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Clomifene Citrate

Last updated on September 18, 2021

(British Approved Name Modified, rINNM)

Drug Nomenclature

Clomifene CitrateSynonyms: Chloramiphene Citrate; Clomifeni Citras; Clomifeno, citrato de; Clomiphene Citrate; Klomifén-citrát; Klomifeenisitraatti; Klomifen-citrát; Klomifencitrat; Klomifeno citratas; MER-41; MRL-41; NSC-35770
BAN: Clomifene Citrate [BANM]
USAN: Clomiphene Citrate
INN: Clomifene Citrate [rINNM (en)]
INN: Citrato de clomifeno [rINNM (es)]
INN: Clomifène, Citrate de [rINNM (fr)]
INN: Clomifeni Citras [rINNM (la)]
INN: Кломифена Цитрат [rINNM (ru)]
Chemical name: A mixture of the E and Z isomers of 2-[4-(2-chloro-1,2-diphenylvinyl)phenoxy]triethylamine dihydrogen citrate
Molecular formula: C26H28ClNO,C6H8O7 =598.1
CAS: 911-45-5 (clomifene); 15690-57-0 ((E)-clomifene); 15690-55-8 ((Z)-clomifene); 50-41-9 (clomifene citrate) ; 7599-79-3 ((E)-clomifene citrate); 7619-53-6 ((Z)-clomifene citrate)
ATC code: G03GB02
Read code: y02cQ

Note. Clomifene may be separated into its Z- and IT-isomers, zu-clomifene and enclomifene.

Pharmacopoeias. In China, Europe, Int, Japan, and US.

European Pharmacopoeia, 6th ed. (Clomifene Citrate). A white or pale yellow, crystalline powder. It contains 30 to 50% of the Z isomer. Slightly soluble in water sparingly soluble in alcohol. Protect from light.

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Clomiphene Citrate). A white to pale yellow, essentially odourless powder. It contains 30 to 50% of the Z isomer. Slightly soluble in water and in chloroform sparingly soluble in alcohol insoluble in ether freely soluble in methyl alcohol.

Adverse Effects

The incidence and severity of adverse effects of clomifene citrate tend to be related to the dose used. The most commonly reported adverse effects are reversible ovarian enlargement and cyst formation, vasomotor flushes resembling menopausal symptoms, and abdominal or pelvic discomfort or pain, sometimes with nausea or vomiting. Ovarian hyper stimulation syndrome has occurred. Breast tenderness, abnormal uterine bleeding, weight gain, headache, and endometrio-sis have also been reported.

Transient visual disturbances such as spots or flashes, after-images, and blurring of vision may occur, and there have been rare reports of cataracts and optic neuritis. Skin reactions such as allergic rashes and urticaria have occasionally been reported and reversible hair loss has been reported rarely. CNS disturbances have included convulsions, dizziness, lightheadedness, nervous tension, fatigue, vertigo, insomnia, and depression. Abnormalities in liver function tests and jaundice have sometimes been reported.

There is an increased risk of multiple births with clomifene therapy, but rarely more than twins. There is also an increased risk of ectopic pregnancy. Although there have been reports of congenital disorders such as neural tube defects or Down’s syndrome in infants born to women treated with clomifene, the role of the drug in the causation of these defects has not been established and the incidence is reported to be similar to that for the general population.

Carcinogen icity

There have been a number of reports suggesting an association between drug therapy to treat infertility by stimulating ovulation and the subsequent development of ovarian cancer. Concern has focused in particular on the use of clomifene citrate and gonadotrophins, and a study has reported an increased risk of ovarian cancer in women who had prolonged clomifene therapy (for one year or more) although not in those who received the drug for a shorter period. No association between gonadotrophin therapy and ovarian cancer was noted in this study.

The conclusions of this study were only tentative, since the numbers who developed ovarian cancer were small it has been pointed out that a successfully achieved pregnancy may reduce the risk of some other cancers, and that the risks and benefits of the procedure are not easy to balance. A review of epi-demiological and cohort studies concluded that clomifene was not associated with any increase in the risk of ovarian cancer when used for less than 12 cycles, but noted conflicting results, limitations of the data, and the need to control for infertility and nulliparity as risk factors for ovarian cancer. Further cohort’ and case-control studies, and pooled analyses, have also found no association between use of clomifene and ovarian cancer.

As a matter of prudence the UK CSM has recommended that clomifene should not normally be used for more than 6 cycles. However, the UK guidelines on the treatment of infertility considered that the limit of 6 cycles related to one course of treatment only. In practice many women required more than one course and it was considered that benefit may be derived from use of up to 12 cycles.

Effects on the CNS

An infertile woman had convulsions when given clomifene citrate only 5 other cases had been reported since 1963.

Effects on the eyes

As mentioned above, clomifene may cause visual disturbances, which resolve on stopping treatment. However, visual symptoms have persisted in a few cases.

Effects on the fetus

After reports of neural tube defects in fetuses conceived after ovulation induction, analyses of congenital defect registers and follow-up studies of clomifene use suggested that the drug might possibly be associated with an increase in risk. However, subsequent studies reported no increased risk, and a pooled analysis of 10 epidemiological studies found no strong evidence to confirm an association.

Further studies have also reported no increased risk of neural tube defects or hypospadias in male offspring after exposure to fertility treatment. However, another case-control study did find a potential association between clomifene and neural tube defects, but noted that because of the low baseline prevalence of the malformation, the absolute risk difference would be small. It is not clear whether the underlying infertility itself affects the risk of congenital defects and whether it may confound the calculated risk associated with clomifene.

Effects on mental function

Acute psychotic reactions with paranoid tendencies have occurred rarely during clomifene use.


Clomifene is contra-indicated in patients with liver disease or a history of liver dysfunction. It should not be used in pregnancy. Clomifene should not be used in women with uterine bleeding that is undiagnosed or caused by hormone-dependent tumours, or in patients with pre-existing mental depression or thrombophlebitis because of the risk of exacerbation. Patients should be warned of the possibility of multiple births.

Clomifene should not be given to women with ovarian cysts, except those with polycystic ovary syndrome, and the lowest doses possible should be used to minimise ovarian enlargement or cyst formation some patients with polycystic ovary syndrome may have an exaggerated response to usual doses of clomifene. Patients should be instructed to report any abdominal or pelvic pain, distension, or weight gain, as this may indicate the presence or enlargement of ovarian cysts. They should also be evaluated for the presence of ovarian cysts before each cycle of treatment.

If abnormal enlargement occurs, clomifene should not be given until the ovaries have returned to pre-treatment size, and subsequent doses should be reduced. Clomifene should be used with caution in patients with uterine fibroids, due to the potential for enlargement of the fibroids.

Treatment should be stopped if visual disturbances develop and the patient warned that this might affect their ability to drive or operate machinery. Long-term cyclic therapy is not recommended, because of the uncertainty regarding increased risk of ovarian cancer: a maximum of 6 cycles of treatment has generally been advised, but see also under Carcinogenicity, above.


Clomifene citrate is absorbed from the gastrointestinal tract. It is metabolised in the liver and slowly excreted via the bile. Unchanged drug and metabolites are excreted in the faeces. The biological half-life is reported to be 5 days although traces are found in the faeces for up to 6 weeks. Enterohepatic recirculation takes place. The E-isomer is reported to be less well absorbed and more rapidly eliminated than the Z-isomer.

Uses and Administration

Clomifene is a nonsteroidal compound that has both oestrogenic and anti-oestrogenic properties, the latter residing principally in the E-isomer. Its action in stimulating ovulation is believed to be related to its anti-oestrogenic properties. It stimulates the secretion of pituitary gonadotrophic hormones, probably by blocking the negative feedback effect of oestrogens at receptor sites in the hypothalamus and pituitary.

Clomifene is the most widely used drug in the treatment of anovulatory infertility. Therapy with clomifene will not be successful unless the woman, though anovulatory, is capable of ovulation and her partner is fertile. It is ineffective in primary pituitary or primary ovarian failure. The usual oral dose is 50 mg of clomifene citrate daily for 5 days, starting on or about the 5th day of the menstrual cycle or at any time if there is amenorrhoea. If ovulation does not occur, a course of 100 mg daily for 5 days may be given starting as early as 30 days after the previous one. Women should be examined for pregnancy and ovarian enlargement or cysts between treatment cycles.

In general, 3 courses of therapy are adequate to assess whether ovulation is obtainable. If ovulation has not occurred, the diagnosis should be re-evaluated. Once ovulation is established, each treatment cycle of clomifene should be started on or about the 5th day of the menstrual cycle. If pregnancy has not occurred after a total of about 6 treatment cycles, licensed product information recommends that no further clomifene therapy should be given (but see also Carcinogenicity). Clomifene has also been used with gonadotrophins.

Clomifene has been used in the treatment of male infertility due to oligospermia to stimulate gonado-trophin release and enhance spermatogenesis, but there is limited convincing evidence of benefit.


British Pharmacopoeia 2008: Clomifene Tablets

The United States Pharmacopeia 31, 2008: Clomiphene Citrate Tablets.

Proprietary Preparations

Argentina: Genozym Serofene

Australia: Clomhexal Clomid Fermil Serophene

Austria: Serophene

Belgium: Clomid Pergotime

Brazil: Clomid Indux Serophene

Canada: Clomid Serophene

Czech Republic: Clomhexal Clostilbegyt Serophene

Denmark: Pergotime

Finland: Clomifen

France: Clomid Pergotime

Germany: Clomhexal

Greece: Serpafar

Hong Kong: Clomid Clostilbegyt Duinum Fertilan Ova-Mit Serophene

Hungary: Clostilbegyt Serophene

India: Clofert Clopreg Fertomid Ovipreg Ovofar Siphene

Indonesia: Blesifen Clomifil Clovertil Fensipros Fertilphen Fertin Genoclom Mestrolin Ofertil Pinfetil Profertil Provula

Ireland: Clomid

Israel: Ikaclomin

Italy: Clomid Prolifen Serofene

Malaysia: Clomid Clostilbegyt Duinum Ova-Mit Ovinum Phenate Serophene

Mexico: Omifin Serophene

The Netherlands: Clomid Serophene

Norway: Pergotime

New Zealand: Phenate Serophene

Philippines: Clomid Clostil I-Clom Ova-Mit

Poland: Clostilbegyt

Por ugal: Dufine

Russia: Clostilbegyt

South Africa: Clomid Clomi-hexal Fertomid Serophene

Singapore: Clomid Clostilbegyt Duinum Ova-Mit Ovinum Phenate Serophene

Spain: Clomifeno Omifin

Sweden: Pergotime

Switzerland: Clomid Serophene

Thailand: Clomid Duinum Ova-Mit Ovinum Serophene

Turkey: Fertilin Gonaphene Klomen Serophene

UK: Clomid

USA: Clomid Serophene

Venezuela: Serophene.

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