Memo:
Pharmacology/Toxicology Review
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
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 Births with Defects |
Findings |
Lovastatin Dose |
Prenatal Exposure |
|
Case 1 |
Malformations: musculoskeletal-upper extremity,
dentofacial & breast, dysmorphic features-ptosis, torticollis,
hemangioma, joint disorder |
unknown |
~2 weeks |
|
Case 2 |
Left hand tag,
non-functional thumb, holoprosencephaly, hydrocephalus |
40 mg |
~6 weeks |
|
Case 3 |
Aortic hypoplasia, atrial
& ventricular septal defect, 20 cerebral dysfunction,
mortality day 2 |
40 mg |
~5 weeks |
|
Case 4 |
Right auditory canal absent [concomittent meds: ethinyl
estradiol/ethynodial diacetate, pseudoephedrine, acetaminophen] |
unknown |
~8 weeks |
|
Case 5 |
5 year old: attention
deficit disorder, seizures, ataxia, abnormal fine motor movement |
unknown |
~ 8 weeks |
|
Data on elective
terminations |
|||
|
Case 1 |
Spina bifida, hydrocephalus |
20 mg |
3 -18 weeks |
The most common birth defects
in the
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: 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.
|
Selected Lovastatin
Reprotoxicity
Studies |
Route |
Doses (m/k/d) |
Maternal NOAEL (m/k/d) |
Exposure Multiple* |
Rat Fetal/Neonate Findings+ |
||||
|
Death |
Skeletal Malformations |
Develop-mental
Delays |
Decrease Weight |
External/ Visceral Malformations |
|||||
|
Segment I (Dosing 15
Days prior to mating through Gestation Day 20) |
|||||||||
|
1. |
Oral |
8,80,800 |
80 8 |
60X 6X |
√ |
√ |
√ |
√ |
√ |
|
2. |
Oral |
2,20,200 |
20 2 |
15X 2X |
√ |
|
|
√ |
|
|
3. |
Oral |
15,240 |
15 |
5X |
√ |
|
|
√ |
√ |
|
Segment II (Dosing
Gestation Day 6-20) |
|||||||||
|
4. |
Oral |
8,80,800 |
80 |
60X |
|
√ |
|
|
|
|
5. |
SC Oral |
12.5,25 400 |
≤25 |
<1X |
√ |
√ @12.5 incomplete ossification |
√ |
√ |
|
|
6. |
Oral |
100,200,400,800 |
100 |
75X |
|
√ |
|
√ |
|
|
7. |
Oral |
100,200,400,800 |
100 |
75X |
|
incomplete ossification |
|
√ |
|
|
Segment III (Dosing
Gestation Day 15-Lactation Day 21) |
|||||||||
|
8. |
Oral |
2,20,200 |
20 |
15X |
√ |
|
√ |
|
|
* OTC therapeutic dose=20 mg/day=AUC0-24h=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/m2
providing a 5X safety margin to the therapeutic dose of 20 mg/day=12 mg/m2). 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/m2 providing a 2X safety margin to the therapeutic dose of 20
mg/day=12 mg/m2) 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.