FEMOSTON 2/10 instructions for use, description of the medicinal product FEMOSTON 2/10: contraindications, side effects, dosages, composition - tablets, coating. shell in the directory of medicinal

Release form and composition

Femoston 2/10 is available in the form of film-coated tablets of two types - pink and light yellow: round, biconvex, with "379" engraved on one side, when broken - a white tablet core with a rough structure (28 pcs. . in a blister - 14 pink tablets and 14 light yellow tablets; in a cardboard pack there are 1, 3 or 10 blisters).

Content of active ingredients in 1 tablet:

pink tablet: estradiol hemihydrate – 2.06 mg, which is equivalent to the content of 2 mg estradiol;
light yellow tablet: estradiol hemihydrate – 2.06 mg, which is equivalent to the content of 2 mg estradiol; dydrogesterone – 10 mg.

Auxiliary components: lactose monohydrate, colloidal silicon dioxide, hypromellose, magnesium stearate, corn starch.

Shell composition:

pink tablet: opadry OY-6957 pink – macrogol 400, hypromellose, titanium dioxide (E171), red iron oxide, yellow iron oxide, black iron oxide, talc;
light yellow tablet: opadry OY-02B22764 yellow – macrogol 400, hypromellose, yellow iron oxide, titanium dioxide (E 171), talc.

Description and types

Femoston is a hormone replacement drug. This type of therapy is most often necessary for women experiencing menopause. The medicine contains estradiol, identical to the real sex hormone of the same name, as well as a substitute for natural progesterone - dydrogesterone. The first hormone compensates for the lack of estrogen, the absence of which causes bone fragility and increases the risk of fractures. Depending on the dosage of the active substance, there are several types of the drug: Femoston 1/5, 1/10 and 2/10.

Pharmacological properties

Pharmacodynamics

Femoston 2/10 is an antimenopausal drug, the therapeutic effect of which is provided by a combination of two hormones. It is used as hormone replacement therapy (HRT) to prevent bone loss in the postmenopausal period and after oophorectomy.

Estradiol is an estrogen identical to endogenous estradiol, the main and most active female sex hormone. Taking estradiol makes it possible to compensate for estrogen deficiency in women upon the onset of menopause and reduce the symptoms of menopause at the beginning of treatment.

Dydrogesterone is a progestogen, its pharmacological effectiveness when taken orally is similar to the activity of progesterone. The presence of dydrogesterone in the tablet helps ensure complete secretory transformation of the endometrium, reducing the risk of developing endometrial hyperplasia, increased by the action of estrogen, during HRT.

Pharmacokinetics

After oral administration, absorption of Femoston 2/10 occurs in the gastrointestinal tract, where micronized estradiol and dydrogesterone are easily and quickly absorbed. The bioavailability of dydrogesterone is 28%.

Estrogen is found in bound and free states. Binding to plasma proteins: estradiol - up to 99% of the dose, of which with albumin - from 30 to 52%, with sex hormone binding globulin (SHBG) - from 46 to 69%; dydrogesterone and its metabolite – more than 90%.

In the liver, estradiol is metabolized to estrone and estrone sulfate. Both metabolites have estrogenic activity; estrone sulfate is characterized by enterohepatic recirculation.

The main metabolite of dydrogesterone is 20alpha-dihydrodydrogesterone (DHD), its maximum concentration in the blood plasma after taking the tablet occurs approximately 1.5 hours later. The plasma concentration of DHD significantly exceeds the initial concentration of dydrogesterone. The absence of estrogenic and androgenic effects is due to the characteristic feature characteristic of all dydrogesterone metabolites - maintaining the 4,6-dien-3-one configuration of the original substance and the absence of 17alpha-hydroxylation.

Estradiol passes into breast milk.

Elimination of estradiol and its metabolites is predominantly carried out by the kidneys in a state conjugated with glucuronic acid.

About 63% of the administered dose of dydrogesterone is excreted by the kidneys. Its total plasma clearance is 6.4 l/min. In urine, DHD is determined to a greater extent in the form of a glucuronic acid conjugate.

Half-life: estradiol - 10-16 hours, dydrogesterone - 5-7 hours, DGD - 14-17 hours.

Dydrogesterone is completely eliminated after 72 hours.

With daily intake of Femoston 2/10, the equilibrium concentration in the blood plasma of estradiol occurs after approximately 5 days, dydrogesterone - after 3 days.

Taking multiple doses does not affect the pharmacokinetic properties of dydrogesterone and its main metabolite.

Contraindications

untreated endometrial hyperplasia;
vaginal bleeding of unknown etiology;
breast cancer, including suspected;
meningioma and other progestogen-dependent tumors, including suspected ones;
endometrial cancer and other estrogen-dependent malignant tumors, including suspected ones;
thrombosis (venous and arterial), including deep vein thrombosis (including medical history);
thromboembolism, myocardial infarction, pulmonary embolism, cerebrovascular disorders of hemorrhagic and ischemic origin (including medical history);
the presence of pronounced or multiple factors of venous or arterial thrombosis due to hereditary or acquired predisposition, including antithrombin III deficiency, protein C or S deficiency, the presence of lupus anticoagulant or antibodies to cardiolipin, prolonged immobilization, severe obesity (body weight index above 30 kg /m2), diseases of the coronary arteries or cerebral vessels, angina pectoris, transient ischemic attacks, atrial fibrillation, complicated lesions of the heart valve apparatus;
malignant neoplasms of the liver;
porphyria;
acute or chronic form of liver disease, until functional parameters of liver tests are normalized (including medical history);
lactase deficiency, glucose-galactose malabsorption syndrome, galactose intolerance;
pregnancy period;
breast-feeding;
individual intolerance to the components of the drug.

Continuation of Femoston 2/10 is contraindicated if liver dysfunction, jaundice, uncontrolled arterial hypertension, or new migraine-like headaches occur during HRT.

It is recommended to prescribe Femoston 2/10 with caution to women with the presence or history of the following diseases and conditions: arterial hypertension, endometriosis, uterine leiomyoma, risk factors for the occurrence of estrogen-dependent neoplasms (including close relatives with breast cancer), liver tumors of benign etiology, epilepsy , diabetes mellitus with or without vascular complications, systemic lupus erythematosus, cholelithiasis, bronchial asthma, severe headache, migraine, otosclerosis, endometrial hyperplasia.

Contraindications to the use of Femoston

Hypersensitivity to the components of the drug; diagnosed or suspected breast cancer, endometrial carcinoma and other hormone-dependent tumors diagnosed or suspected; vaginal bleeding of unknown etiology; untreated endometrial hyperplasia; history of acute deep vein thrombosis, pulmonary embolism or idiopathic venous thromboembolism; arterial thromboembolism, including recent ones (for example, angina pectoris, myocardial infarction); acute and chronic liver diseases, as well as their history in the absence of normalization of functional state indicators; porphyria; established or suspected pregnancy.

Instructions for use of Femoston 2/10: method and dosage

Femoston 2/10 tablets are taken orally, regardless of meals, preferably always at the same time of day, convenient for the woman.

Recommended dosage: 1 pc. 1 time per day.

It is necessary to start taking the drug from the blister with pink tablets (marked with the number 1). After 14 days of taking tablets containing only estradiol (2 mg), followed by the use of light yellow tablets (marked with the number 2), which contain estradiol (2 mg) and dydrogesterone (10 mg). After 28 days, after finishing taking all the tablets from the current blister, therapy is continued by taking pink tablets from the new blister. HRT involves continuous use of the drug.

If you miss taking the next dose of Femoston 2/10 at the prescribed time, the missed tablet can be taken as soon as you remember, if the delay does not exceed 12 hours or the period since taking the previous tablet is no more than 36 hours. Otherwise, it must be taken at the usual time the next day. Skipping the next dose of the drug increases the risk of breakthrough uterine bleeding.

Usually, HRT begins with the prescription of Femoston 1/10; if the therapeutic effect due to estrogen deficiency is insufficient, the dose of estradiol is increased using Femoston 2/10. In this case, namely when switching from a continuous combination therapy regimen, you can start taking a new drug on any day.

When switching from another drug with a continuous sequential or cyclic treatment regimen, you must first complete the current cycle, and only then start taking Femoston 2/10.

Use of the drug Femoston

To initiate and maintain treatment of postmenopausal symptoms, the minimum effective dose should be prescribed for the minimum period of time. Femoston is taken daily in the first 14 days of a 28-day cycle, 1 tablet containing 1 or 2 mg of estradiol, and in the remaining 14 days - daily, 1 tablet containing 1 mg of estradiol and 10 mg of dydrogesterone or 2 mg of estradiol and 10 mg of dydrogesterone. After the end of the 28-day cycle, a new cycle should begin. Treatment must be continuous. The tablets should be taken in the order indicated on the package. Treatment of postmenopausal symptoms Usually begins with taking the drug Femoston, containing 1 mg of estradiol and 10 mg of dydrogesterone. Depending on the clinical effect, the dose is then selected individually. If the severity of symptoms associated with estrogen deficiency does not decrease, the dose can be increased by prescribing a drug that contains 2 mg of estradiol and 10 mg of dydrogesterone. Prevention of osteoporosis When hormone replacement therapy is used, it is necessary to take into account individual tolerance to treatment and that the expected effect of the drug on bone tissue is dose-dependent. Femoston Conti 1 tablet 1 time per day daily, without breaks, regardless of meals. Prevention of osteoporosis When hormone replacement therapy is used, it is necessary to take into account individual tolerance to treatment and that the expected effect of the drug on bone tissue is dose-dependent.

Side effects

general disorders: often - fatigue, malaise, weakness, peripheral edema;
from the nervous system: very often – headache; often – dizziness, migraine;
from the reproductive system and mammary glands: very often - tension in the mammary glands or their soreness; often - metrorrhagia, impaired vaginal secretion, bloody (spotting) discharge in postmenopause, pain in the lower abdomen, vaginal candidiasis, heavy menstrual-like bleeding, acyclic bleeding, scanty or absent menstrual-like bleeding, painful menstrual-like bleeding; uncommon – premenstrual-like syndrome, enlarged mammary glands, increased size of leiomyoma;
from the cardiovascular system: infrequently - increased blood pressure, venous thromboembolism; rarely - myocardial infarction;
from the hepatobiliary system: infrequently - pathologies of the gallbladder, impaired liver function, including in combination with malaise, abdominal pain, asthenia, jaundice;
from the gastrointestinal tract: very often – abdominal pain; often – flatulence, nausea, vomiting;
from the immune system: infrequently - hypersensitivity to estradiol and/or dydrogesterone;
from the skeletal muscles and connective tissue: very often – pain in the lumbar back;
dermatological reactions: often - allergic reactions, in the form of skin rash, itching, urticaria; rarely – angioedema, vascular purpura;
mental disorders: often – nervousness, depression; infrequently – libido disturbance;
infectious diseases: infrequently – cystitis;
other: often – increase in body weight; infrequently – decrease in body weight.

In addition, against the background of combined estrogen-gestagen therapy with the use of Femoston 2/10, the following adverse events may develop:

from the body as a whole: ovarian cancer, endometrial cancer, meningioma and other neoplasms of malignant, benign or unspecified etiology;
from the reproductive system and mammary glands: cervical erosion, fibrocystic mastopathy;
from the cardiovascular system: arterial thromboembolism;
from the gastrointestinal tract: with hypertriglyceridemia - pancreatitis;
from the nervous system: chorea, provoking epilepsy attacks, risk of developing dementia in women who begin hormone replacement therapy over the age of 65 years;
from the hematopoietic system: hemolytic anemia;
from the immune system: systemic lupus erythematosus;
from the organs of vision: increased curvature of the cornea, hypersensitivity to contact lenses;
from connective tissue and skeletal muscles: cramps in the muscles of the lower extremities;
from the genitourinary system: urinary incontinence;
laboratory indicators: increased levels of thyroid hormones;
dermatological reactions: erythema nodosum, erythema multiforme, chloasma and/or melasma;
from the side of metabolism: hypertriglyceridemia;
others: in patients with porphyria – worsening of the disease.

Side effects of the drug Femoston

Common (1–10%): headache, migraine, nausea, abdominal pain, flatulence, leg cramps, breast pain, breakthrough bleeding, spotting, pelvic pain, asthenia, weight loss or gain. Uncommon (≤1%): vaginal candidiasis, increased size of uterine fibroids, depression, changes in libido, irritability, dizziness, venous thromboembolism, gallbladder disease, allergic skin reactions, rash, urticaria, itching, back pain, changes in cervical erosion and amount of cervical secretion, dysmenorrhea, peripheral edema. Rarely (≤0.1%): intolerance to contact lenses, increased corneal curvature, liver dysfunction, which may be accompanied by asthenia, malaise, jaundice and abdominal pain, breast enlargement, premenstrual-like syndrome. Very rare (≤0.01%): hemolytic anemia, hypersensitivity reactions, chorea, myocardial infarction, stroke, vomiting, chloasma and melasma, which may persist after drug discontinuation, erythema multiforme, erythema nodosum, vascular purpura, angioedema, deterioration with porphyria. Breast cancer According to the results of a large number of epidemiological studies and one randomized, placebo-controlled trial (Women Health Initiative - WHI), the overall risk of breast cancer increases with the duration of hormone replacement therapy (HRT) in women who receive this treatment, or who have undergone HRT in the recent past. For estrogen-only HRT, the relative risk (RR) estimate from a re-analysis of data from 51 epidemiological studies (in which estrogen-only HRT was given to more than 80% of all HRT cases) and the Million Women Study (MWS) epidemiological study is similar at 1.35 (95% confidence interval - CI: 1.21-1.49) and 1.30 (95% CI: 1.21-1.40), respectively. Regarding combined HRT (estrogen plus progestogen), several epidemiological studies have reported a higher overall risk of breast cancer than estrogen monotherapy. The MWS study demonstrated that, compared with patients who had never received HRT, use of different types of combined (progestogen plus estrogen) HRT was associated with a higher risk of breast cancer (RR = 2.00, 95% CI: 1 .88-2.12) than with estrogen alone (RR = 1.30, 95% CI: 1.21-1.40) or tibolone (RR = 1.45; 95% CI: 1.25-1. 68). In the WHI study, the risk in all patients was 1.24 (95% CI: 1.01-1.54) after 5.6 years of combined (progestogen plus estrogen) HRT (conjugated equine estrogens - CLE and methylprogesterone acetate - MPA) in comparison with placebo. The absolute risks calculated in the MWS and WHI studies are presented below: Based on the average incidence of breast cancer in developed countries, the MWS study found that approximately 32 out of 1000 women over 50 years of age can be expected to be diagnosed with breast cancer up to 64 who are not receiving HRT; per 1000 women who have recently received or are receiving HRT, the number of additional cases during the corresponding period would represent for those receiving estrogen replacement therapy only 0 to 3 (best estimate = 1.5) if used for 5 years; from 3 to 7 (best score = 5) when used for 10 years; for those receiving combined (estrogen plus progestogen) HRT 5 to 7 (best estimate = 6) when used for 5 years; 18 to 20 (best estimate = 19) when used for 10 years. The WHI study found that after 5.6 years of follow-up in women aged 50 to 79 years, combined estrogen-progestogen HRT (CPE and MPA) would result in an additional 8 cases of invasive breast cancer diagnosed per 10,000 woman-years. According to study statistics, it was found that: per 1000 women in the placebo group, approximately 16 cases of invasive breast cancer would be diagnosed after 5 years; per 1000 women who received combined estrogen + progestogen HRT (CLE and MPA), the number of additional cases will be from 0 to 9 (best estimate = 4) when used for 5 years. The number of additional cases of breast cancer in women who use HRT is similar to that of women who start HRT, regardless of their age at start of use (45 to 65 years). Other adverse reactions reported in association with estrogen/progestogen therapy:

estrogen-dependent neoplasms, both benign and malignant, for example, endometrial cancer, ovarian cancer;
venous thromboembolism, that is, deep vein thrombosis of the lower extremities or pelvis and pulmonary embolism, is more common among women who receive HRT than among those who do not;
arterial thromboembolism;
an increase in the size of neoplasms caused by progestogen (for example, meningioma);
dementia.

Endometrial cancer In women with an intact uterus, the risk of endometrial hyperplasia and cancer increases with the duration of estrogen monotherapy. According to epidemiological studies, the best estimate of risk is that in women who do not take HRT, endometrial cancer can be expected to be diagnosed in approximately 5 in 1000 cases at ages 50 and 65 years. Depending on the duration of treatment and dose of estrogen, the risk of developing endometrial cancer among those taking estrogen alone is 2 to 12 times greater than among those not taking it. Adding a progestogen to estrogen monotherapy significantly reduces this increased risk.

special instructions

Femoston 2/10 should only be prescribed to women with symptoms that cause a significant deterioration in their quality of life, and HRT should be continued until the risk of side effects outweighs the benefits of treatment. Particular caution should be exercised in patients over 65 years of age, since experience with the drug at this age is limited.

The most common adverse events that occur with the combination of estradiol and dydrogesterone include tension and tenderness of the mammary glands, abdominal pain, headache, and back pain.

Before starting or resuming therapy, a woman must undergo a general and gynecological examination and mammography. To take into account possible contraindications and conditions, the prescription of Femoston 2/10 should be based on data on the patient’s complete medical and family history. Based on the clinical picture, the doctor should inform the woman about all the risks associated with hormonal therapy and about those changes in the mammary glands that require consultation with a doctor.

Since HRT is carried out over a long period of time, examinations are recommended during treatment. The doctor determines their frequency and nature for each patient individually, but the frequency of examinations should not be less than once every six months.

The influence of estrogens on the results of laboratory tests to determine glucose tolerance, study of liver and thyroid function should be taken into account.

Compared with women not receiving estrogen monotherapy, its use in patients increases the risk of developing endometrial hyperplasia or cancer from 2 to 12 times, depending on the duration and dose of the drug. Moreover, it remains elevated for another 10 years after estrogen withdrawal. Cyclic use of progestogen reduces the risk of endometrial hyperplasia and cancer increased by estrogen. For timely diagnosis of these diseases, it is advisable to use ultrasound screening and histological examination. At the beginning of treatment, breakthrough or spotting bleeding from the vagina may occur. If such bleeding occurs after several months of therapy or after discontinuation of Femoston 2/10, to exclude a malignant neoplasm, it is necessary to diagnose their cause, including performing an endometrial biopsy.

HRT increases the risk of developing deep vein thrombosis and pulmonary embolism by almost 3 times, especially during the first year of hormone use. Women whose close relatives (mother, father) had thromboembolic complications at a young age, or with a history of recurrent miscarriage, need to undergo a hemostasis study. During anticoagulant therapy, the prescription of Femoston 2/10 is possible only if the benefits of HRT outweigh the potential risk of thromboembolism.

The use of HRT should be discontinued 1–1.5 months before planned surgery with long-term subsequent immobilization. Hormonal therapy can be resumed only after the woman’s mobility has been completely restored.

Symptoms of venous thromboembolism include swelling of the lower extremities, pain, shortness of breath, and sudden chest pain. If they develop while using Femoston 2/10, you should immediately consult a doctor and stop taking the drug.

The incidence of breast cancer diagnosis, which increases with the use of estrogen monotherapy or a combination of estrogen and progestogen, returns to its original level within 5 years after cessation of therapy. The risk of developing breast cancer depends on the duration of therapy and can double after 5 years of combined estrogen-progestogen HRT. Timely diagnosis of breast cancer can make breast engorgement difficult during HRT.

There is a risk of developing ovarian cancer, but it is significantly lower than the risk of breast cancer.

The use of Femoston 2/10 increases the risk of ischemic stroke by 1.5 times; treatment does not affect the occurrence of hemorrhagic stroke.

Since estrogens can retain fluid in the body, this can worsen the condition in patients with impaired kidney and heart function.

With hypertriglyceridemia that occurs while taking Femoston 2/10, the risk of developing pancreatitis increases.

HRT does not improve cognitive function. The increased risk of developing dementia should be taken into account when prescribing the drug to women over 65 years of age.

Femoston 2/10 does not have contraceptive properties.

Impact on the ability to drive vehicles and complex mechanisms

It is recommended to be careful when working with complex mechanisms and driving vehicles, since the drug can cause dizziness, drowsiness and other side effects that affect the speed of psychomotor reactions.

Features of application

Hormone stimulation is a very complex process, far from having a local effect, affecting the entire body. Therefore, it is not surprising that the drug Femoston has a lot of side effects, as well as contraindications for use.

Contraindications

Hormonal drugs have a strong effect on the body, so their use is only possible on the recommendation of a doctor. But even so, it would be useful to carefully study the contraindications, of which there are many in the case of Femoston. Here are a number of circumstances under which patients are not prescribed this medicine:

Acute venous thrombosis
Poor blood circulation in the brain
Mammary cancer
Cancer of the uterus
Chronic liver diseases, acute liver failure
Bleeding in the female genital organs, the causes of which are still unknown
Pulmonary embolism
Porphyrin disease
Individual intolerance to the components of the drug
Pregnancy
Lactation

If the patient's medical history contains information about the risk of developing thrombosis, as well as various liver diseases, including tumors, then Femoston is not prescribed.
Contraindications to the use of this medication also include possible or already discovered neoplasms that depend on the hormones estrogen or progesterone. Important! Even if the diagnosis of cancer has not yet been confirmed, the very assumption is already a reason not to prescribe Femoston.

There is also a list of those to whom hormonal medicine is prescribed with caution, carefully monitoring the patient’s condition during treatment. These are diabetics, asthmatics, hypertension, epileptics, as well as people suffering from migraines, lupus or otosclerosis. You will definitely find a more detailed list of risk groups in the instructions for the drug.

Side effects

Femoston has many side effects. The hormonal drug affects the psyche, the immune, nervous and cardiovascular systems, the gastrointestinal tract, the skin and fiber, the reproductive system, and can also cause general disorders and provoke some diseases.

The most common side effects include the following:

Abdominal pain, nausea, vomiting
Nervousness, depression
Strong headache
Skin rashes
Pain in the lumbar back
Heavy or weak bleeding, pain in the lower abdomen
Candidiasis
Weakness and feeling tired
Weight gain

According to the clinical trial map, the term “often” implies the frequency of occurrence of a particular effect within the range of 1 in 100 - 1 in 10.
Important! Femoston is prescribed when the normal functioning of the body is disrupted and is taken as long as its beneficial effects outweigh the risk of side effects.

Overdose

Hormone substitutes estradiol and dydrogesterone have a low level of toxicity. As has been mentioned more than once, Femoston is taken once a day, at a constant time determined by you.

In case of an overdose, severe tension in the mammary glands, nausea or even vomiting, headache and abdominal pain, and a state of sleepy weakness may occur. Bleeding is also possible. Treatment is determined based on symptoms.

Drug interactions

Simultaneous use of Femoston 2/10 with other medicinal substances/preparations:

anticonvulsants (carbamazepine, phenobarbital, phenytoin), antimicrobial agents (nevirapine, rifabutin, rifampicin, efavirenz), ritonavir, nelfinavir, Hypericum perforatum (St. John's wort) preparations: help increase the metabolism of estrogens and gestagens, the clinical manifestation of which may be increased intensity of bleeding from the vagina;
fentanyl, tacrolimus, theophylline, cyclosporine: may significantly increase their plasma concentration levels.

Interactions of the drug Femoston

The metabolism of estrogens can be enhanced when used simultaneously with substances that activate enzymes (cytochrome P450 systems) that are involved in the metabolism of drugs. These substances include anticonvulsants (eg, phenobarbital, carbamazepine, phenytoin) and antimicrobials (eg, rifampicin, rifabutin, nevirapine, efavirens). Ritonavir and nelvinavir, when used simultaneously with steroid hormones, activate the above enzymes. Herbal preparations, the component of which is St. John's wort (Hypericum perforatum), increase the metabolism of estrogens and progestogens, which can lead to a weakening of their effect and a change in the profile of uterine bleeding. There is no information on the interaction of dydrogesterone with other drugs.

Reviews of Femoston 2/10

Reviews of Femoston 2/10 are quite contradictory. Women for whom the drug helped normalize hormonal levels and become pregnant after many years of lack of conception and disappointing doctors' prognoses describe the effectiveness of the drug using only superlative words. With HRT, therapy significantly improves the general condition, women forget about frequent hot flashes and “wobbly” legs. Patients are recommended to take the pills before bed, which will reduce the unpleasant effects of the drug in the form of nausea and headaches, and also undergo regular medical examinations.

Negative reviews of Femoston 2/10 are given by women who, after 6 months of combination therapy, were diagnosed with the development of a hormone-dependent breast tumor. One of the patients describes that the use of the drug for polycystic ovary syndrome normalized the menstrual cycle without causing noticeable side effects for 3 years, but after discontinuation of therapy, menstruation stopped. And the consequence of taking hormonal pills was a significant increase in weight and swelling.

Doctors give a positive assessment of the effectiveness of Femoston 2/10 when used for the treatment and prevention of conditions arising from premature ovarian failure.