![](media/image1.png){width="1.14375in" height="1.14375in"}

Douglas C. Throckmorton, M.D.

Division of Cardio-Renal Drug Products, HFD-110

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

Tel (301) 594-5365, FAX (301) 594-5494

**Divisional Memorandum**

**[Date]{.smallcaps}:** 10.28.03

**[From]{.smallcaps}:** Douglas C. Throckmorton, M.D., Director

Division of Cardio-Renal Drug Products (DCRDP), HFD-110

**[Subject]{.smallcaps}:** NDA 21-526

**[Name of Drug]{.smallcaps}:** Ranolazine

**[Sponsor]{.smallcaps}:** CV Therapeutics

[**Documents Used For Memo**:]{.smallcaps}

1.  NDA submissions to 21-526, including letter to Robert Temple dated
    10.20.03

2.  Medical/Statistical Efficacy Review, by Shari Targum, M.D. and
    Valeria Friedlin, Ph.D., dated 8.28.03.

3.  Medical Safety Review, by Maryann Gordon, M.D., dated 7.31.03.

4.  Supervisory Medical Officer Review, by Norman Stockbridge, M.D.,
    Ph.D., dated 9.29.03

5.  Reports of bioequivalence study audits, by Nilufer M. Tampal, Ph.D.,
    dated 8.5.03 and C.T. Viswanathan, Ph.D., dated 4.1.03.

6.  Clinical study inspection report, by Robert Shibuya, dated 8.21.03.

7.  Pharmacology/Toxicology Review by Elizabeth Hausner, Ph.D., dated
    9.2.03.

8.  Clinical Pharmaceutics and Biopharmaceutics review, by Nhi Nguyen,
    Ph.D., Atul Bhattaram, Ph.D., and Peter Hinderling, Ph.D., dated
    8.18.03.

9.  Chemistry Reviews, by N. Chidambaram, Ph.D., dated 9.16.03 and
    10.10.03.

10. Carcinogenicity report to the Carcinogenicity Assessment Committee
    (CAC), by Elizabeth Hausner, Ph.D., dated1.31.02.

11. Executive CAC meeting summary, by Joseph Contrera, Ph.D. (for the
    Exec CAC), dated 1.29.02.

12. Memoranda on non-clinical electrophysiological and proarrhythmic
    effects of ranolazine, by John Koerner, Ph.D., dated 9.4.03, and
    10.23.03.

13. Debarment Certification, dated 12.19.02.

# Conclusions

This memorandum constitutes the Divisional memorandum recommendation
that an approvable action be taken for the NDA named above for
ranolazine in the treatment of angina. As summarized below, ranolazine
SR, while efficacious as an antianginal in an undifferentiated
population of patients, including patients receiving sub-maximal
treatment with other antianginals, has sufficient safety concerns to
warrant additional studies prior to approval. The safety concerns are
two-fold:

1)  Delayed cardiac repolarization, manifest by prolongation of the QT
    interval. For reasons discussed below, the available data are not
    reassuring as to ranolazine's arrhythmic potential.

2)  Potential testicular toxicity, manifest as impaired fertility in
    rats. As discussed below, the data are inadequate to determine
    finally whether or not ranolazine has this effect. While no clinical
    signs of toxicity were reported, this is not surprising, and
    additional animal data are needed to characterize the effect of
    ranolazine on the testicle.

Regarding the consequences of the effects of ranolazine on cardiac
repolarization, the most straightforward way to alleviate these concerns
is to provide compelling data supporting novel therapeutic efficacy of
ranolazine (*e.g.*, demonstrating efficacy in a resistant population).
The sponsor has argued that they have identified such populations in
post-hoc analyses of their database, and sufficiently demonstrated
efficacy of ranolazine in that setting. As discussed below, neither the
reviewers nor I am not at all convinced. Alternatively, the sponsor can
argue that these issues do not represent safety concerns. Again, the
attempts to convince the Division that the effects of ranolazine on QT
are not concerning. The arguments, including those based on non-clinical
work by Dr. Antzelovitch, are discussed extensively in the reviews (in
particular, see Dr. Koerner's review). Overall, they are not compelling.
In the end, for a drug like ranolazine, the available efficacy data are
modest at best, and are simply insufficient to bear any significant
safety concerns.

The drug has other issues to be resolved. They do not rise to the same
level as the safety concerns identified above:

1)  There is evidence suggesting a decreased/absent effect of ranolazine
    in women, an effect not related to differences in pharmacokinetics
    of the parent compound. This needs to be addressed in future studies
    or the drug should be clearly labeled to reflect this potential lack
    of efficacy (as the label will necessarily reflect the absence of
    data on non-White populations).

2)  The dissolution testing for release needs to be adjusted per the
    recommendations of the Clinical Pharmacology team review.

# Background and Overview

This submission includes over 200 clinical studies along with numerous
non-clinical studies, stretching back to the early 70s. Much of the
clinical data are of minimal use as regards efficacy of the current
sustained-release formulation, and much of the animal work was done
using a lower standard of quality than is now in place.

# Chemistry

The Chemistry Reviewer, Dr. Chidambaram, identified no deficiencies in
the NDA submission for either the drug substance or product. Ranolazine
has one chiral center, but is synthesized as a racemate (see his Review
#1 for details). The drug product is an extended release product,
achieved by placing the ranolazine in a pH-dependent polymer (dissolves
at pH \>5). The reviewer also identified no deficiencies in any of the
associated Drug Master Files (page 7 of review #2). The categorical
exclusion for the environmental assessment was submitted and found
acceptable.

As regards shelf life, the reviewer recommends the addition of a retest
date of 18 months for the drug substance and an expiration date of 18
months for the drug product, based on the stability data provided.

###### Good Lab Practices Site Reviews

The clinical and analytical portions of study CVT 301-15 (a
bioequivalence study) were inspected. While a number of deficiencies
were identified, none appear critical to the interpretation of the
study.

# Pre-clinical Pharmacology Toxicology

The multitude of non-clinical studies have been reviewed primary by
Elizabeth Hausner, Ph.D., along with some additional review of the 'QT'
studies of ion channel activities by John Koerner, Ph.D.

######## Pharmacology: Receptor/Channel Effects

Ranolazine and its metabolites interact *in vitro* with a number of
receptors and channels, including several relevant for cardiac function:

-   Adrenergic receptors (especially alpha 1A, 1B and 2A)

-   Serotonin receptor (5-HT1A)

-   Calcium channels (both dihydropyridine and benzothiazepine types)

-   Potassium channels and other channels affecting cardiac
    repolarization. John Koerner commented on the system used to assess
    this (in particular the HERG expressed in oocytes), and its
    deficiencies, such that the standard discussion of IC~50~ values is
    not relevant here (see his first memo, page 2). Suffice to say that
    inhibition of IKr was easily demonstrated at micromolar
    concentrations. Several of the metabolites also inhibit IKr, but the
    studies were done only at a single concentration. The effects of
    ranolazine on other relevant channels (*e.g.*, IKs, I~Na~) have been
    the source of significant discussion by Dr. Koerner (his second memo
    deals with this issue heavily). I take from his memos that the
    results are less clear than the sponsor asserts, and as a result
    less reassuring than they wish. As regards action potential
    duration, the sponsor looked at the effects of ranolazine in a
    number of repolarization and arrhythmia models (see Dr. Koerner's
    and Dr. Hausner's reviews for a discussion of their adequacy). Of
    particular interest, ranolazine prolongs the action potential
    duration in the M-cell region under conditions of hypokalemia. This
    is of some concern, as failure to prolong the APD in this region has
    been proposed as a putative marker for a drug that prolongs the QT
    'safely'. The negative findings from the *in vivo* dog studies are
    of limited use for a variety of methodological reasons (see Dr.
    Koerner's first memo, pages 5-7).

-   Miscellaneous other receptor binding: There is also evidence of
    binding to the opioid receptors (with 30% inhibitory concentrations
    of around 100 micromolar), although the significance of this binding
    is not known.

######## Pharmacology: Mechanism of Action

Simply put, any discussion of the mechanism of action is speculative, as
was pointed out by several reviewers. First, as suggested from the
receptor binding data above, ranolazine has a variety of effects on more
standard vascular targets for an antianginal (*e.g.*, calcium channels)
that could easily be linked to antianginal efficacy. There are other,
more speculative, effects that the sponsor has chosen to emphasize when
describing the effects of ranolazine. First, ranolazine does stimulate
an increase in free fatty acid (FFA) and glucose uptake by the
myocardium in disease models (*e.g.*, see CFT303.035-P in dogs with CHF,
page 17 of Dr. Hausner's review). It also appears to decrease lactate
efflux from ischemic myocardium and to protect against
ischemia-reperfusion injury in a number of models, although no positive
controls were included in the studies to provide a comparator for the
relevance of the observed effects). Ranolazine inhibits fatty acid
metabolism in several cardiac injury models (see pages 33-40 of Dr.
Hausner's review for details).

######## Metabolism and Excretion

The metabolism of ranolazine is complex, and species-specific. The
primary Clinical Pharmacology reviewer, Dr. Nguyen concluded that the
primary route of elimination was via CYP 3A4, with a smaller fraction
metabolized by CYP 2D6 (see her page 13). It is also a
substrate/inhibitor of P-glycoprotein, explaining the interaction with
digoxin and 'statins'.

The primary route of excretion for ranolazine is non-renal, with around
3% of an IV dose recovered unchanged in the urine and around 75% of
radioactivity recovered in the feces.

######## Protein Binding

In a single study using human blood from 3 volunteers, 60-64% of
radioactivity was bound to human plasma. Albumin binding was reported as
30% of the radioactivity. There is no evidence that the drug sequesters
in RBCs (see Dr. Hausner's review, page 108).

######## General Toxicology

Many of the toxicology studies had a number of methodological flaws
discussed by the reviewer, in part because they were conducted \>10
years ago at a time when standardization of these studies was less.

Toxicities seen following short-term high doses included sedation,
convulsions and ataxia. It is interesting that acute mortality (within
minutes of drug administration) occurred in both rodent and non-rodent
studies (for instance, see Dr. Hausner's review page 118). This
mortality was associated with convulsions.

Toxicities following chronic administration included convulsions in the
high-dose animals, vomiting, ataxia, subdued behavior and ophthalmic
changes (pupils dilated, pupils non-responsive to light, conjunctival
congestion), with no toxicities in the 3-month toxicity study at 5 mg/kg
dose in dogs. Histopathological findings have not been presented in
clear fashion by the sponsor, despite efforts by Dr. Hausner to obtain
clarification, and apparently not collected from all animals, although
the sponsor asserts there were no compound-related lesions seen in the
high-dose animals.

In the one-year toxicology studies the findings included the ataxia and
subdued behavior seen in the shorter studies (seen at ≥50 mg/kg dose for
rats). There were slight decreases in hemoglobin and slight increases in
reticulocytes counts and LDH, consistent with a hemolytic process seen
in the high-dose groups (200 mg/kg/day in rats).

[Special Toxicology (Cardiac, Adrenal)]{.underline}

#### *Cardiac: Toxicology and ECG Interval Effects of Ranolazine*

No effect on heart rate was seen in a 3-month study in dogs with doses
up to 60 mg/kg/day (see Dr. Hausner's review page 128). Other ECG
parameters are discussed above and by Dr. Koerner and Hausner in their
reviews. No clear signal of concern regarding changes in the QT interval
can be found in the standard cardiac evaluations of the animals, but
methodological flaws prevent this from being reassuring. No arrhythmias
were captured during the standard toxicology studies.

#### *Cardiac: Channel Effects of Ranolazine*

Dr. Koerner's reviews are thorough-going and critical with regard to the
assertion by the sponsor that they have demonstrated that ranolazine is
a 'safe' QT prolonger (see the letter to Dr. Temple dated 10.20.03). To
summarize: the sponsor asserts that the effects of ranolazine on QT are
'fundamentally different from that of drugs known to cause torsade de
pointes, and similar to that of drugs known to increase the QTc without
causing torsades de pointes.' They believe the drug has different
effects on the 'M-cells' of the myocardium, effects that predict a lack
of arrhythmic potential. The M-cell data is derived from work done by
Dr. Antzelevitch with his 'wedge-prep'. In this preparation, an increase
in the transmural dispersion of repolarization is the critical parameter
to be examined (dispersion is associated with an increased arrhythmic
potential in the model). John has made a strong case, I believe, that
even if we accept this argument (it has not been validated either
prospectively or by looking at a large battery of compounds carefully)
ranolazine still causes dispersion under conditions of hypokalemia. The
sponsor has also made a case for effects of ranolazine at multiple
channels, including some that would presumably decrease the arrhythmic
potential (*e.g.*, late sodium current). John is also critical of this
assertion, based on the way the studies in question were conducted, and
the reader is referred to his memoranda for detail.

#### *Other Organ-Specific Toxicities of Ranolazine*

One organ-specific effect of note is an increase in adrenal weight and
vacuolization. While small changes in serum sodium were reported
sporadically in the toxicology studies, no evidence of metabolic effects
of this increased weight was seen in the animal studies. A special study
(see Dr. Hausner's review page 168) suggests an effect of ranolazine to
reduce adrenal hormone production in animals; the clinical consequences
of this are unknown.

A second 'organ-specific' effect of ranolazine comes from the
observation that ranolazine binds to melanin, potentially leading to
accumulation in the retina and in the skin. Again, the clinical
consequences of this binding are unknown, although no
[gross]{.underline} ocular lesions were noted in the animal toxicity
studies.

######## Genetic Toxicology, Carcinogeniticy, Reproductive Toxicity

As reviewed, ranolazine is neither mutagenic nor genotoxic. The *in
vivo* mouse micronuclease assay did not meet the standards for testing
today, and the reviewed concluded the results were 'equivocal', based on
this failing.

With regard to carcinogenicity, the CAC reviewed the two carcinogenicity
studies (rat and mouse) and concluded that 'there were no noteworthy
findings'.

With regard to reproductive toxicology, Dr. Hausner has expressed
concerns regarding the effects of ranolazine on male fertility from the
rat studies (begins on page 187 of her review). Her concerns have also
been addressed by Dr. DeFelice in his secondary review. The following is
an attempt to summarize:

1)  Male reproductive toxicity---there appears to be an effect of high
    doses to decrease male fertility, as measured by decreased
    percentage of successful matings in one study. In the rat fertility
    study, three males in the high-dose group were identified as having
    atrophic testes, thus contributing to the overall decreased
    fertility in that group. This may be related to a direct testicular
    effect or it may be a chance event that these males were all
    apparently in the high-dose group; here the data are not clear. As
    summarized by Dr. DeFelice, no evidence of histopathological effects
    was reported in the long-term rat and dog toxicity studies, but
    whether 'no change' was positively asserted, or simply nothing
    reported needs confirmed. Dr. Hausner has tried to clarify this
    without success with the sponsor. In his review, he believes a
    conservative estimate for the observed testicular toxicity seen in
    rats was at a dose that is 2X the clinical dose, not a reassuring
    multiple (but higher than the 0.03X multiple proposed by Dr.
    Hausner). In the end, I don't think we know enough about this to
    make a final conclusion. What is needed, as a start, is an
    evaluation of the long-term toxicity studies in rats and dogs.

2)  Female reproductive toxicity---no evidence for that was seen by
    either reviewer.

3)  Teratogenicity/ Developmental toxicity---Regarding teratogenicity,
    there was a nominal increase in the incidence of osseous
    malformations in rats exposed to ranolazine, but Dr. DeFelice did
    not view this as evidence for a teratogenic effect; rather, he felt
    it to be a commonly-observed finding in the population, irrespective
    of drug exposure. He otherwise saw no evidence for teratogenic
    effects in the data. Regarding development toxicities, there was
    some delay in development for rats exposed to ranolazine, although
    they 'caught up' by the end of the finals assessment. There was also
    a small decrease in rat newborn survival (around 100 to around 95%
    survival). Dr. DeFelice did not view the small decreases as a signal
    of concern. I do not see this as an approvability issue.

In the end, we don't have enough information to interpret the impaired
fertility seen in the high-dose rats. In particular, absent histological
data from the long-term toxicity studies, we don't know if the
testicular effects were drug-induced or 'spontaneous'. A resolution of
this deficiency will require, at a minimum, re-reading of the relevant
tissue slices from the chronic tox studies conducted in rats and dogs.
If this is not possible, additional studies are warranted. Should an
animal toxicity be identified it will be important to characterize the
clinical consequences of this animal toxicity.

# Clinical Pharmacology and biopharmaceutics

The clinical pharmacology of ranolazine has been reviewed by a number of
the Clinical Pharmacologists, including Dr. Peter Hinderling, Dr. B. Nhi
Nguyen, Dr. Atul Bhattaram, and Dr. Joga Gobburu. Their combined review
is a rich source of information; my summary should serve mainly to send
the reader to that document. In addition, the modeling conducted by the
group provides important additional information on the interactions of
ranolazine with relevant demographics, drugs and disease states with
regard to QT interval prolongation (begins on page 372 of the review).
Some salient points from their reviews:

1\) Ranolazine is well-absorbed, and there is no food effect.

2\) The PK of ranolazine is not linear and not dose-proportional, but
the increases in Cmax and AUC are not large (17 and 34% respectively).
The terminal half-life is between 6 and 9 hours for the SR formulation.

3\) While ranolazine is a racemate, the kinetics of the two forms are
similar.

4\) Ranolazine has a wide intersubject variability with regard to PK (CV
38-76%).

5\) Ranolazine is metabolized via CYP 3A4 and 2D6, along with sulfatases
and glucuronidases. The anticipated drug-drug interactions have been
studied and confirmed (summarized on page 14 of the Clin Pharm review).
It is a substrate/inhibitor of the P-glycoprotein transporter. It
appears to be an inhibitor of 2D6, but at the concentrations likely to
be achieved is not an inhibitor of 3A4 (see Clin Pharm review, page
102-3). The anticipated effects on QT interval related to concentration
of ranolazine were seen for inhibitors of CYP 3A4; less is known for
poor metabolizers related to 2D6.

6\) The pharmacokinetics of ranolazine change with either hepatic or
renal impairment, with increases in both Cmax and AUC in both
populations increasing with increased severity of disease. The
anticipated consequences of increased concentrations on QT were seen
with renal impairment. There was an unanticipated (by me, anyway)
interaction with liver impairment such that a given concentration caused
a larger than anticipated prolongation of QT (see below).

7\) There is a demonstrated relationship between ranolazine
concentration and effect on exercise, and the Agency derived a PK-PD
model for effect on exercise (not done by the sponsor). The Clinical
Pharmacologists concluded the relationship was non-linear relationship,
and the reviewers postulated that minor active metabolites might account
for this observation. The non-linear nature of the relationship appears
to have little consequence as to dosing. The model did not predict a
plateau with regard to efficacy at higher concentrations. The reviewers
also noted that gender was a significant cofactor in the model,
reflecting the decreased effect of ranolazine in women (see Clinical
section below). Their model also predicts an optimal 8-hour interdosing
interval (see page 29 of the review for summary).

###### Biopharmaceutics

Bioequivalence of the to-be-marketed formulation and the clinical
formulation were demonstrated. A biowaiver for lower strengths was
approved given the dose-proportionality and comparable dissolution
testing of the 375 and 500 mg SR strengths. The Divisions has
recommendations about the appropriate dissolution testing to be done for
release (see review page 7 of the Clin Pharm review); these should be
transmitted to the sponsor.

# Medical/Statistical Review

##### [Clinical Audits]{.underline}

Two sites were chosen for auditing because they were high enrollers in a
pivotal trial. No issues were found on either inspection of substance,
and the data, per Dr. Shibuya, 'appear acceptable.' No follow-up actions
were recommended.

##### Efficacy

The reader is referred to the primary reviews for source material. Dr.
Targum has correctly focused her attentions on the two trials conducted
with the SR formulation of ranolazine (studies CVT 3031 and 3033). Both
trials found a significant, if not overwhelming, effect on exercise
tolerance testing (ETT) (see Dr. Targum's review, tables 5 and 6).
Supportive analyses confirming the antianginal effect of ranolazine were
effect seen on time to 1mm ST-segment depression (both studies), the use
of nitrates (reduced with ranolazine in the one studied where it was
measured, CVT 3033) and a reduction in the number of anginal episodes
(from around 3.3 episodes to something around 2.2 episodes in study
3033). The trough effect was noticeably smaller than the peak effect
(for instance, see table 6 from Dr. Targum's review). Some salient
points from her review:

1)  While antianginal efficacy was demonstrated adequately in two
    trials, the dose-response curve for efficacy is quite obscure, with
    little overall difference demonstrated for doses between 750 and
    1500 BID. In study 3033, the doses of 750 and 1000 mg BID were not
    distinguishable from each other (her table, page 28). In study 3031,
    doses of 1000 and 1500 BID were not distinguishable from each other
    (her table, page 44).

2)  As regards the interdosing interval, one trial clearly demonstrated
    antianginal efficacy at trough for the drug given BID. On this
    basis, the reviewer suggested the most appropriate dosing schedule
    remains to be determined. This was based primarily on her conclusion
    that there was a significant 'by period' interaction in the CVT 3031
    trial, which was cross-over in design. When only the first period
    was examined, the trough results were no longer significant (see her
    discussion starting on page 44 of her review). The sponsor contests
    this, but the pharmacokinetics suggest that a more frequent dosing
    regimen could improve the overall efficacy. The clinical evidence is
    less clear-cut (Dr. Stockbridge concluded that a BID regimen was
    defensible, given the \>50% retention of antianginal efficacy at
    trough, see his review, page 4).

3)  There was evidence for persistence of antianginal efficacy, and no
    evidence for rebound angina through 12 weeks (see trial CVT 3033,
    which included a withdrawal period of 48 hours followed by an ETT).
    There is the suggestion in the one trial of significant
    length (3033) of reduced efficacy at weeks 6 and 12, compared with 2
    weeks (her table 6, page 28).

4)  Ranolazine has very small effects on blood pressure and heart rate
    (see table 17-18, and pages 37-38 in Dr. Targum's review).

5)  Ranolazine appears to work on a background of other approved
    antianginals at less than maximal doses. Dr. Targum was not
    convinced that the sponsor had identified a population on
    maximally-tolerated or labeled doses of antianginals, or that they
    had demonstrated efficacy in such a population or populations (see
    her discussion beginning on page 16 of her review).

6)  Like the Clinical Pharmacologists, she concluded that females
    benefited significantly less from ranolazine than men. This is seen
    vividly in the data from CVT 3033 (table 15).

[Sub-Group Analyses of Efficacy]{.underline}

Dr. Targum and Stockbridge have written of the difficulties in sub-set
analyses in this database, derived first and foremost from the marginal
nature of the demonstration of efficacy; any splitting of the overall
population will leave you with small sub-groups and uncertain power to
see anything by noise. For some subsets (non-White) there are simply too
few individuals to even try to look (a thing not to be lost in any
future labeling). For other subsets, women and patients with CHF, there
is some evidence for reduced efficacy that bears a bit more examination.
Dr. Targum has summarized the primary findings from the 3033 study by
gender and presence of CHF on page 31 of her review (table 11). The
decrease in change in exercise tolerance is especially striking for
women, and to a lesser degree for CHF. The Clinical Pharmacology
reviewer, Dr. Hinderling, agreed that there was evidence of decreased
efficacy in women, an effect not attributed to differences in kinetics
(see his comments, page 38 of the Clin Pharm review). The sponsor should
be asked to describe this effect more fully, or be prepared to label the
drug as less efficacious (for a given dose/concentration) in women. The
population with CHF seems less clear, and I would remain silent on it
given the uncertainty of subset analyses.

**Safety**

###### Overall Safety

Dr. Gordon has reviewed the overall safety database, and no alarming
signals for rare (*e.g.*, liver injury) or unanticipated adverse effects
of ranolazine emerge. A number of constitutional adverse events seem
demonstrably higher in the ranolazine group (*e.g.*, see her table on
page 17 from the controlled angina trials---dizziness, constipation,
nausea, asthenia). The majority of these are monitor able (which
provides some reassurance) and they also appear dose-related (which
might limit dose-exposure in some patients---reassuring?). The overall
size of the safety database is small for angina, although the data from
the immediate release experience helps some for lower doses than would
be used here. It's worth noting that only one of the angina trials
exposed subjects to a given dose of drug for more than a week.

###### Effects on QT/QTc

The clinical effects of ranolazine on the QT have summarized by several
other reviewers, most concisely by Dr. Stockbridge. Dr. Bhattaram has
also performed elegant modeling of the available data (begins on page
375 of the Clinical Pharmacology review). Some salient points to make:

1\) That ranolazine prolongs the QT interval is accepted by all parties.
At 1500 mg BID (less than 2X upper dose proposed by the sponsor of 1000
BID), the prolongation is around 12 msec in the overall population. At
this dose, 7.5% of the individuals had QT \>500 msec[^1]. Keeping the
dose below 1000 mg BID would limit the QTc prolongation to somewhat less
than 10 msec, but large inter-subject variability in pharmacokinetics
and drug metabolism will still have individual with larger effects
(suggested by the percentage of outliers).

2\) That ranolazine has a more dramatic effect on the QT interval in
patients with hepatic impairment is accepted by all parties (see table
below). Of interest, the modeling conducted by the sponsor suggests the
relationship between concentration and effect on QT is non-linear(Clin
Pharm review, page 405), although no rationale for this difference from
the findings in patients without hepatic impairment is forwarded
(although Dr. Stockbridge questions whether a non-linear relationship
might not be appropriate for all populations).

QTc Prolongation Following Ranolazine^2^

  ------------------------------------ ----------------------------------
                                       **Change in QT**

  **Population excluding hepatic       2.56 msec per 1000 ng/ml
  impaired**                           ranolazine^1^

  **Hepatic impairment population**    7.10 msec per 1000 ng/ml
                                       ranolazine^1^
  ------------------------------------ ----------------------------------

> 1\. Serum concentration. For reference, the typical doses of
> ranolazine achieve concentrations \<10,000 ng/ml.
>
> 2\. From Clin Pharm review, page 382.

This observed difference in the concentration-effect relationship for QT
prolongation is as dramatic as any I am aware of (we have little data in
this regard, however).

3\) Inhibitors of CYP3A4 increase blood levels by around 2-fold, with
their associated expected effect on QTc interval.

4\) Other ECG markers of uncertain concern include an increase in the
frequency of 'notched' T-waves. At very high levels of ranolazine
(10,000 ng/ml) their frequency was 75% (see Dr. Gordon's review, page
37).

5)  Clinical signs of arrhythmias have apparently not been
    systematically summarized in other reviews.

    a.  Deaths: in a total exposure of 2682 patients there were 29
        deaths on ranolazine through 10.15.01, of which 13 were
        described by the reviewer as 'sudden' (no definition available
        to me, Dr. Gordon's table page 18). This fraction (45%), with
        all its uncertainties, is somewhat higher than other drugs that
        have been approved and do not appear to cause torsade de pointes
        (TdP) (range 0-20%, n=3) and in the range for surveyed drugs
        that cause TdP (30-55%, n=4). However, of the four deaths in
        patients exposed to placebo (all short duration exposure), two
        were defined as 'sudden'. I believe we have too few deaths to
        draw any meaningful reassurance and too little information about
        most of them to draw any meaningful concerns from such analyses.

    b.  Clinical Adverse Events: there were no cases of TdP reported by
        the sponsor. Discontinuations due to dizziness occurred more
        frequently in patients taking ranolazine (1.0% vs. 0.1% in
        placebo, see Dr. Gordon's table 25R). Palpitations and dizziness
        were also reported as adverse events more frequently in the
        ranolazine group in the integrated safety population (2.4% vs
        1.0% and 13.2% vs. 2.9% respectively, Dr. Gordon\'s page 16,
        table 12). Syncope was reported only in patients on the two
        highest doses of ranolazine (see her table page 18).

In the end, this is not a reassuring database. Despite the small
numbers, the clinical events clearly raise some concern, especially for
a drug that does [not]{.underline} decrease heart rate or blood pressure
appreciably (removing other, usual reasons for these events). While
there could be other reasons for each and every one of these clinical
observations, these findings, coupled with the presence of
sub-populations like the hepatically-impaired where ranolazine has much
larger effects on the QT, leads me to conclude that this is a safety
concern that needs to be addressed with a larger safety database (size
undetermined) or offset by substantive evidence of meaningful efficacy
(discussed below).

# Summary

That ranolazine is effective as an antianginal in an undifferentiated
population with angina is not an issue, although the efficacy data for
trough dosing using a BID regimen are not overwhelming and it is unclear
precisely what doses of ranolazine to recommend for use (certainly no
rationale for recommending anything above 1000 mg BID, maybe even 750 mg
BID). The efficacy data also rest on a single trial lasting more than
one week of exposure, a small database, particularly given the
uncertainty about how to dose ranolazine and the suggestion of reduced
efficacy in women. Study 3033 did look at a variety of parameters linked
to antianginal efficacy, and all tell a similar story of modest efficacy
in the population studied. These effects on the symptoms of angina are,
however, insufficient to offset the identified safety concerns (which
include potential testicular toxicity and demonstrated QT prolongation).
The available data, both non-clinical and clinical, do not provide
comfort as to the proarrhythmic risk of this compound. On the contrary,
given the absence of significant hemodynamic effects, the observed
increases in the incidence of dizziness and palpitations give one pause,
even if these adverse events are typically very difficult to interpret.

Given the symptomatic nature of the efficacy claim, and the availability
of other antianginals that lack these issues, additional data are needed
to offset or alleviate the identified safety concerns. As for the
potential testicular toxicity, additional evaluation of currently
available data may well suffice to resolve the issue. As for the QT
effects, the most direct way forward would be to demonstrate a benefit
for ranolazine not shared by other agents (*e.g.*, efficacy in
prospectively-define resistant populations, benefits on more durable
clinical endpoints). The collection of such data would provide an
additional trial to collect more information on the dosing of
ranolazine, and additional safety exposure as well. Given the
availability of other therapies, there is no attraction to considering
these studies as Phase IV commitments.

[^1]: See Dr. Gordon's review, page 55, table 39R. The sponsor disputes
    this figure based on the selection of a single lead rather than any
    lead.