[Federal Register: September 6, 2005 (Volume 70, Number 171)]
[Page 53019]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]



Food and Drug Administration

[Docket No. 2004P-0379]

Determination That Penthrane (Methoxyflurane) Inhalation Liquid, 
99.9 Percent, Was Withdrawn From Sale for Reasons of Safety or 

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.


SUMMARY: The Food and Drug Administration (FDA) has determined that 
Penthrane (methoxyflurane) Inhalation Liquid, 99.9 percent, was 
withdrawn from sale for reasons of safety or effectiveness. The agency 
will not accept or approve abbreviated new drug applications (ANDAs) 
for methoxyflurane inhalation liquid, 99.9 percent.

FOR FURTHER INFORMATION CONTACT: Mary Catchings, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION: In 1984, Congress enacted the Drug Price 
Competition and Patent Term Restoration Act of 1984 (Public Law 98-417) 
(the 1984 amendments), which authorized the approval of duplicate 
versions of drug products approved under an ANDA procedure. ANDA 
sponsors must, with certain exceptions, show that the drug for which 
they are seeking approval contains the same active ingredient in the 
same strength and dosage form as the ``listed drug,'' which is a 
version of the drug that was previously approved. Sponsors of ANDAs do 
not have to repeat the extensive clinical testing otherwise necessary 
to gain approval of a new drug application (NDA). The only clinical 
data required in an ANDA are data to show that the drug that is the 
subject of the ANDA is bioequivalent to the listed drug.
    The 1984 amendments include what is now section 505(j)(7) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)(7)), which 
requires FDA to publish a list of all approved drugs. FDA publishes 
this list as part of the ``Approved Drug Products With Therapeutic 
Equivalence Evaluations,'' which is generally known as the ``Orange 
Book.'' Under FDA regulations, drugs are removed from the list if the 
agency withdraws or suspends approval of the drug's NDA or ANDA for 
reasons of safety or effectiveness, or if FDA determines that the 
listed drug was withdrawn from sale for reasons of safety or 
effectiveness (Sec.  314.162 (21 CFR 314.162)).
    Under Sec.  314.161(a)(1) (21 CFR 314.161(a)(1)), the agency must 
determine whether a listed drug was withdrawn from sale for reasons of 
safety or effectiveness before an ANDA that refers to that listed drug 
may be approved. FDA may not approve an ANDA that does not refer to a 
listed drug.
    Penthrane (methoxyflurane) Inhalation Liquid, 99.9 percent, was the 
subject of NDA 13-056, held by Abbott Laboratories (Abbott). Penthrane 
is a potent inhalation anesthetic indicated to provide anesthesia for 
surgical procedures in which total duration of administration is 
anticipated to be 4 hours or less (not to be used at concentrations 
that provide skeletal muscle relaxation). Penthrane was also indicated 
to provide analgesia in obstetrics and in minor surgical procedures and 
for use by self-administration using hand held inhalers. In the Federal 
Register of August 16, 2001 (66 FR 43017), FDA withdrew approval of NDA 
13-056 for Penthrane after Abbott notified the agency that Penthrane 
was no longer being marketed under NDA 13-056 and requested withdrawal 
of that application. Penthrane was then moved to the ``Discontinued 
Drug Product List'' section of the Orange Book.
    In a citizen petition dated August 25, 2004 (Docket No. 2004P-0379/
CP1), submitted under Sec.  10.30 (21 CFR 10.30), and in accordance 
with Sec.  314.161, AAC Consulting Group requested that the agency 
determine whether Penthrane (methoxyflurane) Inhalation Liquid, 99.9 
percent, was withdrawn from sale for reasons of safety or 
    We have carefully reviewed our files for records concerning the 
withdrawal of Penthrane (methoxyflurane) Inhalation Liquid, 99.9 
percent, including the NDA file for this drug product. We have also 
independently evaluated relevant literature and data for possible 
postmarketing adverse event reports. FDA has determined under 
Sec. Sec.  314.161 and 314.162(a)(2) that Penthrane (methoxyflurane) 
Inhalation Liquid, 99.9 percent, was withdrawn from sale for reasons of 
safety. FDA's review shows that methoxyflurane, a volatile anesthetic 
agent, is associated with serious, irreversible, and even fatal 
nephrotoxicity and hepatotoxicity in humans. FDA has also reviewed the 
latest approved labeling for Penthrane and has determined that this 
labeling is inadequate. FDA believes that the risks of toxicity 
outweigh any potential benefits if methoxyflurane is used according to 
the latest approved labeling. Since the initial approval of Penthrane 
in 1962, with a subsequent finding of efficacy in the Federal Register 
of December 11, 1981 (46 FR 60652), alternative safe and effective 
anesthetics have been approved by FDA and entered the market. FDA has 
determined that new clinical studies are necessary before 
methoxyflurane could be considered for reintroduction to the market. 
The agency has determined, under Sec.  314.161, that Penthrane 
(methoxyflurane) Inhalation Liquid, 99.9 percent was withdrawn from 
sale for reasons of safety. Therefore, Penthrane (methoxyflurane) 
Inhalation Liquid, 99.9 percent, will be removed from the list of drug 
products published in the Orange Book. FDA will not accept or approve 
ANDAs that refer to this drug product.

    Dated: August 29, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-17559 Filed 9-2-05; 8:45 am]