Alfuzosin Hydrochloride for the Treatment of Benign Prostatic Hyperplasia

Mary Lee

Disclosures

Am J Health Syst Pharm. 2003;60(14) 

In This Article

Adverse Effects

Alfuzosin was originally developed as an antihypertensive agent.[23,24] Therefore, cardiovascular effects, such as hypotension, are intrinsic to this drug's pharmacologic profile. However, these adverse reactions are dose related and reported more frequently with higher dosages (i.e., 10-20 mg/day).[22,69] Since lower doses of alfuzosin are used for the treatment of BPH (i.e., 5-10 mg/day), the reported frequency of hypotension and dizziness is less in patients who receive alfuzosin for this indication.

Patients treated with IR alfuzosin have less hypotension and dizziness when compared to patients treated with prazosin.[23,55] The frequency of hypotension and dizziness with alfuzosin is similar to that with terazosin and doxazosin.[24,33,36,37,55] Also, the improved pharmacokinetic profile of ER alfuzosin should cause less cardiovascular adverse effects than the IR formulation,[30] although ER alfuzosin has been associated with these adverse effects.[71] Van Kerrebroeck et al.[27,30] showed that ER alfuzosin10 mg once daily produced vasodilatory adverse effects in 6.3% of treated patients, whereas IR 2.5 mg p.o. thrice daily caused the same adverse effects in 9.4% of patients. When compared with tamsulosin, IR alfuzosin causes more cardiovascular adverse effects.[56]

The cardiovascular effects of alfuzosin are the most common adverse effects of the drug. In a placebo-controlled study, vasodilatory adverse effects were reported by 8.4% of patients receiving alfuzosin 2.5 mg thrice daily, compared with 3.8% of patients receiving placebo.[41] In one multicenter study of 13,389 patients, two thirds of adverse events leading to discontinuation of therapy were due to peripheral vasodilation.[54] These usually occur during the first two weeks of treatment and are readily reversible after discontinuing the drug.[23] The clinical presentation of these adverse effects includes dizziness, orthostatic hypotension, reflex tachycardia, headache, and asthenia. Rare occurrences of first-dose syncope have been reported.[50,72]

Alfuzosin has also been linked with chest pain and myocardial infarction, although a cause-effect relationship has not been elucidated.[73] Alfuzosin may be similar to other α-blockers in that it may enhance the risk of major cardiovascular events in some hypertensive patients.[74]

Alfuzosin's cardiovascular effects appear to be dose related. After single doses of 1.25 and 2.5 mg of alfuzosin were administered to patients with BPH, an asymptomatic lowering of blood pressure occurred in two patients who received the 1.25-mg dose and five patients who received the 2.5-mg dose Patients given the 2.5-mg dose also had a reflex increase in heart rate by 5 beats/min.[25] In a study of healthy volunteers who received 1, 2.5, 5, and 10 mg of alfuzosin, significant decreases in systolic and diastolic blood pressure occurred in patients receiving the 5-mg dose.[24]

It has been suggested that patients over age 75, patients who are taking medications for cardiovascular diseases, and patients with preexisting hypertension are more sensitive to the blood-pressure-lowering effects of α-adrenergic antagonists. In a large postmarketing surveillance study of patients taking alfuzosin 2.5 mg thrice daily, an overall 3.2% withdrawal rate due to cardiovascular problems was reported. Patients over age 75 with concomitant cardiovascular diseases and those taking cardiovascular medications had a 1.5-fold higher withdrawal rate than patients younger than 60 years.[54] However, this has not been consistently observed across other studies.[23,36] In an open-label, observational study of 4018 Spanish outpatients, age had no significant effects on drug efficacy or frequency of adverse effects.[72] However, the patients were not evenly subdivided into various age groups, and only 458 patients (11%) were over 75 years old. Subgroup analysis found that patients age 67 and older had a higher overall frequency of adverse effects and withdrawal rate than did patients less than 67 years of age (30.1% versus 14.1%, respectively).

Alpha-1 adrenergic antagonists have been associated with ejaculation disorders, including retrograde ejaculation, reduced ejaculation volume, and absence of ejaculate, in 4-11% of patients.[75,76] Ejaculation disorders occur more frequently with tamsulosin than with placebo. In an excellent review of the literature comparing the adverse effects of α-adrenergic antagonists, tamsulosin caused abnormal ejaculation in 3-14% of patients in various studies, compared with 0-1% of placebo-treated patients.[33] Hofner it al.[38] reported similar findings. These adverse effects occur because α1-adrenergic antagonists relax the bladder neck, allowing semen to flow into the bladder during ejaculation. As a result, patients complain of decreased ejaculate volume or dry sex. These effects are reversible when the drug is discontinued. They are not life-threatening problems and rarely cause discontinuation of treatment.

It is unclear whether tamsulosin causes more ejaculatory problems than does alfuzosin. Hofner et al.[38] described three separate studies with 830 patients: two studies compared tamsulosin 0.4 mg daily versus placebo and the other study compared alfuzosin 2.5 mg thrice daily with tamsulosin 0.4 mg daily over 12 weeks. In the first comparison trials, tamsulosintreated patients reported abnormal ejaculation more frequently than placebo-treated patients (p < 0.045). In the second trial, less than 1% of tamsulosin-treated patients and no alfuzosin-treated patients reported ejaculation disorders. Patients receiving tamsulosin had a significantly higher overall sexual function score than those receiving placebo (p < 0.05). No difference in drug-related adverse effects occurred when comparing alfuzosin with tamsulosin. For the tamsulosin group, drug-related impotence, decreased libido, and abnormal ejaculation occurred in 2.3%, 0.0%, and 0.8% of patients, respectively. In alfuzosin-treated patients, these adverse effects occurred in 0.8%, 0.0%, and 0.0% of patients. Differences between these drugs' adverse effects were not significant. No other published reports describe ejaculation disorders attributable to alfuzosin therapy. In fact, Lukacs et al.[52] followed more than 7000 alfuzosintreated patients over three years, none of whom reported ejaculation disorders related to alfuzosin.

Alpha-1 adrenergic antagonists cause less erectile dysfunction (impotence) than do other antihypertensives, perhaps because the vasodilatory effects of α1-adrenergic antagonists can enhance the filling of the corpora cavernosa and promote penile erection.[77]

One case of alfuzosin-associated dermatomyositis has been reported. The patient developed severe muscle weakness and tenderness, swelling of the upper arms, an erythematous rash and edema over the malar area and nose bridge, erythematous plaques over the finger joints, and purpura in the periungal area.[78] In addition, the patient had elevated levels of hepatic transaminases, lactate dehydrogenase, creatine kinase, and aldolase. This reaction occurred one year after the start of treatment with alfuzosin. The dosage was not reported. After discontinuing alfuzosin and starting prednisone 1 mg/kg/day, the patient's symptoms disappeared over the ensuing month. However, no cause-effect relationship was established. A subsequent letter to the editor questioned whether alfuzosin caused this, as opposed to an undiagnosed neo-plastic condition in the patient.[79]

Zabala et al.[80] described one patient with severe, acute, mixed cholestatic and heptocellular-type hepatitis that was probably induced by alfuzosin. The patient was a 63-year-old male who had been taking alfuzosin 5 mg twice daily for nine months before being admitted to the hospital for jaundice. He was also taking amiloride for hypertension. Laboratory tests revealed significantly elevated levels of hepatic transaminases, total bilirubin, and alkaline phosphatase and a prolonged prothrombin time, (four times the control value). His platelet count was 93 x 106. Alfuzosin therapy was stopped and laboratory test values returned to near normal over the next six weeks, resulting in rapid correction of the problem.

Other uncommon adverse effects of alfuzosin therapy include nausea, vomiting, diarrhea, skin rash, dry mouth, and asthenia.[23] Alfuzosin may have a low potential to cause central nervous system adverse effects because it poorly penetrates the blood-brain barrier in animal models.[10,72]

Apoptosis (programmed cell death) in prostate cancer cells has been observed in vitro with α1-adrenergic antagonists. This could be potentially beneficial in decreasing prostate volume. However, the clinical importance of this finding is unknown.[31]

Alfuzosin is contraindicated in patients with a hypersensitivity to alfuzosin or other quinazolones. Alfuzosin should be used cautiously in patients who are predisposed to hypotension, including patients with severe coronary artery disease, those taking multiple antihypertensive agents, those with severe volume depletion, patients with severe cardiac arrhythmias, or those with severe orthostatic hypotension. It should be used cautiously in patients undergoing general anesthesia, as hypotension has been reported with the combination. Caution is also warranted when alfuzosin is used in patients with severe hepatic failure, as alfuzosin may accumulate.

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