Medicolegal Issues

Inhaled Insulin: Troubled Drug Rises from the Ashes


Remember all the hype leading up to the approval of the dry-powder formulation of human insulin, produced by means of recombinant DNA technology, a.k.a. inhaled insulin (Exubera)? That was three years ago (January 2006). Remember all the press releases regarding the removal of inhaled insulin from the market? That was October 2007.1,2

Almost immediately after Pfizer “pulled the plug” on inhaled insulin, cases of lung cancer started being reported—albeit it had occurred in Exubera-treated patients that had a history of smoking cigarettes—a contraindication within the drug’s approved label. Some clinicians questioned whether it was due to insulin being a weak growth factor when binding to the type 1 insulin-like growth factor receptor; others wondered if it was related to smoking history.3,4 Three other collaboration efforts for inhaled insulin—NovoNordisk/Aradigm, MannKind, and Alkermes/Eli Lilly AIR insulin— were in the pipeline when Pfizer bowed out of the market. MannKind’s Technosphere insulin and Alkermes/Eli Lilly AIR insulin are still being investigated. Both are in phase 3 clinical trials.5

Market watch

New Indications and Dosage Forms

  • Immune Globulin (Gamunex, Talecris Biotherapeutics Inc.) has received orphan drug status for treating chronic inflammatory demyelinating polyneuropathy (CIPD), a rare autoimmune disorder characterized by progressive weakness and impaired sensory function in the extremities, which affects approximately 25,000 people in the U.S. CIPD leads to weakness, loss of deep tendon reflexes, tingling, and numbness from myelin sheath damage. Gamunex is manufactured from pooled human plasma. Its mechanism is unknown, but it is thought to work by modulating the immune system’s inflammatory response, which damages the myelin sheaths.8
  • Levetiracetam extended-release (Kep-pra XR, UCB Pharma) has been FDA-approved as once-daily, add-on therapy to other antiepileptic agents for patients 16 years of age and older with partial onset seizures.9

New Warnings

The FDA and Genentech informed healthcare professionals of a labeling revision for rituximab (Rituxan). It is related to an additional case and subsequent death from progressive multifocal leukoencephalopathy (PML) in a rheumatoid arthritis patient. The patient developed PML 18 months after the final rituximab dose. The patient was immunologically unstable from cancer chemotherapy, and had received prior biologic agents, which may have contributed to the poor immunologic state. Healthcare professionals need to be aware of the possibility of PML when treating patients with rituximab. Consider it in the differential diagnosis of patients presenting with new onset neurologic manifestations. A neurologist and subsequent testing should be considered as clinically indicated.10

New Information

Pregnancy Categories. Women take, on average, between three to five prescription drugs during pregnancy, with about 6 million U.S. pregnancies each year. In the 1990s, the FDA began recognizing deficiencies in pregnancy and breastfeeding information in prescription drug labeling.

The FDA has proposed a change to the way prescription labels present this information. If approved, this new measure would remove the current letter categories (e.g., A, B, C, D, X) and utilize language to detail fetal risk, clinical considerations, and supporting data. If enacted, it would be formatted into three sections. Whether a pregnancy exposure registry is available also would be included in the new labeling. The lactation section would follow the same format; it would include information on the amount of drug in breast milk and potential effects on the breastfed infant.

Newly approved drugs would follow the new pregnancy category structure, yet older drugs would be phased in gradually.11,12,13

So, contrary to popular belief, inhaled insulin is not dead, yet. These other companies are looking to improve upon what Pfizer lost out on. The AIR system uses a smaller, breathable inhaler, which would fit into a patient’s hand. The inhaled powder has a smaller particle size and a larger surface area, which provides deeper lung penetration of drug.6

More Drugs Via the Pulmonary Route

Aside from asthma, chronic obstructive pulmonary disease, pulmonary hypertension, and cystic fibrosis, where a hospitalist could expect to use pulmonary delivered drugs, other medicines are being investigated for administration via this route. The pulmonary route may be used for tuberculosis (TB), where lower doses can be given since high doses of systemic therapy lead to significant drug toxicity.7

Inhaled vaccines are being developed, including Bacillus Calmette-Guérin (BCG) TB and respiratory syncytial virus (RSV). Parathyroid hormone for osteoporosis, human factor IX for hemophilia, and interferon α-2b for hepatitis B virus, are potential and current inhaled treatments.

New Delivery Systems: Will They Pan Out?

Knowing the lung absorbs biologic drugs with a wide range of molecular weights, solubility, and charges, is a plus for pulmonary delivery. However, pulmonary drug delivery also presents challenges. These include local toxic effects, such as cell injury, edema, and altered tissue defenses. Drug carriers, preservatives, and propellants, such as sulfites, might harm pulmonary tissue or the body.

Safety is one of the biggest concerns when companies develop new drug delivery systems. These inhaled products and methods of delivering inhaled insulin are quickly moving through clinical trials.

Only time will tell when approvals will take place, but it looks as though there will be some innovative insulin products in the near future. TH

Michele B Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.


1. Alvey L. U.S. Food and Drug Administration. FDA ap-proves first ever inhaled insulin combination product for treatment of diabetes. news/2006/NEW01304.html. Published Jan. 27, 2006. Accessed Dec. 1, 2008.

2. U.S. Food and Drug Administration. Drug discontinuations. Published Oct. 19, 2007. Accessed Dec. 1, 2008.

3. von Kriegstein E, von Kriegstein K. Inhaled insulin for diabetes. N Engl J Med. 2007;356:2106-2108.

4. McMahon GT, Arky RA. Inhaled insulin for diabetes. N Engl J Med. 2007;356:497-502.

5. Opar A. Another blow for inhaled protein therapeutics. Nat Rev Drug Discov. 2008;7:189-190.

6. Dubin CH. The state of systemic pulmonary delivery: one year after Exubera’s approval. Nat Rev Drug Discov. 2007;7(4):61-67.

7. Greb E. Inhalable drugs in the launch pad: will they take off? Pharm Tech. 2008;4:48-55.

8. Riley K, Long P. FDA approves treatment for rare neurologic disease. NEWS/2008/NEW01884.html. Published Sept. 12, 2008. Accessed Dec. 1, 2008.

9. Keppra XR approved in the U.S. R/1251192/271964.pdf. Published Sept. 15, 2008. Accessed Sept. 15, 2008.

10. U.S. Food and Drug Administration. 2008 safety alerts for human medical products (drugs, biologics, medical devices, special nutritionals, and cosmetics). Published Sept. 2008. Accessed Sept. 15, 2008.

11. U.S. Food and Drug Administration. Pregnacy and lactation labeling. pregnancy_labeling/default.htm Published June 11, 2008. Accessed Sept. 15, 2008.

12. Cruzan S. U.S. Food and Drug Administration. FDA proposes new rule to provide updated information on the use of prescription drugs and biological products during pregnancy and breast-feeding. www. 41.html. Published May 28, 2008. Accessed Sept. 15, 2008.

13. Peggy P. FDA to take A, B, and C out of pregnancy labeling. tb/9626. Published May 28, 2008. Accessed Sept. 15, 2008.

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