Chlorotrianisene/Ciomifene Citrate 2259
occasionally been reported and reversible halr loss has hypospadias in male offspring" after exposure to fertility Clomifene Citrate IBANM, rJNNMI ® been reported rarely. CNS disturbances have included treatment. However, another case-control study12 did find convulsions, dizziness, lightheadedness, nervous tension, a potential association between clomifene and neural tube fatigue, vertigo, iosomnia, and depression. Abnormalities io defects, but noted that because of the low baselioe preva liver function tests and jaundice have sometimes been lence of the malformation, the absolute risk difference reported. would be small. It is not clear whether the underlyiog There is an increased risk of multiple births with iofertility itself affects the risk of congenital defects and clomifene therapy, but rarely more than twios. There is also whether it may confound the calculated risk associated an iocreased risk of ectopic pregnancy. Although there have with clomifene.9 been reports of congenital disorders such as neural tube I. Cornel MC, et al. Ovulation induction and neural tube defects. Lancet defects or Down's syndrome in iofants born to women 1989; i: 1386. treated with clomifene, the role of the drug in the causation 2. Czeizel A. Ovulation induction and neural tube defects. Lancet 1989; ii: 167. of these defects has not been established and the iocidence is 3. Cuckle H, Wald N. Ovulation induction and neural tube defects. Lancet reported to be similar to that for the general population. 1989; ii: 1281. 4. Cornel MC, et al. Ovulation induction, in-vitro fertilisation, and neural Carcinogenicity. There have been several reports suggest tube defects. Lancet 1989; ii: 1530. 5. Vollset SE. Ovulation induction and neural tube defects. Lancet 1990; ing an association between drug therapy to treat infertility 337: 178. by stimulating ovulation and the subsequent development 6. Mills JL, et al. Risk of neural tube defects in relation to maternal fertility of ovarian cancer.1·5 Concern has focused in particular on and fertility drug use. Lancet 1990; 336: 103-4. the use of clomifene citrate and gonadotrophios, and a 7. Rosa F. Ovulation induction and neural tube defects. Lancet 1990; 336: NOTE. Clomifene may be separated into its Z-and E-isomers, 1327. study has reported an increased risk of ovarian cancer io zuclomifene and enclomifene. 8. Werler MM, et al. Ovulation induction and risk of neural tube defects. women who had prolonged clomifene therapy (for one Lancet 1994; 344: 445-6. Chin., Bur. Int., Jpn, US. Pharmacopoeias. In (see p. vii), and year or more) although not in those who received the 9. Greenland S, Ackerman DL. Clomiphene citrate and neural tube defects: Ph, Bur. 8: (Clomifene Citrate). A white or pale yellow, drug for a shorter period.6 No association between a pooled analysis of controlled epidemiologic studies and recommenda tions for future studies. Fertil Steril l995; 64: 936-41. crystalline powder. It contalns 30 to 50% of the Z isomer. gonadotrophic therapy and ovarian cancer was noted io 10. Whiteman D, et al. Reproductive factors, subfertility, and risk of neural Slightly soluble io water; spariogly soluble in alcohol. this study. The conclusions of this study were only tenta tube defects: a case-control study based on the Oxford Record Linkage Protect from light. tive, sioce the numbers who developed ovarian cancer Study Register. Am J Epidemio/ 2000; 152: 823-8. USP 36: were small; it has been pointed out that a successfully II. S0rensen HT, et al. Use of domifene during early pregnancy and risk of (Clomiphene Citrate). A white to pale yellow, hypospadias: population based case-control study. BMJ 2005; 330: 126- essentially odourless powder. It contalns 30 to 50% of the Z achieved pregnancy may reduce the risk of some other 7. isomer. Slightly soluble io water and io chloroform; cancers, and that the risks and benefits of the procedure 12. Wu YW, et al. Potential assodation between infertility and spinal neural sparingly soluble io alcohol; iosoluble io ether; freely are not easy to balance. 7 A review8 of epidemiological and tube defects in offspring. Birth Defects Res A Clin Mol Teratol2006; 76: 718- 22. soluble io methyl alcohol. cohort studies concluded that clomifene was not asso ciated with any increase in the risk of ovarian cancer when used for less than 12 cycles, but noted conllictiog Effectson mentalfunction. Acute psychotic reactions with Uses and Administration results, limitations of the data, and the need to control for paranoid tendencies have occurred rarely during clomi 1•2 Clomifene is a nonsteroidal compound that has both infertility and nulliparity as risk factors for ovarian cancer. fene use. oestrogenic and anti-oestrogenic properties, the latter Further cohort9•10 and case-control" studies, and pooled 1. Siedentopf F, et al. Clomiphene citrate as a possible cause of a psychotic reaction during infertility treatment. Hum Reprod 1997; 12: 706-7. residiog maioly in the E-isomer. Its action io stimulating 12•13 analyses, have also found no association between use 2. Oyffe I, et al. Clomiphene-induced psychosis. Am J Psychiatry I997; 154: ovulation is believed to be related to its anti-oestrogenic of clomifene and ovarian cancer. 1169-70. properties. It stimulates the secretion of pituitary As a matter of prudence the UK CSM has recommended gonadotrophic hormones, probably by blocking the that clomifene should not normally be used for more than 6 negative feedback effect of oestrogens at receptor sites io cycles.14 UK guidelines on the management of infertility15 Precautions the hypothalamus and pituitary. also recommend that clomifene should be used for a Clomifene is contra-indicated in patients with liver disease Clomifene is used in the treatment of anovulatory maximum of 6 months. or a history of liver dysfunction. It should not be used in infertility (p. 2253.1). Therapy with clomifene will not be I. Fishel S, Jackson P. Follicular stimulation for high tech pregnandes: are pregnancy. Clomifene should not be used in women with successful unless the woman, though anovulatory, is we playing it safe? BMJ I989; 299: 309-1 I. uterine bleediog that is undiagnosed or caused by hormone capable of ovulation and her partner is fertile. It is 2. Kulkarni R, McGarry JM. Follicular stimulation and ovarian cancer. BMJ dependent tumours, or in patients with pre-existing mental 299: I989; 740. depression or thrombophlebitis because of the risk of ineffective in primary pituitary or primary ovarian failure. 3. Dietl J. Ovulation and ovarian cancer. Lancet 1991; 338: 445. The usual oral dose is 50 mg of clomifene citrate daily for 5 4. Willemsen W, et al. Ovarian stimulation and granulosa-cell tumour. exacerbation. Patients should be warned of the possibility of days, startiog on or about the fifth day of the menstrual Lancet 1993; 341: 986-8. multiple births. cycle or at any time if there is amenorrhoea. Ovulation is 5. Tewari K, et al. Fertility drugs and malignant germ-cell t1:1.mourof ovary Clomifene should not be given to women with ovarian in pregnancy. Lancet I998; 351: 957-8. expected to occur about 5 to 10 days after a course of cysts, except those with polycystic ovary syndrome, and the 6. Rossing MA, eta!. Ovarian tumors in a cohort of infertile women. N Engl clomifene, and coitus should be timed to coincide with this. J Med I994; 331: 77-6. lowest doses possible should be used to minimise ovarian If ovulation does not occur, a course of 100 mg daily for 5 7. Whittemore AS. The risk of ovarian cancer after treatment for infertility. enlargement or cyst formation; some patients with days may be given starting as early as 30 days after the N Eng! J Med 1994; 331: 805-6. polycystic ovary syndrome may have an exaggerated 8. Duckitt K. Templeton AA Cancer in women with infertility. Curr Opin . response to usual doses of clomifene. Patients should be previous one. Women should be examined for pregnancy Obstet Gynecol i998; 10: 199-203. and ovarian enlargement or cysts between treatment cycles. 9. Potashnik G, et al. Fertility drugs and the risk of breast and ovarian instructed to report any abdominal or pelvic paio, In general, 3 courses of therapy are adequate to assess cancers: results of a long-term follow-up study. Fertil Steril I999; 71: distension, or weight gain, as this may iodicate the presence whether ovulation is obtaioable. If ovulation has not 853-9. or eniargement of ovarian cysts. They should also be 10. Brinton LA, et al. Ovarian cancer risk after the use of ovulation evaluated for the presence of ovarian cysts before each cycle occurred, the diagnosis should be re-evaluated. Once stimulating drugs. Obstet Gynecol 2004; 103: II94- 1203. ovulation is established, each treatment cycle of clomifene 11. Rossing MA, et a!. A case-control study of ovarian cancer in relation to of treatment. If abnormal enlargement occurs, clomifene should be started on or about the fifth day of the menstrual infertility andthe use of ovulation-inducing drugs. Am J Bpidemiol 2004; should not be given until the ovaries have returned to pre cycle. If pregnancy has not occurred within 3 ovulatory 160: 1070-8. treatment size, and subsequent doses should be reduced. 12. Ness RB, et al. Infertility, fertility drugs, and ovarian cancer: a pooled Clomifene should be used with caution in patients with cycles, further treatment is not recommended. A maximum analysis of case-control studies. Am J Bpidemiol 2002; 155: 217-24. of 6 cycles in total is generally advised (see also 13, Kashyap S, et al. Assisted reproductive technology and the incidence of uterine fibroids, due to the potential for enlargement of the Carcinogenicity, below). ovarian cancer: a meta-analysis. Obstet Gynecol 2004; 103: 785-94. fibroids. Clomifene has been used io the treatment of male I4. CSM/MCA. Clomiphene (Clomid., Serophene): possible association with Treatment should be stopped if visual disturbances ovarian cancer. Current Problems 1995; 21: 7, Also available at: http:// develop and the patient warned that this might affect their infertility due to oligospermia to stimulate gonadotrophin www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName= release and enhance spermatogenesis, but there is liotited CON20 15619&RevisionSelectionMethod=LatestReleased (accessed ability to drive or operate machioery. Long-term cyclic convinciog evidence of benefit. 30106108) therapy is not recommended, because of the uncertainty 15. NICE. Fertility: assessment and treatment for people with fertility regarding increased risk of ovarian cancer, and a maximum problems (issued February 2013). Available at: http://www.nice.org.uk/ of 6 cycles of treatment is generally advised (see also Infertility. Reviews. nicemedia/livef14078162769/62769.pdf (accessed 30/10/13) I. Homburg R. Clomiphene citrate-end of an era? a mini-review. Hum Carcinogenicity, above). Reprod 2005; 2.0: 2043-5 1. 2. cedrin-Dumerin I. Centre !'utilisation du citrate de clomifene dans les Effects on the CNS. An iofertile woman had convulsions infertilites inexpliquees. Gynecol Obstet Ferti1 2006; 34: 61-5. when given clomifene citrate; 1 only 5 other cases had Pharmacokinetics 3. Merviel P. Pour une utilisation raisonnable du citrate de domifene dans been reported sioce 1963. les infertilities inexpliquees. Gynecol Obstet Fertil 2006; 34: 66-9. Clomifene citrate is absorbed from the gastrointestioal tract. I. Rimmington MR, et al. Convulsions after clomiphene citrate. BMJ 1994; 4. The Practice Committee of the American Society for Reproductive It is metabolised io the liver and slowly excreted via the bile. 309: 512. Medidne. Use of clomiphene dtrate in women. Fertil Steril 2006; 86 (5 Unchanged drug and metabolites are excreted in the faeces. suppl): SI87-SI93. The biological half-life is reported to be 5 days although Effects on the eyes. As mentioned above, clomifene may traces are found in the faeces for up to 6 weeks. cause visual disturbances, which resolve on stoppiog treat Enterohepatic recirculation takes place. The E-isomer is Adverse Effects ment. However, visual symptoms have persisted in a few reported to be less well absorbed and more rapidly The incidence and severity of adverse effects of clomifene cases.1 elimioated than the Z-isomer. citrate tend to be related to the dose used. The most 1. Purvin VA. Visual disturbance secondary to clomiphene citrate. Arch commonly reported adverse effects are reversible ovarian Ophthalmol l995; 113: 482-4. References, enlargement and cyst formation, vasomotor flushes 1. Szutu M, et al. Pharmacokinetics of intravenous clomiphene isomers. Br 27: resembliog menopausal symptoms, and abdominal or pelvic Effects onthefetus. After reports of neural tube defects io J Clin Pharmaco/ 1989; 639-40. 2. Ghobadi C, et al. Single-dose pharmacok:inetic study of clomiphene discomfort or pain, sometimes with nausea or vomiting. fetuses conceived after ovulation ioduction, analyses of citrate isomers in anovular patients with polycystic ovary disease. J Clin Ovarian hyperstimulation syndrome has occurred. Breast congenital defect registers and follow-up studies of clomi Pharmacol 2009; 49: 147-54. tenderness, abnormal uterine bleeding, weight gaio, fene use suggested that the drug might possibly be asso headache, and endometriosis have also been reported. ciated with an increase in risk.1-5 However, subsequent �r.�E��!��n.� Transient visual disturbances such as spots or flashes, after studies reported no increased risk, •-• and a pooled analy ...... (details are given in Volume B) images, and blurriog of vision may occur, and there have sis' of 10 epidemiological studies found no strong evidence ProprielaryPreparafions been rare reports of cataracts and optic neuritis. Skin to confirm an association. Further studies have also Single-ingredient Preparafions. Arg. : Genozym; Serofene; Toco reactions such as allergic rashes and urticaria have reported no increased risk of neural tube defects10 or feno; Austral. : Clomhexalt; Clomid; Fermilt; Serophene; Belg,:
The symbol t denotes a preparation no longer actively marketed The symbol ® denotes a substance whose use may be restricted io certain sports (see p. viii) 2260 Sex Hormones and their Modulators
Clomid; Pergotime; Braz.: Clomid; Indux; Serophene; Canad.: dihydroequilin, relative to the labelled content of conju Haemorrhagic disorders. Case reports and small studies Clomid; Serophene; Chile: Serophene; Zimaquin; China: Ferti� gated oestrogens. have described the use of high-dose conjugated oestrogens !an Cz. : Clomhexalt; Clostilbegyt; Denm.: Pergotime; (itJ!!t":); If it is obtained from natural sources it is a buff -coloured in the management of haemorrhagic disorders associated Fin.: Clomifen; Fr.: Clomid; Pergotime; Ger.: Clomhexalt; Gr.: amorphous powder which is odourless or has a slight with renal failure, r "s although it is unclear how oestrogens Serpafar; Hong Kong: Clostilbegyt; Fertilan; Ova-Mitt; might reduce prolonged bleeding times in these patients.6 Serophene; Hung.: Clostilbegyt; India: Clofert; Clomidac; Clo characteristic odour; the synthetic form is a white to light Treatment has been given orally, but an intravenous dose miriv; Clomit; Clopreg; Clowin; Fertifact; Fertik; Fertomid; Fer buff -coloured crystalline or amorphous powder, odourless of 600 micrograms/kg given over 30 to 40 minutes, once ton; Fertova; Fetrop; Folistim; Fulfyn; Mephy; Omidte; Ovi or with a slight odour. Store at a temperature of 25 degrees, preg; Ovitec; Ovobel; Ovofar; Ovuclom; Siphene; Indon.: excursions permitted between 15 degrees and 30 degrees. daily for 5 days, has been reported most often 6 Blesifen; Clomifilt; Clovertilt; Dipthen; Fensipros; Fertilphen; Conjugated oestrogens have also been used in various Fertin; Genoclom; Mestrolint; Ofertil; Pinfetil; Profertil; Provu Synthetic Conjugated Estrogens,A doses in the management of haemorrhagic cystitis la; Irl.: Clomid; Israel: Ikaclomin; Ital. : Clomid; Prolifen; Sero (p. 2347.3), particularly that caused by high-dose cyclo Malaysia: phosphamide therapy (p. 772.3). The successful use of fene; Clomid; Clostilbegyt; Duinum; Ova-Mit; Ovi S�ntretic.·: sonJugated•· ·•· Oestrogens; A; ..Ll'li"lTeTI1cietK!'!e num; Phenate; Mex. : Omifin; Neth.: Clomid; Serophenet; KoHbl()r>�f:Jo9aHHbte :;ldp()reHbt, A 25 mg intravenously for 2 consecutive days has been Norw. : Pergotime; NZ: Phenatet; Serophene; Philipp.: Clo 7 I UN!/ _.::JM:?oifP i!l.S: reported, as has a regimen consisting of a mg/kg mene; Clomid; Clostil; Ferticlo; Fertyl; I-Clom; Ova-Mit; Ovu intravenous dose followed by 5 mg orally for 3 weeks 8 A let; Ovulin; Pol. : Clostilbegyt; Port.: Dufine; Rus.: Clostilbegyt report' of treatment in 10 patients described the use of oral (lCJ:IocTHJI6enn); S.Afr. : Clomid; Clomihexal; Fertomid; Singa conjugated oestrogens in doses of 6 to 12 mg daily. usually pore: Clomid; Clostilbegyt; Duinum; Ova-Mit; Ovinum; Phe in three divided doses, for durations of 5 days to 16 weeks -' Spain: Swed. : CE·ld:Syntbeli<; C)estrogenstB; nate; Profertil; Serophene; Sunophene; Omifin; CbnJ�ga(ecJ r""'""''"'""d""" Another report10 of therapy in 10 children aged between 8 Pergotime; Switz.: Clomidt; Serophene; Thai.: Clomid; Dui KoHbiOr;�poe.a,.H'lht.e ::)<;Tp()reRbl, . B. and 19 years described intravenous doses of 12.5 to 50mg num; Ova-Mit; Ovinum; Serophene; Turk.: Fertilin; Gona CA S ...,.. 74665.8:13-9. Ukr.: twice daily. often for 2 or 3 days, followed by oral doses phene; Klomen; Serophene; UK: Clomid; Clostilbegyt UNII BLqLAK981"R. (KnocTIDI6erHT); USA: Clomid; Serophene; Venez. : Serophene. ranging from 2.5 mg twice daily to 5 mg four times daily for durations of a few days to about 3 weeks. Multi-ingredientPreparations. India: Ovipro-MF. Uses and Administration Oestrogens have also been used in the treatment of other PharmacopoeialPreparations bleeding disorders (see Estradiol, p. 2272.2). BP 2014: Clomifene Tablets; Conjugated oestrogens have actions and uses similar to l. liu YK, etal. Treatment ofuraemic bleeding with conjugated oestrogen. USP 36: Clomiphene Citrate Tablets. those described for estradiol (see p. 2271.2). Lancet 1984; ii: 887-90. When used as menopausal HRT (p. 2244.2) doses of 0.3 2. Livia M, et al. Conjugated estrogens for the management of bleeding 315: to 1.25 mg daily are given oraliy either cyclically or associated with renal failure. N Engl J Med 1986; 731-5. 3. Seth S, Geier TM. Use of conjugated estrogens to control gastrointestinal continuously; in women with a uterus a progestogen is also tract bleeding in two patients with chronic renal failure. Clin Pharm given either cyclically or continuously. Doses of 0.3 to 1988; 7: 906-9. 1.25 mg may also be used for the prevention of 4. Shemin D, et al. Oral estrogens decrease bleeding time and improve 89: postmenopausal osteoporosis, but oestrogen therapy is clinical bleeding in patients with renal failure. Am 1 Med 1990; 436- 40. generally reserved for women who are at significant risk and 5. Heunisch C, et al. Conjugated estrogens for the management of who cannot be given non-hormonal treatment. Topical gastrointestinal bleeding secondary to uremia of acute renal failure. vaginal therapy may be used specifically for menopausal Pharmacotherapy 1998; 18: 210-7. atrophic vaginitis, atrophic urethritis, and kraurosis vulvae; 6. Hedges SJ, et al. Evidence-based treatment recommendations for uremic bleeding. Nat Clin Pract Nephrol 2007; 3: 138-53. 0.5 to 2 g of a 0.0625% cream may be used daily for 3 weeks 7. Kopterides P, et a!. Cyclophosphamide-induced hemorrhagic cystitis of a 4-week cycle. For moderate to severe dyspareunia successfully treated with conjugated estrogens. Am 1 Hematol 200S; 80: associated with menopausal vulvar and vaginal atrophy. a 166-7. topical vaginal dose of 0.5 g may be used twice weekly in a 8. Rodriguez Luna JM, et al. Control of massive hematuria in idiopathic hemorrhagic cystitis after administration of conjugated estrogen. J Urol Profile continuous regimen, or daily for 3 weeks of a 4-week cycle. (Baltimore) 1992; 148: 1524-5. Clostebol acetate has anabolic properties (see Testosterone, In women with an intact uterus, the endometrial safety of 9. Ordemann R, et a!. Encouraging results in the treatment of topical oestrogen therapy is uncertain. The addition of a haemorrhagic cystitis with estrogen-report of 10 cases and review of p. 2305.1) and has been given by intramuscular injection 25: progestogen should be considered, although it might not be the literature. Bone Marrow Transplant 2000; 981-5. and orally. It has also been applied topically to wounds and 10. Heath JA, et a!. Estrogen as treatment of hemorrhagic cystitis in children ulcers, and has been used as an ophthalmological required during low-dose, short-term topical oestrogen and adolescents undergoing bone marrow transplantation. Bone Marrow preparation. treatment. During long-term therapy, these women should Transplant 2006; 37: 523-6. be monitored for evidence of endometrial hyperplasia, Preparations whether or not a progestogen is also used. Adverse Effects and Precautions ...... When given as replacement therapy on a cyclical basis, ProprietaryPreparations (details are given in Volume B) oral doses of 1.25 mg daily are used for primary ovarian As for oestrogens in general (see Estradiol, p. 2273.2). See Single-ingredient Preparations. Chile: Trofodermint. failure, adjusted according to response. Doses of 300 to also under Hormone Replacement Therapy, p. 2246.3 and 625 micrograms daily are usually given for female p. 2250.1. Braz.: Clostemin; Novaderm; Tro Multi�ingredient Preparations. hypogonadism, although higher doses were formerly used. fodermin; Chile: Trofodermin Neomicinat; Ital.: Trofodermin; For the palliative treatment of prostatic carcinoma Effects on the cardiovascular system. In an early study of Mex. : Neobol. (p. 712.3). an oral dose of 1.25 to 2.5mg three times daily men with a previous myocardial infarction, treatment with has been used. A dose of I 0 mg three times daily for at least conjugated oestrogens 5 mg daily was stopped because of a 3 months has been used for palliative treatment of breast higher incidence of subsequent coronary events. 1 More Coniugated Oestrogens carcinoma in men (p. 704. 1) and postmenopausal women over, treatment with the lower 2.5 mg dose was later also Estro ens; kon)u�(o!Cfut;.Estrog�na (p. 702.1). stopped because of suggestions of adverse trends including Co[")jugated
All cross-references refer to entries in Volume A