Clomiphene Citrate

INDICATIONS & USAGE Clomiphene citrate tablets are indicated for the treatment of ovulatory dysfunction in women desiring pregnancy. Impediments to achieving pregnancy must be excluded or adequately treated before beginning clomiphene citrate tablets 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 clomiphene citrate tablets 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.) Clomiphene citrate tablets are indicated only in patients with demonstrated ovulatory dysfunction who meet the conditions described below: Patients who are not pregnant. Patients without ovarian cysts. Clomiphene citrate tablets 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 clomiphene citrate tablets treatment. 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. Patients with normal liver function. In addition, patients selected for clomiphene citrate tablets therapy should be evaluated in regard to the following: 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. Primary Pituitary or Ovarian Failure. Clomiphene citrate tablets therapy cannot be expected to substitute for specific treatment of other causes of ovulatory failure. 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 clomiphene citrate tablets therapy in this population. Other Impediments to Pregnancy. Impediments to pregnancy can include thyroid disorders, adrenal disorders, hyperprolactinemia, and male factor infertility. Uterine Fibroids. Caution should be exercised when using clomiphene citrate tablets 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 clomiphene citrate tablets 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 clomiphene citrate tablets is not known. Although the medical literature suggests various methods, there is no universally accepted standard regimen for combined therapy (i.e., clomiphene citrate tablets in conjunction with other ovulation-inducing drugs). Similarly, there is no standard clomiphene citrate tablets regimen for ovulation induction in in vitro fertilization programs to produce ova for fertilization and reintroduction. Therefore, clomiphene citrate tablets are not recommended for these uses.

DOSAGE & ADMINISTRATION General Considerations The workup and treatment of candidates for clomiphene clomiphene citrate tablets therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. Patients should be chosen for therapy with clomiphene citrate tablets 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 clomiphene citrate tablets. 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 clomiphene citrate tablets. 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 clomiphene citrate tablets. 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 clomiphene citrate tablets 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).

CONTRAINDICATIONS Hypersensitivity Clomiphene citrate tablets are contraindicated in patients with a known hypersensitivity or allergy to clomiphene citrate or to any of its ingredients. Pregnancy Clomiphene citrate tablets use in pregnant women is contraindicated, as clomiphene citrate does not offer benefit in this population. Available human data do not suggest an increased risk for congenital anomalies above the background population risk when used as indicated. However, animal reproductive toxicology studies showed increased embryo-fetal loss and structural malformations in offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks to the fetus (See PRECAUTIONS: Pregnancy). Liver Disease. Clomiphene citrate tablets 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. Clomiphene citrate tablets are contraindicated in patients with abnormal uterine bleeding of undetermined origin (see INDICATIONS AND USAGE). Ovarian Cysts. Clomiphene citrate tablets are contraindicated in patients with ovarian cysts or enlargement not due to polycystic ovarian syndrome (see INDICATIONS AND USAGE and WARNINGS). Other. Clomiphene citrate tablets are 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).

ADVERSE REACTIONS Clinical Trial Adverse Events. Clomiphene citrate, 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*) Adverse Event % 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 *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 clomiphene citrate 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 clomiphene citrate 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 reactions have been identified during the post approval use of clomiphene citrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole : Fever, tinnitus, weakness. Cardiovascular: Arrhythmia, chest pain, edema, hypertension, palpitation, phlebitis, pulmonary embolism, shortness of breath, tachycardia, thrombophlebitis. Central Nervous System : Migraine headache, paresthesia, seizure, stroke, syncope. Dermatologic: Acne, allergic reaction, erythema, erythema multiforme, erythema nodosum, hypertrichosis, pruritus, urticaria. Fetal/Neonatal Anomalies: Abnormal bone development: skeletal malformations of the skull, face, nasal passages, jaw, hand, limb (ectromelia including amelia, hemimelia, and phocomelia), foot (clubfoot), spine and joints Cardiac abnormalities: septal heart defects, muscular ventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, and coarctation of the aorta Chromosomal disorders: Downs syndrome Ear abnormalities and deafness Gastrointestinal tract abnormalities: cleft lip and palate, imperforate anus, tracheoesophageal fistula, diaphragmatic hernia, omphalocele Genitalia abnormalities: hypospadias, cloacal exstrophy Lung tissue malformations Malformations of the eye and lens (cataract) Neoplasms: neuroectodermal tumor, thyroid tumor, hepatoblastoma, lymphocytic, leukemia Nervous system abnormalities: neural tube defects (anencephaly, meningomyelocele), microcephaly, and hydrocephalus Renal abnormalities: renal agenesis and renal dysgenesis Others: dwarfism, mental retardation Gastrointestinal: Pancreatitis. Genitourinary: Endometriosis, ovarian cyst (ovarian enlargement or cysts could, as such, be complicated by adnexal torsion), ovarian hemorrhage, tubal pregnancy, uterine hemorrhage, reduced endometrial thickness. Hepatic: Transaminases increased, hepatitis. …

DRUG INTERACTIONS Drug Interactions Drug interactions with clomiphene citrate 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 clomiphene citrate 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.

DESCRIPTION Clomiphene citrate tablets, USP is an orally administered, nonsteroidal, ovulatory stimulant designated chemically as 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy]triethylamine citrate (1:1). It has the molecular formula of C 26 H 28 ClNO.C 6 H 8 O 7 and a molecular weight of 598.08. It is represented structurally as Clomiphene citrate is a white to off-white crystalline powder. It is freely soluble in methanol; slightly soluble in water and chloroform; sparingly soluble in alcohol; and insoluble in ether. Clomiphene citrate is a mixture of two geometric isomers [cis (zuclomiphene) and trans (enclomiphene)] containing between 30% and 50% of the cis-isomer. Each white to off-white, round, scored uncoated, debossed tablets contains 50 mg clomiphene citrate USP. The tablet also contains the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, maize starch. FDA approved dissolution specification differs from the USP dissolution specification. clomiphene-spl-structure

OVERDOSAGE Signs and Symptoms Toxic effects accompanying acute overdosage of clomiphene citrate have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomiphene citrate 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 LD 50 of clomiphene citrate is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known. Dialysis. It is not known if clomiphene citrate is dialyzable. Treatment In the event of overdose, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. To report SUSPECTED ADVERSE REACTIONS, contact Appco Pharma LLC at 1-855-672-7726 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

HOW SUPPLIED Clomiphene Citrate Tablets, USP, 50 mg are white to off-white, round, flat bevel edged tablets, having scoreline with debossed "OPP" and "1068" on one side and another side is plain packed in PVC/ PVDC Blister. They are supplied in cartons of 10 (NDC 16729-723-44) and 30 (NDC 16729-723-51). Store tablets at controlled room temperature 15° to 30°C (59° to 86°F). Protect from heat, light, and excessive humidity, and store in closed containers. Rx Only Manufactured For: Accord Healthcare, Inc., 8041 Arco Corporate Drive, Suite 200, Raleigh, NC 27617, USA. Manufactured by: Oman Pharmaceutical Products Co. LLC. Plot No. 108, Raysut Industrial city, P.O. Box: 2240, P.C.211, Salalah, Sultanate of Oman. Made in Oman Issued August 2025