PR
APO-ALFUZOSIN
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 11 DOSAGE AND ADMINISTRATION 14 OVERDOSAGE 14 ACTION AND CLINICAL PHARMACOLOGY. 14 STORAGE AND STABILITY 20 DOSAGE FORMS, COMPOSITION AND PACKAGING 21
PHARMACEUTICAL INFORMATION 22 CLINICAL TRIALS 23 DETAILED PHARMACOLOGY 29 TOXICOLOGY 32 REFERENCES 36
PRAPO-ALFUZOSIN Alfuzosin Hydrochloride Prolonged-Release Tablets
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Prolonged-Release Tablets 10 mg | For a complete listing see Dosage Forms, Composition and Packaging section. |
APO-ALFUZOSIN (alfuzosin hydrochloride) is indicated for:
Benign Prostatic Hyperplasia
APO-ALFUZOSIN is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).
Acute Urinary Retention
APO-ALFUZOSIN is indicated as adjunctive therapy with urethral catheterization for Acute Urinary Retention related to BPH and management following catheter removal.
Geriatrics (>65 years of age):
Alfuzosin hydrochloride has been found to be safe and effective when administered at the therapeutic dose (10 mg once-daily) to patients over the age of 65 years.
Women:
APO-ALFUZOSIN is not indicated nor recommended for use in women.
Pediatrics (<18 years):
APO-ALFUZOSIN is not indicated for use in children.
APO-ALFUZOSIN (alfuzosin hydrochloride) is contraindicated in: Patients with a known hypersensitivity to APO-ALFUZOSIN or to any ingredient in the formulation. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. Patients with moderate to severe hepatic insufficiency, since alfuzosin blood levels are increased in these patients (See ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations and Conditions, Hepatic Insufficiency). Combination with other alpha1-blockers. Combination with potent CYP3A4 inhibitors such as ketoconazole, ritonavir and itroconazole, because alfuzosin blood levels and exposure (AUC) are increased (See DRUG INTERACTIONS, Overview).
General
Prostatic carcinoma: Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently coexist. Therefore, patients thought to have BPH should be examined prior to starting therapy with APO-ALFUZOSIN (alfuzosin hydrochloride) to rule out the presence of carcinoma of the prostate. Patients with known hypersensitivity to alpha1-blockers should be closely monitored while on APO-ALFUZOSIN. There are no data available on the effect on driving vehicles. Adverse reactions such as vertigo, dizziness and asthenia may occur essentially at the beginning of treatment. This has to be taken into consideration when driving vehicles and operating machines. Patient should be warned that the tablet should be swallowed whole. Any other mode of administration, such as crunching, crushing, chewing, grinding or pounding to powder should be prohibited. These actions may lead to inappropriate release and absorption of the drug and therefore possible early adverse reactions (see DOSAGE AND ADMINISTRATION, Administration).
Cardiovascular
APO-ALFUZOSIN is not indicated for the treatment of hypertension.
As with all alpha1-blockers in some patients, in particular, patients receiving antihypertensive medications, postural hypotension with or without dizziness or other symptoms may develop within a few hours following administration of APO-ALFUZOSIN. However, these effects are usually transient, occur at the beginning of treatment and do not usually prevent the continuation of treatment. In such cases, the patients should lie down until the symptoms have completely disappeared. As with other alpha1-blockers (alpha1-adrenergic blocking agents), there is a potential for syncope. Patients beginning treatment should be warned of the possible occurrence of such events. Care should be taken when APO-ALFUZOSIN is administered to patients with symptomatic orthostatic hypotension or patients who have had a pronounced hypotensive response to another alpha1-blocker. As with all alpha1-blockers, alfuzosin has been observed to increase heart rate. Caution should be taken in patients with histories of tachyarrhythmia or with certain cardiovascular conditions, such as myocardial ischemia. The heart rate increasing effects of alfuzosin are additive to those of other heart rate increasing drugs (see DRUG INTERACTIONS). Coronary insufficiency: Specific treatment for coronary insufficiency should be continued; however, if angina pectoris reappears or becomes worse, APO-ALFUZOSIN should be discontinued. Patients with congenital QTc prolongation, with a known history of acquired QTc prolongation or who are taking drugs known to increase the QTc interval should be evaluated before and during the administration of alfuzosin. Co-administration of alfuzosin with a drug known to be a QTc prolonging drug should be evaluated by the physician based on individual patient's condition (See ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, Electrocardiography).
Ophthalmologic
Intraoperative Floppy Iris Syndrome (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with some alpha-1-blockers. Cases of IFIS have been observed with alfuzosin hydrochloride use. Ophthalmic surgeons should be informed in advance of cataract surgery of current or past use of alpha-1-blockers, as IFIS may lead to increased procedural complications. The ophthalmologists should be prepared for possible modifications to their surgical technique.Special Populations
APO-ALFUZOSIN is not indicated nor recommended for use in women. No embryotoxic and/or teratogenic effects in the rat and rabbit were observed with alfuzosin hydrochloride. Parameters of male and female fertility, parturition, lactation and pup development were not modified by alfuzosin hydrochloride.
APO-ALFUZOSIN is not indicated nor recommended for use in women. It is unknown if the drug is excreted in human milk.
APO-ALFUZOSIN is not indicated for use in children.
The pharmacokinetics parameters (Cmax and AUC) are not increased in elderly patients when compared to healthy male volunteers. Alfuzosin hydrochloride has been found to be a safe and effective alpha1-blockers when administered at the therapeutic dose (10 mg once-daily) to patients over the age of 65 years.
Adverse Drug Reaction Overview
Dizziness and headache are the most frequent adverse drug reactions with alfuzosin hydrochloride. Alfuzosin hydrochloride was associated with a low incidence of postural symptoms. As with all alpha1-blockers, there is also a potential for syncope. Alfuzosin hydrochloride was not associated with deleterious effects on sexual function.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Safety information was derived from placebo-controlled clinical trials involving 1,608 men with BPH. The safety profile of alfuzosin hydrochloride in the ALFAUR study which included 363 patients with Acute Urinary Retention due to BPH was similar to the safety profile reported in previous BPH studies. In the BPH studies, 4% of patients taking alfuzosin hydrochloride 10 mg prolonged release tablets withdrew from the study due to adverse events, compared with 3% in the placebo group. Dizziness and headache were the most frequent cause in each of the groups, although no single symptom was predominant. The withdrawal rate was similar in the alfuzosin hydrochloride group following long-term use in open-label extension studies for up to 1 year. Table 1 summarizes the treatment-emergent adverse events that occurred in >=2% of patients receiving alfuzosin hydrochloride prolonged-release tablets and placebo, in three 3-month trials. In general, the adverse events seen in long-term use were similar in type and frequency to the events described below for the 3-month trials.
Table 1 - Treatment-Emergent Adverse Events Occurring in >=2% of Patients with BPH treated with Alfuzosin Hydrochloride and with Placebo in 3-Month Placebo-Controlled Clinical Studies
| Alfuzosin Placebo Hydrochloride Adverse Event (N=678) (N=473) |
| General Disorders and Administration Site Conditions Fat igue a 12 (1.8%) 13 (2.7%) |
| Musculoskeletal and Connective Tissue Disorders 15 (2.2%) 10 (2.1%) Joint Disorders b |
| Infection and Infestations Upper respiratory tract infection c 23 (3.4%) 29 (6.1%) |
| Nervous System Disorders Dizziness d 19 (2.8%) 27 (5.7%) Headache 12 (1.8%) 14 (3.0%) |
| a Includes: fatigue and asthenia b Includes: arthritis, arthrosis, arthropathy, arthritis aggravated, arthralgia, and bursitis c Includes: upper respiratory tract infection, rhinitis, sinusitis, laryngitis, pharyngitis d Includes: dizziness and malaise |
Less Common Clinical Trial Adverse Drug Reactions (<1%)
The following adverse events, reported by between 1% and 2% of patients receiving alfuzosin hydrochloride prolonged-release tablets and placebo are listed and are as follows:
Table 2 - Treatment-Emergent Adverse Events Occurring Between 1% and 2% of Patients with BPH treated with Alfuzosin Hydrochloride Prolonged-release Tablets and Placebo in 3-Month Placebo-Controlled Clinical Studies
| Adverse Event | Placebo (N=678) | Alfuzosin Hydrochloride (N=473) |
| Gastrointestinal Disorders | ||
| Abdominal Pain | 7 (1.0) | 7 (1.5) |
| Dyspepsia | 7 (1.0) | 6 (1.3) |
| Constipation | 3 (0.4) | 5 (1.1) |
| Nausea | 4 (0.6) | 5 (1.1) |
| General Disorders and Administration | Site | |
| Conditions | ||
| Influenza-like symptoms | 14 (2.1) | 9 (1.9) |
| Pain | 4 (0.6) | 7 (1.5) |
| Infection and Infestations | ||
| Bronchitis | 5 (0.7) | 7 (1.5) |
| Injury, Poisoning and Procedural Complications | ||
| Inflicted injury a | 3 (0.4) | 6 (1.3) |
| Musculosqueletal and Connective Tissue Disorders | ||
| Back pain b | 11(1.6) | 7 (1.5) |
| Reproductive System and Breast Disorders | ||
| Impotence | 4 (0.6) | 7 (1.5) |
| a Includes: bite and inflicted injury | ||
| b Includes: ischial neuralgia, neuralgia, neuropathy, back pain, and lumbar disc lesion | ||
Reproductive System and Breast Disorders
Impotence and other events related to sexual function are commonly associated with other alpha1-blockers, however, with alfuzosin hydrochloride, there were minimal effects regarding sexual function and ejaculatory disorders/abnormalities with no reports of priapism. Also, no patient discontinued treatment with alfuzosin hydrochloride due to ejaculation disorders. The reported incidence of ejaculation disorders was not associated with the study drug and is consistent with that reported in the untreated population.
Vascular Disorders
Signs and Symptoms of Orthostasis in Clinical Studies
The number of patients with symptoms of orthostasis are summarized in Table 3.
Table 3 - Number (%) of Patients with BPH with Symptoms Possibly Associated with Orthostasis in 3-Month Placebo-Controlled Clinical Studies
Symptoms
Placebo (N=678)
Alfuzosin Hydrochloride Prolonged-release tablets
(N=473)
Dizziness 19 (2.8%) 27 (5.7%)
Hypotension or postural hypotension 0 2 (0.4%)
Syncope 0 1 (0.2%)
Multiple testing for blood pressure changes or orthostatic hypotension was conducted in the three controlled studies. These tests were considered positive for blood pressure decrease if (1) supine systolic blood pressure was <= 90 mmHg, with a decrease >= 20 mmHg versus baseline, and/or (2) supine diastolic blood pressure was <= 50 mmHg, with a decrease >= 15 mmHg versus baseline. The tests were considered positive for orthostatic hypotension if there was a decrease in systolic blood pressure of >= 20 mmHg upon standing from the supine position during the orthostatic tests. The percentage of patients with a positive test at any visit was 7.7% for placebo and 6.6% for alfuzosin hydrochloride prolonged-release tablets, as shown in Table 4.
Table 4 - Number (%) of Patients with BPH with Clinically Meaningful Decreases in Blood Pressure at Any Visit in 3-Month Placebo-Controlled Clinical Studies
Clinically Meaningful Change
Placebo (N=674)
Alfuzosin Hydrochloride Prolonged-Release Tablets
(N=469)
Decreased systolic blood pressure 0 1 (0.2%)
Decreased diastolic blood pressure 3 (0.4%) 4 (0.9%)
Positive orthostatic test 52 (7.7%) 31a (6.6%)
a
N = 471
A subset of patients from Study 1 had blood pressure measurements 12 to 16 hours after the first dose to assess the potential to produce orthostatic hypotension. None of the 35 alfuzosin hydrochloride prolonged release tablet-treated patients showed a positive test for systolic, diastolic, or orthostatic blood pressure change. No age effect on the overall incidence of patients reporting adverse events was observed in the alfuzosin hydrochloride prolonged-release tablet group; elderly patients (>= 65 years) did not experience more vasodilatory adverse events than the younger patients.
Post-Market Adverse Drug Reactions
The following adverse events have also been reported in postmarketing experience: The following frequency rating is used; very common (>= 10%), Common (>= 1% and < 10%), Uncommon (>= 0.1% and < 1%), Rare (>= 0.01% and < 0.1%), Very rare (< 0.01%)
Cardiac Disorders
: Uncommon:tachycardia
Very Rare:angina pectoris in patients with pre-existing coronary artery disease (see also WARNINGS AND PRECAUTIONS, Cardiovascular). Isolated spontaneous cases of QT interval prolongation, ventricular arrhythmias, including Torsade de Pointes, ventricular tachycardia and fibrillation have been reported particularly in patients with preexisting cardiovascular diseases; however, a relationship between these adverse events and the alfuzosin hydrochloride treatment was not clearly established due to concomitant cardiac disorders, concomitant medications or absence of pre-treatment ECG measurement.
Vascular Disorders:
Uncommon:flushing
Gastrointestinal disorders
: Uncommon:diarrhea
General Disorders and Administration Site Conditions
: Uncommon:edema, chest pain
Ear and Labyrinth Disorders:
Uncommon:vertigo
Eye disorders:
Cases of intraoperative floppy iris syndrome have been reported (see WARNINGS AND PRECAUTIONS, Ophthalmologic).
Hepato-biliary disorders:
Cases of hepatocellular injury and cholestatic liver disease have been reported.
Respiratory, thoracic and mediastinal disorders:
Uncommon:Rhinitis.
Skin and Subcutaneous Tissue Disorders:
Uncommon:rash, pruritus Very rare:urticaria, angioedema
Overview
APO-ALFUZOSIN (alfuzosin hydrochloride) is not an inducer or an inhibitor of any of the principal hepatic enzymes involved in the metabolism of other drugs. CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of APO- ALFUZOSIN. Potent CYP3A4 inhibitors, such as ketoconazole, itraconazole and ritonavir, increased alfuzosin hydrochloride blood levels and exposure (AUC). Therefore, APO-ALFUZOSIN should not be co-administered with potent inhibitors of CYP3A4 (See CONTRAINDICATIONS). See Drug-Drug Interactions for details of increased alfuzosin hydrochloride blood levels. As this is only a partial list, the physician is advised to consult current scientific literature regarding other CYP 3A4 competitive inhibitors prior to prescribing APO-ALFUZOSIN if other concomitant medications are used as high blood levels of APO-ALFUZOSIN can result. It is not known how combined exposure of any medications metabolized by the CYP3A4 hepatic enzyme isoform (such as modern alpha1-blockers), herbal remedies (particularly St. John's Wort, Milk thistle) and grapefruit juice may influence the overall efficacy and unwanted side effects of these medications, therefore, caution should be exercised. APO-ALFUZOSIN should be prescribed carefully in combination with antihypertensive drugs (see WARNINGS AND PRECAUTIONS, Cardiovascular and Drug-Drug Interactions, Cardiovascular Drugs).
Drug-Drug Interactions
Imidazole
Ketoconazole
CYP3A4 is the principal hepatic enzyme involved in the metabolism of APO-ALFUZOSIN. Ketoconazole is a strong-potency inhibitor of CYP3A4. Repeated 200 mg daily dosing of
ketoconazole, for seven days
under fed condition. Other parameters such as t
and t
were not modified. The 8-day repeated administration of ketoconazole 400 mg daily
.
Alpha1-Blocker
APO-ALFUZOSIN should not be used in combination with other alpha1-blockers (see CONTRAINDICATIONS).
Anticoagulant
Warfarin
The potential drug interactions of alfuzosin hydrochloride with warfarin were studied in clinical trials. The results showed that alfuzosin hydrochloride can be prescribed without risk of interactions in combination with warfarin.
Beta-Blocker
Atenolol
The potential drug interactions of alfuzosin hydrochloride with atenolol were studied in clinical trials. The results showed that alfuzosin hydrochloride may be used with atenolol taking into account the hypotensive effects specific to drugs in this group.
Calcium Channel Blocker
Diltiazem
Repeated coadministration of 240 mg/day of diltiazem, a moderate-potency inhibitor of CYP3A4, with 7.5 mg/day alfuzosin (equivalent to the exposure with alfuzosin hydrochloride prolonged-release tablets) increased the Cmax and AUC0-24 of alfuzosin 1.5- and 1.3-fold, respectively. Alfuzosin increased the Cmax and AUC0-12 of diltiazem 1.4-fold. No changes in blood pressure were observed.
Cardiotonic Glycoside
Digoxin
Repeated coadministration of alfuzosin hydrochloride and digoxin for 7 days did not influence the steady-state pharmacokinetics of either drug.
Diuretic
Hydrochlorothiazide
The potential drug interactions of alfuzosin hydrochloride with hydrochlorothiazide were studied in clinical trials. The results showed that alfuzosin hydrochloride can be prescribed without risk of interactions in combination with hydrochlorothiazide.
Nitrates
APO-ALFUZOSIN should be prescribed carefully in combination with nitrates.
Histamine H2 Receptor Antagonist
Cimetidine
The potential drug interactions of alfuzosin hydrochloride with cimetidine were studied in clinical trials. The results showed that alfuzosin hydrochloride can be prescribed without risk of interactions in combination with cimetidine.
Inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5)
Tadalafil
The potential drug interaction of alfuzosin hydrochloride with tadalafil was studied in a clinical trial. The results showed that there is no clinically significant hemodynamic interaction between alfuzosin hydrochloride 10 mg once daily and tadalafil 20 mg. APO-ALFUZOSIN can be prescribed in combination with tadalafil.
Sildenafil
The effect on QT/QTc interval of the combination of alfuzosin 10 mg and sildenafil 100 mg has been studied in an electrophysiology trial (See ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, Electrocardiography).
Drug-Food Interactions
APO-ALFUZOSIN should be taken after a meal. It is not known how combined exposure of grapefruit juice may influence the overall efficacy and unwanted side effects of these types of medications, therefore, caution should be exercised.
Drug-Herb Interactions
Interactions with herbal products have not been established. It is not known how combined exposure of herbal remedies (particularly St. John's Wort, Milk thistle) may influence the overall efficacy and unwanted side effects of these medications, therefore, caution should be exercised when taking herbal remedies with these types of medications.
Drug-Laboratory Interactions
Treatment with alfuzosin hydrochloride for up to 12 months produced no clinically significant changes in urinalysis, the routine biochemical and hematologic tests as well as in prostate specific antigen (PSA).
Recommended Dose and Dosage Adjustment
The recommended dosage is one 10 mg APO-ALFUZOSIN (alfuzosin hydrochloride) tablet daily to be taken after the same meal each day.
The recommended dosage is one 10 mg APO-ALFUZOSIN tablet daily after a meal to be taken from the first day of catheterization and continued beyond catheter removal unless there is a relapse of acute urinary retention or disease progression.
Administration
The tablet should be swallowed whole. Any other mode of administration, such as crunching, crushing, chewing, grinding or pounding to powder should be prohibited. These actions may lead to an inappropriate release and absorption of the drug and therefore possible early adverse reactions.
For management of a suspected drug overdose, contact your regional Poison Control Centres. Should overdose of APO-ALFUZOSIN (alfuzosin hydrochloride) 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, vasopressor should then be used and the renal function should be monitored and supported as needed. Alfuzosin hydrochloride is 87% (82 - 90%) protein-bound, therefore, dialysis may not be of benefit.
Mechanism of Action
APO-ALFUZOSIN (alfuzosin hydrochloride), indicated for the treatment of benign prostatic hyperplasia (BPH) and as adjunctive therapy with urethral catheterization for acute urinary retention related to BPH and management following catheter removal, is an uroselective antagonist of post-synaptic a1-adrenoceptors located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra.
Pharmacodynamics
The clinical manifestations of benign prostatic hyperplasia are due to bladder outlet obstruction caused by anatomical (static) and functional (dynamic) factors. The static component is related to an increase in prostate size which may not cause symptoms. The dynamic component is related primarily to an increase in smooth muscle tone in the prostate, prostatic capsule, bladder base, bladder neck, and prostatic urethra. This increased tone is mediated by the activation of a1- adrenoceptors and leads to an increased resistance to urinary voiding and the symptoms of BPH such as a hesitant, interrupted, weak stream; urgency and leaking or dribbling; and/or more frequent urination, especially at night. Alfuzosin hydrochloride blocks a1-adrenoceptors leading to a relaxation of the smooth muscle in the bladder neck and prostate. In animal studies, alfuzosin was shown to be functionally uroselective by preferentially decreasing urethral blood pressure over arterial blood pressure. In human tissue, in vitro, alfuzosin has induced preferential a1-adrenoceptor antagonist activity on prostatic cells relative to renal artery cells. This is illustrated in the figure below:
In placebo-controlled clinical studies in patients with BPH, alfuzosin hydrochloride was shown to: significantly increase urine peak flow rate (Qmax) by 30% which is observed after the first dose significantly reduce detrusor pressure and increase bladder capacity significantly reduce residual urine volume These favourable urodynamic effects lead to an improvement of lower tract irritative and obstructive symptoms without any deleterious effect on sexual function. The Quality of Life Index was also significantly improved by 33% in the alfuzosin hydrochloride prolonged-release tablet - treated patients. In addition, the efficacy of alfuzosin 10 mg OD on peak flow rate and the limited effect on blood pressure have been demonstrated to be related to its pharmacokinetic profile. Moreover, the efficacy on peak flow rate is maintained up to 24 hours after intake. A lower frequency of acute urinary retention was observed in the alfuzosin treated patient than in the untreated patient. ElectrocardiographyThe 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 40 mg dose of alfuzosin was chosen because this dose achieves higher blood levels than those achieved with the co-administration of alfuzosin hydrochloride and ketoconazole 400 mg (CYP3A4 inhibitor). QT interval, obtained with 12-lead ECGs, was measured from 2h to 12h post treatment administration. Table 5 summarizes the mean effect and the maximum mean effect on heart rate (HR) and corrected QT interval (QTc) with different methods of correction [Bazett (QTcB), Fridericia (QTcF) and population-specific (QTcN) correction methods]. There is a trend to lower values for QTc interval changes from QTcBAE QTcF AE QTcN, demonstrating the critical role of the correction formula used to minimize the biased overestimation linked to the heart rate increase. The maximum mean change of heart rate associated with a 10 mg dose of alfuzosin in this study was 3.69 beats/minute and 5.45 beats/minute with 40 mg alfuzosin. The change in heart rate with moxifloxacin was 2.85 beats/minute.
| Mean difference | Largest time-matched analysis (bootstrap adjusted) | ||||
| Parameter | Treatment | Mean change from baseline vs placebo | 95% CI (upper bound) | Estimation of largest time- matched mean difference | 95% CI (upper bound) |
| HR (bpm) | Alfuzosin 10 mg | 1.5 | 3.0 | 3.69 | 5.83 |
| Alfuzosin 40 mg | 3.7 | 5.2 | 5.45 | 7.06 | |
| Moxifloxacin * | 1.5 | 3.0 | 2.85 | 4.26 | |
| QTcB (msec) | Alfuzosin 10 mg | 3.3 | 6.9 | 6.08 | 9.59 |
| Alfuzosin 40 mg | 10.8 | 14.4 | 13.27 | 16.71 | |
| Moxifloxacin * | 11.9 | 15.6 | 12.57 | 16.12 | |
| QTcF (msec) | Alfuzosin 10 mg | 1.6 | 4.3 | 4.01 | 6.68 |
| Alfuzosin 40 mg | 6.9 | 9.5 | 10.73 | 13.49 | |
| Moxifloxacin * | 10.3 | 13.0 | 11.17 | 14.06 | |
| QTcN (msec) | Alfuzosin 10 mg | 0.5 | 3.0 | 2.74 | 5.27 |
| Alfuzosin 40 mg | 4.6 | 7.0 | 9.30 | 12.14 | |
| Moxifloxacin * | 9.4 | 11.9 | 10.78 | 13.67 | |
The maximum mean effect on QTcN 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. A separate post-marketing study evaluated the effect of the co-administration of 10 mg alfuzosin and a drug with similar QT effect size. It was a double-blind, randomized, placebo and active- controlled (moxifloxacin 400 mg), 5-way crossover study conducted in 39 healthy white male subjects aged 19 to 46 years. QT interval, obtained with 12-lead ECGs, was measured from 4h to 12h post treatment administration. Maximum mean effect on HR and QT interval were extracted from a time-matched placebo adjusted analysis. In this study, the maximum mean placebo-substracted QTcN increase of alfuzosin 10 mg alone was 4.41 msec (upperbound 95% CI, 7.09 msec), shown in Table 6 below. The concomitant administration of the two drugs (alfuzosin and sildenafil) showed an increased QT effect when compared with either drug alone. This maximum mean QTcN increase [8.27 msec (UB 95% CI, 10.90 msec)] was not more than additive. Although this study was not designed to make direct statistical comparisons between drugs, the maximum mean QTcN increase with both drugs given together appeared to be lower than the maximum mean QTcN increase seen with the positive control moxifloxacin 400 mg [11.44 msec (UB 95% CI, 14.01 msec)]. The combination of alfuzosin + sildenafil produced a statistically significant increase in the mean heart rate [+ 4 bpm, p<0.0001].
| Mean difference | Largest time-matched analysis (bootstrap adjusted) | ||||
| Parameter | Treatment | Mean change from baseline vs placebo | 95% CI (upper bound) | Estimation of largest time- matched mean difference | 95% CI (upper bound) |
| HR (bpm) | Alfuzosin 10 mg | 1.1 | 2.9 | 3.78 | 5.54 |
| Alfuzosin + Sildenafil | 4.0 | 5.8 | 5.53 | 7.25 | |
| Sildenafil 100 mg | 1.4 | 3.2 | 2.13 | 3.82 | |
| Moxifloxacin * | 1.3 | 3.2 | 2.80 | 4.39 | |
| QTcB (msec) | Alfuzosin 10 mg | 5.0 | 8.8 | 7.49 | 10.68 |
| Alfuzosin + Sildenafil | 13.3 | 17.1 | 14.99 | 18.35 | |
| Sildenafil 100 mg | 6.3 | 10.1 | 7.85 | 11.30 | |
| Moxifloxacin * | 9.4 | 13.2 | 17.18 | 20.72 | |
| QTcF (msec) | Alfuzosin 10 mg | 3.7 | 6.6 | 5.72 | 8.19 |
| Alfuzosin + Sildenafil | 9.5 | 12.4 | 10.47 | 12.97 | |
| Sildenafil 100 mg | 4.8 | 7.7 | 6.40 | 8.97 | |
| Moxifloxacin * | 7.8 | 10.7 | 13.80 | 16.48 | |
| QTcN (msec) * * | Alfuzosin 10 mg | 2.2 | 5.1 | 4.41 | 7.09 |
| Alfuzosin + Sildenafil | 7.0 | 10.0 | 8.27 | 10.90 | |
| Sildenafil 100 mg | 3.5 | 6.4 | 5.26 | 7.87 | |
| Moxifloxacin * | 6.5 | 9.4 | 11.44 | 14.01 | |
* *For the analysis of the mean difference, only QTcNi data are available (QT interval corrected by a subject specific formula)
QT interval prolongation has not been studied in patients with BPH, therefore similar data is not available. This population may suffer from other conditions and have a higher risk to develop QT interval prolongation due to concomitant risk factors or pre-existing cardiovascular disorders. Based on individual patient's condition, monitoring for ECG abnormalities should be considered by the physician during treatment.
Pharmacokinetics
Bioavailability is reduced when alfuzosin hydrochloride is administered under fasting conditions. A consistent pharmacokinetic profile is obtained when alfuzosin hydrochloride is administered following a meal. A mean peak plasma concentration of 12.3 +- 6.6 ng/mL is reached in 6 to 14 hours after a single dose. Under fed conditions and after repeated doses, mean Cmax and Cthrough values are 13.6 (SD = 5.6) and 3.1 (SD = 1.6) ng/mL respectively. Mean AUC0-24 is 194 (SD = 75) mg.h/mL. A plateau of concentration is observed from 3 to 14 hours with concentrations above 8.1 ng/mL (Cav) for 11 hours.
The volume of distribution calculated following intravenous administration is 2.5 L/kg which indicates a distribution into extracellular fluids of the body. Alfuzosin hydrochloride is moderately bound to plasma proteins with the free fraction accounting for 13.3% in healthy volunteers. Fractions bound to serum albumin and a1-glycoproteins are 68.2 and 52.5%, respectively. Salicylic acid, hydrochlorothiazide, diltiazem, digoxin and indomethacin do not affect the binding of alfuzosin hydrochloride to human plasma proteins. Based on in vivo data, it is not likely that alfuzosin hydrochloride will affect the extent of binding of these drugs to human plasma proteins. There is an increase in free fraction in renal insufficiency patients (16.8%) and in patients with hepatic disease (20.8%).
Alfuzosin hydrochloride undergoes metabolism by the liver, with only 11% of the parent compound being excreted as unchanged in the urine. The metabolites which are all inactive are eliminated in the urine (15-30%) and feces (75-91%). Alfuzosin hydrochloride is metabolized by three metabolic pathways (oxidation, O-demethylation, N-dealkylation) which are qualitatively identical to those observed in the animal (rat and dog). CYP3A4 is the principal hepatic enzyme isoform involved in its metabolism.
Following intravenous or oral administration, the elimination of alfuzosin hydrochloride is characterized, in healthy young subjects and in the target population, by a terminal half-life of about 4.8 hours and a total clearance of 0.3 L/h/kg. The apparent half-life of alfuzosin hydrochloride is increased to 9.1 hours in healthy middle- aged volunteers and to 10.1 hours in elderly volunteers.
Special Populations and Conditions
Compared to healthy middle-aged volunteers, the pharmacokinetic parameters of alfuzosin hydrochloride (Cmax and AUC) are not increased in elderly patients.
:
Compared to subjects with normal renal function, the mean Cmax and AUC values of alfuzosin hydrochloride are moderately increased (1.5 to 1.6 fold) in patients with various stages of renal impairment, with no change in the apparent elimination half-life. This change in the pharmacokinetic profile is not considered clinically relevant; and therefore, does not necessitate a dosing adjustment. Alfuzosin hydrochloride prolonged-release tablet has not been evaluated in patients with end-stage renal disease.
After a single oral administration of alfuzosin hydrochloride in patients with severe hepatic insufficiency, the elimination half-life is prolonged. A two-fold increase in Cmax values and a three-fold increase in the AUC is observed. Bioavailability is increased in comparison with that in healthy volunteers (See CONTRAINDICATIONS).
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The pharmacokinetic profile of alfuzosin hydrochloride administered intravenously is not affected by chronic cardiac insufficiency.
Store at room temperature (15-30deg C). Keep in a safe place out of the reach of children.
There are no special handling instructions.
APO-ALFUZOSIN (alfuzosin hydrochloride) 10 mg once-daily prolonged release tablet: Each yellow, round, flat-faced, beveled-edge tablet, engraved "APO" on one side and "ALF" over "10" on the other side, contains 10 mg alfuzosin hydrochloride. Available in bottles of 100 tablets. In addition to the active ingredient, alfuzosin hydrochloride, each tablet also contains the non- medicinal ingredients: dibasic calcium phosphate dihydrate, hydroxypropyl methylcellulose, magnesium stearate, polyvinyl acetate phthalate, and yellow ferric oxide.