My best friend sent this info to me. She's working on a doctorate in pharmacy and has access to great information. So I thought I'd pass it on to you gals. Enjoy! (I did 3 cycles of clomid only to find out that the whole problem was with DH, obgyn misread his results and put me on clomid) Anyway, since then we're adopting 2 great little boys, signing papers soon


CLOMIPHENE CITRATE
Common Tradenames (See Complete Tradename Listing)
CLOMID
SEROPHENE
Class
diagnostic, ovulation
endocrine/metabolic
Dosage, Adult (usual)
Ovulatory dysfunction: 50 mg ORALLY daily for 5 days; if not effective, a second and third course may be given, if necessary, of 100 mg ORALLY daily for 5 days, may be initiated as early as 30 days after the previous course
Dosage, Pediatric, (usual)
safety and efficacy in pediatric patients have not been established
Administration
begin on the 5th cycle day
Monitoring
pelvic examinations should be performed prior to initial
ophthalmological evaluation should be performed in the
How Supplied
50 MG TABLET
Indications
FDA labeled indications
Ovulatory dysfunction
Contraindications
pregnancy
uncontrolled thyroid or adrenal dysfunction
liver disease
abnormal uterine bleeding
endometrial carcinoma
ovarian cysts
organic intracranial lesion
hypersensitivity to clomiphene
Precautions
patient developing visual symptoms
multiple pregnancies may occur
ovarian hyperstimulation syndrome and abnormal ovarian enlargement may occur, lowest dose is suggested to minimize this complication
Adverse Effects
COMMON
abdominal discomfort (5.5%)
blurred vision (1.5%)
insomnia
nervousness
ovarian cysts
ovarian enlargement (13.6%)
vasomotor flushing (10.4%)
SERIOUS
thromboembolism (rare)
Pregnancy Category
X
Breast Feeding
unknown


CLOMIPHENE
CLINICAL APPLICATIONS
4.5 THERAPEUTIC USES
A. DIAGNOSTIC USE - ORGANIC SELLAR LESIONS
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective
DOCUMENTATION: Adult, fair

2. SUMMARY:
- Clomiphene has been somewhat effective in
patients with polycystic ovary syndrome

3. ADULT:
a. Clomiphene in increments of 50 milligrams (up to 200 milligrams/day) during cycles 2 to 5 was added to troglitazone therapy in 18 patients with clomiphene-resistant polycystic ovary syndrome. In 83% of patients (15/18), troglitazone, alone or with clomiphene, induced ovulation and pregnancy was achieved in 39% of patients (7/18) (Mitwally et al, 1999).
b. The use of CLOMIPHENE as an aid to identifying organic sellar and parasellar lesions as a potential underlying cause in patients with hypothalamic amenorrhea of unknown etiology was investigated (Corenblum & Taylor, 1987). A group of 41 patients with hypothalamic amenorrhea of at least 6 months duration and with normal initial roentgenograms and sellar CAT scans was given CLOMIPHENE 100 mg/day for 5 days. Fifteen nonresponders were identified, and these underwent extensive radiologic and pituitary stimulation testing. Six of these nonresponders were subsequently found to have organic sellar or parasellar lesions, while none of the 26 responders were found to have any evidence of these lesions. Follow-up of all patients ranged from 3 to 6 years. Further evaluation of the diagnostic potential of CLOMIPHENE in this setting is warranted.
B. DYSFUNCTIONAL UTERINE BLEEDING
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective
DOCUMENTATION: Adult, fair

C. ESTROGEN REPLACEMENT THERAPY
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective
DOCUMENTATION: Adult, poor

2. ADULT:
a. The use of CLOMIPHENE (a weakly estrogenic antiestrogen) was evaluated for estrogen replacement therapy in treating post-menopausal or castrate women as a potential alternative for those women in whom estrogenic substances are contraindicated (Young et al, 1991). This small 3 month study involved 20 menopausal or castrate women randomly assigned to either 12.5 to 25 milligrams of CLOMIPHENE daily for 25 days of each month or 0.625 milligrams of CONJUGATED estrogens daily for 25 days of each month. The study failed to demonstrate a reduction in vasomotor symptoms with CLOMIPHENE, while significant reduction was seen with CONJUGATED ESTROGENS. FSH levels decreased only slightly with CLOMIPHENE, while significant decrease was seen with CONJUGATED ESTROGENS. Data suggested possible benefits regarding bone metabolism with CLOMIPHENE, although to a lesser extent than with CONJUGATED ESTROGENS. Neither treatment caused changes in total or HDL cholesterol. As expected, CONJUGATED ESTROGENS are more effective than clomiphene for ESTROGEN replacement therapy, however further studies are needed to evaluate the possible role of CLOMIPHENE as an alternative treatment when estrogens are contraindicated.
D. GAMETE INTRAFALLOPIAN TRANSFER
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective
DOCUMENTATION: Adult, poor

2. SUMMARY:
- CLOMIPHENE ovarian stimulation and gamete
intrafallopian transfer (GIFT) were combined
with diagnostic and operative laparoscopy in 62
infertile women to evaluate the efficacy and
cost-savings associated with this combination
procedure (Johns, 1991)

3. ADULT: An average of 3.4 oocytes were retrieved per laparoscopy, and the pregnancy rate among all patients in the study was 25%. The protocol utilized CLOMIPHENE 100 mg/day given on Days 3 through 8 with laparoscopy scheduled for Day 14 or 15. If no LH surge occurred, CHORIONIC GONADOTROPIN 10,000 IU was given 32 to 36 hours prior to laparoscopy. The authors state that the combined procedure is highly cost-effective, but requires a significant amount of flexibility in surgical scheduling (Johns, 1991).
E. GYNECOMASTIA, PUBERTAL
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective; pediatric,
possibly effective
DOCUMENTATION: Adult, fair

2. SUMMARY:
- CLOMIPHENE CITRATE 50 to 100 mg PO daily
has decreased breast size and tenderness
in adolescent males with pubertal gynecomastia
(Le Roith et al, 1980; Stephanas et al, 1977)

- Maximum response usually occurred within
3 months of beginning therapy

3. ADULT:
a. CLOMIPHENE in doses of 15 mg daily for 1 to 3 months was evaluated in the management of adolescent gynecomastia in 12 boys (12 to 19 years of age). Mean breast size decreased by 0 to 36%; only 5 patients experienced a 20% or greater reduction. CLOMIPHENE is not considered satisfactory in these doses for this condition (Plourde et al, 1983).
b. Twenty-eight males, 15 to 19 years old, were treated with CLOMIPHENE CITRATE 100 mg PO daily for 6 months to relieve pubertal gynecomastia. Six patients were non-compliant and of the 22 who completed therapy, 14 had satisfactory reduction of breast size which did not recur (Le Roith et al, 1980).
c. Nineteen males, 12 to 24 years old, were treated with 50 mg CLOMIPHENE PO daily and 18 of them had reduction in breast size (Stephanas et al, 1977). Five of the 18 patients were not satisfied with the amount of breast size reduction and gynecomastia recurred in another 5 patients after CLOMIPHENE therapy was terminated.
F. HYPOGONADISM
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective; pediatric,
possibly effective
DOCUMENTATION: Adult, fair; pediatric, fair

2. ADULT:
a. Luteinizing hormone, FSH, and testosterone levels normalized with clomiphene therapy in a 29-year-old male runner with EXERCISE-INDUCED HYPOGONADISM. The patient received clomiphene 50 mg daily and after 5 weeks achieved normal LH, FSH, testosterone, and free testosterone levels. After 4 months of therapy, improvement was seen in muscle strength, daily morning erections, sense of well-being, and energy. Six weeks after clomiphene was discontinued, hypogonadal symptoms returned. Clomiphene was restarted at 25 mg daily and symptoms improved (Burge et al, 1997).
b. CLOMIPHENE therapy has been effective in treating HYPOTHALAMIC DYSFUNCTION in patients with sickle cell anemia and hypogonadism (Landefeld et al, 1983). In two patients, oral CLOMIPHENE (50 to 100 mg daily) increased luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone to normal and induced puberty in both patients.
c. Anabolic steroid abuse for body building resulted in depression, loss of libido and energy, and patient awareness of beginning testicular atrophy. During work up of this 30-year-old, total testosterone levels were markedly reduced (71 ng/dL; reference range 260-1000 ng/dL). Clomiphene challenge (100 mg daily for 5 days) was given; two weeks later testosterone was 828 ng/dL, mood and libido had improved. Symptom relapse occurred 2 months later, accompanied by a lowered testosterone (301 ng/dL). A full 2-month trial with clomiphene apparently restored his HPA responsiveness, with testosterone at 705 ng/mL, and he remained in eugonadal status with continuing follow-up (Tan & Vasudevan, 2003).
G. INFERTILITY, FEMALE - ANDROGEN EXCESS
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective
DOCUMENTATION: Adult, fair

2. SUMMARY:
- CLOMIPHENE may be effective for induction of
ovulation in patients with elevated levels
of adrenal androgens; the ovulatory response
rate appears to be less in patients
with DHEA-S levels greater than 5 mcg/mL

3. ADULT:
a. The relationship between serum dehydroepiandrosterone sulfate (DHEA-S) and the response to CLOMIPHENE in anovulatory women was evaluated (Hoffmann & Lobo, 1985). Specifically, the relationship between pretreatment levels of serum DHEA-S and ovulation rates were studied. CLOMIPHENE CITRATE was administered to 40 anovulatory women with elevated levels of DHEA-S (29 patients with DHEA-S levels of less than 5 mcg/mL and 11 with levels exceeding 5 mcg/mL). In addition, 59 anovulatory patients with normal DHEA-S levels were administered CLOMIPHENE. Rates of ovulation were similar in patients with elevated and normal DHEA-S levels (75% and 78%, respectively); in patients with elevated DHEA-S levels, the response was greater in patients with levels of less than 5 mcg/mL (83%) as compared to those with higher levels (55%). Pregnancy occurred in 15 of the 40 patients with elevated DHEA-S levels following at least 4 ovulatory cycles, and was not influenced by levels of DHEA-S.
H. INFERTILITY-FEMALE - OVULATORY DYSFUNCTION
FDA Labeled Indication

1. OVERVIEW:
FDA APPROVAL: Adult, yes; pediatric, no
EFFICACY: Adult, effective
DOCUMENTATION: Adult, excellent

2. SUMMARY:
- CLOMIPHENE is effective in the treatment
of anovulatory and oligoovulatory female
infertility

- A nomograph for predicting probability of live
birth after clomiphene citrate treatment is
available (Imani et al, 2002)

3. ADULT:
a. A 2-step nomogram can predict the likelihood of ovulation occurring within 6 months of starting clomiphene citrate (CC) therapy and the probability of a live birth if ovulation occurs. This nomogram applies to women with oligomenorrhea or amenorrhea, normal serum FSH (follicle-stimulating hormone), normal serum prolactin and thyroid-stimulating hormone levels, bleeding response to withdrawal of progestogen, a body mass index (BMI = weight in kilograms/height in meters squared) greater than 18 kg/m(2), age between 19 and 40 years, and a partner with a total motile sperm count above 1 million. The parameters required for predicting ovulation are the woman's serum testosterone (T) and serum sex-hormone binding globulin (SHBG) levels, which are used to determine the free androgen index (FAI = T x 100/SHBG); the BMI; and the cycle history (oligomenorrhea vs amenorrhea). Once the probability of ovulation (within 6 months after initiation of CC therapy) has been determined, the probability of a live birth can be determined with knowledge of the woman's age and cycle history. Choosing a cut-off level (eg, 20%) for the likelihood of achieving a live birth would give clinicians a basis for advising women whether to proceed with CC therapy or to try a different modality, such as weight reduction, exogenous gonadotropins, insulin-sensitizing hormones, or in vitro fertilization (Imani et al, 2002).
b. Clomiphene and prednisone administered to 24 patients who failed to ovulate following clomiphene therapy alone produced high rates of ovulation and pregnancy. Patients received clomiphene 100 to 150 mg/day for days 3 through 9 and prednisone 5 mg each night of the cycle until confirmation of pregnancy. Out of a total of 60 cycles, 44 cycles resulted in ovulation (73%) and 11 patients (46%) conceived. Two pregnancies ended as spontaneous abortions and one was multifetal. No side effects were reported (Isaacs et al, 1997).
c. Nineteen anovulatory infertile women received clomiphene 50 to 150 mg/day which was titrated to the minimum effective ovulation-inducing dosage for days 5 to 9. Patients received clomiphene for up to 6 consecutive ovulatory cycles, until conception, or until the maximum dosage level (150 mg/day) proved ineffective. Sixteen of 19 patients (84%) ovulated in response to clomiphene. Thirteen of 19 patients achieved or maintained ovulation at doses of 50 (n=9) and 100 mg (n=4). The study was completed by nine of 13 ovulatory patients. The length of the follicular phase and lead follicular diameter were consistent with up to 6 consecutive cycles with the minimum ovulation-inducing dosage of clomiphene therapy. Endometrial growth patterns remained consistent with consecutive cycles of therapy (Opsahl et al, 1996).
d. In a review of published studies, the manufacturer reports a pregnancy rate of 35% in 5154 patients with ovulatory dysfunction (Prod Info Serophene(R), 1997).
e. The effect of CLOMIPHENE therapy initiation day (Day 2, 3, 4, or 5) on ovarian response and pregnancy outcome was evaluated retrospectively in 87 anovulatory patients (Wu & Winkel, 1989). No significant differences were seen in frequency of anovulatory cycles, cycles with luteal phase dysfunction, or normal ovulatory cycles between groups; pregnancy rates, live birth rates, abortion rates, and fecundity rates were also similar among all of the groups.
f. Clomiphene in increments of 50 milligrams (up to 200 milligrams/day) during cycles 2 to 5 was added to troglitazone therapy in 18 patients with clomiphene-resistant polycystic ovary syndrome. In 83% of patients (15/18), troglitazone, alone or with clomiphene, induced ovulation and pregnancy was achieved in 39% of patients (7/18) (Mitwally et al, 1999). Clomiphene at a dose ranging from 50 to 200 milligrams/day has been used in patients for anovulation (Deaton et al, 1997; Takahashi et al, 1994; Tiitinen et al, 1993).
g. A dose-dependent increase in the total number of ovarian follicles seen on ultrasound has been demonstrated in anovulatory patients with CLOMIPHENE doses ranging from 50 to 200 mg/day (Shalev et al, 1989). A less significant effect was seen on maturity of follicles relative to the same dosage increase.
h. Anovulatory patients unresponsive to standard doses of CLOMIPHENE CITRATE may be responsive to an incremental dosage regimen. Thirty anovulatory patients previously unresponsive to CLOMIPHENE 200 mg/day for 5 days were treated with an incremental method of CLOMIPHENE CITRATE therapy. Therapy was initiated with 50 mg CLOMIPHENE/day for 5 days. At this time urinary total estrogen excretion was measured and if levels were greater than 20 mcg/24 hours, therapy was discontinued. If levels were below 20 mcg/24 hours, CLOMIPHENE therapy was continued, increasing the dosage by 50 mg/day every 5 days up to a maximum of 250 mg/day. A maximum of 25 days of consecutive therapy resulted in a total dosage of 3750 mg. Twenty-one of the patients (70%) ovulated while on this regimen and 8 patients (27%) conceived. Side effects during this study were minimal, with only one case of ovarian hyperstimulation (O'Herlihy et al, 1981).
I. INFERTILITY, FEMALE - LUTEAL PHASE DEFECT
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective
DOCUMENTATION: Adult, fair

2. SUMMARY:
- CLOMIPHENE appears effective in
enhancing pregnancy rates in women
with low luteal phase progesterone
levels

3. ADULTS:
a. In a study of 18 women with biopsy-defined luteal phase defects, a greater quantity of CLOMIPHENE stimulated preovulatory follicles (follicles greater than 15 mm mean diameter) was associated with a significantly higher relative increase in mean serum progesterone levels in mid-luteal phase, and with a significantly higher frequency of corrected luteal phase defects defined by uterine biopsy (Guzick & Zeleznik, 1990). CLOMIPHENE 100 mg daily for 5 days was given to all patients in the study, and the patients were later divided into 2 groups based upon quantity of preovulatory follicles seen on ultrasound (only one follicle (n=8) versus more than one follicle (n=10)). No relative increase in mean serum progesterone levels was seen in monofollicular patients, and only 2 of these patients had corrected uterine biopsies compared with 8 of 10 patients in the polyfollicular group. No data on pregnancy rates of the 2 groups were presented.
b. CLOMIPHENE 50 to 150 mg/day increased luteal phase progesterone levels in infertile women with inadequate progesterone levels and induced pregnancy in 31 of 69 patients (Hammond & Talbert, 1982).
J. INFERTILITY - IDIOPATHIC
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective
DOCUMENTATION: Adult, fair

2. ADULT:
a. Combination therapy of CLOMIPHENE ovarian stimulation and intrauterine insemination (IUI) with untreated cycles were compared in a crossover study of couples with unexplained infertility. A significantly higher rate of conception occurred with the combination therapy, however, the study design did not allow determination of the contributory effects of CLOMIPHENE in this setting (Deaton et al, 1990).
b. A randomized study of 100 infertile couples with UNEXPLAINED INFERTILITY compared the results of treating the MALE partner empirically with CLOMIPHENE 25 mg daily for 25 days followed by 5 drug-free days, or with placebo (Check et al, 1989). The pregnancy rate after 8 months of investigation was statistically better in the group of couples where the male received CLOMIPHENE (58%) than in the placebo-treated group (16%). There were no statistically significant differences in any of the semen parameters (sperm count, motility, or morphology) between the two groups of males, before or after treatment. No explanation for the increase in fertility with empiric CLOMIPHENE treatment of the male could be derived from the data collected. This low cost, low risk empiric therapy may provide an attractive alternative in couples with idiopathic infertility.
c. The use of CLOMIPHENE ovarian stimulation, CHORIONIC GONADOTROPIN, or both was evaluated in the treatment of idiopathic infertility in a double-blind, randomized, placebo-controlled study involving 148 infertile couples. During the study period, only the group receiving CLOMIPHENE as a single therapy achieved a pregnancy rate (19%) which was significantly higher than that seen in the placebo group (0%) (Fisch et al, 1989).
K. INFERTILITY, MALE
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective
DOCUMENTATION: Adult, good

2. SUMMARY:
- CLOMIPHENE has been effective in some
clinical studies in male infertility

3. ADULT:
a. Clomiphene 100 milligrams orally given daily for 5 days may be useful in males with HYPOFUNCTION OF THE SEMINAL VESICALS. Further studies are needed to evaluate the efficacy of this treatment modality (Gonzales et al, 1998).
b. CLOMIPHENE given by 2 different dosing regimens was compared in 89 oligospermic men (Homonnai et al, 1988). The group receiving CLOMIPHENE 25 mg every other day showed a greater overall sperm improvement response (80%) than the group receiving CLOMIPHENE 25 mg daily for 25 days (50%). Increases in sperm concentration and total sperm count were significantly greater with the lower dose regimen. Pregnancy rates in the study were not significantly different during the 6 month follow-up period.
c. The efficacy of CLOMIPHENE CITRATE 50 mg PO daily was reported in the treatment of OLIGOSPERMIA in a randomized study involving 101 men with low or normal serum FSH levels and infertility in marriages of more than 2 years (Micic & Dotlic, 1985). CLOMIPHENE was given for 6 to 9 months in 56 of the patients, resulting in significant improvement in volume, sperm density and sperm motility as compared to a control group of 45 men. Seven pregnancies occurred in the treated group (12%) with none occurring in the untreated patients (control group). Libido and sexual performance was not altered and gynecomastia did not occur.
d. CLOMIPHENE therapy in men (where the hypothalamic-pituitary-gonadol axis is functional) has improved the sperm count in 25 to 80% of patients (Sorbie & Perez-Marrero, 1984; Schellen, 1982; McConnon, 1979; Epstein, 1977; Check & Rakoff, 1977; Paulson & Wacksman, 1976; Paulson et al, 1975).
e. A review of the efficacy of CLOMIPHENE in male infertility was presented (Sorbie & Perez-Marrero, 1984). CLOMIPHENE had a favorable effect upon sperm count in some oligospermic men, improving semen quality in up to 75% of patients; pregnancy rates as high as 40% were reported.
f. CLOMIPHENE 25 milligrams orally given daily was reported ineffective in the treatment of male infertility in a 12-month placebo-controlled study involving 23 patients (Sokol et al, 1988). Prior to treatment, the patients had sperm concentrations between 0.5 and 20 million/mL, normal serum gonadotropins and testosterone, and a presumably fertile partner. No difference was observed in pregnancy rates between the CLOMIPHENE and placebo group, and no differences were observed between placebo and CLOMIPHENE groups for the sperm penetration assay or semen parameters. CLOMIPHENE therapy did result in increased levels of LH, FSH, testosterone and estradiol as compared to the placebo group; greater LH, FSH, and testosterone responses to gonadotropin-releasing hormone were also observed with CLOMIPHENE.
g. Some studies have indicated no significant increase in spermatozoal motility following CLOMIPHENE therapy (Sorbie & Perez-Marrero, 1984; Wang et al, 1983; Schellen, 1982), whereas others report increased motility (Micic & Dotlic, 1985; Charney, 1979). One in vitro report indicated that CLOMIPHENE exerts depressant effects on sperm motility and fertilizing capacity at both low and high concentrations (0.005 to 50 mcg/mL) (Chan et al, 1985). These effects may be related to the sperm immobilizing capacity of the drug. The clinical significance of these findings are unclear; it is suggested that CLOMIPHENE could exert direct effects on spermatozoa in the reproductive tract of men receiving the drug. More studies are required regarding the effects of CLOMIPHENE on sperm motility.
L. IN VITRO FERTILIZATION AND EMBRYO TRANSFER
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, effective
DOCUMENTATION: Adult, good

2. SUMMARY:
- Relative to placebo, increases oocyte retrieval rate
and pregnancy rate

- Clomiphene challenge test predicts individual
prognosis for success of hyperstimulation protocol

3. ADULT:
a. Ovarian stimulation with clomiphene citrate, combined with an in vitro fertilization (IVF) protocol, yields an acceptable rate of embryo transfer with little monitoring, whereas IVF with unstimulated cycles yields a lower rate. Of 132 infertile couples, 68 women received clomiphene citrate 100 milligrams/day on cycle days 3 to 7 and 64 women received no stimulation. All cycles were followed until the dominant follicle was 17 millimeters (mm) or more (unstimulated cycle) or 20 mm or more (clomiphene citrate cycle), and then HCG (human chorionic gonadotropin) 5000 international units was given at 10:00 hours, followed by oocyte retrieval 35 to 36 hours later. The mean number of follicles developed on the day of HCG injection was 2.5 in the clomiphene citrate group and 1.2 in the unstimulated group (p less than 0.0001). Follicular rupture before oocyte retrieval was significantly higher in unstimulated cycles than following clomiphene citrate (32% vs 16%, p=0.004). Oocyte collection was performed in 95 of 111 (86%) clomiphene citrate-stimulated cycles and in 74 of 114 (65%) of unstimulated cycles. The diameter of the largest follicle was significantly greater in the clomiphene citrate cycles (22 mm) than in the unstimulated cycles (19 mm; p less than 0.0001). Mean follicular volume was greater in those cycles ending with clinical pregnancy than in those without (p=0.042). The fertilization rate in oocytes retrieved from clomiphene citrate cycles was 60% and that in oocytes from unstimulated cycles was 47% (not significantly different). There were significantly more cycles resulting in embryo transfer in the clomiphene citrate group than in the unstimulated group. The pregnancy rate per embryo transfer was 34% in the clomiphene citrate group and 14% in the unstimulated group (p=0.047). Two twin pregnancies occurred in the clomiphene citrate group. Nearly half of the women receiving clomiphene citrate reported side effects: nausea, hot flushes, mammary tenderness, and visual disturbances (Ingerslev et al, 2001).
b. The effectiveness of a CLOMIPHENE CHALLENGE TEST as a means of predicting the prognosis of successful treatment with subsequent CLOMIPHENE ovarian hyperstimulation in combination with in vitro fertilization and embryo transfer was demonstrated (Loumaye et al, 1990). A combined value representing the sum of serum FSH levels from Day 2 and Day 10 of an ovulatory cycle which included CLOMIPHENE 100 mg daily given on Days 5 through 9 was highly correlated with ovarian response (defined by estradiol levels and numbers of follicles, oocytes, and embryos obtained). A combined FSH value greater than 26 mIU/mL obtained in the CLOMIPHENE challenge test was well correlated with a high rate of cancellation of oocyte retrieval procedures due to poor follicular development, with an increased number of ampules of menotropins required to reach follicular maturity, with an increased number of days to reach full follicular development, and with a reduced number of follicles aspirated, oocytes retrieved, and embryos obtained. The individual PROGNOSTIC VALUE of the test was as follows: a normal response to the CLOMIPHENE challenge test indicated a 94% chance to develop 4 or more follicles, while a higher than normal response indicated only a 15% chance of developing 4 or more follicles; an abnormal response indicated a 33% chance of obtaining no oocytes and a 66% chance of obtaining no embryos, compared to a 2% chance of no oocytes and a 13.5% chance of no embryos with a normal challenge test result. Finally, the PREGNANCY RATE associated with combined FSH values up to 26 mIU/ml remained constant in the range from 30 to 40%, but no patients with values greater than 26 mIU/ml became pregnant. Although further prospective evaluation is needed, the CLOMIPHENE challenge test appears to have significant utility in predicting individual prognosis for ovarian hyperstimulation with in vitro fertilization and embryo transfer.
c. An individualized ovarian stimulation protocol consisting of CLOMIPHENE 100 mg/day for 5 days, menotropins (2 vials) daily until follicular diameter reached 14 mm, and CHORIONIC GONADOTROPIN 5000 IU given when follicular diameter exceeded 18 mm, was combined with in vitro fertilization for treating 37 patients with infertility of various etiologies (Ronen et al, 1988). Of 116 recovered oocytes, 78% yielded cleaving embryos, and 36 transfers yielded 10 pregnancies (28%). The ovarian stimulation protocol was guided by the length of the menstrual cycle and the ovarian response. Patients with menstrual cycles less than 28 days in length were given CLOMIPHENE beginning on day 3 of the cycle and MENOTROPINS beginning on day 4. Patients with cycles 28 days or longer were given CLOMIPHENE beginning on day 5 and MENOTROPINS beginning on day 6. The authors suggest that this individualized protocol may yield higher oocyte recovery rates while maintaining oocyte quality, however, the study design did not test this hypothesis.
d. The successful use of a SUPEROVULATION SCHEDULE combining CLOMIPHENE CITRATE, human menopausal gonadotropin and HUMAN CHORIONIC GONADOTROPIN (HCG) was reported in an in vitro fertilization and embryo transfer program (Plachot et al, 1985). An average of 3.5 follicles was promoted in each cycle with this sequential regimen, containing healthy and mature oocytes, which were highly fertilizable when exposed to efficient semen. With this protocol, pregnancy rates range from 5 to 20% per cycle. Patients were administered CLOMIPHENE CITRATE 100 to 150 mg PO daily from days 5 to 9 of the cycle, with additional hMG injections on days 6, 8, and 10. On day 11 of the cycle, plasma estradiol (E2) levels were generally 1000 pg/mL; when E2 values corresponded to 300 to 400 pg/mL and growing follicles were greater than 18 mm in diameter, 5000 IU of hCG was administered. When E2 levels at day 11 did not exceed 500 pg/mL, an additional 225 IU of hMG was given daily until an adequate E2/follicle ratio was observed.
M. LACTATION SUPPRESSION
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective
DOCUMENTATION: Adult, good

2. SUMMARY:
- CLOMIPHENE therapy in variable doses and
schedules has been effective in suppressing
lactation and GALACTORRHEA (Kalir et al, 1975;
Sas et al, 1973; Weir, 1971; Larraine & Bell,
1966), but no suppression of milk secretion
or serum prolactin was reported in 10 patients
who received 100 mg CLOMIPHENE daily for 7 days
in a double-blind, controlled study (Canales
et al, 1977)

N. OVARIAN REMNANT SYNDROME - USE IN
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective
DOCUMENTATION: Adult, poor

2. SUMMARY:
- A case of persistent severe pelvic pain with
premenopausal gonadotropin levels due to
residual ovarian tissue despite multiple
surgical procedures which included hysterectomy
and bilateral oophorectomy was reported
(Kaminski et al, 1990)

3. ADULT:
a. CLOMIPHENE 100 mg/day for 10 days was given as an aid to localizing the remnant tissue before surgery. Preoperative pelvic ultrasound revealed a 5.0 X 3.5 X 6.2 cm cystic mass (not seen in previous ultrasounds) which contained 3 follicles . The cystic ovarian tissue was subsequently removed and the patient recovered uneventfully with no further complaint of pelvic pain. CLOMIPHENE appears to be effective in this relatively uncommon setting.
O. POLYCYSTIC OVARY DISEASE
1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no
EFFICACY: Adult, possibly effective
DOCUMENTATION: Adult, fair

2. SUMMARY:
- Clomiphene has been somewhat effective in patients
with polycystic ovary syndrome

3. ADULT:
a. Clomiphene in increments of 50 milligrams (up to 200 milligrams/day) during cycles 2 to 5 was added to troglitazone therapy in 18 patients with clomiphene-resistant polycystic ovary syndrome. In 83% of patients (15/18), troglitazone, alone or with clomiphene, induced ovulation and pregnancy was achieved in 39% of patients (7/18) (Mitwally et al, 1999).
b. CLOMIPHENE 100 mg/day for 5 days was utilized in 27 women with polycystic ovary syndrome and examined the endocrinological and ovarian responses to treatment to determine the cause of ovulation failure in the subset of patients who did not ovulate following CLOMIPHENE (n=9). Eight of the 9 treatment failures demonstrated no follicular development despite appropriate rises and peaks in serum gonadotropins, suggesting that a common cause of CLOMIPHENE resistance in polycystic ovary syndrome is absence of an ovarian response despite an appropriate endocrine response (Polson et al, 1989).
c. The combination of CLOMIPHENE CITRATE 50 to 100 milligrams daily (from cycle day 5 to 9), DEXAMETHASONE 0.5 to 1 milligrams daily and BROMOCRIPTINE 2.5 to 5 milligrams daily was reported effective in the treatment of resistant polycystic ovarian disease in 8 women (Homburg et al, 1988). All patients had been resistant to therapy with CLOMIPHENE and DEXAMETHASONE; some patients were also resistant to HUMAN MENOPAUSAL GONADOTROPIN and human chorionic gonadotropin. All patients were anovulatory prior to combination therapy. Decreases in the LH:FSH ratio were observed, as well as reductions in prolactin and androgen levels to normal. All 8 patients became pregnant within 5 to 11 treatment cycles and ultimately delivered normal babies. It is recommended that the combination be considered in resistant cases of polycystic ovarian disease, prior to human menopausal gonadotropin and HUMAN CHORIONIC GONADOTROPIN therapy or surgery.


CAUTIONS
3.1 CONTRAINDICATIONS
A. Pregnancy
B. Liver disease/dysfunction
C. Endometrial carcinoma
D. Abnormal uterine bleeding
E. Organic intracranial lesion such as a pituitary tumor
F. Uncontrolled thyroid or adrenal dysfunction
G. Hypersensitivity to clomiphene
3.2 PRECAUTIONS
A. Perform pelvic examination prior to initial treatment and then repeat before each subsequent treatment course (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000)
B. Ophthalmological evaluation in the patient developing visual symptoms (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000)
C. Multiple pregnancies may occur (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000)
D. Ovarian hyperstimulation syndrome and abnormal ovarian enlargement may occur (lowest dose is suggested to minimize this complication) (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000)
3.3 ADVERSE REACTIONS
3.3.1 BLOOD
A. THROMBOEMBOLISM
1. The rare occurrence of thromboembolic events, including pulmonary embolism, arterial occlusion and phlebitis, has been reported (between 0.01% and 0.1% of patients). A relationship between clomiphene treatment and these adverse effects, if any, has not been confirmed (Prod Info Serophene(R), 2000).
3.3.3 CENTRAL NERVOUS SYSTEM
A. NEUROLOGIC EFFECTS
1. Nervousness, insomnia, headache, psychosis, dizziness, light-headedness, and seizures are described.
B. NEUROLOGIC FINDINGS
1. SUMMARY:
a. Central nervous system symptoms occurring during clomiphene therapy have included NERVOUSNESS (2% of patients), INSOMNIA (2%). The following adverse effects occur in less than 1% of patients, HEADACHE, dizziness and lightheadedness, depression and/or fatigue (Prod Info Serophene(R), 2000).DYSEQUILIBRIUM has been reported with the use of clomiphene 200 milligrams/day (mg/day) for treatment of metastatic breast cancer (Haskell et al, 1977). In a study involving 6714 patients, 58 complained of headache and 55 of DIZZINESS and LIGHTHEADEDNESS during clomiphene therapy (Macgregor et al, 1968). CONVULSIONS have been reported rarely following administration of clomiphene (Reynolds, 1999). Although the relationship to clomiphene is not known, during a post-marketing study, migraine headache, paresthesia, seizure, stroke and syncope were reported (Prod Info Serophene(R), 1994; Prod Info Clomid(R), 1996).
C. PSYCHIATRIC FINDINGS
1. SUMMARY:
a. Clomiphene-induced PSYCHOSIS was reported in two patients with no prior psychiatric history. One 27-year-old woman was taking 175 milligrams/day (mg/day) for 3 weeks and 10 days before admission had become frightened, anxious, irritable, hypervigilant and had complained of insomnia. Clomiphene was discontinued and haloperidol 15 mg/day was initiated; however it was discontinued due to severe akathisia and parkinsonism. The patient improved and was discharged after 6 electro-convulsive therapy (ECT) sessions.
b. The second case was a 25-year-old man who took clomiphene 50 milligrams/day (mg/day) for 2 weeks to treat infertility. He experienced irritability, suspiciousness, labile effect, delusions of reference, persecution, and megalomania with auditory hallucinations. He was given haloperidol 10 mg/day and symptoms slowly diminished over a 2-month period (Oyffe et al, 1997).
3.3.4 ENDOCRINE/METABOLIC
A. ENDOCRINE EFFECTS
1. Vasomotor flushing is the most common side-effect. Mastalgia, gynecomastia, weight gain, pituitary bleeding, and ovarian disorders are described.
B. GYNECOMASTIA
1. SUMMARY:
a. A 32-year-old male taking clomiphene 25 milligrams (mg) orally daily (25 days monthly) for 8 months developed CYSTIC GYNECOMASTIA. After 4 months, clomiphene therapy was reinstituted, and symptoms returned necessitating bilateral mastectomy (Check et al, 1978).
C. MASTALGIA
1. SUMMARY:
a. BREAST TENDERNESS has occurred in approximately 2% of patients receiving clomiphene (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000).
D. OVARIAN DISORDERS
1. SUMMARY:
a. Ovarian hyperstimulation syndrome has been reported after therapeutic use of clomiphene. Early effects may include nausea, vomiting, diarrhea and weight gain (Prod Info Clomid(R), 1996).
2. LITERATURE REPORTS:
a. In severe forms effects may include gross ovarian enlargement, ovarian hemorrhage, and ovarian torsion (Prod Info Clomid(R), 1996).
E. PITUITARY BLEEDING
1. SUMMARY:
a. A 34-year-old who conceived after 2 cycles of clomiphene (50 milligrams (mg) daily) for 5 days) developed preeclampsia and blurred vision at 31 weeks gestation. After a Cesarean section at 32 weeks gestation, a craniotomy confirmed ANTERIOR PITUITARY HEMORRHAGE. The pituitary stimulation by clomiphene may have caused or aggravated this condition (Nagulesparan & Roper, 1978).
F. POSTMENOPAUSAL SYMPTOMS
1. SUMMARY:
a. Vasomotor FLUSHING is the most common side effect of clomiphene therapy, occurring in approximately 1 in 7 patients. Vasomotor symptoms are generally not severe and resemble menopausal flushing. These symptoms subside quickly following withdrawal of treatment (Prod Info Serophene(R), 2000).
G. METABOLIC EFFECTS
1. Weight gain has occurred in patients receiving clomiphene.
H. WEIGHT GAIN
1. SUMMARY:
a. Weight gain has occurred in less than 1% of patients receiving clomiphene (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000).
3.3.5 GASTROINTESTINAL
A. GASTROINTESTINAL EFFECTS
1. Nausea, vomiting, abdominal/pelvic discomfort, and premenstrual phenomenon are described.
B. GASTROINTESTINAL FINDINGS
1. SUMMARY:
a. Abdominal discomfort, nausea and vomiting, and premenstrual disorder have occurred. Nausea and vomiting occur in approximately 2.2% of patients receiving therapeutic doses. Abdominal discomfort, described as abdominal/pelvic discomfort and distension and bloating, has been reported in 5.5% of women during therapeutic use (Macgregor et al, 1968; Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000; Prod Info Clomid(R), 1996).
2. LITERATURE REPORTS:
a. In a study of 6714 female patients receiving clomiphene 50 to 100 milligrams (mg) orally daily for 5 days, 122 complained of NAUSEA or VOMITING and 410 of ABDOMINAL/PELVIC DISCOMFORT (Macgregor et al, 1968).
b. The manufacturer indicates that nausea and vomiting occur in approximately 2% of patients (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000).
c. ABDOMINAL DISCOMFORT has occurred in 1 in 15 patients, according to the manufacturer. Abdominal discomfort may resemble ovulatory (Mittelschmerz) or PREMENSTRUAL PHENOMENON, or that due to ovarian enlargement (Prod Info Serophene(R), 2000).
3.3.6 KIDNEY/GENITOURINARY
A. GENITOURINARY EFFECTS
1. Unfavorable cervical mucus, antiestrogenic effects, polyuria, menstrual disorders, ectopic pregnancy, ovarian enlargement and ovarian hyperstimulation are described.

B. ECTOPIC PREGNANCY
1. SUMMARY:
a. A case-control study (Marchbanks et al, 1985) has suggested that clomiphene citrate therapy may increase the risk of ectopic pregnancy.
C. GENITOURINARY FINDINGS
1. SUMMARY:
a. UNFAVORABLE CERVICAL MUCUS, defined as a decrease in the quality or quantity of cervical mucus, may result from the use of clomiphene (Randall & Templeton, 1991). These effects may be related to treatment failure in some patients (Bateman et al, 1990; Eden et al, 1989; Yagel et al, 1992).
2. LITERATURE REPORTS:
a. Exogenous estrogen in the form of micronized estradiol 2 milligrams (mg) daily or conjugated estrogens 5 mg daily given on days 9 to 15 was compared with placebo in 12 infertility patients receiving clomiphene who repeatedly had poor cervical mucus scores; however, neither estrogen resulted in improved cervical mucus scores (Bateman et al, 1990).
b. ANTIESTROGENIC EFFECTS of clomiphene on the uterus may include the absence of an increase in uterine volume and an inhibition of endometrial thickening, both of which are processes that would normally occur during the follicular phase. These antiestrogenic effects have been observed in normally ovulating study subjects in comparison with untreated ovulatory cycles, and these effects could be related to treatment failure in some patients (Eden et al, 1989).
c. Ethinyl estradiol 20 micrograms/day (mcg/day) for 7 days beginning with day 10 of the cycle has been shown to reverse the inhibition of uterine volume increase and endometrial thickening caused by clomiphene (Yagel et al, 1992).
D. MENSTRUAL DISORDERS
1. SUMMARY:
a. Abnormal UTERINE BLEEDING reportedly occurs in approximately 1% of patients (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000).
E. OVARIAN CYSTS
1. SUMMARY:
a. Ovarian enlargement, ovarian pain, and endometrial cysts are described (AMA, 1983; Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000; Macgregor et al, 1968; Gabos, 1979).
2. LITERATURE REPORTS:
a. CYSTIC OVARIAN ENLARGEMENT has occurred in 10 to 15% of patients (AMA, 1983).
b. When given in recommended doses, abnormal ovarian enlargement is considered infrequent, although the usual cyclic variation of ovarian size may be exaggerated. MID-CYCLE OVARIAN PAIN (MITTELSCHMERZ) may be accentuated with the drug. With prolonged use of higher doses, ovarian enlargement and cyst formation (generally luteal) may occur, and the luteal phase of the menstrual cycle may be prolonged. The patient with polycystic ovary syndrome may be unusually sensitive to clomiphene (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000).
c. MASSIVE OVARIAN ENLARGEMENT has occurred rarely. Abnormal ovary enlargement generally regresses spontaneously and conservative treatment is indicated (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000).
d. Maximal ovarian enlargement generally occurs several days following withdrawal of clomiphene. If the patient complains of pelvic pain while receiving the drug, a careful examination is indicated. If enlargement of the ovary occurs, withdrawal of the drug is indicated until ovaries have returned to pretreatment size, and the dose or duration of the next course should be reduced. OVARIAN ENLARGEMENT and cyst formation following clomiphene treatment regresses spontaneously after several days or weeks following discontinuation of the drug (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000).
e. Once ovaries return to pretreatment size, the patient may be given a course of lower doses of clomiphene plus human chorionic gonadotropin (hCG) when cervical mucous appears favorable (AMA, 1990).
f. In a study of 6714 women receiving clomiphene 50 to 100 milligrams/day (mg/ day) for 5 days, 803 developed ovarian enlargement (Macgregor et al, 1968).
g. The development of ovarian ENDOMETRIAL CYSTS was reported in 4 women who conceived after therapy with clomiphene (50 milligrams (mg) daily for 5 days) (Gabos, 1979). Two of these patients had a prior history of endometriosis and 2 had histories suggestive of endometriosis.
F. OVARIAN HYPERSTIMULATION
1. SUMMARY:
a. Ovarian hyperstimulation syndrome (OHSS) has developed after 2 courses of clomiphene 50 to 100 milligrams (mg) daily for 5 days (Roland, 1970; Scommegna & Lash, 1969).
2. LITERATURE REPORTS:
a. A 38-year-old woman developed ovarian hyperstimulation syndrome one year after taking clomiphene citrate for anovulation. She had taken the treatment for only 3 cycles, at 50 mg daily for 5 days starting on the fifth day of menses. She presented with amenorrhea for 5 weeks and a 12-day history of lower abdominal pain. She had abdominal distension and tenderness but no palpable masses. A diagnostic laparoscopy revealed a complex left ovarian mass with predominantly solid areas. About 1 liter of straw colored ascitic fluid was present. A left oophorectomy was performed. The overall features were consistent with moderate to severe ovarian hyperstimulation syndrome (Mitchell et al, 2001).
G. POLYURIA
1. SUMMARY:
a. Increased urination and urinary frequency is described (Macgregor et al, 1968; Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000).
2. LITERATURE REPORTS:
a. In a study of 6714 female patients receiving clomiphene 50 to 100 milligrams (mg) orally (PO) daily for 5 days, 49 complained of INCREASED URINATION (Macgregor et al, 1968).
b. An increase in urinary frequency reportedly occurs in less than 1% of patients, according to the manufacturer (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000).
3.3.7 LIVER
A. HEPATIC EFFECTS
1. Hepatic enzymes and reports of hepatitis are described.
B. HEPATIC ENZYMES INCREASED
1. SUMMARY:
a. Elevated transaminases, as well as occasional reports of hepatitis, have been reported in post-marketing surveillance programs. Incidence of events remains unknown (Prod Info Clomid(R), 1996).
3.3.8 OCULAR
A. EYE EFFECTS
1. Visual disturbances, including scintillating scotomata, visual blurring, visual acuity impairment, and retinal function changes are described.
B. VISUAL FINDINGS
1. SUMMARY:
a. VISUAL DISTURBANCES occur in 1 in 50 patients receiving clomiphene (Prod Info Serophene(R), 2000; Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000; Macgregor et al, 1968; Roch et al, 1967).
2. LITERATURE REPORTS:
a. Visual symptoms appear to be dose-related and consist primarily of blurring, or spots or flashes (SCINTILLATING SCOTOMATA). These symptoms subside within several days to several weeks following discontinuation of clomiphene. Visual symptoms may occur more frequently (or be accentuated by) exposure to a more brightly lit environment (Prod Info Serophene(R), 1997).
b. Visual acuity is not generally affected by the drug, however rare cases of VISUAL BLURRING followed by progressive and severe diminution of visual acuity have been reported. VISUAL ACUITY IMPAIRMENT is reversible upon discontinuing the drug. Rarely, electroretinographic RETINAL FUNCTION CHANGES have been observed (Prod Info Clomid(R), 2000; Prod Info Serophene(R), 2000).
c. In a study involving 6714 women receiving clomiphene 50 to 100 milligrams (mg) orally daily for 5 days, 94 complained of visual disturbances (Macgregor et al, 1968).
d. In a study involving 58 women, 4 developed visual disturbances including scotomata, abnormal visual fields and abnormal visual acuity. Symptoms recurred on rechallenge in 3 patients and disappeared during therapy in 1 patient (Roch et al, 1967).
e. Visual disturbances (described as blurring, spots or flashes {scintillating scotomata}) occur in 2% of patients receiving clomiphene (Prod Info Clomid(R), 1996; Prod Info Serophene(R), 1994).
f. Symptoms tend to increase with total dose or length of therapy, but visual disturbances generally return to normal at approximately 3 days post dose (Prod Info Clomid(R), 1996; Prod Info Serophene(R), 1994).
3.3.10 SKIN
A. DERMATOLOGIC EFFECTS
1. Vasomotor flushing, allergic dermatitis, hair loss and urticaria are described.
B. DERMATOLOGIC FINDINGS
1. SUMMARY:
a. Adverse effects include vasomotor flushing (10.4%), urticaria, and allergic dermatitis (Macgregor et al, 1968; Prod Info Serophene(R), 2000).
2. LITERATURE REPORTS:
a. In a study involving 6,714 women, 36 developed URTICARIA and/or ALLERGIC DERMATITIS during clomiphene therapy (Macgregor et al, 1968).
b. Urticaria and allergic dermatitis occur in less than 1% of patients (Prod Info Serophene(R), 2000).
c. Reversible HAIR LOSS has occurred in less than 1% of patients receiving the drug (Prod Info Serophene(R), 2000).
3.3.12 OTHER
A. OVERDOSE See POISINDEX(R) Management "CLOMIPHENE"
B. OTHER EFFECTS
1. Breast, liver, ovarian, and testicular cancers are described with clomiphene use.
C. CANCER-BREAST
1. SUMMARY:
a. Breast cancer is described in two women after clomiphene therapy (Bolton, 1977).
2. LITERATURE REPORTS:
a. BREAST CANCER occurred in 2 women (28 and 29 years of age) after clomiphene 50 milligrams orally daily for 5 days (3 cycles). Both patients had conceived; cancer was diagnosed in 1 patient in the third month of pregnancy and termination of the pregnancy was necessary. She eventually succumbed to cancer. Cancer was diagnosed in the second patient following the birth of her second child but she responded to treatment. Neither patient had family history of breast cancer (Bolton, 1977). Relation of clomiphene to breast cancer is unknown.
D. CANCER-HEPATIC
1. SUMMARY:
a. Various liver neoplasms (hepatic hemangiosarcoma, liver cell adenoma, hepatocellular carcinoma) have been reported, but the causal relationship remains uncertain (Prod Info Clomid(R), 1996).
2. LITERATURE REPORTS:
a. A 30-year-old female treated with clomiphene (dose not specified) for 3 months conceived but LIVER CARCINOMA was diagnosed 10 days following delivery (Thalassinos et al, 1974). Association with the drug is not clear.
b. Clomiphene citrate therapy (12 grams in 24 months) was associated with LIVER-CELL ADENOMA in a 25-year-old woman (Carrasco et al, 1984). However, it is difficult to establish a cause/effect relationship and the occurrence of adenoma in this patient may have been coincidental.
E. CANCER-OVARIAN
1. SUMMARY:
a. Bilateral malignant melanomas of the ovaries are described in a patient taking clomiphene for infertility (Fuller, 1999; Whittemore et al, 1992).
2. LITERATURE REPORTS:
a. Bilateral malignant melanomas of the ovary were discovered in a 34-year-old woman 1 month after clomiphene stimulation for infertility. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, and an appropriate staging procedure for presumed ovarian malignancy were performed. Fifteen years earlier she had a mole removed from her forearm with unknown histopathologic type. It was presumed that her forearm was the primary site of malignant melanoma. A workup for metastases involving the abdomen, pelvis, and chest was completed and no further lesions were noted. Seven days after discharge the patient presented with headache, nausea, and vomiting. A computerized tomographic scan of the head showed 3 lesions compatible with metastatic melanoma of the brain. The patient died 21 days from the time of original diagnosis of disseminated metastases. The author suggests that women undergoing ovulation induction therapy undergo screening for existing melanomas. These patients should also receive counseling regarding a possible association between medication use and stimulation of cutaneous melanomas or metastatic recurrence of melanoma (Fuller, 1999).
b. An increased risk of invasive epithelial ovarian cancer has been found among women who have been treated with FERTILITY DRUGS (no specific drug has been implicated) according to a collaborative analysis of 12 US case-control studies (Whittemore et al, 1992). This epidemiologic report was comprised of 2,197 white ovarian cancer cases and 8,893 white controls, of which a subgroup of 622 cancer cases and 1101 controls was utilized to determine the odds ratios with respect to fertility drug use. The odds ratio among all women who received fertility drugs was somewhat elevated at 2.8 (95% CI 1.3 to 6.1) whereas the odds ratio among nulligravid women who received fertility drugs was greatly elevated at 27 (95% CI 2.3 to 315.6). This report has been criticized for several reasons. First, the percentage of nulligravid infertile controls who used fertility drugs in this report (about 4%) was much lower than the percentage of infertile women in the US who are estimated by some investigators to have used fertility drugs (about 30%) (Marrs & Hartz, 1993). By contrast, the percentage of nulligravid ovarian cancer cases in this report who had used fertility drugs was close to the estimate (about 35%). It has been contended that the odds ratio would not be significantly increased if the controls were representative of fertility drug use in the general population of infertile women. Second, women lacking a history of infertility were used as a reference in calculating the odds ratio rather than those with positive histories of infertility, although a statistically significant increase in risk remains after recalculation of the data using positive histories as a reference (Spirtas et al, 1993). Third, the small numbers of nulligravid women and of women with a history of infertility resulted in wide confidence intervals. Overall, the results of the study sound a note of caution about possible long-term consequences of fertility drug use. Further epidemiological study is needed to determine if the association is truly drug-related and if a particular drug is responsible for the increase in risk.
F. CANCER-TESTICULAR
1. SUMMARY
a. A 28-year-old male developed a TERATOMA and SEMINOMA in an atrophied testis after 21 weeks of therapy with enclomiphene transisomer of clomiphene 1 milligram daily. The anti-estrogen therapy may have stimulated the growth of an existing tumor (Reyes & Fairman, 1973).
3.4 TERATOGENICITY/EFFECTS IN PREGNANCY
A. TERATOGENICITY
1. U.S. Food and Drug Administration's Pregnancy Category X (Briggs et al, 1994).
See Drug Consult reference: "PREGNANCY RISK CATEGORIES"
2. Australian Drug Evaluation Committee's (ADEC) Category B3 (ADEC, 1996).
3. Of 1803 births facilitated with clomiphene therapy, birth defects occurred in 45 infants (2.5%). The cumulative rate of congenital abnormalities does not appear to exceed that of the general population (Prod Info Serophene(R), 2000). However, the manufacturer discourages the use of clomiphene during pregnancy.
4. ANENCEPHALY has been described in newborns of mothers receiving 1 to 5 courses of clomiphene 50 to 100 mg/day (Biale et al, 1978; Dyson & Kohler, 1973).
5. A 26-year-old female who took 3 courses of 50 mg/day clomiphene of which the last course was taken during early pregnancy, gave birth to a male infant with low Apgar scores. The infant was noted to have ESOPHAGEAL ATRESIA which required surgery, but died at 48 hours of age. Autopsy revealed a PATENT DUCTUS ARTERIOSUS, ABSENCE OF LEFT KIDNEY, A-V SEPTAL DEFECTS, esophageal atresia with broncho-esophageal fistula, HYPOSPADIAS and hydronephrotic right kidney and ureter (Ylikorkala, 1975).
3.5 DRUG INTERACTIONS
3.5.1 DRUG-DRUG COMBINATIONS
A. DANAZOL
1. Summary: Concomitant danazol and clomiphene therapy has been reported to result in inhibition of response to clomiphene (Sherins et al, 1971).
2. Severity: not specified
3. Onset: not specified
4. Documentation: poor
B. ESTRADIOL
1. Summary: Concomitant ethinyl estradiol and clomiphene therapy has been reported to result in suppression of response to ethinyl estradiol (Van Campenhout et al, 1968; Vaitukaitis et al, 1971).
2. Severity: not specified
3. Onset: not specified
4. Documentation: poor
C. GONADORELIN
1. Summary: Clomiphene citrate may cause ovarian hyperstimulation when used concomitantly with gonadorelin acetate(Prod Info Lutrepulse(R), 1991).
2. Severity: not specified
3. Onset: not specified
4. Documentation: poor
4.0 CLINICAL APPLICATIONS
4.1 MONITORING PARAMETERS
4.1.1 THERAPEUTIC
A. FEMALE INFERTILITY
1. Elevation of plasma FSH and LH
2. Elevation of plasma progesterone for 4 to 9 days after LH peak
3. Elevation in basal body temperature corresponding to ovulation; patients should maintain a basal body temperature chart
4. Cervical mucus (Spinnbarkeit test).
5. Onset of menses 25 to 33 days after therapy
6. Pregnancy test
7. Women who have had subclinical pregnancy losses (determined by hCG assay) during CLOMIPHENE treated cycles have an increased likelihood of achieving a term pregnancy compared with women who have not had a subclinical pregnancy loss during CLOMIPHENE treated cycles (Batemen et al, 1992). Pregnancy testing may therefore provide an additional benefit with regard to predicting subsequent normal conception.
B. MALE INFERTILITY
1. Elevation of plasma FSH and LH
2. Elevation of sperm count
4.1.2 TOXIC
A. Ovarian size
4.2 PATIENT INSTRUCTIONS
CLOMIPHENE (KLO-mi-feen):
- Treats ovulation problems in women who want to become
pregnant.
BRAND NAME(S): Clomid(R), Milophene(R), Serophene(R)
WHEN YOU SHOULD NOT TAKE THIS MEDICINE:
- Do not use this medicine if you have had an allergic
reaction to clomiphene, are pregnant (or think you
might be pregnant), or if you have liver disease, cysts
on the ovaries, enlarged ovaries, or unusual vaginal
bleeding.
HOW TO TAKE AND STORE THIS MEDICINE
TABLETS:
- Take this medicine exactly as your doctor ordered.
- Your doctor will tell you how much to take and when
to start.
- Take your medicine at the same time every day.
- You should be checked for pregnancy or ovulation by
your doctor between treatments.
- You may need to take and record your basal body
temperature every day - ask your doctor.
- Store at room temperature. Keep clomiphene away from
heat, moisture, and light.
- Keep all medicine out of the reach of children.
IF YOU MISS A DOSE:
- Take the missed dose as soon as you remember.
- Tell your doctor if you have missed any doses,
because this may affect your treatment.
DRUGS AND FOODS TO AVOID:
Ask your doctor or pharmacist before taking any other
medicine, including over-the-counter products.
WARNINGS:
- If you think you might be pregnant, stop taking this
medicine and tell your doctor.
- Talk to your doctor before taking this medicine if
you have thyroid problems.
- Multiple births (such as twins or triplets) are
possible when taking clomiphene.
- This medicine may cause changes in vision such as
blurring or trouble focusing. If this becomes
severe, tell your doctor. Be careful driving or
operating machinery.
SIDE EFFECTS
Call your doctor right away if you have any of these side
effects:
- Severe lower stomach pain
- Nausea, vomiting
- Weight gain.
- Blurred vision
If you have problems with these less serious side effects,
talk with your doctor.
- "Hot flashes"
- Breast tenderness
- Dizziness
- Nervousness or trouble sleeping
- Headache
- Stomach pain and bloating
- Mood changes
IF YOU HAVE OTHER SIDE EFFECTS THAT YOU THINK ARE CAUSED BY
THIS MEDICINE, TELL YOUR DOCTOR.

4.3 PLACE IN THERAPY
A. CLOMIPHENE CITRATE is used for the treatment of female infertility. CLOMIPHENE CITRATE should be used only after establishment of ovulatory dysfunction, physiologic indications of normal endogenous estrogen, and normal liver function; and after exclusion of primary pituitary or ovarian failure, and thyroid or adrenal disease (Prod Info Clomid(R), 2000; Prod Info Serophene(R),2000). Although gonadotropin therapy is more effective than CLOMIPHENE for inducing ovulation, the expense and time required warrants initial trials of CLOMIPHENE in women with a functioning pituitary-hypothalamus-gonadal axis.


CAUTIONS
3.3 ADVERSE REACTIONS
3.3.1 BLOOD
A. THROMBOEMBOLISM
1. The rare occurrence of thromboembolic events, including pulmonary embolism, arterial occlusion and phlebitis, has been reported (between 0.01% and 0.1% of patients). A relationship between clomiphene treatment and these adverse effects, if any, has not been confirmed (Prod Info Serophene(R), 2000).
3.3.3 CENTRAL NERVOUS SYSTEM
A. NEUROLOGIC EFFECTS
1. Nervousness, insomnia, headache, psychosis, dizziness, light-headedness, and seizures are described.
B. NEUROLOGIC FINDINGS
1. SUMMARY:
a. Central nervous system symptoms occurring during clomiphene therapy have included NERVOUSNESS (2% of patients), INSOMNIA (2%). The following adverse effects occur in less than 1% of patients, HEADACHE, dizziness and lightheadedness, depression and/or fatigue (Prod Info Serophene(R), 2000).DYSEQUILIBRIUM has been reported with the use of clomiphene 200 milligrams/day (mg/day) for treatment of metastatic breast cancer (Haskell et al, 1977). In a study involving 6714 patients, 58 complained of headache and 55 of DIZZINESS and LIGHTHEADEDNESS during clomiphene therapy (Macgregor et al, 1968). CONVULSIONS have been reported rarely following administration of clomiphene (Reynolds, 1999). Although the relationship to clomiphene is not known, during a post-marketing study, migraine headache, paresthesia, seizure, stroke and syncope were reported (Prod Info Serophene(R), 1994; Prod Info Clomid(R), 1996).
C. PSYCHIATRIC FINDINGS
1. SUMMARY:
a. Clomiphene-induced PSYCHOSIS was reported in two patients with no prior psychiatric history. One 27-year-old woman was t