CLOMIPHENE
DESCRIPTION:
FERTOMID (clomiphene citrate tablets USP) is an orally administered, nonsteroidal,
ovulatory stimulant designated chemically as 2-( p- (2-chloro-1,2-
diphenylvinyl)phenoxyl) triethylamine citrate (1:1). It has the molecular
formula of C26H28CINO . C5H8O7 and a molecular weight of 598.09.
Clomiphene citrate is a white to pale yellow, essentially odorless, crystalline
powder. It is freely soluble in methanol; soluble in ethanol; slight soluble in
acetone, water, and chloroform; and insoluble in ether.
FERTOMID is a mixture of two geometric isomers (cis (zuclomiphene) and trans
(enclomiphene)) containing between 30% and 50% of the cis-isomer.
Each white scored tablet contains 50 mg clomiphene citrate USP. The tablet also
contains the following inactive ingredients: corn starch, lactose, magnesium
stearate, pregelatinized corn starch, and sucrose.
ACTIONS/CLINICAL PHARMACOLOGY:
ACTION
FERTOMID is a drug of considerable pharmacologic potency. With careful selection
and proper management of the patient, FERTOMID 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 citrate
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 antiestrogenic effects,
which may vary from one species to another. Some data suggest that zuclomiphene
has greater estrogenic activity then enclomiphene.
Clomiphene citrate has no apparent progestational, androgenic, or antiandrogenic
effects and does not appear to interfere with pituitary-adrenal or pituitary-
thyroid function.
Although there is no evidence of a "carryover effect" of FERTOMID, spontaneous
ovulatory menses have been noted in some patients after FERTOMID therapy.
PHARMACOKINETICS
Based on early studies with 14C-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
FERTOMID therapy.
CLINICAL STUDIES:
During clinical investigations, 7578 patients received FERTOMID, 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.
TABLE 1. OUTCOME OF REPORTED PREGNANCIES IN CLINICAL TRIALS (N = 2369)
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Total Number Survival
Outcome of Pregnancies Rate
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Pregnancy Wastage
Spontaneous Abortions 483*
Stillbirths 24
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Live Births
Single Births 1697 98.16%**
Multiple Births 165 83.26%**
* Includes 28 ectopic pregnancies, 4 hydatidiform 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%.
INDICATIONS AND USAGE:
FERTOMID is indicated for the treatment of ovulatory dysfunction in women desiring
pregnancy. Impediments to achieving pregnancy must be excluded or adequately
treated before beginning FERTOMID therapy. Those patients most likely to achieve
success with clomiphene therapy include patients with polycystic ovary syndrome
(see WARNINGS: Ovarian Hyperstimulation Syndrome), amenorrhea-galactorrhea
syndrome, psychogenic amenorrhea, post-oral-contraceptive amenorrhea, and
certain cases of secondary amenorrhea of undetermined etiology.
Properly timed coitus in relationship to ovulation is important. A basal body
temperature graph or other appropriate tests may help the patient and her
physician determine if ovulation occurred. Once ovulation has been established,
each course of FERTOMID should be started on or about the 5th day of the cycle.
Long-term cyclic therapy is not recommended beyond a total of about six cycles
(including three ovulatory cycles). See DOSAGE AND ADMINISTRATION and
PRECAUTIONS.)
FERTOMID is indicated only in patients with demonstrated ovulatory dysfunction who
meet the conditions described below (see CONTRAINDICATIONS):
1. Patients who are not pregnant.
2. Patients without ovarian cysts. FERTOMID should not be used in patients with
ovarian enlargement except those with polycystic ovary syndrome. Pelvic
examination is necessary prior to the first and each subsequent course of FERTOMID
treatment.
3. Patients without abnormal vaginal bleeding. If abnormal vaginal bleeding is
present, the patient should be carefully evaluated to ensure that neoplastic
lesions are not present.
4. Patients with normal liver function.
In addition, patients selected for FERTOMID therapy should be evaluated in regard
to the following:
1. ESTROGEN LEVELS. Patients should have adequate levels of endogenous estrogen
(as estimated from vaginal smears, endometrial biopsy, assay of urinary
estrogen, or from bleeding in response to progesterone). Reduced estrogen
levels, while less favorable, do not preclude successful therapy.
2. PRIMARY PITUITARY OR OVARIAN FAILURE. FERTOMID therapy cannot be expected to
substitute for specific treatment of other causes of ovulatory failure.
3. ENDOMETRIOSIS AND ENDOMETRIAL CARCINOMA. The incidence of endometriosis and
endometrial carcinoma increases with age as does the incidence of ovulatory
disorders. Endometrial biopsy should always be performed prior to FERTOMID therapy
in this population.
4. OTHER IMPEDIMENTS TO PREGNANCY. Impediments to pregnancy can include thyroid
disorders, adrenal disorders, hyperprolactinemia, and male factor infertility.
5. UTERINE FIBROIDS. Caution should be exercised when using FERTOMID in patients
with uterine fibroids due to the potential for further enlargement of the
fibroids.
There are no adequate or well-controlled studies that demonstrate the
effectiveness of FERTOMID in the treatment of male infertility. In addition,
testicular tumors and gynecomastia have been reported in males using clomiphene.
The cause and effect relationship between reports of testicular tumors and the
administration of FERTOMID is not known.
Although the medical literature suggests various methods, there is no
universally accepted standard regimen for combined therapy (ie, FERTOMID in
conjunction with other ovulation-inducing drugs). Similarly, there is no
standard FERTOMID regimen for ovulation-induction in In Vitro fertilization
programs to produce ova for fertilization and reintroduction. Therefore, FERTOMID
is not recommended for these uses.
CONTRAINDICATIONS:
HYPERSENSITIVITY
FERTOMID is contraindicated in patients with a known hypersensitivity or allergy
to clomiphene citrate or to any of its ingredients.
PREGNANCY
FERTOMID should not be administered during pregnancy. FERTOMID may cause fetal harm
in animals (see Animal Fetotoxicity). Although no causative evidence of a
deleterious effect of FERTOMID therapy on the human fetus has been established,
there have been reports of birth anomalies which, during clinical studies,
occurred at an incidence within the range reported for the general population
(see Fetal/Neonatal Anomalies and Mortality: ADVERSE REACTIONS).
To avoid inadvertent FERTOMID administration during early pregnancy, appropriate
tests should be utilized during each treatment cycle to determine whether
ovulation occurs. The patient should be evaluated carefully to exclude
pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment
cycle. The next course of FERTOMID therapy should be delayed until these
conditions have been excluded.
FETAL/NEONATAL ANOMALIES AND MORTALITY. The following fetal abnormalities have
been reported subsequent to pregnancies following ovulation induction therapy
with FERTOMID during clinical trials. Each of the following fetal abnormalities
were reported at a rate of <1% (experiences are listed in order of decreasing
frequency): Congenital heart lesions, Down syndrome, club foot, congenital gut
lesions, hypospadias, microcephaly, harelip and cleft palate, congenital hip,
hemangioma, undescended testicles, polydactyly, conjoined twins and teratomatous
malformation, patent ductus arteriosus, amaurosis, arteriovenous fistula,
inguinal hernia, umbilical hernia, syndactyly, pectus excavatum, myopathy,
dermoid cyst of scalp, omphalocele, spina bifida occulta, ichthyosis, and
persistent lingual frenulum. Neonatal death and fetal death/stillbirth in
infants with birth defects have also been reported at a rate of <1%. The overall
incidence of reported birth anomalies from pregnancies associated with maternal
FERTOMID ingestion during clinical studies was within the range of that reported
for the general population.
In addition, reports of birth anomalies have been received during postmarketing
surveillance of FERTOMID (see ADVERSE REACTIONS).
ANIMAL FETOTOXICITY. Oral administration of clomiphene citrate to pregnant rats
during organogenesis at doses of 1 to 2 mg/kg/day resulted in hydramnion and
weak, edematous fetuses with wavy ribs and other temporary bone changes. Doses
of 8 mg/kg/day or more also caused increased resorptions and dead fetuses,
dystocia, and delayed parturition, and 40 mg/kg/day resulted in increased
maternal mortality. Single doses of 50 mg/kg caused fetal cataracts, while 200
mg/kg caused cleft palate.
Following injection of clomiphene citrate 2 mg/kg to mice and rats during
pregnancy, the offspring exhibited metaplastic changes of the reproduction
tract. Newborn mice and rats injected during the first few days of life also
developed metaplastic changes in uterine and vaginal mucosa, as well as
premature vaginal opening and anovulatory ovaries. These findings are similar to
the abnormal reproductive behavior and sterility described with other estrogens
and antiestrogens.
In rabbits, some temporary bone alterations were seen in fetuses from dams given
oral doses of 20 or 40 mg/kg/day during pregnancy, but not following 8
mg/kg/day. No permanent malformations were observed in those studies. Also,
rhesus monkeys given oral doses of 1.5 to 4.5 mg/kg/day for various periods
during pregnancy did not have any abnormal offspring.
LIVER DISEASE. FERTOMID therapy is contraindicated in patients with liver disease
or a history of liver dysfunction (see also INDICATIONS AND USAGE and ADVERSE
REACTIONS).
ABNORMAL UTERINE BLEEDING. FERTOMID is contraindicated in patients with abnormal
uterine bleeding of undetermined origin (see INDICATIONS AND USAGE).
OVARIAN CYSTS. FERTOMID is contraindicated in patients with ovarian cysts or
enlargement not due to polycystic ovarian syndrome (see INDICATIONS AND USAGE
and WARNINGS).
OTHER. FERTOMID is contraindicated in patients with uncontrolled thyroid or
adrenal dysfunction or in the presence of an organic intracranial lesion such as
pituitary tumor (see INDICATIONS AND USAGE).
WARNINGS:
VISUAL SYMPTOMS
Patients should be advised that blurring or other visual symptoms such as spots
or flashes (scintillating scotomata) may occasionally occur during therapy with
FERTOMID. These visual symptoms increase in incidence with increasing total dose
or therapy duration and generally disappear within a few days or weeks after
FERTOMID is discontinued. Patients should be warned that these visual symptoms may
render such activities as driving a car or operating machinery more hazardous
than usual, particularly under conditions of variable lighting.
These visual symptoms appear to be due to intensification and prolongation of
afterimages. Symptoms often first appear or are accentuated with exposure to a
brightly lit environment. While measured visual acuity usually has not been
affected, a study patient taking 200 mg FERTOMID daily developed visual blurring
on the 7th day of treatment, which progressed to severe diminution of visual
acuity by the 10th day. No other abnormality was found, and the visual acuity
returned to normal on the 3rd day after treatment was stopped.
Ophthalmologically definable scotomata and retinal cell function
(electroretinographic) changes have also been reported. A patient treated during
clinical studies developed phosphenes and scotomata during prolonged FERTOMID
administration, which disappeared by the 32nd day after stopping therapy.
Postmarketing surveillance of adverse events has also revealed other visual
signs and symptoms during FERTOMID therapy (see ADVERSE REACTIONS).
While the etiology of these visual symptoms is not yet understood, patients with
any visual symptoms should discontinue treatment and have a complete
ophthalmological evaluation carried out promptly.
OVARIAN HYPERSTIMULATION SYNDROME
The ovarian hyperstimulation syndrome (OHSS) has been reported to occur in
patients receiving clomiphene citrate therapy for ovulation induction. In some
cases, OHSS occurred following cyclic use of clomiphene citrate therapy or when
clomiphene citrate was used in combination with gonadotropins. Transient liver
function test abnormalities suggestive of hepatic dysfunction, which may be
accompanied by morphologic changes on liver biopsy, have been reported in
association with ovarian hyperstimulation syndrome (OHSS).
OHSS is a medical event distinct from uncomplicated ovarian enlargement. The
clinical signs of this syndrome in severe cases can include gross ovarian
enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural
effusion. In addition, the following symptoms have been reported in association
with this syndrome: pericardial effusion, anasarca, hydrothorax, acute abdomen,
hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian
hemorrhage, deep venous thrombosis, torsion of the ovary, and acute respiratory
distress. The early warning signs of OHSS are abdominal pain and distention,
nausea, vomiting, diarrhea, and weight gain. Elevated urinary steroid levels,
varying degrees of electrolyte imbalance, hypovolemia, hemoconcentration, and
hypoproteinemia may occur. Death due to hypovolemic shock, hemoconcentration, or
thromboembolism has occurred. Due to fragility of enlarged ovaries in severe
cases, abdominal and pelvic examination should be performed very cautiously. If
conception results, rapid progression to the severe form of the syndrome may
occur.
To minimize the hazard associated with occasional abnormal ovarian enlargement
associated with FERTOMID therapy, the lowest dose consistent with expected
clinical results should be used. Maximal enlargement of the ovary, whether
physiologic or abnormal, may not occur until several days after discontinuation
of the recommended dose of FERTOMID. Some patients with polycystic ovary syndrome
who are unusually sensitive to gonadotropin may have an exaggerated response to
usual doses of FERTOMID. Therefore, patients with polycystic ovary syndrome should
be started on the lowest recommended dose and shortest treatment duration for
the first course of therapy (see DOSAGE AND ADMINISTRATION).
If enlargement of the ovary occurs, additional FERTOMID therapy should not be
given until the ovaries have returned to pretreatment size, and the dosage or
duration of the next course should be reduced. Ovarian enlargement and cyst
formation associated with FERTOMID therapy usually regress spontaneously within a
few days or weeks after discontinuing treatment. The potential benefit of
subsequent FERTOMID therapy in these cases should exceed the risk. Unless surgical
indication for laparotomy exists, such cystic enlargement should always be
managed conservatively.
A causal relationship between ovarian hyperstimulation and ovarian cancer has
not been determined. However, because a correlation between ovarian cancer and
nulliparity, infertility, and age has been suggested, if ovarian cysts do not
regress spontaneously, a thorough evaluation should be performed to rule out the
presence of ovarian neoplasia.
PRECAUTIONS:
GENERAL
Careful attention should be given to the selection of candidates for FERTOMID
therapy. Pelvic examination is necessary prior to FERTOMID treatment and before
each subsequent course (see CONTRAINDICATIONS and WARNINGS).
INFORMATION FOR PATIENTS
The purpose and risks of FERTOMID therapy should be presented to the patient
before starting treatment. It should be emphasized that the goal of FERTOMID
therapy is ovulation for subsequent pregnancy. The physician should counsel the
patient with special regard to the following potential risks:
VISUAL SYMPTOMS: Advise that blurring or other visual symptoms occasionally may
occur during or shortly after FERTOMID therapy. Warn that visual symptoms may
render such activities as driving a car or operating machinery more hazardous
than usual, particularly under conditions of variable lighting (see WARNINGS).
The patient should be instructed to inform the physician whenever any unusual
visual symptoms occur. If the patient has any visual symptoms, treatment should
be discontinued and complete ophthalmologic evaluation performed.
ABDOMINAL/PELVIC PAIN OR DISTENTION: Ovarian enlargement may occur during or
shortly after therapy with FERTOMID. To minimize the risks associated with ovarian
enlargement, the patient should be instructed to inform the physician of any
abdominal or pelvic pain, weight gain, discomfort, or distention after taking
FERTOMID (see WARNINGS).
MULTIPLE PREGNANCY: Inform the patient that there is an increased chance of
multiple pregnancy, including bilateral tubal pregnancy and coexisting tubal and
intrauterine pregnancy, when conception occurs in relation to FERTOMID therapy.
The potential complications and hazards of multiple pregnancy should be
explained.
PREGNANCY WASTAGE AND BIRTH ANOMALIES: The physician should explain the assumed
risk of any pregnancy, whether ovulation is induced with the aid of FERTOMID or
occurs naturally. The patient should be informed of the greater risks associated
with certain characteristics or conditions of any pregnant woman, eg, age of
female and male partner, history of spontaneous abortions, Rh genotype, abnormal
menstrual history, infertility history, organic heart disease, diabetes,
exposure to infectious agents such as rubella, familial history of birth
anomaly, that may be pertinent to the patient for whom FERTOMID is being
considered. Based upon the evaluation of the patient, genetic counseling may be
indicated.
The overall incidence of reported birth anomalies from pregnancies associated
with maternal FERTOMID ingestion during the investigational studies was within the
range of that reported in published references for the general population. (See
CONTRAINDICATIONS: Pregnancy.)
During clinical investigation, the experience from patients with known pregnancy
outcome (Table 1) shows a spontaneous abortion rate of 20.4% and stillbirth rate
of 1.0%. (See ACTIONS/CLINICAL PHARMACOLOGY.)
DRUG INTERACTIONS
Drug interactions with FERTOMID have not been documented.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Long-term toxicity studies in animals have not been performed to evaluate the
carcinogenic or mutagenic potential of clomiphene citrate.
Oral administration of FERTOMID to male rats at doses of 0.3 or 1 mg/kg/day caused
decreased fertility, while higher doses caused temporary infertility. Oral doses
of 0.1 mg/kg/day in female rats temporarily interrupted the normal cyclic
vaginal smear pattern and prevented conception. Doses of 0.3 mg/kg/day slightly
reduced the number of ovulated ova and corpora lutea, while 3 mg/kg/day
inhibited ovulation.
PREGNANCY
Pregnancy Category X. (See CONTRAINDICATIONS).
NURSING MOTHERS
It is not known whether FERTOMID is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised if FERTOMID is administered to
a nursing woman. In some patients, FERTOMID may reduce lactation.
OVARIAN CANCER
Prolonged use of clomiphene citrate tablets USP may increase the risk of a
borderline or invasive ovarian tumor (see ADVERSE REACTIONS).
DRUG INTERACTIONS:
Drug interactions with FERTOMID have not been documented.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
CLINICAL TRIAL ADVERSE EVENTS. FERTOMID, at recommended dosages, is generally
well tolerated. Adverse reactions usually have been mild and transient and most
have disappeared promptly after treatment has been discontinued. Adverse
experiences reported in patients treated with clomiphene citrate during clinical
studies are shown in Table 2.
TABLE 2. INCIDENCE OF ADVERSE EVENTS IN CLINICAL STUDIES
(EVENTS GREATER THAN 1%)
(N = 8029*)
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Adverse Event %
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Ovarian Enlargement 13.6
Vasomotor Flushes 10.4
Abdominal-Pelvic Discomfort/
Distention/Bloating 5.5
Nausea and Vomiting 2.2
Breast Discomfort 2.1
Visual Symptoms 1.5
Blurred vision, lights, floaters, waves,
unspecified visual complaints, photophobia,
diplopia, scotomata, phosphenes
Headache 1.3
Abnormal Uterine Bleeding 1.3
Intermenstrual spotting, menorrhagia
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* Includes 498 patients whose reports may have been duplicated in the event
totals and could not be distinguished as such. Also, excludes 47 patients
who did not report symptom data.
The following adverse events have been reported in fewer than 1% of patients in
clinical trials: Acute abdomen, appetite increase, constipation, dermatitis or
rash, depression, diarrhea, dizziness, fatigue, hair loss/dry hair, increased
urinary frequency/volume, insomnia, light- headedness, nervous tension, vaginal
dryness, vertigo, weight gain/loss.
Patients on prolonged FERTOMID therapy may show elevated serum levels of
desmosterol. This is most likely due to a direct interference with cholesterol
synthesis. However, the serum sterols in patients receiving the recommended dose
of FERTOMID are not significantly altered. Ovarian cancer has been infrequently
reported in patients who have received fertility drugs. Infertility is a primary
risk factor for ovarian cancer; however, epidemiology data suggest that
prolonged use of clomiphene may increase the risk of a borderline or invasive
ovarian tumor.
POSTMARKETING ADVERSE EVENTS
The following adverse experiences were reported spontaneously with FERTOMID: The
cause and effect relationship of the listed events to the administration of
FERTOMID is not known.
DERMATOLOGIC: Acne, allergic reaction, erythema, erythema multiforme, erythema
nodosum, hypertrichosis, pruritus
CENTRAL NERVOUS SYSTEM: Migraine headache, paresthesia, seizure, stroke,
syncope
PSYCHIATRIC: Anxiety, irritability, mood changes, psychosis
VISUAL DISORDERS: Abnormal accommodation, cataract, eye pain, macular edema,
optic neuritis, photopsia, posterior vitreous detachment, retinal hemorrhage,
retinal thrombosis, retinal vascular spasm, temporary loss of vision
CARDIOVASCULAR: Arrhythmia, chest pain, edema, hypertension, palpitation,
phlebitis, pulmonary embolism, shortness of breath, tachycardia,
thrombophlebitis
MUSCULOSKELETAL: Arthralgia, back pain, myalgia
HEPATIC: Transaminases increased, hepatitis
NEOPLASMS: Liver (hepatic hemangiosarcoma, liver cell adenoma, hepatocellular
carcinoma); breast (fibrocystic disease, breast carcinoma); endometrium
(endometrial carcinoma); nervous system (astrocytoma, pituitary tumor,
prolactinoma, neurofibromatosis, glioblastoma, multiforme, brain abscess); ovary
(luteoma of pregnancy, dermoid cyst of the ovary, ovarian carcinoma);
trophoblastic (hydatiform mole, choriocarcinoma); miscellaneous (melanoma,
myeloma, perianal cysts, renal cell carcinoma, Hodgkin's lymphoma, tongue
carcinoma, bladder carcinoma); and neoplasms of offspring (neuroectodermal
tumor, thyroid tumor, hepatoblastoma, lymphocytic leukemia)
GENITOURINARY: Endometriosis, ovarian cyst (ovarian enlargement or cysts could,
as such, be complicated by adnexal torsion), ovarian hemorrhage, tubal
pregnancy, uterine hemorrhage
BODY AS A WHOLE: Fever, tinnitus, weakness
OTHER: Leukocytosis, thyroid disorder
FETAL/NEONATAL ANOMALIES. The following fetal abnormalities have also been
reported during postmarketing surveillance: delayed development; abnormal bone
development including skeletal malformations of the skull, face, nasal passages,
jaw, hand, limb (ectromelia including amelia, hemimelia, and phocomelia), foot,
and joints; tissue malformations including imperforate anus, tracheoesophageal
fistula, diaphragmatic hernia, renal agenesis and dysgenesis, and malformations
of the eye and lens (cataract), ear, lung, heart (ventricular septal defect and
tetralogy of Fallot), and genitalia; as well as dwarfism, deafness, mental
retardation, chromosomal disorders, and neural tube defects (including
anencephaly).
DRUG ABUSE AND DEPENDENCE:
Tolerance, abuse, or dependence with FERTOMID has not been reported.
OVERDOSAGE:
SIGNS AND SYMPTOMS
Toxic effects accompanying acute overdosage of FERTOMID have not been reported.
Signs and symptoms of overdosage as a result of the use of more than the
recommended dose during FERTOMID therapy include nausea, vomiting, vasomotor
flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with
pelvic or abdominal pain. (See CONTRAINDICATIONS: Ovarian Cyst.)
ORAL LD50. The acute oral LD50 of FERTOMID is 1700mg/kg in mice and 5750 mg/kg in
rats. The toxic dose in humans is not known.
DIALYSIS: It is not known if FERTOMID is dialyzable.
TREATMENT
In the event of overdose, appropriate supportive measures should be employed in
addition to gastrointestinal decontamination.
DOSAGE AND ADMINISTRATION:
GENERAL CONSIDERATIONS
The workup and treatment of candidates for FERTOMID therapy should be supervised
by physicians experienced in management of gynecologic or endocrine disorders.
Patients should be chosen for therapy with FERTOMID only after careful diagnostic
evaluation (see INDICATIONS AND USAGE). The plan of therapy should be outlined
in advance. Impediments to achieving the goal of therapy must be excluded or
adequately treated before beginning FERTOMID. The therapeutic objective should be
balanced with potential risks and discussed with the patient and others involved
in the achievement of a pregnancy.
Ovulation most often occurs from 5 to 10 days after a course of FERTOMID. Coitus
should be timed to coincide with the expected time of ovulation. Appropriate
tests to determine ovulation may be useful during this time.
RECOMMENDED DOSAGE
Treatment of the selected patient should begin with a low dose, 50 mg daily (1
tablet) for 5 days. The dose should be increased only in those patients who do
not ovulate in response to cyclic 50 mg FERTOMID. A low dosage or duration of
treatment course is particularly recommended if unusual sensitivity to pituitary
gonadotropin is suspected, such as in patients with polycystic ovary syndrome
(see WARNINGS: Ovarian Hyperstimulation Syndrome).
The patient should be evaluated carefully to exclude pregnancy, ovarian
enlargement, or ovarian cyst formation between each treatment cycle.
If progestin-induced bleeding is planned, or if spontaneous uterine bleeding
occurs prior to therapy, the regimen of 50 mg daily for 5 days should be started
on or about the 5th day of the cycle. Therapy may be started at any time in the
patient who has had no recent uterine bleeding. When ovulation occurs at this
dosage, there is no advantage to increasing the dose in subsequent cycles of
treatment. If ovulation does not appear to occur after the first course of
therapy, a second course of 100 mg daily (two 50 mg tablets given as a single
daily dose) for 5 days should be given. This course may be started as early as
30 days after the previous one after precautions are taken to exclude the
presence of pregnancy. Increasing the dosage or duration of therapy beyond 100
mg/day for 5 days is not recommended.
The majority of patients who are going to ovulate will do so after the first
course of therapy. If ovulation does not occur after three courses of therapy,
further treatment with FERTOMID is not recommended and the patient should be
reevaluated. If three ovulatory responses occur, but pregnancy has not been
achieved, further treatment is not recommended. If menses does not occur after
an ovulatory response, the patient should be reevaluated. Long-term cyclic
therapy is not recommended beyond a total of about six cycles (see PRECAUTIONS).
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