Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Nilutamide). A white or almost white powder. Very slightly soluble in water; freely soluble in acetone; soluble in anhydrous ethanol. Protect from light.

Adverse Effects and Precautions

As for Flutamide. Interstitial pneumonitis has occurred in patients receiving nilutamide, and the drug is contra-indicated in those with severe respiratory insufficiency.

Effects on the eyes. Reversible visual disturbances, particularly delayed dark adaptation, have been associated with nilutamide. Although some consider such visual disturbances to be mild and generally well tolerated, others suggest that these, together with alcohol intolerance and, more seriously, effects on the lung, mean that other nonsteroidal anti-androgens should be preferred.

Interactions

Patients receiving nilutamide may exhibit intolerance to alcohol.

Pharmacokinetics

Nilutamide is rapidly and completely absorbed from the gastrointestinal tract. It is extensively metabolised although it may inhibit its own metabolism to some extent after multiple doses. About 60% of an oral dose of nilutamide is eliminated in the urine and less than 10% in the faeces, with an elimination half-life of 41 to 49 hours.

Uses and Administration

Nilutamide is a nonsteroidal anti-androgen that is used similarly to flutamide in the treatment of prostatic carcinoma. It is given orally in a dose of 300 mg daily, usually starting on the same day that the patient undergoes orchidectomy or receives treatment with a gonadorelin analogue. Dosage may be reduced to 150 mg daily after 1 month.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed

Argentina: Anandron; Australia: Anandron; Brazil: Anandron; Canada: Anandron; Czech Republic: Anandron; Denmark: Anandron¤; Finland: Anandron¤; France: Anandron; Greece: Anandron; Hungary: Anandron; Mexico: Anandron; Netherlands: Anandron; Norway: Anandron¤; Portugal: Anandron; Sweden: Anandron; United States: Nilandron

Nilutamide

Nilutamide (Nilandron) is indicated for add-on therapy following surgical or chemical castration. The drug promotes disease regression, prolongs survival, and decreases bone pain. In one double-blind, randomized multicenter study comparing 225 castrated patients who received nilutamide and 232 castrated patients who received placebo, patients in the nilutamide group showed a longer progression-free survival (21.2 months in the nilutamide group versus 14.7 months in the placebo group), a longer median overall survival (27.3 months versus 23.6 months), and significant improvements in bone pain (54% versus 37%). Side effects, experienced by 86% of nilutamide patients, included hot flashes (28% incidence in treated patients and 22% in placebo patients) and transient night blindness (13% in treated patients and 1% in placebo patients). Less frequent side effects seen in clinical studies were nausea, constipation, and dizziness. Two serious side effects were pulmonary toxicity (2% incidence of interstitial pneumonitis) and hepatotoxicity (1% incidence of hepatitis or marked increases in liver enzymes).

The recommended dosage of nilutamide is six 50-mg tablets once daily for 30 days, followed by three 50 mg tablets once daily, with therapy beginning the same day or the day after surgical castration.

Mitoxantrone

Mitoxantrone (Novantrone) is indicated for hormone-resistant prostate cancer when given in combination with corticosteroids. Available for about 10 years for the treatment of acute non-lymphocytic leukemia, mitoxantrone is also under investigation for metastatic breast cancer and non-Hodgkin’s lymphoma. The drug was approved for prostate cancer on the strength of one open-label Canadian study showing that mitoxantrone plus prednisone significantly reduced bone pain in patients who had failed hormone therapy. The unblinded Canadian study involved 161 patients whose cancer had progressed despite castration and antiandrogen therapy (estrogen, luteinizing-hormone-releasing hormone agonists, cyproterone acetate, or flutamide). Patients were randomized to mitoxantrone 12 mg/m2 IV every three weeks plus 5 mg oral prednisone twice daily, or to prednisone alone. Patients who did not respond to prednisone alone were crossed over to mitoxantrone plus prednisone.

Overall, 38% of patients in the mitoxantrone plus prednisone group reported pain relief (or reduction in analgesic use) compared with 12% of patients on prednisone alone. The duration of pain relief was 33 weeks for the combination and eight weeks for prednisone alone. Also, mitoxantrone delayed progression of the disease (time to progression was 24 weeks compared to 10 weeks for prednisone alone) and reduced prostate specific antigen levels (PSA dropped 75% or more in 27% of patients receiving mitoxantrone compared with 5% of patients on prednisone alone). The most common side effects were nausea, hair loss, fatigue, weight loss and infection, and the most serious side effects were left ventricular dysfunction and myelosuppression. Despite the side effects, mitoxantrone therapy was associated with improvements in the quality of life, both physical and functional.

Current pharmacotherapy for Benign Prostatic Hyperplasia (BPH) is based on agents that relax the smooth muscles of prostatic urethra and stroma and those that deprive acinar cells of androgen.

Various agents have been tried in the treatment of BPH (Table). They may be broadly grouped into those affecting the dynamic component of urethral obstruction, namely the smooth muscle and prostatic stroma, and those affecting the glandular elements by androgen deprivation. The mechanism of action of many agents claimed to be useful in Benign Prostatic Hyperplasia is not clearly understood.

Caine has suggested that obstruction due to Benign Prostatic Hyperplasia occurs because of two factors: a dynamic component is thought to occur as a result of the contraction of smooth muscles of the prostate and prostatic urethra and is mediated mostly by adrenergic receptors; and a mechanical component of obstruction is related to the presence of a mass of hyperplastic acinar or stromal tissue that compresses and narrows the urethral lumen. There is some evidence that the presence and density of stromal content in BPH may relate to the severity of obstruction.

Current understanding of the biologic mechanisms of obstruction is limited and does not extend to two common clinical facts. The first is that the size of the prostate does not always correlate with the severity of symptoms or objective signs of obstruction. The second is the discrepancy between the histologic changes of BPH and the presence and severity of symptoms. From a physiologic standpoint, five conditions in patients with symptoms of “BPH” may exist singly or in combination. These are prostatic urethral obstruction, impaired detrusor contractility, detrusor instability, sensory urgency, and primary vesical neck obstruction. All these conditions likely result from varying combinations of prostatic enlargement and subtle neurologic dysfunction, all due to age-related central nervous system degeneration. Alternatively, a hyperplastic prostate during growth may disrupt normal sphincteric function. Thus, it is not surprising that prostatectomy fails to relieve symptoms of prostatism in about 20% of patients because the symptoms may be caused by poorly understood deficits in neurosensory pathways regulating micturition and sphincteric function.

Transurethral prostatectomy is the most common surgical procedure currently performed for the treatment of Benign Prostatic Hyperplasia. Outcome analyses have questioned the results of transurethral resection of the prostate (TURP). Patients undergoing TURP have been reported to be at greater risk from cardiovascular death than patients undergoing open prostatectomy. Recently these findings were disputed, and it was reported that transurethral resection for BPH does not increase long-term mortality and that comorbid illnesses and older age probably account for the apparent increase in long-term mortality after TURP. The morbidity of the procedure remains unchanged, however. In a review in 1962, the morbidity after transurethral resection of the prostate was reported to be 18% and the mortality 2.5%. More recently, the American Urological Association (AUA) cooperative study of 3,885 patients after the procedure revealed an overall complication rate of 18% and 0.2% mortality. Thus, the search for alternative therapies has been prompted by patients’ preferences for less invasive forms of treatment without prohibitive side effects. Apart from pharmacotherapy, other methods undergoing trials for the treatment of Benign Prostatic Hyperplasia include laser ablation, microwave hyperthermia, and prostatic stents. Ultimately, the role of surgical treatment and newer modalities must be based on relative effectiveness, cost, morbidity, effect on quality of life, expectations, and treatment preferences of patients.