Bruno Clomid For Women Infertility
- Clomid contains a medicine called clomifene citrate.
- This belongs to a group of medicines called ovulation stimulants.
- It works by stimulating the release of eggs from the ovary (ovulation).
- Clomid is used for some types of infertility, in women who are not ovulating properly.
The active ingredient of Clomid is Clomiphene citrate, a non-steroidal synthetic oestrogen agent for oral use, which stimulates ovulation in women with anovulatory cycles and cycles with insufficient luteal phase.
Clomiphene is a mixture of two geometric isomers (cisclomiphene and transclomiphene), and was isolated during research of analogs and derivatives of chlorotrianisene, which were identified for use in the treatment of oestrogen-dependent pathologies and for stimulating ovulation. The numerous pharmaco-biological studies in animals reported that clomiphene acts as a weak oestrogen and as anti-oestogen. The drug has demonstrated to be able to block the estral cycle of the normal rat, to inhibit the uterophic effects of oestrogens in normal and castrated rats, to obstruct the antiovulatory action of natural oestrogens and to inhibit the fixation of natural oestrogens in the specific uterin, breast, and hypothalamus receptors.
The anti-oestrogen activity of clomiphene seems to be associated with the explicit central hypothalamus and pituitary activity. The compound, thanks to its inhibitory activity of the hypothalamus oestrogen-receptors and the subsequent increased release of pituitary gonadotropin (in particular FSH which specifically acts on the mechanisms of follicle maturation in the ovaries), fakes enhanced physiological premenstrual follicular-stimulating gonadotropin release in a way that this, in turn, stimulates follicle maturation, which occurs normally at the beginning of each mentrual period. Clomiphene, therefore, prepares the ground for subsequent ovulation which is induced from the positive feedback triggered by the elevated levels of oestrogens produced in the pituitary gland.
Clomiphene has neither androgenous nor antiandrogenous activity; has no effect on the pituitary-addrenal and the pituitary-thyroid functions; does not modify the ecographical baseline, nor has any influence on normal levels of arterial pressure and respiration, not even at doses greately superior to the recommended dose. The drug can increase base temperature, but does not modify nor accentuate the normal appearance of vaginal cytology typical of progestinic activity.
Studies with C-14 labeled clomiphene in rats indicate that it is readily absorbed after oral administration and is excreted principally in the faces. The body half-life of C-14 derived from administered clomiphene was 24 hours in the rat (I.P.) and 48 hours in the monkey (IV).
Enterohepatic recirculation was demonstrated in both rat and monkey. After 6 days of treatment in the latter, when approximately 90% of the administered dose was already eliminated mainly via the faeces, and in part via the urine, the maximum residual concentration of 14C was observed in the liver and in the bile; while minimal quantities were observed in the adrenal glands, in the eye, the pancreas, pituitary gland, and in the ovaries. After intravenous administration, high levels of 14C were observed in the eye in rat, rabbit, and monkey. The distribution pattern of the two isomers in the various tissues and organs was similar to the clomiphene contained in mixture of cis and transclomiphene;higher concentrations were observed in liver, adrenal glands, eye, ovaries, and pituitary gland. High affinity of the transclomiphene with adipose tissue was observed, which explains the slow and biphasic excretion rate of this isomer.
Clinical studies in humans with the drug marked with 14C have demonstrated that absorption is rapid, after oral administration, and that elimination occurs predominantly in through the faeces (51% within 5 days) while residual matter and its metabolites are slowly eliminated in 5 weeks, most probably through an enterohepatic circulatory pool. In patients treated with 100 mg of clomiphene concentrations of the two isomers (14.6 ng/mL of cisclomifene and 30.4 ng/mL of transclomifene) were observed in the plasma after 3 hours from administration; at a dose of 150 mg, concentrations were 42.3 and 80.9 ng/mL respectively.
Metabolism of Clomiphene in experimental animals resulted in the formation of desethylclophene, 4 hydroxylclomiphene and clomiphene-N-oxide.
Preclinical safety data
Acute toxicity from clomiphene is very low, after both oral and parenteral administration. From studies in various laboratories in the mouse, DL50 values were 1700-1919 mg/kg for oral administration, 350-390 mg/kg for intraperitoneal administration, and 86 mg/kg for intravenous administration. In the rat acute toxicity levels were even lower; 5504-5750 mg/kg for oral administration, 449-530 mg/kg for intraperitoneal administration.
This information demonstrates that the values of DL50 calculated from studies with mouse and rat after oral administration are respectively about 1919 e 5750 times higher than the doses of drug recommended in humans.
The results of comparative test performed after intraperitoneal and oral administration demonstrated that there were no substantial differences between the values of DL50 for clomiphene the values for its two isomers cisclomiphene transclomiphene.
Results of chronic toxicity tests for repeated treatments via oral administration in 53 weeks in rat and dog (5, 15, 40 mg/kg/day) and in 180 days in minipig (5, 40 mg/kg/day) demonstrated that clomiphene, at doses higher than those used in therapy, can determine adverse effects that are attributable to the peculiar pharmacodynamic activity of the compound. The body weight variations and the appearance of alopecia observed are associated with the product’s oestrogen activity, it is known that oestrogens reduce body weight and modifies hair growth.
Cataract in the rat can be the consequence of the activity of clomiphene on cholesterol metabolism, due to the increase of desmosterol. Toxic effects on both female and male reproductive systems, are associated to the mechanism of activity on the central nervous system peculiar to clomiphene. Administration of clomiphene at doses higher than those used in therapy in mouse, rat, and rabbit during reproductive studies demonstrated adverse effects on fertility, on gestation, and on foetal and neonatal development.
These modiflcations, which are attributable to the oestrogen activity of clomiphene, seem to be influenced by the animal species used in the experiment, considering that teratogenous effects were not observed in the monkey even at doses remarkably superior to those used in women.
Results of mutagenesis conducted in vitro using Ames tests and DNA repair systems, and tests conducted in vivo by evaluating chromosome aberrations and micronuclei were negative in that they did not prove any mutagenous effects induced by Clomiphene.
Clomid is indicated for the treatment of ovulatory failure in women desiring pregnancy and in whom ovulatory disorder is demonstrated. Good levels of endogenous oestrogens (as estimated from vaginal smears, endometrial biopsy, assay of urinary oestregen, or endometrial bleeding in response to progesterone) provide a favourable prognosis; a low level of oestregen does not preclude successful outcome of therapy.
Pregnancy and lactation:
The product must not be administered during pregnancy and lactation. To avoid inadvertent administration of Clomid during the first period of pregnancy, it is adviceable to measure temperature during all treatment cycles.
Treatment with Clomid is contraindicated in patients with liver disease or history of liver dysfunction.
Abnormal uterine bleeding:
Treatment with Clomid is contraindicated in patients with abnormal uterine bleeding of undetermined origin.
Diagnosis before treatment with Clomid:
Before starting treatment and before each subsequent therapy cycle, an accurate examination of the pelvis is mandatory. Clomid should not be administered in the presence of an ovarian cyst (or ovarian endometriosis) since further enlargement of the ovaries is hazardous.
Temporary visual symptoms, such as blurring, spots, flashes, may occasionally occur during treatment with Clomid. Visual symptoms may render activities such as driving or operating machinery, more hazardous than usual, particularly under conditions of variable lighting. If visua sympoms occur, treatment with Clomid should be discontinued.
Ovarian hyperstimulation during treatment with Clomid:
The patients should be instructed to inform the physician of any abdominal or pelvic pain, weight gain, discomfort or distension. Maximal enlargment of the ovary induced by Clomid, whether physiological or abnormal, may not occur until several days after discontinuation of the recommended dose of Clomid. The patient who complains of abdominal or pelvic pain after administration of Clomid should be accurately examined. If abnormal enlargement occurs, Clomid should not be administered until the ovaries have returned to pre-treatment size, and dosage and duration of the subsequent cycle should be reduced. Experience has demonstrated that ovarian enlargement and cyst formation associated with Clomid usually regress spontaneously within a few days or weeks after discontinuing treatment.
Clinical experience has demonstrated that the chance of multiple pregnancy is increased when conception occurs during a cycle of Clomid therapy. In a group of 2369 pregnancies studied, 2.183 (92,1%) were single, 165 (6,9%) twin, 11 (0,5%) triplet, 7 (0,3) quadruplet e 3 (0,13%) quintunplet. Therefore 186 pregnancies (equal to 7.9%) were multiple. Both the patient and partner must be advised, before starting treatment, that multiple pregnancy is a possibility and of all relative potential complications. Of the 165 twin pregnancies the ratio of monozigotic and dizigotic twins was 1:5. The overall incidence of reported malformations from pregnancies associated with Clomid use is similar to that reported in literature for the general population. A possible increase in the risk of trisomy defects and Down’s Syndrome has been suggested, but the reported observations are too few to confirm or not confirm this hypothesis that would justify the need for systemic amniocentesis a part from the other factors such as advanced age or family history. The frequency of pregnancy interruption or foetal death has been reported at 21.4% (miscarrage at 19%), ectopic pregnancies at 1.18% while hydatidiform mole, foetus papyraceous, and stillbirths were reported at 0.17, 0.04, and 1.01% respectively.
There is some evidence that lactation can be reduced in terms of both quantity and time. Before starting treatment and before each subsequent therapy cycle, an accurate examination of the pelvis is mandatory. Clomid should not be administered in the presence of an ovarian cyst (or ovarian endometriosis) since further enlargement of the ovaries is hazardous. Particolar attention must be paid to those patients in advanced maternity age due to the higher incidence of anovulation disorders and the increased risk of endometrial cancer. Equal importance must be given to any abnormal bleeding before treatment; in particular accurate examinations should be performed in order to exclude neoplastic diseases. In both cases endometrial biopsy must be performed.
Before treatment with Clomid epatic functionality must be clinically examined. In order to minimise the risk of abnormal ovarian enlargement associated with Clomid, the patients should be administered the lowest dose able to obtain positive results. Patients with polycystic ovary syndrome may obtain exaggerated therapeutic responses from normal doses of Clomid. In such cases dose and duration of each cycle should be reduced. It is also important to control that the maximun ovarian enlargement, whether physiological or abnormal, does not occur until many days after discontinuation of the recommended doses of Clomid.
For those patients that regularly practice sport: unnecessary therapeutic use of Clomid is considered doping and anti-doping tests can result posiitive
Pregnancy and lactation:
The product must not be administered during pregnancy or lactation.
Effect on ability to drive and use machines:
See under Visual Symptoms above.
No clinically relevant interaction with other drugs.
At the recommended doses adverse effects are not prominent and rarely interfere with treatment. The more commonly reported adverse effects include flushes, abdominal-pelvic discomfort (bloating, pain), rarely nausea, vomiting, constipation, diarrhea, ovarian enlargement, visual blurring (see “Special warnings and precautions for use“) and scotomy.
Rare cases of cataract have been reported.
Other less frequent adverse effects reported during treatment are: nausea or vomiting, increased nervous tension, fatigue, giddines or sense emptiness in the head, insomnia, breast pain, heavy menstruation, urticaria or allergic dermatitis, erythema multiforme, ecchymosis and angioneural edema, weight gain, polyuria or pollakiuria. In a few patients, nearly always during prolonged treatment, modest reversible hair loss has been reported.
Bromsulphalein (BSP) retention of greater than 5% was reported in 32 of 141 patients in whom it was measured. Other hepatic functionality tests were normal. In a later study in which patients were given 6 consecutive monthly cycles of Clomid (50 or 100 mg/day for 3 days) or matching placebo, BSP tests were done on 94 patients. Values in excess of 5% retention were recorded in 11 patients, 6 of whom treated with Clomid and 5 with placebo. One patient taking Clomid 50 mg/day developed jaundice on the 19th day of treatment; liver biopsy revealed bile stasis without evidence of hepatitis.
Dosage & Administration
In the patient who has had no recent menstruation/uterine bleeding, therapy may be started at any time. If uterine bleeding is planned to be induced with progestin, or if spontaneous bleeding occurs immediately before therapy, the regimen of 50 mg daily for 5 days should be started on the 5th day of bleeding.
When ovulation occurs at this dosage, there is no advantage in increasing the dose in subsequent treatment cycles. It must be emphasised that if the first cycle of therapy fails, a second cycle may be started with 100 mg daily (two 50 mg tablets as a single daily dose) for 5 days.
This cycle may be started 30 days after the previous cycle. Increase of the dosage or duration of therapy beyond 100 mg/day for 5 days must not be undertaken. A third cycle of therapy may be undertaken at the same dosage and duration. If ovulatory menses have not occurred after three cycles, the diagnosis should be re-evaluated. Prolonged treatment beyond the above-mentioned limits is not recommended in the patient who does not demonstrate evidence of ovulation.
The majority of patients demonstrate an ovulatory response some time during the three cycles of therapy. Clomid must not be administered as monthly maintenance therapy in those patients with recurring cycles of anovulation after interruption of the treatment.
Acute toxic effects have not been reported. Possible signs and symptoms of chronic intoxication are nausea and/or vomiting, vasomotory flushes, visual blurring and scotomy, abdominal and pelvic pain, weight gain and ascites.
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