Kathy Hitchens, PharmD, MSBA

Kathy Hitchens, PharmD, MSBA, is a medical writer who lives in Indianapolis.

Julie Lux, who is spokeswoman for Schering-Plough and its generic subsidiary Warrick Pharmaceuticals, acknowledged that her company is working on the transition, stepping up its production of Proventil HFA to meet existing needs while simultaneously reducing the production of CFC albuterol products. The plan is that sometime in the next few months, Warrick will completely cease production of generic albuterol.  

Is this conversion expected to cause any drug shortages? Lux doesn't expect them. "Schering-Plough has been steadily working with the FDA over the past couple of years to ensure an adequate supply of the drug."  

Warrick Pharmaceuticals has facilitated conversations about the transition by placing a prominent warning on albuterol packaging. It states: 

IMPORTANT: Inhalers like this one are being discontinued due to environmental impact. For more information, go to 

The mechanics of the propellant transition are not as simple as one might think; CFC and HFA products are not generically equivalent. Changing propellants alters drug bioavailability. And not only are HFA-MDI drugs not bioequivalent to their CFC counterparts, they are not bio-equivalent to each other, either. Binaso commented, "The HFA products are all BX-rated-that is they're not substitutable for each other." As a result, pharmacists must contact prescribers to obtain new prescriptions.  

The lack of bioequivalence also suggests that some patients may respond better to one branded inhaler than another. Ideally, transitioning the patient to an HFA inhaler now (while CFC-MDIs are still available) allows time to determine what works best. Binaso stated, "One thing we've learned over the years, I think, is that treatment has to be individualized."  

Some patients who have already switched from CFC-to HFA-MDIs, have voiced concerns that the HFA products do not work. They don't feel the same "thrust" into their lungs from the HFA propellant as from the CFC propellant, they say. Studies have shown the products are effective; the HFA-delivered drug just "feels" different, Binaso commented. "That's where we have the opportunity to educate the patients that the technology has gotten better."  

Binaso emphasized that the MDI transition is also an ideal opportunity for pharmacists "to provide counseling to the patient on the proper technique for using an inhaler." Published studies have repeatedly shown that many individuals do not use inhalers correctly, and with repeated use over time, attention to proper inhalation technique declines. Talking to an individual about his MDI also offers an opportunity for pharmaceutical care to assess asthma control. If an albuterol inhaler is being used for rescue more than two to three times a week, guidelines state, asthma is inadequately controlled and drug therapy may need to be modified.   

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As part of the 1987 international Montreal Protocol treaty to reduce/eliminate substances depleting the ozone layer, CFC (chlorofluorocarbon) propellants in albuterol metered-dose inhalers (MDIs) are gradually being replaced by HFAs (hydrofluoro-alkanes). The transition need not be complete until Dec. 31, 2008, when albuterol CFC-MDIs must be discontinued as mandated by the Food & Drug Administration. But the change is well under way. As Patty Johnson, spokeswoman for GlaxoSmithKline, noted, "We [GSK] already transitioned to Ventolin HFA MDI in early 2006."

R.Ph.s can facilitate switch to HFA inhalers

Patients with bisphonphonate-related osteonecrosis of the jaw (BRON) complain of jaw pain and trouble chewing. The jaw may appear swollen and inflamed on one side, and sometimes bone becomes exposed. Osteonecrosis means bone death. It can be very difficult to treat. 

The American Association of Oral and Maxillofacial Surgeons (AAOMS) recently issued a position paper on BRON. Earlier this year bisphosphonate drug labeling (both oral and intravenous) was modified to warn about the possibility of this complication. In addition, the American Dental Association Council on Scientific Affairs has issued recommendations for dental management during oral bisphosphonate therapy.  

With intravenous bisphosphonate therapy, there are three possible management scenarios. Ideally, before a patient is started on therapy, Marx commented, "he or she should get the mouth cleaned up. The dentist can take out teeth that are bad; cure gum disease, treat dental disease; 75% of BRON is associated with invasive dental procedures."  

The second scenario occurs after a patient has been on intravenous bisphosphonate therapy for some time. "We then advise avoiding all invasive procedures, if possible. Don't take teeth out; don't put dental implants in, don't do gum surgery unless there's no other recourse."   

The third scenario is when the patient already has exposed bone, i.e., osteonecrosis of the jaw. "In those cases, we advise a nonsurgical approach: antibiotics and chlorhexidine," said Marx. "With the oral bisphosphonates, the problem is different," he explained. "The exposed bone problem is less severe; it's more treatable and predictable."  

Marx's research has substantiated that BRON is related to oral aminobisphosphonates-bisphosphonates that contain nitrogen. It has been reported with alendronate (Fosamax, Merck) and risedronate (Actonel, Procter & Gamble). He noted that ibandronate (Boniva, Roche) is probably too new to demonstrate BRON, although it, too, is an oral aminobisphosphonate.  

It is also time-related, Marx commented. "The first three years on a bisphosphonate, there is little, if any, problem. After three years, you start seeing an increase in the number and severity of cases." Since concomitant corticosteroid therapy use also increases risk, Marx recommends judicious drug choice and length of therapy. But when oral bisphosphonate therapy exceeds three years, or has occurred with corticosteroid therapy, the AAOMS paper recommends greater than a three-month holiday before invasive dental procedures. "If you stop the oral bisphosphonate-that's the thing to do-the bone recovers," said Marx.  

While the guidelines do not predict the likelihood of BRON from dental surgery, Marx's research-to be published in the 

Oral and Intravenous Bisphosphonate-Induced Osteonecrosis of the Jaws: History, Etiology, Prevention, and Treatment, 

describe using the C-terminal telopeptide concentration test (CTx) in identifying risk. He recommends that, when oral bisphosphonate therapy has been used for more than three years, patients be tested prior to an invasive dental procedure to determine risk, and, if necessary, to delay a procedure while the bone recovers.  

Although jaw osteonecrosis is a rare complication of bisphosphonate therapy, the sheer numbers of bisphonphonate Rxs filled annually suggest this rare side effect may affect thousands of patients. Bisphosphonates are indicated for treating hypercalcemia of malignancy, multiple myeloma, bone metastases of solid tumors and Paget's disease, and for the treatment and prevention of osteoporosis.

Beware of bisphosphonates and jaw disorder

The race is on. For both Type 1 and Type 2 diabetes, manufacturers are vying for pole positions with new therapeutic strategies that promise better disease management, improved quality of life, and ultimately prevention of diabetes complications. 

In Type 1 diabetes, a major thrust is toward the development of an artificial pancreas to better control the disease, preventing or minimizing disease complications. Technologies that could comprise the first steps toward this goal are already in place, including DexCom Inc.'s STS Continuous Glucose Monitoring System (approved in 2005) and Medtronic Inc.'s (recently approved) Guardian REAL-Time System as well as the MiniMed Paradigm REAL-Time System that combines a continuous insulin sensor with an insulin pump.  

Trials of Abbott's FreeStyle Navigator Continuous Glucose Monitoring System are also encouraging. Simultaneously, in clinical trials, drugs are attempting to halt the autoimmune attack that destroys the beta cells, a major pathology of Type 1 diabetes.  

At this time, however, the fly in the ointment is that systems are not reimbursed by insurers and can result in an out-of-pocket expense greater than $300 per month. JDRF intends to address this problem in the near future with a study documenting cost-effectiveness to aid in obtaining reimbursement.  

Using the system allows individuals to see the effects on blood glucose levels of food, exercise, and trends over time, allowing modification for better diabetes control. Although currently approved only for individuals age 18 and older, some trials of the MiniMed Paradigm REAL-Time System are being conducted in adolescents. "The kids who have been wearing it have really seen a lot of benefit," reported Buckingham. "What they are worried about is that when they get to the end of the study [because it's a research device], they have to give it back. And they're saying 'No, you can't have it back.'" They are generally looking at their blood sugar 20 times a day, he said. 

But as Kowalski pointed out, these technological advances are moving toward a vision of JDRF-a closed-loop system-an artificial pancreas that is also in early testing. "What you'll find is that even with these sensors, it's still tough," he said. "It's a tremendous step forward, but it's not the magic bullet. If you have somebody-a six-year-old or a 75-year-old-who doesn't understand his or her diabetes well, you need automated control."  

Kowalski believes that a device that senses the blood glucose, calculates and adjusts the insulin dose, and then injects it is currently the most promising means of preventing diabetes complications. "That'll be the tremendous step forward for people with diabetes." But, he continued, "it's not the end goal for JDRF. The end goal is to walk away from diabetes completely through a biological cure."  

The race is on. For both Type 1 and Type 2 diabetes, manufacturers are vying for pole positions with new therapeutic strategies that promise better disease management, improved quality of life, and ultimately prevention of diabetes complications.

Author | Kathy Hitchens, PharmD, MSBA

Articles

R.Ph.s can facilitate switch to HFA inhalers

Beware of bisphosphonates and jaw disorder

New drugs offer hope to diabetes patients