1. Food and Drug Administration Division of Pulmonary and Allergy Drug Products DSaRM Advisory Committee May 5, 2004 Permeability of LDPE Vials: A clinical perspective Eugene J. Sullivan, MD, FCCP Division of Pulmonary and Allergy Drug Products

2. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 2 Overview:  Introduction  Drug Products  Patient Populations  Potential sources of contaminants  Potential adverse effects of contaminants  Difficulties monitoring for adverse effects  Summary and Discussion

3. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 3 Introduction 1/2  The topic for discussion today is how best to minimize the potential for medication errors, given the clinical concerns regarding low density polyethylene (LDPE) containers.  This presentation will review these clinical concerns, in order to provide background for the discussions today.

4. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 4 Introduction 2/2  The clinical concerns can be summarized as follows:  Many inhalation drug products are packaged in low density polyethylene (LDPE) containers  LDPE is permeable to volatile chemicals  Numerous volatile chemicals exist in the immediate packaging environment  Volatile chemicals may have irritant, as well as toxicologic effects  Because these effects may be poorly tolerated by patients, efforts should be made to minimize the potential for contamination of inhalation drug products

5. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 5 Drug Products  Examples of inhalation drug products packaged in LDPE containers include:  Albuterol sulfate  Ipratropium bromide  Albuterol/Ipratropium  Metaproterenol  Levalbuterol  Cromolyn sodium  Budesonide  Tobramycin

6. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 6 Drug Products  These are inhalation solutions (or suspensions) intended for delivery by nebulizer  Manufacturing processes are very carefully controlled in order to maintain a high standard of product purity  They may be used in a regular dosing schedule (e.g. QID) or as-needed, when symptoms flare  Bronchodilator inhalation solutions (albuterol, etc) are commonly used in the inpatient and acute care setting (hospital wards, ED, ICU)

7. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 7 Patient Populations  These inhalation drug products are used by patients with various pulmonary disorders:  asthma  COPD (chronic obstructive pulmonary disease: chronic bronchitis and emphysema)  cystic fibrosis  These diseases are characterized by:  fixed or variable obstruction to airflow  histologic abnormalities (e.g. airway inflammation)  allergic propensity (atopy) (asthma)  airway hyperresponsiveness

8. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 8 Patient Populations  Asthmatic patients are known to react adversely to chemical irritants  Acute bronchospasm (wheezing and SOB)  Patients with severe asthma may react to very low doses of inhaled chemicals/irritants perfumes, cleaning agents, smoke methacholine challenge testing  Many asthmatic patients also develop bronchospasm from inhaled allergens  Early and late phase responses

9. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 9 Potential Sources of Contaminants  Labels  Glues, inks, lacquers  Secondary bulk packaging (eg cartons)  Glues, inks  FDA analytical survey of approved inhalation solutions marketed in LDPE containers  29 of 37 samples tested positive for volatile chemicals that were presumed to have originated in the packaging materials

10. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 10 Potential Adverse Effects  Irritant effects  Immunologic effects  Toxicologic injury  Carcinogenicity

11. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 11 Difficulties in Monitoring for Adverse Effects  Adverse effects may mimic symptoms for which the drug is being used (bronchospasm)  Therefore, adverse effects would not likely be recognized and reported.  Although modest bronchospasm related to irritant contaminant may lead to reduced efficacy, this may not be detected.  Even more significant bronchospasm related to irritant contamination would likely be attributed to refractory underlying disease.

12. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 12 Summary 1/2  Many inhalation drug products are packaged in low density polyethylene (LDPE) containers  LDPE is permeable to volatile chemicals  Numerous volatile chemicals exist in the immediate packaging environment

13. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 13 Summary 2/2  Various volatile chemicals have been identified in these products  Volatile chemicals may have irritant, as well as toxicologic effects  Because these effects may be poorly tolerated by patients, efforts should be made to minimize the potential for contamination of inhalation drug products

14. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 14 Discussion 1/2  This line of reasoning led in part to the development of the Draft Guidance entitled “Inhalation Drug Products Packaged in Semipermeable Container Closure Systems” (July, 2002)  The Draft Guidance recommends that measures be taken to limit chemical contamination of these products  Alternative approaches to paper labels (e.g. embossing/debossing)

15. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 15 Discussion 2/2  The move away from paper labels has introduced a new concern: medication errors. The issue of how best to minimize the potential for medication errors will be the topic for today’s discussion.