+-----------------+----------------------------------------------------+
| **MEMORANDUM**  | **DEPARTMENT OF HEALTH AND HUMAN SERVICES**        |
|                 |                                                    |
|                 | **PUBLIC HEALTH SERVICE**                          |
|                 |                                                    |
|                 | **FOOD AND DRUG ADMINISTRATION**                   |
|                 |                                                    |
|                 | **CENTER FOR DRUG EVALUATION AND RESEARCH**        |
+-----------------+----------------------------------------------------+

**Date: DRAFT\*\*\*DRAFT\*\*\*DRAFT 6/19/02**

**From:** Michael F Johnston, R.Ph. Safety Evaluator\
Allen Brinker, M.D, Medical Officer

Division of Drug Risk Evaluation (HFD-430)

Office of Drug Safety

Judy Staffa, Ph.D., Epidemiologist

Jeanine Best, MSN, RN, PNP, Regulatory Health Project Manager

Division of Surveillance, Research, and Communications Support (HFD-410)

Office of Drug Safety

**Through:** Julie Beitz, M.D., Director

Division of Drug Risk Evaluation (HFD-430)

Office of Drug Safety

Anne Trontell, M.D., Director

Division of Surveillance, Research, and Communications Support (HFD-410)

Office of Drug Safety

##### To: Douglas Throckmorton, M.D., Director

> Division of Cardio-Renal Drug Products, HFD-110

**Subject:** REVIEW OF RISK MANAGEMENT PLAN FOR OMAPATRILAT (RMPO)

> (BMS-186716-01, IND 48,035, Serial Nos. 468 and 474; Bristol-Myers
> Squibb)

**[EXECUTIVE SUMMARY]{.underline}**

The Office of Drug Safety (ODS) has reviewed the Risk Management Plan
for Omapatrilat (BMS-186716-01, IND 48,035, Serial Nos. 468 and 474;
Bristol-Myers Squibb Pharmaceutical Research Institute).

In controlled hypertension trials submitted in the original NDA filed in
1999, eight patients were hospitalized for omapatrilat associated
angioedema. Four of these patients experienced life-threatening events
requiring intubation/ tracheostomy. BMS has recently submitted results
of the OCTAVE Trial in which 25,000 hypertensive patients were
randomized to either omapatrilat or enalapril. Two patients developed
life-threatening angioedema on omapatrilat in this study. The risk of
angioedema was 2-3 times greater in black patients (relative to
non-black patients) and in current smokers (relative to former or
non-smokers). On May 8, 2002 BMS submitted a proposal for risk
management strategies to be implemented during marketed use of
omapatrilat. A meeting with DCRDP and ODS representatives on May 16
prompted BMS to submit a revised proposal on June 11. The cornerstone of
these proposals is that angioedema lends itself to management through
education of the patient, prescriber and pharmacist. This review
discusses BMS' risk management proposals in light of this premise.

Despite the use of a lower starting dose (10 mg), exclusion of patients
with previous allergic and anaphylactic responses to medications, and a
protocol specified 2-hour observation period, life-threatening
angioedema was observed in the OCTAVE trial. Blacks and current smokers
are at the highest risk of angioedema, but non-black patients and
non-black, non-smokers are also at increased risk. Thus it should be
assumed that all patients prescribed omapatrilat are at some risk for
the development of angioedema.

We believe that education will not prevent cases of angioedema but may
reduce poor outcomes associated with severe angioedema such as
endotracheal intubation and death. This assumption greatly depends on
whether angioedema is a condition that is amenable to self-diagnosis by
a patient who has not experienced it before, and whether there is
sufficient time to intervene once symptoms have begun.

### ODS notes that drug products with high frequencies of anaphylaxis and hypersensitivity reactions, namely intravenous contrast agents and iron products, are typically administered in supervised medical settings prepared to handle airway compromise. In the situation where patients self-manage anaphylaxis or angioedema outside of a medical setting - in the context of known hypersensitivity reactions to insect stings - the patient has had previous experience of life-threatening allergic symptoms to guide self-care. 

We believe that additional evidence is needed to assure that patient
education regarding risks of angioedema will be uniformly effective in
mitigating severe outcomes. While it is plausible that some patients may
benefit from education and counseling, it is not known which patients
will benefit most. It is possible that some patients will overutilize
healthcare systems for nonserious events that are likely to resolve on
their own. Conversely, underutilization of healthcare services may
result since education may not reach or persuade all individuals at
risk. Apart from dialing 9-1-1, there are no proposed systems approaches
to ensure that timely medical attention will be given to those patients
with rapidly progressive angioedema symptoms.

ODS notes several shortcomings of the proposed postmarketing
surveillance plan. Systems approaches and methods to assess the
effectiveness of risk management strategies for omapatrilat need further
development. Based on the information available, we doubt whether severe
angioedema associated with omapatrilat can be adequately managed by a
program primarily focused on education. We believe it is unlikely that
the proposed risk management plan will reduce the risk of severe
omapatrilat associated angioedema to a level generally observed with
currently marketed ACE inhibitors.

**[INTRODUCTION / BACKGROUND]{.underline}**

Omapatrilat is the first of a new class of medications, the
vasopeptidase inhibitors, under study for the treatment of hypertension
and chronic heart failure. The vasopeptidase inhibitors block the
actions of angiotensin-converting enzyme and neutral endopeptidase
providing dual effects on the physiologic systems for regulating sodium
and fluid homeostasis resulting in inhibition of the
renin-angiotensin-aldosterone system and producing vasodilation.

Bristol-Myers Squibb (BMS) submitted NDA 21-188 to FDA's Division of
Cardio-Renal Drug Products (DCRDP) in late 1999 for the use of
omapatrilat in patients with hypertension. In controlled hypertension
trials submitted in NDA 21-188, eight patients experienced omapatrilat
associated angioedema requiring hospitalization (6 black, 2 non-black
patients). Of these eight cases, four (2 black, 2 non-black patients)
progressed to require intubation/ tracheostomy. These four cases
occurred among 6,662 patients within two weeks of taking a starting dose
of 20 mg daily; all recovered. Concerns related to the severe angioedema
seen during the initial clinical trials, resulted in a March 17, 2000
meeting between BMS and DCRDP. At this meeting, Dr. Raymond Lipicky,
then DCRDP Director, informed BMS that in light of the fact that none of
the ACE inhibitors displayed angioedema of this severity in the
pre-approval stage, BMS needed to find a way to "make this problem go
away" or the approval of omapatrilat was at risk.

After the March 2000 meeting and in response to Dr. Lipicky's request,
BMS initiated the larger (n = 25,302), double-blinded Omapatrilat
Cardiovascular Treatment Versus Enalapril (OCTAVE) clinical trial in
which omapatrilat was compared to enalapril in a 24 week study in
uncontrolled hypertensive patients. This multi-center, multi-country
trial specifically excluded patients with a history of angioedema,
anaphylaxis, contraindication or hypersensitivity to ACE inhibitors or
Angiotensin II receptor blockers, drug-related urticaria or chronic
urticaria, or a history of rash in response to two or more drug classes.
The omapatrilat starting dose was also reduced to 10 mg daily with
subsequent increases to 20 mg, 40 mg, and 80 mg at two-week intervals.
Enalapril was started at 5 mg daily and titrated up to 40 mg. All
patients were observed for two hours following study drug initiation and
titration to the second dose level (omapatrilat 20 mg or enalapril 10
mg). OCTAVE investigators were provided instructions from enalapril
product labeling as a guide to angioedema treatment. Treatment
facilities were not required to have onsite resuscitation
support/equipment but had to be located within an hour of such support.
An Adjudication Committee of experts external to BMS reviewed all
possible cases of angioedema in blinded fashion.

In OCTAVE, patients randomized to omapatrilat experienced a 3-fold
higher rate of angioedema than those taking enalapril (2.17% vs. 0.68%).
Angioedema with omapatrilat was most often characterized by swelling of
the lip (53%), face (32%), tongue (28%), neck (21%) and eyelids (16%), a
pattern similar to that of enalapril. Symptoms associated with the
swelling included flushing or facial redness (22% with omapatrilat, 28%
with enalapril), difficulty swallowing (15% with omapatrilat, 9% with
enalapril), and difficulty speaking (12% with omapatrilat, 6% with
enalapril). In the OCTAVE trial, there were two cases of
life-threatening airway obstruction, both on the omapatrilat arm
(n=12,609). One case occurred in a black female who presented after 10
weeks of therapy (at a daily dose of 80 mg) and progressed over several
hours to the need for intubation / tracheostomy. The second case was in
a non-black female and current smoker who experienced an anaphylactic
reaction with airway compromise within 15 minutes of receiving the first
10 mg dose of omapatrilat but responded to subcutaneous epinephrine. In
addition to these two life-threatening cases, 17 patients on the
omapatrilat arm were hospitalized for severe angioedema as compared to
two patients on enalapril. These patients did not require mechanical
ventilation.

The time course of evolution of angioedema symptoms was variable, but
tended to occur earlier in omapatrilat-treated patients than in
enalapril-treated patients. Of the 274 angioedema events occurring on
omapatrilat, a third or 88 occurred on the first day of therapy; nearly
two-thirds of these within the first two hours. Of the 86 angioedema
events occurring on enalapril, only 3 occurred on the first day, with
one of these occurring in the first two hours. *At a meeting on June 18,
2002 BMS indicated that the majority of patients developed symptoms
outside of the doctor's office and sought medical attention within hours
of symptom onset. BMS has committed to submit additional information
regarding the time course of severe angioedema events with omapatrilat
from its clinical trials experience.* Angioedema events on both drugs
occurred throughout the 24 week period of the study. There did not
appear to be an increased risk of angioedema with dose titration for
either drug.

In order to address this repeated result of higher incidence and greater
severity of angioedema with omapatrilat, on May 16, 2002 BMS presented
to members of the DCRDP, Office of Drug Safety (ODS), and Division of
Drug Marketing, Advertising, and Communication (DDMAC) their proposal
for a risk management plan for omapatrilat. This plan proposes, through
education of the patient, prescriber, and pharmacist, to minimize the
incidence of severe angioedema. Pages 16-17 of the BMS May 8, 2002
meeting submission (prepared for the May 16, 2002 meeting) note that the
effectiveness of the plan is based upon the following principles:

1.  Angioedema, due to its symptoms and characteristic presentation,
    lends itself to management through education of the patient,
    prescriber, and pharmacist;

2.  The time course, symptomatology, risk factors and treatment for
    angioedema have been identified. Two groups (blacks and smokers)
    have been clearly identified as higher risk;

3.  BMS is committed to "establishing awareness of angioedema and to
    implementation" of the plan as an integral part of the marketing and
    launch of omapatrilat;

4.  BMS has proposed research plans to assure key messages concerning
    risk of angioedema are understood by patients, prescribers, and
    pharmacists;

5.  Post-marketing surveys of the plan's effectiveness, surveillance
    programs, and post-marketing studies will assure that the risk
    management plan works in the "real world"; and,

6.  "System approaches are widely considered required elements of risk
    management. Specifically, the FDA has encouraged stakeholders to
    devise and participate in programs that incorporate checks and
    balances, redundancies, and other systems approaches to assure
    products are used appropriately."

In response to comments from DCRDP and ODS at the May 16, 2002 meeting,
BMS submitted a revised risk management plan on June 14, 2002 (document
dated June 11, 2002). This submission makes modifications to the
original plan and changes the name of the plan to the "Risk Management
Plan for Omapatrilat" (RMPO).

Per BMS, the Risk Management Plan for Omapatrilat ensures that the
following goals are adopted for marketed use (pages 5-6 of the May 8
submission and expanded on page 4 of the June 11 submission):

1.  Omapatrilat is used only in patients for whom drug is indicated/
    appropriate;

2.  Prescribing physicians and dispensing pharmacists have adequate
    knowledge of the benefits and risks of omapatrilat, and are capable
    of counseling patients effectively and recognizing angioedema;

3.  Omapatrilat is administered and patients are followed in a way that
    minimizes the rate and severity of angioedema;

4.  Patients who are prescribed omapatrilat are knowledgeable of the
    importance of blood pressure normalization, treatment compliance,
    and are aware of the signs and symptoms of angioedema and will take
    appropriate action if these signs and symptoms occur; and

5.  Effectiveness of the plan will be monitored, specifically in regard
    to the occurrence of angioedema and compliance measures implemented.

*In a teleconference on June 14, 2002 between Dr. Anthony Waclawski of
BMS and ODS staff, the scope and focus of BMS' presentation at the July
Advisory Committee was briefly discussed. At that time, BMS provided ODS
with a three-page draft version of their description of the RMPO to be
included in an Appendix to their Advisory Committee Briefing Document.
It was agreed that only a limited presentation of the RMPO would be made
at the upcoming Advisory Committee meeting with references made to
future development of the components of the risk management program
being a cooperative effort between BMS and the FDA.*

**[RELEVANT PRODUCT LABELING]{.underline}**

Proposed angioedema-related wording for omapatrilat (Vanlev) from draft
labeling dated December 12, 2001 is included as Appendix (1). BMS noted
in their May 8, 2002 meeting package "final labeling will be completed
following upcoming discussions with the FDA Cardio-Renal Division, and
will be intended to both optimize benefit and minimize risk." This
labeling should be considered an early draft at this time.

**[EVALUATION OF ANGIOEDEMA RISK IN OCTAVE TRIAL]{.underline}**

BMS' evaluation of angioedema risk revealed a 2-3-fold increase in risk
for black patients (relative to non-black patients) and for current
smokers (relative to former and non-smokers). A 1-2-fold increase in
risk was also identified for female patients, patients with seasonal
allergies, and former smokers.

Allen Brinker, M.D., developed the following table based on the OCTAVE
dataset (as supplied by Norman Stockbridge, M.D., DCRDP) to assess the
risk of omapatrilat associated angioedema in other subsets of patients
(i.e., non-black patients and non-black non-smokers).

+--------------+-----------+------------+---------------+------------+
|              | Enalapril | O          | Omapatrilat   | O          |
|              |           | mapatrilat |               | mapatrilat |
|              | (OCTAVE   |            | (OCTAVE --    |            |
|              | --        | (OCTAVE -- | non-black     | (OCTAVE -- |
|              |           |            | patients      |            |
|              | all       | all        | only)         | only       |
|              | patients) | patients)  |               | non-black, |
|              |           |            |               |            |
|              |           |            |               | non-       |
|              |           |            |               | smokers\*) |
+--------------+-----------+------------+---------------+------------+
| Relative     | 1.0       | 3.1        | 2.6           | 2.0        |
| Risk for     |           |            |               |            |
| Angioedema - | (88 /     | (272 /     | (201 /        | (130 /     |
|              | 12,557)   | 12,609)    | 11,101)       | 9,152)     |
| All          |           |            |               |            |
| Severities   |           |            |               |            |
|              |           |            |               |            |
| (frequency)  |           |            |               |            |
+--------------+-----------+------------+---------------+------------+
| Relative     | 1.0       | 9.5        | 7.4           | 4.8        |
| Risk for     |           |            |               |            |
| Angioedema - | (2 /      | (19 /      | (13 / 11,101) | (7 /       |
|              | 12,557)   | 12,609)    |               | 9,152)     |
| Hospitalized |           |            |               |            |
| only         |           |            |               |            |
|              |           |            |               |            |
| (frequency)  |           |            |               |            |
+--------------+-----------+------------+---------------+------------+

\*Includes both non-black never (n=5,780) and former (n=3,372) smokers

As shown in this table, the risk for angioedema of all severities with
omapatrilat decreases from 3.1 to 2.0 in comparison to enalapril with
restriction to (1) non-black patients and (2) non-black, non-smokers.
For the subset of hospitalized cases of angioedema, the relative risk
only falls from 9.5 to 4.8. Thus, despite restriction to only non-black
non-smokers, we could expect angioedema-related hospitalizations to
occur some 5-fold more frequently in association with omapatrilat in
this subset as compared to enalapril.

Based on OCTAVE, omapatrilat-associated angioedema is both more frequent
(relative risk of 3) and associated more frequently with severe outcomes
(relative risk of 9) in comparison to enalapril. However, there is no
evidence to date of hyperacute angioedema with omapatrilat (as per N.
Stockbridge). In other words, the initial presentation appears similar
for both drugs, but omapatrilat-associated angioedema appears to
progress more frequently to a stage requiring hospitalization. This
suggests that omapatrilat-associated angioedema may be either more
rapidly aggressive and/or resistant to therapy than angioedema seen with
enalapril. If this is true, it becomes even more critical for patients
prescribed omapatrilat, compared to ACE inhibitors, to recognize
symptoms early and seek prompt medical attention. BMS has committed to
provide additional information on the time course of angioedema for
omapatrilat compared with other anti-hypertensives from its clinical
trials experience.

As BMS expects that omapatrilat "may eventually be used by hundreds of
thousands of patients" (page 41 of the May 8 submission), angioedema
rates from OCTAVE (in the preceding table) were transformed to assess
their impact following drug launch. The table below represents cases of
angioedema expected in a hypothetical population of 100,000 under the
hypothesis that the OCTAVE results are generalizable.

+---------------------+-----------+-----------+-----------+-----------+
| N = 100,000         | Enalapril | Om        | Om        | Om        |
|                     |           | apatrilat | apatrilat | apatrilat |
|                     | (all      | (all      |           |           |
|                     | patients) | patients) | (         | (only     |
|                     |           |           | non-black | n         |
|                     |           |           | only)     | on-black, |
|                     |           |           |           | non-s     |
|                     |           |           |           | mokers\*) |
+=====================+===========+===========+===========+===========+
| Expected number of  | 701       | 2,157     | 1,811     | 1,420     |
| patients with       |           |           |           |           |
| angioedema --       |           |           |           |           |
|                     |           |           |           |           |
| All severities      |           |           |           |           |
+---------------------+-----------+-----------+-----------+-----------+
| Expected number of  | 16        | 151       | 117       | 77        |
| patients with       |           |           |           |           |
| angioedema -        |           |           |           |           |
|                     |           |           |           |           |
| Hospitalized only   |           |           |           |           |
+---------------------+-----------+-----------+-----------+-----------+

\*Includes both non-black never and former smokers

# 

# [EVALUATION OF PATIENT EDUCATION]{.underline}

The RMPO will provide patient education brochures for use by healthcare
professionals to convey important risk information to patients. These
materials will be tested to ensure patient comprehension. In addition, a
Patient Package Insert (PPI) that will follow the Q&A Medication Guide
format will be developed and tested for comprehension. The PPI will be
contained within sample and trade packages of omapatrilat. A novel
pharmacist-to-patient counseling program is also proposed (June 11, 2002
submission). Patients would call a toll-free number to receive
counseling by a pharmacist who would reinforce information provided by
the physician regarding the signs and symptoms of angioedema. Upon
completion of this activity, the counseling pharmacist will provide the
patient with a code number. The patient must present the code number to
the retail pharmacist and the pharmacist must verify the number at the
time the prescription is filled. Jeanine Best contributed the following
comments.

## Managing Risk of Angioedema via Patient Education

**Risk Factor Awareness**. BMS has not provided a complete message
regarding the risks of angioedema with omapatrilat in the draft Patient
Package Insert submitted to date. Based on OCTAVE, BMS documents five
key risk factors for angioedema with omapatrilat: black race, current or
former smoking, female gender, and seasonal allergies. BMS proposes
cautionary language for only two of these risk factors, current smoking
and black race. These two factors were selected based on BMS's
definition that a 2-fold elevation in the risk of angioedema is
"clinically meaningful". ODS notes that even though the other risk
factors for angioedema (e.g., female gender, seasonal allergies, former
smoking) do not elevate risk by more than 100%, they do elevate risks by
approximately 50% (range 47-52%; see page 14 of the May 8, 2002 BMS
meeting package). As such, efforts to prevent the occurrence of
angioedema by advising cautious use in blacks and current smokers
incompletely capture the populations identified as having an increased
risk of this event with omapatrilat.

As documented in Dr. Brinker's section above, the risk for angioedema in
patients without risk factors of black race and smoking remains elevated
above that of enalapril. Thus, patient educational materials should
emphasize that all patients prescribed omapatrilat are at risk for
angioedema, but that this risk is higher for some patients than others.

**Risk Prevention versus Mitigation**. BMS's risk management program is
best described as a risk mitigation program. Their program, if
successful, may reduce severe and life-threatening outcomes of
angioedema once it occurs by educating patients to seek prompt medical
attention. The program will not likely prevent the occurrence of
angioedema itself. This is analogous to alerting patients to the early
signs and symptoms of liver injury from drugs in order to prevent
progression to liver failure; by stopping drug treatment and instituting
corrective therapy early in the course of injury, severe outcomes are
hoped to be prevented.

Key to any risk mitigation strategy is the assumption that there is
sufficient time and adequate means to intervene between early signs and
symptoms and the occurrence of severe injury. A second and related
assumption is that patients can be adequately educated to quickly and
accurately self-diagnose early symptoms of angioedema.

In the case of angioedema associated with omapatrilat, there may not be
sufficient time to intervene between the onset of symptoms and
life-threatening respiratory compromise. The OCTAVE study data indicate
in a first-dose setting that angioedema occurs more commonly and quickly
with omapatrilat (64% of cases within 2 hours of dosing) than with
enalapril (33% of cases in the same time period). One omapatrilat
patient developed respiratory compromise within minutes of her first
dose of 10 mg, presumably during a protocol-specified 2-hour observation
period. She responded to subcutaneous epinephrine and avoided
intubation. Had the patient not been observed during the event it is
possible that she would have done less well. It is also uncertain what
value education would have played in this case; if her symptom course
had been rapidly progressive, there may not have been sufficient time to
intervene. These concerns are valid whether omapatrilat associated
angioedema occurs with the first dose or with some later dose. BMS has
committed to submit additional information regarding the time course of
severe angioedema events with omapatrilat from its clinical trials
experience.

Based on available data, there appears to be no clear relationship
between the severity of symptoms and the time course during which
symptoms evolve (per Dr. Stockbridge, DCRDP). Thus, it is not possible
to predict the time course for medically significant angioedema in a
given patient who develops it in association with omapatrilat use. A
potential consequence of this is that many more omapatrilat patients
will seek medical attention for nonserious events than is probably
necessary. Conversely, patients may choose to ignore symptoms and delay
therapy.

Critical to the determination of whether there is adequate time to
intervene between symptom onset and progression to severe angioedema is
the question of whether patients who have never before experienced
angioedema can be adequately educated to reliably self-diagnose the
early symptoms of angioedema. With rapidly progressing and potentially
fatal events, there may be little if any time for patients to check
different sources of information to validate their experiences. BMS
should provide data to demonstrate that patient education and counseling
can ensure the ability to self-diagnose and appropriately manage a
previously unknown, rapidly developing, potentially life-threatening
event. In particular, this ability needs to be demonstrated in a diverse
population, particularly in individuals with low literacy, before
proceeding. Alternatives to reach low or illiterate populations (such as
video or audio materials) may merit exploration.

Drug products with high frequencies of anaphylaxis and hypersensitivity
reactions, namely intravenous contrast agents and iron products, are
typically administered in supervised medical settings prepared to handle
airway compromise, and/or carry labeled warnings that they should be
used in settings where epinephrine is immediately available (e.g., iron
dextran injection). The only known situation where patients self-manage
anaphylaxis or angioedema outside of a medical setting is in the context
of known hypersensitivity reactions (e.g., to insect stings). In these
instances, the reactions are due to uncontrollable exposures (not
routine drug administration) and the patient has previous experience of
life-threatening allergic symptoms to guide self-care.

In summary, ODS believes that all patients prescribed omapatrilat are at
some risk for the development of angioedema and that this risk is higher
than for currently marketed ACE inhibitors. It is unlikely that the RMPO
will reduce the risk of omapatrilat associated angioedema to a level
generally observed for these other agents. Additional evidence is needed
to assure that patient education regarding risks of angioedema will be
uniformly effective in mitigating severe outcomes. While it is plausible
that some patients may benefit from education and counseling, it is not
known which patients will benefit most. It is possible that some
patients will overutilize healthcare systems for nonserious events that
are likely to resolve on their own. Conversely, underutilization of
healthcare services may result since education may not reach or persuade
all individuals at risk. Apart from dialing 9-1-1, there are no proposed
systems approaches to ensure that timely medical attention will be given
to those patients with rapidly progressive angioedema symptoms.

##### Patient Package Insert

Notwithstanding concerns that the risk of severe angioedema is unlikely
to be mitigated sufficiently by patient education, there are also
concerns with the proposal to use a PPI rather than a Medication Guide
for patient education. Medication Guides are appropriate to the
potential seriousness of the angioedema, their distribution is legally
required, and the effectiveness of their communication format has been
established through extensive research and experience. Medication Guides
also guarantee parity of generics manufacturers and innovators in
patient education.

Severe angioedema is a serious and significant risk to public health and
so meets at least the first of the 3 triggering criteria for a
Medication Guide \[21 CFR § 208.1(c)(1)(2)(3)\]:

(1) "The drug product is one for which patient labeling could help
    prevent serious

> adverse events."

(2) "The drug product is one that has serious risk(s) (relative to
    benefits) of which patients should be made aware because information
    concerning the risk(s) could affect patients' decision to use, or
    continue to use, the product."

(3) "The drug product is important to health and patient adherence to
    directions for use is crucial for the drug's effectiveness."

In addition, the second criterion may be met in consideration of the
many therapeutic options available to treat hypertension. The risks of
omapatrilat relative to its benefits merit discussion in the context of
alternative medications within the ACE inhibitor class and others to
treat hypertension. Such products do not carry the same risk of
angioedema seen with omapatrilat in clinical trials.

Medication Guides are required by law to be distributed at the time of
dispensing. This requirement does not apply to PPIs. A Patient Package
Insert packaged in unit-of-use packaging and formatted like a Medication
Guide may operate effectively as a Medication

Guide, but it will not have the force of the law and could present
problems when or if generics enter the market. PPIs are discretionary.
Proper formatting, font size, and mandatory distribution could not be
assured for a generic manufacturer of omapatrilat unless the innovator
had a Medication Guide.

In their most recent submission, the sponsor has proposed a "Q&A"
Medication Guide format for their PPI. In light of data supporting the
effectiveness of the Medication Guide format, ODS recommends that all
PPIs be placed in Medication Guide format. The Medication Guide format
may be modified with appropriate data to justify doing so. Promotional
language should be removed and full review of content for comprehension
by low literacy populations would be required for approval of either a
Medication Guide or a PPI for omapatrilat.

##### EVALUATION OF POSTMARKETING SURVEILLANCE PROPOSAL

BMS has proposed a three-pronged postmarketing surveillance program for
omapatrilat. These approaches were expanded in the June 11, 2002
submission and are currently under review. Briefly these approaches are:

1)  Intensive surveillance of a national hospital and emergency
    department database to estimate the relative frequency of
    life-threatening angioedema (i.e., resulting in intubation or
    death);

2)  A prospective cohort registry study in 10,000 patients to assess
    whether the frequency of less severe angioedema is similar to that
    observed in the OCTAVE trial; this venue would offer the opportunity
    to periodically survey patients regarding their angioedema events
    and whether physician or pharmacist efforts to educate them were
    effective; and,

3)  Evaluation of spontaneously reported adverse events using specific
    data collection forms to retrieve important clinical information,
    including pharmacotherapy, intubation/ tracheostomy, hospitalization
    or death.

-   **Epidemiologic Assessment of Severe Angioedema (Case Control
    Study)**

Judy Staffa, Ph.D., has provided the following comments on this
component of the proposed surveillance program.

BMS has stated that they will use Premier Inc's hospital database to
conduct surveillance of emergency room visits and hospital admissions
for severe angioedema to determine the proportion of angioedema
associated with omapatrilat and ACE inhibitors. Further, they will use
these data in conjunction with IMS HEALTH data to examine nationwide
exposure to omapatrilat and ACE inhibitors in relation to the proportion
of angioedema cases related to omapatrilat or ACE inhibitor use, in an
ecologic analysis. BMS also proposes to conduct a pilot study to
evaluate the Premier dataset for the surveillance of angioedema. This
study is designed to capture angioedema cases in the Premier dataset
between 1999-2001 and characterize them by demographics, encounter type
(emergency department vs. inpatient) and severity (pharmacotherapy,
intubation or death). A sample of cases will undergo medical record
review to verify diagnosis and ascertain drug exposures, prior history
of angioedema, allergies, smoking status, diabetes, race, age and
gender. The pilot study would offer the opportunity to evaluate a
process for rapid case ascertainment (avoiding data lags) and document
the data flow process including time at which data subsets will be
available.

The rationale behind these proposed studies is unclear to ODS. BMS
states, "the primary goal of the post-marketing surveillance will be to
ascertain the rate of angioedema observed during actual use of
omapatrilat in the market place". However, it would seem more
appropriate if the purpose of using these data was to determine whether
the risk management program is effective. If so, then a set level of
"acceptable risk" for angioedema associated with omapatrilat should be
negotiated with FDA and the studies powered to detect these levels.
Without a baseline assessment of some type, though, it would be
difficult to attribute any success to the program itself, unless the
assumption is made that the risk would be at the level seen in the
OCTAVE trial. This is a questionable assumption, since it is well known
that adverse reactions occur in real world settings at a higher
frequency than in clinical trials of select patient populations. Thus,
the rate of angioedema during actual use of omapatrilat would be
expected to be even higher than that seen in the trials. Determining the
rate of angioedema would also mandate the use of numerator and
denominator data from the same source, such as in a cohort or registry,
rather than an "ecologic analysis" of numerators from Premier and
denominators from IMS HEALTH, as was proposed.

We agree that the Premier data are of high quality, and that it is
likely possible to identify emergency room visits and admissions for
angioedema within a short time period (e.g., the 2-3 weeks referred to
in the proposal). Our major concern with this strategy is that the
sample size of several hundred hospitals is too small to pick up a
sufficient number of angioedema cases attributed to one specific cause,
such as omapatrilat, for which prevalence of use will not likely be high
in the population. This may lead to underestimation of the true
incidence of angioedema associated with omapatrilat.

In addition, although the numbers of discharges for the most common
principal diagnoses associated with hospitalization in Premier hospitals
can be nationally projected, and match up favorably with data from the
National Center for Health Statistics' National Hospital Discharge
Survey, we are not aware of any evidence to suggest that diagnoses
stratified by specific cause will also reliably project. For example, it
may be possible to project total hospitalizations for angioedema from
the Premier hospital sample to all U.S. hospitals, but that does not
mean it is possible or wise to attempt to project the subgroups of
angioedema due to different causes. We believe that there are many
factors that undermine this subgroup projection, including geographical
differences in patterns of drug use, third-party payor influence on
prescribing practices and differences in patient demographics throughout
the country. These factors may impact on the representativeness of
Premier hospitals in relation to the approximately 5,000 hospitals
throughout the U.S. with regard to the prevalence of use of various ACE
inhibitors, including omapatrilat, in the hospitals' catchment area.
Therefore, we do not agree that this proposed strategy would effectively
monitor for all, or even most, cases of severe angioedema associated
with omapatrilat.

In summary, the rationale, methods, statistical power and biases of the
proposed Premier, Inc. studies suffer from numerous deficiencies in
assessing real-world rates of angioedema with omapatrilat. Full and
accurate ascertainment could be better served using a patient registry
with periodic follow-up for adverse event detection.

-   **Assessment and Reporting of Spontaneous Reports of Angioedema**

BMS plans to systematically collect data on angioedema cases and has
drafted a questionnaire to be used by staff at the BMS AE Call Center
(Appendix 4 of the June 11, 2002 submission). Data elements targeted for
collection include race, smoking status, gender, relevant history,
duration of therapy, and detailed descriptions of the adverse events in
terms of severity and outcomes. BMS proposes to report all serious cases
of angioedema in omapatrilat users to the FDA on an expedited basis
(i.e., fatal, life-threatening, hospitalized and medically serious
cases). BMS will also provide estimates of drug use and summaries of
nonserious cases with a frequency to be determined upon further
discussion with FDA.

BMS also proposes evaluating other adverse events in the context of
their background rates. Data from Premier Network, the Veteran's
Administration and United HealthCare Network may be utilized depending
on omapatrilat use within these systems.

ODS agrees that submission of serious angioedema reports on an expedited
basis as 15 day reports may more quickly help to identify additional
risk factors which may in turn allow for improved labeling and/or
education. In addition, spontaneous reports may be able to detect
off-label use or non-compliance with RMPO elements. Current MedWatch
reports do not have a field that explicitly captures race. Race
information is voluntary. We support BMS' efforts to obtain and report
information on race to the extent that this is possible.

**[THE BMS RISK MANAGEMENT PLAN for OMAPATRILAT /
DISCUSSION]{.underline}**

The RMPO emphasizes the use of educational programs designed to reach
the patient, prescriber, and pharmacist at three stages of the treatment
process: pre-therapy, therapy initiation, and during ongoing therapy.
Educational materials are under development by BMS and will contain
simple graphic/text information designed to teach and reinforce the
critical messages concerning the benefits and risks of omapatrilat. BMS
plans to include these messages on all trade and sample packaging and in
all physician, patient, and pharmacist programs.

The table below lists some of the proposed elements of the sponsor's
RMPO with comments/discussion points as collected from ODS staff
members.

+-------------+------------+------------------------------------------+
| **Proposed  | **BMS      | **Office of Drug Safety Comments /       |
| RMPO        | Comments/  | Discussion Points**                      |
| Element**   | R          |                                          |
|             | ationale** |                                          |
+=============+============+==========================================+
| 1\. Limit   | Use should | -   BMS should specify in what           |
| use to      | be         |     population the risk-benefit is truly |
| patients in | reserved   |     favorable for omapatrilat. Is there  |
| which       | for        |     a treatment-refractory population of |
| omapatrilat | patients   |     hypertensive patients who might      |
| is          | in whom    |     merit this drug over other HTN       |
| indicated/  | be         |     treatment options?                   |
| appropriate | nefit/risk |                                          |
|             | is CLEARLY | -   Even with removal of higher risk     |
|             | favorable  |     populations (blacks, current         |
|             |            |     smokers), use of omapatrilat is      |
|             |            |     associated with 2-3 times the        |
|             |            |     angioedema risk of enalapril.        |
|             |            |                                          |
|             |            | -   Current draft labeling lists         |
|             |            |     contraindications only for patients  |
|             |            |     with known hypersensitivity to       |
|             |            |     omapatrilat and in patients with a   |
|             |            |     history of angioedema. With regard   |
|             |            |     to blacks and/or current smokers,    |
|             |            |     BMS states, "such patients may       |
|             |            |     benefit from omapatrilat but should  |
|             |            |     be followed carefully". It must be   |
|             |            |     remembered that patients were        |
|             |            |     excluded from the OCTAVE trial with  |
|             |            |     other risk factors for developing    |
|             |            |     angioedema but treatment in these    |
|             |            |     patients is not contraindicated.     |
|             |            |                                          |
|             |            | -   The process of identifying           |
|             |            |     allergies/sensitivities is often     |
|             |            |     difficult and unreliable.            |
+-------------+------------+------------------------------------------+
| 2\.         | This       | -   Education on the subject of the      |
| Patients,   | knowledge  |     signs and symptoms of angioedema to  |
| physicians  | may        |     patients, physicians and pharmacists |
| and         | prevent    |     will not prevent angioedema but may  |
| pharmacists | "some"     |     reduce the severity of outcomes seen |
| must be     | cases from |     (intubation, tracheotomy) if there   |
| familiar    | p          |     is sufficient time to intervene.     |
| with signs  | rogressing |     Reducing severe outcomes is greatly  |
| and         |            |     dependent on the patient's ability   |
| symptoms of |            |     to self-diagnose angioedema as well  |
| angioedema  |            |     as on immediate availability of      |
|             |            |     medical care.                        |
|             |            |                                          |
|             |            | -   All patients are at risk of          |
|             |            |     developing angioedema, although some |
|             |            |     are at greater risk than others.     |
|             |            |                                          |
|             |            | -   Unlike some other medical conditions |
|             |            |     (i.e., pregnancy, Q-T prolongation,  |
|             |            |     etc.) in which high-risk populations |
|             |            |     may be identified prior to           |
|             |            |     initiating drug therapy, no          |
|             |            |     laboratory test or procedure is      |
|             |            |     available to identify patients who   |
|             |            |     may have an elevated risk for        |
|             |            |     angioedema.                          |
|             |            |                                          |
|             |            | -   Patients prescribed omapatrilat      |
|             |            |     should have no prior history of      |
|             |            |     angioedema, and so it may be         |
|             |            |     challenging to educate them on the   |
|             |            |     rapid recognition of symptoms they   |
|             |            |     have not previously experienced.     |
|             |            |                                          |
|             |            | -   Options such as limiting omapatrilat |
|             |            |     to certain specialty prescribers,    |
|             |            |     although not proposed by BMS, would  |
|             |            |     be problematic because of the        |
|             |            |     primary care nature of treating      |
|             |            |     hypertensive disease.                |
|             |            |                                          |
|             |            | -   It is unclear whether BMS intends to |
|             |            |     limit prescribing by extended health |
|             |            |     care providers (nurse practitioners, |
|             |            |     physicans assistants, etc.).         |
+-------------+------------+------------------------------------------+
| 3\.         | Increased  | -   Although this statement is true, it  |
| Physicians  | risks for  |     seems that "particular caution" must |
| must        | angioedema |     be applied to all patients taking    |
| exercise    | (2-3 fold) |     omapatrilat. See Dr. Brinker's       |
| particular  | over the   |     section above.                       |
| caution     | general    |                                          |
| when        | hy         | -   Particular cautions are not          |
| treating    | pertensive |     specified in the proposed label so   |
| blacks and  | p          |     clinicians are left in the dark      |
| patients    | opulation. |     about what to do in actual practice  |
| with a      | Careful    |     (e.g., prescribe to these groups     |
| current     | con        |     only if they have ready access to    |
| smoking     | sideration |     emergency medical services? etc).    |
| history     | of         |                                          |
|             | potential  |                                          |
|             | benefit    |                                          |
|             | should be  |                                          |
|             | undertaken |                                          |
|             | prior to   |                                          |
|             | treating   |                                          |
|             | each of    |                                          |
|             | these      |                                          |
|             | high-risk  |                                          |
|             | groups.    |                                          |
+-------------+------------+------------------------------------------+
| 4\.         | Titration  | -   Would agree with increasing/         |
| Increasing  | method     |     titrating doses as was utilized in   |
| Dose to 20  | utilized   |     OCTAVE, however dose titration is    |
| mg after    | in OCTAVE  |     not a formal part of                 |
| 10-14 days  |            |     risk-management.                     |
| (then to 40 |            |                                          |
| mg and 80   |            |                                          |
| mg over two |            |                                          |
| week        |            |                                          |
| intervals)  |            |                                          |
+-------------+------------+------------------------------------------+
| 5\. Regular | Since risk | -   The June 11 submission suggests that |
| contact     | of         |     patients would have access to a      |
| with        | angioedema |     pharmacist counseling service on an  |
| patients    | appears to |     ongoing basis.                       |
| should take | persist    |                                          |
| place       | (albeit at | -   Pharmacist counselors could place    |
| w/patients  | a low      |     out-going calls to patients to       |
| reminded of | rate)      |     reinforce awareness of the risk of   |
| the         |            |     angioedema.                          |
| benefits    |            |                                          |
| and risks   |            | ```{=html}                               |
| as well as  |            | <!-- -->                                 |
| the actions |            | ```                                      |
| to take     |            | -   These activities will help reinforce |
| should      |            |     patient education on signs and       |
| symptoms    |            |     symptoms of angioedema. Again,       |
| occur.      |            |     likely won't prevent angioedema but  |
|             |            |     may reduce poor outcomes.            |
+-------------+------------+------------------------------------------+
| 6\.         | Helps to   | -   Verification step will increase the  |
| Pharmacists | ensure     |     burden of the retail pharmacist.     |
| should      | that the   |                                          |
| verify that | patient is | ```{=html}                               |
| patients    | educated   | <!-- -->                                 |
| have a code | about      | ```                                      |
| number at   | angioedema | -   What ensures that verification will  |
| the time of | when the   |     be done routinely?                   |
| dispensing  | first      |                                          |
| (this       | pr         | -   Will prescriptions be denied if the  |
| number      | escription |     code number is not available or      |
| signifies   | is filled. |     verifiable?                          |
| that they   |            |                                          |
| have        |            | ```{=html}                               |
| undergone   |            | <!-- -->                                 |
| pharmacist  |            | ```                                      |
| counseling) |            | -   Verification procedure does not      |
|             |            |     occur in the event that the patient  |
|             |            |     is given office samples; angioedema  |
|             |            |     risk is present even with the first  |
|             |            |     dose.                                |
+-------------+------------+------------------------------------------+

**[CONCLUSION]{.underline}**

BMS is to be commended for undertaking the large multi-center OCTAVE
trial in an attempt to evaluate the severe angioedema events seen in
earlier (and smaller) clinical trials. The results of OCTAVE reinforce
that the problem continues to exist and occurs at all doses. Compared
with enalapril, angioedema is more frequent, more severe and occurs
sooner in omapatrilat users.

Although two at-risk populations (blacks and current smokers) have been
identified, we note that a 2-3-fold increase in angioedema with
omapatrilat compared to enalapril still appears to exist even after
these higher risk groups are excluded. Thus, it should be assumed that
all patients prescribed omapatrilat are at some risk for the development
of angioedema. Despite the use of a lower starting dose (10 mg),
exclusion of patients with previous allergic and anaphylactic responses
to medications, and a protocol specified 2-hour observation period,
life-threatening angioedema was observed in the OCTAVE trial.

Several questions remain regarding omapatrilat associated angioedema,
including:

1.  In light of other antihypertensives on the market, what is an
    acceptable risk for

> angioedema with omapatrilat? Is the risk of angioedema as observed in
> the OCTAVE
>
> trial acceptable in the marketplace?
>
> 2\. For what patient population would omapatrilat be considered
> appropriate therapy?

3.  Is angioedema a condition that is amenable to self-diagnosis by
    patients?

4.  Will the RMPO proposed by BMS effectively minimize the risk of
    severe angioedema to a level generally observed for marketed ACE
    inhibitors?

5.  How will the effectiveness of the RMPO be evaluated? What are the
    benchmarks of success for a program intended to manage angioedema?

The BMS RMPO attempts to educate patients, prescribers, and pharmacists
with the goal of decreasing the incidence of severe angioedema by trying
to ensure that angioedema will be recognized early by patients. The
program will not likely prevent the occurrence of angioedema itself. Key
to the success of the RMPO is the assumption that there is sufficient
time and adequate means to intervene between early signs and symptoms
and the occurrence of severe injury. A second and related assumption is
that patients can be adequately educated to quickly and accurately
self-diagnose early symptoms of angioedema.

We believe that the sponsor needs to provide additional evidence to
assure that patient education regarding risks of angioedema will be
uniformly effective in mitigating severe outcomes. While it is plausible
that some patients may benefit from education and counseling, it is not
known which patients will benefit most. It is possible that some
patients will overutilize healthcare systems for nonserious events that
are likely to resolve on their own. Conversely, underutilization of
healthcare services may result since education may not reach or persuade
all individuals at risk. Apart from dialing 9-1-1, there are no proposed
systems approaches to ensure that timely medical attention will be given
to those patients with rapidly progressive angioedema symptoms.

The primary care nature of hypertension and its treatments also makes
prescriber and pharmacist education a significant challenge and would
make it difficult to restrict omapatrilat to specific prescribers or
pharmacies, as some recent risk management plans have done.

Based on the information available, the Office of Drug Safety doubts
whether severe angioedema associated with omapatrilat can be effectively
managed by a program primarily focused on education. We believe it is
unlikely that the proposed risk management plan will reduce the risk of
severe omapatrilat associated angioedema to a level generally observed
with currently marketed ACE inhibitors.

Reviewed By: Concur:

[\_***\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_***\_\_\_]{.underline}
[\_\_\_\_\_**\_\_\_\_\_\_\_\_\_\_**\_\_\_\_\_\_\_\_\_\_\_\_\_]{.underline}

Michael F. Johnston, R.Ph. Claudia Karwoski, Pharm.D.

Safety Evaluator Team Leader

CC: HFD-400 MHimmel/PSeligman

HFD-410: ATrontell/JBest/JStaffa

HFD-430: Drug Files(omapatrilat)/
JBeitz/ATrontell/CKarwoski/MJohnston/SLu/

CKortepeter/PGuinn/SBirdsong

HFD-110: Division File/IND 48,035/NDA 21-288/DThrockmorton/NStockbridge/

> CLocicero/JPelayo

HFD-2 MedWatch

Electronic File Name (Final Version): omipatRM06.XX.02.doc

**Appendix 1.**

**Angioedema-Related Wording from Proposed Omapatrilat (Vanlev)
Labeling:**

1\. Black Box Warning at Beginning of Label:

+-----------------------------------------------------------------------+
| **USE IN BLACK PATIENTS**                                             |
|                                                                       |
| **VANLEV can cause an increased incidence and severity of angioedema  |
| in black patients compared to non-black patients. The benefits and    |
| risks of prescribing VANLEV to black patients should be considered    |
| carefully before initiating treatment. See WARNINGS: Angioedema.**    |
+-----------------------------------------------------------------------+

2\. Contraindications Section:

CONTRAINDICATIONS

> VANLEV is contraindicated in patients with a known sensitivity to
> omapatrilat, or any other component of this formulation, and in
> patients with a history of angioedema.

3\. WARNINGS Section:

**WARNINGS:**

**Angioedema**

> **VANLEV can cause an increased incidence and severity of angioedema
> in black patients compared to non-black patients. The benefits and
> risks of prescribing VANLEV to black patients should be considered
> carefully before initiating treatment.**
>
> **Angioedema most commonly presents as superficial swelling of the
> eyelids, face or lips, or may involve the tongue, glottis, and/or
> larynx. It may occur at any time during treatment. If a patient
> develops angioedema, VANLEV should be discontinued immediately and
> appropriate therapy and monitoring should be provided until complete
> and sustained resolution of the signs and symptoms has occurred.**
>
> **Rarely, patients treated with VANLEV have developed airway
> compromise associated with angioedema. Angioedema associated with
> laryngeal edema can be fatal. Where there is involvement of the
> tongue, glottis or larynx, likely to cause airway compromise,
> appropriate therapy such as parenteral catecholamines (e.g.
> subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL),
> corticosteroids and/or measures necessary to ensure a patent airway
> (including orotracheal intubation), should be promptly provided.**
>
> **Administration of VANLEV should be initiated at a dose of 10 mg once
> daily for 2 weeks and titrated to the maintenance dose to achieve
> blood pressure control according to the JNC-VI Guidelines. Initiating
> therapy at a higher dose may increase the risk of severe angioedema,
> including laryngeal edema and airway compromise.**
>
> The incidence and severity of angioedema with VANLEV and enalapril
> were carefully examined in the 25,166 patient OCTAVE study. VANLEV was
> administered using a starting dose of 10 mg once daily for 2 weeks.
> All patients were then titrated to 20 mg once daily for 2 weeks and
> then electively titrated to 40 and 80 mg once daily. Enalapril was
> administered using a starting dose of 5 mg once daily for 2 weeks. All
> patients were then titrated to 10 mg once daily for 2 weeks and
> electively titrated to 20 and 40 mg once daily. Overall, 12,609
> patients received VANLEV in the OCTAVE study, including 1,300 black
> patients.
>
> *[Incidence]{.underline}*
>
> In the OCTAVE study, the overall incidence of angioedema during the 24
> weeks of treatment was 2.17% in patients who received VANLEV versus
> 0.68% in patients who received enalapril. The relative risk for
> angioedema with omapatrilat compared to enalapril was 3.17 (95% CI
> 2.52 to 4.12). The incidence of angioedema associated with either
> treatment was approximately three times higher in black compared to
> non-black patients (Table 6).
>
> Table 6: Comparative Incidence of Angioedema in the OCTAVE Study

+--------------------------------------------+-------------------------+
| **Patient Group**                          | **Incidence**           |
|                                            |                         |
|                                            | **(%)**                 |
+--------------------------------------------+-------------------------+
| Overall                                    | 2.17                    |
|                                            |                         |
| VANLEV (n=12609)                           | 0.68                    |
|                                            |                         |
| Enalapril (n=12557)                        |                         |
+--------------------------------------------+-------------------------+
| Black Patients                             | 5.54                    |
|                                            |                         |
| VANLEV (n=1300)                            | 1.62                    |
|                                            |                         |
| Enalapril (n=1237)                         |                         |
+--------------------------------------------+-------------------------+
| Non-Black Patients                         | 1.79                    |
|                                            |                         |
| VANLEV (n=11309)                           | 0.58                    |
|                                            |                         |
| Enalapril (n=11320)                        |                         |
+--------------------------------------------+-------------------------+

> *[Risk Factors]{.underline}*
>
> VANLEV can cause an increased incidence and severity of angioedema in
> black patients compared to non-black patients. The benefits and risks
> of prescribing VANLEV to black patients should be considered carefully
> before initiating treatment. In the OCTAVE study, the incidence of
> angioedema with VANLEV in smokers was higher than the overall
> population. Prior treatment with an ACE inhibitor did not appear to
> affect the risk of developing angioedema with VANLEV. Patients with a
> history of angioedema of any etiology should not take VANLEV (see
> **CONTRAINDICATIONS**).
>
> *[Severity]{.underline}*
>
> Rarely, patients treated with VANLEV have developed airway compromise
> associated with angioedema. There were 2 events of airway compromise
> in the OCTAVE study, both in VANLEV treated patients. One of the
> events was an anaphylactic reaction in a non-black patient which
> occurred shortly after the first dose (10 mg) and responded promptly
> to treatment with epinephrine (see **WARNINGS: Anaphylaxis)**. The
> other event was a case of progressive oropharyngeal and laryngeal
> swelling in a black patient that occurred during maintenance therapy
> with VANLEV 80 mg, and required intubation/tracheotomy prior to
> resolution.
>
> There was no airway compromise in the remaining events. The most
> common manifestation for both VANLEV and enalapril treated patients
> was face or lip swelling. Tongue swelling, difficulty swallowing and
> difficulty speaking were more common findings in VANLEV treated
> patients whereas face and eyelid swelling and flushing/facial redness
> were more common in enalapril treated patients.
>
> *[Relationship to Dose]{.underline}*
>
> Out of 12,609 patients (including 1,300 black patients) who received
> VANLEV starting at 10 mg in the OCTAVE study, one black patient
> experienced severe angioedema requiring intubation/tracheotomy. In
> 3361 patients who received a starting dose of 20 mg once daily in
> controlled hypertension clinical trials other than OCTAVE, there were
> 4 cases of severe angioedema requiring intubation and/or tracheotomy,
> 2 of which occurred in 645 black patients treated. **Administration of
> VANLEV should be initiated at a dose of 10 mg once daily for 2**
> **weeks and titrated to the maintenance dose to achieve blood pressure
> control according to the JNC-VI Guidelines**. **Initiating therapy at
> a higher dose may increase the risk of severe angioedema, including
> laryngeal edema and airway compromise.**
>
> After initiation of treatment with VANLEV 10 mg in the OCTAVE study,
> treatment with higher doses of VANLEV did not significantly increase
> the risk of angioedema compared to lower doses. If treatment with
> VANLEV is interrupted for several days or longer, treatment should be
> reinstituted at a dose of 10 mg once daily for 2 weeks and retitrated
> to the maintenance dose to achieve blood pressure control.
>
> *[Time Course of Onset]{.underline}*
>
> In OCTAVE, the incidence of angioedema during the first day of dosing
> was 0.70%. Most of these first day events occurred within 4 hours.
> With chronic treatment, the risk of angioedema decreased sharply over
> time. The incidence of angioedema for weeks 1-4 was approximately
> 1.36% compared to 0.10% for weeks 21-24.
>
> *[Management]{.underline}*
>
> **If a patient develops angioedema, VANLEV should be discontinued
> immediately and appropriate therapy and monitoring should be provided
> until complete and sustained resolution of the signs and symptoms has
> occurred.**
>
> **Angioedema associated with laryngeal edema can be fatal.** **Where
> there is involvement of the tongue, glottis or larynx, likely to cause
> airway compromise, appropriate therapy such as parenteral
> catecholamines (e.g. subcutaneous epinephrine solution 1:1000 (0.3 mL
> to 0.5 mL), corticosteroids and/or measures necessary to ensure a
> patent airway (including orotracheal intubation), should be promptly
> provided.**
>
> Most of the patients who developed angioedema during the OCTAVE study
> received no treatment or treatment with an antihistamine only.
> Epinephrine or corticosteroids were provided to approximately 40% of
> the patients who developed angioedema while receiving VANLEV. With
> cessation of study therapy and prompt treatment, there were no serious
> clinical sequelae for any of the events. Approximately half the events
> associated with VANLEV resolved within one day and 90% resolved within
> 1 week.
>
> *[Information for Patients]{.underline}*
>
> Patients should be informed about the signs and symptoms of angioedema
> and instructed to be cognizant of any face or neck swelling while
> receiving VANLEV. Angioedema may present as superficial swelling of
> the eyelids, face or lips, or may involve the oropharynx including the
> tongue, glottis or larynx. The patient should be advised to stop
> taking VANLEV and notify the physician if superficial swelling
> involving the eyelids, face or lips occurs. If there is involvement of
> the oropharynx, including the tongue, glottis or larynx, the patient
> should stop taking VANLEV, notify the physician, and seek medical
> attention immediately.

4\. In the "Information for Patients" section:

Angioedema

> Patients should be informed about the signs and symptoms of angioedema
> and instructed to be cognizant of any face or neck swelling while
> receiving VANLEV. Angioedema may present as superficial swelling of
> the eyelids, face or lips, or may involve the oropharynx including the
> tongue, glottis or larynx. The patient should be advised to stop
> taking VANLEV and notify the physician if superficial swelling
> involving the eyelids, face or lips occurs. If there is involvement of
> the oropharynx including the tongue, glottis or larynx, the patient
> should stop taking VANLEV, notify the physician, and seek medical
> attention immediately.
>
> (see **WARNINGS: Angioedema**).

5\. In the "Adverse Reactions" section:

The OCTAVE Study

> Other than angioedema (see **WARNINGS: Angioedema**), the tolerability
> of VANLEV was similar to enalapril.
>
> **Angioedema**
>
> The incidence and severity of angioedema associated with VANLEV and
> enalapril were carefully examined in the OCTAVE study (see **WARNINGS:
> Angioedema**).