Increases in prothrombin time have been noted in patients receiving long- term warfarin therapy after Flulem was initiated. Therefore, close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when EULEXIN (Flulem) Capsules are administered concomitantly with warfarin.
EULEXIN (Flulem) Capsules, 125 mg, are available as opaque, two- toned brown capsules, imprinted with "Schering 525†. They are supplied as follows:
NDC 0085-0525-05 - Bottles of 500
NDC 0085-0525-03 - Unit Dose packages of 100 (10 x 10†s)
NDC 0085-0525-06 - Bottles of 180
Store between 2 o and 30 o C (36 o and 86 o F). Protect the Unit Dose packages from excessive moisture.
Before taking Flulem,
- tell your doctor and pharmacist if you are allergic to Flulem or any other medications.
- tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention anticoagulants (''blood thinners'') such as warfarin (Coumadin).
- tell your doctor if you smoke and if you have or have ever had any inherited blood diseases such as glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or hemoglobin M disease.
- you should know that Flulem is only for use in men. If taken by pregnant women, Flulem can harm the fetus. Women who are or may become pregnant should not take Flulem. If you take Flulem while you are pregnant, call your doctor.
- ask your doctor about the safe use of alcoholic beverages while you are taking Flulem. Flulem may cause facial flushing, and drinking alcohol can make it worse.
It is contraindicated to use Flulem in patients with a hypersensitivity to Flulem or in those with the severe hepatic disease.
It is advised to not concomitantly use Flulem alongside drugs such as idelalisib and ivacaftor as this will result in serious adverse effects. Idelalisib strongly inhibits the enzyme CYP3A4 in the liver and intestines resulting in increasing the level of Flulem in the body. A metabolite of Ivacaftor, M1, has the same effect potentially if taken with Flulem. Other drugs with similar effects on the CYP3A4 enzyme but with less serious complications are crofelemer, dabrafenib, elvitegravir, cobicistat, emtricitabine, tenofovir, iloperidone, letermovir, and mitotane. These drugs do not necessarily require alternatives, but patients should be monitored closely for adverse effects. Other drugs that come with precautions are teriflunomide which inhibits CYP1A2 leading to increased levels of Flulem in the serum and warfarin. Flulem increases the effects of warfarin leading to increased prothrombin time in patients taking both. Other substances to be mindful of when treating a patient with Flulem are maitake and taurine. Maitake is a mushroom with possible antitumor effects as shown in animal and in-vitro trials. Maitake has been shown to increase serum levels of Flulem. Taurine is an organic compound that found its way into popular energy drinks. Flulem has been shown to interact with taurine, but it is unknown the significance of this interaction.
What are some other side effects of Flulem?
All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
- Hot flashes.
- Upset stomach or throwing up.
- Enlarged breasts.
- Lowered interest in sex.
- Not able to get or keep an erection.
These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.
Flulem (FLUT) is an antiandrogen which interferes the binding of androgen to androgen receptor in target organs. Effects of FLUT on spermatogenesis have recently been summarized by Anahara et al. (2008) . Both neonatal and adult mice showed morphological abnormalities in the testis after subcutaneous injections of FLUT at 0.012 mg kg −1 b.w. for 5 days. FLUT apparently exerts its effects via depolymerization of actin bundles at the apical ES but not basal ES by tyrosine phosphorylation of cortactin ( Anahara et al. 2006a,b ) ( Table 3 ). However, FLUT seems to target cortactin specifically at the apical ES but not at the basal ES. Cortactin is an F-actin binding protein and its tyrosine phosphorylation status is directly correlated to actin bundle remodeling in chinese hamster ovarian (CHO) cells ( Fan et al. 2004 ), as well as centrosome separation during mitosis ( Wang et al. 2008 ). Cortactin was localized to the heads of elongated spermatids when examined by immunohistochemistry. When mice were treated with FLUT at 0.012 mg kg −1 b.w. for 5 days, the protein level of cortactin was significantly reduced at stages VI–IX of the seminiferous epithelial cycle, concomitant with a significant increase in tyrosine phosphorylated cortactin protein in the testis ( Anahara et al. 2006a,b ). Besides its effects on disrupting the association between Sertoli–germ cell at the apical ES, subcutaneous administration of FLUT was shown to perturb the Sertoli–Sertoli cell interaction by downregulating the expression of TJ protein occludin in rat testis ( Gye and Ohsako 2003 ). It is likely that FLUT mediates its effects on cell junctions by blocking androgen action in the testis since testosterone has been shown to upregulate occludin expression in Sertoli cell cultures ( Chung and Cheng 2001 ) and promote junction integrity at the BTB ( Yan et al. 2008a ).
Table 3 . Effects of Flulem on cell junctions in the testis
Why is this medication prescribed?
Flulem is used together with a luteinizing hormone-releasing hormone agonist (LHRH; a type of hormonal injection such as leuprolide , goserelin , or triptorelin ) to treat certain types of prostate cancer. Flulem is in a class of medications called nonsteroidal antiandrogens. It works by blocking the effects of androgen (a male hormone) to stop the growth and spread of cancer cells.
Flutam > Flulem is a synthetic nonsteroidal drug that is a competitive antagonist of the androgen receptor. After oral administration, Flulem undergoes extensive first-pass metabolism with formation of several oxidized metabolites. Formation of electrophilic metabolites is catalyzed via CYP3A and CYP1A . Experimental studies in rat hepatocytes suggest that toxicity from the electrophilic metabolites occurs through depletion of hepatocyte GSH, which is accompanied by oxidative stress. Toxicity to mitochondria is manifested by depression of mitochondrial respiration and ATP formation, but the study did not report whether mitochondrial toxicity was due to depletion of mitochondrial GSH.
Liver injury presents with marked elevations of bilirubin and a wide range in elevation of serum aminotransferases. The predominant histological feature determined on autopsy is marked-to-massive hepatic necrosis. In a multicenter study of 905 patients treated with Flulem, liver tests with elevations >4×ULN occurred in 0.8% of patients . According to postmarketing surveillance, severe liver disease due to Flulem has occurred in 46 patients with 20 fatalities . The rate of serious liver injury is estimated to be 3 per 10,000 Flulem users, based on the number of prescriptions written.
In animal studies, Flulem 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 Flulem administration.
Absorption: Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritiumlabeled Flulem to human volunteers showed that the drug is rapidly and completely absorbed. Following a single 250 mg oral dose to normal adult volunteers, the biologically active alphahydroxylated metabolite reaches maximum plasma concentrations in about 2 hours, indicating that it is rapidly formed from Flulem. Food has no effect on the bioavailability of Flulem.
Distribution: In male rats administered an oral 5 mg/kg dose of 14 C-Flulem neither Flulem nor any of its metabolites is preferentially accumulated in any tissue except the prostate. Total drug levels were highest 6 hours after drug administration in all tissues. Levels declined at roughly similar rates to low levels at 18 hours. The major metabolite was present at higher concentrations than Flulem in all tissues studied. Following a single 250 mg oral dose to normal adult volunteers, low plasma concentrations of Flulem were detected. The plasma half-life for the alpha-hydroxylated metabolite of Flulem is approximately 6 hours. Flulem, in vivo , at steady-state plasma concentrations of 24 to 78 ng/mL is 94% to 96% bound to plasma proteins. The active metabolite of Flulem, in vivo , at steady-state plasma concentrations of 1556 to 2284 ng/mL, is 92% to 94% bound to plasma proteins.
Metabolism: The composition of plasma radioactivity, following a single 200 mg oral dose of tritium-labeled Flulem to normal adult volunteers, showed that Flulem is rapidly and extensively metabolized, with Flulem comprising only 2.5% of plasma radioactivity 1 hour after administration. At least 6 metabolites have been identified in plasma. The major plasma metabolite is a biologically active alpha-hydroxylated derivative which accounts for 23% of the plasma tritium 1 hour after drug administration. The major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl) phenol.
Excretion: Flulem and its metabolites are excreted mainly in the urine with only 4.2% of the dose excreted in the feces over 72 hours.
Plasma Pharmacokinetics of Flutam >
Adverse Events During Late Radiation Phase (after 90 days of radiation therapy)
(n= 231) LHRH-A + EULEXlN Capsules + Radiation %All
(n= 235) Radiation Only
Additional adverse event data was 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 multi-center clinical trial comparing EULEXIN (Flulem) Capsules + LHRH agonist versus placebo + LHRH agonist.
The most frequently reported (greater than 5%) adverse experiences during treatment with EULEXIN (Flulem) 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) Flulem + LHRH agonist %All
Mechanism of Action
Flulem is a nonsteroidal antiandrogen that competitively binds androgen receptors throughout the body. This inhibits cell growth in prostate cancer by inhibiting testosterone’s stimulatory effects. The drug has a half-life of 6 hours, meaning dosing will have to occur a minimum of 3 times a day to maintain adequate serum levels. The liver metabolizes Flulem mainly via the CYP3A4 and other cytochrome enzymes such as CYP1A2. Flulem is primarily excreted in the urine, with less than 5% being excreted in the feces.
Flulem , a synthetic anti-androgen used in the treatment of prostate cancer, has led to asymptomatic elevations of serum transaminases and clinically significant injury that mainly manifests as biochemically hepatocellular. There have been multiple examples of severe hepatic necrosis with fulminant liver failure. 1041–1043 Explants have shown massive necrosis, and biopsies severe acute hepatitis, with or without mild cholestasis. There appears be to an increased risk of Flulem liver injury in patients with underlying chronic viral hepatitis. 1044
Cyproterone, another anti-androgen used for prostate cancer, has been implicated in several cases of severe, sometimes fatal hepatocellular damage, 1045–1047 and biochemical evidence of injury in up to 25% of patients. Biopsies have shown acute cholestatic hepatitis, with submassive necrosis at autopsy. HCC has developed during cyproterone therapy in noncirrhotic livers, but the link remains controversial. 1048
Rare cases of acute liver failure have been reported with both bicalutamide 1049 and nilutamide. 1050
Flulem to Treat Prostate Cancer
The U.S. Food and Drug Administration (FDA) approved the use of Flulem in the country on June 1996. It is commercialized under the brand name Eulexin to be used in the therapeutic areas of endocrinology, nephrology, oncology, family medicine, and urology. The approval was based on a study submitted by the pharmaceutical company Schering-Plough, which revealed the effectiveness of Flulem for the treatment of locally confined Stage B2-C carcinoma of the prostate in combination with LHRH agonists and radiation therapy.
Flulem is prescribed as a tablet to be taken three times a day with a glass of water. Despite the encouraging results of the treatment with Flulem, there are also potential side effects associated to it. The most common adverse events include hot flushes and sweats, which affect three out of five men treated (60%), lowered interest in having sex (libido) and problems getting an erection (impotence), which affect about three out of 10 (30%) men but may stop after the end of the treatment, as well as breast tenderness and swelling, which occur in one out of 10 (10%) men treated.