Eulexin (Flutamide)

Each tablet contains:

Flutamide ............................. 250 mg

Excipient, cbp 1 tablet.

FLIMUTALMR Tablets is indicated in combination with bilateral orchiectomy or LHRH analogue for the treatment of locally advanced prostate cancer (stage B2 or C) or metastatic (stage D2).

Flutamide is a nonsteroidal antiandrogen, probably acts after conversion in vivo to 2-hidroxiflutamida, which is a potent competitive inhibitor of the binding of dihydrotestosterone to androgen receptors.

Absorption: Flutamide is rapidly and completely absorbed from the gastrointestinal tract.

Distribution: The maximum plasma concentration is reached after 1 hour of dosing. The binding of flutamide to proteins is very high (94 to 96% for flutamide and 92 to 94% for alpha-hydroxy metabolite hidroxiflutamida at steady state).

In geriatric volunteers time to maximum concentration after administration of a single dose is 1.9 hours and 2.7 hours flutamide hidroxiflutamida.

Metabolism of flutamide biotransformation is the liver, rapid and extensive. Have identified at least six metabolites. The main metabolite found in plasma is hidroxiflutamida, alpha-hydroxy derivative biologically active.

Another metabolite is 4-nitro-3-fluoro-methylaniline, which can cause toxicity similar to that produced by aniline (eg, cholestatic jaundice, hemolytic anemia, methemoglobinemia) in susceptible individuals.

Elimination: The elimination of flutamide is primarily renal, only 4.2% of the dose is excreted in the feces after 72 hours. The half-life of elimination of active metabolite hidroxiflutamida is approximately 6 hours.

In elderly patients the value extends to about 8 hours after single dose administration, is slightly prolonged in patients with chronic damage of renal function (creatinine clearance <29 ml / min).

Mechanism of action: nonsteroidal antiandrogens bind to cytosol androgen receptors and competitively inhibit uptake and / or binding of androgens to target tissues, thereby interfering with the action of androgens at the cellular level also decreases your metabolism of C-19 steroids by cytochrome P-450.

Prostate carcinoma is androgen-sensitive, the ablation of endogenous androgen activity inhibits tumor growth and causes regression of this. Antiandrogenic effects of these drugs complement medical or surgical treatment (therapy-releasing hormone analogues of luteinizing hormone [LHRH] or bilateral orchiectomy), resulting in inhibition or cessation of testicular androgen production (but not adrenal).

Flutamide increases the release of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and causes an increase in plasma concentrations of testosterone and dihydrotestosterone, but because it causes inhibition of the binding of androgens to their receptors intracellular results in a blocking effect of androgens.

When administered in conjunction with an LHRH analog, non-steroidal antiandrogens inhibit the temporary increase in plasma concentrations of testosterone and acute reaction may occur before the steady decrease in testosterone production when was the initiation of therapy with an LHRH analogue.

When non-steroidal anti-androgens are administered as single agents, inhibit the negative feedback response to testosterone by the hypothalamus. In patients who have not undergone surgical castration, this effect results in an increase in serum testosterone, and consequently of estrogens.

FLIMUTALMR Tablets is contraindicated in cases of:

Hypersensitivity to flutamide or any component of the formula.
Conditions predisposing to aniline toxicity, such as deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemoglobin M disease, smoking, snuff increases the risk of toxicity associated with exposure to aniline such as methemoglobinemia, hemolytic anemia and cholestatic jaundice as a metabolite of flutamide is a derivative methylaniline.
Deterioration of liver function. Should be carefully considered use of flutamide, especially in patients with liver function damage moderate or severe, as this can cause severe hepatotoxicity, which can have particularly serious consequences in patients with preexisting damage of liver function.
Pregnancy. It is essential to use adequate contraception when flutamide is being given to women of childbearing age (when given flutamide for the treatment of hirsutism) due to risk having to suffer the male fetus feminization.
Lactation. Not recommended due to its potential to cause adverse toxic effects in the infant.

FLIMUTALMR Tablets should be used with caution in patients with cardiovascular disease because of the possibility that this fluid retention. There have been no studies with nonsteroidal antiandrogens in pediatric patients. Not established the safety and efficacy. Should be considered potential adverse effects on sexual development of young men.

Studies to date have not demonstrated geriatrics-specific problems that would limit the use of any nonsteroidal anti-androgens in geriatric patients.

Although the half-life of elimination of flutamide and its active metabolite hidroxiflutamida increases in older people, do not need a dose adjustment based on age.

If a nonsteroidal antiandrogen is administered to a woman of childbearing age, it must be used in conjunction with a suitable contraceptive method because of the risk to the fetus to suffer feminized male. It is not known if any of the nonsteroidal antiandrogens is distributed into breast milk. However, if a woman should receive a nonsteroidal antiandrogen, it is recommended to avoid breastfeeding because of potential risks to the infant is exposed.

Patient Monitoring: The assessments listed below may be of particular importance in monitoring patients during the administration of flutamide, as well as other tests may be authorized in certain patients depending on their status:

Liver function tests: It is recommended to be carried out periodically during therapy with flutamide. Treatment should be discontinued immediately if evidence of liver damage (eg transaminase values ​​double or triple the normal limit) in the absence of liver metastasis or if signs and symptoms of hepatotoxicity such as jaundice, itching, urine dark, fatigue, persistent anorexia, abdominal pain or tenderness in the upper right quadrant, symptoms similar to influenza unexplained gastrointestinal symptoms and no diagnosis. Hepatotoxicity is usually reversible after therapy is discontinued.

Prostate specific antigen (PSA) levels, may be useful in assessing response to treatment should be reassessed disease progression in patients if the values ​​are elevated during therapy.

Methemoglobin concentration, monitoring is recommended in patients susceptible to toxicity due to aniline.

Appropriate use of medication:

It is important not to take more or less medication than the amount prescribed.
Take the medicine at the same time every day.
It is important to follow doctor's instructions for the concomitant use of LHRH analogues (if the patient has not undergone bilateral orchiectomy).
It is important to the continuity of the drug despite adverse effects.
Seek medical advice if vomiting occurs shortly after taking the drug.
If you forget the medicine. This should be taken as soon as possible. When not remember if it was administered, it is preferable not to take it and wait until the time of the next dose to take, this way you avoid taking a double dose.

The following adverse effects / side have been reported during concomitant use of flutamide with an analogue of the hormone-releasing hormone (LHRH).

The reported effects occurred in long-term studies in patients with stage D2 prostate carcinoma.
Effects that require medical attention: hemolytic anemia, macrocytic anemia, leukopenia, methemoglobinemia, hepatitis or jaundice, including cholestatic jaundice, hypertension, mental depression, neuropathy, neuromuscular symptoms, pulmonary, rash, thrombocytopenia, hepatotoxicity progressive hepatic encephalopathy, hepatic necrosis.

Effects that require medical attention only if they are continuous or bothersome: diarrhea, impotence or decreased sexual desire, nausea, vomiting, confusion, dizziness, drowsiness, headache, nervousness, sleep disturbances. Hot flashes are also presented, which do not require medical attention.

In a study conducted in a relatively short time in which drugs were prescribed in conjunction with radiotherapy for the disease in stage B2 or C, the reported side effects (diarrhea, cystitis, rectal bleeding, proctitis and hematuria) showed no significant difference or an increase in frequency compared to those manifested when given only radiotherapy.

The clinical trials that used a placebo and flutamide, showed that many adverse effects, especially realacionados with low androgenic activity (hot flashes, impotence, loss of libido and gynecomastia) can occur using only an analog LHRH or bilateral orchiectomy. Besides the effects already listed, urogenital effects have been reported including hematuria, urinary tract infections and dysuria or urinary retention during treatment with flutamide.

Such symptoms commonly occur in men with prostate cancer and may improve as a result of tumor regression during therapy adrogГ©nica successful.

Medicines containing one of the following drugs, depending on the amount present can interact with flutamide: coumarin-derivative anticoagulants: Caution is advised and increase monitoring of prothrombin time (PT) if you start treatment with flutamide in a patient stabilized with an anticoagulant derived from coumarin. Increases have been presented in PT after the initiation of therapy with flutamide in patients receiving warfarin therapy long term.

Alanine aminotransferase (ALT [SGPT]) levels. Aspartate aminotransferase (AST [SGOT]) levels. There may be an increase, can rarely be indicative of hepatitis or jaundice. Serum alkaline phosphatase. May increase. Serum bilirubin. Blood urea nitrogen (BUN). Serum creatinine. The concentration can be increased. Plasma estradiol. Plasma testosterone. There may be an increase in the concentration if a patient has not undergone bilateral orchiectomy, is given a nonsteroidal antiandrogen without the use of an LHRH analogue. Hemoglobin. WBC. May decrease.

Although not established a causal relationship have been reported malignant breast tumors in two men receiving flutamide. In carcinogenicity studies in animals developed adenomas in testicular interstitial cells, breast adenomas, adenocarcinomas and fibroadenomas in male rats that received daily oral doses of 10, 30 and 50 mg / kg (which produce peak concentrations equivalent to 1, 2 3 and 4 times, respectively, the concentration produced in humans by therapeutic doses).

No evidence of mutagenicity in the Ames Salmonella mutagenesis assay microsomal or dominant lethal test in rats. Flutamide monotherapy caused a reduction in sperm count in a 6-week studies in humans. In animal studies, flutamide had no effect on estrus cycle and caused no interference with the mating behavior of male and female rats that received daily 25 or 75 mg / kg prior to mating.

Although males treated daily with 150 mg / kg (30 times the minimum effective antiandrogenic dose) showed an inhibition of mating, mating behavior returned to normal after the drug was discontinued. The conception in rats decreased at all dose levels. Also suppression of spermatogenesis occurred in rats that were given 3, 8, or roughly 17 times the human dose for 52 weeks and in dogs that were administered 1.4, 2.3 and 3.7 times the human dose for 78 weeks.

It is recommended FLIMUTALMR 3 tablets daily. When flutamide is used for the treatment of carcinoma in stage B2 or C, treatment should be started simultaneously or 24 hours before starting therapy with an LHRH analogue. Treatment with both drugs should start 8 weeks before radiation therapy and continue during the administration of the latter. When flutamide is used in conjunction with an LHRH analogue for the treatment of carcinoma matastГЎsico (stage D2), therapy should be started simultaneously or 24 hours before starting therapy with the LHRH analogue. Patients taking nonsteroidal anti-androgen should be under the supervision of a physician experienced in cancer chemotherapy.

Not established a single dose symptoms could result in potentially life threatening. Doses as high as 1.500 mg daily (twice the usual daily dose), administered for 36 weeks in clinical trials, gynecomastia caused softening of breasts, increased concentrations of liver enzymes, all of which have been reported with the administration Usual adult dose.

Signs of overdose in animals studied included: hypoactivity, piloerection, ataxia, lacrimation, anorexia, emesis, methemoglobinemia and slow breathing. In chronic toxicity studies in beagle dogs, flutamide caused chronic cardiac lesions including myxomatous degeneration, intra-arterial fibrosis, myocardial acidophilic degeneration, vasculitis and perivasculitis in 2 of 10 animals that were given 25 mg / kg per day for 78 weeks and in 3 of 16 animals that were given daily 40 mg / kg per day for 78 weeks and in 3 of 16 animals that were given daily 40 mg / kg for 2 to 4 years.

These doses produced hidroxiflutamida concentrations of 1 to 12 times greater than those present in humans receiving therapeutic doses. There is no specific antidote for overdosage with flutamide. Vomiting can be induced if the patient is conscious and not vomit spontaneously. It is unlikely that dialysis remove significant amounts of medicine as it is extensively bound to proteins. Recommended general supportive measures, including frequent monitoring of vital signs and close observation of the patient and the treatment of the symptoms observed.

Package with 30, 60 and 90 tablets of 250 mg of flutamide / tablet.

Store at room temperature to no more than 30C and dry place, protected from light.

Exclusive literature for physicians.
Its sale requires a prescription.
Keep out of reach of children.
This medication should not be used during pregnancy and lactation.
Annex instructive read.
This medication should be administered only by medical specialists in oncology and
experience in cancer chemotherapy.

Made in Mexico by:

CRYOPHARMA LABORATORIES, SA de CV



HEAR-03360200199/R2003

1. Martindale. The Extra Pharmacopoeia, 32th Edition, 1999, pg. 537. 2. Goodman & Gilman. The Pharmacological Basis of Therapeutics. 9th Edition, 1996. pp. 1276, 1453. 3. Drug information for the Health Care Professional USP DI 2000. 20th Edition. Volume I. pp. 236-241. 4. Remington: The Science and Practice of Pharmacy, 19th Edition. Volume II 1995. pg. 1251.