Medicolegal Issues

Two New Inhaled Insulin Products


 

Two new insulin products were recently FDA-approved, Exubera (inhaled human insulin, Pfizer/Nektar) and Levemir (insulin detemir, Novo Nordisk). These new insulins are important to hospitalists because admitted patients may be receiving them, patients may ask about them, and other members of the healthcare team may have questions, as well.

Nektar Therapeutics has been developing noninvasive macromolecules for inhaled delivery systems for many years. To develop Exubera (their first FDA-approved product), they collaborated with Pfizer and Sanofi-Aventis. Other Nektar products are not as far along in the U.S. drug approval process.

Exubera (inhalation powder, insulin human) was FDA-approved on January 27, 2006, and is expected to be on pharmacy shelves in June or July of this year. Exubera was also recently approved in Europe but is not available there yet, either. Exubera is short-acting and was approved for use in Types 1 and 2 diabetes mellitus in conjunction with oral agents, or with a basal insulin for basal/bolus dosing.

Peak Exubera levels occur in ~49 minutes (range 30-90 minutes) compared with regular insulin with a peak in 105 minutes (range, 60-240 minutes). In an open-label, 12-week, randomized, controlled trial Exubera improved glycemic control when substituted for or added to oral combination therapy (n=309) in adult Type 2 diabetes patients. There was a small decrease in HbA1c of ~1.4% in the Exubera-treated monotherapy patients. When Exubera was combined with two oral agents (an insulin sensitizer and a secretagogue), the HbA1c decreased ~1.9%. Patients who used only oral agents had an insignificant decrease in HbA1c (0.2%).

Investigators offered Types 1 and 2 diabetics open-label use of inhaled insulin for up to four years. The patients have maintained long-term glycemic control.

The Exubera inhaler device weighs 4 ounces and is about the size of a closed eyeglass case. Carrying the device may be problematic for some because of its size. Common side effects include cough, shortness of breath, sore throat, dry mouth, and hypoglycemia. Exubera is not recommended for 1) patients who have recently quit smoking (within six months); 2) current smokers; 3) asthmatics; or 4) those with bronchitis or emphysema.

Because Exubera is a new product that has not been available in other countries, its long-term safety is unknown. Pfizer is, however, committed to long-term safety and efficacy studies. Monitoring parameters specific to Exubera include: 1) baseline pulmonary function tests (PFTs); and 2) follow-up PFTs every six-12 months until more is known about the drug’s pulmonary safety.

These new insulins are important to hospitalists because admitted patients may be receiving them, patients may ask about them, and other members of the healthcare team may have questions, as well.

The Word on the Street

Exubera’s manufacturers will likely target this agent to the population that will provide them with the greatest market potential (largest profit). Likely candidates will be those with poorly controlled diabetes on >2 oral agents; these patients will likely need more than another oral agent to improve their glycemic control. Pfizer may choose to market Exubera against insulin sensitizers such as rosiglitazone or pioglitazone —especially when it comes to pharmacoeconomics because the ‘glitazones are not yet available generically and are thus higher cost items.

Ease of use for Exubera versus injected insulin may be the sole advantage for this new agent. Some say that if Exubera is used as a tool for diabetics to get insulin treatment earlier (versus injected insulin), diabetic complications may be minimized; however, medication compliance will play a large role. The medical literature is full of articles regarding non-compliance/non-adherence with asthma inhalers, including improper inhaler use and non-use of these devices. So unless inhaled insulin can significantly improve outcomes compared with the inexpensive injections and other available therapies (e.g., insulin sensitizers), its place on health-system formularies may be limited at best.

Another Inhaled Option

Novo Nordisk received initial FDA approval for its long-acting, basal insulin analog—insulin detemir—on June 17, 2005. Subsequent approval for use in the pediatric population came on October 20, 2005. Levemir is expected on U.S. pharmacy shelves any day. Levemir has been approved in 53 countries worldwide, and has been available in Europe since March 2004.

Levemir is a basal insulin, similar to Lantus (glargine, Sanofi-Aventis), and is approved for use in adults with Types 1 and 2 diabetes and in children with Type 1 diabetes.

It is recommended that Levemir be dosed once- or twice-daily subcutaneously. Pharmacokinetically Levemir has a relatively flat action profile with a mean duration of action ranging between 5.7–23.2 hours (data from clinical trials). Following subcutaneous administration, insulin detemir has a slower, more prolonged absorption over 24 hours compared with NPH insulin. Maximum serum concentrations occur within six to eight hours following administration.

A common side effect of insulin therapies is hypoglycemia. Other side effects common to human insulins include allergic reactions, injection site reactions, lipodystrophy, pruritus, and rash. A beneficial effect obtained in some of the Levemir clinical studies was weight loss (0.2 to 0.3-kg), which occurred in several Type 1 patients. Comparatively, the Type 1 patients who received NPH insulin noted weight gain (0.4 to 1.4-kg) over the six-12 month timeframe.

There are no specific monitoring parameters for insulin detemir, except for general management of the diabetic patient (e.g., fasting blood sugar, glycosylated hemoglobin, eye exam, podiatry).

At its launch, insulin detemir will be available in 10mL vials as well as in the Levemir FlexPen. The FlexPen will require the use of NovoFine 30- or 31-gauge disposable needles. TH

Michele Kaufman is based in New York City.

References—Exubera

  • Hollander PA, Blonde L, Rowe R, et al. 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;27:2356-2362.
  • Skyler JS, Weinstock RS, Raskin P, et al. The Inhaled Insulin Phase III Type 1 Diabetes Study Group. Use of inhaled insulin in a basal/bolus insulin regimen in Type 1 diabetic subjects: a 6-month, randomized, comparative trial. Diabetes Care. 2005 Jul:28(7):1630-1635.
  • Rosenstock J, Zinman B, Murphy LJ, et al. Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in Type 2 Diabetes—a randomized, controlled trial. Ann Intern Med. 2005 Oct 18;143(8):549-588.
  • The Pink Sheet, February 14, 2006; Volume 68, Number 7.Available at www.fda.gov/bbs/topics/news/2006/NEW01304.html. Last accessed March 8, 2006.

References—Levemir

  • Levemir (insulin detemir [rDNA origin] injection) package insert. Novo Nordisk, Inc. Princeton, NJ; October 2005.
  • Goldman JD, Lee KW. Insulin detemir—a new basal insulin analog. nn Pharmacother. 2005;39:502-507.
  • Home P, Bartley P, Russell-Jones D, et al. Insulin detemir offers improved glycemic control compared with NPH insulin in people with Type 1 diabetes—a randomized clinical trial. Diabetes Care. 2004;27:1081-1087. Available at http://press.novonordisk-us.com/internal.aspx?rid=318. Last accessed March 1, 2006.

Fast Pharma Updates

New Warnings

Elidel cream (pimecrolimus, Novartis) and Protopic ointment (tacrolimus, Astellas—formerly Fujisawa):

New Dosage Form

Zegerid capsules (omeprazole/sodium bicarbonate, Santarus):

  • The only immediate-release proton-pump inhibitor (PPI) capsule available;
  • Other dosage forms include: powder for oral suspension in doses of 20- and 40-mg (cartons of 30). The powder packets are to be administered as a suspension or for nasogastric (NG) or orogastric (OG) use (stop enteral feedings ~3 hours before and one hour after Zegerid administration);
  • FDA-approved for the short-term treatment of active duodenal ulcer, gastric ulcer, gastroesophageal reflux disease, and for the maintenance of healing of erosive esophagitis;
  • Dosing and administration: Take on an empty stomach at least one hour prior to a meal;
  • It has a unique pharmacokinetic profile compared to other PPIs: plasma levels are rapidly reached within ~30 minutes. A median 24-hour pH >4 from ~12 to 18 hours depending on the formulation and dose (data from seven-day repeat dosing clinical trials) used;
  • Due to the formulation with sodium bicarbonate, carefully administer it to patients that must limit their sodium intake. The capsules contain 300-mg of sodium/dose and Zegerid packets contain 460-mg sodium/dose;
  • A Zegerid chewable tablet in 20- and 40-mg doses is currently pending at the FDA;
  • The benefits of Zegerid capsules over other available PPIs is not clearly evident; and
  • Additional information at:

New Indication

Rituxan injection (rituximab, Genentech/Biogen) received FDA-approval on March 1, 2006, for the treatment of adult patients with active rheumatoid arthritis (RA). Other FDA-approved indications for rituximab include: 1) For the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, non-Hodgkin’s lymphoma, and 2) for the first-line treatment of diffuse large B-cell, CD20-positive, non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or other anthracycline-based chemotherapy regimens.

Rituxan is available in 100-mg and 500-mg sterile, preservative-free, single use vials, and is administered by intravenous infusion. Rituximab is also marketed in Europe under the name MabThera.

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