[Memo: Pharmacology/Toxicology Review]{.underline}

Pharmacology/Toxicology NDA 21-213

Mevacor Daily 20 mg/(OTC lovastatin)/Merck

**Introduction:** Merck is proposing to market Mevacor (lovastatin) 20
mg/day in an OTC setting as an adjunct to diet and exercise in
individuals with LDL 130-170 mg/dl and multiple risk factors for heart
disease. Mevacor OTC is proposed for men ≥45 years and post-menopausal
women ≥55 years. Mevacor was the first approved HMG-CoA reductase
inhibitor (statin) and has been marketed as a prescription-only drug
since 1987 to lower cholesterol. The weight of evidence from two decades
of animal reproductive/developmental toxicity studies demonstrates that
Mevacor has the potential to induce skeletal malformations and
developmental delays in the fetus/neonate irrespective of the presence
of maternal toxicity. This differs from Merck's current interpretation
of the nonclinical developmental studies and served as a basis for their
request for a change in pregnancy category designation in the Mevacor
label.

HMG-CoA reductase is the rate limiting enzyme in de novo cholesterol
biosynthesis which converts hydroxymethylglutaryl-CoA to mevalonic acid.
Lovastatin is a lactone pro-drug that is converted to the active open
acid form by plasma and tissue esterases. Merck proposes that fetal
skeletal malformations observed in rats given high doses of Mevacor
(≥400 mg/kg/day) are secondary to maternal toxicity produced early
during gestation and that this toxicity is pharmacologically based.
Therefore studies with co-administered mevalonate; the metabolic product
of HMG-CoA reductase were performed to eliminate the maternal toxicity
and hence prevent the fetal skeletal malformations observed with
Mevacor. Additional studies using subcutaneous instead of oral
administration of Mevacor prevented the maternal toxicity (forestomach
acanthosis, hyperkeratosis) and the skeletal anomalies according to the
sponsor. Merck proposes that any developmental delays observed in
post-natal rats was spurious and occurred at significant multiples of
clinical exposures and therefore are not a clinical concern. However
this conclusion is based on a limited post-natal neurodevelopmental
assessment following direct dosing of neonatal rats which inadequately
addressed the original concern for post-natal neurodevelopmental
abnormalities because of the limited scope of the study design.

The original nonclinical safety assessment of lovastatin included
developmental toxicity studies (fertility, embryo-fetal, and pre- and
postnatal development) in rat and rabbit with lovastatin and its active
metabolite (open acid form). Additional developmental studies were
performed following market approval in 1987 through 1999. In 1999 Merck
submitted NDA 21-213 for a 10 mg nonprescription form of lovastatin for
the treatment of elevated cholesterol for primary prevention of coronary
heart disease. Prescription Mevacor is labeled as Pregnancy Category X
as are all of the statins based on the findings in animals and the
established inhibitory effects on cholesterol synthesis by members of
this drug class. The Pregnancy Category X designation is equivalent to a
contraindication for use of a product during pregnancy based on studies
in animals or experience in humans demonstrating adverse fetal effects
whereby the fetal risk outweighs the benefit of drug exposure to the
mother. The battery of reproductive toxicity studies conducted for
lovastatin using standard study designs inadequately assess potential
drug effects on neuronal developmental processes that occur in the
post-natal rat (e.g. myelination) and during the second and third
trimester in humans. This contention was supported by the CDER PTCC
Reprotoxicity Committee and members of the Pharmacology/ Toxicology
Senior Leadership Team. Both groups recommended additional postnatal
neurodevelopmental studies to address this data gap based on findings in
the prior developmental studies and the potential clinical concern.

A neurodevelopmental toxicity study using direct dosing of neonatal rats
was recommended to include evaluations of exposure, establishment of a
NOEL (no observed effect level), and detailed brain histology and
behavioral/developmental/functional assessments. Merck submitted a dose
range finding study and definitive study protocols on 5/22/01. The
Division and the CDER PTCC Reprotoxicity Committee provided detailed
feedback on the protocol design in advice letters of 7/01, 5/02, 11/02
and 10/03. The final study reports were submitted for review 4/04.

**Nonclinical Safety Issue Relevant to Clinical Use**: Clinical data
obtained during pregnancy is very limited, but does exist. The numbers
of cases are too few to demonstrate any correlation; however the
pregnancy outcomes do not allay concern. An April 8, 2004 letter to NEJM
examining adverse event reports (AEs) in the FDA AERS database from
1987-2001 finds 5 cases associated with CNS and limb deficiency
anomalies from 52 cases of lovastatin exposure during pregnancy. These
abnormalities are exceedingly rare in the general population. In 2/5 of
these cases pregnant women were exposed to doses at or below the
proposed OTC dose of 20 mg/day.

The Office of Drug Safety (ODS) was consulted to update the pregnancy
outcome data from the FDA AERS database of *in utero* exposure to
statins; 25/195 cases were reported for lovastatin. These 25 cases
involved 9 elective terminations, 4 spontaneous terminations, 1 unknown
outcome and 11 live births. Among the live births 6 cases had normal
outcomes, 4 had birth defects and 1 had other complications as outlined
in the following table. Data were available on one of the elective
terminations.

+----------+--------------------------------+-----------+-------------+
| Live     | Findings                       | L         | Prenatal    |
| Births   |                                | ovastatin | Exposure    |
| with     |                                | Dose      |             |
| Defects  |                                |           |             |
+----------+--------------------------------+-----------+-------------+
| Case 1   | Malformations:                 | unknown   | \~2 weeks   |
|          | musculoskeletal-upper          |           |             |
|          | extremity, dentofacial &       |           |             |
|          | breast, dysmorphic             |           |             |
|          | features-ptosis, torticollis,  |           |             |
|          | hemangioma, joint disorder     |           |             |
+----------+--------------------------------+-----------+-------------+
| Case 2   | Left hand tag, non-functional  | 40 mg     | \~6 weeks   |
|          | thumb, holoprosencephaly,      |           |             |
|          | hydrocephalus                  |           |             |
+----------+--------------------------------+-----------+-------------+
| Case 3   | Aortic hypoplasia, atrial &    | 40 mg     | \~5 weeks   |
|          | ventricular septal defect,     |           |             |
|          | 2^0^ cerebral dysfunction,     |           |             |
|          | mortality day 2                |           |             |
+----------+--------------------------------+-----------+-------------+
| Case 4   | Right auditory canal absent    | unknown   | \~8 weeks   |
|          |                                |           |             |
|          | \[concomittent meds: ethinyl   |           |             |
|          | estradiol/ethynodial           |           |             |
|          | diacetate, pseudoephedrine,    |           |             |
|          | acetaminophen\]                |           |             |
+----------+--------------------------------+-----------+-------------+
| Case 5   | 5 year old: attention deficit  | unknown   | \~ 8 weeks  |
|          | disorder, seizures, ataxia,    |           |             |
|          | abnormal fine motor movement   |           |             |
+----------+--------------------------------+-----------+-------------+
| Data on  |                                |           |             |
| elective |                                |           |             |
| term     |                                |           |             |
| inations |                                |           |             |
+----------+--------------------------------+-----------+-------------+
| Case 1   | Spina bifida, hydrocephalus    | 20 mg     | 3 -18 weeks |
+----------+--------------------------------+-----------+-------------+

The most common birth defects in the US are cardiac and circulatory at
260.4/100,000 live births followed by musculoskeletal and connective
tissue defects at 239.4/100,000 live births (\~0.2%) according to the
National Vital Statistics System
\[http://www.cdc.gov/nchs/data/nvsr/nvsr49/nvsr49_01.pdf\]. The number
of reported exposures is small and the true rate of occurrence for the
reported defects is unknown because these reported cases were
spontaneous reports to the AERS database. A causal association between
*in utero* statin exposure and identified birth defects cannot be made
based on the current information. ODS suggests that latent effects such
as birth defects are best captured through a registry system which is
not available for statins.

**Nonclinical studies**: Animal reproductive toxicity studies are
designed to address the potential for adverse developmental (*in utero*)
risk. Standard reproductive study designs focus on *in utero* exposure
before/during conception (Segment I), organogenesis (Segment II) and
through lactation (Segment III). These studies are designed to assess
acute toxic effects with some sensitivity. However they are not designed
to evaluate subtle or long-term effects.

[Skeletal/Developmental Abnormalities:]{.underline} Merck contends that
reproductive studies performed 1980-1999 revealed skeletal anomalies in
rats at maternally toxic doses (≥400 mg/kg/day). The observed fetal
skeletal abnormalities are likely attributable to fetal nutritional
deficits due to reductions in maternal food intake and body weight,
secondary to acute maternal forestomach edema/inflammation leading to
acanthosis/hyperkeratosis with repeated oral dosing. The forestomach is
an organ specific to the rat and therefore this toxicity is not relevant
to humans. Although the cellular mechanism is unknown, Merck suggests
that marked up-regulation of the forestomach HMG-CoA reductase in the
modified squamous epithelium is possible. This has been demonstrated in
rodent hepatocytes following lovastatin treatment (PNAS 85:5264-5268,
1988; Fd Chem Toxic 29(9):621-628, 1991). Merck contends that the HMG
CoA reductase up-regulation resulting in forestomach histopathology in
the rat is reversible with mevalonate co-administration, substantiating
the pharmacologic basis of the lovastatin induced effect on the rodent
forestomach. However, maternal mortality during gestation is observed
with co-administration of mevalonate. It appears that the mortality is a
result of esophageal erosion/perforation which is usually indicative of
a gavage error; however, it is only the mevalonate treated dose groups
that have this finding which is reproduced in two separate studies.
There are fetal skeletal findings in the mevalonic acid co-administered
groups consistent with the other reprotoxicity studies with lovastatin
alone. Merck's basis for establishing that fetal skeletal anomalies are
the result of maternal toxicity follows: 1) Elimination of maternal
toxicity by alternate dosing regimens (e.g. SC to avoid forestomach
toxicity seen with oral administration) eliminates all fetal skeletal
abnormalities despite maintaining comparable or greater maternal and
fetal drug exposure levels; 2) The dose response for fetal skeletal
abnormalities is identical to that for incidence and severity of
maternal toxicity. This is consistent with a literature report that
dietary nutrient deficiencies in rats can produce vertebral, rib and
sternebral malformations; 3) Maternal, embryonic, and fetal exposures to
lovastatin during the critical period for osteogenesis (GD 15) do not
correlate with the presence of skeletal abnormalities; 4) Suppression of
fetal mevalonate concentration does not correlate with the presence of
skeletal abnormalities.

Based on the animal data reviewed over the past 20 years (1980-1999)
fetal toxicity including mortality, body weight decrements, skeletal
malformation and behavioral/learning delays in the absence of maternal
toxicity was observed at drug exposures comparable to the low
therapeutic dose range (10-20 mg/day). The Division's interpretation of
the reproductive toxicity findings with Mevacor differ from Merck.

<table>
<colgroup>
<col style="width: 18%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 6%" />
<col style="width: 13%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 13%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2"><p><strong>Selected Lovastatin</strong></p>
<p><strong>Reprotoxicity Studies</strong></p></td>
<td rowspan="2"><strong>Route</strong></td>
<td rowspan="2"><p><strong>Doses</strong></p>
<p><strong>(m/k/d)</strong></p></td>
<td rowspan="2"><p><strong>Maternal</strong></p>
<p><strong>NOAEL</strong></p>
<p><strong>(m/k/d)</strong></p></td>
<td rowspan="2"><p><strong>Exposure</strong></p>
<p><strong>Multiple*</strong></p></td>
<td colspan="5">Rat Fetal/Neonate Findings<sup>+</sup></td>
</tr>
<tr class="even">
<td><strong>Death</strong></td>
<td><p><strong>Skeletal</strong></p>
<p><strong>Malformations</strong></p></td>
<td><strong>Develop-mental Delays</strong></td>
<td><p><strong>Decrease</strong></p>
<p><strong>Weight</strong></p></td>
<td><p><strong>External/</strong></p>
<p><strong>Visceral</strong></p>
<p><strong>Malformations</strong></p></td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Segment I (Dosing 15 Days prior to mating
through Gestation Day 20)</strong></td>
</tr>
<tr class="even">
<td>1.</td>
<td>Oral</td>
<td>8,80,800</td>
<td><p>80</p>
<p>8</p></td>
<td><p>60X</p>
<p>6X</p></td>
<td>√</td>
<td>√</td>
<td>√</td>
<td>√</td>
<td>√</td>
</tr>
<tr class="odd">
<td>2.</td>
<td>Oral</td>
<td>2,20,200</td>
<td><p>20</p>
<p>2</p></td>
<td><p>15X</p>
<p>2X</p></td>
<td>√</td>
<td></td>
<td></td>
<td>√</td>
<td></td>
</tr>
<tr class="even">
<td>3.</td>
<td>Oral</td>
<td>15,240</td>
<td>15</td>
<td>5X</td>
<td>√</td>
<td></td>
<td></td>
<td>√</td>
<td>√</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Segment II (Dosing Gestation Day
6-20)</strong></td>
</tr>
<tr class="even">
<td>4.</td>
<td>Oral</td>
<td>8,80,800</td>
<td>80</td>
<td>60X</td>
<td></td>
<td>√</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>5.</td>
<td><p>SC</p>
<p>Oral</p></td>
<td><p>12.5,25</p>
<p>400</p></td>
<td>≤25</td>
<td>&lt;1X</td>
<td>√</td>
<td><p>√</p>
<p>@12.5 incomplete ossification</p></td>
<td>√</td>
<td>√</td>
<td></td>
</tr>
<tr class="even">
<td>6.</td>
<td>Oral</td>
<td>100,200,400,800</td>
<td>100</td>
<td>75X</td>
<td></td>
<td>√</td>
<td></td>
<td>√</td>
<td></td>
</tr>
<tr class="odd">
<td>7.</td>
<td>Oral</td>
<td>100,200,400,800</td>
<td>100</td>
<td>75X</td>
<td></td>
<td>incomplete ossification</td>
<td></td>
<td>√</td>
<td></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Segment III (Dosing Gestation Day 15-Lactation
Day 21)</strong></td>
</tr>
<tr class="odd">
<td>8.</td>
<td>Oral</td>
<td>2,20,200</td>
<td>20</td>
<td>15X</td>
<td>√</td>
<td></td>
<td>√</td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

\* OTC therapeutic dose=20 mg/day=AUC~0-24h~=30±15 ng h/ml ; + No
maternal toxicity defined as \>10% decrease in body weight gain or
forestomach toxicity

At ≤5 X therapeutic exposure following a 20 mg/day lovastatin dose,
fetal mortality, and decreased body weight is observed. At therapeutic
exposures ≥6X following a 20 mg/day dose neonatal developmental delays
are observed in free-fall righting reflex, negative geotaxis, auditory
startle response, swimming, and reduced latency in the open field test,
and incomplete skeletal ossification is seen. At higher exposures of
\>25X therapeutic exposure, skeletal malformations are observed
consisting of increased supernumerary ribs, incomplete bone
ossification, and wavy ribs. Animal studies have indicated that Mevacor
(lactone) crosses the placenta and is secreted in milk compared to
plasma (1:1.5). The cholesterol source in rat embryos is obtained from
the yolk sac or placenta (maternal source); de novo synthesis
contributes a minor portion of fetal cholesterol. Since lovastatin and
other hydrophobic HMG CoA reductase inhibitors can enter fetal
circulation there is still a clinical concern for fetal findings
following exposure during organogenesis. A rat maternal NOAEL=80
mg/kg/day (AUC=1900 ng h/ml on GD 20) is suggested based on the data
presented. Fetal/F1 pup mortality, decreased weight gain, skeletal
findings (wavy ribs) and incomplete ossification are observed
reproducibly in prior reprotoxicity studies in litters exposed to 2-80
mg/kg/day, but are unexplained. Developmental/behavioral effects showed
a similar pattern. This would suggest a rat developmental NOAEL\<2
mg/kg/day (less than clinical exposure at 20 mg/day based on body
surface area).

The majority of studies were performed in rat however similar effects
were seen in a limited number of studies in rabbits and mice. Rabbits
show a developmental NOAEL at ≤ 5 mg/kg/day (or 60 mg/m^2^ providing a
5X safety margin to the therapeutic dose of 20 mg/day=12 mg/m^2^). In
rabbit visceral abnormalities are seen at 15 mg/kg/day (15X exposure
following a 20 mg/day clinical dose) with higher doses of 25 mg/kg/day
being lethal in dams. Rat maternal drug transfer is 20-40% whereas in
rabbit it is only 2%.

Similarly, in an oral mouse Segment II study testing 8, 80, 800
mg/kg/day, maternal toxicity is not evident but skeletal malformations
are increased at 80 and 800 mg/kg/day by 6/24, 8/24 litters respectively
versus 4/24 control litters. Visceral variations in 3/24 litters given
800 mg/kg/day versus 1/24 control litters were observed. A mouse
developmental NOAEL= 8 mg/kg/day (or 24 mg/m^2^ providing a 2X safety
margin to the therapeutic dose of 20 mg/day=12 mg/m^2^) was established.

Studies of lovastatin co-administered with either mevalonic acid or
cholesterol appeared to attenuate the more severe fetal malformations,
however some fetal skeletal toxicity is observed (wavy ribs, incomplete
ossification etc.) despite the addition of mevalonate. This supports the
original conclusion that the fetal findings result from disruption of
cholesterol biosynthesis as an extension of the pharmacologic activity
of lovastatin. Merck concludes that fetotoxic effects at maternally
toxic doses of lovastatin are not a function of reduced cholesterol
biosynthesis (decreased fetal plasma mevalonate). Rather they conclude
that fetotoxicity at maternally toxic doses of Mevacor is a function of
reduced cholesterol biosynthesis in the forestomach. HMG-CoA reductase
required for mevalonate synthesis is tissue bound (endoplasmic
reticulum). Hence, tissue levels of mevalonate could be different than
plasma levels, as suggested by Merck's attribution of reduced rat
forestomach mevalonate as causative of maternal toxicity during
developmental studies.

  ----------------------- ----------------------- -----------------------
  Lovastatin              Plasma Mevalonate       
                          Levels (ng/ml)          

  Dose/Route (mg/kg/day)  Maternal                Fetal

  Oral 80                 10                      29

  Oral 400                11                      45

  SC 12.5                 8                       36

  SC 25                   11                      39
  ----------------------- ----------------------- -----------------------

Differences in the timing of developmental processes across species are
not generally addressed in interpretation of standard reproductive
toxicology studies. This becomes important in particular developmental
events. For example, myelination occurs in the rat during postnatal
weeks 2-4. The standard reprotoxicity test battery does not extensively
evaluate postnatal developmental processes, particularly neurological
maturation to any significant effect. The majority of myelination occurs
in humans during the second and third trimester. This implies that the
nonclinical animal studies with standard designs did not evaluate this
process at all. Furthermore, limited first trimester clinical exposure
would also not be relevant to address this potential risk. Therefore, a
limited postnatal neurodevelopmental assessment following direct dosing
in neonatal rats was recommended. The results of this study suggested a
NOAEL of 5 mg/kg/day (20X clinical exposure following a 20 mg/day dose
based on AUC) based on a delay in learning/short-term memory assessment
(passive avoidance test) at 10 mg/kg/day. The neurological evaluation
was minimal and standard general toxicology endpoints were not assessed
in the neonatal rat following direct dosing. The study represents the
only "new" data provided by Merck which still does not significantly
address the concern originally identified. Merck included a passive
avoidance test as the sole measure of cognitive function in the direct
dosed neonatal rat study. The Agency suggested on several occasions that
a more sensitive test of learning and memory in which a learning
acquisition curve can be demonstrated (e.g. complex water maze) was
preferred. The neonatal rat study was designed to evaluate acute toxic
effects on neurologic development, but does not assess delayed effects
of a developmental insult because in a neonate, organ structure is
already complete. In order to assess this, dosing would have to
encompass a longer period of exposure (e.g. *in utero* through weaning).

**Conclusion:** Extensive reproductive toxicology studies with
lovastatin performed from 1980-1999 using standard study designs
demonstrate consistent findings of fetal mortality, body weight
decrements, skeletal malformations, and behavioral/learning delays in
the absence of maternal toxicity. Merck suggests that the skeletal
malformations are a function of maternal forestomach toxicity. Based on
the well established effect of statins on cholesterol synthesis,
behavioral/learning delays in prior developmental studies and the
knowledge that major neurodevelopment occurs postnatal in the rat,
additional neurodevelopmental assessments of lovastatin were
recommended. A limited neurodevelopmental assessment following direct
dosing of neonatal rats was performed which suggests a no observed
adverse effect level (NOAEL) of 5 mg/kg/day (exposure 20X a clinical
dose of 20 mg/day based on AUC). This is based on a delay in a
learning/short-term memory assessment (passive avoidance test) at 10
mg/kg/day. This neonatal rat study was designed to evaluate an acute
developmental insult and is limited in the scope of its evaluation to
address the developmental concerns outlined. This neonatal rat study was
the only new information submitted in support of the proposed change in
pregnancy category and to address the potential fetal/neonatal clinical
concerns. Previous developmental studies have shown neonatal
developmental delays in reflexes; free-fall righting, negative geotaxis,
auditory startle in addition to delays in swimming and reduced latency
in the open field test at exposures at approximately ≥ 6X clinical
exposure following a 20 mg/day Mevacor dose. At higher exposures (\>25X)
skeletal malformations occur. Generally fetal mortality and decreased
body weight are observed at the proposed clinical exposure (≤5X clinical
exposure following 20 mg/day Mevacor). However some of these
developmental studies have shown these effects at exposures less than
clinical exposure following a 20 mg/day Mevacor dose. Therefore risk to
the fetus can not be excluded following clinical exposure and Mevacor
should remain contraindicated during pregnancy.

Abbreviations: NOAEL-no observed adverse effect level, GD-gestation day,
AUC-area under the curve, NOEL-no observed effect level, CHD-coronary
heart disease, NEJM-New England Journal of Medicine, SC-subcutaneous,
OTC-over the counter.