FDA Sends Jazz Warning Letter Over FazaClo Brochure
SILVER SPRING, Md., Sept. 19, 2012 - The FDA today posted on its website a warning letter sent to Jazz Pharmaceuticals regarding a patient brochure for schizophrenia drug FazaClo. The letter is below.
DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health
Service
Food and Drug Administration Silver Spring, MD 20993
Bruce C. Cozadd Chairman and Chief Executive Officer Jazz
Pharmaceuticals 3180 Porter Drive Palo Alto, CA 94304
RE: NDA #021590
FazaClo® (clozapine, USP) Orally Disintegrating Tablets
MA #66
WARNING LETTER
Dear Mr. Cozadd:
The Office of Prescription Drug Promotion (OPDP) of the U.S. Food
and Drug Administration (FDA) has reviewed a direct-to-consumer
(DTC) patient brochure (FZCL-10/008) for FazaClo® (clozapine,
USP) Orally Disintegrating Tablets (FazaClo) submitted by Azur
Pharma, Inc. (Azur),1 now Jazz Pharmaceuticals (Jazz), under cover
of Form FDA 2253. The patient brochure is false or misleading
because it omits and minimizes important risk information
associated with FazaClo, broadens the approved indication of the
drug, presents unsubstantiated superiority claims, and overstates
the drug’s efficacy. Thus, the patient brochure misbrands
FazaClo in violation of the Federal Food, Drug, and Cosmetic Act
(the FD&C Act), 21 U.S.C. 352(a) & 321(n). Cf. 21CFR 202.1
(e)(5)(i), (iii); (e)(6)(i), (ii); (e)(7)(viii). These violations
are concerning from a public health perspective because they
suggest that FazaClo is safer and more effective than has been
demonstrated.
Background
Below is the indication and summary of the most serious and most
common risks associated with the use of FazaClo.2,3
Treatment-Resistant Schizophrenia
FazaClo® (clozapine, USP) is indicated for the management of
severely ill
schizophrenic patients who fail to respond adequately to standard
drug treatment for
schizophrenia. Because of the significant risk of agranulocytosis
and seizure
1 Azur Pharma, Inc. was acquired by Jazz Pharmaceuticals on January
18, 2012. 2 This information is for background purposes only and
does not necessarily represent the risk information that should be
included in the promotional piece(s) cited in this letter. 3 The
approved product labeling (PI) for FazaClo referenced in this
letter is the most recent version, dated January 9, 2012
associated with its use, FazaClo® (clozapine, USP) should be
used only in patients
who have failed to respond adequately to treatment with appropriate
courses of
standard drug treatments for schizophrenia, either because of
insufficient
effectiveness or the inability to achieve an effective dose due to
intolerable adverse
effects from those drugs.
. . .
Reduction in the Risk of Recurrent Suicidal Behavior in
Schizophrenia or
Schizoaffective Disorders
FazaClo® (clozapine, USP) is indicated for reducing the risk of
recurrent suicidal behavior in patients with schizophrenia or
schizoaffective disorder who are judged to be at chronic risk for
reexperiencing suicidal behavior, based on history and recent
clinical state. Suicidal behavior refers to actions by a patient
that put him/herself at risk for death. . . .
FazaClo is associated with a number of serious risks, many of which
are potentially fatal, including Boxed Warnings for
agranulocytosis, seizures, myocarditis, other adverse
cardiovascular and respiratory effects and increased mortality in
elderly patients with dementia-related psychosis. FazaClo is
contraindicated in patients with a previous hypersensitivity to
clozapine or any other component of this drug; in patients with
myeloproliferative disorders, uncontrolled epilepsy, paralytic
ileus, or a history of clozapineinduced agranulocytosis or severe
granulocytopenia; and in severe central nervous system (CNS)
depression or comatose states from any cause. Furthermore, FazaClo
should not be used simultaneously with other agents having a
well-known potential to cause agranulocytosis or otherwise suppress
bone marrow function. The PI also contains Warnings regarding
eosinophilia; QT interval prolongation; neuroleptic malignant
syndrome (NMS); tardive dyskinesia (TD); and hyperglycemia and
diabetes mellitus. In addition, the PI includes Precautions
regarding, among other things, avoiding extended treatment in
patients failing to show an acceptable level of clinical response
and periodically re-evaluating the need for continuing treatment in
patients exhibiting beneficial clinical responses; cardiomyopathy;
fever; pulmonary embolism; phenylketonurics; hepatitis;
anticholinergic toxicity associated with the eye, gastrointestinal
(GI) system, and prostate; and interference with cognitive and
motor performance.
As stated in the PI, FazaClo is associated with the following
common adverse reactions (incidence of greater than 5%): CNS
complaints, including drowsiness/sedation, dizziness/vertigo,
headache, and tremor; autonomic nervous system complaints,
including salivation, sweating, dry mouth, and visual disturbances;
cardiovascular findings, including tachycardia, hypotension, and
syncope; GI complaints, including constipation and nausea; and
fever.
Reference ID: 3190672
Omission and Minimization of Risk Information
Promotional materials are misleading if they fail to reveal facts
that are material in light of the representations made by the
materials or with respect to consequences that may result from the
use of the drug as recommended or suggested by the materials.
The patient brochure is misleading because it presents numerous
efficacy claims regarding FazaClo, but omits and minimizes
important material risks associated with the drug. For example,
while the patient brochure discloses some information regarding the
Boxed Warning for agranulocytosis on page 8, it fails to include
the important material fact that agranulocytosis is a potentially
life-threatening adverse reaction. The patient brochure also fails
to state that patients must have a baseline white blood cell (WBC)
count and absolute neutrophil count (ANC) before initiation of
treatment, as well as weekly for 4 weeks following discontinuation
of FazaClo. In addition, while the patient brochure states that
“during the first 6 months . . . your blood will be tested
for its white blood cell count every week. The next 6 months
you’ll be tested just every other week,” it fails to
include the material fact that, only after acceptable WBC counts
and ANCs have been maintained during the first 6 months of
treatment, can a patient then be monitored every 2 weeks for the
next 6 months.
Furthermore, while the patient brochure includes the statement:
“Please see the enclosed Full Prescribing Information,
Including BOXED WARNINGS regarding . . . seizures, dementia-related
psychosis in elderly patients, myocarditis and other adverse
cardiovascular and respiratory effects” (emphasis original)
on page 8, it fails to include important material facts about each
of these significant risks associated with FazaClo. Specifically,
the patient brochure fails to include the important information
that elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk for death, and that
FazaClo is not approved for use in these patients. It also fails to
include the information that FazaClo should be used with caution in
patients with a history of seizures or other predisposing factors
and that patients should be advised not to engage in activity where
sudden loss of consciousness could cause serious risk to themselves
or others. Furthermore, the brochure does not disclose that there
is an increased risk of potentially fatal myocarditis in patients
treated with clozapine, especially in the first month of treatment,
or that orthostatic hypotension, with or without syncope, can occur
with clozapine treatment and be accompanied by respiratory and/or
cardiac arrest.
The patient brochure also completely omits other important risks
associated with FazaClo, including all contraindications; warnings
such as QT interval prolongation, neuroleptic malignant syndrome
(NMS), tardive dyskinesia (TD), hyperglycemia and diabetes
mellitus; and precautions, such as interference with cognitive and
motor performance. It also fails to disclose any information
regarding common adverse reactions associated with the use of
FazaClo.
In addition, the brochure minimizes the risks of FazaClo by failing
to present risk information in a manner reasonably comparable with
the presentation of claims relating to theeffectiveness of the
drug. Specifically, while there are numerous efficacy claims
throughout the patient brochure, there is no discussion of risk
information until page 8 of the 12-page patient brochure, and it is
relegated to a brief, incomplete disclosure under the heading
“Side effects” (emphasis original).
We acknowledge that page 3 of the patient brochure contains the
statement, “Please see page 8 for important safety
information” (emphasis original), and that page 8 of the
patient brochure includes the statement “Please see the
enclosed Full Prescribing Information . . .” (emphasis in
original). However, this does not mitigate the misleading omission
and minimization of risk information in this brochure.
By omitting and minimizing information regarding the serious risks
associated with FazaClo, the brochure misleadingly suggests that
FazaClo is safer than has been demonstrated by substantial evidence
or substantial clinical experience.
Broadening of Indication
Promotional materials are misleading if they suggest that a drug is
useful in a broader range of conditions or patients than has been
demonstrated by substantial evidence or substantial clinical
experience.
Page 4 of the patient brochure states:
FazaClo is a medication prescribed to treat the symptoms of
schizophrenia and
schizoaffective disorders in patients who have not had good results
with other
medications. FazaClo also reduces the risk of recurrent suicidal
behavior in
patients with these disorders.
This claim is misleading because it suggests that FazaClo is
indicated for the overall treatment of schizoaffective disorder.
However, according to the INDICATIONS AND USAGE section of the PI,
FazaClo is only indicated for reducing the risk of recurrent
suicidal behavior in patients with schizoaffective disorder, not
for overall treatment of the disorder itself. In addition, page 6
of the patient brochure contains a presentation titled, “What
is schizoaffective disorder?” (emphasis original), that
states, “Patients may have crying spells, feelings of
hopelessness, fatigue or insomnia, and also may suffer from periods
of lack of concentration, unrealistically grand thoughts, or
emotional highs.” This presentation further contributes to
the misleading impression that FazaClo is indicated to treat the
symptoms of schizoaffective disorder in general.
The claim on page 4 mentioned above also fails to adequately define
the patient population for which FazaClo is approved in the
management of treatment-resistant schizophrenia. Specifically, the
INDICATIONS AND USAGE section of the PI states that,
“FazaClo® (clozapine, USP) is indicated for the
management of severely ill schizophrenic patients who fail to
respond adequately to standard drug treatment for
schizophrenia.” (emphasis added)
By suggesting that FazaClo is indicated for the overall treatment
of schizoaffective disorder and failing to adequately define the
patient population for which FazaClo is approved in the management
of treatment-resistant schizophrenia, the patient brochure
misleadingly implies that FazaClo is useful in a broader range of
conditions or patients than has been demonstrated by substantial
evidence or substantial clinical experience.
Unsubstantiated Superiority Claims
Promotional materials are misleading if they represent or suggest
that a drug is safer or more effective than another drug, when this
has not been demonstrated by substantial evidence or substantial
clinical experience.
Page 4 of the patient brochure makes the following claim:
Researchers say that clozapine, the active ingredient in FazaClo,
is the most
effective medication for reducing or eliminating symptoms in
patients who have
not had success with other products.
This claim misleadingly suggests that clozapine is more effective
than all other schizophrenia treatments when this has not been
demonstrated by substantial evidence or substantial clinical
experience. While we acknowledge that clozapine has been
demonstrated to be more effective than chlorpromazine and is the
only product currently approved to treat severely ill schizophrenic
patients who fail to respond adequately to standard drug treatment
for schizophrenia, FDA is not aware of adequate, well-controlled
studies demonstrating that clozapine is more effective than all
other products for treatment-resistant schizophrenia.
In addition, page 7 of the patient brochure makes the claim
(emphasis original):
• “How FazaClo (clozapine, USP) Orally Disintegrating
Tablets may help
. . .
o FazaClo generally produces little or none of the restlessness,
stiffness, shakiness, or tremor you may have experienced with other
medications.”
This claim misleadingly suggests that FazaClo is superior to other
available treatments for schizophrenia based on its risk profile.
FDA is not aware of substantial evidence or substantial clinical
evidence to support this claim. As stated in the ADVERSE REACTIONS
section of the PI, FazaClo is associated with adverse reactions,
such as tremor (6%), restlessness (4%), akathisia (e.g., motor
restlessness) (3%), rigidity (3%), hyperkinesia (e.g.,
involuntary/uncontrolled muscle movement) (1%), and epileptiform
movements/myoclonic jerks (e.g., involuntary contraction of muscle
groups) (1%).
Overstatement of Efficacy
Promotional materials are misleading if they contain
representations or suggestions that a drug is better or more
effective than has been demonstrated by substantial evidence or
substantial clinical experience.
The patient brochure makes the following claims (emphasis
original):
•
“FazaClo can be highly effective in relieving distressing
symptoms such as agitation, unusual thoughts, hearing voices, . .
.lack of motivation, and lack of interest in social
activities.” (Page 3)
•
“How FazaClo (clozapine, USP) Orally Disintegrating Tablets
may help
o Over a period of time, symptoms like voices or unusual thoughts
usually diminish or disappear.” (Page 7)
These claims misleadingly imply that treatment with FazaClo will
improve the specific individual symptoms of agitation, unusual
thoughts, hearing voices, lack of motivation, and lack of interest
in social activities. However, FDA is not aware of substantial
evidence or substantial clinical experience to support these
claims. The effectiveness of clozapine for treatment-resistant
schizophrenia was demonstrated in a clinical trial studying its
effect on the Brief Psychiatric Rating Scale (BPRS) total score,
the cluster of four key BPRS items (conceptual disorganization,
hallucinatory behavior, suspiciousness, and unusual thought
criteria), and the Clinical Global Impression (CGI) scale.
Demonstrating an effect on the composite total scores of these
scales does not demonstrate an effect on an individual component of
these scales. Therefore, the clinical study used to demonstrate
efficacy of clozapine is not considered substantial evidence to
support claims of efficacy in treating the individual symptoms of
schizophrenia listed above.
Page 7 of the patient brochure claims, “You may experience
renewed interest in attending school, or holding a job; and you may
want to join in more social activities with your family and
friends.” This claim misleadingly implies that FazaClo will
improve a patient’s academic, work, or social functioning.
The FDA is not aware of substantial evidence or substantial
clinical experience to support this claim. As noted above, the
effectiveness of clozapine was demonstrated in a clinical trial
studying its effect on the BPRS total score, a cluster of four key
BPRS items, and the CGI scale. These rating scales do not measure a
patient’s academic, work, or social functioning, and thus the
clinical study used to demonstrate efficacy of clozapine is not
considered substantial evidence to support a claim that clozapine
improves a patient’s academic, work, or social functioning.
If you have data to support this claim, please submit them to FDA
for review.
In addition, the patient brochure claims:
• “[C]lozapine, the active ingredient in FazaClo, is the
most effective medication for reducing or eliminating symptoms. .
.” (Page 4, underlined emphasis added)
This claim and the aforementioned claim on page 7 that treatment
with FazaClo will cause symptoms to “disappear” are
misleading because they suggest that the outcome of treatment with
FazaClo is the complete resolution of symptoms in patients with
treatment-resistant schizophrenia. In addition, page 3 of the
brochure states, “A new road to recovery...Your health care
professional has just started you or someone you love on a new road
to recovery by prescribing FazaClo (clozapine, USP) Orally
Disintegrating Tablets” (bolded emphasis original, underlined
emphasis added). This statement, in the context of claims that
FazaClo will “eliminate” symptoms, or cause them to
“disappear,” further contributes to the misleading
impression that the outcome of treatment with FazaClo is the
complete resolution of symptoms in patients with
treatment-resistant schizophrenia. However, the improvements in the
BPRS total score, cluster of four key BPRS items, and CGI scale
seen in patients at the end of the 6-week clinical trial used to
demonstrate efficacy of clozapine do not support claims implying
elimination of treatment-resistant schizophrenia symptoms or
recovery. Furthermore, the clinical trial did not evaluate the
long-term effect of clozapine in patients with treatment-resistant
schizophrenia to determine if patients experienced improvement with
no relapses or tolerability issues that would cause discontinuation
of the drug, and that treatment with clozapine had a sustained
effect or response for the schizophrenic patient. Therefore, the
clinical trial does not constitute substantial evidence to support
claims implying elimination or disappearance of symptoms. If you
have data to support these claims, please submit them to FDA for
review.
Conclusion and Requested Action
For the reasons discussed above, the patient brochure misbrands
FazaClo in violation of the FD&C Act, 21 U.S.C 352(a) &
321(n). Cf. 21 CFR (e)(5)(i), (iii); (e)(6)(i), (ii);
(e)(7)(viii).
OPDP requests that Jazz immediately cease the dissemination of
violative promotional materials for FazaClo such as those described
above. Please submit a written response to this letter on or before
October 2, 2012 stating whether you intend to comply with this
request, listing all promotional materials (with the 2253
submission date) for FazaClo that contain violations such as those
described above, and explaining your plan for discontinuing use of
such violative materials. Because the violations described above
are serious, we request, further, that your submission include a
comprehensive plan of action to disseminate truthful,
non-misleading, and complete corrective messages about the issues
discussed in this letter to the audience(s) that received the
violative promotional materials. In order to clearly identify the
violative promotional piece(s) and/or activity and focus on the
corrective message(s), OPDP recommends that corrective piece(s)
include a description of the violative promotional piece(s) and/or
activity, include a summary of the violative message(s), provide
information to correct each of the violative message(s), and be
free of promotional claims and presentations. To the extent
possible, corrective messaging should be distributed using the same
media, and generally for the same duration of time and with the
same frequency that the violative promotional material was
disseminated.
Please direct your response to the undersigned at the Food and Drug
Administration, Center for Drug Evaluation and Research, Office of
Prescription Drug Promotion, Division of Consumer Drug Promotion,
5901-B Ammendale Road, Beltsville, Maryland 20705-1266 or by
facsimile at (301) 847-8444. Please note that the Division of Drug
Marketing, Advertising, and Communications (DDMAC) has been
reorganized and elevated to the Office of Prescription Drug
Promotion (OPDP). OPDP consists of the Immediate Office, the
Division of Professional Drug Promotion (DPDP) and the Division of
Consumer Drug Promotion (DCDP). To ensure timely delivery of your
submissions, please use the full address above and include a
prominent directional notation (e.g. a sticker) to indicate that
the submission is intended for OPDP. In addition, OPDP recently
migrated to a different tracking system. Therefore, OPDP letters
will now refer to MA numbers instead of MACMIS numbers. Please
refer to the MA #66 in addition to the NDA number in all future
correspondence relating to this particular matter. OPDP reminds you
that only written communications are considered official.
The violations discussed in this letter do not necessarily
constitute an exhaustive list. It is your responsibility to ensure
that your promotional materials for FazaClo comply with each
applicable requirement of the FD&C Act and FDA implementing
regulations.
Failure to correct the violations discussed above may result in FDA
regulatory action, including seizure or injunction, without further
notice.
Sincerely,
{See appended electronic signature page}
Robert Dean, MBA Director Division of Consumer Drug Promotion
Office of Prescription Drug Promotion
Reference ID: 3190672
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This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
/s/
ROBERT T DEAN 09/18/2012
Reference ID: 3190672
Posted: September 2012
