Guidance for Industry
Clozapine Tablets: In Vivo Bioequivalence
and In Vitro Dissolution Testing
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version of this document]
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
June 2005
BP
Revision I
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http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
June 2005
BP
Revision 1
Guidance for Industry
Clozapine Tablets: In Vivo Bioequivalence
and In Vitro Dissolution Testing
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer any
rights for or on any person and does not operate to bind FDA or
the public. You can use an alternative approach if it satisfies
the requirements of the applicable statutes and regulations. If
you want to discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number
listed on the title page of this guidance.
I.
INTRODUCTION
This guidance provides recommendations for
sponsors of abbreviated new drug applications (ANDAs) designing
bioequivalence studies for generic clozapine products. This
document revises the recommendations provided in a guidance on the
same topic issued in November 1996. In the 1996 guidance, the
Agency recommended that doses of clozapine tablets be administered
to healthy subjects as well as to the appropriate patient population
in bioequivalence studies for generic clozapine products. Because a
high number of healthy subjects experienced serious adverse effects
such as hypotension, bradycardia, syncope, and asystole during
clozapine bioequivalence studies, FDA is recommending that studies
not be conducted using healthy subjects. In addition, a single-dose
study using a 12.5 mg dose is no longer recommended. Instead, this
guidance recommends a multiple-dose bioequivalence study conducted
in patients using the highest dosage strengths (e.g., 100 mg
tablets).
The protocols described in this guidance are
designed to reduce the likelihood of adverse events or, if adverse
events should occur, to ensure that adequate treatment is available.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required.
Clozapine, a dibenzodiazepine derivative with
potent antipsychotic properties, is indicated for the management of
patients with severe schizophrenia who fail to respond adequately to
standard antipsychotic drug treatment. A significant risk of
agranulocytosis and seizures associated with its use is a major
factor restricting wide use of clozapine in psychiatric practice.
The FDA recommends that treatment with
clozapine begin with one-half of a 25 milligram (mg) tablet (12.5
mg) once or twice daily and that treatment be continued with daily
dosage increments of 25-50 mg per day, if well tolerated, to achieve
a target dose of 300 to 400 mg per day by the end of 2 weeks. While
many patients respond adequately at doses between 300 and 600 mg per
day, it may be necessary to raise the daily dose to between 600 and
900 mg to obtain an acceptable response. Dosing should not exceed
900 mg per day.
In humans,
clozapine from 25 mg and 100 mg tablets is equally bioavailable
relative to a clozapine solution. Following a dosage of 100 mg
twice a day, the average steady-state peak plasma concentration
occurs at an average of 2.5 hours (range 1-6 hours) after dosing.
Food does not appear to affect clozapine systemic bioavailability.
The mean elimination half-life of clozapine after a single 75 mg
dose is 8 hours (range 4-12 hours), compared to a mean steady-state
half-life of 12 hours (range 4-66 hours) following 100 mg twice a
day dosing. The elimination half-life increases significantly upon
multiple dosing relative to single-dose administration, raising the
possibility of concentration dependent pharmacokinetics. However,
at steady-state, linearly dose-proportional changes have been
observed in AUC, peak, and minimum clozapine plasma concentrations
after administration of 37.5 mg, 75 mg, and 150 mg (twice daily).
Orthostatic hypotension with or without syncope
can occur with clozapine treatment. Orthostatic hypotension is more
likely to occur during initial titration in association with rapid
dose escalation and may even occur with the first dose. Due to the
hypotensive effects associated with administration of clozapine to
healthy subjects, the original recommendations in a guidance on
clozapine tablets published in November 1996 are being changed.
This document revises and supersedes the previous version of the
guidance. The Agency currently recommends that steady-state studies
to evaluate the bioequivalence of clozapine products be performed
only on patients who are already receiving an established
maintenance dose of an approved clozapine product and have failed to
respond adequately to standard antipsychotic drug treatment. The
Agency believes that the previously recommended study design using
half tablets in healthy subjects was adequate to establish
bioequivalence of generic clozapine products; however, the safety
concerns associated with the use of clozapine in healthy subjects
are significant, and it is recommended that this practice not be
continued.
Applicants may
consult FDA’s Approved Drug Products with Therapeutic Equivalence
Evaluations (Orange Book) for the appropriate reference product.
The test batch or lot
should be manufactured under production conditions and should be at
least 10% of the size of the largest lot planned for full
production, or a minimum of 100,000 units, whichever is larger.
The assayed potency of the reference product should not differ from
that of the test product by more than 5%.
The objective of this steady-state
bioequivalence study is to compare the rate and extent of absorption
of a generic formulation with a reference formulation when
administered at equal doses, as labeled.
Potential sponsors
should consider the following study design. This study is
appropriate for institutionalized or noninstitutionalized patients.
Procedures should be in place to ensure medication compliance in
either setting.
The study would be
conducted in patients who are receiving a stable daily dose of
clozapine administered in equally divided doses at 12-hour
intervals. Patients who are receiving multiples of 100 mg every 12
hours would be eligible to participate in the study of the 100 mg
strength by continuing their established maintenance dose.
According to the randomization schedule, an equal number of patients
would receive either the generic formulation (Treatment A) or the
reference formulation (Treatment B) in the same dose as administered
prior to the study every 12 hours for 10 days.
Patients would then
be switched to the other product for a second period of 10 days. No
washout period is necessary between the two treatment periods.
After the study is completed, patients could be continued on their
current dose of clozapine using an approved clozapine product as
prescribed by their clinicians.
Before the study
begins, the proposed protocol must be approved by an institutional
review board (IRB).
The FDA recommends
that applicants enroll a sufficient number of patients to ensure
adequate statistical power.
Patients should
receive study treatment A or B with 240 milliliters (ml) of water at
fixed 12-hour intervals for 10 days, using multiples of the 100 mg
strength.
Blood samples should
be collected over a dosing interval on day 10, following preliminary
sampling on days 7, 8, and 9 to confirm steady-state conditions.
The last dose of clozapine to be taken before blood sampling for
each period should be administered at the clinical site to assure
exact timing of sampling.
To enter into this
study, patients should be appropriate candidates for clozapine
therapy (as stated in product labeling) and have been taking a
stable dose of clozapine for at least three months. Patients should
be otherwise healthy as determined by physical examination, medical
history, and routine hematologic and biochemical tests.
Outpatients should be
hospitalized for at least 2 days during the collection of each set
of pharmacokinetic samples. The clinical and analytical
laboratories used for the study should be identified in the study
report, along with the names, titles, and curriculum vitae of the
medical and scientific/analytical directors.
White blood cell (WBC)
counts should be monitored and clozapine treatment modified, if
necessary, in accordance with the agranulocytosis warning in the
labeling of the reference listed drug product. Patients requiring
modification of clozapine treatment should be dropped from the study
and provided with prompt medical care. Blood pressure, heart rate,
and body temperature should be monitored during the study and
immediate medical care provided for any significant abnormalities.
Patients should fast for at least 8
hours prior to and 4 hours after the administration of the morning
dose of the test or reference treatment on day 10 of each period
(i.e., the days on which blood samples are to be collected to assess
the concentration-time curve). All meals on day 10 should be
standardized during the study.
Water may be allowed, except for 1 hour
before and 1 hour after drug administration, when no liquid should
be permitted other than that needed for drug dosing.
Patients with any of the following
should be excluded from the study:
·
A history of allergic reactions to clozapine or other
chemically related psychotropic drugs
·
Concurrent primary psychiatric or neurological
diagnosis, including organic mental disorder, severe tardive
dyskinesia, or idiopathic Parkinson’s disease
·
A total white blood cell count below 4000/ml, or an
absolute neutrophil count below 2000/ml
·
A history of granulocytopenia or myeloproliferative
disorders (drug-induced or idiopathic)
·
Significant orthostatic hypotension (i.e., a drop in
systolic blood pressure of 30 mm Hg or more and/or a drop in
diastolic blood pressure of 20 mm Hg or more on standing)
·
Concurrent use of antihypertensive medication or any
medication that might pre-dispose to orthostatic hypotension
·
A medical or surgical condition that might interfere
with the absorption, metabolism, or excretion of clozapine
·
A history of epilepsy or risk for seizures
·
Concurrent use of other drugs known to suppress bone
marrow function
·
Expected changes in concomitant medications during the
period of study
·
Positive tests for drug or alcohol abuse at screening
or baseline
·
A history of alcohol or drug dependence by
Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV)
criteria during the 6-month period immediately prior to study entry
·
Compliance with outpatient medication schedule not
expected
·
History of multiple syncopal episodes
Venous blood samples should be
collected after the day 10 morning dose to assess the
concentration-time curve at predose (0 hours) and at 0.25, 0.5, 1.0,
1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0 hours. The
predose blood sampling should include at least three successive
trough level samples (Cmin). These samples should be
collected on the last 3 days of dosing in each period to ensure that
steady-state blood plasma/serum levels are achieved in each study
period.
C.
Other Recommendations
·
Patients should be confined for at least 12 hours
after the first dose of the test and reference products.
·
Patients should remain in the supine position for the
first 6 hours after the first dose, even if they were previously on
a stable dose of clozapine.
·
Patients should be adequately hydrated. This may be
achieved by administering 240 ml of water before the overnight fast,
240 ml of water one hour before dosing, 240 ml of water with the
study dose, and 240 ml of water every 2 hours for 6 hours
post-dosing.
·
Patients must be adequately informed of possible
cardiovascular adverse effects in the consent form.
The following pharmacokinetic data
should be used for the evaluation of bioequivalence of the multiple
dose study:
·
Individual and mean blood drug concentration levels
·
Individual and mean trough levels (Cmin ss)
·
Individual and mean peak levels (Cmax ss)
·
Calculation of individual and mean steady-state AUCinterdose
(AUCinterdose is AUC during a dosing interval at
steady-state)
·
Individual and mean percent fluctuation [ =100 * (Cmax
ss – Cmin ss)/Caverage ss]
·
Individual and mean time to peak concentration
The log-transformed
AUC and Cmax data should be analyzed statistically using
analysis of variance. The 90% confidence interval for the ratio of
the geometric means of the pharmacokinetic parameters (AUC and Cmax)
should be within 80-125%. Fluctuation for the test product should
be evaluated for comparability with the fluctuation of the reference
product. The trough concentration data should also be analyzed
statistically to verify that steady-state was achieved prior to
Period 1 and Period 2 pharmacokinetic sampling.
Patient medical
histories, physical examination and laboratory reports, and all
incidents of possible adverse reactions should be reported.
Dissolution testing on 12 dosage units
of the test product versus 12 units of the reference product should
be conducted for all strengths. The lot used in the biostudy should
be used for dissolution testing as well. The United States
Pharmacopeia (USP) method is recommended for this product. Sampling
times of 15, 30, 45 and 60 minutes are recommended.
The percent of label
claim dissolved at each specified testing interval should be
reported for each individual dosage unit. The mean percent
dissolved, the range (highest, lowest) of dissolution, the
coefficient of variation (relative standard deviation), and
similarity comparisons of dissolution profiles (f2 calculations)
should be reported.
Content uniformity
testing on the test product lots should be performed as described in
the latest edition of the USP.
Waiver of in vivo bioequivalence study
requirements for the lower strengths of a generic product can be
granted if the following conditions are met:
1.
The in vivo study on the 100 mg tablet is acceptable.
2.
The strengths are proportionally similar in active and
inactive ingredients to the strength tested in vivo.
3.
All strengths meet an appropriate in vitro dissolution test.
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Date created: June 17, 2005 |