Drug Criteria & Outcomes

Breathe Your Way to Tighter Glycemic Control

By Jeremy Roop, PharmD Candidate
Auburn (AL) University Harrison School of Pharmacy

Is inhaled insulin (Exubera®, insulin human [rDNA origin]) really as efficacious as regular humulin insulin subcutaneous (RHISQ)? Is it really just as simple as taking a breath or does complicated dosing create a barrier that makes it difficult for patients to self manage their disease?

Investigations into the use of inhaled insulins started as early as the 1920s; however, it wasn't until the 1970s that Wigley et al1 demonstrated an insulin-induced hypoglycemic effect in rabbits using inhaled aerosolized regular insulin delivered via a nebulizer.2

Dosing and Administration

Exubera is the first of these inhaled insulin products to come to market. Its dry powder formulation allows delivery of a high dose of insulin per puff, allows it to stay stable at room temperature, and prevents microbial growth.3 It has a faster onset of action than lispro insulin and a duration of action similar to that of regular insulin,4,5 but with a lower incidence of hypoglycemia.6-8 Exubera should be given 10 minutes prior to meals to allow time for absorption (it takes about 30 minutes for onset of action), which can complicate its use in hospitals.

Exubera provides similar HbA1C results as RHISQ, and proves superior to oral therapy with metformin.9 Type 1 diabetic patients still have to inject their long-acting insulin in the morning but pre-meal rapid-acting insulin doses can be replaced with Exubera, thus greatly decreasing the number of needle sticks that a patient must endure throughout the day.9 This reduction can be especially beneficial to elderly patients who may have limited dexterity or vision problems. Exubera also eliminates insulin mixing, which can complicate traditional insulin therapy regimens.9

More importantly, insulin therapy is sometimes delayed in Type 2 diabetics or reserved as a therapeutic backup for oral hypoglycemics. Initiating insulin therapy early could optimize glycemic control and minimize or delay long-term complications.2 Insulin therapy may be delayed for a variety of reasons, including fear of needles, weight gain, or expense of supplies.2 Because Exubera is inhaled instead of injected, it may eliminate at least one of these obstacles and help hasten insulin therapy in patients that may otherwise object to frequent injections.

Dosing Consultation Necessary

Exubera dosing can be complicated and require considerable explanation and consultation, which may prove to be as significant a barrier to effective treatment as issues related to traditional insulin therapy. Exubera is supplied in either 1 mg or 3 mg blisters. Dosage is weight-based, but three 1 mg blisters provide considerably more insulin than one 3 mg blister. If the patient requires a 3 mg dose and doesn't have one 3 mg blister, then they should substitute two 1 mg blisters instead. In addition, 1 mg of Exubera is equivalent to three units of insulin, but one 3 mg blister of Exubera is equivalent to only eight units of insulin.10 Patients also should be instructed to combine blisters so the least number are used per dose.

Further complicating therapy for Type 1 diabetics is that Exubera has to be used in combination with a long-acting insulin and the patient will be forced to think in milligrams of Exubera and units of insulin on a daily basis. This intricate dosing system may confuse some patients and present a therapeutic barrier for the elderly or those transitioning from oral therapy to a combination regimen of insulin and Exubera.

Exubera Kit Pricing and Maintenance

The Exubera Kit contains an inhaler, replacement chamber, 180 x 1 mg dose blisters and 90 x 3 mg dose blisters (enough drug for 30 days of therapy at a 15 mg daily dose) and two release units; it costs $155. Additional Combination Packs provide 30 days of medication at doses of either 12 mg or 15 mg a day and include two release units; this regimen cost $116 and $145, respectively. The inhaler device itself requires once-weekly cleaning and the release unit should be replaced every two weeks.

Cost may be an issue for some patients. Also, the multiple parts contained in Exubera inhalers may get misplaced or broken. The blisters containing powder for inhalation could be mistakenly swallowed or accidentally punctured, the latter introducing moisture and causing the powder to become unstable.

Complications, Interactions, Adverse Effects

Careful patient counseling by physicians and pharmacists can overcome the majority of the complications associated with Exubera. Determining an appropriate starting dose, on the other hand, is something that may require some clinical experience to perfect. Currently, Exubera dosing guidelines recommend using a weight-based strategy to determine starting doses.10 However, patients that have received insulin previously may possess a greater degree of insulin resistance and initial weight-based dosing may not account for this patient-to-patient variability. Initiating doses based on weight should be done cautiously and with careful attention to patient history and insulin experience.

Exubera is inhaled but has no impact on the physiology or structure of normal lungs.9 No increase in cell proliferation has been observed but studies are limited in duration, and current recommendations include baseline pulmonary function tests (PFTs), PFTs at six months, and again after one year of treatment. PFTs should be repeated if patients experience greater than a 20% decline from baseline and Exubera should be discontinued if the decline is confirmed.9-11

Use by patients with underlying lung disease such as asthma or COPD is not recommended since trials evaluating safety in these populations have not been undertaken.2 Also, patients with poorly controlled or unstable lung disease should not use Exubera.2,11 More importantly, smokers or anyone who has quit smoking within the last six months should avoid using Exubera. Studies show that smoking enhances absorption of Exubera by about 50%, making dosing highly unpredictable and unsafe.9

Interactions with other inhaled medications haven't been thoroughly studied and until these interactions are better understood, patients should be instructed to avoid using Exubera at the same time as any other inhaled medication.11 Health care providers should carefully discuss appropriate management strategies with their patients.

Currently, many patients that have successfully used Exubera appear to be satisfied with it. Study participants were consistently more satisfied with Exubera than with subcutaneous insulin dosing as indicated by patients completing a satisfaction survey after a 12-week study.12 Most patients also tolerated Exubera well. The most commonly reported adverse drug effects were cough, dyspnea, dry mouth, bitter taste, and hypoglycemia.

The Huntsville (AL) Hospital formulary policy allows patients already stable on Exubera to continue using the product while in the hospital. However, inpatients will not be started on Exubera because of extensive educational requirements during initiation of therapy and the great potential for medication errors in the hospital setting.

Conclusion

Exubera doesn't represent a perfect dosing system but it's a step in the right direction for many patients. In the outpatient setting, initially selecting patients that are willing to take an active part in their health care is especially important. This is where Medication Therapy Management services (MTM), which are already providing chronic disease state management in many parts of the country, are particularly useful. In areas where dedicated MTM services aren't available, an attentive community pharmacist will be integral to this process, not only to identify likely candidates for therapy, but also to help implement monitoring. Exubera is a prime example of a medication that will need to be coupled with close monitoring by professionals to ensure positive outcomes.

To effectively educate health care providers, Pfizer has decided on a phased release program that will initially target only a few prescribers in each community before marketing channels open to the masses. Pfizer hopes that this slow and sustained release approach will help lessen the learning curve associated with Exubera and give health care practitioners an opportunity to familiarize themselves with educational materials before they have to deal with a large number of patients. This stepwise approach may increase the success and safe use of Exubera and sufficiently arm health care teams with the knowledge they need to resolve the numerous issues and potentially serious problems that can emerge if patients are left to manage Exubera therapy on their own.

Pfizer has taken a huge step toward the development of a novel, more patient-friendly drug delivery system for insulin, in an effort to make it easier for patients to self-manage their diabetes. In spite of the numerous issues related to inhaled insulin, it still holds considerable promise for many diabetics. If patients are properly educated, compliance, glycemic control, and patient satisfaction will improve while complications and ADRs decline. Diligent patient education and monitoring will be required in both inpatient and outpatient settings to prevent sighs of relief from turning into sighs of frustration.

References

  1. Wigley FM, Londono JH, Wood SH, et al. Insulin across respiratory mucosae by aerosol delivery. Diabetes 1971; 20:552-556.
  2. Soule P, Capoccia K. Inhaled insulin: Exubera. Ann Pharmacother 2003; 39:842-853.
  3. Newhouse MT. Tennis anyone? The lungs as a new court for systemic therapy. CMAJ 1999; 161:1,287-1,288.
  4. Heinemann L, Traut T, Heise T. Time-action profile of inhaled insulin. Diabet Med 1997; 14:63-72.
  5. Heise T, Rave K, Bott S, et al. Time-action profile of an inhaled insulin preparation in comparison to insulin lispro and regular insulin (abstract 39-OR). Diabetes 2000; 49(suppl 1):A10.
  6. Quattrin T, Belanger A, Bohannon NJV, et al, for the Exubera Phase III Study Group. Efficacy and safety of inhaled insulin (Exubera) compared to subcutaneous insulin therapy in patients with Type 1 diabetes: Results of a 6-month, randomized, comparative trial. Diabetes Care 2004; 27:2,622-2,627.
  7. Hollander PA, Blonde L, Rowe R, et al, for the Exubera Phase III Study Group. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with Type 2 diabetes: Results of a 6-month, randomized comparative trial. Diabetes Care 2004; 27:2,356-2,362.
  8. Belanger A, for the Exubera Phase III Study Group. Efficacy and safety of inhaled insulin (Exubera) compared to subcutaneous insulin therapy in patients with Type 2 diabetes: Results of a 6-month, randomized, comparative trial (abstract 808). Diabetologia 2002; 45:(suppl 2):A260.
  9. Patel A, White C, Coleman C. Exubera: An orally inhaled insulin. Formulary 2005;40:429-436.
  10. Exubera dosing guide.
  11. Exubera package insert.
  12. Gerber RA, Cappelleri JC, Kourides IA, et al. Treatment satisfaction with inhaled insulin in patients with type I diabetes: A randomized controlled trial. Diabetes Care 2001; 24:1,556-1,559.