Clomiphene Citrate 50 mg

Clomiphene Citrate 50 mg (Clomifene (as clomifene citrate)) · ATC G03GB02

Ovulation stimulant · selective estrogen receptor modulator

Each tablet contains Clomiphene Citrate 50 mg.

For the full list of excipients, see section 6.1.

Tablet for oral administration.

Therapeutic indications

Management of selected endocrine conditions, including ovulation induction and restoration of gonadotropin drive, as determined by a physician.

Posology and method of administration

Take orally as directed by a physician. Swallow whole with water. Do not exceed the prescribed dose.

Contraindications

Known hypersensitivity to the active substance. Pregnancy and breastfeeding. History of thromboembolic disease. Use under specialist supervision only.

Special warnings and precautions for use

Keep out of the reach and sight of children. Contains a substance prohibited in sport (WADA).

Interaction with other medicinal products

Gonadotrophins (hCG, hMG, recombinant FSH)

Additive ovarian stimulation; sequential or combined use markedly increases the risk of ovarian hyperstimulation syndrome and multiple pregnancy, and requires ultrasound and hormonal monitoring.

Tamoxifen and other selective oestrogen receptor modulators

Competition at the same receptor sites with unpredictable net agonist or antagonist effect; concurrent use is not recommended.

Oestrogens and combined hormonal contraceptives

Restore hypothalamic negative feedback and thereby oppose the gonadotrophin-raising action of clomifene, reducing or abolishing its therapeutic effect.

Aromatase inhibitors (e.g. letrozole, anastrozole)

Both act to lower oestrogenic feedback; combination produces additive elevation of FSH and LH with a greater risk of over-response, and should only be undertaken under specialist supervision.

Bexarotene

Has been reported to alter the metabolism and effectiveness of ovulation-inducing agents; contraception and treatment response should be reviewed where the two are used together.

Ursodeoxycholic acid

May reduce the effect of clomifene; the combination has been associated with diminished treatment response.

Use in special populations

Pregnancy and breastfeeding

Contraindicated in pregnancy. Pregnancy must be excluded before each treatment course; clomifene confers no benefit once conception has occurred and animal data indicate foetal harm at high exposures. It may suppress lactation and it is not known whether it is excreted in human milk; use during breastfeeding is not recommended.

Paediatric population

Not indicated. Safety and efficacy have not been established in children or adolescents, and interference with the hypothalamic–pituitary–gonadal axis before completion of puberty and epiphyseal fusion is not appropriate.

Elderly

There is no established indication in the elderly. Where prescribed to older men for hypogonadotrophic hypogonadism, the higher background prevalence of prostatic disease, erythrocytosis and cardiovascular disease requires baseline assessment and periodic monitoring.

Renal impairment

No specific dose recommendation is available; elimination is largely hepatic and biliary, but clinical data in renal impairment are lacking and administration should proceed with caution under supervision.

Hepatic impairment

Contraindicated in the presence of liver disease or a history of hepatic dysfunction, since clomifene is extensively metabolised by the liver and undergoes enterohepatic recirculation; impaired clearance may prolong exposure and increase toxicity.

Ophthalmological and visual monitoring

Patients experiencing any visual disturbance should discontinue and be assessed; visual symptoms are usually reversible on withdrawal but persistent defects have been reported. Driving or operating machinery should be avoided while vision is affected.

Athletes

Clomifene is prohibited at all times, in and out of competition, under Section S4 (Hormone and Metabolic Modulators) of the WADA Prohibited List as an anti-oestrogenic substance. Detection of parent drug or metabolites constitutes an anti-doping rule violation regardless of therapeutic intent.

Undesirable effects

Reproductive system and breast

Ovarian enlargement, ovarian hyperstimulation syndrome, pelvic or abdominal discomfort, intermenstrual spotting, menorrhagia, breast tenderness, endometrial thinning and hostile cervical mucus, multiple gestation

Eye

Blurred vision, scotomata, photophobia, floaters, diplopia, reduced visual acuity and prolonged after-images; visual symptoms are a recognised class effect and warrant immediate discontinuation and ophthalmological assessment

Nervous system

Headache, dizziness, light-headedness, insomnia

Vascular and general

Hot flushes or vasomotor flushing, fatigue, weight gain

Gastrointestinal

Nausea, vomiting, abdominal distension, dyspepsia

Psychiatric

Nervousness, irritability, mood lability, depressed mood

Hepatobiliary

Transient elevation of hepatic transaminases; hepatocellular injury has been reported rarely

Skin and subcutaneous tissue

Rash, urticaria, allergic dermatitis, reversible hair loss

Overdose

Signs and symptoms following overdosage are extensions of the pharmacological action and may include nausea, vomiting, vasomotor flushing, visual disturbance including scotomata and blurring, abdominal or pelvic pain and ovarian enlargement with ascites. There is no specific antidote and no established role for dialysis; management is symptomatic and supportive, with particular attention to fluid balance and to the detection and management of ovarian hyperstimulation, which may develop or worsen for several days after ingestion. Ophthalmological review is indicated where visual symptoms occur.

Pharmacodynamic properties

Clomifene citrate is a non-steroidal triphenylethylene selective oestrogen receptor modulator (ATC G03GB02), supplied as a mixture of the geometric isomers enclomifene and zuclomifene, which differ in receptor kinetics and potency. Its principal action is competitive antagonism at oestrogen receptors within the hypothalamus, which blocks the negative feedback exerted by circulating oestradiol on gonadotrophin-releasing hormone pulsatility. The resulting increase in GnRH pulse frequency stimulates pituitary release of follicle-stimulating hormone and luteinising hormone; in anovulatory women this drives follicular recruitment, maturation and an LH surge culminating in ovulation, whereas in men it raises endogenous LH and consequently intratesticular and serum testosterone. Clomifene retains weak partial oestrogen agonist activity at some peripheral sites, which underlies the anti-oestrogenic effects observed on cervical mucus and the endometrium.

Pharmacokinetic properties

Clomifene citrate is readily absorbed from the gastrointestinal tract after oral administration, with peak plasma concentrations reached within approximately 6 hours. It undergoes hepatic metabolism, principally by demethylation and hydroxylation with subsequent glucuronide conjugation, and enters an enterohepatic recirculation that prolongs residence in the body. Elimination is predominantly biliary and faecal, with a smaller urinary contribution. The two isomers differ markedly in disposition: enclomifene is cleared relatively rapidly with a half-life of the order of a few days, whereas zuclomifene is eliminated very slowly and is detectable in plasma for weeks after a course, with the mixture commonly quoted as having a half-life of about 5 to 7 days; residues have been recovered in faeces up to 6 weeks after administration.

List of excipients

Lactose monohydrate, maize starch, pregelatinised maize starch, povidone K30, colloidal anhydrous silica, magnesium stearate. Uncoated white tablet, wet-granulated to give a uniform 50 mg granulation with reproducible dissolution.

Excipient warnings

Contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Incompatibilities

Not applicable to this dosage form.

Shelf life

36 months from the date of manufacture in the unopened container.

After first opening

No special in-use storage requirements. Keep the tablets in the intact blister until immediately before administration; once pushed through the foil a tablet should be taken at once or discarded.

Storage

Store below 25 °C in a dry place. Keep tablets in the outer carton until use.

Container

50 uncoated tablets in PVC–aluminium push-through blisters (10 tablets per blister, 5 blisters per carton), in a tamper-evident, GS1-serialised outer carton with the patient leaflet. Primary packaging materials are qualified to ISO 15378. Not all pack sizes may be marketed.

Disposal

No special requirements for handling. Any unused medicinal product or waste material, including partially used blisters and the outer carton, should be disposed of in accordance with local requirements; do not dispose of via wastewater or household waste.

Pack

50 Tablets

GTIN

05012345678916

Serial

8529 6307 4185 16

LOT

CC2702B

MFG

04 / 2027

EXP

04 / 2030

Every carton carries a GS1 DataMatrix and a verification code; a pack can be checked at ergopharm.net/verify.

Ergopharm Advanced Research Centre, Tandalja, Vadodara, Gujarat 390012, India. For Export Only.

Report a suspected adverse reaction or quality defect to pv@ergopharm.net.