Flutamide

Flutamide is indicated for the treatment of advanced prostatic carcinoma in which suppression of testosterone effects is indicated. Flutamide may be used in combination with an LHRH agonist, both on commencement of treatment or as an adjunctive therapy in patients already receiving an LHRH agonist.

Flutamide may also be used in surgically castrated patients.

Posology Adults and older people:

One tablet three times daily at 8 hour intervals. When Flutamide is used as initial treatment with an LHRH agonist, a reduction in severity of the flare reaction may be achieved if treatment with Flutamide is initiated before the LHRH agonist.

Consequently, it is recommended that treatment with Flutamide should commence simultaneously or at least 24 or more hours before the LHRH agonist. The administration of Flutamide should begin 8 weeks prior to radiotherapy and continue for its duration, or for 12 weeks pre-prostatectomy.

In patients with impaired liver function, long-term treatment with Flutamide should only be initiated after careful assessment of the individual benefits and risks. Flutamide should be administered with caution in patients with impaired renal function.

Method of administration For oral use. The tablets are to be taken preferably after food.

Monotherapy The undesirable effects of flutamide most frequently reported are gynaecomastia and/or breast tenderness, sometimes accompanied by periods of galactorrhoea. These reactions often disappear with the suspension of the treatment or reduction of the dose.

It has been proven that flutamide has a low cardiovascular risk potential, significantly less than that of diethylstilboestrol. Combined treatment The undesirable effects most frequently reported during combined treatment of flutamide with an LHRH agonist were hot flushes, reduced libido, erectile dysfunction, diarrhoea, nausea and vomiting.

With the exception of diarrhoea, these are known undesirable effects of LHRH agonists alone, with a similar frequency. The high rate of occurrence of gynaecomastia observed with monotherapy with Flutamide decreased greatly in combined treatment.

In clinical trials, no significant difference was observed in the rate of occurrence of gynaecomastia between the placebo group and the group treated with flutamide and LHRH agonists. g. 4) Hepatic dysfunction, jaundice Very rare Cholestatic jaundice, hepatic encephalopathy, liver cell necrosis, hepatotoxicity with fatal outcome Skin and subcutaneous tissue disorders Rare Urticaria, pruritus, ecchymosis, alteration of the hair growth pattern and loss of hair (head) Rash Very rare Photosensitivity reactions Photosensitivity reactions, erythema, ulcers, bullous eruptions, epidermal necrolysis Musculoskeletal and connective tissue disorders Rare Muscle cramps Neuromuscular symptoms, reduced bone mineral density, osteoporotic disorders, arthralgia, myalgia Renal and urinary disorders Rare Genitourinary tract symptoms, dysuria, changes in urinary frequency, change in urine colour to amber or yellow-green Reproductive system and breast disorders Very common Gynaecomastia and/or breast pain, breast tenderness, galactorrhoea Decreased libido, impotence Uncommon Gynaecomastia Rare Reversible increase of serum testosterone levels, reduced sperm counts, decreased libido General disorders and administration site conditions Common Somnolence, tiredness Rare Oedema, asthenia, malaise, thirst, chest pain, hot flushes, weakness Oedema, injection site irritation Investigations Common Transient abnormal liver function Changes in liver function Rare Elevated blood urea nitrogen (BUN) values, elevated serum creatinine values * There have been a few cases reported of malignant breast neoplasms in male patients treated with flutamide.

One of them consisted of the aggravation of a lump that had been detected previously, three or four months prior to commencing monotherapy with flutamide in a patient with benign prostatic hypertrophy. After the excision, a diagnosis was made of slightly differentiated ductal carcinoma.

The other case consisted of gynaecomastia and a lump, observed, respectively, two to six months after the start of monotherapy with flutamide to treat an advanced prostate carcinoma. Nine months after the treatment began, the lump was removed and a moderately differentiated invasive ductal tumour was diagnosed in T4N0M0, G3 state.

The high incidence of gynaecomastia seen with flutamide monotherapy is generally reduced with combination therapy. Micronodular alterations of the body of breast can uncommonly occur. An increase in serum testosterone is initially possible during monotherapy with flutamide.

In addition, hot flushes and changes in hair character can occur. Following the marketing of flutamide, cases of acute renal failure, interstitial nephritis, and myocardial ischemia have been reported with frequency unknown. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

1.

INDICATIONS AND USAGE

Eulexin ® capsules are indicated for use in combination with LHRH-agonists for the management of locally confined Stage B 2 -C and Stage D 2 metastatic carcinoma of the prostate. Stage B 2 -C Prostatic Carcinoma Treatment with Eulexin ® capsules and the goserelin acetate implant should start eight weeks prior to initiating radiation therapy and continue during radiation therapy.

Stage D 2 Metastatic Carcinoma To achieve benefit from treatment, Eulexin ® capsules should be initiated with the LHRH-agonist and continued until progression.

DOSAGE AND ADMINISTRATION

The recommended dosage is 2 capsules 3 times a day at 8 hour intervals for a total daily dose of 750 mg.

ADVERSE REACTIONS

Stage B 2 -C Prostatic Carcinoma Treatment with Eulexin ® capsules and the goserelin acetate implant did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing Eulexin ® + goserelin acetate implant + radiation versus radiation alone.

The most frequently reported (greater than 5%) adverse experiences are listed below: Adverse Events During Acute Radiation Therapy (within first 90 days of radiation therapy) (n=231) Goserelin Acetate Implant + Eulexin ® + Radiation (n=235) Radiation Only % All % All Rectum/Large Bowel 80 76 Bladder 58 60 Skin 37 37 Adverse Events During Late Radiation Phase (after 90 days of radiation therapy) (n=231) Goserelin Acetate Implant + Eulexin ® + Radiation (n=235) Radiation Only % All % All Diarrhea 36 40 Cystitis 16 16 Rectal Bleeding 14 20 Proctitis 8 8 Hematuria 7 12 Additional adverse event data were collected for the combination therapy with radiation group over both the hormonal treatment and hormonal treatment plus radiation phases of the study.

Adverse experiences occurring in more than 5% of patients in this group, over both parts of the study, were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%). Stage D 2 Metastatic Carcinoma The following adverse experiences were reported during a multicenter clinical trial comparing Eulexin ® + LHRH agonist versus placebo + LHRH agonist.

The most frequently reported (greater than 5%) adverse experiences during treatment with Eulexin ® capsules in combination with an LHRH agonist are listed in the table below. For comparison, adverse experiences seen with an LHRH agonist and placebo are also listed in the following table.

(n=294) Eulexin ® + LHRH agonist (n=28) Placebo + LHRH agonist % All % All Hot Flashes 61 57 Loss of Libido 36 31 Impotence 33 29 Diarrhea 12 4 Nausea/Vomiting 11 10 Gynecomastia 9 11 Other 7 9 Other GI 6 4 As shown in the table, for both treatment groups, the most frequently occurring adverse experiences (hot flashes, impotence, loss of libido) were those known to be associated with low serum androgen levels and known to occur with LHRH agonists alone.

The only notable difference was the higher incidence of diarrhea in the Eulexin ® + LHRH agonist group (12%), which was severe in 5% as opposed to the placebo + LHRH agonist (4%), which was severe in less than 1%. In addition, the following adverse reactions were reported during treatment with Eulexin ® + LHRH agonist.

Cardiovascular System: hypertension in 1% of patients.

Central Nervous System :

CNS (drowsiness/confusion/depression/anxiety/nervousness) reactions occurred in 1% of patients. Gastrointestinal System : anorexia 4%, and other GI disorders occurred in 6% of patients. Hematopoietic System : anemia occurred in 6%, leukopenia in 3%, and thrombocytopenia in 1% of patients.

Liver and Biliary System : hepatitis and jaundice in less than 1% of patients. Skin : irritation at the injection site and rash occurred in 3% of patients. Other: edema occurred in 4%, genitourinary and neuromuscular symptoms in 2%, and pulmonary symptoms in less than 1% of patients.

In addition, the following spontaneous adverse experiences have been reported during the marketing of Eulexin ® : hemolytic anemia,macrocytic anemia,methemoglobinemia, sulfhemoglobinemia, photosensitivity reactions (including erythema, ulceration, bullous eruptions, and epidermal necrolysis) and urine discoloration.

The urine was noted to change to an amber or yellow-green appearance which can be attributed to the Eulexin ® and/or its metabolites. Also reported were cholestatic jaundice, hepatic encephalopathy, and hepatic necrosis. The hepatic conditions were often reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with use of Eulexin ® .

Malignant breast neoplasms have occurred rarely in male patients being treated with Eulexin ® capsules.

Abnormal Laboratory Test Values :

Laboratory abnormalities including elevated SGOT, SGPT, bilirubin values, SGGT, BUN, and serum creatinine have been reported.

CONTRAINDICATIONS

Eulexin ® capsules are contraindicated in patients who are hypersensitive to Eulexin ® or any component of this preparation. Eulexin ® capsules are contraindicated in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment).

FLUTAMIDE (flutamide) is indicated:  For use in combination with LHRH agonistic analogues (such as leuprolide acetate) for the treatment of metastatic prostatic carcinoma (stage D2). To achieve the benefit of the adjunctive therapy with FLUTAMIDE, treatment must be started simultaneously using both drugs.

 As an adjunctive therapy to orchiectomy, in order to achieve complete androgen blockade.  FLUTAMIDE in combination with LHRH agonists are also indicated prior to and during definitive external beam radiotherapy for patients with bulky locally advanced Stage B2 and Stage C prostatic carcinoma.

See 4 DOSAGE AND ADMINISTRATION. 1 Pediatrics Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. 2 Geriatrics Geriatrics (>65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness.

3 Pharmacokinetics.

1 Pediatrics Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. 2 Geriatrics Geriatrics (>65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness.

3 Pharmacokinetics. 2 CONTRAINDICATIONS FLUTAMIDE (flutamide) is contraindicated in:  Patients who are hypersensitive to flutamide or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

For a complete listing, See

1 Adverse Reaction Overview The most frequently reported adverse reactions to flutamide monotherapy are gynecomastia and/or breast tenderness, sometimes accompanied by galactorrhe a. These reactions disappear upon discontinuation of treatment or reduction in dosage.

The incidence of gynecomastia is reduced greatly when flutamide is administered concomitantly with a LHRH agonist. 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. The most frequently reported (greater than 5%) adverse experiences during treatment with flutamide in combination with a LHRH agonist are listed in the table below.

For comparison, adverse experiences seen with a LHRH agonist and placebo are also listed in the following table. Table 2 - Adverse reactions with an incidence of ≥ 5% Flutamide + LHRH-agonist (n=294) Placebo + LHRH-agonist (n=285) % All % All Hot Flashes 61 57 Loss of Libido 36 31 Impotence 33 29 Diarrhea 12 4 Nausea/Vomiting 11 10 Gynecomastia 9 11 Other 7 9 Other GI 6 4 PrFLUTAMIDE (flutamide) Page 11 of 27 As shown in the table, for both treatment groups, the most frequently occurring adv erse experiences (hot flashes, loss of libido, impotence) were those known to be associated with low serum androgen levels and known to occur with LHRH-agonists alone.

The only notable difference between these treatment groups was the higher incidence of diarrhea in the flutamide + LHRH-agonist group (12%; severe in 5%) as compared to the placebo + LHRH-agonist group (4%; were severe in less than 1%).

In addition, the following adverse reactions were reported during treatment with flutamide + LHRH-agonist. No causal relatedness of these reactions to drug treatment has been made, and some of the adverse experiences reported are those that commonly occur in elderly patients.

Cardiovascular System:

Hypertension in 1% of patients. Rarely thrombophlebitis, pulmonary embolism, myocardial infarction.

Central Nervous System:

CNS (drowsiness/confusion/depression/anxiety/nervousness) reactions occurred in 1% of patients. Rarely insomnia, tiredness, headache, dizziness, weakness, malaise, blurred vision and decreased libido have been reported.

Endocrine System:

Gynecomastia in 9% of patients. Rarely breast tenderness sometimes accompanied by galactorrhea.

Gastrointestinal System:

Nausea/vomiting occurred in 11%; diarrhea 12%, anorexia 4%, and other gastro-intestinal disorders occurred in 6% of patients. Increased appetite, indigestion and constipation have also been reported.

Hematopoietic System:

Anemia occurred in 6% of patients, leukopenia 3%, thrombocytopenia 1%.

Liver and Biliary System:

Clinically evident hepatitis and jaundice occurred in <1% of patients.

Skin:

Irritation at the injection site and rash occurred in 3% of patients. Photosensitivity reactions have been reported in five patients.

Other:

Pruritus, ecchymosis, herpes zoster, thirst, lymphedema, lupus-like syndrome, hematuria, reduced sperm counts have been reported rarely in long-term treatment. Edema occurred in 4% of patients; neuromuscular, genitourinary symptoms occurred in 2% of patients.

Interstitial lung disease occurred in <1% of patients. 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings Laboratory Values: Reported abnormal laboratory test results include elevated SGOT (AST), SGPT (ALT); elevated blood urea nitrogen (BUN) and bilirubin levels; less frequently, elevated serum creatinine levels and elevated gamma-glutamyl transferase levels have been reported.

5 Post-Market Adverse Reactions In addition, the following adverse experiences have been reported during world -wide marketing of flutamide: hemolytic anemia, macrocytic anemia, methemoglobinemia, sulfhemoglobinemia, photosensitivity reactions- including erythema, ulcerations, bullous eruptions, and epidermal necrolysis - and change in urine colour to an amber or yellow-green appearance, which can be attributed to flutamide and/or its metabolites.

Also observed were cholestatic jaundice, hepatic encephalopathy and hepatic necrosis. The hepatic conditions were usually reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with use of flutamide.

Cardiac failure, sudden cardiac deaths have been reported. Hyperglycemia and aggravated diabetes mellitus have been reported very rarely. Two reports of malignant male breast neoplasms in patients being dosed with flutamide have been reported.

One involved aggravation of a pre-existing nodule which was first detected three to four months before initiation of flutamide monotherapy in a patient with benign prostatic hypertrophy. After excision, this was diagnosed as a poorly differentiated ductal carcinoma.

The other report involved gynecomastia and a nodule noted two and six months respectively, after initiation of flutamide monotherapy for treatment of advanced prostatic carcinoma. Nine months after the initiation of therapy, the nodule was excised and diagnosed as a moderately differentiated invasive ductal tumor staged T4N0M0, G3, no metastases had advanced.

FLUTAMIDE (flutamide) is contraindicated in:  Patients who are hypersensitive to flutamide or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, See 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

 Patients with severe hepatic impairment. FLUTAMIDE has not been studied in women and is not indicated for this population, particularly for nonserious or nonthreatening conditions.