GAITHERSBURG, MdThe Oncologic Drugs Advisory Committee (ODAC)
has unanimously recommended the approval of Busulfex Injection
(busulfan, Orphan Medical) in combination with other chemotherapeutic
agents and/or radiation as a conditioning regimen prior to
hematopoietic progenitor cell transplantationbut only in
chronic myelogenous leukemia (CML).
The panel voted against recommending that the FDA approve Busulfex
for use in acute myelogenous leukemia, acute lymphocytic leukemia,
myelodysplastic syndrome, and malignant lymphomas. Members found that
the company did not provide substantial evidence of the safety and
efficacy of the drug in these cancers.
Busulfex is an injectable form of busulfan, an oral drug that has
been in use since the 1960s to prepare patients for bone marrow and
peripheral blood stem cell transplants. The injectable formulation
was developed by researchers at M.D. Anderson to counter the vomiting
and difficulties of ensuring a consistent dose that occur with the
Of the expected 20,000 bone marrow transplants in the United States
this year, about 4,000 patients with the five cancers for which
Orphan Medical sought approval would be potential candidates for the
drug, the company said. We do not expect the introduction of
Busulfex to change standard practice, but rather to be a substitute
for the oral product, said Dayton R. Reardan, PhD, head of
regulatory affairs for Orphan Medical.
The company supported its new drug application with two phase II
clinical trials that assessed myeloablation, engraftment, and safety
in patients treated with Busulfex; clinical studies that assessed the
pharmacokinetic profile of the injection form vs the oral form of
busulfan; and a literature review to determine in which diseases
there existed substantial evidence to support the safety and efficacy
of oral busulfan in stem cell transplantation.
The literature review was undertaken after the FDA agreed that a
complete and comprehensive literature review could offer evidence of
oral busulfans efficacy and safety in a transplant setting.
The first study included 42 autologous transplant patients treated at
five centers; the second included 61 allogeneic transplant patients
treated at seven centers. Patients in each study received 0.8 mg/kg
of Busulfex injected every 6 hours for 4 days beginning 7 days before transplant.
All patients in both studies achieved engraftment, Borje S.
Andersson, MD, PhD, told the committee. Among autologous patients,
the median time to engraftment was 10.5 days with 100% engraftment,
compared with median graft times of 25 to 32 days and failures rates
of 1.6% to 1.7% with use of the oral agent as found in the autologous literature.
Allogeneic transplant patients had a 13-day median time to
engraftment and 100% engraftment, compared with median engraftment
times of 19 to 20 days and failure rates of 2.3% to 6.1% with the
oral agent as found in the literature.
One autologous patient (2.4%) suffered veno-occlusive disease,
compared with rates of 3.2% to 6.1% in the literature. There were no
deaths in the first 100 days post-transplant, compared with rates of
6.5% to 15% in the literature.
Among the allogeneic patients, 3 of 61 (4.9%) suffered veno-occlusive
disease, according to Jones criteria, compared with 5.9% to 12% in
the literature, and eight patients (13.1%) died in the first 100
days, compared with rates of 4.1% to 21% in the literature.
A major problem with oral busulfan is that patients must take huge
quantities of the druga 154-lb patient would have to take 35
oral busulfan tablets to equal one injection, noted William P.
Vaughan, MD, of the University of Alabama.
Another problem is that the oral drug causes frequent vomiting.
Orphan Medical presented evidence that Busulfex reduced vomiting. Use
of the injectable drug resulted in no loss of drug due to vomiting;
consistency of dosing; and stable bioavailability.
The companys literature review of the use of oral busulfan
involved 43 studies published from 1964 to 1997. In its review, FDA
included another 16 articles.
FDA reviewer Donna Griebel, MD, said that the agencys analysis
found a similar pharmacokinetics profile for both the oral and
injectable formulations, and comparable myeloablation and
engraftment. ODAC agreed 15 to 0 that Busulfex has a similar but not
superior pharmacokinetic profile to oral busulfan.
However, the FDA staffs literature review concluded that the
evidence only supported the safety and efficiency of oral busulfan in
CML, Dr. Griebel said. ODAC members agreed in a 15 to 0 vote. In
split votes, they rejected recommending approval of the injectable
drug for use in the other four cancers for which the company had
sought a marketing indication.
Dr. Griebel also raised a potential safety issue regarding an
inactive ingredient in Busulfex, dimethylacetamid (DMA), that has not
been FDA approved for use in humans. Repeated dosing studies
have shown hepatic injury in animals and humans, she said.
Similarly, high doses have been reported to cause neurologic
symptoms in humans.
Robert Temple, MD, of the FDA, assured ODAC members that approval of
Busulfex would not give blanket approval to dimethylacetamid.