Active ingredients: Clomiphene (Clomiphene citrate)
CLOMID 50 mg tablets
Why is Clomid used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Clomiphene citrate, active ingredient of CLOMID, is a synthetic, non-steroidal estrogen, effective in inducing ovulation in women with anovulatory cycles and with insufficient luteal phase cycles.
THERAPEUTIC INDICATIONS
CLOMID is indicated in the treatment of states of lack of ovulation in patients wishing to become pregnant, when sufficient ovarian function has been ascertained. Good levels of endogenous estrus genes (detectable by vaginal smears, biopsy of the endome trio, urinary estrogen dosage or haemorrhage in response to progesterone) constitute favorable prognostic elements. A reduced level of estrogen does not always rule out successful treatment
Contraindications When Clomid should not be used
CLOMID should not be administered during pregnancy, as malformations have been observed in rats and rabbits to which the drug was administered during pregnancy. To avoid inadvertently administering CLOMID during early pregnancy, basal temperature should be measured during treatment cycles.
CLOMID is contraindicated in patients with active liver disease or with known history of hepatic dysfunction.
CLOMID is also contraindicated in patients with menometrorrhagia and in carriers of hormone-dependent neoformations.
Precautions for use What you need to know before taking Clomid
Diagnosis before CLOMID therapy
It is mandatory to perform a thorough examination of the pelvis before treatment and must be repeated before each subsequent therapeutic cycle. CLOMID should not be administered in the presence of an ovarian cyst (or endometriosis involving the ovaries) due to the danger of further enlargement. For the same reason, caution should be exercised in the use of clomiphene in the presence of uterine fibroids.
Visual disturbances
Should transient visual disturbances arise during therapy with CLOMID, such as blurring, spots, flashing (see "Special warnings"), treatment with CLOMID must be stopped immediately.
Ovarian hyperstimulation during CLOMID therapy
Patients should be advised to inform their physician in the event of abdominal or pelvic pain, weight gain, signs or sensation of abdominal distension.
The maximal CLOMID-induced ovarian enlargement, whether physiological or abnormal, does not occur until several days after discontinuation of the recommended dose of CLOMID. due caution to careful abdominal and pelvic examination. If ovary enlargement occurs, CLOMID should be suspended until the ovaries have returned to their pre-treatment size and the dosage or duration of the next cycle should be reduced. Experience has shown that ovarian enlargement and cyst formation in conjunction with CLOMID therapy spontaneously regress a few days or weeks after stopping treatment.
Interactions Which drugs or foods can modify the effect of Clomid
There are no known clinically relevant interactions with other drugs.
Warnings It is important to know that:
Clinical experience has shown that the incidence of multiple pregnancies is increased when conception occurred during a course of CLOMID therapy. In a group of 2369 pregnancies studied, 2183 (92.1%) were single, 165 (6.9% twin), 11 (0.5%) trigeminal, 7 (0.3%) quadruplet, and 3 (0 , 13%) with five births. Therefore, 186 pregnancies (equal to 7.9%) were multiple.
Both the patient and the partner must be advised, before starting treatment, of these possibilities and of the potential complications of multiple pregnancies. Of the 165 twin pregnancies, the ratio of homozygous to dizygotic twins was 1 to 5.
The overall incidence of pregnancy malformations associated with the use of CLOMID was within the limits of that reported in the general population in the literature. A possible increase in the risk of trisomies and Down syndrome has been suggested, but the scarcity of observations does not allow to date to confirm or not this hypothesis and therefore to justify the systematic amniocentesis, in the absence of other factors such as age. advanced or family history. The frequency of abortion or fetal death was 21.4% (spontaneous abortion in 19%), that of ectopic pregnancy was 1.18% while 0.17, 0.04 and 1.01% corresponded to hydatiform mole, papyrus fetus and stillbirth respectively.
Use during pregnancy and during lactation.
CLOMID should not be administered during established and suspected pregnancy. In some cases, a reduction in milk supply and in the lactation period has been observed.
Effects on ability to drive and use of machines.
The occasional occurrence of transient visual disturbances, such as fogging, spots, flashing, can affect driving a motor vehicle or operating machinery especially when there are variable light conditions (see "Precautions for use").
For those who practice sports: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests. The drug is not contraindicated for subjects suffering from celiac disease.
Dosage and method of use How to use Clomid: Dosage
In patients who have not had a recent period, treatment can be started at any time.
If the intention is to induce the flow by administration of progestogens or if it occurs spontaneously immediately before the scheduled therapy, the treatment of 50 mg per day for 5 days should start approximately from the 5th day of the cycle.
When ovulation occurs at this dose there is no advantage in increasing the doses in subsequent treatment cycles.
For the purposes of a possible pregnancy, the "importance of" an appropriate temporal choice for coitus must be emphasized.
If ovulation does not appear after the first course of therapy, a second 5-day therapeutic course can be started with 100 mg / day (2 tablets of 50 mg in a single daily dose).
This course of therapy can begin 30 days after the previous one.
Treatment with doses or duration exceeding 100 mg / day for 5 days should never be undertaken. An eventual 3 cycle of therapy can be instituted in the same way. If ovulatory menstruation is not achieved after 3 cycles, a re-examination of the diagnosis should be made.
However, it is not advisable to prolong therapy beyond the limits indicated above in patients with no signs of ovulation.
The majority of patients exhibit an ovulatory response within 3 courses of treatment. CLOMID should not be administered as monthly maintenance therapy in those patients who recur anovulatory cycles after discontinuation of treatment.
Prolonged use of clomiphene may increase the risk of invasive ovarian metaplasias or malignancies.
Overdose What to do if you have taken too much Clomid
No cases of acute intoxication have been reported. Possible signs and symptoms of chronic intoxication are: nausea and / or vomiting, vasomotor flushing, blurred vision and scotomas, abdominal and / or pelvic pain, weight gain and ascites.
Side Effects What are the side effects of Clomid
At the recommended doses the side effects are not conspicuous and rarely affect the treatment. The most common side effects include: hot flashes, abdominal discomfort (feeling of swelling, or aching or pain), more rarely nausea, vomiting, constipation and diarrhea, enlarged ovaries, clouding of vision (see " "Usage" and "Special Warnings" precautions) and scotomas.
Rare cases of cataracts and optic neuritis have been reported.
Other less frequently reported complaints during therapy are: nausea or vomiting, increased nervous tension, fatigue, dizziness or a slight light-headedness in the head, insomnia, breast pain, more abundant menstruation, urticaria or allergic dermatitis, erythema multiforme, ecchymosis and angioneurotic edema, weight gain, polyuria or pollakiuria. In very few patients a modest, reversible hair loss was also found, almost always during prolonged cycles of therapy.
There have been cases of endometriosis and exacerbation of pre-existing endometriosis during therapy with clomiphene.
There are isolated reports of emergence or aggravation of endocrine-dependent neoplasms. Epileptic seizures have rarely been reported.
It is advisable to communicate to the treating physician any undesirable effects, not included in this leaflet, which may occur during the treatment.
Laboratory tests
Bromosulfonphthalein (BSF) retention greater than 5% has been reported in 32 of the 141 patients in which it was measured. Other liver function tests were usually normal.
In a subsequent study, in which patients were subjected to 6 consecutive monthly cycles of CLOMID (50 and 100 mg per day for 3 days) and a placebo, the BSF tests were performed in 94 patients. Retention values higher than 5% were found in 11 patients of which 6 treated with CLOMID and 5 with placebo. One patient developed jaundice on day 19 of treatment (50 mg per day); liver biopsy revealed biliary stasis with no obvious signs of hepatitis.
Expiry and Retention
WARNING: do not use the medicine after the expiry date indicated on the outer package. Remember that the expiry date refers to the product in intact packaging, correctly stored.
Storage: No special storage precautions.
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH OF CHILDREN
Composition and pharmaceutical form
COMPOSITION
One tablet contains:
Active ingredient: Clomiphene citrate 50 mg. Excipients: Sucrose; Lactose; Soluble corn starch; Magnesium stearate; Cornstarch; Yellow iron oxide.
PHARMACEUTICAL FORM AND PACKAGING
- Box of 10 tablets of 50 mg in blister.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
CLOMID
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One 320 mg tablet contains:
Active ingredient: clomiphene citrate 50 mg
Excipients: sucrose 67.50 mg, lactose 67.50 mg, soluble corn starch 25 mg, magnesium stearate 3 mg, corn starch 106.752 mg, yellow iron oxide 0.248 mg
03.0 PHARMACEUTICAL FORM
Tablets
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
CLOMID is indicated in the treatment of states of lack of ovulation in patients wishing to become pregnant, when satisfactory ovarian function has been ascertained. Good levels of endogenous estrogens (detectable by vaginal smears, endometrial biopsy, urinary estrogen dosage or haemorrhage in response to progesterone) are favorable prognostic elements; a reduced level of estrogen does not always exclude the success of the treatment.
04.2 Posology and method of administration
In patients who have not had a recent period, treatment can be started at any time. If the intention is to induce the flow by administration of progestogens or if the same occurs spontaneously immediately before the scheduled therapy, the treatment of 50 mg per day for 5 days should start approximately from the 5th day of the cycle.
When ovulation occurs at this dose there is no advantage in increasing the doses in subsequent treatment cycles. For the purposes of a possible pregnancy, the "importance of" an appropriate temporal choice for coitus must be emphasized. If ovulation does not appear after the first course of therapy, a second 5-day therapeutic course can be started with 100 mg / day (2 tablets of 50 mg in a single daily dose).
This course of therapy can begin 30 days after the previous one. Treatment with doses or duration exceeding 100 mg / day for 5 days should never be undertaken. A possible 3rd cycle of therapy can be instituted in the same way. If ovulatory menstruation is not achieved after 3 cycles, a re-examination of the diagnosis should be made.
However, it is not advisable to prolong therapy beyond the limits indicated above in patients with no signs of ovulation. The majority of patients exhibit an ovulatory response within 3 courses of treatment. CLOMID should not be administered as monthly maintenance therapy in those patients who recur anovulatory cycles after discontinuation of treatment.
04.3 Contraindications
Pregnancy: malformations have been observed in rats and rabbits given CLOMID during pregnancy; therefore the drug should not be administered during pregnancy.
To avoid inadvertently administering Clomid during early pregnancy, basal temperature should be measured during all treatment cycles.
Hepatopathies: CLOMID therapy is contraindicated in patients with liver disease in progress or with ascertained liver dysfunction in the history.
Menometrorrhagia: CLOMID is contraindicated in patients with menometrorrhagia.
04.4 Special warnings and appropriate precautions for use
Diagnosis before CLOMID therapy:
It is mandatory to perform a thorough examination of the pelvis before treatment and must be repeated before each subsequent therapeutic cycle.
CLOMID should not be administered in the presence of an ovarian cyst (or endometriosis involving the ovaries) due to the danger of further enlargement of the ovaries.
Visual disturbances:
During therapy with CLOMID, transient visual disturbances may occasionally arise, such as blurring, spots, flashing. They can affect the normal performance of certain activities (such as driving a vehicle or operating machinery) especially when there are variable lighting conditions.
If they appear, CLOMID treatment must be permanently discontinued.
Ovarian hyperstimulation during CLOMID therapy:
Patients should be advised to inform their physician in the event of abdominal or pelvic pain, weight gain, signs or sensation of abdominal distension. Maximal CLOMID-induced ovarian enlargement, whether physiological or abnormal, does not occur until several days after discontinuation of the recommended dose of CLOMID. Patient complaining of pelvic pain after administration of CLOMID should undergo careful examination. Enlargement of the ovary occurs, CLOMID should be suspended until the ovaries have returned to their pre-treatment size and the dosage or duration of the next cycle reduced. Experience has shown that ovarian enlargement and cyst formation in conjunction with CLOMID therapy spontaneously regress a few days or weeks after stopping treatment.
Multiple pregnancies:
Clinical experience has shown that the incidence of multiple pregnancies is increased when conception occurred during a course of CLOMID therapy. In a group of 2,369 pregnancies studied, 2,183 (92.1%) were singles, 165 (6.9% twin), 11 (0.5%) triplets, 7 (0.3%) quadruplets, and 3 (0.13) %) with five births. Therefore, 186 pregnancies (equal to 7.9%) were multiple. Both patient and partner should be advised of these possibilities and the potential complications of multiple pregnancies before starting treatment. Of the 165 twin pregnancies, the ratio of homozygous to dizygotic twins was 1 to 5.
The overall incidence of pregnancy malformations associated with the use of CLOMID was within the limits of that reported to the general population in the literature. A possible increase in the risk of trisomies and Down syndrome has been suggested, but the scarcity of observations does not allow today to confirm or not this hypothesis and therefore to justify systematic amniocentesis, in the absence of other factors such as age. advanced or family history.
The frequency of abortion or fetal death was 21.4% (spontaneous abortion in 19%), that of ectopic pregnancy was 1.18% while 0.17, 0.04 and 1.01% corresponded to hydatiform mole, papyrus fetus and stillbirth respectively.
Feeding time:
In some cases, a reduction in milk supply and in the lactation period has been observed.
A thorough examination of the pelvis should be performed prior to treatment and repeated before each subsequent course of therapy. CLOMID should not be administered in the presence of ovarian cyst due to the danger of further enlargement of the ovaries. Particular attention should be paid to patients in an advanced stage of reproductive life due to the higher incidence of anovulatory disorders or the increased tendency to the onset of endometrial carcinomas. Similar attention should be paid to patients with abnormal bleeding before treatment; in particular, it is necessary to ensure that the presence of neoplastic lesions has not escaped observation. In both categories of patients it is necessary to perform a biopsy of the endometrium. Therapy with CLOMID must always be preceded by a clinical assessment of liver function. In order to minimize the risk of abnormal ovarian enlargement, the lowest dose of CLOMID suitable to give a positive result should be used.Some patients with polycystic ovary syndrome may have an exaggerated response to normal doses of CLOMID. In this case, reduced doses and cycle lengths are recommended. Finally, it must be borne in mind that the maximum enlargement of the ovary, whether physiological or abnormal, does not occur until several days after the suspension of the recommended doses of CLOMID.
04.5 Interactions with other medicinal products and other forms of interaction
There are no known clinically relevant interactions with other drugs.
04.6 Pregnancy and lactation
The drug should not be used during pregnancy and breastfeeding
04.7 Effects on ability to drive and use machines
See section 4.4 "Special warnings and precautions for" use "
04.8 Undesirable effects
At the recommended doses the side effects are not conspicuous and rarely affect the treatment. The most common side effects include: hot flashes, abdominal discomfort (bloating, or achiness or pain), more rarely nausea, vomiting, constipation and diarrhea, enlarged ovaries, blurred vision (see "Warnings and Precautions") and scotomas.
Rare cases of cataracts have been reported.
Other less frequently reported disorders during therapy are:
nausea or vomiting, increased nervous tension, fatigue, dizziness or slight lightheadedness in the head, insomnia, breast pain, heavy periods, urticaria or allergic dermatitis, erythema multiforme, ecchymosis and angioneurotic edema, weight gain, polyuria or pollakiuria. Modest, reversible hair loss was also found in very few patients, almost always during prolonged courses of therapy.
Laboratory tests:
Bromosulfonphthalein retention greater than 5% has been reported in 32 of the 141 patients in which it was measured. Other liver function tests were usually normal.
In a subsequent study, in which patients received 6 consecutive monthly courses of CLOMID (50 and 100 mg / day for 3 days) and a placebo, BSF trials were performed in 94 patients. Retention values higher than 5% were found in 11 patients of which 6 treated with CLOMID and 5 with placebo. One patient developed jaundice on day 19 of treatment (50 mg per day); liver biopsy revealed biliary stasis with no obvious signs of hepatitis.
04.9 Overdose
No cases of acute intoxication have been reported.
Possible signs and symptoms of chronic intoxication are: nausea and / or vomiting, vasomotor flushing, blurred vision and scotomas, abdominal and / or pelvic pain, weight gain and ascites.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
The active principle of CLOMID is represented by clomiphene citrate, synthetic estrogen for oral use, non-steroidal, effective in inducing ovulation in women with anovulatory cycles and with insufficient luteal phase cycles. Clomiphene is made up of a racemic mixture of two isomers, respectively called cisclomiphene and transclomiphene, and has been isolated in the course of research on analogues and derivatives of chlorotrianisene, whose use had been highlighted in the treatment of estrogen-dependent pathological situations and in the ability to induce ovulation. Numerous pharmaco-biological studies conducted in animals have shown that clomiphene acts as a weak estrogen and anti-estrogen. The drug was found to be able to block the oestrus cycle in normal rats, to prevent the uterotrophic effect of estrogens in normal or neutered rats, to hinder the antiovulatory action of natural estrogens and to prevent the fixation of true natural estrogens at the level of specific uterine, mammary and possibly hypothalamic receptors. The anti-estrogenic activity of clomiphene appears to be linked to a central action carried out on the hypothalamus and on the pituitary gland. The compound, thanks to the blocking action of the hypothalamic estrogen receptors and the consequent increase in the secretion of pituitary gonadotropins (in particular of the FSH which acts specifically on the mechanisms of follicular maturation at the ovarian level), mimics the physiological premenstrual increase of the follicle gonadotropin - stimulating so that this, in turn, can start the maturation of a series of follicles, as normally occurs at the beginning of each cycle. Clomiphene, therefore, creates the conditions for the subsequent ovulation induced by the feed. positive back that the high estrogenic rates reached will produce at the pituitary level. Clomiphene is devoid of both an androgenic and antiandrogenic action; it does not determine effects on the pituitary-adrenal axis and on the pituitary-thyroid axis; it does not modify, even at doses significantly higher than those recommended in the clinic, the basal ultrasound tracing, nor does it affect the normal values relating to blood pressure and breathing. The drug determines an increase in the basal temperature, while it does not modify, or in some cases it accentuates, the normal appearance of the vaginal cytological modifications typical of progestin activity.
05.2 Pharmacokinetic properties
Clomiphene is rapidly absorbed after oral administration and is predominantly excreted via the faeces. The plasma half-life, in studies conducted with the labeled product, was estimated at 24 hours for intravenous administration in rats and 48 hours for intravenous administration in monkeys.
The existence of an entero-hepatic circulation was evidenced in both the rat and the monkey. In the latter animal species, after six days from oral treatment, when about 90% of the administered dose had already been eliminated in the faeces and, to a lesser extent, in the urine, the maximum residual concentration of 14C was found in the liver and bile; while minimal amounts were found in adrenals, ocular tissue, pancreas, pituitary and ovaries. Intravenously, high levels of 14C were found in ocular tissue in both rats and rabbits and monkeys. The pattern of distribution of the two isomers in the various tissues and organs was very similar to that of clomiphene containing the mixture of the cis and trans forms of clomiphene, as the highest concentrations were obtained in the liver, adrenal gland, eye, ovary and pituitary. a greater affinity of transclomiphene for adipose tissue, this would lead to explain the slow and biphasic excretion of this isomer.
Studies conducted in humans with the 14C-labeled drug also indicated that absorption, after oral administration, is rapid and that elimination occurs mainly with the faeces, for 51% within the first 5 days, while the compound residue and its metabolites are slowly eliminated over the next 5 weeks, most likely through an enterohepatic recirculatory pool. In patients treated with 100 mg of clomiphene, concentrations of the two isomers equal to 14.6 ng / ml and 30.4 ng / ml respectively for cisclomiphene and transclomiphene; at the dose of 150 mg these values were respectively 42.3 and 80.9 mg / ml.
Clomiphene is metabolised by microsomal enzymes of the experimental animal to form desethylclomiphene, 4-hydroxyclomiphene and clomiphene-N-oxide.
05.3 Preclinical safety data
The acute toxicity of clomiphene is very low both for oral and parenteral administration. In mice, the LD50 obtained in the various laboratories was 1700-1919 mg / kg orally, 350-390 mg / kg intravenously and 86 mg / kg intravenously. In rats, the acute toxicity is even lower, resulting in the oral LD50 of 5504-5750 mg / kg and the endoperitoneal route of 449-530 mg / kg. These data indicate that the LD50 values calculated in mice and rats by the oral route are respectively about 1919 and 5750 times higher than the doses of the drug recommended in the clinic. The results of the comparative tests performed by endoperitoneal and oral route also indicated that there are no substantial differences between the LD50 values found for clomiphene and for its two exomers cisclomiphene and transclomiphene.
The results of chronic toxicity tests for 53 weeks repeated oral treatments in the rat and dog (doses of 5, 15 and 40 mg / kg / day) and 180 days in the minipig (5.40 mg / kg / day ) found that the administration of clomiphene can cause, only at doses higher than those used in therapy, some undesirable effects that must be attributed to the peculiar pharmacodynamic activity of the compound. In fact, the variations found in body weight and the appearance of alopecia can be related to the estrogenic activity carried out by the drug, as it is known that estrogens suppress body weight and produce alterations in hair growth. The appearance of cataracts in rats can occur. be a consequence of the action exerted by clomiphene on the metabolism of cholesterol which results in an increase in desmosterol. The toxic effects found on the reproductive system, both in males and females, may represent the result of the pharmacological activity carried out by clomiphene, with particular reference to its peculiar mechanism of action at a central level. Clomiphene administered to mice, rats and rabbits during reproduction studies resulted in undesirable effects on fertility, gestation and fetal and neonatal development at doses generally higher than those recommended in the clinic. These modifications, which must be attributed to the estrogenic action of the drug, seem to be conditioned by the animal species used in the experiments, considering that no teratogenic effects were detected in monkeys even at doses significantly higher than those used in women.
Mutagenicity tests carried out in vitro by means of the Ames and DNA repair tests and those carried out in vivo by the evaluation of chromosomal aberrations in the micronucleus test gave negative results in the sense that they did not show mutagenic effects exerted by clomiphene.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sucrose, lactose, soluble corn starch, magnesium stearate, corn starch, yellow iron oxide
06.2 Incompatibility
No specific cases of incompatibility have been highlighted.
06.3 Period of validity
5 years.
06.4 Special precautions for storage
None.
06.5 Nature of the immediate packaging and contents of the package
Carton containing 10 tablets of 50 mg
06.6 Instructions for use and handling
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07.0 MARKETING AUTHORIZATION HOLDER
BRUNO FARMACEUTICI S.p.A. - Via Delle Ande, 15 - 00144 ROME
08.0 MARKETING AUTHORIZATION NUMBER
Code no. 020773026
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
June 2000
10.0 DATE OF REVISION OF THE TEXT
June 2000
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