Flutamide-TL - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate, microcrystalline cellulose, povidone K25, croscarmellose sodium, sodium lauryl sulfate, silicon dioxide colloid, magnesium stearate.

Film sheath: Opadrai II (yellow) 85F220031 [polyvinyl alcohol, macrogol 4000, talc, titanium dioxide, iron oxide yellow].

Description:

Round biconvex tablets, covered with a film coating of yellow color. On the cross section, the core is light yellow in color.

Pharmacotherapeutic group:Antitumor agent - antiandrogen

ATX: & nbsp

L.02.B.B.01 Flutamide

Pharmacodynamics:

Flutamide is a non-steroidal antiandrogenic antitumor drug. Competitively blocks the interaction of androgens with their cellular receptors. The mechanism of action is based on inhibition of androgen uptake and / or inhibition of androgen binding in target cell nuclei. Its ability to inhibit the action of testosterone at the cellular level is in addition to drug castration caused by gonadotropin-releasing hormone (GnRH) agonists. The target organ of the pharmacological action of flutamide is the prostate gland and seminal vesicles. Flutamide does not possess estrogenic, antiestrogenic, progestagenic and anti-gestagenic activity.

Pharmacokinetics:

Flutamide when ingested quickly and completely absorbed from the gastrointestinal tract, undergoing biotransformation in the liver. Metabolized to form the main biologically active metabolite - α-hydroxylated derivative flutamide (2-oxyflutamide), the maximum concentration of which is achieved after 2 hours and is detected within 8 hours after taking the drug.94-96% flutamide and 92-94% active metabolite bind to plasma proteins. The half-life of the active metabolite is 6 hours (in elderly patients - 8 hours). It is mainly excreted by the kidneys (46%), through the intestine - by 4.2% within 72 hours. After repeated administration of flutamide inside 250 mg 3 times a day, the equilibrium concentration of the drug and its active metabolite in the blood serum is reached after the fourth dose of the drug.

Indications:

Metastatic prostate cancer when suppression of testosterone is indicated:

- at the beginning of treatment in combination with GnRH agonists;

- as an additional drug in patients already receiving therapy with GnRH agonists;

- in patients with surgical castration;

- in patients in whom other types of hormone therapy were ineffective or with intolerance of such treatment.

Contraindications:

- Hypersensitivity to flutamide or any other component in the formulation.

- Severe hepatic insufficiency.

- Child age (safety and efficacy not established).

Carefully:

The drug should be used with caution in patients with moderate hepatic insufficiency, renal insufficiency, cardiovascular diseases, in patients with a tendency to thrombosis, with congenital lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome (since the formulation contains lactose).

Pregnancy and lactation:

Flutamide is not intended for use in women.

Dosing and Administration:

Tablets are taken preferably after eating, not liquid, with a small amount of liquid.

Inside, 250 mg every 8 hours (1 tablet 3 times a day). In case of achieving a positive effect, the drug is used until signs of progression of the tumor develop.

In the case of combined therapy with GnRH agonists, both drugs can be prescribed concomitantly or the preparation of Flutamide-TL is started 3 days before the first admission of agonist GnRH.

Side effects:

Monotherapy

The most common unfavorable side effects of flutamide reported have been gynecomastia and / or stress in the breast, sometimes accompanied by galactorrhea. These reactions usually disappear after discontinuation of treatment or dose reduction. Flutamide demonstrates a weak ability to disrupt cardiovascular worksystems; compared with diethylstilbestrol this violation is much less pronounced.

Combination Therapy

The most frequent side effects of combined therapy with flutamide and GnRH agonists reported were "blood flushes", decreased sexual desire, impotence, diarrhea, nausea, and vomiting. With the exception of diarrhea, the remaining indicated side effects are possible with the admission of GnRH agonists alone, and they develop at a comparable frequency.

The high incidence of gynecomastia observed with monotherapy with flutamide was significantly lower with combination therapy. In clinical studies, there was no significant difference in the incidence of gynecomastia between the placebo group and the group receiving flutamide (tablets or capsules) and the GnRH agonist.

Undesirable reactions are classified according to the frequency of their development as follows: very often (≥1 / 10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely (from ≥1 / 10,000 to <1/1000), very rarely (<1/10 000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

When using the drug as a monotherapy

Infectious and parasitic diseases

Rarely: herpes zoster.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Rarely: malignant neoplasm of mammary glands in men *.

Violations of the blood and lymphatic system

Rarely: lymphogenous edema.

Immune system disorders

Rarely: lupus-like syndrome.

Disorders from the metabolism and nutrition

Often: increased appetite;

Rarely: lack of appetite (anorexia).

Disorders of the psyche

Often: insomnia;

Rarely: anxiety, depression.

Disturbances from the nervous system

Rarely: dizziness, headache.

Disturbances on the part of the organ of sight

Rarely: blurred vision.

Heart Disease

Frequency unknown: interval lengthening QT.

Vascular disorders

Rarely: "tides" of blood to the face (sensation of heat).

Violations from the side of the gastrointestinal tract

Often: diarrhea, nausea, vomiting;

Rarely: nonspecific symptoms from the gastrointestinal tract, heartburn, constipation.

Disturbances from the liver and .zhelchevyvodayuschih ways

Often: hepatitis.

Disturbances from the skin and subcutaneous tissues

Rarely: skin itch, ecchymosis (hemorrhages in the skin or mucous membranes shell);

Rarely: photosensitivity reaction;

Frequency unknown: changes in hair structure.

Violations of the genitals and the breast

Often: gynecomastia and / or chest pain, galactorrhea;

Rarely: decreased libido, decreased production of seminal fluid;

Frequency unknown: increase in the concentration of testosterone in the blood plasma (in initial period of therapy).

General disorders and disorders at the site of administration

Often: feeling tired;

Rarely: edema, general weakness, malaise, thirst, chest pain.

Impact on the results of laboratory and instrumental research

Often: transient violations of the liver.

* There have been several reports of malignant neoplasms of the breast in male patients receiving flutamide in tablets. One report dealt with a compaction in the breast that was first discovered 3 or 4 months before the onset of monotherapy with flutamide in a patient with benign prostatic hyperplasia.After excision of the formation, a low-differentiated ductal carcinoma was diagnosed.

Another report dealt with gynecomastia and a node seen at 2 and 6 months after the onset of monotherapy with flutamide for common prostate cancer. In 9 months after the beginning of treatment the node was excised and it was diagnosed moderately differentiated invasive ductal carcinoma, stage T4N0M0, G3.

Sometimes micronodular lesion of the breast can develop. At the onset of monotherapy with flutamide, serum testosterone levels may increase; in addition to this, there may be "tides" and changes in the nature of the hair.

During the post-registration period, there were reports of cases of acute renal failure, interstitial nephritis and myocardial ischemia, lymphodemia,ovysheniya arterial pressure, interstitial pneumonitis, dyspnea, cough; their frequency is unknown.

When combined therapy with GnRH agonists

Violations of the blood and lymphatic system

Rarely: anemia, leukopenia, thrombocytopenia;

Rarely: hemolytic anemia, macrocytic anemia, methemoglobinemia, sulfogemoglobinemia.

Disorders from the metabolism and nutrition

Rarely: lack of appetite (anorexia);

Rarely: hyperglycemia, aggravation of the severity of the treatment of diabetes.

Disorders of the psyche

Rarely: anxiety, depression.

Disturbances from the nervous system

Rarely: confusion, nervousness, numbness.

Heart Disease

Frequency unknown: interval lengthening QT.

Vascular disorders

Often: "tides" of blood to the face (sensation of heat);

Rarely: increased blood pressure;

Frequency unknown: thromboembolism.

Disturbances from the respiratory system, chest and mediastinal organs

Rarely: symptoms from the respiratory system, including shortness of breath, interstitial lung disease.

Disorders from the gastrointestinal tract

Often: diarrhea, nausea, vomiting;

Rarely: nonspecific symptoms from the gastrointestinal tract.

Disturbances from the liver and bile ducts

Infrequently: hepatitis;

Rarely: hepatic insufficiency, jaundice;

Rarely: Cholestatic jaundice, hepatic encephalopathy, necrosis hepatocytes, fatal outcome as manifestations of severe hepatic insufficiency against the background of hepatotoxic action of the drug.

Disturbances from the skin and subcutaneous tissues

Rarely: skin rash;

Rarely: photosensitivity reaction; erythema, ulceration of the skin integuments, epidermal necrolysis.

Disturbances from musculoskeletal and connective tissue

Rarely: Symptoms of neuromuscular conduction disorders (numbness, paresthesia, myalgia and / or myasthenia gravis in the hands, hands, feet, legs).

Disorders from the kidneys and urinary tract

Rarely: pollakiuria, nocturia, incontinence;

Rarely: change of color of urine to amber or greenish-yellow.

Ongenital and thoracic disruption

Often: decreased libido, impotence;

Infrequently: gynecomastia;

Rarely: dyspareunia.

General disorders and disorders in the place of attention

Rarely: edema, irritation at the injection site.

Impact on the results of laboratory and instrumental research

Rarely: increased urea and / or creatinine concentrations in plasma blood.

Cases of development of such undesirable effects as acute renal failure, interstitial nephritis, myocardial ischemia, micro-nodular changes in breast tissue are described.It is not possible to assess the incidence of these unwanted effects.

Overdose:

Symptoms: when administered at a dose of 1500 mg / day for 36 weeks, there is gynecomastia, tension in the breast, an increase in activity of aspartate aminotransferase.

Treatment: gastric lavage. There is no specific antidote. In case of an overdose, if the patient is conscious and without spontaneous vomiting, vomiting should be induced. It is necessary to apply symptomatic therapy with constant monitoring of the patient and vital functions. Hemodialysis is ineffective.

Interaction:

The interaction between flutamide and leuprorelin not described; nevertheless, when co-prescribing, it is necessary to take into account the possible side effects of each of these drugs.

Prothrombin time should be carefully monitored in patients receiving oral anticoagulants, due to the possibility of lengthening prothrombin time against the background of flutamide administration. You may need to adjust the dose of anticoagulants.

When combined with flutamide and theophylline it is possible to increase the concentration of theophylline in the blood plasma, since the latter is subjected to primary metabolism by isoenzyme CYP1A2 cytochrome P450, responsible for the conversion of flutamide to the active metabolite 2-oxyflutamide.

On the background of flutamide therapy, drugs that have a hepatotoxic effect should be prescribed only in cases where the potential benefit exceeds the possible risk of therapy. Due to the known toxic effects of flutamide on the liver and kidneys, alcohol should be avoided during therapy with the drug.

When carrying out antiandrogen therapy, the interval can be extended QT. In this regard, special care should be taken when it is necessary to prescribe medications that can cause lengthening of the interval QT and / or lead to the development of pirouette-type arrhythmias, including class I antiarrhythmicsquinidine, disopyramide), class III (amiodarone, sotalol, dofetilide, ibutilide), other antiarrhythmic drugs, as well as methadone, moxifloxacin, antipsychotics, etc.

Special instructions:

Treatment with flutamide should appoint a specialist.

In combination therapy with GnRH agonists, it is recommended to begin taking flutamide at least 3 days before the admission of the GnRH agonist, as in this case the likelihood of development and severity of side effects induced by GnRH agonists will decrease.

When combined therapy with GnRH agonists, it is recommended to pay attention to the control of glucose and / or glycosylated hemoglobin in the blood in patients, as there is a decrease in glucose tolerance, which can lead to diabetes mellitus or loss of glycemic control in patients with previously established diabetes mellitus.

Combination therapy with GnRH agonists can adversely affect bone mineral density, which increases the risk of pathological fractures. Prevention and treatment of bone complications is recommended.

In the case of hepatic failure, long-term therapy with flutamide should be used only after a thorough assessment of the benefit-risk relationship. Before the start of treatment should be carried out a laboratory study of liver function. Treatment with flutamide should not begin with a more than 2-3-fold increase in the activity of "hepatic" transaminases in the serum.

As against the background of treatment with flutamide, it was reported about an increase in the activity of "liver" transaminases, the development of cholestatic jaundice, liver necrosis and hepatic encephalopathy, it is necessary to consider the possibility of a periodic laboratory study of liver function. The liver function usually returned to its original state after the drug was discontinued; however, there were 3 reports of fatal outcomes due to severe liver damage associated with the use of flutamide. Appropriate laboratory tests to assess liver function should be performed every patient once a month for the first 4 months, and then periodically or with the development of the first signs / symptoms of hepatic function disorder (itching, darkening of urine, persistent loss of appetite, jaundice, tension in the right hypochondrium or are not explainable by other causes of influenza-like symptoms). Flutamide therapy should be discontinued in the presence of laboratory signs of liver damage or with clinical jaundice in the absence of biopsy-confirmed metastases in the liver or with a more than 2-3-fold increase in the activity of "hepatic" transaminases in the serum in patients without pathological signs. Flutamide is indicated for use only in male patients.During treatment, measures should be taken to prevent conception.

Flutamide should be used with caution in patients with impaired renal function.

Flutamide can cause an increase in testosterone, estradiol in the plasma, leading to a fluid retention. In severe cases, this can lead to an increased risk of angina and heart failure. For this reason flutamide should be used with caution in patients with cardiovascular disease. Flutamide can enhance peripheral edema or swelling in the ankle area in patients prone to these conditions.

Increasing the level of estradiol can contribute to the development of thromboembolic complications.

Men who receive long-term therapy with flutamide in the absence of chemical or surgical castration should regularly check the spermogram. Antiandrogenic therapy may contribute to lengthening the interval QT. Before prescribing flutamide, patients with lengthening of the interval QT in the history or presence of factors that may lead to lengthening of the interval QT, as well as patients taking concomitant medications that can cause prolongation of the interval QT, the physician should assess the benefit-risk relationship, including the possible development of pirouette-type arrhythmia in such patients.

Effect on the ability to drive transp. cf. and fur:

Because of the likelihood of side effects such as drowsiness, headache and confusion, care should be taken when practicing potentially dangerous activities that require a high concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 250 mg.

Packaging:

For 7 or 10 tablets in a contour mesh box made of a combination film (polyvinyl chloride / polyvinylidene chloride) and foil of aluminum printed lacquered.

To 20, 84, 90 or 100 tablets in a can of polymer (made of polyethylene or polypropylene) for drugs, sealed with a polymer cover (made of polyethylene or polypropylene) with a desiccant and control of the first opening.

Each can, 12 contour packs of 7 tablets or 2. 9 or 10 contour packs of 10 tablets together with the instructions for use are placed in a pack of cardboard boxes.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004340

Date of registration:13.06.2017

Expiration Date:13.06.2022

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

TECHNOLOGY OF DRUGS, LTD. Russia

Information update date: & nbsp23.10.2017

Illustrated instructions

Instructions

Flutamide-TL (Flutamide-TL)