Active ingredients: Medroxyprogesterone (Medroxyprogesterone acetate)
FARLUTAL 150 mg / 3 ml Suspension Injectable for intramuscular use
Farlutal package inserts are available for pack sizes:- FARLUTAL 150 mg / 3 ml Suspension Injectable for intramuscular use
- Farlutal 250 mg tablets, Farlutal 500 mg tablets, Farlutal 500 mg / 5 ml oral suspension, Farlutal 1 g / 10 ml oral suspension
- Farlutal 10 mg Tablets, Farlutal 20 mg Tablets
- FARLUTAL 500 mg / 2.5 ml Suspension Injectable for Intramuscular Use, FARLUTAL 1 g / 5 ml Suspension Injectable for Intramuscular Use
Why is Farlutal used? What is it for?
THERAPEUTIC CATEGORY
Progestin.
THERAPEUTIC INDICATIONS
Endometriosis, secondary amenorrhea, palliative treatment of hormone-dependent neoplasms (urogenital system and breast).
Contraindications When Farlutal should not be used
Hypersensitivity to the active substance or to any of the excipients.
Medroxyprogesterone (MPA) is contraindicated in patients with the following conditions:
- known or suspected pregnancy
- bleeding of an undetermined nature
- severe liver failure
- suspected or early stage breast cancer
Precautions for use What you need to know before taking Farlutal
The use of the specialty with estrogens, progestogens and their combinations should not be allowed during pregnancy; in childbearing age it must be preceded by a pregnancy test.
The preparation can lead to the formation of buttock infiltrates; it is therefore advisable to shake the suspension before use and inject it deeply into internal muscular areas.
Interactions Which drugs or foods can modify the effect of Farlutal
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Concomitant administration of Farlutal with aminoglutethimide can significantly depress the bioavailability of Farlutal and the therapeutic effect can be reduced.
Patients using high doses of FARLUTAL should be advised of the decrease in efficacy with the use of aminoglutethimide.
Medroxyprogesterone acetate (MPA) is metabolised primarily by hydroxylation via CYP3A4 in vitro. No specific drug-drug interaction studies have been conducted to evaluate the clinical effects of CYP3A4 inducers or MPA inhibitors.
Warnings It is important to know that:
- In the case of vaginal bleeding, a diagnostic assessment is recommended.
- Since progestogens can cause some degree of fluid retention, conditions that may be affected by this factor should be monitored.
- Patients with a history of clinical depression should be carefully monitored during therapy with medroxyprogesterone.
- A decrease in glucose tolerance was noted during progestogen treatment. For this reason, diabetic patients should be kept under close surveillance during progestogen therapy.
- Pathologists (laboratory) should be advised of the patient's use of medroxyprogesterone if endometrial or endocervical tissue is examined.
- The physician / laboratory should be advised that the use of medroxyprogesterone may decrease the levels of the following endocrine markers:
- to. plasma / urine steroids (e.g. cortisol, estrogen, pregnanediol, progesterone, testosterone)
- b. Plasma / urine gonadotropins (e.g. LH and FSH)
- c. Sex hormone binding globulin
- If there is a sudden partial or total loss of vision or in the case of exophthalmos, diplopia or migraine, before continuing the treatment, perform an ophthalmic check in order to exclude the presence of papillae edema and retinal vascular lesion.
- Medroxyprogesterone has not been associated with the induction of thrombotic or thromboembolytic disorders, however its use is not recommended in patients with a history of venous thromboemolism (VTE). It is recommended that medroxyprogesterone treatment be discontinued in patients who develop VTE.
- Medroxyprogesterone can cause Cushingoid symptoms.
- Some patients on medroxyprogesterone may experience suppressed adrenal function. Medroxyprogesterone can decrease blood levels of ACTH and hydrocortisone.
- The physician / laboratory must be informed that in addition to the endocrine biomarkers listed in the section "Special warnings and appropriate precautions for use, the use of medroxyprogesterone for oncological indication may also determine a" partial adrenal insufficiency (decreased response of the pituitary axis adrenal) during the metopyrone test, thus demonstrating the ability of the adrenal cortex to respond to ACTH before administering metopyrone.
- Administration of both single and multiple doses of medroxyprogesterone may result in prolonged anovulation with amenorrhea and / or irregular menstrual flows.
- Hypercalcemia in patients with bone metastases.
- Hepatic insufficiency (see "Contraindications" section).
- Kidney failure.
Age is not a limiting factor in therapy, however progestin treatment can mask the onset of climacteric.
Reduction in bone mineral density
The reduction in serum estrogen levels due to medroxyprogesterone acetate may result in a reduction in bone mineral density in premenopausal women. This reduction in bone mineral density is of particular concern during adolescence and early adulthood, critical periods for bone growth. Bone reduction is greater with increasing duration of use and may not be completely reversible. It is not known whether the use of injectable medroxyprogesterone by younger women could lead to a reduction in bone mass and increased risk of osteoporotic fractures in later life. In both adult and adolescent women, the reduction in bone mineral density during treatment appears to be substantially reversible and ovarian estrogen production is increased after medroxyprogesterone for injectable use is interrupted.
A retrospective cohort study to evaluate the effect of injectable medroxyprogesterone on the incidence of bone fractures was conducted in 312,395 contraceptive women in the UK. Fracture incidence rates (IRRs) were compared between medroxyprogesterone users and non-users.
The incidence rate ratio for each fracture during the follow-up period (every 5.5 years) was 1.41 (95% CI 1.35, 1.47). Comparisons were made between the sub-cohorts (N = 166,367) during the follow-up period and the six months prior to the first recorded contraceptive treatment between the data obtained before and after that period. Comparing medroxyprogesterone users and non-users, the percentage of "incidence per fracture" before treatment "(IRR 1.28, 95% CI 1.07, 1.53) was compared to the percentage of" incidence "after treatment". (IRR 1.37, 95% CI 1.29, 1.45). The overall results of this study lead to the conclusion that the higher incidence of fractures among medroxyprogesterone users is mainly due to other factors rather than medroxyprogesterone exposure. over two years) for birth control or endometrial treatments only if other similar treatments are not adequate. Medroxyprogesterone should be evaluated when a woman requires continued long-term use of the drug. In adolescent women, the interpretation data on medroxyprogesterone should take into account the patient's age and skeletal maturity.
Other methods of birth control or endometrial treatments should be considered in risk / benefit analyzes in women with osteoporotic risk factors such as:
- Chronic use of tobacco and / or alcohol
- Chronic use of drugs that can reduce bone mass, eg. anticonvulsants or corticosteorides
- Reduction in body mass index or eating disorders, eg. anorexia nervosa or bulimia
- Bone metabolism disorders
- Strong family history of osteoporosis
- Prolonged anovulation with amenorrhea and / or menstrual disturbances may follow the administration of a single or multiple injectable dose of medroxyprogesterone.
All patients are advised to take an adequate amount of calcium and vitamin D.
In the absence of comparable data, the risks identified in the Women 's Health Initiative Study (WHI) should also be considered similar to other dosages of estrogen conjugated with oral medroxyprogesterone acetate and in the case of other combinations and related pharmaceutical forms. to hormone therapy.
Breast cancer
An increased risk of breast cancer has been reported following the use of oral estrogen-progestogen combinations in postmenopausal women. Results derived from a randomized, placebo-controlled clinical trial, the WHI clinical trial, and epidemiological studies have reported an increased risk of breast cancer in women who have been taking the estrogen-progestogen combination as hormone therapy for several years. The excess risk increases with duration of use, as revealed by the WHI study with conjugated equine estrogens (CEE) plus MPA, and observational studies. An increase in abnormal mammograms with the use of estrogen plus progestogen has also been reported, requiring further evaluation.
Cardiovascular diseases
Estrogen alone or in combination with progestogens should not be taken for the prevention of cardiovascular disease. Several prospective, randomized studies on the long-term effects of combined estrogen-progestogen treatment in postmenopausal women have shown an increased risk of cardiovascular events such as myocardial infarction, coronary artery disease, stroke and venous thromboembolism.
Coronary artery disease
There is no evidence from randomized, controlled clinical trials of cardiovascular benefits from the continuous combined use of conjugated estrogens (CEE) and medroxyprogesterone acetate (MPA). Two extended clinical trials (WHI CEE / MPA and Heart and Estrogen / progestin Replacement Study- HERS) showed a possible increased risk of cardiovascular morbidity in the first year of treatment and no overall benefit.
In WHI's WHI CEE / MPA study, an increased risk of coronary events (defined as non-fatal myocardial infarction and fatal coronary artery disease) was observed in women taking CEE / MPA compared to those receiving placebo (37 vs. 30 per 10,000 people per year). An increased risk of venous thromboembolism was observed in the first year of treatment and persisted throughout the observation period.
Stroke
In the WHI CEE / MPA study, an increased risk of stroke was observed in women taking CEE / MPA compared to those receiving placebo (29 vs. 21 per 10,000 people per year). The increased risk was observed in the first year of treatment and persisted throughout the observation period.
Venous thromboembolism / pulmonary embolism
Hormone therapy is associated with a higher relative risk of venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. In the WHI CEE / MPA study of the WHI, twice the frequency of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, was observed in women taking CEE / MPA compared to those receiving placebo. The increased risk was observed in the first year of treatment and persisted throughout the observation period (see section Special warnings).
Dementia
The WHIMS (Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, of CEE / MPA administration, showed an increased risk of probable dementia in postmenopausal women aged 65 and over. years.
In addition, CEE / MPA therapy did not prevent mild cognitive impairment (MCI) in these women. The use of hormone therapy (HT) to prevent dementia or mild cognitive impairment in women 65 years of age and older is not recommended.
Ovarian cancer
Some epidemiological studies have found that the use for five or more years of estrogen products alone or of estrogen plus progestogens in postmenopausal women has been associated with an increased risk of ovarian cancer. Patients who used it. in the past estrogen products alone or estrogen plus progestogens did not present any increased risk of ovarian cancer. Other studies did not show any significant association. The WHI CEE / MPA study reported that estrogen plus progestogens increased the risk of ovarian cancer, but this risk is not statistically significant.In one study, women using HRT showed an increased risk of fatal ovarian cancer.
Recommendations on history and physical examination
A complete medical history should be taken before starting hormone therapy. The pre-treatment and periodic physical examination must pay particular attention to blood pressure, pelvic, abdominal organs and breasts, including cervical cytology.
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medication.
Pregnancy
Medroxyprogesterone acetate is not recommended in pregnant women. Some data suggest a possible relationship between the administration of progestins in the first trimester of pregnancy and the presence of genital malformations in fetuses in particular circumstances.
Newborns born to unexpected pregnancies, occurring 1 or 2 months after medroxyprogesterone acetate injection, may be at increased risk of low birth weight, which, consequently, is associated with an increased risk of neonatal death. The attributable risk is low as the probability of pregnancy is low while using medroxyprogesterone acetate There is no definitive information for the other formulations of medroxyprogesterone acetate.
If the patient becomes pregnant while using this drug, she should be advised of the potential risk to the fetus.
Feeding time
Medroxyprogesterone and its metabolites are excreted in breast milk. There is no evidence to suggest that this poses a risk to the infant.
Effects on ability to drive and use machines
The effect of medroxyprogesterone acetate on the ability to drive and use machines has not been systematically evaluated.
Important information about some of the ingredients:
FARLUTAL contains methyl para-hydroxybenzoate. It can cause allergic reactions (even delayed) and, exceptionally, bronchospasm.
FARLUTAL contains propyl para-hydroxybenzoate. It can cause allergic reactions (even delayed) and, exceptionally, bronchospasm.
Farlutal contains less than 1mmol (23mg) sodium per vial, ie it is virtually "sodium free".
Dosage and method of use How to use Farlutal: Dosage
Endometriosis: 50 mg per week or 100 mg every two weeks for at least six months.
Secondary amenorrhea: after estrogen treatment, inject 50 mg as a single dose on day 15 of the artificial cycle.
Palliative treatment of hormone-dependent neoplasms: the dosage generally varies, depending on the location, from 1,000 to 3,000 mg per week (to be divided into 2-3 administrations: deep intramuscular injections). Normally the lower dosages were used in ca. of the endometrium, the highest ones in the breast in the advanced and metastatic phase.
Farlutal can be suitably combined with other anti-neoplastic treatment modalities (chemotherapy, radiotherapy).
Overdose What to do if you have taken too much Farlutal
No data are known about it.
In case of accidental ingestion / intake of an excessive dose of FARLUTAL, notify your doctor immediately or go to the nearest hospital.
If you have any questions about the use of FARLUTAL, ask your doctor or pharmacist.
Side Effects What are the side effects of Farlutal
Like all medicines, FARLUTAL can cause side effects, although not everybody gets them
Table of adverse reactions (in gynecological and oncological use)
* The frequency of these AEs was calculated based on data from 4 clinical studies in cancer patients involving approximately 1300 patients
Additional adverse events reported in the post-marketing setting
Rare cases of osteoporosis including osteoporotic fractures in patients taking intramuscular medroxyprogesterone acetate have been reported post-marketing.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly via the national reporting system at "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". more information on the safety of this medicine. "
Expiry and Retention
Expiry: see the expiry date indicated on the package.
WARNING: Do not use the medicine after the expiry date indicated on the package.
The expiry date refers to the product in intact packaging, correctly stored.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
Keep this medicine out of the sight and reach of children.
COMPOSITION
Each bottle contains: active ingredient: medroxyprogesterone acetate 150 mg.
Excipients: macrogol "4000"; polysorbate "80"; methyl-para-hydroxybenzoate; propyl-para-hydroxybenzoate; sodium chloride: sodium carmellose; water for injections.
PHARMACEUTICAL FORM AND CONTENT
Suspension for injection for intramuscular use
FARLUTAL 150 mg / 3 ml, 1 bottle
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
FARLUTAL 150 MG / 3 ML INJECTABLE SUSPENSION FOR INTRAMUSCULAR USE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
FARLUTAL 150 mg / 3 ml INJECTABLE SUSPENSION FOR INTRAMUSCULAR USE
Each 3ml bottle contains:
active ingredient: medroxyprogesterone acetate 150 mg.
Excipients with known effects: methyl para-hydroxybenzoate; propyl para-hydroxybenzoate, sodium chloride.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Suspension for injection.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Endometriosis, secondary amenorrhea, palliative treatment of neoplasms
hormone-dependent (urogenital system and breast).
04.2 Posology and method of administration
Administer intramuscularly only.
Endometriosis: 50 mg per week or 100 mg every two weeks for at least six months.
Secondary amenorrhea: after estrogen treatment, inject 50 mg as a single dose on day 15 of the artificial cycle.
Palliative treatment of hormone-dependent neoplasms: the dosage generally varies, depending on the location, from 1,000 to 3,000 mg per week (to be divided into 2-3 administrations: deep intramuscular injections).
Normally the lower dosages were used in ca. of the endometrium, the highest ones in the breast in the advanced and metastatic phase.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients, listed in section 6.1.
Medroxyprogesterone (MPA) is contraindicated in patients with the following conditions:
• known or presumed pregnancy
• bleeding of an undetermined nature
• severe hepatic insufficiency
• suspected or early stage breast cancer
04.4 Special warnings and appropriate precautions for use
• In the case of vaginal bleeding, a diagnostic investigation is recommended.
• Since progestogens can cause some degree of fluid retention, conditions that may be affected by this factor should be monitored.
• Patients with a history of clinical depression should be carefully monitored during therapy with medroxyprogesterone.
• A decrease in glucose tolerance has been noted during treatment with progestogens. For this reason, diabetic patients should be kept under close surveillance during progestogen therapy.
• Pathologists (laboratory) should be informed of the patient's use of medroxyprogesterone if endometrial or endocervical tissue is examined.
• The physician / laboratory should be advised that the use of medroxyprogesterone may decrease the levels of the following endocrine markers:
to. plasma / urine steroids (e.g. cortisol, estrogen, pregnanediol, progesterone, testosterone)
b. Plasma / urine gonadotropins (e.g. LH and FSH)
c. Sex hormone binding globulin
• If there is a sudden partial or total loss of vision or in the case of exophthalmos, diplopia or migraine, before continuing the treatment, perform an ophthalmic check in order to rule out the presence of papillae edema and retinal vascular lesion.
• Medroxyprogesterone has not been associated with the induction of thrombotic or thromboembolytic disorders, however its use is not recommended in patients with a history of venous thromboemolism (VTE). It is recommended that medroxyprogesterone treatment be discontinued in patients who develop VTE.
• Medroxyprogesterone can cause Cushingoid symptoms.
• Some patients being treated with medroxyprogesterone may experience suppressed adrenal function. Medroxyprogesterone can decrease blood levels of ACTH and hydrocortisone.
• The physician / laboratory should be informed that in addition to the endocrine biomarkers listed in the section "Special warnings and appropriate precautions for use (section 4.4)", the use of medroxyprogesterone for oncological indication may also result in "partial adrenal insufficiency (decrease response of the pituitary-adrenal axis) during the metopyrone test. Thus it is necessary to demonstrate the ability of the adrenal cortex to respond to ACTH before administering metopyrone.
• Administration of both single and multiple doses of medroxyprogesterone may result in prolonged anovulation with amenorrhea and / or irregular menstrual flows.
• Hypercalcemia in patients with bone metastases.
• Hepatic insufficiency (see section 4.3 "Contraindications").
• Kidney failure
Age is not a limiting factor in therapy, however progestin treatment can mask the onset of climacteric.
The preparation can lead to the formation of buttock infiltrates; it is therefore advisable to shake the suspension before use and inject it deeply into internal muscular areas.
Reduction of Bone Mineral Density
The reduction in serum estrogen levels due to medroxyprogesterone acetate may result in a reduction in bone mineral density in premenopausal women. This reduction in bone mineral density is of particular concern during adolescence and early adulthood, critical periods for bone growth. Bone reduction is greater with increasing duration of use and may not be fully reversible. It is not known whether the use of injectable medroxyprogesterone by younger women may lead to a reduction in bone mass and increased risk of osteoporotic fractures in later life. In both adult and adolescent women, the reduction in bone mineral density during treatment appears to be substantially reversible and the production of ovarian estrogen increased after medroxyprogesterone for injectable use is discontinued (see section 5.1 - Pharmacodynamic properties).
A retrospective cohort study to evaluate the effect of injectable medroxyprogesterone on the incidence of bone fractures was conducted in 312,395 contraceptive women in the UK. Fracture incidence rates (IRRs) were compared between medroxyprogesterone users and non-users. The incidence rate ratio for each fracture during the follow-up period (every 5.5 years) was 1.41 (95% CI 1.35, 1.47) Comparisons were made between the sub-cohorts (N = 166,367) during the follow-up period and the six months prior to the first recorded contraceptive treatment between the data obtained before and after that period. users or not of medroxyprogesterone, the percentage of "incidence per fracture" before treatment "(IRR 1.28, 95% CI 1.07, 1.53) was compared to the percentage of" incidence "after treatment" ( IRR 1.37, 95% CI 1.29, 1.45). The overall results of this study lead to the conclusion that the higher incidence of fractures among medroxyprogesterone users is mainly due to other factors rather than exposure to medroxyprogesterone.
Medroxyprogesterone for injectable use should be used long-term (e.g. over two years) for birth control or endometrial treatments only if other similar treatments are not adequate. Medroxyprogesterone should be evaluated when a woman needs long-term continuous use of the drug. In adolescent women, the interpretation of medroxyprogesterone data should take into account the patient's age and skeletal maturity.
Other methods of birth control or endometrial treatments should be considered in risk / benefit analyzes in women with osteoporotic risk factors such as:
• Chronic use of tobacco and / or alcohol
• Chronic use of drugs that can reduce bone mass, eg. anticonvulsants or corticosteroids
• Reduction of body mass index or eating disorders, eg. anorexia nervosa or bulimia
• Bone metabolism disorders
• Strong family history of osteoporosis
• Prolonged anovulation with amenorrhea and / or menstrual disturbances may follow the administration of a single or multiple injectable dose of medroxyprogesterone
All patients are advised to take an adequate amount of calcium and vitamin D.
In the absence of comparable data, the risks identified in the Women 's Health Initiative Study (WHI) clinical trial (see section 5.1 - Pharmacodynamic properties) should also be considered similar to other dosages of estrogen conjugated with oral and oral medroxyprogesterone acetate. case of other combinations and pharmaceutical forms related to hormone therapy.
Breast cancer
An increased risk of breast cancer has been reported following the use of oral estrogen-progestogen combinations in postmenopausal women. Results derived from a randomized, placebo-controlled clinical trial, the WHI clinical trial, and epidemiological studies (see section 5.1 - Pharmacodynamic properties) have reported an increased risk of breast cancer in women who have been taking the estrogen-progestogen combination as hormone therapy for several years. The excess risk increases with duration of use, as revealed by the WHI study with conjugated equine estrogens (CEE) plus MPA, and observational studies. An increase in abnormal mammograms with the use of estrogen plus progestogen has also been reported, requiring further evaluation.
Cardiovascular diseases
Estrogen alone or in combination with progestogens should not be taken for the prevention of cardiovascular disease. Several prospective, randomized studies on the long-term effects of combined estrogen-progestogen treatment in postmenopausal women have shown an increased risk of cardiovascular events such as myocardial infarction, coronary artery disease, stroke and venous thromboembolism.
Coronary artery disease
There is no evidence from randomized, controlled clinical trials of cardiovascular benefits from the continuous combined use of conjugated estrogens (CEE) and medroxyprogesterone acetate (MPA). Two extended clinical trials (WHI CEE / MPA and Heart and Estrogen / progestin Replacement Study- HERS) (see section 5.1 - Pharmacodynamic properties) showed a possible increased risk of cardiovascular morbidity in the first year of treatment and no overall benefit.
In WHI's WHI CEE / MPA study, an increased risk of coronary events (defined as non-fatal myocardial infarction and fatal coronary artery disease) was observed in women taking CEE / MPA compared to those receiving placebo (37 vs. 30 per 10,000 people per year). An increased risk of venous thromboembolism was observed in the first year of treatment and persisted throughout the observation period.
Stroke
In the WHI CEE / MPA study, an increased risk of stroke was observed in women taking CEE / MPA compared to those receiving placebo (29 vs. 21 per 10,000 people per year). The increased risk was observed in the first year of treatment and persisted throughout the observation period.
Venous thromboembolism / pulmonary embolism
Hormone therapy is associated with a higher relative risk of venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. In the WHI CEE / MPA study of the WHI, twice the frequency of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, was observed in women taking CEE / MPA compared to those receiving placebo. The increased risk was observed in the first year of treatment and persisted throughout the observation period (see section 4.4 - Special warnings and special precautions for use).
Dementia
The WHIMS study (Women 's Health Initiative Memory Study (WHIMS) (see section 5.1 - Pharmacodynamic properties), an ancillary study of WHI, related to the administration of CEE / MPA, showed an increased risk of probable dementia in post-graduate women. menopause aged 65 years or older.
In addition, CEE / MPA therapy did not prevent mild cognitive impairment (MCI) in these women. The use of hormone therapy (HT) to prevent dementia or mild cognitive impairment in women 65 years of age and older is not recommended.
Ovarian cancer
Some epidemiological studies have found that the use for five or more years of estrogen products alone or of estrogen plus progestogens in postmenopausal women has been associated with an increased risk of ovarian cancer. Patients who used it. in the past estrogen products alone or estrogen plus progestogens did not present any increased risk of ovarian cancer. Other studies did not show any significant association. The WHI CEE / MPA study reported that estrogen plus progestogens increased the risk of ovarian cancer, but this risk is not statistically significant.In one study, women using HRT showed an increased risk of fatal ovarian cancer.
Recommendations on history and physical examination
A complete medical history should be taken before starting hormone therapy. The pre-treatment and periodic physical examination should pay particular attention to blood pressure, pelvic, abdominal and sinus organs, including cervical cytology.
Important information about some of the ingredients:
FARLUTAL contains methyl para-hydroxybenzoate. It can cause allergic reactions (even delayed) and, exceptionally, bronchospasm.
FARLUTAL contains propyl para-hydroxybenzoate. It can cause allergic reactions (even delayed) and, exceptionally, bronchospasm.
Farlutal contains less than 1mmol (23mg) sodium per vial, ie it is virtually "sodium free".
04.5 Interactions with other medicinal products and other forms of interaction
Concomitant administration of FARLUTAL with aminoglutethimide can significantly depress the bioavailability of FARLUTAL.
Patients using high doses of FARLUTAL should be warned of decreased efficacy with the use of aminoglutethimide.
FARLUTAL can be suitably combined with other anti-neoplastic treatment modalities (chemotherapy, radiotherapy).
Medroxyprogesterone acetate (MPA) is metabolised primarily by hydroxylation via CYP3A4 in vitro. No specific drug-drug interaction studies have been conducted to evaluate the clinical effects of CYP3A4 inducers or MPA inhibitors.
04.6 Pregnancy and lactation
Pregnancy
Medroxyprogesterone acetate is contraindicated in pregnant women.
Some data suggest a possible relationship between the administration of progestins in the first trimester of pregnancy and the presence of genital malformations in fetuses in particular circumstances.
Newborns born to unexpected pregnancies, occurring 1 or 2 months after medroxyprogesterone acetate injection, may be at increased risk of low birth weight, which, consequently, is associated with an increased risk of neonatal death. The attributable risk is low as the probability of pregnancy is low while using medroxyprogesterone acetate There is no definitive information for the other formulations of medroxyprogesterone acetate.
If the patient becomes pregnant while using this drug, she should be advised of the potential risk to the fetus.
Feeding time
Medroxyprogesterone and its metabolites are excreted in breast milk. There is no evidence to suggest that this poses a risk to the infant (see section 5.2 - Pharmacokinetic properties).
04.7 Effects on ability to drive and use machines
The effect of medroxyprogesterone acetate on the ability to drive and use machines has not been systematically evaluated.
04.8 Undesirable effects
Table of adverse reactions (in gynecological and oncological use)
* The frequency of these AEs was calculated based on data from 4 clinical studies in cancer patients involving approximately 1300 patients
Additional adverse events reported in the post-marketing setting
Rare cases of osteoporosis including osteoporotic fractures in patients taking intramuscular medroxyprogesterone acetate have been reported post-marketing.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions that occur after authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system at: "www.agenziafarmaco.gov.it/it/responsabili".
04.9 Overdose
No data are known in this regard.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: hormones and related substances - progestogens.
ATC code: L02AB02.
Medroxyprogesterone acetate is an orally and parenterally active progesterone derivative.
FARLUTAL, administered parenterally in the recommended doses to women with an adequate level of endogenous estrogens, transforms the proliferative endometrium into secretory endometrium. Its antitumor activity, when administered at pharmacological doses, is due to the action carried out at the level of the hypothalamus axis. - pituitary-gonads, at the level of estrogen receptors and on the metabolism of steroids at the tissue level.
Due to its prolonged action and the difficulty of predicting the timing of withdrawal bleeding after administration, FARLUTAL is not recommended in secondary amenorrhea or bleeding caused by uterine dysfunction. In these conditions Oral therapy is recommended.
Reduction in bone mineral density
There are no studies on the effects of medroxyprogesterone acetate on the reduction of bone mineral density when administered at high parenteral doses (e.g. oncological use).
However, a clinical study in adult women of childbearing age who received 150mg of medroxyprogesterone acetate every 3 months intramuscularly for contraceptive purposes showed an average reduction of 5.4% in lumbar spine bone mineral density. over 5 years, with at least partial recovery of bone density during the first two years after discontinuation of treatment. A similar clinical study in adolescent women, given medroxyprogesterone acetate 150 mg every 3 months intramuscularly to contraceptive purpose, demonstrated similar reductions in bone mineral density, which were even more pronounced during the first two years of treatment and which, again, were at least partially reversible once treatment was stopped.
05.2 Pharmacokinetic properties
Medroxyprogesterone acetate (MPA) is rapidly absorbed from the gastrointestinal tract and vagina. After IM administration, there is a slow absorption of MPA. Peak serum concentrations are observed after 2-6 hours (oral administration) and after 4-20 days (IM administration). The apparent half-life ranges from approximately 30-60 hours after oral administration to approximately 6 weeks after IM administration. MPA is 90-95% bound to plasma proteins. It crosses the blood brain barrier and is secreted in milk. MPA it is eliminated in the faeces and urine.
05.3 Preclinical safety data
Toxicological data relating to studies conducted on experimental animals using medroxyprogesterone acetate are as follows:
• LD50, oral administration - Mouse: higher than 10,000 mg / kg.
• LD50, intraperitoneal administration - Mouse: 6.985 mg / kg.
Following oral administration to rats and mice (334 mg / kg / day) and to dogs (167 mg / kg / day) treated for 30 days, no toxic effect was shown.
Chronic toxicity studies conducted on rats and dogs at doses of 3, 10 and 30 mg / kg / day treated for 6 months did not show any toxic effects at the tested levels.
At higher doses, only the appearance of the expected hormonal effects was observed.
Teratogenic studies conducted on pregnant Beagle dogs, treated at doses of 1, 10 and 50 mg / kg / day by oral administration, revealed clitoral hypertrophy in female pups born from animals treated at the highest dose.
No abnormalities were found in the male pups.
The subsequent investigation carried out to verify the reproductive capacities of the females given birth from animals treated with medroxyprogesterone acetate, did not show any decrease in fertility.
Long-term toxicity studies conducted in monkeys, dogs and rats with parenteral administration of medroxyprogesterone acetate have shown the following effects:
1) Beagle dogs, treated at doses of 3 and 75 mg / kg every 90 days for 7 years, developed mammary lumps which were also observed in some control animals.
The nodules seen in the control animals were intermittent, while the nodules that appeared in the drug treated animals were larger, more numerous, persistent, and two of the animals treated at the higher dose developed malignant mammary tumors.
2) Two monkeys, treated at a dose of 150 mg / kg every 90 days for 10 years, developed undifferentiated carcinoma of the uterus, which did not appear in the monkeys of the control group and in those treated at doses of 3 and 30 mg / kg every 90 days for 10 years.
Mammary nodules of an intermittent nature were seen in the animals of the control group and in those treated at doses of 3 and 30 mg / kg, but not in the group that received the dose of 150 mg / kg.
At the autopsy (after 10 years) the nodules were found only in 3 of the monkeys of the group treated at the dose of 30 mg / kg.
The histopathological examination revealed that these nodules were hyperplastic in nature.
3) In the rat treated for 2 years, there was no evidence of any alteration at the level of the uterus and breasts.
Mutagenicity studies conducted using the Salmonella Microsome test (Ames test) and the Micronucleus test, have shown that medroxyprogesterone acetate has no mutagenic activity.
Other studies did not reveal any changes in fertility in the first and second generation of the animals observed.
It has not yet been ascertained whether the above observations can also be referred to in humans.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Macrogol 4000; polysorbate 80; methyl-para-hydroxybenzoate; propyl-para-hydroxybenzoate; sodium chloride; carmellose sodium; water p.p.i.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Glass bottle with rubber stopper and aluminum cap.
1 bottle of 150 mg, 3 ml.
06.6 Instructions for use and handling
No special instructions for disposal.
07.0 MARKETING AUTHORIZATION HOLDER
Pfizer Italia S.r.l. - via Isonzo, 71 - 04100 Latina
08.0 MARKETING AUTHORIZATION NUMBER
FARLUTAL 150 mg / 3 ml AIC n. 015148075
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
June 2005
10.0 DATE OF REVISION OF THE TEXT
AIFA determination of 08 September 2015