Withdrawal of Xigris
25 October 2011 - 11:21PM
UK Regulatory
TIDMLEL
Date: October 25, 2011
For Release: Immediately
Refer to: (317) 651-5567 - Tina Gaines, Lilly Bio-Medicines Communications
(317) 655-6874 - Phil Johnson, Investor Relations
Lilly Announces Withdrawal of Xigris® Following
Recent Clinical Trial Results
INDIANAPOLIS, IN - Eli Lilly and Company (NYSE: LLY) announces withdrawal of
its Xigris®[drotrecoginalfa (activated)] product in all markets following
results of the PROWESS-SHOCK study, which showed the study did not meet the
primary endpoint of a statistically significant reduction in 28-day all-cause
mortality in patients with septic shock. The company is working with regulatory
agencies on this withdrawal, and is in the process of notifying health care
professionals and clinical trial investigators.
"While there were no new safety findings, the study failed to demonstrate that
Xigris improved patient survival and thus calls into question the benefit-risk
profile of Xigris and its continued use," said Timothy Garnett, M.D., Lilly's
Senior Vice President and Chief Medical Officer. "Patients currently receiving
treatment with Xigris should have treatment discontinued, and Xigris treatment
should not be initiated for new patients."
"We believe the original Xigris approval was appropriate and these recent
results were quite unexpected," Garnett added. "A contributing factor to these
study results could be advances in the standard of care for treating severe
sepsis over the past 10 years."
Xigris was approved in the United States by the Food and Drug Administration
(FDA) in November 2001, and was licensed in the European Union in 2002. The
PROWESS-SHOCK study was initiated in March of 2008 as a condition for continued
market authorization in Europe. Lilly committed to conduct a new
placebo-controlled clinical trial to help refine appropriate patient
identification for treatment with Xigris and to confirm the benefit-risk
profile of the product.
BioCritica, Inc. has sales and marketing rights for Xigris in the United States
and Puerto Rico, and Lilly sells and markets Xigris in other countries.
Patients, physicians, pharmacists, or other healthcare professionals with
additional questions about Xigris should contact The Lilly Answer Center at
1-800-LillyRx or visit www.Lilly.com.
About Severe Sepsis
Sepsis is a common and deadly disease. Severe sepsis can develop as a
complication after common illnesses such as pneumonia and bacterial infections,
and is characterized by an overwhelming systemic response to infection which
can rapidly lead to organ failure and ultimately death.
About Xigris
Xigris (drotrecogin alfa [activated]) is a recombinant form of human Activated
Protein C. It is administered by intravenous infusion. Based on the results of
the PROWESS study the U.S. Food and Drug Administration approved Xigris in
November 2001 for the reduction of mortality in adult patients with severe
sepsis who have a high risk of death (e.g., as determined by APACHE II). Xigris
is not indicated in adult patients with severe sepsis and a lower risk of death
(e.g., APACHE II score <25). Xigris is not indicated in pediatric patients. In
2002, the EMA licensed Xigris for the treatment of adult patients with severe
sepsis with multiple organ failure when added to best standard care.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
Xigris increases the risk of bleeding. Xigris is contraindicated in the
following clinical situations where bleeding could lead to significant
morbidity or death:
* Active internal bleeding
* Recent (within 3 months) hemorrhagic stroke
* Recent (within 2 months) intracranial or intraspinal surgery, or severe
head trauma
* Trauma with an increased risk of life-threatening bleeding
* Presence of an epidural catheter
* Intracranial neoplasm or mass lesion or evidence of cerebral herniation
WARNINGS and PRECAUTIONS
Bleeding is the most common serious adverse effect associated with Xigris
therapy. Each patient being considered for therapy with Xigris should be
carefully evaluated and anticipated benefits weighed against potential risks
associated with therapy.
Certain conditions, many of which led to exclusion from the Phase 3 trial
(PROWESS), are likely to increase the risk of bleeding with Xigris therapy.
Therefore, for patients with severe sepsis who have one or more of the
following conditions, the increased risk of bleeding should be carefully
considered when deciding whether to use Xigris therapy:
* Concurrent therapeutic dosing of heparin to treat an active thrombotic or
embolic event
* Platelet count <30,000 x 106/L, even if the platelet count is increased
after transfusions
* Prothrombin time-INR >3.0
* Recent (within 6 weeks) gastrointestinal bleeding
* Recent administration (within 3 days) of thrombolytic therapy
* Recent administration (within 7 days) of oral anticoagulants or
glycoprotein IIb/IIIa inhibitors
* Recent administration (within 7 days) of aspirin >650 mg per day or other
platelet inhibitors
* Recent (within 3 months) ischemic stroke
* Intracranial arteriovenous malformation or aneurysm
* Known bleeding diathesis
* Chronic severe hepatic disease
* Any other condition in which bleeding constitutes a significant hazard or
would be particularly difficult to manage because of its location
Should clinically important bleeding occur, immediately stop the infusion of
Xigris. Continued use of other agents affecting the coagulation system should
be carefully assessed. Once adequate hemostasis has been achieved, continued
use of Xigris may be reconsidered.
Mortality In Patients with Single Organ Dysfunction and Recent Surgery
Among the small number of patients in PROWESS, with single organ dysfunction
and recent surgery (surgery within 30 days prior to study treatment), all-cause
mortality was numerically higher in the Xigris group (28 day: 10/49; in
hospital: 14/48) compared with the placebo group (28 day: 8/49; in hospital: 8/
47).
In an analysis of the subset of patients with single organ dysfunction and
recent surgery from the ADDRESS study, which enrolled septic patients not at
high risk of death, all cause mortality was also higher in the Xigris group (28
day: 67/323; in hospital: 76/325) compared with the placebo group (28 day: 44/
313; in hospital: 62/314). Single organ dysfunction patients with recent
surgery may not be at high risk of death irrespective of APACHE II score.
Therefore, these patients may not be among the indicated population.
Patients on Prophylactic Heparin when Xigris is Initiated
Clinicians should consider continuing heparin for venous thromboembolism (VTE)
prophylaxis when initiating Xigris, unless discontinuation is medically
necessary. In a randomized study of prophylactic heparin versus placebo in 1935
adult severe sepsis patients treated with Xigris, mortality and the rate of
serious adverse events were increased in the subgroup of 434 patients whose
heparin was stopped on study entry by randomization to placebo plus Xigris.
This finding was based on prospectively defined exploratory subgroup analyses;
however, the explanation for the finding is unclear. The safety of prophylactic
heparin when concomitantly administered with Xigris in adult patients with
severe sepsis was evaluated with low molecular weight heparin enoxaparin (40 mg
every 24 hours) and unfractionated sodium heparin (5000 U every 12 hours), but
was not evaluated with unfractionated sodium heparin 5000 U when dosed every 8
hours.
Invasive Procedures
Invasive procedures increase the risk for bleeding with Xigris. Such
procedures, including arterial and central venous punctures, should be
minimized during the Xigris infusion. Puncture of a noncompressible site should
be avoided during the infusion. Xigris should be discontinued 2 hours prior to
undergoing an invasive surgical procedure or procedures with an inherent risk
of bleeding. Once adequate hemostasis has been achieved, Xigris may be
restarted 12 hours after surgery and major invasive procedures or immediately
after uncomplicated less invasive procedures.
ADVERSE REACTIONS
Bleeding is the most commonly reported adverse reaction in patients receiving
Xigris therapy. Patients administered Xigris as treatment for severe sepsis
experience many events which are potential sequelae of severe sepsis and may or
may not be attributable to Xigris therapy. In severe sepsis clinical trials,
there were no types of non-bleeding adverse events suggesting a causal
association with Xigris. In the PROWESS study, serious bleeding events were
observed during the 28-day study period in 3.5% of Xigris-treated and 2.0% of
placebo-treated patients. The difference in serious bleeding occurred primarily
during infusion.
The incidence of intracranial hemorrhage (ICH) during the study period was 0.2%
for Xigris treated patients and 0.1% for placebo treated patients. ICH has been
reported in patients receiving Xigris in non-placebo controlled trials with an
incidence of approximately 1% during the infusion period. The risk of ICH may
be increased in patients with risk factors for bleeding such as severe
coagulopathy and severe thrombocytopenia.
*APACHE (Acute Physiology And Chronic Health Evaluation).
DR HCP ISI 091010
For more information, see full prescribing information at http://pi.lilly.com/
us/xigris.pdf.
About Eli Lilly and Company
Lilly, a leading innovation-driven corporation, is developing a growing
portfolio of pharmaceutical products by applying the latest research from its
own worldwide laboratories and from collaborations with eminent scientific
organizations. Headquartered in Indianapolis, Ind., Lilly provides answers -
through medicines and information - for some of the world's most urgent medical
needs. Additional information about Lilly is available at www.lilly.com.
This press release contains forward-looking statements about Xigris and
reflects Lilly's current beliefs. As with any pharmaceutical product, there are
substantial risks and uncertainties in the process of development and
commercialization. For further discussion of these and other risks and
uncertainties, see Lilly's filings with the United States Securities and
Exchange Commission. Lilly undertakes no duty to update forward-looking
statements.
# # #
__________________________
Xigris® (drotrecogin alfa [activated]) is a registered trademark of Eli Lilly
and Company
P-LLY
Eli Lilly and Company
Lilly Corporate Center
Indianapolis, Indiana 46285
U.S.A.
www.lilly.com
Angus DC et al. Crit Care Med 2001; 29,: 1303-10
END
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