The following adverse reactions have been identified during post approval use of alfuzosin hydrochloride extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
General disorders: edema
Cardiac disorders: tachycardia, chest pain, angina pectoris in patients with pre-existing coronary artery disease, atrial fibrillation
Gastrointestinal disorders: diarrhea
Hepatobiliary disorders: hepatocellular and cholestatic liver injury (including cases with jaundice leading to drug discontinuation)
Respiratory system disorders: rhinitis
Reproductive system disorders: priapism
Skin and subcutaneous tissue disorders: rash, pruritis, urticaria, angioedema Vascular disorders: flushing
During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in some patients on or previously treated with alpha adrenergic antagonists [see Warnings and Precautions (5.7)].
Alfuzosin hydrochloride extended-release tablets are contraindicated for use with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, or ritonavir, since alfuzosin blood levels are increased. [see Contraindications (4), Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].
The pharmacokinetic and pharmacodynamic interactions between alfuzosin hydrochloride extended-release tablets and other alpha adrenergic antagonists have not been determined. However, interactions may be expected, and alfuzosin hydrochloride extended-release tablets should not be used in combination with other alpha adrenergic antagonists [see Warnings and Precautions (5.4)].
There may be an increased risk of hypotension/postural hypotension and syncope when taking alfuzosin hydrochloride extended-release tablets concomitantly with anti-hypertensive medication and nitrates [see Warnings and Precautions (5.1)].
Caution is advised when alpha adrenergic antagonists agents, including alfuzosin hydrochloride extended-release tablets are co-administered with PDE5 inhibitors. Alpha adrenergic antagonists and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension [see Warnings and Precautions (5.4) ].
Pregnancy Category B. Alfuzosin hydrochloride extended-release tablets are not indicated for use in women, and there are no studies of alfuzosin in pregnant women.
Alfuzosin was not teratogenic, embryotoxic or fetotoxic in rats at plasma exposure levels (based on AUC of unbound drug) up to 1200 times (maternal oral dose of 250 mg/kg/day) the maximum recommended human dose (MRHD) of 10 mg. In rabbits administered up to 3 times the MRHD (based on body surface area) (maternal oral dose of 100 mg/kg/day) no embryofetal toxicity or teratogenicity was observed. Gestation was slightly prolonged in rats at exposure levels (based on AUC of unbound drug) approximately 12 times (greater than 5 mg/kg/day oral maternal dose) the MRHD, but difficulties with parturition were not observed.
Alfuzosin hydrochloride extended-release tablets are not indicated for use in the pediatric population.
Additional information regarding a clinical study in which efficacy was not demonstrated in pediatric patients ages 2 to 16 years is approved for Sanofi-Aventis U.S. LLC’s alfuzosin hydrochloride extended-release tablets. However, due to Sanofi-Aventis U.S. LLC’s marketing exclusivity rights, this drug is not labeled with that pediatric information.
Of the total number of subjects in clinical studies of alfuzosin hydrochloride, 48% were 65 years of age and over, whereas 11% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) ]
Systemic exposure was increased by approximately 50% in pharmacokinetic studies of patients with mild, moderate, and severe renal impairment [see Clinical Pharmacology (12.3)]. In phase 3 studies, the safety profile of patients with mild (n=172) or moderate (n=56) renal impairment was similar to the patients with normal renal function in those studies. Safety data are available in only a limited number of patients (n=6) with creatinine clearance below 30 mL/min; therefore, caution should be exercised when alfuzosin hydrochloride is administered in patients with severe renal impairment [see Warnings and Precautions (5.2)].
The pharmacokinetics of alfuzosin hydrochloride have not been studied in patients with mild hepatic impairment. Alfuzosin hydrochloride is contraindicated for use in patients with moderate or severe hepatic impairment [see Contraindications (4), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].
Should overdose of alfuzosin hydrochloride extended-release tablets lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, then the administration of intravenous fluids should be considered. If necessary, vasopressors should then be used, and the renal function should be monitored and supported as needed. Alfuzosin is 82% to 90% protein bound; therefore, dialysis may not be of benefit.
Each alfuzosin hydrochloride extended-release tablet contains 10 mg alfuzosin hydrochloride as the active ingredient. Alfuzosin hydrochloride is a white to off-white powder that melts at 231° to 233°C. It is freely soluble in water, sparingly soluble in alcohol, and practically insoluble in dichloromethane.
Alfuzosin hydrochloride is (R,S)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furancarboxamide hydrochloride. The empirical formula of alfuzosin hydrochloride is C19 H27 N5 O4 •HCl. The molecular weight of alfuzosin hydrochloride is 425.92. Its structural formula is:
The tablet also contains the following inactive ingredients: dibasic calcium phosphate dihydrate (USP), hydroxypropyl methylcellulose (USP), magnesium stearate (NF), polyvinyl acetate phtalate (NF) and yellow ferric oxide (NF).
Alfuzosin is a selective antagonist of post-synaptic alpha1 -adrenoreceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra.
Alfuzosin exhibits selectivity for alpha adrenergic receptors in the lower urinary tract. Blockade of these adrenoreceptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow and a reduction in symptoms of BPH.
Cardiac Electrophysiology The effect of 10 mg and 40 mg alfuzosin on QT interval was evaluated in a double-blind, randomized, placebo and active-controlled (moxifloxacin 400 mg), 4-way crossover single dose study in 45 healthy white male subjects aged 19 to 45 years. The QT interval was measured at the time of peak alfuzosin plasma concentrations. The 40 mg dose of alfuzosin was chosen because this dose achieves higher blood levels than those achieved with the co-administration of alfuzosin hydrochloride extented-release tablets and ketoconazole 400 mg. Table 3 summarizes the effect on uncorrected QT and mean corrected QT interval (QTc) with different methods of correction (Fridericia, population-specific and subject-specific correction methods) at the time of peak alfuzosin plasma concentrations. No single one of these correction methodologies is known to be more valid. The mean change of heart rate associated with a 10 mg dose of alfuzosin in this study was 5.2 beats/minute and 5.8 beats/minute with 40 mg alfuzosin. The change in heart rate with moxifloxacin was 2.8 beats/minute.
Table 3. Mean QT and QTc changes in msec (95% CI) from baseline at Tmax (relative to placebo) with different methodologies to correct for effect of heart rate.
|Alfuzosin 10 mg||-5.8 (-10.2, -1.4)||4.9 (0.9, 8.8)||1.8 (-1.4, 5.0)||1.8 (-1.3, 5.0)|
|Alfuzosin 40 mg||-4.2 (-8.5, 0.2)||7.7 (1.9, 13.5)||4.2 (-0.6, 9.0)||4.3 (-0.5, 9.2)|
|Moxifloxacin* 400 mg||6.9(2.3, 11.5)||12.7 (8.6, 16.8)||11.0 (7.0, 15.0)||11.1(7.2, 15.0)|
The QT effect appeared greater for 40 mg compared to 10 mg alfuzosin. The effect of the highest alfuzosin dose (four times the therapeutic dose) studied did not appear as large as that of the active control moxifloxacin at its therapeutic dose. This study, however, was not designed to make direct statistical comparisons between the drugs or the dose levels. There has been no signal of Torsade de Pointes in the extensive post-marketing experience with alfuzosin outside the United States.
A separate post-marketing QT study evaluated the effect of the co-administration of 10 mg alfuzosin with a drug of similar QT effect size. In this study, the mean placebo-subtracted QTcF increase of alfuzosin 10 mg alone was 1.9 msec (upperbound 95% CI, 5.5 msec). The concomitant administration of the two drugs showed an increased QT effect when compared with either drug alone. This QTcF increase [5.9 msec (UB 95% CI, 9.4 msec)] was not more than additive. Although this study was not designed to make direct statistical comparisons between drugs, the QT increase with both drugs given together appeared to be lower than the QTcF increase seen with the positive control moxifloxacin 400 mg [10.2 msec (UB 95% CI, 13.8 msec)]. The clinical impact of these QTc changes is unknown.
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