FDA Advisory Committee Votes in Favor of Zyprexa for Two Adolescent Indications
June 10 2009 - 5:30PM
PR Newswire (US)
ADELPHI, Md., June 10 /PRNewswire-FirstCall/ -- The U.S. Food and
Drug Administration (FDA) Psychopharmacologic Drugs Advisory
Committee (PDAC) voted that Zyprexa(R) (olanzapine), an atypical
antipsychotic, is effective and acceptably safe for the acute
treatment of schizophrenia or manic or mixed episodes associated
with bipolar I disorder in adolescents aged 13-17 years old. The
panel supported the FDA and Lilly's position that if Zyprexa is
approved for the two indications, prescribers should consider other
treatment options first for adolescent patients. "This Committee of
experts spent two days discussing the science of a difficult topic
being debated in media, doctors' offices and living rooms across
the country," said John Hayes, M.D., vice president of Lilly
Research Laboratories. "Today's Committee vote is an important step
toward providing help and hope to the many teens suffering from
severe mental illness." FDA will consider the panel's
recommendations in its review of the supplemental New Drug
Applications that Lilly submitted for Zyprexa. The FDA takes the
advice of its Advisory Committees into consideration when deciding
whether to approve new indications, but is not bound by their
recommendations. For the proposed schizophrenia indication, the
panel voted 11-5, with two abstentions, that Zyprexa's
effectiveness had been demonstrated, and voted 10-4, with four
abstentions, that these data demonstrated acceptable safety. For
the proposed indication for manic or mixed episodes associated with
bipolar I disorder, the panel voted 17-0, with one abstention, that
Zyprexa's effectiveness had been demonstrated, and voted 11-4, with
three abstentions, that these data demonstrated acceptable safety.
The Committee examined findings from two pivotal clinical trials of
Zyprexa in adolescents with schizophrenia or bipolar I disorder,
including a six-week double-blind, placebo-controlled trial to
assess the efficacy and safety of Zyprexa in 72 adolescents (aged
13-17 years old) with schizophrenia; and a three-week, randomized,
double-blind, placebo-controlled trial to assess the efficacy and
safety of Zyprexa in 107 adolescents (aged 13-17 years) with acute
manic or mixed episodes associated with bipolar I disorder. In
these studies, adolescents taking Zyprexa experienced significant
improvements in their schizophrenia and bipolar symptoms on various
efficacy measures. Symptoms of schizophrenia include acute episodes
of delusions, hallucinations and long-term impairments such as
diminished emotion, lack of interest and depressive signs and
symptoms(1). Manic symptoms of bipolar I disorder include long
periods of euphoria, restlessness, behaving impulsively and being
easily distracted(2). A mixed bipolar state occurs when symptoms of
depression and mania are experienced at the same time(3). In
addition to the two placebo-controlled studies, the Committee
reviewed extensive Zyprexa safety data relevant to adolescents.
Increased weight, appetite, and sedation were among the most common
adverse events observed in adolescents. Weight gain was greatest in
adolescents who were overweight or obese when they began treatment.
Significant weight gain was also observed in patients who were of
normal weight at baseline. Although no clinical trials comparing
adolescents to adults were conducted, data from the adolescent
trials were compared to those from the adult trials. The types of
adverse events observed in adolescents treated with Zyprexa were
similar to those seen in adults. The incidence and magnitude of
changes in weight, prolactin, triglyceride, cholesterol and hepatic
enzyme levels were greater in adolescents than adults. Sedation was
also more common in adolescents than adults. "Because weight gain
and some of the metabolic changes are more likely to occur and to
be more pronounced in adolescents compared to adults, we agreed
with the FDA that in many cases other available treatment options
should be considered before Zyprexa when treating adolescents,"
said Dr. Hayes. About Schizophrenia in Adolescents Schizophrenia
affects about 1 percent of Americans(4). A substantial portion of
first psychotic breaks for schizophrenia occur in adolescence. It
has been estimated that 39 percent of males and 23 percent of
females with schizophrenia experience onset of the disease before
the age of 19(5). Studies have suggested that early-onset
schizophrenia is associated with worse long-term outcomes compared
to onset of illness in adulthood(6). About Bipolar Disorder in
Adolescents Bipolar disorder affects approximately 5.7 million
American adults, or about 2.6 percent of the U.S. population age 18
and older in a given year(7). It has an estimated prevalence of 0.1
percent to 2 percent among adolescents(8). Lifetime prevalence of
bipolar I disorder in community samples has varied from 0.4 percent
to 1.6 percent(9). It has been estimated that 20 percent of all
patients with bipolar disorder experience their first manic episode
during adolescence, with the peak age of onset for this group of
patients occurring between 15 and 19 years of age(10). Early onset
of bipolar disorder is associated with greater severity of illness
and more functional impairment(11). Safety information for Oral
Zyprexa (olanzapine) Zyprexa is indicated in adults in the United
States for the acute and maintenance treatment of schizophrenia,
acute mixed and manic episodes of bipolar I disorder, and
maintenance treatment of bipolar I disorder. Zyprexa is not
approved for the treatment of patients with dementia-related
psychosis. Elderly patients with dementia-related psychosis treated
with antipsychotic drugs are at an increased risk of death. In
addition, compared to elderly patients with dementia-related
psychosis taking a placebo, there was a significantly higher
incidence of cerebrovascular adverse events in elderly patients
with dementia-related psychosis treated with Zyprexa. The
possibility of a suicide attempt is inherent in schizophrenia and
bipolar I disorder. Close supervision of high-risk patient should
accompany drug therapy. As with all antipsychotic medications, a
rare and potentially fatal condition known as Neuroleptic Malignant
Syndrome (NMS) has been reported with Zyprexa. If signs and
symptoms appear, immediate discontinuation is recommended. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered
mental status and evidence of autonomic instability (irregular
pulse or blood pressure, tachycardia, diaphoresis and cardiac
dysrhythmia). Additional signs may include elevated creatinine
phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal
failure. Hyperglycemia, in some cases associated with ketoacidosis,
coma, or death, has been reported in patients treated with atypical
antipsychotics, including Zyprexa. While relative risk estimates
are inconsistent, the association between atypical antipsychotics
and increases in glucose levels appears to fall on a continuum and
Zyprexa appears to have a greater association than some other
atypical antipsychotics. Physicians should consider the risks and
benefits when prescribing Zyprexa to patients with an established
diagnosis of diabetes mellitus, or having borderline increased
blood glucose level. Patients taking Zyprexa should be monitored
regularly for worsening of glucose control. Patients starting
treatment with Zyprexa should undergo fasting blood glucose testing
at the beginning of treatment and periodically during treatment.
Any patient treated with atypical antipsychotics should be
monitored for symptoms of hyperglycemia including polydipsia,
polyuria, palyphagia, and weakness. Patients who develop symptoms
of hyperglycemia during treatment should undergo fasting blood
glucose testing. Undesirable alterations in lipids have been
observed with Zyprexa use. Clinical monitoring, including baseline
and follow-up lipid evaluations in patients using Zyprexa, is
advised. Clinically significant, and sometimes very high,
elevations in triglyceride levels and modest mean elevations in
total cholesterol have been observed with Zyprexa use. Potential
consequences of weight gain should be considered prior to starting
Zyprexa. Patients receiving Zyprexa should receive regular
monitoring of weight. As with all antipsychotic treatment,
prescribing should be consistent with the need to minimize Tardive
Dyskinesia (TD). The risk of developing TD and the likelihood that
it will become irreversible are believed to increase as the
duration of treatment and the total cumulative dose of
antipsychotic increase. The syndrome may remit, partially or
completely, if antipsychotic treatment is withdrawn. Zyprexa may
induce orthostatic hypotension associated with dizziness,
tachycardia, bradycardia, and in some patients, syncope, especially
during the initial dose-titration period. Particular caution should
be used in patients with known cardiovascular disease,
cerebrovascular diseases, or those predisposed to hypotension.
Other potentially serious adverse events include seizures, elevated
prolactin levels, cognitive and motor impairment, body temperature
elevation, and trouble swallowing. The most common
treatment-emergent adverse event associated with Zyprexa use in
adults in placebo-controlled, short-term schizophrenia and bipolar
mania trials was somnolence. Other common events were dizziness,
weight gain, personality disorder (COSTART term for nonaggressive
objectionable behavior), constipation, akathisia, postural
hypotension, dry mouth, asthenia, dyspepsia, increased appetite and
tremor. Full prescribing information, including boxed warning, is
available at http://www.zyprexa.com/. About Lilly 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 http://www.lilly.com/.
Zyprexa(R) (olanzapine, Lilly) P-LLY This press release contains
forward-looking statements about Zyprexa. These statements reflect
management's current beliefs; however, as with any pharmaceutical
product there are risks and uncertainties in the process of
research and development, regulatory review, and commercialization.
There is no guarantee that Zyprexa will be approved for the acute
treatment of schizophrenia or manic or mixed episodes associated
with bipolar I disorder in adolescents, or that, if approved, it
will be commercially successful. 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. (1) The National
Institute for Mental Illness. "About Mental Illness: Early Onset
Schizophrenia." Available at
http://www.nami.org/Template.cfm?Section=by_illness&template=/ContentManagemen
t/ContentDisplay.cfm&ContentID=10430. Accessed 4.20.09 (2) The
Child & Adolescent Bipolar Foundation. About Pediatric Bipolar
Disorder. Available at:
http://www.bpkids.org/site/PageServer?pagename=lrn_about. Accessed
May 4, 2009. (3) The National Institute of Mental Health. About
Mental Illness: Bipolar Disorder. Available at:
http://www.nami.org/Template.cfm?Section=By_Illness&template=/ContentManagemen
t/ContentDisplay.cfm&ContentID=13108. Accessed 6.7.2009 (4) The
National Institute of Mental Health. What is Schizophrenia?
Available at:
http://www.nimh.nih.gov/health/publications/schizophrenia/what-is-schizophreni
a.shtml. Accessed May 4, 2009. (5) Loranger, AW (1984): Sex
difference in age of onset of schizophrenia. Archives of General
Psychiatry; 41: 157-161 (6) Fleischhaker, C. et al. Long-term
Course of Adolescent Schizophrenia. Schizophrenia Bulletin 2005
31(3):769-780; doi:10.1093/schbul/sbi014. Available at:
http://schizophreniabulletin.oxfordjournals.org/cgi/content/full/31/3/769.
Accessed May 4, 2009. (7) Kessler RC, Chiu WT, Demler O, Walters
EE. Prevalence, severity, and comorbidity of twelve-month DSM-IV
disorders in the National Comorbidity Survey Replication (NCS-R).
Archives of General Psychiatry, 2005 Jun;62(6):617-27. (8) Mauricio
Tohen et al. (2007). Olanzapine versus Placebo in the Treatment of
Adolescents with Bipolar Mania. Am J Psychiatry 2007, 164:
1547-1556 (9) Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, pg. 385. Available at:
http://www.dsmivtr.org/. Accessed 6.3.2009 (10) Korn, M. (2002).
Building Foundations Toward Recovery in Bipolar Disorder. Retrieved
July 17, 2008 from http://www.medscape.com/viewarticle/441618;
NARSAD (1996). How Prevalent are Mood Disorders in Children and
Adolescents? Retrieved July 17, 2008 from
http://www.narsad.org/news/newsletter/specialreports/archchildmood.html
(11) Axelson D et al. (2006). Phenomenology of children and
adolescents with bipolar spectrum disorders. Archives of General
Psychiatry; 63(10):1139-48. (Logo:
http://www.newscom.com/cgi-bin/prnh/20031219/LLYLOGO)
http://www.newscom.com/cgi-bin/prnh/20031219/LLYLOGODATASOURCE: Eli
Lilly and Company CONTACT: Jamaison Schuler, +1-317-847-9617; David
Shaffer, +1-317-614-5106
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