Cardiovascular and Renal Drugs Advisory Committee Meeting
The Cardio-Renal Advisory Committee is asked
to opine on the next steps in the Ranexa development program. Ranexa
(ranolazine) is under development for use as an anti-anginal agent. It is
unclear which of its pharmacological properties contribute to clinical
efficacy, but the Agency's review concluded that it is an effective antianginal
drug.
The letter (
1.
ICH E1 recommends that drugs intended
for chronic use have a safety database that includes at least 1500 individuals
treated with relevant doses and 100 patients treated for at least one year.
Greater exposure is recommended if there are specific concerns. The table below
summarizes the available data for ranolazine.
|
Form |
Dose |
Duration |
Patient |
|||
|
Any |
>30 d |
>90 d |
>365 d |
|||
|
IV |
Any |
77 |
(Not
available) |
1 |
||
|
IR |
Any |
1299 |
430 |
|||
|
400
TID |
518 |
¾ |
||||
|
SR |
Any |
1460 |
852 |
740 |
503 |
1285 |
|
³500 BID |
1359 |
852 |
740 |
503 |
1283 |
|
|
³1000 BID |
825 |
536 |
376 |
149 |
557 |
|
Evaluate
the following as factors influencing the need for additional safety data:
1.1.
Availability of other approved
antianginals.
1.2.
The nature of the efficacy demonstrated
to date (i.e., symptomatic effects in general population).
1.3.
Available safety data from short-term
studies of the IV formulation.
1.4.
Available safety data from short-term
studies using the immediate release formulation.
1.5.
Overall safety profile from the
available data with the sustained release formulation.
1.6.
Available data pertaining to cardiac
repolarization:
1.6.1.
Pre-clinical data, including absence of
after-depolarizations.
1.6.2.
Relationship between plasma
concentration and QT interval prolongation (e.g., steepness, ‘plateau’ of
effect).
1.6.3.
Drug-drug (ketoconazole, verapamil,
diltiazem), and drug-disease (hepatic impairment) interactions, including
effects not clearly mediated by metabolic inhibition, and combinations of
these.
1.6.4.
Lack of Torsade de Pointes in the
clinical database.
1.6.5.
Other cardiac adverse effects reported
in the database.
2.
Evaluate the following as factors
influencing the need for additional efficacy
data:
2.1.
Available data on effects of ranolazine
on rate-pressure product or maximum oxygen utilization.
2.2.
Available controlled experience with
the sustained release formulation in trials of duration greater than 1 week.
2.3.
Available information on the
dose-response relationship for exercise tolerance.
2.4.
Effects of ranolazine on hemodynamic
parameters (e.g., vital signs and rate-pressure product).
2.5.
The magnitude of the effect of
ranolazine on exercise tolerance.
2.6.
Accumulated data on the use of
ranolazine together with other antianginals.
2.7.
The effects of ranolazine on ‘hard’
clinical outcomes (e.g., death, MI).
3.
What additional data, if any, are
needed for ranolazine to obtain a claim for…
3.1.
…use in an unrestricted population with
angina?
3.2.
…use restricted, because of a concern
about effects on repolarization, to a 'resistant' population?
3.2.1.
If additional data are needed, what
would constitute 'resistant'?
· Patients
who remain symptomatic despite treatment with maximally tolerated or labeled
doses of one other antianginal.
· Patients
who remain symptomatic despite treatment with maximally tolerated or labeled
doses of more than one other
antianginal.
· Patients
with specific characteristics that would suggest they would not tolerate one or
more classes of antianginal drug (e.g., patients with low blood pressure, low
heart rate).
3.2.2.
Would further characterization of
dose-response be necessary in the target population?
4.
If further study of effectiveness is
needed, …
4.1.
…what range of doses should be studied?
4.2.
…what duration of controlled exposure
should be studied?
4.3.
…what considerations should be given to
demographics?