Flutamide Pliva (Tablets) Instructions for Use

Marketing Authorization Holder

Pliva Hrvatska, d.o.o. (Croatia)

ATC Code

L02BB01 (Flutamide)

Active Substance

Flutamide (Rec.INN registered by WHO)

Dosage Form

Flutamide Pliva

Tablets 250 mg: 100 pcs.

Dosage Form, Packaging, and Composition

Tablets are light yellow in color, round, with a beveled edge.

Excipients: microcrystalline cellulose, corn starch, lactose monohydrate, sodium lauryl sulfate, colloidal silicon dioxide, magnesium stearate.

10 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Antiandrogenic drug with antitumor activity

Pharmacotherapeutic Group

Antineoplastic agent, antiandrogen

Pharmacological Action

Antitumor drug, non-steroidal antiandrogen. Competitively blocks the interaction of androgens with their cellular receptors.

The mechanism of action is based on the inhibition of androgen uptake and/or inhibition of androgen binding in the nuclei of target tissue cells. Its ability to counteract the action of testosterone at the cellular level complements the drug-induced “castration” caused by GnRH agonists. The target organs of the pharmacological action of flutamide are the prostate gland and seminal vesicles.

Flutamide does not possess estrogenic, antiestrogenic, progestogenic, or antiprogestogenic activity.

Pharmacokinetics

Absorption, Distribution, and Metabolism

The drug is completely and rapidly absorbed after oral administration, undergoing biotransformation in the liver. The main metabolite found in blood plasma, whose C_max is reached after 2 hours, is the biologically active α-hydroxylated derivative (2-hydroxyflutamide).

After repeated oral administration of flutamide at 250 mg 3 times/day, a steady-state concentration of the drug and its active metabolite in plasma is achieved after the fourth dose of flutamide.

94-96% of flutamide and 92-94% of the α-hydroxylated metabolite are bound to proteins.

Excretion

The drug is excreted from the body mainly by the kidneys; approximately 4.2% is excreted in feces within 72 hours. The T_1/2 of the active metabolite from plasma is about 6 hours (in elderly patients — 8 hours after a single dose and 9.6 hours at steady-state concentration).

Indications

Treatment of metastatic prostate cancer when suppression of testosterone action 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 for whom other types of hormone therapy have been ineffective, or in case of intolerance to such treatment.

ICD codes

Dosage Regimen

Administer orally at a dose of 250 mg three times daily, maintaining an 8-hour interval between doses.

Continue therapy as long as a positive clinical response is observed; discontinue upon evidence of disease progression.

For combination therapy with a GnRH agonist, initiate both agents simultaneously.

Alternatively, begin Flutamide Pliva 3 days prior to the first administration of the GnRH agonist to achieve initial androgen blockade.

In patients with surgical castration, use the standard monotherapy regimen of 250 mg every 8 hours.

Do not adjust the dose for mild to moderate hepatic impairment; however, monitor liver function closely.

The drug is contraindicated in patients with severe hepatic insufficiency.

Swallow the tablet whole with a sufficient amount of water, with or without food.

Adhere strictly to the prescribed schedule to maintain consistent therapeutic drug levels.

Adverse Reactions

The frequency of adverse effects is presented according to the following gradation: common (≥10%), uncommon (from 1% to 10%), rare (< 1%).

When using the drug in monotherapy

From the endocrine system common – gynecomastia and/or breast pain, sometimes accompanied by galactorrhea (these phenomena disappear after discontinuation of treatment or dose reduction); rare – decreased libido, hot flashes (sensation of heat, increased sweating). With long-term treatment, suppression of spermatogenesis has been noted.

From the digestive system uncommon – diarrhea, nausea, vomiting, increased appetite, transient liver dysfunction, hepatitis; rare – anorexia, heartburn, constipation, dyspepsia, hepatitis or jaundice (including cholestatic), liver necrosis, hepatic encephalopathy, increased transaminase activity (these side effects are usually reversible after discontinuation of therapy, however, there have been reports of fatal outcomes due to severe liver failure during flutamide therapy).

From the CNS uncommon – insomnia, increased fatigue; rare – headache, dizziness, weakness, blurred vision, anxiety, depression.

Dermatological reactions rare – subcutaneous hemorrhages, herpes zoster, skin itching, lupus-like syndrome; in some cases – increased photosensitivity reactions (including erythema, skin ulcerations, bullous rash, epidermal necrolysis).

From the hematopoietic system rare – thrombocytopenia; in some cases – hemolytic anemia, macrocytic anemia, methemoglobinemia.

From the body as a whole thirst, chest pain, edema (fingers, feet, legs), increased blood pressure; sometimes patients experience a change in urine color from amber to yellow-green.

When treating in combination with GnRH agonists

From the endocrine system common – hot flashes (sensation of heat, increased sweating), decreased libido, impotence (the frequency of these side effects is the same as with monotherapy with GnRH agonists); uncommon – gynecomastia.

From the digestive system common – diarrhea, nausea, vomiting (the frequency of these side effects, except for diarrhea (more pronounced when used in combination with flutamide), is the same as with monotherapy with GnRH agonists); uncommon – loss of appetite; rare – liver failure, hepatitis, cholestatic jaundice, liver necrosis, hepatic encephalopathy.

From the hematopoietic system uncommon – anemia, leukopenia, thrombocytopenia.

From the CNS uncommon – drowsiness, depression, confusion, anxiety, neurosis.

Other uncommon – edema, symptoms of neuromuscular disorders, difficulty urinating, increased blood pressure; rare – respiratory distress, increased photosensitivity, methemoglobinemia.

Contraindications

• Severe hepatic insufficiency;
• Childhood (safety and efficacy have not been established);
• Hypersensitivity to flutamide or any other component of the drug.

With caution the drug should be used in patients with reduced liver function, with a tendency to thrombosis and in cardiovascular diseases, as well as in conditions predisposing to aniline intoxication (one of the metabolites of flutamide is a methylaniline derivative), including glucose-6-phosphate dehydrogenase deficiency, smoking, hemoglobinopathy (M-hemoglobin).

Use in Hepatic Impairment

With caution the drug should be used in patients with reduced liver function. Contraindication: severe hepatic insufficiency.

Pediatric Use

Contraindication: childhood (safety and efficacy have not been established).

Special Precautions

Treatment with Flutamide Pliva should be carried out under the control of serum liver enzyme activity (once a month for the first 4 months and then regularly).

In case of an increase in liver enzyme activity by 2-3 times compared to the upper limit of normal and/or the appearance of jaundice in the absence of liver metastases, the use of Flutamide Pliva should be discontinued.

Patients should be warned that they should immediately consult a doctor if the first symptoms of liver dysfunction appear, such as skin itching, darkening of urine, nausea, vomiting, persistent loss of appetite, yellowing of the skin or sclera, painful sensations in the right hypochondrium, or flu-like symptoms.

In patients who have not undergone surgical or medical castration, spermatogenesis analysis should be performed during long-term treatment. Taking flutamide may lead to an increase in blood levels of testosterone and estradiol, which may cause fluid retention in the body. Special attention should be paid to patients with cardiovascular diseases, also prone to edema formation.

Overdose

Treatment if the patient is conscious and without spontaneous vomiting, vomiting should be induced. Symptomatic therapy should be applied with constant monitoring of the patient and vital functions. Due to the high degree of plasma protein binding, hemodialysis is practically ineffective.

Drug Interactions

Due to the possible enhancement of the anticoagulant effect with simultaneous use of warfarin and flutamide, the dose of the anticoagulant should be selected under the control of prothrombin time.

Simultaneous administration of flutamide with other hepatotoxic drugs, as well as alcohol, should be avoided.

Against the background of simultaneous administration of theophylline and flutamide, an increase in the level of theophylline in the blood was noted, which is possibly due to the presence of a common metabolic pathway for these drugs.

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.