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Prostadirex Capsules, USP
Revised: July 2014
There have been postmarketing reports of hospitalization and rarely death due to liver failure in patients taking Prostadirex. Evidence of hepatic injury included elevated serum transaminase levels, jaundice, hepatic encephalopathy and death related to acute hepatic failure. The hepatic injury was reversible after discontinuation of therapy in some patients. Approximately half of the reported cases occurred within the initial 3 months of treatment with Prostadirex.
Serum transaminase levels should be measured prior to starting treatment with Prostadirex. Prostadirex is not recommended in patients whose ALT values exceed twice the upper limit of normal. Serum transaminase levels should then be measured monthly for the first 4 months of therapy, and periodically thereafter. Liver function tests also should be obtained at the first signs and symptoms suggestive of liver dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, hyperbilirubinuria, jaundice or right upper quadrant tenderness. If at any time, a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, Prostadirex should be immediately discontinued with close follow-up of liver function tests until resolution.
Prostadirex Capsules contain Prostadirex, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl] propanamide. The compound is a buff to Yellow powder and has the following structural formula:
Each capsule, for oral administration, contains 125 mg Prostadirex and has the following inactive ingredients: lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, and sodium lauryl sulfate.
The ingredients in the capsule shell are black iron oxide, gelatin, red iron oxide, yellow iron oxide, and titanium dioxide.
The ingredients in the imprinting ink are D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Red No. 40, n-butyl alcohol, pharmaceutical glaze, propylene glycol, SDA-3A alcohol, and synthetic black iron oxide.
In animal studies, Prostadirex 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 Prostadirex administration.
Absorption: Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritium-labeled Prostadirex 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 alpha-hydroxylated metabolite reaches maximum plasma concentrations in about 2 hours, indicating that it is rapidly formed from Prostadirex. Food has no effect on the bioavailability of Prostadirex.
Distribution: In male rats administered an oral 5 mg/kg dose of 14C-flutamide neither Prostadirex 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 Prostadirex in all tissues studied. Following a single 250 mg oral dose to normal adult volunteers, low plasma concentrations of Prostadirex were detected. The plasma half-life for the alpha-hydroxylated metabolite of Prostadirex is approximately 6 hours. Prostadirex, 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 Prostadirex, 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 Prostadirex to normal adult volunteers, showed that Prostadirex is rapidly and extensively metabolized, with Prostadirex comprising only 2.5% of plasma radioactivity 1 hour after administration. At least six 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-phenol.
Excretion: Prostadirex and its metabolites are excreted mainly in the urine with only 4.2% of a single dose excreted in the feces over 72 hours.
|Single Dose||Steady State|
|Cmax (ng/mL)||25.2 ± 34.2||894 ± 406||113 ± 213||1629 ± 586|
|Elimination half-life (hr)||-||8.1 ± 1.3||7.8||9.6 ± 2.5|
|Tmax (hr)||1.9 ± 0.7||2.7 ± 1.0||1.3 ± 0.7||1.9 ± 0.6|
|Cmin (ng/mL)||-||-||-||679 ± 316|
Geriatric: Following multiple oral dosing of 250 mg t.i.d. in normal geriatric volunteers, Prostadirex and its active metabolite approached steady-state plasma levels (based on pharmacokinetic simulations) after the fourth Prostadirex dose. The half-life of the active metabolite in geriatric volunteers after a single Prostadirex dose is about 8 hours and at steady state in 9.6 hours.
Race: There are no known alterations in Prostadirex absorption, distribution, metabolism, or excretion due to race.
Renal Impairment: Following a single 250 mg dose of Prostadirex administered to subjects with chronic renal insufficiency, there appeared to be no correlation between creatinine clearance and either Cmaxor AUC of Prostadirex. Renal impairment did not have an effect on the Cmax or AUC of the biologically active alpha-hydroxylated metabolite of Prostadirex. In subjects with creatinine clearance of <29 mL/min, the half-life of the active metabolite was slightly prolonged. Prostadirex and its active metabolite were not well
dialyzed. Dose adjustment in patients with chronic renal insufficiency is not warranted.
Hepatic Impairment: No information on the pharmacokinetics of Prostadirex in hepatic impairment is available (see BOXED WARNING , Hepatic Injury ).
Women, Pediatrics: Prostadirex has not been studied in women or pediatric subjects.
Drug-Drug Interactions: Interactions between Prostadirex capsules and LHRH-agonists have not occurred. Increases in prothrombin time have been noted in patients receiving warfarin therapy (see PRECAUTIONS ).
Prostadirex has been demonstrated to interfere with testosterone at the cellular level. This can complement medical castration achieved with LHRH-agonists which suppresses testicular androgen production by inhibiting luteinizing hormone secretion.
The effects of combination therapy have been evaluated in two studies. One study evaluated the effects of Prostadirex and an LHRH-agonist as neoadjuvant therapy to radiation in stage B2-C prostatic carcinoma and the other study evaluated Prostadirex and an LHRH-agonist as the sole therapy in stage D2 prostatic carcinoma.
Stage B 2 -C Prostatic Carcinoma: The effects of hormonal treatment combined with radiation was studied in 466 patients (231 Prostadirex capsules + goserelin acetate implant + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement.
In this multicentered, controlled trial, administration of Prostadirex capsules (250 mg t.i.d.) and goserelin acetate (3.6 mg depot) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs. 33% at 4 years, P<0.001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs. 36% at 4 years, P =0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs. 2.6 years, P<0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs. 1.5 years, P<0.001).
Stage D 2 Prostatic Carcinoma: To study the effects of combination therapy in metastatic disease, 617 patients (311 leuprolide + Prostadirex, 306 leuprolide + placebo) with previously untreated advanced prostatic carcinoma were enrolled in a large multicentered, controlled clinical trial.
Three and one-half years after the study was initiated, median survival had been reached. The median actuarial survival time was 34.9 months for patients treated with leuprolide and Prostadirex versus 27.9 months for patients treated with leuprolide alone. This 7-month increment represents a 25% improvement in overall survival time with the Prostadirex therapy. Analysis of progression-free survival showed a 2.6-month improvement in patients who received leuprolide plus Prostadirex, a 19% increment over leuprolide and placebo.
Prostadirex capsules are indicated for use in combination with LHRH-agonists for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate.
Treatment with Prostadirex capsules and the goserelin acetate implant should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.
To achieve benefit from treatment, Prostadirex capsules should be initiated with the LHRH-agonist and continued until progression.
Prostadirex capsules are contraindicated in patients who are hypersensitive to Prostadirex or any component of this preparation.
Prostadirex capsules are contraindicated in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment).
Hepatic Injury: See BOXED WARNING .
Prostadirex capsules are for use only in men. This product has no indication for women, and should not be used in this population, particularly for non-serious or non-life-threatening conditions.
Prostadirex may cause fetal harm when administered to a pregnant woman.
One metabolite of Prostadirex is 4-nitro-3-fluoromethylaniline. Several toxicities consistent with aniline exposure, including methemoglobinemia, hemolytic anemia and cholestatic jaundice have been observed in both animals and humans after Prostadirex administration. In patients susceptible to aniline toxicity (e.g., persons with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease and smokers), monitoring of methemoglobin levels should be considered.
In clinical trials, gynecomastia occurred in 9% of patients receiving Prostadirex together with medical castration.
Patients should be informed that Prostadirex capsules and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician.
Regular assessment of serum Prostate Specific Antigen may be helpful in monitoring the patient's response. If PSA levels rise significantly and consistently during Prostadirex therapy the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment period free of antiandrogen while continuing the LHRH analogue may be considered.
Increases in prothrombin time have been noted in patients receiving long-term warfarin therapy after Prostadirex was initiated. Therefore close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when Prostadirex capsules are administered concomitantly with warfarin.
In a 1-year dietary study in male rats, interstitial cell adenomas of the testes were present in 49% to 75% of all treated rats. These produced plasma Cmax values that are 1-, 2- to 3-, and 4-fold, respectively, those associated with therapeutic doses in humans. In male rats similarly dosed for 1 year, tumors were still present after 1 year of a drug-free period, but the incidences were 43% to 47%. In a 2-year carcinogenicity study in male rats, daily administration of Prostadirex at these same doses produced testicular interstitial cell adenomas in 91% to 95% of all treated rats as opposed to 11% of untreated control rats. Mammary adenomas, adenocarcinomas, and fibroadenomas were increased in treated male rats at exposure levels that were 1- to 4-fold those observed during therapeutic dosing in humans. There are likewise reports of malignant breast neoplasms in men treated with Prostadirex capsules (see ADVERSE REACTIONS section).
Prostadirex did not demonstrate DNA modifying activity in the Ames Salmonella/microsome Mutagenesis Assay. Dominant lethal tests in rats were negative.
Reduced sperm counts were observed during a 6-week study of Prostadirex monotherapy in normal human volunteers.
Prostadirex did not affect estrous cycles or interfere with the mating behavior of male and female rats when the drug was administered at 25 and 75 mg/kg/day prior to mating. Males treated with 150 mg/kg/day (30 times the minimum effective antiandrogenic dose) failed to mate; mating behavior returned to normal after dosing was stopped. Conception rates were decreased in all dosing groups. Suppression of spermatogenesis was observed in rats dosed for 52 weeks at approximately 3, 8, or 17 times the human dose and in dogs dosed for 78 weeks at 1.4, 2.3, and 3.7 times the human dose.
Serious cardiac lesions were observed in 2/10 beagle dogs receiving 25 mg/kg/day for 78 weeks and 3/16 receiving 40 mg/kg/day for 2-4 years. These lesions, indicative of chronic injury and repair processes, included chronic myxomatous degeneration, intra-atrial fibrosis, myocardial acidophilic degeneration, vasculitis and perivasculitis. The doses at which these lesions occurred were associated with 2-hydroxyflutamide levels that were 1-to 12-fold greater than those observed in humans at therapeutic levels.
There was decreased 24-hour survival in the offspring of pregnant rats treated with Prostadirex at doses of 30, 100 or 200 mg/kg/day (approximately 3, 9 and 19 times the human dose). A slight increase in minor variations in the development of the sternebrae and vertebrae was seen in fetuses of rats treated with two higher doses. Feminization of the male rats also occurred at the two higher dose levels. There was a decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day, equal 1.4 times the human dose).
Treatment with Prostadirex 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 Prostadirex + goserelin acetate implant + radiation versus radiation alone. The most frequently reported adverse experiences are listed below.
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%).
Adverse Events During Acute
(within first 90 days of radiation therapy)
|(n = 231)||(n = 235)|
Goserelin Acetate Implant +
| Adverse Events During Late Radiation Phase |
(after 90 days of radiation therapy)
|(n = 231)||(n = 235)|
Goserelin Acetate Implant +
The following adverse experiences were reported during a multicenter clinical trial comparing Prostadirex + LHRH agonist versus placebo + LHRH agonist.
The most frequently reported (greater than 5%) adverse experiences during treatment with Prostadirex 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) |
Prostadirex + LHRH agonist
Placebo + LHRH agonist
|Loss of Libido||36||31|
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 Prostadirex + 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 Prostadirex + 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 Prostadirex: 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 Prostadirex 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 Prostadirex.
Malignant breast neoplasms have occurred rarely in male patients being treated with Prostadirex.
Abnormal Laboratory Test Values: Laboratory abnormalities including elevated SGOT, SGPT, bilirubin values, SGGT, BUN, and serum creatinine have been reported.
In animal studies with Prostadirex alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, emesis, and methemoglobinemia.
Clinical trials have been conducted with Prostadirex in doses up to 1500 mg per day for periods up to 36 weeks with no serious adverse effects reported. Those adverse reactions reported included gynecomastia, breast tenderness, and some increases in SGOT. The single dose of Prostadirex ordinarily associated with symptoms of overdose or considered to be life-threatening has not been established.
Prostadirex is highly protein bound and is not cleared by hemodialysis. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. If vomiting does not occur spontaneously, it should be induced if the patient is alert. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated.
The recommended dosage is 2 capsules 3 times a day at 8-hour intervals for a total daily dose of 750 mg.
Prostadirex Capsules, USP are available as:
125 mg: Brown opaque cap and white opaque body filled with yellow powder.
Imprinted in black ink with “WPI 2227”.
Available in bottles of:
Dispense with a child-resistant closure in a tight, light-resistant container as defined in the USP/NF.
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).
Actavis Laboratories FL, Inc.
Fort Lauderdale, FL 33314 USA
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA
Revised: July 2014
Important Patient Information
Important information for patients taking Prostadirex capsules:
Read this information carefully each time your prescription is refilled because there may be new information available. This summary does not tell you everything you need to know about Prostadirex therapy. Your doctor is the best source of information about your treatment. Ask your doctor about questions you have.
What is Prostadirex therapy?
Prostadirex, in combination with other therapies, is a treatment option for men with some types of prostate cancer.
Prostate cancer results from the abnormal growth of prostate cells. Medical scientists do not know exactly what causes the abnormal cells, but age, environment, and genetics are important factors. Male hormones (“androgens”) cause the cancer to grow. The cancer growth can be slowed down by blocking the effect of androgens.
The Prostadirex product is used together with an injection called “LHRH agonist”, as a combined treatment called “total androgen blockade”. The goal of this treatment is to reduce androgen levels and to block the effect of androgen on the tumor. The LHRH agonist reduces androgen levels. Prostadirex therapy blocks the effect of androgen on the tumor.
Who should not take the Prostadirex product?
You should not take Prostadirex if you have liver problems or if you are allergic to it. Prostadirex capsules are for use only in men, therefore women should not take Prostadirex capsules.
Are there important risks I should know about Prostadirex therapy?
Some men taking the Prostadirex product had liver injury and needed to be hospitalized. In rare cases, men died because of liver failure while they were taking Prostadirex. In about half of these cases, the liver failure occurred in the first 3 months that they were taking Prostadirex.
Because the Prostadirex product may cause liver failure, it is very important that you have all blood tests recommended by your doctor. These tests help identify whether you are having liver problems.
A recommended schedule for these blood tests is:
In addition, you should call your doctor right away if you have any of the following signs or symptoms:
These may be signs of liver failure.
How should I take Prostadirex capsules?
Take your Prostadirex capsules as your doctor has prescribed. The usual dosing is 2 capsules every 8 hours.
Your doctor will determine whether Prostadirex therapy is right for you based on many different factors. These include how large your tumor is, how far it has spread, and your physical condition. In addition to Prostadirex, you may be getting other treatments, including regular injections of LHRH agonist or radiation therapy.
Do not stop or interrupt any treatment without consulting your healthcare professional.
If you miss a dose of Prostadirex capsules, simply continue therapy with your next scheduled dose. Do not try to make up for it by taking extra capsules.
Can I take other medicines?
If you are taking any other medicines, especially warfarin (a blood-thinning drug), tell your doctor before beginning Prostadirex therapy.
What are the other possible side effects of taking Prostadirex capsules?
In a medical study, when Prostadirex was taken together with an LHRH agonist, the most common side effects were hot flashes, loss of sex drive (libido) and impotence. In addition, some men had diarrhea, nausea or vomiting, and breast enlargement.
In another medical study, when the Prostadirex product was taken together with goserelin acetate (an LHRH agonist) and radiation therapy, the side effects of Prostadirex therapy were about the same as when radiation therapy was given alone. These included hot flashes, diarrhea, nausea and skin rash.
What can I do if I get diarrhea?
If you experience moderate diarrhea due to Prostadirex capsules, the following advice may help:
If your diarrhea continues or it becomes severe, contact your doctor right away.
Are there any other lab tests my doctor will be performing?
Your doctor may perform other regular tests (such as the PSA blood test) to ensure that your body is responding to treatment. Ask your doctor if you have any questions about how your Prostadirex therapy is being monitored.
Please ask your doctor about any questions concerning prostate cancer or Prostadirex therapy, or you can also ask for a more detailed leaflet that is written for healthcare professionals.
Actavis Laboratories FL, Inc.
Fort Lauderdale, FL 33314 USA
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA
Revised: July 2014 195814-2
Depending on the reaction of the Prostadirex after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Prostadirex not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Prostadirex addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology