Alfuzosin Hydrochloride

The tablet also contains the following inactive ingredients: hypromellose, lactose monohydrate, povidone and magnesium stearate.

Meets USP Dissolution Test 4.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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 coadministration of alfuzosin hydrochloride extended-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.

The QT effect appeared greater for 40 mg compared to 10 mg alfuzosin. The effect of the highest alfuzosin dose (4 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 coadministration 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.

12.3 Pharmacokinetics

The pharmacokinetics of alfuzosin have been evaluated in adult healthy male volunteers after single and/or multiple administration with daily doses ranging from 7.5 mg to 30 mg, and in patients with BPH at doses from 7.5 mg to 15 mg.

Absorption

The absolute bioavailability of alfuzosin hydrochloride extended-release tablets 10 mg under fed conditions is 49%. Following multiple dosing of 10 mg alfuzosin hydrochloride extended-release tablets under fed conditions, the time to maximum concentration is 8 hours. C_max and AUC_0-24 are 13.6 (SD = 5.6) ng/mL and 194 (SD = 75) ng·h/mL, respectively. Alfuzosin exhibits linear kinetics following single and multiple dosing up to 30 mg. Steady-state plasma levels are reached with the second dose of alfuzosin hydrochloride extended-release tablets administration. Steady-state alfuzosin plasma concentrations are 1.2- to 1.6-fold higher than those observed after a single administration.

As illustrated in Figure 1, the extent of absorption is 50% lower under fasting conditions. Therefore, alfuzosin hydrochloride extended-release tablets should be taken with food and with the same meal each day [see Dosage and Administration (2)].

Distribution

The volume of distribution following intravenous administration in healthy male middle-aged volunteers was 3.2 L/kg. Results of in vitro studies indicate that alfuzosin is moderately bound to human plasma proteins (82% to 90%), with linear binding over a wide concentration range (5 to 5,000 ng/mL).

Metabolism

Alfuzosin undergoes extensive metabolism by the liver, with only 11% of the administered dose excreted unchanged in the urine. Alfuzosin is metabolized by three metabolic pathways: oxidation, O-demethylation, and N-dealkylation. The metabolites are not pharmacologically active. CYP3A4 is the principal hepatic enzyme isoform involved in its metabolism.

Excretion

Following oral administration of ¹⁴C-labeled alfuzosin solution, the recovery of radioactivity after 7 days (expressed as a percentage of the administered dose) was 69% in feces and 24% in urine. Following oral administration of alfuzosin hydrochloride extended-release tablets 10 mg, the apparent elimination half-life is 10 hours.

Specific Populations

In a pharmacokinetic assessment during phase 3 clinical studies in patients with BPH, there was no relationship between peak plasma concentrations of alfuzosin and age. However, trough levels were positively correlated with age. The concentrations in subjects ≥ 75 years of age were approximately 35% greater than in those below 65 years of age.

The pharmacokinetic profiles of alfuzosin hydrochloride extended-release tablets 10 mg in subjects with normal renal function (CL_CR > 80 mL/min), mild impairment (CL_CR 60 to 80 mL/min), moderate impairment (CL_CR 30 to 59 mL/min) and severe impairment (CL_CR < 30 mL/min) were compared. These clearances were calculated by the Cockcroft-Gault formula. Relative to subjects with normal renal function, the mean C_max and AUC values were increased by approximately 50% in patients with mild, moderate, or severe renal impairment [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].

The pharmacokinetics of alfuzosin have not been studied in patients with mild hepatic impairment. In patients with moderate or severe hepatic insufficiency (Child-Pugh categories B and C), the plasma apparent clearance (CL/F) was reduced to approximately one-third to one-fourth that observed in healthy subjects. This reduction in clearance results in 3- to 4-fold higher plasma concentrations of alfuzosin in these patients compared to healthy subjects. Therefore, alfuzosin hydrochloride extended-release tablets are contraindicated in patients with moderate to severe hepatic impairment [see Contraindications (4), Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].

Alfuzosin hydrochloride extended-release tablets are not indicated for use in the pediatric population [see Indications and Usage (1.1) and Use in Specific Populations (8.4)].

Drug-Drug Interactions

CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of alfuzosin.

Repeated oral administration of 400 mg/day of ketoconazole, a potent inhibitor of CYP3A4, increased alfuzosin C_max by 2.3-fold and AUC_last by 3.2-fold, following a single 10 mg dose of alfuzosin.

In another study, repeated oral administration of a lower (200 mg/day) dose of ketoconazole increased alfuzosin C_max by 2.1-fold and AUC_last by 2.5-fold, following a single 10 mg dose of alfuzosin.

Therefore, alfuzosin hydrochloride extended-release tablets are contraindicated for coadministration with potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, or ritonavir) because of increased alfuzosin exposure [see Contraindications (4), Warnings and Precautions (5.4) and Drug Interactions (7.1)].

Repeated coadministration of 240 mg/day of diltiazem, a moderately-potent inhibitor of CYP3A4, with 7.5 mg/day (2.5 mg 3 times daily) alfuzosin (equivalent to the exposure with alfuzosin hydrochloride extended-release tablets) increased the C_max and AUC_0-24 of alfuzosin 1.5- and 1.3-fold, respectively. Alfuzosin increased the C_max and AUC_0-12 of diltiazem 1.4-fold. Although no changes in blood pressure were observed in this study, diltiazem is an antihypertensive medication and the combination of alfuzosin hydrochloride extended-release tablets and antihypertensive medications has the potential to cause hypotension in some patients [see Warnings and Precautions (5.1)].

In human liver microsomes, at concentrations that are achieved at the therapeutic dose, alfuzosin did not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6 or 3A4 isoenzymes. In primary culture of human hepatocytes, alfuzosin did not induce CYP1A, 2A6 or 3A4 isoenzymes.

Multiple dose administration of an immediate-release tablet formulation of alfuzosin 5 mg twice daily for 6 days to six healthy male volunteers did not affect the pharmacological response to a single 25 mg oral dose of warfarin.

Repeated coadministration of alfuzosin hydrochloride extended-release tablets 10 mg and digoxin 0.25 mg/day for 7 days did not influence the steady-state pharmacokinetics of either drug.

Repeated administration of 1 g/day cimetidine increased both alfuzosin C_max and AUC values by 20%.

Single administration of 100 mg atenolol with a single dose of 2.5 mg of an immediate-release alfuzosin tablet in eight healthy young male volunteers increased alfuzosin C_max and AUC values by 28% and 21%, respectively. Alfuzosin increased atenolol C_max and AUC values by 26% and 14%, respectively. In this study, the combination of alfuzosin with atenolol caused significant reductions in mean blood pressure and in mean heart rate. [see Warnings and Precautions (5.1)].

Single administration of 25 mg hydrochlorothiazide did not modify the pharmacokinetic parameters of alfuzosin. There was no evidence of pharmacodynamic interaction between alfuzosin and hydrochlorothiazide in the eight patients in this study.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of a drug-related increase in the incidence of tumors in mice following dietary administration of 100 mg/kg/day alfuzosin for 98 weeks (13 and 15 times the maximum recommended human dose [MRHD] of 10 mg based on AUC of unbound drug) in females and males, respectively. The highest dose tested in female mice may not have constituted a maximally tolerated dose. Likewise, there was no evidence of a drug-related increase in the incidence of tumors in rats following dietary administration of 100 mg/kg/day alfuzosin for 104 weeks (53 and 37 times the MRHD in females and males, respectively).

Alfuzosin showed no evidence of mutagenic effect in the Ames and mouse lymphoma assays, and was free of any clastogenic effects in the Chinese hamster ovary cell and in vivo mouse micronucleus assays. Alfuzosin treatment did not induce DNA repair in a human cell line.

There was no evidence of reproductive organ toxicity when male rats were administered oral doses of several hundred times (250 mg/kg/day for 26 weeks) the MRHD of alfuzosin. No impairment of fertility was observed following oral (gavage) administration to male rats at doses of up to 125 mg/kg/day for 70 days. Estrous cycling was inhibited in rats and dogs at approximately 12 and 18 times the MRHD respectively (doses of 25 mg/kg and 20 mg/kg, respectively), but did not result in impaired fertility in female rats.

14 CLINICAL STUDIES

Three randomized placebo-controlled, double-blind, parallel-arm, 12-week trials were conducted with the 10 mg daily dose of alfuzosin. In these three trials, 1,608 patients [mean age 64.2 years, range 49 to 92 years; Caucasian (96.1%), Black (1.6%), Asian (1.1%), Other (1.2%)] were randomized and 473 patients received alfuzosin hydrochloride extended-release tablets 10 mg daily. Table 4 provides the results of the three trials that evaluated the 10 mg dose.

There were two primary efficacy variables in these three studies. The International Prostate Symptom Score (IPSS, or AUA Symptom Score) consists of seven questions that assess the severity of both irritative (frequency, urgency, nocturia) and obstructive (incomplete emptying, stopping and starting, weak stream, and pushing or straining) symptoms, with possible scores ranging from 0 to 35 with higher numerical scores on the IPSS total symptom score representing greater severity of symptoms. The second efficacy variable was peak urinary flow rate. The peak flow rate was measured just prior to the next dose in study 2 and on average at 16 hours post-dosing in trials 1 and 3.

There was a statistically significant reduction from baseline to last assessment (Week 12) in the IPSS total symptom score versus placebo in all three studies, indicating a reduction in symptom severity (Table 5 and Figures 2, 3, and 4).

Peak urinary flow rate was increased statistically significantly from baseline to last assessment (Week 12) versus placebo in trials 1 and 2 (Table 5 and Figures 5, 6 and 7).

Mean total IPSS decreased at the first scheduled observation at Day 28 and mean peak flow rate increased starting at the first scheduled observation at Day 14 in trials 2 and 3 and Day 28 in trial 1.

16 HOW SUPPLIED/STORAGE AND HANDLING

Alfuzosin Hydrochloride Extended-release Tablets, USP are available containing 10 mg of alfuzosin hydrochloride, USP.

The 10 mg tablets are white to off-white, round, unscored tablets debossed with M on one side of the tablet and Z5 on the other side.

NDC 0378-5005-77
bottles of 90 tablets

NDC 0378-5005-05
bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from light and moisture.

Keep alfuzosin hydrochloride extended-release tablets out of the reach of children.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Patient Information Leaflet with each prescription.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling.

17.1 Hypotension/Syncope

Patients should be told about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when beginning alfuzosin hydrochloride extended-release tablets, and they should be cautioned about driving, operating machinery, or performing hazardous tasks during this period. This is important for those with low blood pressure or who are taking antihypertensive medications or nitrates [see Warnings and Precautions (5.1)].

17.2 Intraoperative Floppy Iris Syndrome

Patients should be instructed to tell their ophthalmologist about their use of alfuzosin hydrochloride extended-release tablets before cataract surgery or other procedures involving the eyes, even if the patient is no longer taking alfuzosin hydrochloride extended-release tablets [see Warnings and Precautions (5.6)].

17.3 Priapism

Patients should be advised about the possibility of priapism resulting from treatment with alfuzosin hydrochloride extended-release tablets and medications in the same class. Although this reaction is extremely rare, but if not brought to immediate medical attention, can lead to permanent erectile dysfunction (impotence) [see Warnings and Precautions (5.7)].

17.4 Instructions of Use

Alfuzosin hydrochloride extended-release tablets should be taken with food and with the same meal each day.

Patients should be advised not to crush or chew alfuzosin hydrochloride extended-release tablets.

PATIENT INFORMATION LEAFLET
ALFUZOSIN HYDROCHLORIDE EXTENDED-RELEASE TABLETS, USP
(al fue′ zoe sin hye′′ droe klor′ ide)
10 mg

Read the Patient Information that comes with alfuzosin hydrochloride extended-release tablets before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or your treatment. You and your doctor should talk about all your medicines, including alfuzosin hydrochloride extended-release tablets, now and at your regular checkups.

What is the most important information I should know about alfuzosin hydrochloride extended-release tablets?

Alfuzosin hydrochloride extended-release tablets can cause serious side effects, including a sudden drop in blood pressure, especially when you start treatment. This may cause you to faint, or to feel dizzy or lightheaded. 

• •Your risk of having this problem may be increased if you take alfuzosin hydrochloride extended-release tablets with certain other medicine that lowers blood pressure:
  • •medicines for high blood pressure
  • •a nitrate medicine for angina

    Ask your doctor if you are not sure if you are taking one of these medicines.

• • Do not drive, operate machinery, or do any dangerous activities until you know how alfuzosin hydrochloride extended-release tablets affect you. This is especially important if you already have a problem with low blood pressure or take medicines to treat high blood pressure.
• •If you begin to feel dizzy or lightheaded, lie down with your legs and feet up. If your symptoms do not improve call your doctor.

See the section “What are the possible side effects of alfuzosin hydrochloride extended-release tablets?” for more information about side effects.

What are alfuzosin hydrochloride extended-release tablets?

Alfuzosin hydrochloride extended-release tablets are a prescription medicine that is called an “alpha-blocker”. Alfuzosin hydrochloride extended-release tablets are used in adult men to treat the symptoms of benign prostatic hyperplasia (BPH). Alfuzosin hydrochloride extended-release tablets may help to relax the muscles in the prostate and the bladder which may lessen the symptoms of BPH and improve urine flow.

Before prescribing alfuzosin hydrochloride extended-release tablets, your doctor may examine your prostate gland and do a blood test called a prostate specific antigen (PSA) test to check for prostate cancer. Prostate cancer and BPH can cause the same symptoms. Prostate cancer needs a different treatment.

Alfuzosin hydrochloride extended-release tablets are not for use in women or children.

Some medicines called “alpha-blockers” are used to treat high blood pressure. Alfuzosin hydrochloride extended-release tablets are not for the treatment of high blood pressure.

Who should not take alfuzosin hydrochloride extended-release tablets?

Do not take alfuzosin hydrochloride extended-release tablets if you:

• •have certain liver problems
• •take antifungal medicines like ketoconazole (Nizarol^®*) or itraconazole (Sporanox^®*)
• •take anti-HIV medicines like ritonavir (Norvir^®*, Kaletra^®*)
• •are allergic to alfuzosin hydrochloride or any of the ingredients in alfuzosin hydrochloride extended-release tablets. See the end of this leaflet for a complete list of ingredients in alfuzosin hydrochloride extended-release tablets.

Before taking alfuzosin hydrochloride extended-release tablets, tell your doctor if you:

• •have liver problems
• •have kidney problems
• •have had low blood pressure, especially after taking another medicine. Signs of low blood pressure are fainting, dizziness, and lightheadedness.
• •have a heart problem called angina
• •or any family members have a rare heart condition known as congenital prolongation of the QT interval.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Some of your other medicines may affect the way alfuzosin hydrochloride extended-release tablets work and cause serious side effects. See “What is the most important information I should know about alfuzosin hydrochloride extended-release tablets?”.

Especially tell your doctor if you take:

• •another alpha blocker medicine
• •a medicine to treat high blood pressure
• •a medicine to treat angina
• •a medicine to treat erectile dysfunction (ED)
• •the antifungal medicines like ketoconazole (Nizoral^®*) or itraconazole (Sporanox^®*)
• •the anti-HIV medicine like ritonavir (Norvir^®*, Kaletra^®*)

Ask your doctor or pharmacist if you are not sure if your medicine is one of those listed above.

What you need to know while taking alfuzosin hydrochloride extended-release tablets

• •If you have an eye surgery for cataract (clouding of the eye) planned, tell your ophthalmologist that you are using alfuzosin hydrochloride extended-release tablets or have previously been treated with an alpha-blocker.

How do I take alfuzosin hydrochloride extended-release tablets?

• •Take alfuzosin hydrochloride extended-release tablets exactly as your doctor prescribes it.
• •Take alfuzosin hydrochloride extended-release tablets after the same meal each day. Do not take it on an empty stomach.
• •Swallow the alfuzosin hydrochloride extended-release tablet whole. Do not crush, split, or chew alfuzosin hydrochloride extended-release tablets.
• •If you take too much alfuzosin hydrochloride extended-release tablets call your local poison control center or emergency room right away.

What are the possible side effects of alfuzosin hydrochloride extended-release tablets?

Alfuzosin hydrochloride extended-release tablets can cause serious side effects, including:

• • See “What is the most important information I should know about alfuzosin hydrochloride extended-release tablets?”.
• • A painful erection that will not go away. Alfuzosin hydrochloride extended-release tablets can cause a painful erection (priapism), which cannot be relieved by having sex. If this happens, get medical help right away. If priapism is not treated, you may not be able to get an erection in the future.

The most common side effects with alfuzosin hydrochloride extended-release tablets are:

• •dizziness
• •headache
• •tiredness

Call your doctor if you get any side effect that bothers you.

These are not all the side effects of alfuzosin hydrochloride extended-release tablets. For more information ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store alfuzosin hydrochloride extended-release tablets?

• •Store alfuzosin hydrochloride extended-release tablets at 20° to 25°C (68° to 77°F).
• •Protect from light and moisture.

Keep alfuzosin hydrochloride extended-release tablets and all medicines out of the reach of children.

General information about alfuzosin hydrochloride extended-release tablets:

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use alfuzosin hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not give alfuzosin hydrochloride extended-release tablets to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about alfuzosin hydrochloride extended-release tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about alfuzosin hydrochloride extended-release tablets that is written for health professionals.

You may also call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) for more information.

What are the ingredients of alfuzosin hydrochloride extended-release tablets?

Active ingredient: alfuzosin hydrochloride

Inactive ingredients: hypromellose, lactose monohydrate, povidone and magnesium stearate.

*The brands listed are registered trademarks of their respective owners.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

REVISED SEPTEMBER 2013
AFZN:R4ppt

PRINCIPAL DISPLAY PANEL - 10 mg

NDC 0378-5005-77

Alfuzosin HCl
Extended-release
Tablets, USP
10 mg

PHARMACIST: Dispense the accompanying
Patient Information Leaflet to each patient.

Rx only 90 Tablets

Each tablet contains:
Alfuzosin
hydrochloride, USP 10 mg

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Protect from light and moisture.

Usual Dosage: See accompanying
prescribing information.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Mylan.com

RM5005MM1