Aspergillus and the Azoles in 2015

TOP November 2015 Vol 8 No 4 - Supportive Care
Meg Barbor, MPH

Austin, TX-Three advanced azole agents are now being used to treat invasive aspergillosis, and strengths and weaknesses exist for each of them, according to research presented by James S. Lewis II, PharmD, at the 11th annual Hematology/Oncology Pharmacy Association conference.

Voriconazole: The Gold Standard

Voriconazole is approved for the treatment of patients with invasive aspergillosis and invasive candidiasis. It is available in generic form, and although prophylaxis data exist, they have not been FDA approved.

"It is the current gold standard for invasive aspergillosis," said Dr Lewis, Adjunct Associate Professor, Division of Pharmacotherapy, College of Pharmacy, The University of Texas at Austin. Voriconazole is broad spectrum, has high oral bioavailability, and is available in intravenous (IV) and oral formulations, the latter of which is now generic.

One of the drawbacks of using voriconazole is an increased risk for skin cancer in patients taking the drug. "This is something we really need to watch for with long-term use, especially in places where there is a lot of sun exposure," Dr Lewis stated. "It's unfortunate, though, that this information seems to be developing mostly within the dermatology literature."

He added that the bioavailability of the drug-initially thought to be approximately 90%-was likely only about 60 to 70%. Cytochrome P450 interactions with voriconazole are extensive, and there is still ongoing debate about when and when not to base doses on weight. In addition, higher levels of the drug are prone to causing central nervous system disturbances, liver function test abnormalities, and hallucinations.

Posaconazole: The Broadest Spectrum

Posaconazole is approved for prophylaxis in high-risk patients; treatment data exist, but are not FDA approved. "With the new formulations I don't see any reason whatsoever why you could not use posaconazole if you chose to, other than because of the price," Dr Lewis said.

"Posaconazole in 2015 is the drug we all wanted in 2001," according to Dr Lewis. It is the broadest spectrum azole antifungal, and has demonstrated mortality benefit in select populations. The tablets and IV infusions have solved the bioavailability issues; the oral suspension is inferior, whereas the tablets are more predictable.

One of posaconazole's limitations is the ambiguity surrounding its saturable absorption. "We see the same thing with the suspension as we do with the tablets," explained Dr Lewis. "We don't really know the levels of saturable absorption."

There are still numerous drug interactions associated with the use of posaconazole, but because pH issues appear to be less significant in tablets than they are with the suspension, tablets are a much better formulation, he added.

Isavuconazole: The New Kid

Isavuconazole is approved for the treatment of invasive aspergillosis, as well as invasive mucormycosis. "Candida is missing, but that indication is apparently coming down the road," he added. No prophylaxis data currently exist for this drug.

"The spectrum of isavuconazole lies somewhere between voriconazole and posaconazole, but leans more towards posaconazole," Dr Lewis stated. Isavuconazole is FDA approved, but has not been launched yet.

At this point, isavuconazole is indicated for the treatment of invasive aspergillosis-which makes it very similar to voriconazole-and is also indicated for the treatment of invasive mucormycosis.

However, Dr Lewis warned that the package insert outlining the indications of isavuconazole for the treatment of mucormycosis may be misleading. "If you go through the treatment data in the package insert, you'll see that the indication is based on a 40% response rate for invasive mucormycosis, and on the fact that we know 100% of patients died with no treatment," he explained. "The label should have said 'use for mucormycosis when amphotericin B is not an option.'"

One of the biggest concerns discussed is that physicians will look at the date on the package insert and think that, based on the indication, isavuconazole is the same as amphotericin B. "I don't think this labeling really warrants a primary therapy indication for invasive mucormycosis," he added.

There is currently no comparative data available for primary therapy between amphotericin B and isavuconazole.

"We now have 3 advanced azoles which are pretty similar, but...I think there are too many subtleties involved with each of them to say that they are interchangeable," explained Dr Lewis. "And we're still learning about isavuconazole."

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Last modified: February 11, 2016