The Second FDA Approved Inhaled Insulin - LECOM Education System

The Second FDA Approved Inhaled Insulin

Thursday, 05 February 2015

Anna Liu, PharmD Candidate; Marcus W. Campbell, PharmD, BC-ADM

In the United States, 29.1 million people have diabetes.Patients are prescribed insulin due to insulin deficiency (type 1 diabetes) or insulin resistance (type 2 diabetes). Injectable insulin has been available since the 1920s. Insulin is the single most effective agent at controlling blood glucose levels and lowering hemoglobin A1C, however patient satisfaction and compliance are often barriers to use. Injectable insulin can induce undesirable complications including weight gain, and hypoglycemic risk. An alternative route of administration that bypasses or minimizes these complications while providing similar glycemic benefits is of interest.

Due to the lungs’ large surface area, inhaled insulin is a feasible alternative for insulin drug delivery. In June 2006, the FDA approved the first inhaled insulin for diabetes under the trade name Exubera® (insulin human [rDNA origin]). The rapid-acting inhaled powder insulin was administered to the lungs through a bulky hand-held inhalation device. The device delivered powder insulin in blisters that contained 1 and 3 mg doses, approximately 3 and 9 units, respectively.2 Safety and efficacy clinical trials were conducted in approximately 2,500 adult patients with type 1 or type 2 diabetes. The studies found that Exubera® reached peak insulin concentration faster than regular insulin at 49 minutes and 105 minutes, respectively. In type 1 diabetes, Exubera® was used with basal insulin, replacing meal time insulin. In type 2 diabetes, it was used as monotherapy or combination therapy with an oral anti-diabetic agent or basal insulin.

Although Exubera® provided optimism for the possibility of a new insulin delivering device, there were challenges with the product. Many clinicians were concerned with the long-term effects of insulin administration through the lungs. Cough was the most common respiratory side effect, and pulmonary function tests showed changes in lung function.Prior to therapy, FEV1 assessment was recommended. Exubera® was not recommended in patients with declining lung function, asthma, COPD, or baseline FEV1 <70%.4 There were also complications with the delivery method and dosing. Patients who required high doses of insulin required multiple blisters at each administration. Improper inhalation technique led to inadequate drug administration.

The concerning changes in lung function, requirement of pulmonary testing, and complications with the delivery method gave Exubera® an unfavorable safety profile. Exubera® was discontinued by Pfizer not due to safety concerns, but lack of demand. The size of the bulky delivery device (25 cm in length) made the product unpopular with patients.5

On June 27, 2014, the FDA approved the second rapid-acting inhaled insulin under the trade name Afrezza® (MannKind Corporation).6 Similar to Exubera®, this new insulin is for adult type 1 and type 2 diabetic patients. The primary difference is the size of the drug delivery device. The insulin powder is administered through a drug-device combination product. The device (called Dreamboat®) is the size of a whistle. Afrezza® cartridges are available in two strengths: 4 units and 8 units. Multiple cartridges are needed if a patient requires more than 8 units. It is not a substitute for basal insulin and is recommended to be administered before each meal.7 After inhalation, the insulin dissolves rapidly and reaches the bloodstream within 12 to 15 minutes. A decline in circulating levels of insulin is seen approximately 180 minutes after administration.8

Safety and effectiveness were assessed in approximately 1,026 type 1 and 1,991 type 2 diabetic patients. Less weight gain and a reduced risk of hypoglycemia versus injectable rapid-acting analogs were observed. In type 1 diabetic patients, mealtime Afrezza® was compared to mealtime insulin aspart; both groups received basal insulin. At 24 weeks, a significant A1C reduction was seen in the Afrezza® group. However, Afrezza®provided a smaller reduction in A1C compared to insulin aspart. In type 2 diabetic patients, Afrezza® was compared to placebo inhalation in combination with oral anti-diabetic drugs. After 24 weeks of treatment, Afrezza® with oral anti-diabetic drugs showed a statistically significant reduction in A1C compared to the placebo group.

There are concerns of possible lung complications with long-term use of Afrezza®. Non-productive cough was the most common respiratory side effect seen in clinical trials. The FDA approved Afrezza® with a Risk Evaluation and Mitigation Strategy and black box warning stating the risk of acute bronchospasm in patients with chronic lung disease. Patients with asthma and COPD are not advised to use Afrezza®. Prior to therapy initiation, physical examinations and FEV1 measurements are recommended. The FDA is also requiring post-marketing studies regarding potential risk of pulmonary malignancy and long-term effect of pulmonary function.9

Although Afrezza® is less efficacious when compared to injectable insulin and has similar concerns of possible lung complications as Exubera®, it may still find a place in therapy.  Afrezza® can be utilized as a potential substitute in the subset of patients who prefer an alternative route of administration and require less insulin. An appeal of Afrezza® is the sizing of the delivery device. It provides patients with a distinct route of administration as well as easy storage. MannKind Corporation and Sanofi officially launched Afrezza® at the beginning of February 2015 and it is now available to pharmacies nationwide.

  1. CDC: Centers for Disease Control and Prevention [Internet]. Altanta: Centers for Disease and Prevention. National Diabetes Statistics Report, 2014; 2014 Jun 23 [cited 2014 Jul 15]; [about 1 screen]. Available from: https://www.cdc.gov/diabetes/library/reports/reportcard.html
  2. Al-Tabakha M.M, Arida A.I. Recent Challenges in Insulin Delivery Systems: A Review. Indian Journal of Pharmaceutical Sciences. 2008;70(3):278-286.
  3. FDA: U.S. Food and Drug Administration Protecting and Promoting Your Health [Internet]. c2014. Silver Spring: Food Drug Administration. FDA approves Afrezza®to treat diabetes 2014 Jun 27 [cited 2014 Jul 15]; [about 2 and 3 screens]. Available from: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm403122.htm
  4. Selam J.L. Inhaled Insulin: Promises and Concerns. Journal of Diabetes Science and Technology. 2008; 2(2):311-315.
  5. Heinemann L. The Failure of Exubera: Are We Beating a Dead Horse? Journal of Diabetes Science and Technology. 2008;2:518-529.
  6. FDA: U.S. Food and Drug Administration Protecting and Promoting Your Health [Internet]. c2014. Silver Spring: Food Drug Administration. FDA approves Afrezza®to treat diabetes. 2014, Jun 27 [cited 2014 Jul 15. Available from: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm403122.htm
  7. MannKind. Medication Guide Afrezza®(insuling human) inhalation powder; 2014 Jun [cited 2014 Jul 15]; Available from: www.mannkindcorp.com/Collateral/Documents/English-US/Afrezza_MedGuide-IFU.pdf
  8. MannKind. MannKind Corporation Announces FDA Approval of Afrezza®; A Novel, Rapid-Acting Inhaled Insulin for the Treatment of Diabetes; 2014, Jun 27 [cited 2014 Jul 15]; Available from: https://www.news.mannkindcorp.com/phoenix.zhtml?c=147953&p=irol-newsArticle&ID=1943390
  9. FDA: U.S. Food and Drug Administration Protecting and Promoting Your Health [Internet]. c2014. Silver Spring: Food Drug Administration. FDA approves Afrezza® to treat diabetes 2014 Jun 27 [cited 2014 Jul 15]; [about 2 and 3 screens]. Available from: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm403122.htm
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