In the course of preparation of requirements to the safety and efficacy of medicines based on up-to-date scientifically grounded information on the clinical use of drugs containing as an active substance estriol in the form of a drug - vaginal suppositories, 0.5 mg, the need to unify and supplement the instructions for the use of these medications with the following information was identified.
The sections "Pharmacodynamics" and "Pharmacokinetics" should be supplemented and presented in the following edition:
" Farmakodesinamika
The active substance of the drug is estriol - an analogue of the natural female hormone estriol. He replenishes the estrogen deficiency in postmenopausal women and weakens postmenopausal symptoms. The most effective use of estriol in the treatment of urogenital disorders. In the case of atrophy of the mucous membrane of the lower sections of the urogenital tract estriol helps normalize the epithelium of the urinary and genital tract and helps restore normal microflora and physiological pH in the vagina.As a result, the resistance of the epithelium of the urinary and genital tract to infection and inflammation increases; decreases dryness of the mucosa and itching in the vagina, soreness in sexual intercourse, the likelihood of vaginal and urinary tract infections; therapy with estriol helps to normalize urination and prevents incontinence.
Unlike other estrogens, estriol has a short period of action (in the nuclei of endometrial cells it is retained for a short period of time). It is assumed that a one-time administration of a daily dose is not causes proliferation of the endometrium. Therefore, cyclic progestogen administration is not required and no "bleeding" bleeding occurs.
Pharmacokinetics
Absorption
When intravaginal application of estriol is provided, optimal bioavailability in the site of action. Estriol absorbed and enters the total blood flow, which is manifested by a rapid increase in the concentration of unbound estriol in plasma. After intravaginal administration at a dose of 0.5 mg, the maximum concentration of estriol (100 pg / ml) in plasma is observed 1-2 h after administration.
Distribution
In plasma, 90% of estriol binds to albumin. Unlike other estrogens, almost does not bind to the globulin that binds the sex hormones.
Metabolism
Metabolism of estriol is mainly in the transition to a conjugated and unconjugated state with intestinal hepatic recirculation.
Excretion
Estriol, being the final product of metabolism, is mainly excreted by the kidneys in a related form. Only a small part (about 2%) is excreted through the intestine, mainly in the form of unbound estriol. The half-life of estriol is about 6-9 hours. "
The section "Indications for Use" should be supplemented and presented in the following edition:
"Replacement hormone therapy (HRT): treatment of mucosal atrophy of lower urinary tract and genital tract associated with estrogen deficiency in postmenopausal women.
Pre- and postoperative therapy of women in the postmenopausal period with surgical intervention with vaginal access.
As a diagnostic aid in obtaining atrophic cervical smear ".
The section "Contraindications" and "With caution" should be supplemented and presented in the following edition:
- hypersensitivity to estriol and / or to any of the excipients of the drug;
- diagnosed, in history or suspected breast cancer (BC);
- diagnosed estrogen-dependent tumors or suspected of them (eg, endometrial cancer);
bleeding from the vagina of an unclear etiology;
- untreated endometrial hyperplasia;
- presence of venous thromboembolism (VTE) at present or in anamnesis (deep vein thrombosis, pulmonary embolism);
- confirmed thrombophilic disorders (eg, protein C deficiency, protein S or antithrombin III, etc.);
- arterial thrombosis or thromboembolism (ATE), including myocardial infarction, stroke, cerebrovascular disorders; or prodromal conditions (including transient ischemic attack, angina pectoris);
- liver disease in the acute stage or liver disease in history, after which the liver function indicators did not return to normal;
- porphyria;
- Pregnancy and the period of breastfeeding ".
The section "With caution" should be supplemented and presented in the following edition:
"Under the close supervision of a doctor estriol should be used, if available, including in the history, any of the following diseases / conditions or risk factors:
- Leiomyoma (fibroids of the uterus) or endometriosis;
- risk factors for thrombosis and thromboembolism;
- risk factors for estrogen-dependent tumors (including the presence in family history of breast cancer in relatives of the 1st line (mother, sisters));
- arterial hypertension;
- benign liver tumors (eg, liver adenoma);
- diabetes mellitus with or without diabetic angiopathy;
- cholelithiasis;
- jaundice (including anamnesis during previous pregnancy);
- chronic heart or kidney failure;
- Migraine or severe headache;
- systemic lupus erythematosus;
- Endometrial hyperplasia in the anamnesis;
- epilepsy;
- bronchial asthma;
otosclerosis;
- familial hyperlipoproteinemia;
- pancreatitis. "
The section "Application during pregnancy and during breast-feeding" should be presented in the following edition:
"Pregnancy
The use of the drug during pregnancy is contraindicated.
Breastfeeding period
The use of the drug in the period of breastfeeding is contraindicated. "The section "Method of application and dosing regimen" should be revised and presented in the following edition:
"Intravaginally, the evening before bedtime." The suppository should be administered deep in the vagina.
In the treatment of mucosal atrophy of the lower parts of the urinary and genital tract associated with estrogen deficiency in postmenopausal women:
For 0.5 mg (1 suppository per day daily for the first 2-3 weeks (maximum to 4 weeks), then gradually reduce the dose, based on the dynamics of symptoms, at 0.5 mg (1 suppository) - 2 times in a week.
Pre and postoperative therapy for postmenopausal women with vaginal interventions:
0.5 mg (1 suppository) per day for 2 weeks before surgery; 0.5 mg (1 suppository) 2 times a week for 2 weeks after the operation.
As an auxiliary tool for diagnosis of atrophic cervical smear:
0.5 mg (1 suppository) every other day for 1 week before taking the next smear.
In case of a miss, it is necessary to enter the suppository immediately, as soon as the patient remembers this (2 suppositories per day should not be given), then the administration of the drug is carried out in accordance with the usual dosing regimen.
For the treatment of symptoms of estrogen deficiency in postmenopausal women, the lowest effective dose should be administered within the shortest period of time. "
In the section "Side effect" it is necessary to correct and supplement the information on undesirable reactions when using estriol:
"Undesirable reactions (HP) usually occur in 3-10% of patients, can occur at too high a dose. Usually HP disappear after the first weeks of treatment.
In the literature data and the post-marketing period, the following HP:
Metabolic and Nutritional Disorders: Frequency Unknown: fluid retention.
Disorders from the gastrointestinal tract: frequency unknown: nausea.
Violations of the genitals and mammary gland: the frequency is unknown: breast tenderness, chest pain, acyclic spotting.
General disorders and disorders at the site of administration: Frequency unknown: itching and irritation at the injection site.
Combined therapy with progestogens reported the following HP:
- benign and malignant estrogen-dependent neoplasias, incl.endometrial cancer, breast cancer (a two-fold increase in breast cancer is observed in women with a duration of combined estrogen-progestogenic drugs for more than 5 years, with monotherapy with estrogen - the risk of breast cancer is significantly lower);
- diseases of the gallbladder;
- Chloasma, erythema multiforme, erythema nodosum, hemorrhagic purpura;
- Possible dementia at the onset of HRT in a continuous regime after 65 years;
- Long-term use of estrogen as monotherapy and in combination with gestagen for HRT is associated with a slight increase in the risk of ovarian cancer (in the Million Women study, an additional case of 2500 women was recorded for 5 years in HRT;
- HRT is associated with a 1.3-fold relative increase in the risk of developing VTE (deep vein thrombosis or pulmonary embolism), an increased risk of this complication occurs in the first year of HRT;
- there is a slight increase in the risk of developing coronary artery disease in patients over the age of 60 with HRT by a combination of estrogen and progestogen;
- HRT with an estrogen mono-drug or a combination of estrogen and progestagen is associated with a 1.5-fold increase in the relative risk of ischemic stroke (the risk of hemorrhagic stroke during HRT is not increasing).
The section "Interaction with other medicinal products" should be supplemented and presented in the following edition:
"Metabolism of estrogens and progestogens can increase with the simultaneous use of microsomal liver enzymes with inductor preparations, in particular with cytochrome P450 isoenzymes, such as antiepileptic agents (phenobarbital, phenytoin, carbamazepine), antibacterial and antiviral agents (for example, rifampicin, rifabutin, nevirapine, efavirenz). Ritonavir and nelfinavir, although they are potent inhibitors of metabolism, when applied in combination with sex hormones exhibit inducing properties. Herbal preparations containing St. John's wort (Hypericum Perforatum), can also induce estrogen metabolism.
Elevated estrogen metabolism can lead to a decrease in their clinical effect. "
The section "Special instructions" should be supplemented and presented in the following edition:
"HRT for the treatment of symptoms of estrogen deficiency should be done only with regard to symptoms adversely affecting the quality of life of a woman.At least once a year, a thorough evaluation of the "benefit-risk" ratio should be carried out, the continuation of therapy is justified only if the benefit of using the drug over the risk is exceeded. There is limited evidence of the risks associated with HRT in the treatment of premature menopause. In view of the low absolute risk in younger women, the "benefit-risk" ratio is more favorable for them than for the elderly.
Medical Examination / Surveillance
Before starting or resuming HRT after its interruption, it is necessary to collect a detailed individual and family history, conduct a general and gynecological examination (including examination of the mammary glands and pelvic organs). During the period of therapy it is recommended to conduct periodic medical examinations, the frequency and nature of which is determined individually. A woman should be informed of the need to inform the doctor about possible changes in the mammary glands. Surveys, including appropriate imaging techniques, such as mammograms, should be performed in accordance with currently accepted survey standards and, depending on each specific case.
Reasons for immediate withdrawal of therapy
Therapy should be discontinued immediately if there are contraindications and if the following conditions occur:
- jaundice or worsening of liver function;
- significant increase in blood pressure;
- occurrence of a headache as migraine;
pregnancy.
Hyperplasia and endometrial cancer
To prevent stimulation of the endometrium, the daily dose of estriol should not exceed 1 suppository (0.5 mg estriol) per day. Do not use this maximum dose for more than 4 weeks. One epidemiological study found that prolonged oral administration of estriol at low doses could increase the risk of endometrial cancer. The risk rises as the duration of treatment increases and returns to baseline values one year after discontinuation of the drug. Basically, the risk of minimally invasive and highly differentiated tumors increases. When bloody discharge / bleeding from the vagina appears, an appropriate examination is necessary. The patient should be informed of the need to inform the doctor in case of bleeding.
Mammary cancer
Long-term HRT increases the risk of breast cancer in women receiving combined therapy with estrogen and progestogen and, possibly, estrogen alone. In women receiving combined estrogen + progestogen therapy for more than 5 years, an increase in the risk of breast cancer by 2 times was noted. With monotherapy with estrogen, the risk increase is significantly lower than when combined with progestogen. Limited data indicate that there is no risk of developing breast cancer with estriol.
HRT, in particular combination preparations, can increase the density of mammograms. This can complicate radiological detection of breast cancer.
Ovarian Cancer
Ovarian cancer develops much less frequently than breast cancer. Prolonged monotherapy with estrogen (at least for 5-10 years) was associated with a small increase in the risk of ovarian cancer. The results of some studies indicate that HRT combined preparations have a similar or slightly lower risk. It is unknown whether the risk of long-term use of low-level estrogen (such, estriol) from that with monotherapy with other estrogens.
VTE
HRT is associated with an increased risk of developing VTE (deep vein thrombosis or pulmonary embolism) 1.3-3 times. The likelihood of developing VTE is higher during the first year of HRT use than at a later date. In patients with a confirmed thrombophilic condition, the risk of VTE is high, and HRT may be further increase it. In connection with which such women have HRT is contraindicated.
The generally accepted risk factors for VTE are estrogen intake, advanced age, extensive surgical interventions, prolonged immobilization, obesity (BMI> 30 kg / m2), pregnancy / postpartum period, systemic lupus erythematosus and cancer. There is no consensus on the possible role of varicose veins in the development of VTE. After any surgical intervention, VTE should be prevented. In case of prolonged immobilization due to planned surgery, HRT should be temporarily discontinued 4-6 weeks before surgery and should be resumed only after the full mobility of the woman is restored.
In the absence of VTE in a woman's history, but in the presence of thrombosis at the age of less than 50 years, the closest relatives,it is recommended to conduct a screening survey, having previously discussed all of its limitations (screening can detect only a number of thrombophilic disorders). If a violation is found that does not correspond to the disease in relatives, or if a "severe" defect is found (for example, an antithrombin III deficiency, a protein S or protein C, or a combination of these defects) HRT estriol is contraindicated.
For women receiving long-term anticoagulant treatment, careful consideration of the "benefit-risk" ratio of HRT is required.
In case of VTE development, therapy with the drug should be stopped immediately. A woman should be informed of the need for immediate medical attention if there are possible signs of thromboembolic complications (for example, edema or soreness in the veins of the lower limb, sudden chest pain, dyspnea, etc.).
Ischemic heart disease (CHD)
In randomized controlled clinical trials, there was no evidence that HRT combined preparations or estrogen alone could prevent the development of a heart attack myocardium in women with IHD and without it.
Monotherapy with estrogen
According to randomized controlled clinical trials, in women with a history of hysterectomy, the risk of IHD with estrogen alone does not increase. The absolute risk of coronary heart disease increases somewhat with HRT combined (estrogen + gestagen) drugs in patients older than 60 years.
Ischemic stroke
HRT combined preparations and estrogen monotherapy are associated with an increased risk of ischemic stroke by a factor of 1.5. The relative risk with age and time after the onset of menopause does not change. However, the initial risk of stroke largely depends on age, respectively, and the overall risk of ischemic stroke in the background of HRT increases with age. The risk of hemorrhagic stroke with HRT is not increased.
Other states
Estrogens can cause fluid retention, and therefore patients with chronic cardiac and renal insufficiency should be under close medical supervision.
Estriol is a weak antagonist of gonadotropin and has no other significant effects on the endocrine system.
It is necessary to closely monitor women with pre-existing hypertriglyceridemia,because in rare cases HRT estrogens caused a significant increase in the concentration of triglycerides in the blood plasma, which led to the development of pancreatitis.
Estrogen causes an increase in the concentration of thyroxine binding globulin, resulting in increased total circulating thyroid hormone, measured as total associated with proteins iodine; concentration T4 or concentration T3.
It may also increase the concentration of other plasma proteins (renin-angiotensin-Substrate, alpha-1-antitrypsin, ceruloplasmin).
Cognitive function does not improve with HRT. There is evidence of an increased risk of dementia among women in the event of combined HRT drugs or estrogen alone in a continuous operation after 65 years. "
In the "Leave Conditions" section, you must specify "By Prescription". The basis for making changes to this section (transfer from OTC to prescription status) is as follows:
1. The main area of application of drugs containing estriol, suppositories vaginal, - ZGT, therefore before the use of estriol, a doctor's consultation is necessary, since There is a fairly wide range of possible serious HP, including, for example:
- 1.3-fold relative increase in risk of VTE (deep vein thrombosis or pulmonary embolism);
- a 1.5-fold increase in the relative risk of ischemic stroke in HRT using an estrogen mono-drug or a combination of estrogen and progestogen;
- fluid retention in the use of estrogens, and therefore patients with chronic cardiac and renal insufficiency should be under close medical supervision.
2. The use of estriol, suppositories vaginal, involves a preliminary consultation with a doctor to exclude, including in a history, a number of diseases / conditions or risk factors that are reflected in the sections "Contraindications" and "With caution." It is also necessary to conduct a general and gynecological examination (including examination of the mammary glands and pelvic organs). During the period of therapy it is recommended to conduct periodic medical examinations and at least once a year, a thorough evaluation of the "benefit-risk" ratio should be carried out. The continuation of estrogen treatment is justified only if the benefit of the drug over the risk is exceeded.
3. Prolonged monotherapy with estrogen (for 5-10 years) is associated with a slight increase in the risk of ovarian cancer. In women receiving combined estrogen plus progestogen therapy for more than 5 years, the risk of developing breast cancer has increased by a factor of 2. According to the epidemiological study, prolonged oral administration of estriol in low doses may increase the risk of endometrial cancer.
4. The status of the reference preparation Ovestin, suppositories vaginal 0.5 mg, (Aspen Pharma Trading Limited, Ireland) in several countries (Germany, Switzerland, New Zealand, etc.) prescription.