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CLOMIPHENE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) ClomiPHENE citrate is a nonsteroidal ovulatory stimulant.

Specific Substances

    1) 2-(p-(2-chloro-1,2-diphenylvinyl)phenoxy) trethylamine citrate (1:1)
    2) Chloramiphene citrate
    3) Clomifene citrate
    4) MER-41
    5) MRL-41
    6) NSC 35770
    7) Molecular Formula: C26-H28-ClNO.C6-H8-O7
    8) CAS 911-45-5
    9) Chloramiphene
    10) Clomifene

Available Forms Sources

    A) FORMS
    1) ClomiPHENE citrate is available as 50 mg tablet (Prod Info CLOMID(R) oral tablets, 2012).
    B) USES
    1) ClomiPHENE citrate is indicated for the treatment of ovulatory failure in patients desiring pregnancy (Prod Info CLOMID(R) oral tablets, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: ClomiPHENE citrate, also known as Clomid(R), is a nonsteroidal ovulatory stimulant and is indicated for the treatment of ovulatory failure in patients desiring pregnancy. It may also be used in the treatment of corpus luteum insufficiency, male infertility, hypothalamic-pituitary-gonadal axis dysfunction in males, and for ovarian function studies.
    B) PHARMACOLOGY: The mechanism stimulating ovulation is unknown, but is believed to be related to its antiestrogenic properties. The ovulatory response to clomiPHENE is mediated through increased output of pituitary gonadotropins, which stimulates the maturation of the ovarian follicle and development of the corpus luteum by increasing follicle stimulating hormone and luteinizing hormone release. Ovulation occurs 6 to 12 days after a course of therapy.
    C) TOXICOLOGY: ClomiPHENE is category X in pregnancy. It should not be utilized in patients with liver disease, thrombophlebitis, pregnancy, ovarian cysts (exception is those with polycystic ovarian syndrome), hormone-dependent tumors, uterine fibroids, or abnormal bleeding.
    D) EPIDEMIOLOGY: ClomiPHENE ingestion is an uncommon cause of poisoning. Ingestions are usually unintentional and rarely result in severe manifestations.
    E) WITH THERAPEUTIC USE
    1) Cystic ovarian enlargement occurs in 10% to 15% of patients. Other effects include flushing, abdominal discomfort, distention, bloating, nausea and vomiting, and central nervous system effects (ie, nervousness, blurry vision, spots, scotomata, insomnia, dizziness, and headache).
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Includes flushing abdominal pain, ovarian enlargement, pelvic pain, nausea, vomiting, visual blurring, spots or flashes, and scotomata. Mild ovarian hyperstimulation symptoms include nausea, vomiting, diarrhea, and weight gain.
    2) SEVERE TOXICITY: Severe ovarian hyperstimulation syndrome may include gross ovarian enlargement, ascites, dyspnea, oliguria, pleural effusion, pericardial effusion, anasarca, acute abdominal pain, hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian hemorrhage, ovarian torsion, deep venous thrombosis, respiratory distress, electrolyte imbalances, hypovolemia, hypoproteinemia, hemoconcentration, and shock.
    0.2.20) REPRODUCTIVE
    A) ClomiPHENE is classified as FDA pregnancy category X. Maternal toxicity (ie, abortion, ectopic pregnancies) and embryo-fetal toxicity (ie, heart defects, spina bifida, and tissue malformations), and minor skeletal anomalies have been reported with human and animal studies. ClomiPHENE should not be administered to a pregnant woman.

Laboratory Monitoring

    A) Laboratory studies are generally unnecessary since clomiPHENE overdose patients manifest mild signs and symptoms.
    B) Monitor serum electrolytes, liver function, renal function, and urinalysis after significant overdose or in suspected ovarian hyperstimulation syndrome.
    C) Consider monitoring acetaminophen and salicylate concentrations after deliberate overdose.
    D) Monitor fluid intake and output, daily weight, abdominal girth, and clinical evidence of thromboembolic events in patients with suspected ovarian hyperstimulation syndrome.
    E) Ultrasound may be useful to monitor for ascites or ovarian cysts.
    F) Monitor chest radiograph in patients with respiratory distress or suspected hydrothorax.
    G) ClomiPHENE levels are not readily available or clinically useful in guiding management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Most exposures are mild and require only supportive care.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Support respiratory and cardiovascular function as needed. For patients with severe ovarian hyperstimulation syndrome, initiate intravenous hydration, monitor fluid input and output, and initiate deep venous thrombosis prophylaxis.
    C) DECONTAMINATION
    1) PREHOSPITAL: In general, no gastrointestinal decontamination is needed in the prehospital setting.
    2) HOSPITAL: Overdose is unlikely to cause severe intoxication; activated charcoal is likely unnecessary in cases of clomiPHENE as the sole ingestant. Consider activated charcoal if more toxic coingestants are involved.
    D) AIRWAY MANAGEMENT
    1) Airway management is not likely to be an issue. Provide supportive care.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Because of its large molecular weight, hemodialysis or other forms of enhanced elimination are of no benefit.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with unintentional ingestions may be observed at home if asymptomatic.
    2) OBSERVATION CRITERIA: Symptomatic patients with uncontrollable nausea, vomiting, or abdominal pain should be evaluated in a healthcare facility. Patients may be discharged if asymptomatic 6 hours after ingestion. Patients with deliberate overdose should be evaluated in a healthcare facility.
    3) ADMISSION CRITERIA: Symptomatic patients requiring ongoing supportive care may need admission. Patients with evidence of ovarian hyperstimulation syndrome may require admission.
    4) CONSULT CRITERIA: Severe poisoning does not usually occur with clomiPHENE; however, if concerned about ovarian hyperstimulation syndrome, consult an obstetrician/gynecologist or specialist in reproductive medicine.
    H) PITFALLS
    1) Failure to consider ovarian hyperstimulation syndrome in patients utilizing clomiPHENE. ClomiPHENE overdose patients generally do well with supportive care. Pay attention to coingestants.
    I) PHARMACOKINETICS
    1) ClomiPHENE is readily absorbed when taken orally, with peak plasma levels occurring 6.5 hours after ingestion. It is metabolized by the liver with enterohepatic recirculation. Half-life is 5 to 7 days.
    J) DIFFERENTIAL DIAGNOSIS
    1) Ovarian hyperstimulation syndrome

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. The highest reported tolerated dose in adults is 200 mg.
    B) THERAPEUTIC DOSE: The recommended dose of clomiPHENE citrate is 50 mg (1 tablet) daily for 5 days. If the patient does not ovulate after the first course of therapy, a second course of 100 mg (maximum dose) may be given as a single daily dose.

Clinical Effects

Summary Of Exposure

    A) USES: ClomiPHENE citrate, also known as Clomid(R), is a nonsteroidal ovulatory stimulant and is indicated for the treatment of ovulatory failure in patients desiring pregnancy. It may also be used in the treatment of corpus luteum insufficiency, male infertility, hypothalamic-pituitary-gonadal axis dysfunction in males, and for ovarian function studies.
    B) PHARMACOLOGY: The mechanism stimulating ovulation is unknown, but is believed to be related to its antiestrogenic properties. The ovulatory response to clomiPHENE is mediated through increased output of pituitary gonadotropins, which stimulates the maturation of the ovarian follicle and development of the corpus luteum by increasing follicle stimulating hormone and luteinizing hormone release. Ovulation occurs 6 to 12 days after a course of therapy.
    C) TOXICOLOGY: ClomiPHENE is category X in pregnancy. It should not be utilized in patients with liver disease, thrombophlebitis, pregnancy, ovarian cysts (exception is those with polycystic ovarian syndrome), hormone-dependent tumors, uterine fibroids, or abnormal bleeding.
    D) EPIDEMIOLOGY: ClomiPHENE ingestion is an uncommon cause of poisoning. Ingestions are usually unintentional and rarely result in severe manifestations.
    E) WITH THERAPEUTIC USE
    1) Cystic ovarian enlargement occurs in 10% to 15% of patients. Other effects include flushing, abdominal discomfort, distention, bloating, nausea and vomiting, and central nervous system effects (ie, nervousness, blurry vision, spots, scotomata, insomnia, dizziness, and headache).
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Includes flushing abdominal pain, ovarian enlargement, pelvic pain, nausea, vomiting, visual blurring, spots or flashes, and scotomata. Mild ovarian hyperstimulation symptoms include nausea, vomiting, diarrhea, and weight gain.
    2) SEVERE TOXICITY: Severe ovarian hyperstimulation syndrome may include gross ovarian enlargement, ascites, dyspnea, oliguria, pleural effusion, pericardial effusion, anasarca, acute abdominal pain, hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian hemorrhage, ovarian torsion, deep venous thrombosis, respiratory distress, electrolyte imbalances, hypovolemia, hypoproteinemia, hemoconcentration, and shock.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Visual symptoms, including blurred vision, lights, floaters, waves, visual complaints, photophobia, diplopia, scotomata, and phosphenes has occurred in 1.5% (n=8029) of patients receiving clomiPHENE citrate(Prod Info ClomiPHENE citrate oral tablets, 2010).
    2) During a clinical trial, a patient experienced blurred vision 7 days after beginning clomiPHENE, 200 mg daily. The patient's vision progressively worsened by the 10th day of treatment. Three days after discontinuing clomiPHENE, the patient's vision returned to normal (Prod Info ClomiPHENE citrate oral tablets, 2010).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches were reported in 1.3% (n=8029) of women who received clomiPHENE during clinical trials (Prod Info ClomiPHENE citrate oral tablets, 2010).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) During clinical trials, dizziness, fatigue, insomnia, nervousness, lightheadedness, and vertigo were reported in less than 1% (n=8029) of women taking clomiPHENE (Prod Info ClomiPHENE citrate oral tablets, 2010).
    b) Although the relationship to clomiPHENE is not known, during a postmarketing study, migraine headache, paresthesia, seizure, stroke, and syncope were reported (Prod Info ClomiPHENE citrate oral tablets, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting occur in approximately 2.2% (n=8029) of patients receiving therapeutic doses during clinical trials (Prod Info ClomiPHENE citrate oral tablets, 2010).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal discomfort, described as abdominal/pelvic discomfort and distension and bloating, has been reported in 5.5% (n=8029) of women receiving clomiPHENE during clinical trials (Prod Info ClomiPHENE citrate oral tablets, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevated transaminases, as well as, occasional reports of hepatitis, have been reported in postmarketing surveillance programs; the causal relationship remains uncertain. Incidence of events remains unknown (Prod Info ClomiPHENE citrate oral tablets, 2010).
    b) Transient abnormalities of liver function tests and morphologic changes observed on liver biopsy have been reportedly associated with the development of ovarian hyperstimulation syndrome (Prod Info ClomiPHENE citrate oral tablets, 2010)

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) HYPERSTIMULATION OF OVARIES
    1) WITH THERAPEUTIC USE
    a) Ovarian hyperstimulation syndrome has been reported after therapeutic use of clomiPHENE. Early effects may include nausea, vomiting, abdominal pain and distention, diarrhea, and weight gain (Prod Info ClomiPHENE citrate oral tablets, 2010).
    b) In severe cases, gross ovarian enlargement, ascites, dyspnea, oliguria, pleural effusion, pericardial effusion, anasarca, acute abdomen, hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian hemorrhage, ovarian torsion, deep venous thrombosis, respiratory distress, electrolyte imbalances, hypovolemia, hypoproteinemia, hemoconcentration, shock, and death may occur (Prod Info ClomiPHENE citrate oral tablets, 2010).
    c) Ovarian hyperstimulation syndrome (OHSS) has developed after 2 courses of clomiPHENE 50 to 100 mg daily for 5 days (Roland, 1970; Scommegna & Lash, 1969).
    d) CASE REPORT: A 38-year-old woman developed ovarian hyperstimulation syndrome 1 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).
    B) HYPERTROPHY OF OVARY
    1) WITH THERAPEUTIC USE
    a) Ovarian enlargement has been reported in 13.6% (n=8029) of women receiving clomiPHENE during clinical trials (Prod Info ClomiPHENE citrate oral tablets, 2010).
    b) Cystic ovarian enlargement has occurred in 10% to 15% of patients (AMA Department of Drugs, 1983).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Vasomotor flushing has been reported in 10.4% (n=8029) of patients receiving clomiPHENE citrate (Prod Info ClomiPHENE citrate oral tablets, 2010).

Reproductive

    3.20.1) SUMMARY
    A) ClomiPHENE is classified as FDA pregnancy category X. Maternal toxicity (ie, abortion, ectopic pregnancies) and embryo-fetal toxicity (ie, heart defects, spina bifida, and tissue malformations), and minor skeletal anomalies have been reported with human and animal studies. ClomiPHENE should not be administered to a pregnant woman.
    3.20.2) TERATOGENICITY
    A) EMBRYO/FETAL RISK
    1) In clinical trials of pregnant mothers administered clomiPHENE, fetal abnormalities reported at a rate of less than 1% included the following: congenital heart lesions, Down syndrome, hypospadias, microcephaly, hemangioma, polydactyly, patent ductus arteriosus, and spina bifida occulta. Neonatal death and fetal death/stillbirth of infants with birth defects have occurred at a rate of less than 1%. In postmarketing surveillance of clomiPHENE, fetal abnormalities have been reported including: delayed development, abnormal bone development, tissue malformations, heart defects (ie, ventricular septal defect and tetralogy of Fallot), as well as dwarfism, deafness, mental retardation, chromosomal disorders, and neural tube defects, including anencephaly (Prod Info clomiphene citrate oral tablets, 2013).
    2) A 26-year-old woman who took 3 courses of clomiPHENE 50 mg/day 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).
    B) CONGENITAL MALFORMATION
    1) Use of either clomiPHENE or letrozole for induction of ovulation did not increase the risk of congenital malformations compared with natural conception. The mean birthweight of babies in the clomiPHENE group was significantly lower than those in the letrozole and natural conception groups. Structural malformations and chromosomal abnormalities were observed in 2.9% of infants in the natural conception group compared with 2.5% in the letrozole group and 3.9% in the clomiPHENE group. Ventricular septal defect was reported in 1 patient in the natural conception group. Malformations in the letrozole group included paraumbilical hernia, congenital deafness, club foot, and albinism. In the clomiPHENE group, there were reports of congenital heart disease, duplication of urethra, cleft lip and palate, inguinal hernia, and neural tube defect. There were 2 reports of Down's syndrome in the clomiPHENE group (Sharma et al, 2014).
    C) ANIMAL STUDIES
    1) LACK OF EFFECT- There was no evidence of teratogenicity in offspring of animals administered oral clomiPHENE at doses of 1.5 to 4.5 mg/kg/day (Prod Info clomiphene citrate oral tablets, 2013).
    2) In pregnant animals treated with oral clomiPHENE citrate 1 to 2 mg/kg/day, hydramnion, edematous fetuses with wavy ribs and other temporary bone changes were reported. With clomiPHENE doses of 8 mg/kg/day, increased resorptions and dead fetuses, dystocia, and delayed parturition occurred. Maternal mortality increased with 40 mg/kg/day doses. Additionally, single clomiPHENE doses of 50 mg/kg and 200 mg/kg caused fetal cataracts and cleft palate, respectively (Prod Info clomiphene citrate oral tablets, 2013).
    3) In studies of animals treated with injectable clomiPHENE citrate 2 mg/kg, metaplastic changes of the reproductive tract were reported in offspring. Newborns developed uterine and vaginal mucosa metaplastic changes, and premature vaginal opening, and anovulatory ovaries during the first few days of life (Prod Info clomiphene citrate oral tablets, 2013).
    4) In studies of pregnant animals given oral clomiPHENE 20 or 40 mg/kg/day, temporary bone alterations were observed in fetuses; there were no anomalies reported following a dose of 8 mg/kg/day. None of these studies demonstrated any permanent malformations (Prod Info clomiphene citrate oral tablets, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified clomiPHENE as FDA pregnancy category X (Prod Info clomiphene citrate oral tablets, 2013).
    2) Use is contraindicated during pregnancy. Do not administer this drug to a pregnant woman (Prod Info clomiphene citrate oral tablets, 2013).
    B) PREGNANCY TESTING
    1) Perform appropriate tests during each treatment cycle to avoid inadvertent exposure during early pregnancy (Prod Info clomiphene citrate oral tablets, 2013).
    C) ABORTION
    1) In clinical trials of 2369 pregnant women treated with clomiPHENE, 483 spontaneous abortions (20.4%), including 28 ectopic pregnancies, 4 hydatidiform moles, and 1 fetus papyraceous, and 24 stillbirths (1%) were reported (Prod Info clomiphene citrate oral tablets, 2013; Prod Info SEROPHENE(R) oral tablets, 2002).
    2) In a trial of 488 infertile women, 209 of which were able to conceive with clomiPHENE, the incidence of adverse pregnancy outcomes, including spontaneous abortion and ectopic pregnancy, were not significantly increased in this group compared with the general population (Nunley et al, 1985).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) Lactation studies with clomiPHENE have not been conducted in humans, and it is not known whether it is excreted into human milk. ClomiPHENE administration may reduce lactation in some patients (Prod Info clomiphene citrate oral tablets, 2013; Prod Info SEROPHENE(R) oral tablets, 2002).
    2) Exercise caution when administering to a lactating woman (Prod Info clomiphene citrate oral tablets, 2013).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Decrease fertility was reported in male animals following administration of clomiPHENE 0.3 or 1 mg/kg/day. Temporary infertility was reported with higher doses (Prod Info clomiphene citrate oral tablets, 2013).
    2) Temporary interruption of the normal cyclic vaginal smear pattern and prevention of conception was reported in female animals administered oral clomiPHENE 0.1 mg/kg/day. Doses of 0.3 mg/kg/day resulted in a reduced number of ovulated ova and corpora lutea. Ovulation was inhibited with doses of 3 mg/kg/day (Prod Info clomiphene citrate oral tablets, 2013).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) Carcinogenicity studies in humans have not been reported.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) Long term carcinogenicity studies in animals have not been initiated (Prod Info Serophene(R), 1994; (Prod Info Clomid(R), clomiphene citrate, 1996).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Laboratory studies are generally unnecessary since clomiPHENE overdose patients manifest mild signs and symptoms.
    B) Monitor serum electrolytes, liver function, renal function, and urinalysis after significant overdose or in suspected ovarian hyperstimulation syndrome.
    C) Consider monitoring acetaminophen and salicylate concentrations after deliberate overdose.
    D) Monitor fluid intake and output, daily weight, abdominal girth, and clinical evidence of thromboembolic events in patients with suspected ovarian hyperstimulation syndrome.
    E) Ultrasound may be useful to monitor for ascites or ovarian cysts.
    F) Monitor chest radiograph in patients with respiratory distress or suspected hydrothorax.
    G) ClomiPHENE levels are not readily available or clinically useful in guiding management of overdose.
    4.1.2) SERUM/BLOOD
    A) Monitor serum electrolytes, liver function, and renal function after significant overdose or in suspected ovarian hyperstimulation syndrome.
    B) Consider monitoring acetaminophen and salicylate concentrations after deliberate overdose.
    C) ClomiPHENE levels are not readily available or clinically useful in guiding management of overdose.
    4.1.3) URINE
    A) Monitor fluid intake and output in patients with suspected ovarian hyperstimulation syndrome.
    4.1.4) OTHER
    A) OTHER
    1) CHEST RADIOGRAPH
    a) Monitor chest radiograph in patients with respiratory distress or suspected hydrothorax.
    2) MONITORING
    a) Monitor daily weight, abdominal girth, and clinical evidence of thromboembolic events in patients with suspected ovarian hyperstimulation syndrome.
    b) Ultrasound may be useful to monitor for ascites or ovarian cysts.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Symptomatic patients requiring ongoing supportive care may need admission. Patients with evidence of ovarian hyperstimulation syndrome may require admission.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with unintentional ingestions may be observed at home if asymptomatic.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Severe poisoning does not usually occur with clomiPHENE; however, if concerned about ovarian hyperstimulation syndrome, consult an obstetrician/gynecologist or specialist in reproductive medicine.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients with uncontrollable nausea, vomiting, or abdominal pain should be evaluated in a healthcare facility. Patients may be discharged if asymptomatic 6 hours after ingestion. Patients with deliberate overdose should be evaluated in a healthcare facility.

Monitoring

    A) Laboratory studies are generally unnecessary since clomiPHENE overdose patients manifest mild signs and symptoms.
    B) Monitor serum electrolytes, liver function, renal function, and urinalysis after significant overdose or in suspected ovarian hyperstimulation syndrome.
    C) Consider monitoring acetaminophen and salicylate concentrations after deliberate overdose.
    D) Monitor fluid intake and output, daily weight, abdominal girth, and clinical evidence of thromboembolic events in patients with suspected ovarian hyperstimulation syndrome.
    E) Ultrasound may be useful to monitor for ascites or ovarian cysts.
    F) Monitor chest radiograph in patients with respiratory distress or suspected hydrothorax.
    G) ClomiPHENE levels are not readily available or clinically useful in guiding management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) In general, no gastrointestinal decontamination is needed in the prehospital setting.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Overdose is unlikely to cause severe intoxication; activated charcoal is likely unnecessary in cases of clomiPHENE as the sole ingestant. Consider activated charcoal if more toxic coingestants are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Most exposures are mild and require only supportive care. For patients with severe ovarian hyperstimulation syndrome, initiate intravenous hydration, monitor fluid input and output, and initiate deep venous thrombosis prophylaxis.
    B) MONITORING OF PATIENT
    1) Laboratory studies are generally unnecessary since clomiPHENE overdose patients manifest mild signs and symptoms.
    2) Monitor serum electrolytes, liver function, renal function, and urinalysis after significant overdose or in suspected ovarian hyperstimulation syndrome.
    3) Consider monitoring acetaminophen and salicylate concentrations after deliberate overdose.
    4) Monitor fluid intake and output, daily weight, abdominal girth, and clinical evidence of thromboembolic events in patients with suspected ovarian hyperstimulation syndrome.
    5) Ultrasound may be useful to monitor for ascites or ovarian cysts.
    6) Monitor chest radiograph in patients with respiratory distress or suspected hydrothorax.
    7) ClomiPHENE levels are not readily available or clinically useful in guiding management of overdose.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Due to the large molecular weight of clomiPHENE (approximately 580), dialysis and similar techniques are not anticipated to be beneficial.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. The highest reported tolerated dose in adults is 200 mg.
    B) THERAPEUTIC DOSE: The recommended dose of clomiPHENE citrate is 50 mg (1 tablet) daily for 5 days. If the patient does not ovulate after the first course of therapy, a second course of 100 mg (maximum dose) may be given as a single daily dose.

Therapeutic Dose

    7.2.1) ADULT
    A) 50 mg (1 tablet) daily for 5 days. If the patient does not ovulate after the first course of therapy, a second course of 100 mg (maximum dose) may be given as a single daily dose for 5 days (Prod Info CLOMID(R) oral tablets, 2012).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The highest reported tolerated dose is 200 milligrams (Jacobson, 1968; Kistner et al, 1966) Shalev et al, 1989).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 390 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 1700 mg/kg (RTECS , 2001)
    3) LD50- (ORAL)RAT:
    a) 5750 mg/kg (RTECS , 2001)

References

General Bibliography

    1) AMA Department of Drugs: AMA Drug Evaluations, 5th. American Medical Association, Chicago, IL, 1983.
    2) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    3) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    4) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    5) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    6) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    7) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    8) Jacobson A: Plasma gonadotropins during clomiphene induced ovulatory cycles. AM J Obstet Gynecol 1968; 102:284-290.
    9) Kistner RW, Lewis JL, & Steiner GJ: Effect of clomiphene citrate on endometrial hyperplasia in the premenopausal female. Cancer 1966; 19:115-126.
    10) MacGillivray J & Klopper A: Clomiphene. Practitioner 1968; 200:727.
    11) Mikkelson TJ, Kroboth PD, & Cameron WJ: Single dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertil Steril 1986; 46:392-396.
    12) Mitchell SY, Fletcher HM, & Williams E: Ovarian hyperstimulation syndrome associated with clomiphene citrate. West Indian Med J 2001; 50(3):227-229.
    13) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    14) Nunley WC, Batemen BG, & Kitchin JD: Reproductive performance of patients treated with clomiphene citrate. South Med J 1985; 78:31-33.
    15) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    16) Product Information: CLOMID(R) oral tablets, clomiphene citrate oral tablets. Sanofi-Aventis U.S. LLC (per FDA), Bridgewater, NJ, 2012.
    17) Product Information: ClomiPHENE citrate oral tablets, ClomiPHENE citrate oral tablets. Teva Pharmaceuticals USA (per DailyMed), Sellersville, PA, 2010.
    18) Product Information: Clomid(R), clomiphene citrate. Merrell Pharmaceuticals, Inc, Kansas City, MO, 1996.
    19) Product Information: SEROPHENE(R) oral tablets, clomiphene citrate oral tablets. Serono,Inc, Rockland, MA, 2002.
    20) Product Information: clomiphene citrate oral tablets, clomiphene citrate oral tablets. Watson Laboratories, Inc. (per DailyMed), Corona, CA, 2013.
    21) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires July/31/2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    22) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    23) Roland M: Problems of ovulation induction with clomiphene citrate with report of a case of ovarian hyperstimulation. Obstet Gynecol 1970; 35:55-62.
    24) Scommegna A & Lash SR: Ovarian overstimulation, massive ascites, and singleton pregnancy after clomiphene. JAMA 1969; 207:753-755.
    25) Sharma S, Ghosh S, Singh S, et al: Congenital malformations among babies born following letrozole or clomiphene for infertility treatment. PLoS One 2014; 9(10):e108219.
    26) Ylikorkala A: Congenital anomalies and clomiphene. Lancet 1975; 2:1262.