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

Auxiliary substances', mannitol, sodium lauryl sulfate, povidone K30, purified water, microcrystalline cellulose, silicon dioxide colloidal anhydrous, sodium starch glycollate, magnesium stearate.

Description:Round biconvex tablets of light yellow color, without dividing risks.

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 the 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:

When ingested, the drug is fully and rapidly absorbed, subject to biotransformation in liver with the formation of a biologically active a-hydroxylated derivative (2-oxyflutamide). The time to reach the maximum concentration of the active metabolite is 2 hours, the connection with proteins is 94-96%. From the body the drug is excreted mainly with urine. Approximately 4.2% is excreted with feces within 72 hours. The half-life of the active metabolite from the plasma is about 6 hours (in elderly patients - 8 hours after a single dose and 9.6 hours at a stable concentration).After repeated administration of flutamide 250 mg three times a day, a stable level of drug concentration and its active metabolite in plasma was achieved after a fourth dose of flutamide.

Indications:

Treatment of 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 when intolerance of such treatment.

Contraindications:

- Hypersensitivity to flutamide or other components of the drug.

- Severe hepatic impairment

Carefully:Flutamide should be used with caution in patients with reduced liver function, with a tendency to thrombosis and cardiovascular disease, as well as in conditions predisposing to intoxication aniline (one of the metabolites flutamide - methylanilinated derivative): deficiency of glucose-6-phosphate dehydrogenase, smoking, hemoglobinopathy (M hemoglobin)

Dosing and Administration:

Inside, 250 mg 3 times a day every 8 hours. When achieve a positive effect of the drug is applied until signs of progression appear tumor disease.

In the case of combined therapy with GnRH agonists, both can be administered concomitantly or taken flutamide begin three days before the first admission of agonist GnRH.

In the case of radiotherapy flutamide appoint 8 weeks before the beginning and continue to take flutamide during the entire time of radiation therapy.

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 shows a weak ability to disrupt the functioning 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 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 administration of the 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 a GnRH agonist.

When determining the frequency, the following generally accepted indicators were used: very often (> 1/10), often (> 1/100 to <1/10), sometimes (> 1/1000 to <1/100), rarely (> 1/10 000 to <1/1 000) and very rarely (<1/10 000), and is also unknown (estimates based on available data can not be performed).

Class systems bodies		Monotherapy		Combined therapy with agonists GnRG
Deviations from the norm revealed in laboratory studies
Often:	Transitory impairment of liver function
Rarely:			Increase in the concentration of urea and creatinine in serum
Violations of the blood and lymphatic system
Rarely:	Lymphedema		Anemia, leukopenia, thrombocytopenia
Highly rarely:			Hemolytic anemia, macrocytic anemia, methemoglobinemia, sulfemoglobinemia
Disturbances from the nervous system
Rarely:		Dizziness, headache		Hnumbness, confusion, nervousness
Disturbances on the part of the organ of sight
Rarely		Visual disturbances
Respiratory, thoracic and mediastinal disorders
Highly rarely:				Pulmonary manifestations (eg, dyspnea), interstitial lung involvement
Disorders from the digestive system
Highly often:				Diarrhea, nausea, vomiting
Often:		Diarrhea, nausea, vomiting
Rarely:		Gastrointestinal disorders of unknown etiology heartburn, constipation		Gastrointestinal disorders of unclear etiology
Disorders from the urinary system
Rarely:				Urogenital symptoms
Highly rarely				Change of color of urine to amber or greenish-yellow
Disturbances from the skin and subcutaneous tissue
Rarely:		Itching, ecchymosis		Rash
Rarely:		Photosensitivity		Photosensitivity, erythema, ulcers, epidermal necrolysis
Disturbances from the musculoskeletal system and connective tissue
Rarely:				Symptoms neuromuscular disorders
Disorders of nutrition and metabolism
Often:		Increased appetite
Rarely:		Anorexia		Anorexia
Rarely:				Hyperglycemia, exacerbation of diabetes mellitus
Infections and invasions
Rarely:		Shingles lichen
Neoplasms are benign, malignant and unspecified (including cysts and polyps)
Highly rarely:		Breast augmentation in men *
Disorders from the vascular system
Often:				"Tides"
Rarely:		"Tides"		Increased blood pressure
Unknown:				Thromboembolism
Systemic disorders and complications at the site of administration
Often:		Increased fatigue
Rarely:		Swelling, weakness, malaise, thirst, pain in the chest		Edema, irritation at the injection site
Immune system disorders
Rarely:		SLE - a similar syndrome
Disorders from the hepatobiliary system
Often:		Hepatitis
Sometimes:				Hepatitis
Rarely:				Violation of the function of the liver, jaundice
Highly				Cholestatic
rarely:				jaundice, hepatic encephalopathy, hepatocellular necrosis, hepatotoxicity with fatal outcome
Disorders from the reproductive system and mammary gland
Highly		Gynecomastia and / or		Decreased sexual
often:		pain in the breast, galactorrhea		impulses, impotence
Sometimes:				G inecomastia
Rarely:		Reducing sexual desire, reducing the formation of sperm
Mental disorders
Often:		Insomnia
Rarely:		Anxiety, depression		Depression, anxiety

* There have been several reports of malignant neoplasms of the breast in patients with men taking flutamide in tablets. In one report, it was a compaction in the mammary gland, which was first discovered three or four 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 two and six months, respectively, after the onset of monotherapy with flutamide for common prostate cancer. Nine months after the start of treatment, the node was excised and a moderately differentiated invasive ductal carcinoma, stage T4N0M0, G3 was diagnosed. 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; their frequency is unknown.

Overdose:In clinical trials in which flutamide was taken at doses up to 1500 mg / day for a period up to 36 weeks, about serious adverse side effects reactions were not reported. There were reports of gynecomastia, tenderness in the mammary gland and a slight increase in the level of transaminases (ACT). The association of the usual single dose of flutamide with symptoms of overdose or the development of life-threatening conditions has not been established. One patient suffered a single dose of more than 5 g without any side effects.

In case of an overdose, if the patient is conscious and without spontaneous vomiting, vomiting should be induced. Gastric lavage may be required. Because the flutamide largely associated with proteins, dialysis may not do any good in the treatment of overdose.It is necessary to apply symptomatic therapy with constant monitoring of the patient and vitally important indicators.

Interaction: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.

Patients receiving oral anticoagulant therapy after initiating flutamide treatment showed an increase in prothrombin time. For this reason, careful monitoring of prothrombin time is recommended and correction of the anticoagulant dose may be required when co-administration of flutamide with oral anticoagulants.

There have been reports of an increase in the concentration of theophylline in plasma.

Simultaneous reception of another potentially hepatotoxic drug should be carried out only after a thorough assessment of the benefit-risk ratio. Given the known potential hepato- and nephrotoxicity of the drug, excessive drinking should be avoided.

Special instructions:

Treatment with flutamide should be prescribed by a specialist.When combined therapy with GnRH agonists is recommended, begin taking flutamide at least three 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.

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 more than two or threefold 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; but there were three reports of deaths 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 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 more than two- and three-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.

Effect on the ability to drive transp. cf. and fur:Studies of the effect of flutamide on the ability to drive vehicles and control mechanisms have not been conducted. However, when there are such undesirable phenomena as increased fatigue, dizziness and blurred consciousness, one should refrain from performing these activities.

Form release / dosage:

Tablets of 250 mg.

Packaging:

For 21 tablets in a blister, four blisters in a pack of cardboard

Storage conditions:

List B. Store at a temperature of 15 to 25 ° C.

KEEP OUT OF THE REACH OF CHILDREN!

Shelf life:

3 years.

The drug should not be used after the expiration date indicated on the package

Terms of leave from pharmacies:On prescription

Registration number:П N015647 / 01

Date of registration:24.03.2009

The owner of the registration certificate:Orion CorporationOrion Corporation Finland

Manufacturer: & nbsp

ORION CORPORATION Finland

Information update date: & nbsp23.20.2015

Illustrated instructions

Instructions

Flutamide (Flutamide)