Flutamide

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUTAMIDE (FLUTAMID)

Composition:

Active substance: flutamide;

1 tablet contains 250 mg of flutamide;

Excipients: mannitol (E 421), sodium lauryl sulfate, povidone K-30, microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical characteristics: pale yellow, biconvex, round, uncoated tablets.

Pharmacotherapeutic group. Antineoplastic and immunomodulating medicinal products. Medicinal products used in endocrine disorders. Hormone antagonists and related agents. Antiandrogenic agents. ATC code L02B B01.

Pharmacological properties.

Pharmacodynamics.

Flutamide is an antiandrogenic agent with a nonsteroidal structure. Flutamide and its metabolites have no agonistic or antagonistic properties towards glucocorticoid, estrogen, progesterone, or mineralocorticoid receptors.

Flutamide blocks androgen receptors of target cells in the prostate gland, hypothalamus, and pituitary gland, thereby inhibiting the biological effects of endogenous androgens. However, flutamide does not suppress the action of gonadotropin-releasing hormone (GnRH) produced by the hypothalamus on androgen-mediated secretion, nor does it affect pituitary sensitivity to GnRH. This leads to an increased concentration of gonadotropic hormones (luteinizing and follicle-stimulating hormones), resulting in stimulation of testosterone hyperproduction.

Flutamide and its metabolites inhibit the interaction of dihydrotestosterone with nuclear androgen receptors. Receptor blockade may also occur at the level of the cell membrane and cytoplasm. The main metabolite is 2-hydroxyflutamide. Its affinity for androgen receptors is 25 times higher than that of flutamide, making it the active form of flutamide.

Combining flutamide with chemical or surgical castration results in suppression of both testicular and adrenal androgen effects.

Pharmacokinetics.

After oral administration, flutamide is well absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 2 hours. Studies using tritium-labeled flutamide indicate its rapid metabolism into the biologically active form—2-hydroxyflutamide—and other metabolites. The elimination half-life of the drug is 5 ̶ 6 hours. There are approximately 10 metabolites of flutamide. More than 90% of flutamide and 2-hydroxyflutamide is bound to plasma proteins. The drug is primarily eliminated via the kidneys. Approximately 4% of the administered dose is excreted in feces.

Special populations

Renal and hepatic impairment

Since flutamide is extensively metabolized in the liver and primarily excreted by the kidneys, patients with renal or hepatic disease may experience a significant impact on the elimination pathways of flutamide and its metabolites. However, clear dosage adjustment recommendations for flutamide in patients with renal or hepatic impairment have not been established.

Clinical characteristics.

Indications.

Treatment of locally advanced or metastatic prostate cancer, as monotherapy
(with or without orchidectomy) or in combination with luteinizing hormone-releasing hormone (LHRH) agonists, in patients who have not previously received any treatment or who have failed to respond or developed resistance to hormonal therapy or are intolerant to it, with the aim of achieving maximum androgen blockade.

In combined therapy, as one of the agents for the treatment of locally confined prostate cancer B2–C2 (T2b–T4), to reduce tumor volume, enhance tumor control, and prolong the time to disease progression.

Contraindications.

Hypersensitivity to flutamide or to any of the excipients of the medicinal product.

Severe hepatic impairment (baseline liver enzyme levels should be assessed prior to initiating treatment).

Children and adolescents (under 18 years of age).

Interaction with other medicinal products and other forms of interaction.

No interaction between flutamide and leuprolide has been observed. If flutamide and LHRH agonists are used concomitantly, the potential adverse effects of both agents should be considered.

In patients receiving long-term warfarin therapy, an increase in prothrombin time has been observed after administration of flutamide. Therefore, the optimal dose of anticoagulant should be carefully adjusted.

Concomitant use of flutamide and theophylline may lead to increased plasma concentrations of theophylline.

Concomitant use of flutamide and potentially hepatotoxic medicinal products should be avoided.

There is a potential for interaction when flutamide is used concomitantly with paracetamol and opioid analgesics.

Flutamide may slow the metabolism of corticosteroids.

Alcohol consumption should be avoided during treatment.

Since androgen deprivation therapy may prolong the QT interval, concomitant use of flutamide with medicinal products that prolong the QT interval or that are capable of inducing torsades de pointes/ventricular fibrillation, such as class IA (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic agents, methadone, moxifloxacin, neuroleptics, etc., should be carefully evaluated.

Special precautions for use

In combination therapy with GnRH agonists, treatment with Flutamide should be initiated at least 3 days prior to the administration of GnRH agonists, which helps to reduce inflammatory hyperemia compared to simultaneous initiation of therapy.

Treatment must be administered under physician supervision.

Prolonged use of flutamide in patients with hepatic impairment is possible only after careful assessment of potential benefits and risks.

Liver function tests should be performed prior to initiating treatment. Treatment with the drug should not be initiated in patients with serum transaminase levels exceeding the upper limit of normal by 2–3 times.

Liver function should be monitored throughout the entire treatment period, particularly in patients who have not undergone orchidectomy, as adverse reactions such as cholestatic jaundice, hepatic necrosis, changes in transaminase levels, and hepatic encephalopathy have been reported. Appropriate laboratory testing should be performed monthly during the first 4 months of treatment and periodically thereafter, and at the first signs or symptoms of hepatic dysfunction (pruritus, dark urine, persistent anorexia, jaundice, mild pain in the right upper quadrant of the abdomen, or general weakness).

Treatment with the drug should be discontinued even in the absence of clinical symptoms if liver dysfunction is confirmed by laboratory tests or if jaundice develops in the absence of biopsy-confirmed liver metastases, particularly if jaundice persists or serum transaminase levels exceed the upper limit of normal by 2–3 times. Hepatic dysfunction is usually reversible upon discontinuation of flutamide. However, there have been reports of fatal outcomes due to severe liver injury associated with flutamide use.

Flutamide may prolong the QT interval.

The physician should assess the benefit-risk ratio, including the potential for development of torsades de pointes-type arrhythmias, prior to initiating flutamide therapy in patients with a history of QT prolongation or risk factors for QT prolongation, and in patients receiving concomitant medications that may prolong the QT interval.

The drug is intended for use in men only. Appropriate contraceptive methods should be used during therapy.

Patients with renal impairment should be closely monitored during flutamide therapy. Patients should be informed that flutamide and drugs used for medical castration must be used in combination and that treatment should not be discontinued or doses changed without prior consultation with a physician.

In case of cyanosis, patients should be evaluated for methemoglobinemia, which may occur in overdose.

In patients who have not undergone orchidectomy, sperm counts should be periodically assessed during prolonged treatment. Since flutamide therapy increases plasma levels of testosterone and estradiol, fluid retention may occur. In severe cases, fluid retention may increase the risk of angina and heart failure; therefore, the drug should be used with caution in patients with cardiovascular disorders. Flutamide may exacerbate edema or swelling of the ankle joint in patients predisposed to these symptoms. Furthermore, increased estradiol levels may elevate the risk of thromboembolism.

Oligospermia may occur during prolonged flutamide use. In such cases, regular quantitative sperm analysis is advisable.

Endocrinology and metabolism

Impaired glucose tolerance has been observed in men during combined androgen blockade. This may manifest as new-onset diabetes mellitus or inadequate glycemic control in patients with pre-existing diabetes. Monitoring of blood glucose and/or glycated hemoglobin (HbA1c) should be considered in patients receiving flutamide in combination with GnRH agonists.

Musculoskeletal system / bone density changes

It is known that androgen therapy reduces bone mineral density and increases the risk of osteoporotic fractures. The risk of fractures increases with the duration of combined androgen blockade. These adverse effects may be more pronounced in patients who already have age-related osteoporosis at the time of prostate cancer diagnosis.

Bone mineral density measurements should be performed regularly to identify patients at high risk of fractures.

Bone mineral density should be measured at the start of therapy and no later than one year after initiation of therapy. Additional measurements may be performed at annual intervals in men with bone mineral density values close to osteoporosis or in men with reduced bone mineral density, depending on life expectancy.

In patients with significant risk factors for reduced bone mineral density and/or bone mass, such as chronic alcohol consumption and/or smoking, suspected or confirmed family history of osteoporosis, or chronic use of medications that reduce bone mass (e.g., antiepileptic drugs or corticosteroids), combined androgen blockade may further increase the risk. These patients require careful assessment of risks and benefits before initiating therapy.

Interstitial lung disease / pneumonitis

Interstitial lung disease has been reported in patients receiving flutamide therapy. Respiratory symptoms such as dyspnea should be monitored during the first weeks of treatment.

Flutamide contains mannitol, which may have a mild laxative effect.

Flutamide contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

The drug is intended for use in men only. Appropriate contraceptive methods should be used during therapy.

Ability to affect reaction speed when driving or operating machinery

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. During flutamide treatment, adverse reactions such as fatigue, dizziness, and partial impairment of consciousness may occur. In such cases, patients should refrain from driving or operating machinery.

Dosage and Administration

The drug should be taken orally, 1 tablet (250 mg) three times daily after meals, every 8 hours. The daily dose is 750 mg.

In combined therapy with LHRH agonists, administration of Flutamide should be initiated at least 3 days prior to the start of LHRH agonist therapy.

Flutamide should be administered starting 8 weeks before the initiation of radiation therapy and continued throughout the entire course of radiation, or 12 weeks prior to prostatectomy.

If laboratory tests indicate liver damage or jaundice, and the patient has no biopsy-confirmed metastases, treatment with flutamide should be discontinued or the dose reduced, even though clear dosage recommendations are lacking (see sections "Contraindications", "Special Warnings and Precautions for Use", "Adverse Reactions").

Children

There is no information regarding the use of the drug in children (under 18 years of age); therefore, the use of the drug in this patient population is not recommended.

Overdose

In animal experiments, flutamide caused hypoactivity, piloerection, respiratory depression, ataxia and/or lacrimation, anorexia, sedation, vomiting, and methemoglobinemia.

Clinical data indicate that administration of flutamide at daily doses up to 1500 mg for 36 weeks does not cause serious adverse effects. Occasionally, gynecomastia, breast tenderness, and transient changes in liver transaminase levels may occur. A single dose of flutamide (up to 5 g) does not cause symptoms of overdose and is not life-threatening.

The overdose or dose of the drug that may cause life-threatening symptoms has not been established.

Due to the high degree of plasma protein binding of flutamide, it cannot be removed by dialysis. As with the management of overdose of any drug, the possibility of concomitant intake of multiple drugs by the patient should be considered. General supportive measures for monitoring and maintaining vital functions are indicated. Gastric lavage may be required.

Adverse Reactions

The most common adverse reactions during monotherapy with Flutamide are gynecomastia and/or breast tenderness, sometimes accompanied by galactorrhea. These reactions usually resolve after discontinuation of treatment or dose reduction.

Cardiovascular disorders occur significantly less frequently compared to diethylstilbestrol use.

In combined therapy with flutamide and a GnRH agonist, the most frequently reported adverse effects were hot flushes, decreased libido, impotence, diarrhea, nausea, and vomiting. These adverse effects—except diarrhea—are observed with similar frequency during monotherapy with GnRH agonists.

Gynecomastia typically occurs during flutamide therapy, but its incidence is considerably lower with combined therapy. Clinical trials showed no significant difference in the incidence of gynecomastia between the placebo group and the group receiving combined treatment with flutamide and a GnRH agonist.

Flutamide causes transient elevations in liver transaminases due to hepatitis.

In some cases, liver damage has been fatal.

Adverse reaction frequency categories are defined as follows:
Common (≥ 1/100 to < 1/10),
Uncommon (≥ 1/1000 to < 1/100),
Rare (≥ 1/10000 to < 1/1000),
Very rare (< 1/10000),
Frequency not known (cannot be estimated from available data).

Monotherapy

Infections and infestations

Rare: Herpes zoster.

Blood and lymphatic system disorders

Rare: Lymphedema.

Anemia, leukopenia, thrombocytopenia, methemoglobinemia, ecchymoses.

Metabolism and nutrition disorders

Common: Increased appetite.

Rare: Anorexia.

Psychiatric disorders

Common: Insomnia.

Rare: Depression, anxiety.

Nervous system disorders

Rare: Dizziness, headache.

Somnolence.

Immune system disorders

Rare: Lupus-like syndrome.

Eye disorders

Rare: Blurred vision.

Cardiac disorders

Rare: Flushing, hypertension.

Frequency not known: QT interval prolongation.

Cardiovascular disorders.

Respiratory, thoracic and mediastinal disorders

Rare: Dyspnea, pneumonia.

Very rare: Cough.

Gastrointestinal disorders

Common: Diarrhea, nausea, vomiting, increased appetite.

Rare: Non-specific gastrointestinal complaints, heartburn, constipation.

Gastrointestinal dysfunction, stomach pain, gastric disorders, ulcer-like pain, stomatitis, dyspepsia, colitis.

Hepatobiliary disorders

Common: Hepatitis.

Jaundice, increased liver function test values.

Liver disorders usually resolve after discontinuation of flutamide; severe toxic hepatitis, liver necrosis, and hepatic encephalopathy (these adverse reactions are usually reversible and resolve after discontinuation of therapy). Isolated fatal cases related to liver damage due to the drug have been reported.

Renal and urinary disorders

Increased blood urea and creatinine levels (the severity of this adverse effect usually does not require dose reduction or discontinuation of the drug), green discoloration of urine.

Skin and subcutaneous tissue disorders

Rare: Itching, subcutaneous hemorrhage, urticaria, ecchymosis.

Very rare: Photosensitivity.

Rash, alopecia; at the beginning of flutamide therapy, reversible changes in hair structure, altered hair growth, hair loss may occur.

Reproductive system and breast disorders

Very common: Gynecomastia and/or breast pain, galactorrhea.

Rare: Decreased libido, reduced spermatogenesis.

Breast changes; at the beginning of monotherapy with flutamide, a reversible increase in plasma testosterone levels may occur, along with breast pain.

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

Very rare: Breast tumors in males.

Several cases of malignant breast tumors in males receiving flutamide have been reported. In one case, a pre-existing nodule in a patient receiving flutamide monotherapy for benign prostatic hyperplasia became malignant after 3–4 months of treatment. After surgical removal, poorly differentiated ductal carcinoma was diagnosed. In another case, gynecomastia and breast tumors were observed 2 and 6 months, respectively, after initiation of flutamide monotherapy for advanced prostate cancer.

Nine months after the start of treatment, the tumor was surgically removed and moderately differentiated invasive ductal carcinoma at stage T4N0M0, G3 was diagnosed.

General disorders

Common: Increased fatigue.

Rare: Edema, weakness, malaise, thirst, substernal pain.

Fever.

Musculoskeletal and connective tissue disorders

Rare: Muscle spasms.

Investigations

Common: Transient liver function abnormalities.

Flutamide use may lead to increased serum testosterone levels at the beginning of treatment.

Cases of acute renal failure, interstitial nephritis, and myocardial ischemia have been reported in association with flutamide treatment; frequency is unknown.

Combined therapy

Blood and lymphatic system disorders

Rare: Anemia, leukopenia, thrombocytopenia.

Very rare: Hemolytic anemia, macrocytic anemia, methemoglobinemia, sulfhemoglobinemia, megaloblastic anemia.

Metabolism and nutrition disorders

Rare: Anorexia.

Very rare: Hyperglycemia, exacerbation of diabetes mellitus.

Psychiatric disorders

Rare: Depression, anxiety.

Restlessness, neurosis, somnolence, insomnia, irritability.

Nervous system disorders

Rare: Numbness, confusion, nervousness, lethargy.

Signs of neuromuscular disorders.

Cardiac disorders

Very common: Hot flushes.

Rare: Hypertension.

Frequency not known: Thromboembolism, QT interval prolongation.

Cases of thrombophlebitis, pulmonary embolism, and myocardial infarction have been reported.

Respiratory, thoracic and mediastinal disorders

Very rare: Pulmonary symptoms (e.g., dyspnea), interstitial lung disease.

Dyspnea.

Gastrointestinal disorders

Very common: Diarrhea, nausea, vomiting.

Rare: Non-specific gastrointestinal complaints.

Hepatobiliary disorders

Uncommon: Hepatitis.

Rare: Liver function abnormalities, jaundice.

Very rare: Cholestatic jaundice, hepatic encephalopathy, liver necrosis, fatal cases due to severe liver damage associated with flutamide use.

Elevated liver enzymes, bilirubin, and blood urea nitrogen.

Skin and subcutaneous tissue disorders

Rare: Rash.

Very rare: Photosensitivity, erythema, ulcers, epidermal necrolysis.

Itching, blistering.

Renal and urinary disorders

Rare: Urinary tract symptoms, discoloration of urine to amber or yellow-green.

Dysuria, altered frequency of urination.

Reproductive system and breast disorders

Very common: Decreased libido, impotence.

Uncommon: Gynecomastia.

Musculoskeletal and connective tissue disorders

Rare: Neuromuscular symptoms (including muscle weakness, paresthesia, cramps).

Arthralgia, myalgia, decreased bone mineral density.

Investigations

Rare: Increased blood urea and elevated serum creatinine concentration.

General disorders

Rare: Edema, injection site irritation.

Hot flushes, abdominal pain.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C. Keep the blister in the outer carton to protect from light. Keep out of reach of children.

Packaging. 21 tablets per blister; 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Orion Corporation.

Manufacturer's address. Joensuunkatu 7, 24100 Salo, Finland.