INFORMATION FOR HEALTH PROFESSIONALS
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Yellow, biconvex tablet, 9.5 mm in diameter.
PHENATE is a triarylethylene compound (related to chlorotrianisene and triparanol). It is a non-steroidal agent taken by mouth which stimulates ovulation in a high percentage of appropriately selected anovulatory women. The ovulatory response to cyclic PHENATE therapy appears to be mediated through increased output of pituitary gonadotrophins, which in turn stimulates the maturation and endocrine activity of the ovarian follicle and the subsequent development and function of the corpus luteum. The role of the pituitary is indicated by increased urinary excretion of gonadotrophins and the response of the ovary, as manifested by increased urinary oestrogen excretion.
Clomiphene citrate is absorbed from the gastro-intestinal 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 treatment of ovulatory failure in women wishing to become pregnant. PHENATE is indicated only in patients with ovarian dysfunction. Commonly associated diagnoses include polycystic ovary syndrome, lactation amenorrhoea syndrome, psychogenic amenorrhoea, and certain cases of secondary amenorrhoea of undetermined aetiology. An additional indication is post-oral contraceptive amenorrhoea.
The recommended dose for the first course of PHENATE is 50 mg (one tablet) daily for five days. When ovulation occurs at this dosage there is no advantage in increasing the dose in subsequent cycles of treatment. If ovulation occurs at this dosage but is not followed by pregnancy, subsequent courses for a total maximum of six cycles of PHENATE treatment may be administered.
If ovulation appears not to have occurred after the first course of therapy, a second course of 100 mg daily (two 50 mg tablets given as a single daily dose) for five days should be given. If ovulatory menses do not occur, this dose may be repeated for two additional cycles but failure to induce ovulation after three consecutive cycles at this dosage should constitute an adequate therapeutic trial. If, however, ovulation does occur at this dosage but is not followed by pregnancy, subsequent courses for a total maximum of 6 cycles of PHENATE treatment may be administered.
Therapy may be started at any time in a patient who has had no recent uterine bleeding but if progestin-induced bleeding is planned, or if spontaneous uterine bleeding occurs prior to therapy, the course of PHENATE should be started on or about the fifth day of the cycle.
Although there is no evidence that clomiphene has a harmful effect on the human foetus, clomiphene does damage rat and rabbit foetuses when given in high doses to the pregnant animal. Therefore, clomiphene should not be administered during pregnancy. To avoid inadvertent clomiphene administration during early pregnancy, the basal body temperature should be recorded throughout all treatment cycles, and the patient should be carefully observed to determine whether ovulation occurs. If the basal temperature following clomiphene is biphasic and is not followed by menses, the patient should be examined carefully and should have a pregnancy test.
PHENATE should not be given to patients with known liver disease or a history of liver dysfunction.
PHENATE should not be given until the cause of the bleeding has been determined. It is most important to ensure that neoplastic lesions are not overlooked.
Patients should be advised that blurring or other visual symptoms may occasionally occur during PHENATE therapy. The significance of these symptoms is not yet understood. If they do occur PHENATE should be discontinued and a complete ophthalmological evaluation should be made. No further courses of PHENATE should be administered.
Careful evaluation and selection of patients and close attention to dosage instructions, contraindications and side effects are mandatory. Since PHENATE is indicated only in patients with ovarian dysfunction, other possible causes of infertility should be excluded or treated before giving PHENATE.
Pelvic examination should be made before each course of PHENATE is given.
Since PHENATE stimulates the ovaries, it may cause abnormal ovarian enlargement due to over stimulation in some patients. With the exception of patients with polycystic ovary syndrome, PHENATE should not be given in the presence of an ovarian cyst, since further enlargement of the ovary may occur. Patients known to have polycystic ovaries should be given the smallest dose possible of PHENATE with expectation of favourable results. It should be borne in mind that maximal ovarian enlargement may not occur until several days after the treatment cycle is completed. Patients who complain of pelvic pain after receiving clomiphene should be examined with care. If enlargement of the ovary occurs, additional courses of PHENATE should not be given until the ovaries have returned to pre-treatment size, and then a shorter course or smaller dose should be administered. Ovarian enlargement and cyst formation that is occasionally associated with clomiphene therapy regresses spontaneously within a few days or weeks after discontinuing treatment. Unless surgical indication for laparotomy exists, such cystic enlargement should be managed conservatively.
The incidence of multiple pregnancy is increased when conception takes place during a cycle in which clomiphene is given. In a large series of closely monitored patients who became pregnant after receiving clomiphene, there were 6.9% (165) twins, 0.5% (11) triplets, 0.3% (7) quadruplets, and 0.13% (1) quintuplets. Of these multiple pregnancies, 357 live infants were born of 165 multiple births. After excluding 60 neonatal deaths, 297 survived, including 27 of 61 live infants from triplet, quadruplet, and quintuplet pregnancies. In addition, one sextuplet pregnancy has been reported in a patient treated with clomiphene. Patients (and their husbands) should be advised of the possibility and potential complications of multiple pregnancy associated with clomiphene therapy.
Side effects are not prominent and infrequently interfere with treatment when the recommended dosage of clomiphene is given.
Side effects are dose-related being more frequent and more severe when higher doses of clomiphene are administered.
The more common side effects are hot flushes, abdominal discomfort (distension, bloating, pain or soreness), ovarian enlargement and visual blurring. The vasomotor symptoms resembling menopausal hot flushes are not usually severe and disappear soon after treatment is discontinued. Abdominal symptoms are most often related to ovulatory (Mittelschmerz) or pre-menstrual phenomena, or to ovarian enlargement. At recommended dosage the normal variation in ovarian size may be exaggerated. Rare instances of massive ovarian enlargement and rupture of a lutein cyst with haemoperitoneum have been reported.
Visual symptoms, described usually as "blurring" or spots or flashes (scintillating scotomata), increase in incidence with increasing total dose and disappear within a few days or weeks after clomiphene is discontinued. These symptoms appear to be due to intensification and prolongation of after images. Symptoms often first appear or are accentuated with exposure to a more brightly lit environment. While measured visual acuity has not generally been affected, one patient taking 200 mg daily developed visual blurring on the seventh day of treatment, which progressed to severe diminution of visual acuity by the tenth day. No other abnormality was found, and the visual acuity returned to normal on the third day after treatment was stopped. One patient treated during clinical studies developed scotomata during prolonged clomiphene administration, which disappeared by the 32nd day after stopping therapy. In a 34 year old patient who had taken three courses of clomiphene, slit-lamp microscopic examination showed a mild amount of posterior cortical subcapsular capacity in each eye. Ophthalmoscopic examination revealed normal findings. The ocular diagnosis was posterior cortical "senile" cataracts. Ophthalmologically definable scotomata and retinal cell function (electroretinographic) changes have also been reported.
Other less frequently reported symptoms included nausea or vomiting, increased nervous tension, depression, fatigue, dizziness or lightheadedness, insomnia, headache, breast soreness, heavier menses, intramenstrual spotting, weight gain, urticaria and allergic dermatitis, increased urinary frequency, and moderate reversible hair loss.
Defects at birth have been reported in 58 infants from 2,369 delivered pregnancies in mothers treated with clomiphene. Four of the infants were in the abortion/still-birth category, 14 were from multiple pregnancies, and the remaining were single births. The defects have included Down's syndrome (5 infants), congenital heart lesions (8 infants), microcephaly (2 infants), harelip and cleft palate (2 infants), hypospadias (3 infants), undescended testes (2 infants), club foot, (4 infants), gastrointestinal malformations (4 infants), congenital hip (2 infants) and polydactyly (both of twins). Eight of the total of 58 infants were born to 7 of 158 mothers who received (inadvertently) a course of clomiphene during the first 6 weeks after conception.
Clomiphene when given continuously for prolonged periods, may interfere with cholesterol synthesis. Serum from patients treated in this way appears to have elevated desmosterol levels. In patients taking recommended doses of clomiphene serum sterol patterns are not significantly altered.
Bromosulphophthalein (BSP) retention of greater than 5% has been reported in 32 of 141 patients in whom it was measured. Other liver function tests were usually normal. Retention was usually minimal unless associated with prolonged continuous clomiphene administration or with apparently unrelated liver disease. In some patients, pre-existing BSP retention decreased even though clomiphene therapy was continued. One patient developed jaundice on the 14th day of clomiphene therapy, liver biopsy revealed bile stasis without evidence of hepatitis. Clomiphene has not been reported to cause significant abnormality in the haematopoietic or renal system, the protein bound iodine or in serum cholesterol.
Nil.
Nil.
Store below 25°C. Protect from light.
Prescription Medicine.
Tablets (50mg) in blister strips in packs of 5.
Nil.
Mylan New Zealand Limited
PO Box 11-183
Ellerslie
AUCKLAND
Telephone 09-579-2792
2 February 2009