Flutamide

Pharmaceuticals

Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Antineoplastic agents

Pharmaceuticals -> Listed in ZINC15

Pharmaceutical

5.66e-03 g/L

>41.4 [ug/mL] (The mean of the results at pH 7.4)

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Hormones and antihormones

111.5-112.5

111 - 113 °C

154.9 Ų [M-H]- [CCS Type: DT; Buffer gas: N2; Ionization: ESI-; Dataset: TOXCAST; Source Identifier: DTXSID7032004]

160 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

154.25 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Danger

H302+H312+H332 (29.8%): Harmful if swallowed, in contact with skin or if inhaled [Warning Acute toxicity, oral; acute toxicity, dermal; acute toxicity, inhalation]

P203, P260, P261, P264, P270, P271, P273, P280, P301+P317, P302+P352, P304+P340, P317, P318, P319, P321, P330, P362+P364, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 94 reports by companies from 15 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H361: Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

Acute Tox. 4 (88.3%)

Reproductive toxicity - Category 2

Chronic therapy with flutamide is associated with elevations in serum aminotransferase levels in up to 62% of patients, but marked elevations (above 5 times ULN) in only 3% to 5%. Most of these abnormalities are transient, asymptomatic and do not require dose adjustment or drug discontinuation. However, in 0.1% to 1% of patients, acute liver injury with symptoms and jaundice arises which can be prolonged, severe and even fatal. The latency of onset ranges widely from 1 to 10 months (Cases 2 and 3), averaging 3 months. Allergic manifestations are rare as are autoantibodies. The pattern of liver enzyme elevations is most commonly hepatocellular, but many cases with cholestatic and mixed patterns have been described. Liver failure with a requirement for emergency liver transplantation or fatality has been described in many publications with 20 fatal cases reported from the FDA MedWatch program during the first 5 years of its availability. Fatal cases have been reported in children and young women being treated for hirsutism or acne (Case 1).

Flutamide comes with a black box warning due to the risk of hepatic failure. Hospitalization and death have occurred, although rarely, due to flutamide use; this is due to cholestatic hepatitis, which leads to failure. Cholestatic hepatitis results from the mitochondrial toxicity that occurs due to flutamide's major metabolite, hydroxyflutamide. This metabolite inhibits enzymes that are necessary for the electron transport chain within the mitochondria of the hepatocyte, leading to a halt of cellular respiration and, ultimately, cellular death. Hepatic failure would most likely be evident within the first three months of use. If the hepatic injury does occur in a patient, discontinuation of flutamide may help reverses the injury. Estimates of the rate at which this adverse effect occurs are three persons in 10,000 or 0.03% of all patients who use the drug. Due to this risk, it is advisable to perform liver function tests if symptoms suggest hepatic dysfunction. Such signs to watch for are abdominal pain, anorexia, nausea, vomiting, jaundice, and right upper quadrant pain and tenderness. Recommendations are to discontinue therapy if jaundice develops or if alanine aminotransferase increased to two times the upper limit of normal.

There is a risk for severe hepatic injury leading to hepatic failure. There is a potential for aniline toxicity, which may cause methemoglobinemia or hemolytic anemia. The risk of cardiovascular disease may increase due to androgen deprivation.

Flutamide is a nonsteroidal antiandrogen that blocks the action of both endogenous and exogenous testosterone by binding to the androgen receptor. In addition Flutamide is a potent inhibitor of testosterone-stimulated prostatic DNA synthesis. Moreover, it is capable of inhibiting prostatic nuclear uptake of androgen.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Flutamide

vMost-DILI-concern

8

Box warning

DOI:10.1016/j.drudis.2016.02.015

L02BB01

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Flutamide is a nonsteroidal antiandrogen. In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen, e.g. castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration.

Flutamide is a nonsteroidal antiandrogen that blocks the action of both endogenous and exogenous testosterone by binding to the androgen receptor. In addition Flutamide is a potent inhibitor of testosterone-stimulated prostatic DNA synthesis. Moreover, it is capable of inhibiting prostatic nuclear uptake of androgen.

Flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration.

Flutamide has known human metabolites that include 2-hydroxy-flutamide.

Flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration. Route of Elimination: Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of a single dose excreted in the feces over 72 hours. Half Life: The plasma half-life for the alpha-hydroxylated metabolite of flutamide (an active metabolite) is approximately 6 hours.

76W6J0943E

FLUTAMIDE

Mechanisms of Action [MoA] - Androgen Receptor Antagonists

Established Pharmacologic Class [EPC] - Androgen Receptor Inhibitor

Flutamide is an Androgen Receptor Inhibitor. The mechanism of action of flutamide is as an Androgen Receptor Antagonist.

FLUTAMIDE

Compounds which inhibit or antagonize the biosynthesis or actions of androgens.

Antineoplastic agents that are used to treat hormone-sensitive tumors. Hormone-sensitive tumors may be hormone-dependent, hormone-responsive, or both. A hormone-dependent tumor regresses on removal of the hormonal stimulus, by surgery or pharmacological block. Hormone-responsive tumors may regress when pharmacologic amounts of hormones are administered regardless of whether previous signs of hormone sensitivity were observed. The major hormone-responsive cancers include carcinomas of the breast, prostate, and endometrium; lymphomas; and certain leukemias. (From AMA Drug Evaluations Annual 1994, p2079)

Rapidly and completely absorbed.

Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of a single dose excreted in the feces over 72 hours.

Use (kg; approx.) in Germany (2009): >1000

For the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate