# Presentation: 092670

## Benefit and Managing the Risk

*Dr. Neville Jackson*

## Benefit

**As efficacious as short-acting SC regular insulin in patients with type 1 diabetes or  insulin requiring type 2 diabetes **
**Effective in type 2 DM used alone, in combination with basal insulin, and in combination with oral agent**
**Provides long-term glycemic control in both type 1 and type 2 diabetes **
**Most patients preferred INH over previous SC insulin and OA treatments**

## Risks

**Hypoglycemia event rates as for other insulins**
**Increased insulin antibodies compared to injected insulins**
- No association with clinical outcomes
**Pulmonary effects**
- Cough – mostly post-inhalational
- PFT declines – small, early, non-progressive, reversible
- Risk management plan to explore mechanism and follow the longer-term effect

## Risk Minimization and Proposed Studies

|  | Activities to Minimize Risk |  |  |  |  |  | Ongoing/Proposed Studies and Activities to Assess Risk  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | Label |  | HCP Edu/Cust. Care |  | Blister Package Differentia-tion |  | Large Simple Trial (5 yr) | LT PFT Safety  (5 yr) | Epi Lung Cancer (12 yr) | Asthma/ COPD | Ped.  | Mecha-nistic | Enhanced Pharmaco-vigilance Program |
| Important Identified Risks  |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Change in Pulmonary Function |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Impact of Smoking |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Important Potential Risks  |  |  |  |  |  |  |  |  |  |  |  |  |  |
| 1 and 3 mg Dose Inequivalence |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Increased Insulin Antibody Levels |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Asthma and COPD |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Rare Pulmonary Events |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Limited Information  |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Congestive Heart Failure |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Very Elderly Subjects (75 yrs) |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Pregnancy |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Children and Adolescents |  |  |  |  |  |  |  |  |  |  |  |  |  |

## Education and Customer Care

**Labeling **
**Call center**
**Healthcare professional training **
**Patient training support**
- Instruction video
- Instruction manual
- Quick reference guide
**Device replacement**
**Enhanced pharmacovigilance to increase the follow up on the reporting of rare respiratory adverse events**

## Use of 1 mg and 3 mg Blisters in the Clinical Program

**1 mg and 3 mg blisters were used safely and effectively in the clinical program**
**All patients were dispensed 1 mg and 3 mg blisters at treatment initiation**
**Patients were instructed to self-titrate by 1 mg increments, dependent upon home glucose monitoring**
**Instructions were given to use as few blisters as possible at each dosing session **

## Use of Doses in Phase 3 Efficacy Studies

**Dose (mg insulin, nominal)**

**Percent of Patients**

## Proposed Dosing Information for the Label

| Patient Weight | Initial Dose per Meal | Approximate IU Dose | Number of  1 mg Blisters per Dose | Number of  3 mg Blisters per Dose |
| --- | --- | --- | --- | --- |
| 30 to 39.9 kg | 1 mg per meal | 3 IU | 1 | - |
| 40 to 59.9 kg | 2 mg per meal | 6 IU | 2 | - |
| 60 to 79.9 kg | 3 mg per meal | 8 IU | - | 1 |
| 80 to 99.9 kg | 4 mg per meal | 11 IU | 1 | 1 |
| 100 to 119.9 kg | 5 mg per meal | 14 IU | 2 | 1 |
| 120 to 139.9 kg | 6 mg per meal | 16 IU | - | 2 |

## Assuring Safe Use of 1 & 3 mg Blisters

**Education of patients to self-titrate by 1 mg increments**
**Clear tactile and visual differentiation of the blisters**
**Education of physicians to closely monitor patients on initiation of INH therapy **
**Manage the risk of ****substitution of 1 x 3 mg with 3 x 1 mg blisters by clear labeling, including**** secondary packaging, and education**
**Where unavoidable substitution is necessary, specific instructions to use 2 x 1 mg in place of 1 x 3 mg**

## Risk Management - Protocols

|  | Ongoing | Proposed | Start | End |
| --- | --- | --- | --- | --- |
| Large Simple Trial (5-year) (1069) |  |  | 2006 | 2014 |
| Long-Term PFT Safety Studies    (5-year) (1022/1029) |  |  |  | 2012 |
| Epidemiology Lung Cancer Study (12-year) (1071) |  |  | 2006 | 2019 |
| Asthma (1028) |  |  |  | 2008 |
| COPD (1030) |  |  |  | 2011 |
| Mechanistic Studies |  |  |  |  |
| BAL (1052/1053) |  |  |  | 2006 |
| Clinical Mechanistic Study |  |  | 2006 | 2008 |
| PreClinical Mechanistic Study |  |  | 2006 | 2007 |
| Expanded Analysis of existing PFTs in database |  |  | 2005 | 2006 |
| Pediatric Studies |  |  | 2006 | 2009 |

## Multinational, Long-term Large Simple Trial to Evaluate Pulmonary Safety

**Objectives**
- Persistent decline in FEV1 of 20% or more
- Serious respiratory adverse events
**Enroll 5,000 patients - North America, Europe, LA**
- Broad entry criteria as per approved label
- Recruitment from primary care practices with diverse patient population
- Targeted recruitment of 5-10% very elderly (75 years)
**Randomization to Exubera or usual care for 5 years **
**Spirometry measurements (FEV****1****) at baseline and then prospectively, consistent with approved label**
**Follow up per usual medical care with concomitant medications permitted**
**All randomized patients followed for collection of SAEs even if they discontinue treatment**