Flutamide - instructions for use, doses, side effects, contraindications

Excipients: lactose monohydrate (sugar milk) - 216,50 mg, microcrystalline cellulose - 80,00 mg, corn starch - 65,00 mg, povidone-K25 - 20,00 mg, sodium lauryl sulfate - 12,00 mg, magnesium stearate - 3, 25 mg, silicon dioxide colloid - 3.25 mg.

Description:Round flat cylindrical tablets from white with a yellowish shade to light yellow color with a risk on one side and a facet from two sides.

Pharmacotherapeutic group:Antitumor agent, antiandrogen

ATX: & nbsp

L.02.B.B.01 Flutamide

Pharmacodynamics:

Flutamide is a non-steroidal antiandrogenic antitumor agent. 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 the drug "castration" caused by gonadotropin-releasing hormone (GnRH) agonists. Organs - the targets of the pharmacological action of flutamide are 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, is metabolized in the liver. Metabolized with the formation of the main biologically active metabolite - α-hydroxylated derivative flutamide (2-oxyflutamide), the maximum concentration of which in the blood plasma is 2 hours and is detected within 8 hours after taking the drug.94-96% flutamide and 92-94% 2-oxyfluamide bind to blood plasma proteins. The half-life of 2-hydroxyflutamide is 6 hours (in elderly patients 8 hours).

It is mainly excreted by the kidneys - 46%, through the intestine - 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 treatment for patients already receiving therapy with GnRH agonists;

- in patients with surgical castration;

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

Contraindications:

- Hypersensitivity to flutamide or any other component of the drug;

- severe hepatic impairment;

- age to 18 years (efficacy and safety not established).

Carefully:

With caution, the drug should be used in patients with impaired liver function,renal failure, cardiovascular disease, in patients with a propensity to thrombosis under conditions predisposing to intoxication aniline (one metabolite of flutamide - metilanilinovoe derivative): deficiency of glucose-6-phosphate dehydrogenase, smoking, hemoglobinopathies (M- hemoglobin); with lactase deficiency, lactose intolerance, glucose-galactose with malabsorption.

Pregnancy and lactation:

Flutamide is not intended for use in women.

Dosing and Administration:

Tablets taken orally, preferably after the meal is not liquid, squeezed small amount of liquid.

Inside, 250 mg every 8 hours (1 tablet 3 times a day). If the therapeutic effect is achieved, the drug is used until signs of progression of the tumor develop.

In the case of simultaneous therapy with GnRH agonists, both drugs can be used simultaneously or the drug intake Flutamide begin 3 days before the first admission of agonist GnRH.

In the case of radiation therapy, the drug Flutamide appoint 8 weeks before its onset and continue taking the drug throughout the entire period of radiation therapy.

Side effects:

Monotherapy

The most common side effects of flutamide were 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 the work of the cardiovascular system, compared with diethylstilbestrol this violation is much less pronounced.

Combination Therapy

The most frequent side effects of combined therapy with flutamide and GnRH agonists were "hot flashes" of blood, decreased libido, impotence, diarrhea, nausea, and vomiting. With the exception of diarrhea, the remaining said side effects are possible with the use 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.

According to the World Health Organization, the undesirable effects are classified according to their frequency of development as follows: Often (≥10%); often (≥1% and <10%); infrequently (≥0.1% and <1%); rarely (≥0.01% and <0.1%); rarely (<0,01 %); frequency unknown (insufficient data to estimate the frequency of development).

	Monotherapy	Combination therapy with GnRH agonists
Deviations from the norm, identified in laboratory studies
Often:	Transient disorders of liver function
Rarely:		Increase in the concentration of urea and creatinine in the blood plasma
Violations of the blood and lymphatic system
Rarely:	Lymphedema	Anemia, leukopenia, thrombocytopenia
Rarely:		Hemolytic anemia, megaloblastic anemia, methemoglobinemia, sulfogemoglobinemia
Disturbances from the nervous system
Rarely:	Headache, dizziness	Confusion, nervousness, numbness
Disturbances on the part of the organ of sight
Rarely:	Visual impairment
From the respiratory system
Rarely:	Interstitial pneumonitis, dyspnoea
Rarely:	Cough	Pulmonary manifestations (eg, dyspnea), interstitial lung involvement
Disorders from the gastrointestinal tract
Often:		Diarrhea, nausea, vomiting
Often:	Diarrhea, nausea, vomiting
Rarely:	Gastrointestinal disorders of unclear etiology, heartburn, constipation	Gastrointestinal disorders of unclear etiology
Disorders from the kidneys and urinary tract
Rarely:		Pollakiuria, nocturia, incontinence
Rarely:		Change of color of urine to amber or greenish-yellow
Disturbances from the skin and subcutaneous tissues
Rarely:	Itching, ecchymosis	Rash
Rarely:	Photosensitivity	Photosensitivity, erythema, ulceration of the skin, epidermal necrolysis
Frequency unknown:	Changes in hair structure
Disturbances from musculoskeletal and connective tissue
Rarely:		Symptoms of neuromuscular disorders
Metabolic disorders
Often:	Increased appetite
Rarely:	Anorexia	Anorexia
Rarely:		Hyperglycemia, exacerbation of diabetes mellitus
Infectious and parasitic diseases
Rarely:	Shingles
Benign, malignant and unspecified neoplasms (including cysts and polyps)
Rarely:	Neoplasm of the breast in men *
Heart Disease
Frequency unknown:	QT interval extension	QT interval extension
Vascular disorders
Often:		"Tides"
Rarely:	"Tides"	Increased blood pressure
Frequency unknown:	Increased blood pressure	Thromboembolism
General disorders and disorders at the site of administration
Often:	Increased fatigue
Rarely:	Swelling, chest pain, weakness, malaise, thirst	Swelling, irritation at the injection site
Immune system disorders
Rarely:	Lupus-like syndrome
Disturbances from the liver and bile ducts
Often:	Hepatitis
Infrequently:		Hepatitis
Rarely:		Violation of the function of the liver, jaundice
Rarely:		Cholestatic jaundice, hepatic encephalopathy, hepatocellular necrosis, hepatotoxicity with fatal outcome
Violations of the genitals and mammary gland
Often:	Gynecomastia and / or chest pain, galactorrhea	Reducing sexual desire, impotence
Infrequently:		Gynecomastia
Rarely:	Reducing sexual desire, reducing the formation of sperm	Dyspareunia
Frequency unknown	An increase in the concentration of testosterone in the blood plasma (in the initial period of therapy)
Disorders of the psyche
Often:	Insomnia
Rarely:	Anxiety, depression	Depression, anxiety

* There were several reports of malignant neoplasms of the breast in patients with men taking flutamide. 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, respectively, after the initiation of flutamide therapy 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, an increase in plasma testosterone levels is possible; 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 (the frequency is unknown).

Overdose:

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

Treatment: gastric lavage.There is no specific antidote. Symptomatic therapy, constant monitoring of vital functions.

Hemodialysis is ineffective.

Interaction:

With the simultaneous use of indirect anticoagulants and flutamide, anticoagulant action may be enhanced. A careful monitoring of prothrombin time is recommended and correction of the anticoagulant dose may be required.

With the simultaneous use of flutamide and theophylline, an increase in the concentration of theophylline in the blood plasma is possible.

Joint use with other potentially hepatotoxic agents is possible only with a careful analysis of the risk / benefit ratio. Given the known possible hepato- and nephrotoxicity of flutamide, excessive use of ethanol should be avoided.

Interactions between flutamide and leuprorelin were not observed, however, combined therapy with flutamide with GnRH agonists should take into account possible side effects of each drug.

Because antiandrogen therapy can contribute to lengthening the interval QT, the simultaneous use of flutamide and drugs should be carefully evaluated, which contribute to the lengthening of the interval QT, or drugs that can lead to the development of pirouette-type arrhythmias, such as antiarrhythmic drugs of class IA (eg, quinidine, disopyramide) or class III (for example, amiodarone, sotalol, dofetil, ibutilide), methadone, moxifloxacin, antipsychotics, etc.

Special instructions:

Treatment with flutamide should be prescribed by a specialist.

When combined therapy with GnRH agonists is recommended to begin taking the drug Flutamide at least 3 days before the first admission of the GnRH agonist, as in this case the likelihood of development and severity of GnRH agonist-induced side effects will decrease.

When combined therapy with GnRH agonists, it is recommended that attention be paid to monitoring the concentration 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 presence of violations of the liver, the use of flutamide for a long period of time is possible only with a careful analysis of the risk / benefit ratio. The use of the drug in patients with severe impairment of liver function is contraindicated (see section "Contraindications.")

Before starting treatment with the drug Flutamide it is necessary to evaluate the liver function. Treatment with flutamide should not begin with an increase in the activity of liver transaminases in the blood plasma by more than 2-3 times.

Treatment with drug Flutamide should be carried out under the control of the activity of "hepatic" transaminases in the blood. The liver function usually returned to its original state after the drug was discontinued; but there are 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 during the first 4 months of therapy and periodically thereafter or when developing the first signs / symptoms of impaired hepatic function (itching, darkening of urine, persistent loss of appetite, jaundice,tension in the right hypochondrium or unexplained 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 "liver" transaminases in blood plasma without pathological signs.

During treatment, it is possible to increase plasma concentrations of testosterone and estradiol, which can cause fluid retention in the body. 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.

An increase in the plasma concentration of estradiol can lead to an increase in the frequency of thromboembolic complications.

Flutamide should be used with caution in patients with renal insufficiency.

Antiandrogenic therapy may contribute to lengthening the interval QT. Before using the drug Flutamide in patients with lengthening of the interval QT in the anamnesis or with the presence of factors that may lead to lengthening of the interval QT, as well as in patients taking concomitant medications that can cause prolongation of the interval QT, the physician should assess the benefit / risk ratio, including the possible development of pirouette-type arrhythmia in such patients.

Long-term therapy in patients without drug or surgical castration requires regular monitoring of the spermatogram.

The drug is indicated for use only in men. During treatment with the drug Flutamide it is necessary to use reliable methods of contraception.

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

During the period of therapy, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions (risk of drowsiness, headache, confusion).

Form release / dosage:

Tablets 250 mg.

Packaging:

For 10, 20 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 10, 20, 30, 50, 84 or 100 tablets in cans of polyethylene terephthalate for medicines or polypropylene for drugs sealed with high-pressure polyethylene caps with a first-opening control or polypropylene caps with a "push-turn" system or lids made of Low pressure with control of the first autopsy.

One jar or 1, 2, 3, 4, 5 or 10 contour mesh packages together with the instruction for use are placed in a cardboard package (bundle).

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004441

Date of registration:01.09.2017

Expiration Date:01.09.2022

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Information update date: & nbsp02.10.2017

Illustrated instructions

Instructions

Flutamide (Flutamide)