CLINICAL PHARMACOLOGY
Action
Clomiphene citrate tablets USP is a drug of considerable
pharmacologic and proper management of the patient, clomiphene
citrate tablets USP potency. With careful selection has
been demonstrated to be a useful therapy for the anovulatory
patient desiring pregnancy.
Clomiphene citrate is capable of interacting with estrogen-receptor-containing
tissues, including the hypothalamus, pituitary, ovary,
endometrium. vagina, and cervix it may compete with estrogen
for estrogen-receptor-binding sites and may delay replenishment
of intracellular estrogen receptors. Clomiphene crtrate
initiates a series of endocrine events culminating in
a preovulatory gonadotropin surge and subsequent follicular
rupture. The first endocrine event in response to a course
of clomiphene therapy, is an increase in the release of
pituitary gonadotropins. This initiates steroidogenesis
and folliculogenesis resulting in growth of the ovarian
follicle and an increase in the circulating level of estradiol.
Following ovulation, plasma progesterone and estradiol
rise and fall as they would in a normal ovulatory cycle.
Available data suggest that both the estrogenic and antiestrogenic
properties of clomiphene may participate in the initiation
of ovulation. The two clomiphene isomers have been found
to have mixed estrogenic and antrestrogenic effects, which
may vary from one species to another. Some data suggest
that zuclomiphene has greater estrogenic activity then
enclomrphene.
Clomiphene citrate has no apparent progestational, androgenic,
or antrandrogenic effects and does not appear to interfere
with pituitary-adrenal or pituitary-thyroid function.
Although there is no evidence of a carryover effect of
clomiphene citrate tablets USP, spontaneous ovulatory
menses have been noted in some patients after clomiphene
citrate tablets USP therapy.
Pharmacokinetics
Based on early studies with 14 C-labeled clomiphene citrate,
the drug was shown to be readily absorbed orally in humans
and excreted principally in the feces. Cumulative urinary
and fecal excretion of the 14C averaged about 50% of the
oral dose and 37% of an intravenous dose after 5 days.
Mean urinary excretion was approximately 8% with fecal
excretion of about 42 %.
Some 14C label was still present in the feces 6 weeks
after administration Subsequent single-dose studies in
normal volunteers showed that zuclomiphene (CIS) has a
longer half-life than enclomiphene (trans). Detectable
levels of zuclomiphene persisted for longer than a month
in these subjects. This may be suggestive of stereo-specific
enterohepatic recycling or sequestering of the zuclomiphene.
Thus, it is possible that some active drug may remain
in the body during early pregnancy in women who conceive
in the menstrual cycle during clomiphene citrate tablets
USP therapy.
CLINICAL STUDIES
During clinical investigations, 7578 patients received
clomiphene citrate tablets USP some of whom had impediments
to ovulation other than ovulatory dysfunction (see INDICATIONS
AND USAGE). In those clinical trials successful therapy
characterized by pregnancy occurred in approximately 30%
of these patients.
There were a total of 2635 pregnancies reported during
the clinical trial period. Of those pregnancies, information
on outcome was only available for 2369 of the cases. Table
1 summarizes the outcome of these cases.
Of the reported pregnancies, the incidence of multiple pregnancies
was 7.98% : 6.9% twin, 0.5% triplet, 0.3% quadruplet, and
0.1 % quintuplet. Of the 165 twin pregnancies for which
sufficient information was available, the ratio of monozygotic
to dizygotic twins was about 1:5. Table 1 reports the survival
rate of the live multiple births. A sextuplet birth was
reported after completion of original clinical studies:
none of the sextuplets survived (each weighed less than
400 g). although each appeared grossly normal.
Outcome of Reported Pregnancies in Clinical
Trials
(n = 2369)
|
|
Outcome
|
Total Number
of Pregnancies
|
Survival
Rate
|
| Pregnancy
Wastage |
| Spontaneous
Abortions |
483-
|
|
| Stillbirths
|
23
|
|
| Live
Births |
| Single
Births |
1697
|
98.16%
|
| Multiple
Births |
165
|
83.26%+
|
-
Includes 28 ectopic pregnancies, 4 hydatiform moles
and 1 fetus papyraceous.
+ Indicates percentage of surviving infants
from these pregnancies.
|
The overall survival of infants from multiple pregnancies
including spontaneous abortions, stillbirths, and neonatal
deaths is 73%.
|
|
