 214) compared to the addition of pre-meal metformin to continued sulfonylurea therapy (n = 196). Subjects were stratified according to their HbA_1c at Week -1. Two strata were defined: a low HbA1c stratum (HbA_1c ≥8% to ≤9.5%) and a high HbA_1c stratum (HbA_1c >9.5 to ≤12%).

EXUBERA in combination with sulfonylurea was superior to metformin and sulfonylurea in reducing HbA_1c values from baseline in the high stratum group. EXUBERA in combination with sulfonylurea was comparable to metformin in combination with sulfonylurea in reducing HbA_1c values from baseline in the low stratum group. The rate of hypoglycemia was higher after the addition of EXUBERA to sulfonylurea than after the addition of metformin to sulfonylurea. The percentage of patients reaching target HbA_1c values of 8% and 7% was comparable between treatment groups in both strata, as was reduction in fasting plasma glucose (see Table 4).

Another 24-week, randomized, open-label, active-control study (Study F) was conducted in patients with type 2 diabetes, currently receiving metformin therapy. This study was designed to assess the safety and efficacy of the addition of pre-meal EXUBERA to continued metformin therapy (n = 234) compared to the addition of pre-meal glibenclamide to continued metformin therapy (n = 222). Subjects in this study were also stratified to one of two strata as defined in Study E.

EXUBERA in combination with metformin was superior to glibenclamide and metformin in reducing HbA_1c values from baseline and achieving target HbA_1c values in the high stratum group. EXUBERA in combination with metformin was comparable to glibenclamide in combination with metformin in reducing HbA_1c values from baseline and achieving target HbA_1c values in the low stratum group. The rate of hypoglycemia was slightly higher after the addition of EXUBERA to metformin than after the addition of glibenclamide to metformin. Reduction in fasting plasma glucose was comparable between treatment groups (see Table 4).

Table 4: Results of Two 24-Week, Active-Control, Open-Label Trials in Patients With Type 2 Diabetes Previously On Oral Agent Therapy (Studies E and F)

Study E Study F

Exubera + SU ¹ Met+ SU Exubera + SU Met+ SU Exubera + Met Gli + Met Exubera + Met Gli + Met

High stratum ² Low stratum High stratum Low stratum

Sample Size 113 103 101 93 109 103 125 119

HbA_1c (%)

  Baseline mean 10.5 10.6 8.8 8.8 10.4 10.6 8.6 8.7

  Adj. mean change from baseline -2.2 -1.8 -1.9 -1.9 -2.2 -1.9 -1.8 -1.9

    EXUBERA minus OA ³ -0.38^, p = 0.002 -0.07 -0.37^, p = 0.004 0.04

    95% CI for treatment difference (-0.63, -0.14) (-0.33, 0.19) (-0.62, -0.12) (-0.19, 0.27)

Fasting Plasma Glucose (mg/dL)

  Baseline mean 241 237 197 198 223 243 187 196

  Mean change from baseline -46 -47 -48 -52 -42 -40 -46 -49

    EXUBERA minus OA 1 4 -2 4

    95% CI for treatment difference (-11, 12) (-8, 16) (-14, 10) (-7, 15)

Subjects with end-of-study HbA_1c < 8%American Diabetes Association treatment Action Level at the time of study conduct 48.7% 44.7% 81.2% 73.1% 72.5% 56.3% 80.8% 86.6%

Subjects with end-of-study HbA_1c < 7% 20.4% 14.6% 30.7% 32.3% 33.9% 17.5% 40.0% 42.9%

Body Weight

  Baseline mean (kg) 80.8 79.5 79.9 81.9 88.3 87.8 90.3 88.2

  Adj. mean change from baseline (kg) 3.6 -0.0 2.4 -0.3 2.8 2.5 2.0 1.6

    EXUBERA minus OA 3.60 2.67 0.26 0.38

    95% CI for treatment difference (2.81, 4.39) (1.84, 3.51) (-0.70, 1.21) (-0.52, 1.27)

¹ SU = sulfonylurea, Met = metformin, Gli = glibenclamide
² Low stratum = entry HbA1c ≥8.0% to ≤9.5%; high stratum = entry HbA1c >9.5% to ≤12%
³ A negative treatment difference favors EXUBERA

Use in Patients Previously Treated With Subcutaneous Insulin

A 24-week, randomized, open-label, active-control study (Study G) was conducted in insulin-treated patients with type 2 diabetes to assess the safety and efficacy of EXUBERA administered pre-meal TID with a single nighttime injection of Humulin^® U Ultralente^® (n = 146) compared to subcutaneous regular human insulin administered BID (pre-breakfast and pre-dinner) with BID injection of NPH human insulin (n = 149). In this study, the mean age was 57.5 years (range: 23–80), 66% of the subjects were male and the mean body mass index was 30.3 kg/m².

The reductions from baseline in HbA_1c, percent of patients reaching an HbA_1c level of <8% (per American Diabetes Association treatment Action Level at time of study conduct) and an HbA_1c level of <7%, as well as the rates of hypoglycemia, were similar between treatment groups. EXUBERA-treated patients had a greater reduction in fasting plasma glucose than patients in the comparator group. The results for Study G are shown in Table 5.

Table 5: Results of a 24-Week, Active-Control, Open-Label Trial in Patients With Type 2 Diabetes Previously Treated With Subcutaneous Insulin (Study G)

Study G EXUBERA (TID) + UL (QD) SC R (BID) + NPH (BID)

Sample Size 146 149

UL = Humulin^® U Ultralente^®; SC R = subcutaneous regular human insulin

HbA_1c (%)

  Baseline mean 8.1 8.2

  Adj. mean change from baseline -0.7 -0.6

    EXUBERA minus SC RA negative treatment difference favors EXUBERA -0.07

    95% CI for treatment difference (-0.31, 0.17)

Fasting Plasma Glucose (mg/dL)

  Baseline mean 152 159

  Adj. mean change from baseline -22 -6

    EXUBERA minus SC R -16.36

    95% CI for treatment difference (-27.09, -5.36)

Patients with end-of-study HbA_1c < 8%American Diabetes Association treatment Action Level at the time of study conduct 76.0% 69.1%

Patients with end-of-study HbA_1c < 7% 45.2% 32.2%

Body Weight

  Baseline mean (kg) 90.6 89.0

  Adj. mean change from baseline (kg) 0.1 1.3

    EXUBERA minus SC R -1.28

    95% CI for treatment difference (-1.96, -0.60)

End of study daily insulin dose

  Short-acting insulin 16.6 mg1 mg inhaled insulin from Exubera is approximately equivalent to 3 IU of subcutaneously injected regular human insulin. See DOSAGE AND ADMINISTRATION 25.5 IU

  Long-acting insulin 37.9 IU 52.3 IU

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