Three-year data show olanzapine LAI safety findings consistent with
oral olanzapine except for injection-related events INDIANAPOLIS,
May 18 /PRNewswire-FirstCall/ -- Eli Lilly and Company presented
today data on the short- and long-term efficacy and safety of
olanzapine long-acting injection (LAI) in the treatment of adults
with schizophrenia or schizoaffective disorder. Olanzapine LAI is
an investigational formulation that combines the atypical
antipsychotic Zyprexa(R) (olanzapine) with pamoic acid, allowing
for the sustained delivery of olanzapine for up to four weeks.
Results from a 190-week interim analysis of a six-year, ongoing,
open-label study (HGKB), showed that adults with schizophrenia or
schizoaffective disorder treated with olanzapine LAI had a
discontinuation rate of 46.3 percent. The most common reason for
discontinuation was the patient's decision (23.4 percent) followed
by adverse events (6.7 percent). Safety findings were consistent
with those observed with oral olanzapine, with the exception of
injection-related events, including post-injection
delirium/sedation syndrome (PDSS), which is characterized by
sedation- and/or delirium-related symptoms following injection.
"Discontinuation of medication plays a major role in schizophrenia
relapse," said Holland Detke, Ph.D., clinical research scientist at
Lilly. "Four out of five patients who stop taking their medications
after a first episode of schizophrenia will have a relapse. The
more relapses a patient has, the more difficult it becomes for them
to recover from each successive relapse."(1) Also presented today
were eight-month interim results from a two-year, ongoing, open
label study (HGLQ) that showed patients with schizophrenia could be
switched to olanzapine LAI from a previous antipsychotic, either
using a direct switch or while tapering their previous
antipsychotic medication. No significant difference was found in
overall rate of treatment discontinuation or mean change in PANSS
score, two standard measures of treatment effectiveness in
schizophrenia, among patients who were switched directly to
olanzapine LAI and those who were tapered. Additionally, no
significant differences were seen in the overall number of
treatment-emergent adverse events, changes in laboratory measures
or mean weight change. Regulatory reviews for olanzapine LAI are
ongoing in the United States and other countries. Olanzapine LAI is
approved in the European Union under the brand name Zypadhera(R)
for maintenance treatment of adults with schizophrenia who have
been sufficiently stabilized during acute treatment with oral
olanzapine. Additional olanzapine LAI data presented today at the
annual meeting of the American Psychiatric Association include: an
analysis of the role of oral supplementation in the administration
of long-acting antipsychotics; an analysis of PDSS; and a
meta-analysis of olanzapine LAI, olanzapine and haloperidol data.
Additionally, a cost-effectiveness simulation analysis comparing
olanzapine LAI to risperidone LAI, haloperidol LAI and oral
olanzapine was presented. About HGKB The primary objective of this
ongoing open-label study is to examine the long-term safety and
tolerability of olanzapine LAI. Current results are from an interim
analysis, with maximum treatment duration of 190 weeks. Adult
patients with schizophrenia or schizoaffective disorder (N=931)
were enrolled following one of three randomized, controlled studies
of olanzapine LAI, in which patients had been randomly assigned to
oral olanzapine, olanzapine LAI or placebo. During the open-label
extension, all patients received flexibly-dosed olanzapine LAI at
injection intervals of approximately two to four weeks. At time of
analysis, rate of study discontinuation was 46.3 percent.
Discontinuation rate at 18 months was 34.3 percent. The most common
reasons for discontinuation were patient's decision (23.4 percent),
followed by adverse events (6.7 percent). Adverse events in greater
than or equal to five percent of patients were increased weight,
insomnia, anxiety, somnolence, headache and inflammation of the
nasal passages and upper pharynx (nasopharyngitis). Safety findings
were consistent with those observed with oral olanzapine, with the
exception of injection related events, including PDSS. There were
26 occurrences of PDSS. All of these patients recovered within 72
hours. Mean weight change was +1.88 kg, with 32.1 percent of
patients experiencing greater than or equal to seven percent weight
gain. Percentages of patients who increased from normal to high on
fasting glucose, random total cholesterol, or random triglycerides
were 5.5 percent, 5.2 percent and 14.3 percent, respectively. Mean
Clinical Global Impressions-Severity scores remained stable
throughout (2.9 at baseline to 2.8 at endpoint). About HGLQ The
primary objective of this two-year, ongoing open-label study is to
compare the treatment effectiveness of the oral and long-acting
formulations of olanzapine in adult outpatients with schizophrenia
considered at risk for relapse. The eight-month interim analysis of
this study was conducted in order to compare the safety and
effectiveness of direct switch versus taper of previous
antipsychotic medication when changing to olanzapine LAI. Analyses
were based on eight-month data from only those patients treated
with olanzapine LAI (N=264). Patients received olanzapine LAI every
four weeks with a starting dose of 405 mg and flexible dosing
thereafter. Investigators, at their discretion, could either
directly switch patients or taper their previous antipsychotic
medication during the first two weeks of treatment. At the time of
study entry, patients were either receiving typical antipsychotics
(N=63), atypical antipsychotics (N=188) or not receiving any
antipsychotics at all (N=34). Of those receiving atypical
antipsychotics, 76 were taking oral olanzapine and 16 were on an
injectable antipsychotic medication other than olanzapine LAI. Of
264 total patients, 150 (56.8 percent) were switched directly and
the rest were tapered. The two groups did not significantly differ
in discontinuation rate (direct: 29.3 percent, taper: 28.9
percent), and there was no significant difference between the
groups on PANSS total score mean change at any visit up to eight
months (direct: -1.5, taper: -3.4, from a mean baseline of 56.7).
Treatment-emergent adverse events in greater than or equal to five
percent of patients were: increased weight (10.2 percent), insomnia
(8.3 percent), anxiety (6.8 percent), somnolence (6.8 percent) and
increased appetite (5.7 percent). The switch groups did not
significantly differ in mean weight change, with an average weight
gain of 2.0 kg, nor did they significantly differ in terms of
laboratory analytes. About PDSS PDSS describes a range of signs and
symptoms similar to those observed with oral olanzapine overdose
that have been seen in 0.07 percent of olanzapine LAI injections in
clinical trials as of February 22, 2009. These signs/symptoms
include: sedation (ranging from mild in severity to
unconsciousness) and/or delirium (including confusion,
disorientation, agitation, anxiety or other cognitive impairment).
Other symptoms can include extrapyramidal symptoms (such as
restlessness, muscle stiffness, random movements and tremors),
difficulty articulating words (dysarthria), loss of coordination
(ataxia), aggression, dizziness, weakness, hypertension and
convulsions. As of February 22, 2009, across all clinical trials,
PDSS events have been seen in approximately 2 percent of patients,
all of whom have recovered. The majority of these patients have
chosen to continue treatment with olanzapine LAI. Lilly has
proposed a comprehensive plan to the FDA in order to help ensure
the appropriate identification and management of PDSS. About
Long-acting Injectable Antipsychotic Medications The World
Federation of Societies of Biological Psychiatry (WFSBP) guidelines
state that poor or partial treatment compliance is a major problem
in the long-term treatment of schizophrenia.(2) Long-acting
antipsychotic formulations have been associated with improved
treatment adherence and reduced treatment failures.(3) By
administering long-acting medications, healthcare professionals
know when patients have received their medication and can
immediately detect non-adherence when a patient fails to return for
a scheduled injection.(4) Different from both oral and injected
short-acting formulations, long-acting formulations of
antipsychotics allow for stable concentrations of the active drug
to remain at a therapeutic range for an extended period of time.(5)
About Schizophrenia Schizophrenia is a severe and debilitating
illness with symptoms such as delusions (false beliefs that cannot
be corrected by reason), hallucinations (usually in the form of
non-existent voices or visions), disorganized speech and severe
disorganized or catatonic behavior. These signs and symptoms are
associated with marked social or occupational dysfunction. Features
of schizophrenia consist of characteristic signs and symptoms that
have been present for a significant portion of time during a
one-month period, with some signs of the disorder persisting for at
least six months.(6) In addition to these symptoms, patients with
schizophrenia are at greater risk for medical comorbidities than
the general population. 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 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.
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, elevated liver enzymes, 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 first-in-class and best-in-class
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/. This
press release contains forward-looking statements about the safety
and efficacy of olanzapine long acting injection (LAI) and reflects
Lilly's current beliefs. However, as with any investigational
pharmaceutical product, there are substantial risks and
uncertainties in the process of research, development, regulatory
milestones and commercialization. There is no guarantee that
olanzapine LAI will be approved for the treatment of schizophrenia
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. "Expert Consensus Guideline Series," J Clin
Psychiatry, 1999:60 (suppl 11). 2. Falkai P., Wobrock T., Lieberman
J., Glenthoj B.,Gattaz W.F., Moller H.J & Wfsbp Task Force On
Treatment Guidelines For Schizophrenia. The World Journal of
Biological Psychiatry, 2006; 7(1): 5/40 3. Maxine X. Patel and
Anthony S. David. Why aren't depot antipsychotics prescribed more
often and what can be done about it? Advances in Psychiatric
Treatment (2005) 11: 203-211. 4. Kane J.M et al. Guidelines for
depot antipsychotic treatment in schizophrenia. European
Neuropsychopharmacology, Volume 8, Number 1, 1 February 1998, pp.
55-66(12). p. 58. 5. Maxine X. Patel and Anthony S. David. Why
aren't depot antipsychotics prescribed more often and what can be
done about it? Advances in Psychiatric Treatment (2005) 11:
203-211. 6. American Psychiatric Association. Diagnostic and
Statistical Manual of Mental Disorders, fourth edition, 2000, pp.
298. P-LLY (Logo:
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