Femoston^® conti (Tablets) Instructions for Use

Marketing Authorization Holder

Abbott Healthcare Products, B.V. (Netherlands)

Manufactured By

Abbott Biologicals, B.V. (Netherlands)

Contact Information

ABBOTT LABORATORIES LLC (Russia)

ATC Code

G03FA14 (Dydrogesterone and estrogens)

Active Substances

Dydrogesterone (Rec.INN registered by WHO)

Estradiol (Rec.INN registered by WHO)

Dosage Form

Femoston® conti

Film-coated tablets, 5 mg+1 mg: 28 or 84 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets orange-pink in color, round, biconvex, engraved with “379” on one side; the appearance of the tablet on the cross-section: white, rough surface.

Excipients: lactose monohydrate, hypromellose (HPMC 2910), corn starch, colloidal silicon dioxide, magnesium stearate; film coating film coating mixture Orange I* [hypromellose (HPMC 2910), macrogol 400, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172)].

* A ready-made film coating of identical composition may be used, for example, Opadry OY-8734.

28 pcs. – blisters (1) – cardboard packs.
28 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Anticlimacteric drug

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; gestagens in combination with estrogens; gestagens and estrogens, fixed combinations

Pharmacological Action

Mechanism of action and pharmacodynamic effects

The drug Femoston^® conti is a combined drug for HRT and contains 2 active substances: the estrogen estradiol and the progestagen dydrogesterone.

One of the active substances of the drug is synthetic 17β-estradiol, identical in chemical composition and biological action to the endogenous female human sex hormone estradiol. Estradiol compensates for the deficiency of estrogens in the body of a postmenopausal woman and relieves the symptoms of menopause within the first weeks of therapy.

HRT with Femoston^® conti prevents bone loss in the postmenopausal period or after oophorectomy.

The progestagen dydrogesterone is effective when taken orally and has activity similar to parenterally administered progesterone. When conducting HRT, the use of dydrogesterone provides a full secretory transformation of the endometrium, thereby reducing the risk of endometrial hyperplasia while taking estrogen.

Pharmacokinetics

Estradiol

Absorption

The absorption of estradiol depends on the particle size, micronized estradiol is rapidly absorbed from the gastrointestinal tract. The table below shows the mean values of the steady-state pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulfate (E1S) for an estradiol dose of 1 mg.

Distribution

Estrogen can be found in both bound and free states. About 98-99% of the estradiol dose binds to plasma proteins, of which 30-52% binds to albumin and about 46-69% to sex hormone-binding globulin (SHBG).

Metabolism

After oral administration, estradiol is rapidly metabolized. The main unconjugated and conjugated metabolites are estrone and estrone sulfate. These metabolites may exhibit estrogenic activity themselves or after conversion to estradiol. Estrone sulfate may undergo intrahepatic metabolism.

Estrone sulfate may undergo intrahepatic metabolism.

Excretion

Estrone and estradiol are excreted in the urine, mainly in the form of glucuronides. T_1/2 is 10-16 h.

Estrogens are excreted in the milk of nursing mothers.

Time and dose dependence of estradiol concentration

With daily oral administration of the drug tablets at a dosage of 1 mg + 5 mg, a stable concentration of estradiol is achieved after 5 days of administration, most often by 8-11 days.

Dydrogesterone

Absorption

After oral administration, it is rapidly absorbed from the gastrointestinal tract. T_max from 0.5 to 1.5 h. The absolute bioavailability of dydrogesterone at an oral dose of 20 mg (compared to 7.8 mg IV) is 28%.

The table shows the mean values of the steady-state pharmacokinetic parameters of dydrogesterone and dihydrodydrogesterone (DHD) for dydrogesterone at a dose of 5 mg.

After a single dose, food delays the C_max of dydrogesterone in plasma by about 1 h, which leads to a decrease in the C_max of dydrogesterone in plasma by about 20%, without affecting the extent of exposure of dydrogesterone and DHD.

Distribution

After oral administration of dydrogesterone, the apparent V_d is significant and is about 22000 L. Dydrogesterone and DHD bind to plasma proteins by more than 90%.

Metabolism

After oral administration, dydrogesterone is rapidly metabolized to DHD. The concentration of the main metabolite 20α-dihydrodydrogesterone (DHD) peaks at the same time as dydrogesterone. The concentration of DHD in blood plasma is significantly higher than that of dydrogesterone. The AUC and C_max ratios of DHD and dydrogesterone are approximately 25 and 20, respectively. The mean T_1/2 of dydrogesterone and DHD is about 15 h. A common feature of all metabolites is that the configuration of the parent compound 4,6-diene-3-one remains unchanged and the absence of 17α-hydroxylation. This explains the absence of estrogenic and androgenic effects of dydrogesterone.

Excretion

After oral administration of labeled dydrogesterone, an average of 63% of the dose is excreted in the urine. The apparent total clearance of dydrogesterone from plasma in the body is high and is approximately 20 L/min. Complete elimination of dydrogesterone occurs within 72 h. DHD is excreted in the urine mainly in the form of a glucuronic acid conjugate.

Time and dose dependence of dydrogesterone concentration

The pharmacokinetics are linear, both after single and multiple dosing in the range from 2.5 to 20 mg. Comparison of single and multiple dose kinetics shows that the pharmacokinetics of D and DHD do not change as a result of repeated dose administration.

C_ss of dydrogesterone is reached after 3 days of treatment.

Indications

• menopausal hormone therapy (HRT) for disorders caused by estrogen deficiency in postmenopausal women (not earlier than 12 months after the last menstruation);
• Prevention of osteoporosis in postmenopausal women at high risk of fractures with intolerance or contraindications to the use of other drugs for the prevention of osteoporosis.

ICD codes

Dosage Regimen

The tablets should be taken orally with water, regardless of meals, preferably at the same time of day.

HRT with Femoston^® conti for natural menopause should not be started earlier than 12 months after the last menstruation. In the case of menopause after surgery (bilateral oophorectomy, hysterectomy with appendages), treatment can be started immediately.

Each package is designed for a 28-day course of the drug. Femoston^® conti is taken daily in a continuous regimen, 1 tablet/day for 28 days.

Immediately after the end of the 28-day cycle, you should start taking Femoston^® conti from a new package.

To initiate and continue HRT for disorders caused by estrogen deficiency, the combination of dydrogesterone + estradiol should be used at the lowest effective dose and for the shortest period of time. Depending on the clinical response, the hormone dose may be adjusted later.

When switching from another HRT drug with a continuous sequential or cyclic regimen, the current cycle should be completed and the next day after completion, switch to taking Femoston^® conti.

For women who have not previously received HRT, or when switching from another continuous combined HRT regimen, Femoston^® conti can be started on any day.

If the patient misses a tablet, it should be taken within 12 hours of the usual time of administration. If more than 12 hours have passed, the missed tablet should not be taken, and the next day the tablet should be taken at the usual time. Missing a dose of the drug may increase the likelihood of “breakthrough” uterine bleeding or “spotting” bloody discharge.

Special patient groups

Experience with the drug in elderly patients (≥65 years) is limited.

There are no indications for the use of Femoston^® conti in children and adolescents under 18 years of age.

Adverse Reactions

In clinical studies in patients receiving therapy with the combination of estradiol + dydrogesterone, the most common were: headache, abdominal pain, breast tension/tenderness and back pain.

Adverse reactions possible during therapy with the combination of dydrogesterone+estradiol are distributed by system-organ classes with an indication of the frequency of their occurrence according to WHO recommendations: very common (>1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from available data).

* Adverse reactions presented in spontaneous reports but not observed in clinical studies.

Description of selected adverse reactions

Other adverse reactions caused by the use of the combination of estrogen and progestagen (including estradiol + dydrogesterone)

Benign, malignant and unspecified neoplasms estrogen-dependent benign and malignant neoplasms, including endometrial cancer and ovarian cancer; increase in the size of meningioma.

Immune system disorders systemic lupus erythematosus.

Metabolism and nutrition disorders hypertriglyceridemia.

Nervous system disorders likelihood of developing dementia, chorea, provocation of epileptic seizures.

Vascular disorders arterial thromboembolism.

Gastrointestinal disorders pancreatitis (in patients with hypertriglyceridemia).

Skin and subcutaneous tissue disorders erythema multiforme.

Renal and urinary disorders urinary incontinence.

Reproductive system and breast disorders fibrocystic mastopathy, cervical erosion.

Congenital and hereditary disorders worsening of concomitant porphyria.

Investigations increased concentration of thyroid hormones in blood plasma.

Risk of developing breast cancer

In women taking combined estrogen-progestagen-containing drugs for 5 years or more, the risk of breast cancer is up to 2 times higher. The increase in risk in women receiving HRT with estrogen alone was smaller compared to women receiving combined estrogen-progestagen HRT. The degree of risk increase depends on the duration of therapy.

The following are estimated absolute risk values determined from the results of the largest randomized placebo-controlled trial (WHI study) and the largest meta-analysis of prospective epidemiological studies.

Largest meta-analysis of prospective epidemiological studies

Estimated additional risk of breast cancer after 5 years of treatment in women with BMI 27 (kg/m²)

Note since the incidence of breast cancer differs in EU countries, the number of additional cases of breast cancer also changes proportionally.

Estimated additional risk of breast cancer after 10 years of use in women with BMI 27 (kg/m²)

* Taking into account the background incidence in women with BMI 27 (kg/m2) in England in 2015.

Note since the baseline incidence of breast cancer cases is different in each EU country, the number of additional breast cancer cases will also differ in proportional terms.

WHI studies (USA) – additional risk of breast cancer after 5 years of use

¹When the analysis was limited to women who had never used HRT prior to study inclusion, no increased risk was found during the first 5 years of treatment; after 5 years, the risk was higher than in never-users of HRT.

² A group of women in the WHI study with a removed uterus, in whom no increased risk of breast cancer was found.

Endometrial cancer (EC)

Postmenopausal women with an intact uterus. The risk of EC is approximately 5 cases per 1000 women with a uterus not using HRT. Women with a uterus are not recommended estrogen-only HRT preparations, as this increases the risk of EC. Depending on the duration of estrogen monotherapy and the dose, the increased risk of EC according to epidemiological studies ranges from 5 to 55 additional diagnosed cases per 1000 women aged 50-65 years.

Adding a progestogen to estrogen monotherapy for at least 12 days of the cycle significantly reduces this increased risk. In the MWS (Million Women Study), the use of combined (cyclic or continuous) HRT regimens for 5 years did not increase the risk of endometrial cancer (relative risk – 1 (0.8-1.2)).

Ovarian cancer

The use of estrogen-only HRT or combined estrogen and progestogen HRT was associated with a slight increase in the risk of diagnosed ovarian cancer. Data from a meta-analysis of 52 epidemiological studies indicate an increased risk of developing ovarian cancer in women currently using HRT compared to women who have never used HRT (risk ratio 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking HRT for 5 years, this resulted in approximately one additional case per 2000 patients. In women aged 50 to 54 years who did not take HRT, approximately two women out of 2000 are diagnosed with ovarian cancer over 5 years.

Risk of venous thromboembolism

With HRT, the relative risk of venous thromboembolism, i.e., deep vein thrombosis or pulmonary embolism, increases by 1.3-3.0 times. This complication is more likely in the first year of HRT than in subsequent years. The results of the WHI study are presented below.

WHI study (USA). Additional risk of VTE over 5 years of use

³Studies involving women with a history of hysterectomy.

Risk of coronary heart disease is slightly increased in the group of combined HRT users over the age of 60.

Risk of ischemic stroke

Taking estrogen-only and combined HRT preparations is associated with an increase in the relative risk of developing ischemic stroke up to 1.5 times. The risk of hemorrhagic stroke does not increase during HRT.

The relative risk does not depend on age or duration of HRT, but since the baseline risk is highly dependent on age, the overall risk of stroke in women on HRT increases with age.

WHI study, combined. Additional risk of ischemic stroke⁴ over 5 years of use

⁴ Ischemic and hemorrhagic stroke are not separated.

Contraindications

• Hypersensitivity to dydrogesterone, estradiol or to any excipient in the preparation;
• Pregnancy and breastfeeding period (see section "Pregnancy and lactation");
• Diagnosed or suspected breast cancer, or history thereof;
• Diagnosed or suspected estrogen-dependent malignancies (e.g., endometrial cancer);
• Diagnosed or suspected progestogen-dependent neoplasms (e.g., meningioma);
• Vaginal bleeding of unknown etiology;
• Untreated endometrial hyperplasia;
• Current or history of thrombosis (arterial and venous) and thromboembolism (including deep vein thrombosis, pulmonary embolism, myocardial infarction, angina pectoris);
• Identified hereditary or acquired predisposition to arterial or venous thrombosis/thromboembolism, e.g., antithrombin III deficiency, protein C deficiency, protein S deficiency;
• Current or history of acute or chronic liver diseases (until liver function test results normalize), including malignant liver tumors;
• Porphyria.

With caution

The use of HRT preparations, including Femoston^® conti, requires caution in the presence of any of the following diseases/conditions and risk factors

• Uterine leiomyoma, endometriosis;
• Presence of risk factors for estrogen-dependent tumors (e.g., first-degree relatives with breast cancer);
• Arterial hypertension;
• Benign liver tumors;
• Diabetes mellitus, both with and without vascular complications;
• Cholelithiasis;
• Migraine or severe headache;
• Systemic lupus erythematosus;
• History of endometrial hyperplasia;
• Epilepsy;
• Bronchial asthma;
• Otosclerosis.

Use in Pregnancy and Lactation

Pregnancy

The use of Femoston^® conti during pregnancy is contraindicated.

If pregnancy occurs while taking the drug, its use should be discontinued immediately.

Breastfeeding period

The use of Femoston^® conti during breastfeeding is contraindicated.

Fertility

Femoston^® conti is not used in women of reproductive age.

Use in Hepatic Impairment

Contraindicated in current or history of acute or chronic liver diseases (until laboratory parameters of liver function normalize), including malignant liver tumors.

Use in Renal Impairment

Should be used with caution in renal failure.

Pediatric Use

Not intended for use in children.

Geriatric Use

Experience with the drug in women over 65 years of age is limited.

Special Precautions

The drug is prescribed only in the presence of symptoms that adversely affect the quality of life. In all patients receiving HRT, a benefit/risk assessment should be performed at least once a year. Therapy should be continued as long as the benefit of taking the drug outweighs the risk of adverse reactions.

Experience with the drug in women over 65 years of age is limited.

Data on risks associated with HRT in the case of premature menopause are limited. Due to the low level of absolute risk in younger women, the benefit/risk ratio may be more favorable for them than for older women.

Medical examination

Before prescribing or resuming Femoston^® conti, a complete medical and family history should be taken and a general and gynecological examination (including breasts) of the patient should be performed to identify possible contraindications and conditions requiring precautions. During the use of Femoston^® conti, periodic examinations are recommended, the frequency and nature of which are determined individually, but at least once every 6 months. Mammography is advisable for additional breast examination. Women should be informed about possible breast changes that should be reported to their doctor.

The use of estrogens may affect the results of the following laboratory tests: glucose tolerance test, thyroid and liver function tests.

The drug should be discontinued immediately if the following conditions/diseases occur

• Jaundice or liver dysfunction;
• Uncontrolled arterial hypertension;
• Migraine-like headache first occurring during the use of HRT preparations;
• Pregnancy.

Hyperplasia and endometrial cancer

The risk of developing hyperplasia and endometrial cancer when using estrogen-only HRT preparations depends on the dose and duration of treatment and increases from 2 to 12 times compared to patients not receiving therapy; the risk may remain elevated for up to 10 years after discontinuation of therapy.

Women with an intact uterus are not recommended to use estrogen-only HRT preparations due to the increased risk of endometrial cancer.

Cyclic use of a progestogen (for at least 12 days of a 28-day cycle), or use of a continuous combined HRT regimen in women with an intact uterus prevents the increased risk of hyperplasia and endometrial cancer associated with estrogen intake.

For timely diagnosis, ultrasound screening is advisable, and if necessary, histological (cytological) examination should be performed.

Vaginal bleeding

During the first months of taking the drug, "breakthrough" bleeding and/or scanty vaginal spotting may occur. If such bleeding appears some time after the start of therapy or continues after discontinuation of treatment, their cause should be determined. Endometrial biopsy may be performed to rule out malignancy.

Venous thromboembolism

HRT is associated with a 1.3-3-fold risk of developing venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. The development of such an event is most likely during the first year of HRT.

If there is a family history of thrombosis/thromboembolism in first-degree relatives under the age of 50, as well as a history of recurrent miscarriage, a hemostasis study should be performed (only part of the coagulation system disorders are detected during screening). A thorough assessment of the expected benefit to the possible risk of HRT is necessary in patients taking anticoagulants on a continuous basis.

If a thrombophilic condition is identified in a family member and/or in case of the seriousness or severity of the defect (e.g., antithrombin III deficiency, protein S or C deficiency, or a combination of defects), Femoston^® conti is contraindicated.

Since patients with diagnosed thrombophilic conditions have an increased risk of developing venous thromboembolism, the prescription of Femoston^® conti, which increases this risk, is contraindicated.

In most cases, risk factors for VTE include: use of estrogens, advanced age, major surgery, prolonged immobilization, obesity (BMI >30 kg/m²), pregnancy or postpartum period, systemic lupus erythematosus and cancer. There is no consensus on the possible role of varicose veins in the development of VTE.

In the postoperative period, VTE prophylaxis is mandatory.

If prolonged immobilization is required after planned surgery, the drug should be discontinued 4-6 weeks before surgery and not resumed until the woman’s mobility is fully restored.

If VTE develops after the start of therapy, the drug should be discontinued, and patients should be informed that they must immediately consult their doctor if any symptoms of thrombosis/thromboembolism appear (e.g., pain or swelling in the lower limbs, sudden chest pain, shortness of breath).

Breast cancer (BC)

Clinical study results indicate an increased risk of developing BC in women receiving HRT with estrogen monotherapy or combined preparations (estrogen + progestogen). This risk depends on the duration of HRT. In women taking combined HRT preparations for more than 5 years, the risk of developing BC may increase up to 2 times.

Estrogen-only therapy . According to the WHI study, no increased risk of developing BC was observed in women with prior hysterectomy receiving estrogen-only HRT.

Combined estrogen and progestogen therapy. Results from the randomized placebo-controlled WHI (Women’s Health Initiative) study and a meta-analysis of prospective epidemiological studies showed an increased risk of developing BC in women taking combined HRT preparations (estrogen + progestogen). The increased risk of BC is observed after approximately 3 (1-4) years of HRT.

Most observational studies showed a small increase in the risk of BC, and this risk was significantly lower in women taking combined estrogen and progestogen therapy.

Data from the results of a large-scale meta-analysis indicate a decrease in the increased risk of BC after discontinuation of HRT. The time required to return to the baseline risk level depends on the duration of therapy. If HRT was used for more than 5 years, the increased risk of developing BC may persist for 10 years or more.

Ovarian cancer

Ovarian cancer is much less common than breast cancer. Epidemiological data from a large-scale meta-analysis indicate a slight increase in the risk of developing ovarian cancer for women receiving HRT as estrogen monotherapy or combined estrogen and progestogen therapy.

The study data (increased risk) become more evident with therapy duration of more than 5 years, and after its discontinuation, the risk gradually decreases over time. Results from a number of other studies, including WHI, indicate that combined HRT is associated with a similar or slightly lower risk of developing ovarian cancer.

Risk of ischemic stroke

Combined estrogen and progestogen therapy or estrogen-only therapy is associated with an increase in the relative risk of ischemic stroke by 1.5 times. The risk of hemorrhagic stroke does not increase with HRT.

The relative risk does not depend on age, time of menopause onset, or duration of therapy. However, the baseline risk is highly dependent on age, thus the overall risk of stroke in women receiving HRT will increase with age.

Coronary heart disease (CHD)

Randomized controlled clinical trials found no evidence of a protective effect of HRT against myocardial infarction in women with/without CHD who received combined estrogen and progestogen HRT or estrogen-only HRT.

Combined estrogen and progestogen therapy. The relative risk of CHD during the use of combined estrogen and progestogen HRT is slightly increased. Since the absolute risk of CHD is highly dependent on age, the number of additional cases of CHD due to combined HRT in healthy premenopausal women is very small, but it increases with age. The risk is slightly higher in women over 60 years of age.

Other conditions

Estrogens can cause fluid retention, which may adversely affect patients with impaired renal and cardiac function. This group of patients should be under medical supervision.

Patients with hypertriglyceridemia while taking HRT preparations should also be under medical supervision, as there are reports of very rare cases of a significant increase in plasma triglyceride concentrations, which contributes to the development of pancreatitis.

Exogenous estrogens may cause or exacerbate symptoms of hereditary and acquired angioedema.

Estrogens increase the concentration of thyroxine-binding globulin, leading to a general increase in the concentration of circulating thyroid hormones (measured by protein-bound iodine determination), thyroxine (T4) concentration – chromatographic or radioimmunoassay or triiodothyronine (T3) – radioimmunoassay. The labeled triiodothyronine uptake test shows an increased concentration of thyroxine-binding globulin. Concentrations of free T3 and T4 hormones are usually unchanged. Concentrations of other plasma binding proteins (e.g., transcortin and sex hormone-binding globulin) may also increase, leading to increased concentrations of circulating glucocorticosteroids and sex hormones.

Concentrations of free or biologically active hormones are unchanged. An increase in the concentration of other plasma proteins (angiotensinogen/renin system, α-1-antitrypsin, ceruloplasmin) is possible.

HRT does not improve cognitive function. There are reports of an increased risk of developing dementia in women who started HRT (combined or estrogen-only) after the age of 65.

Femoston^® conti is not a contraceptive.

Elevated ALT

During clinical studies with patients receiving treatment for hepatitis C virus (HCV) infections with the combined regimen of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, elevation of ALT more than 5 times the upper limit of normal was significantly more frequent in women using medicinal products containing ethinylestradiol, such as combined hormonal contraceptives. Furthermore, also among patients receiving glecaprevir/pibrentasvir, elevated ALT activity was observed in women using medicinal products containing ethinylestradiol, such as combined hormonal contraceptives. In women using medicinal products that contain estrogens other than ethinylestradiol, such as estradiol, the frequency of ALT elevation was the same as in women not taking any estrogens; however, due to the limited number of women taking estradiol-type estrogens, caution should be exercised when co-administering ombitasvir/paritaprevir/ritonavir with the combined regimen consisting of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as with the regimen consisting of glecaprevir/pibrentasvir (see section "Drug Interactions").

Excipients

Patients with lactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome should not take this drug.

Effect on the ability to drive vehicles and operate machinery

The drug does not have a significant effect on the ability to drive vehicles and operate machinery.

Overdose

Estradiol and Dydrogesterone are substances with low toxicity.

Symptoms may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/weakness, withdrawal bleeding.

Treatment symptomatic therapy should be administered.

Drug Interactions

Effect of other drugs on the estrogen + progestogen combination

The metabolism of estrogen and progestogen may be enhanced with the simultaneous use of drugs that are inducers of hepatic microsomal enzymes of the cytochrome P450 system (isoenzymes CYP2B6, 3A4, 3A5, 3A7): anticonvulsants (phenobarbital, carbamazepine, phenytoin), antimicrobial and antiviral drugs (rifampicin, rifabutin, nevirapine, efavirenz).

Herbal preparations containing St. John’s wort (Hypericum perforatum) may enhance the metabolism of estrogen and progestogen.

Ritonavir and nelfinavir, although known as strong inhibitors of CYP3A4, A5, A7, may enhance the metabolism of sex hormones when used concomitantly.

Clinically, increased metabolism of estrogens and progestogens may manifest as a decrease in the drug’s effect and a change in the intensity of vaginal bleeding.

Effect of MHT with estrogens on other drugs

Hormonal contraceptives containing estrogens have been reported to significantly reduce lamotrigine plasma concentrations when used concomitantly due to enhanced lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between MHT drugs and lamotrigine has not been studied, a similar interaction is expected to exist and may lead to reduced seizure control in women when used concomitantly.

Pharmacodynamic drug interactions

In clinical trials in patients with hepatitis C virus receiving the combined regimen of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, elevation of ALT more than 5 times the upper limit of normal was significantly more frequent in women using medicinal products containing ethinylestradiol, such as combined hormonal contraceptives. In women using medicinal products containing estrogens other than ethinylestradiol, such as estradiol, the frequency of ALT elevation was the same as in women not receiving any estrogens; however, due to the limited number of women taking estradiol-type estrogens, caution should be exercised with the concomitant use of ombitasvir/paritaprevir/ritonavir with the combined regimen consisting of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as with the regimen consisting of glecaprevir/pibrentasvir (see the “Special Precautions” section).

Effect of estrogen on other drugs

Estrogens may affect the metabolism of other drugs by competitively binding to enzymes (CYP450) involved in their biotransformation. This should be considered for drugs with a narrow therapeutic index, such as tacrolimus and cyclosporine A (CYP3A4, 3A3), fentanyl (CYP3A4), and theophylline (CYP1A2), as this type of interaction may lead to an increase in the plasma concentration of the aforementioned drugs to toxic levels. Therefore, careful monitoring of drug intake over a long period and possibly a dose reduction of tacrolimus, fentanyl, cyclosporine A, and theophylline may be required.

Studies on interactions with other drugs have not been conducted.

Storage Conditions

Store at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.