Mylan-Doxazosin Product Monograph

ACTIONS AND CLINICAL PHARMACOLOGY

The mechanism of action of doxazosin mesylate is selective blockade of alpha₁ subtype of post-synaptic, post-junctional alpha-adrenergic receptors.

Pharmacodynamics

Hypertension

Administration of doxazosin mesylate results in a reduction in systemic vascular resistance. In patients with hypertension there is little change in cardiac output. Maximum reductions in blood pressure usually occur 2-6 hours after dosing and are associated with a small increase in standing heart rate. Doxazosin mesylate has a greater effect on blood pressure and heart rate in the standing position. Tolerance has not been observed in long-term therapy.

Systolic and diastolic blood pressure is lowered in both the supine and standing positions. In clinical trials, blood pressure responses were measured at the end of the dosing interval (24 hours), with the usual supine response 6-11 mm Hg systolic and 5-9 mm Hg diastolic. The response in the standing position tended to be larger by 3-5 mm Hg. Peak blood pressure effects (1-6 hours) were larger by about 50-75% (i.e., trough values were about 55-70% of peak effect), with the larger peak-trough differences seen in systolic pressures. There was no apparent difference in the blood pressure response of Caucasians and Blacks or of patients above and below age 65.

During controlled clinical studies, predominantly normocholesterolemic patients receiving doxazosin mesylate had small but statistically significant reductions in total serum cholesterol (2.7%) and LDL cholesterol (4.3%), and increase in the HDL/total cholesterol ratio (4.3%) relative to placebo. No significant changes were observed in high-density lipoprotein fraction and triglycerides compared to placebo.

Benign Prostatic Hyperplasia (BPH)

Benign Prostatic Hyperplasia (BPH) is a common cause of urinary outflow obstruction in aging males. Severe BPH may lead to urinary retention and renal damage. A static and a dynamic component contribute to the symptoms and reduced urinary flow rate associated with BPH. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma.

However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck. The degree of tone in this area is mediated by α₁-adrenoceptors, which are present in high density in the prostatic stroma, prostatic capsule and bladder neck. Blockage of the α₁-receptor decreases urethral resistance and may relieve the obstruction and BPH symptoms. In 30 to 70% of patients with symptomatic BPH, placebo has also shown a remarkable and sometimes dramatic effect in controlled short-term studies.

The symptoms may subside or fade away without treatment in approximately 20% of patients.

Doxazosin antagonizes phenylephrine-induced contractions, in vitro, in the human prostate. Doxazosin is bound with high affinity to the α_1A-adrenoceptor subtype, thought to be the predominant functional type in the prostate.

The effect of doxazosin mesylate in BPH is thought to result from selective blockade of the α_1A-adrenoceptors located in the prostatic muscular stroma, capsule and bladder neck. This action results in relief of the urinary outlet obstruction and symptomatology associated with BPH.

In controlled clinical trials in over 900 patients, the efficacy of doxazosin mesylate was evaluated. In two studies doxazosin mesylate 4-8 mg once daily significantly improved maximum urinary flow rate (MFR) by 2.3- 3.3 mL/sec (placebo 0.1-0.7 mL/sec).

Significant improvements were usually noticed within two weeks of commencing doxazosin mesylate treatment and a significantly larger proportion of patients (32-42%) responded with MFR improvements ≥ 3 mL/sec (placebo 13-17%). Average flow rate also improved with

doxazosin mesylate treatment, (1.3-2.1 mL/sec vs placebo 0.2-0.3 mL/sec). Doxazosin mesylate also resulted in a significant relief of the obstructive and irritative symptoms associated with BPH.

Using invasive urodynamics in a controlled clinical trial in 43 BPH patients, doxazosin mesylate 2 mg improved MFR 3.4 mL/sec, and reduced urethral resistance 7.5-13.5 cmH₂O (placebo, MFR - 0.6 mL/sec and resistance of 3.3 cmH₂O).

In a 29-week controlled BPH trial in 100 patients, doxazosin mesylate was significantly more effective than placebo in improving urinary flow rates and reducing BPH symptoms; the effect was sustained over the entire treatment period. No tolerance to the effect of doxazosin mesylate on urodynamics or BPH symptomatology was observed in patients treated for up to 4 years in open-label studies.

Both hypertensive and normotensive BPH patients treated with doxazosin mesylate demonstrate statistically significant improvements in urodynamics and symptomatology compared to placebo.

Pharmacokinetics

After oral administration of therapeutic doses of doxazosin mesylate absorption occurs with peak blood levels at about two hours. Bioavailability is approximately 65%. Food has little or no effect on the bioavailability.

Approximately 98% of the circulating drug is bound to plasma proteins. Plasma elimination is biphasic with a terminal elimination half-life of about 22 hours. There is an accumulation of plasma doxazosin levels following steady state dosing, consistent with the terminal elimination half-life.

In a study of elderly hypertensive patients the pharmacokinetic parameters of doxazosin at steady state were similar to those observed in a previous study of young and elderly healthy subjects who received a single oral dose of doxazosin mesylate.

In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar with morning and evening dosing regimens. Doxazosin mesylate may, therefore, be administered as a single daily morning or evening dose (see DOSAGE and ADMINISTRATION).

Doxazosin mesylate is extensively metabolized, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. Excretion is mainly via the feces with 9% of the dose excreted in urine as doxazosin (<0.5%) or metabolites. Less than 5% is excreted as the unchanged drug, mainly in the feces.

The disposition of doxazosin mesylate in patients with renal insufficiency is similar to that in patients with normal renal function. Only limited data are available in patients with liver impairment and on the effects of drugs known to influence hepatic metabolism (e.g., cimetidine) (see PRECAUTIONS – Use in Patients with Impaired Liver Function).

A randomized, 2-way, crossover bioavailability study of MYLAN-DOXAZOSIN 2 mg tablets and the Canadian Reference Product, CARDURA-2^® (Astra Pharma Inc., Canada) in normal, healthy, male volunteers (n = 28) was conducted under fasting conditions. The pharmacokinetic data calculated for MYLAN-DOXAZOSIN and CARDURA-2^® are presented below:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

DOXAZOSIN MESYLATE TABLETS

* Mylan Pharmaceuticals ULC (formerly Genpharm ULC), Toronto, Ontario

^† Distributed by Astra Pharma Inc. (Mississauga, Ontario, Canada). Manufactured by Pfizer Canada Inc. (Kirkland, Quebec, Canada).

^§ Expressed as arithmetic mean (CV%) only.

^║ Expressed as arithmetic mean (CV%) only.

INDICATIONS AND CLINICAL USE

Hypertension

MYLAN-DOXAZOSIN (doxazosin mesylate) is indicated in the treatment of mild to moderate essential hypertension. It is employed in a general treatment program in association with a thiazide diuretic and/or other antihypertensive agents, as needed, for proper patient response.

MYLAN-DOXAZOSIN may be tried as a sole therapy in those patients for whom treatment with other agents caused adverse effects or is inappropriate.

Benign Prostatic Hyperplasia (BPH)

MYLAN-DOXAZOSIN is also indicated for the treatment of symptoms of benign prostatic hyperplasia (BPH). The onset of effect is rapid, with improvement in peak flow and symptoms observed within 1-2 weeks. The effect on these variables was maintained over the entire study duration (up to 4 years). MYLAN-DOXAZOSIN may be used in BPH patients who are either hypertensive or normotensive. While the reduction in blood pressure in normotensive patients with BPH is clinically insignificant, patients with hypertension and BPH have both conditions effectively treated with doxazosin monotherapy (see DOSAGE and ADMINISTRATION for dosage regimens).

A number of clinical conditions can mimic symptomatic BPH (i.e., stricture of urethra, stricture of bladder neck, urinary bladder stones, neurogenic bladder dysfunction secondary to diabetes, Parkinsonism, etc.). These conditions should therefore be ruled out before doxazosin therapy is initiated.

CONTRAINDICATIONS

It is contraindicated in patients with a known sensitivity to MYLAN-DOXAZOSIN (doxazosin mesylate) or quinazolines.

WARNINGS

Syncope and "First Dose" Effect

Doxazosin mesylate can cause marked hypotension, especially postural hypotension and syncope in association with the first dose or first few doses of therapy. A similar effect can occur if therapy is reinstated following interruption for more than a few doses. Postural effects are most likely to occur between 2 and 6 hours after dose.

In controlled studies of doxazosin mesylate the incidence of syncopal episodes was 0.7%. An initial dose of 1 mg/day resulted in a 4% incidence of postural side effects with no cases of syncope. In controlled clinical trials for BPH in normotensive patients, there was a 0.2% occurrence of syncope with doxazosin mesylate. In controlled trials in patients with both BPH and hypertension receiving doxazosin mesylate, the incidence of syncope was 0.8%.

The likelihood of syncopal episodes or excessive hypotension can be minimized by limiting the initial dose of doxazosin mesylate to 1 mg, by increasing the dosage slowly, and by introducing any additional antihypertensive drugs into the patient’s regimen with caution (see DOSAGE AND ADMINISTRATION).

Patients should be advised of the possibility of syncopal and orthostatic symptoms, and to avoid driving or hazardous tasks for 24 hours: after the initial dose of doxazosin mesylate, after the dose is increased, and after interruption of therapy when treatment is resumed. They should be cautioned to avoid situations where injury could result should syncope occur.

If syncope occurs, the patient should be placed in the supine position. If this measure is inadequate, volume expansion with intravenous fluids or vasopressor therapy may be used. A transient hypotensive response is not a contraindication to further doses of doxazosin mesylate.

Orthostatic Hypotension

While syncope is the most severe orthostatic effect of doxazosin mesylate, other symptoms of lowered blood pressure such as dizziness, lightheadedness or vertigo can occur. These were common in clinical trials in hypertension, occurring in up to 23% of all patients treated and causing discontinuation of therapy in about 2%. In placebo-controlled titration trials, there was an increased frequency of orthostatic effects in patients given 8 mg or more (10%) compared to patients given 1-4 mg (5%) or placebo (3%).

In placebo-controlled trials in BPH, the incidence of orthostatic hypotension with doxazosin mesylate was ≤ 1%. With maintenance doses of up to 8 mg/day in normotensive patients with BPH, the average decreases in both sitting and standing blood pressure were small: 5/2 mm Hg with doxazosin mesylate and 1/1 mm Hg with placebo.

Patients with occupations in which such events represent potential problems should be treated with particular caution.

Concomitant administration of doxazosin with a PDE-5 inhibitor such as sildenafil, tadalafil or vardenafil, should be used with caution as it may lead to symptomatic hypotension.

Patients should be advised of the need to lie down when symptoms of lowered blood pressure occur, and to be careful when arising from a lying position. If dizziness, lightheadedness or

palpitations are bothersome, they should be reported to the physician so that dose adjustment can be considered. Patients should also be told that drowsiness or somnolence can occur with MYLAN-DOXAZOSIN, requiring caution in people who must drive or operate heavy machinery.

If hypotension occurs, place the patient in the recumbent position and institute supportive measures as necessary.

Priapism

Rarely (probably less frequently than once in every several thousand patients), α₁-antagonists such as doxazosin have been associated with priapism. Because this condition can lead to permanent impotence if not promptly treated, patients should be advised about the seriousness of the condition.

Hematological Events

Analysis of hematologic data from patients receiving doxazosin mesylate in controlled clinical trials showed that the mean white blood cell (WBC) (n=474) and mean neutrophil counts (n=419) were decreased by 2.4% and 1.0% respectively, compared to placebo. A search through a data base of 2,400 patients revealed 4 cases in which drug-related neutropenia could not be ruled out. Two had a single low value on the last day of treatment. Two had stable, non-progressive neutrophil counts in the 1000/mm³ range over periods of 20 and 40 weeks. No patients became symptomatic as a result of the low WBC or neutrophil counts.

In BPH patients treated with doxazosin, the incidence of clinically significant WBC abnormalities was 0.4%.

In post-marketing experience, rare cases of hematopoietic events such as leukopenia and thrombocytopenia have been reported.

Hepatic Events

In post-marketing experience, rare cases of abnormal liver function tests, cholestasis, jaundice and hepatitis have been reported.

Peripheral Edema

Fluid retention resulting in weight gain may occur during MYLAN-DOXAZOSIN therapy. In placebo-controlled monotherapy trials, patients receiving doxazosin mesylate gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo-treated patients. The overall incidence of body weight gain reported as a side effect in controlled clinical trials was 0.8%.

PRECAUTIONS

General

MYLAN-DOXAZOSIN therapy does not modify the natural history of benign prostatic hyperplasia (BPH). It does not retard or stop the progression of BPH, nor does it improve urine flow sufficiently to significantly reduce the residual urine volume. However, significant reduction of the mean residual volume have been shown in patients with baseline residual volumes of > 50 mL. The patient may continue to be at risk of developing urinary retention and other BPH complications during doxazosin therapy.

Long-Term Safety and Efficacy

The long-term safety and efficacy (i.e., > 4 years) has not yet been established for the use of doxazosin in the treatment of benign prostatic hyperplasia.

Prostatic Cancer

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 MYLAN-DOXAZOSIN therapy to rule out the presence of carcinoma of the prostate. MYLAN-DOXAZOSIN should not be used in patients with PSA > 10 ng/mL unless cancer of the prostate has been ruled out.

Ophthalmologic

The 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 alpha₁ blockers. As IFIS may lead to increased procedural complications during the operation, current or past use of alpha blockers should be made known to the ophthalmologic surgeon in advance of surgery.

Use in Patients with Impaired Liver Function

As with any drug wholly metabolized by the liver, doxazosin should be administered with caution to patients with evidence of impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism.

Use in Patients with Impaired Renal Function

The use of MYLAN-DOXAZOSIN in patients with impaired renal function requires careful monitoring. Clinical studies indicate that the disposition of doxazosin mesylate in patients with renal insufficiency is similar to that in patients with normal renal function, however accumulation of the drug with chronic dosing may occur. Less than 10% of the dose of doxazosin is excreted in the urine as unchanged drug and metabolites.

Concomitant Conditions

MYLAN-DOXAZOSIN should not be prescribed to patients with symptomatic BPH who have the following concomitant conditions:

Chronic urinary retention, high residual urine (over 200 mL), peak urine flow of 5 mL/sec or less, history of prior prostatic surgery, chronic fibrous or granulomatous prostatitis, urethral stricture, history of pelvic irradiation, presence of prostatic calculi, presence of large median lobe of prostate, presence of calculi in urinary bladder, recent history of epididymitis, gross hematuria, presence of neurogenic bladder dysfunction (diabetes mellitus, Parkinsonism, uninhibited neurogenic bladder, etc.), hydronephrosis, presence of carcinoma of the prostate. Nor should doxazosin be prescribed to patients having experienced a myocardial infarction, transient ischemic attacks, or cerebrovascular accident within the past 6 months.

Use in Pregnancy

There are no studies in pregnant women. MYLAN-DOXAZOSIN is not recommended in pregnant women unless the potential benefit outweighs the potential risk to mother and fetus.

Doxazosin mesylate crosses the placental barrier.

Studies in pregnant rabbits and rats at daily oral doses of up to 40 and 20 mg/kg, respectively, have revealed no evidence of teratogenic effect. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival, an increase in embryomortality as well as increases in fetal and placental weights.

In peri- and post-natal studies in rats, postnatal development at maternal doses of 40 or 50 mg/kg/day of doxazosin was delayed as evidenced by slower body weight gain and a slightly later appearance of anatomical features and reflexes.

Use in Nursing Mothers

Studies in lactating rats indicate that doxazosin accumulates in rat breast milk. It is not known whether this drug is excreted in human milk. Caution should be exercised when MYLAN-DOXAZOSIN is administered to a nursing mother and in general, nursing should be interrupted.

Use in Children

The use of MYLAN-DOXAZOSIN is not recommended in children since safety and efficacy have not been established.

Use in Elderly

MYLAN-DOXAZOSIN should be used cautiously in elderly patients because of the possibility of postural hypotension. There was an age-related trend towards an increased incidence of postural hypotension and postural dizziness in elderly hypertensive patients treated with this drug.

Cardiac Toxicity in Animals

An increased incidence of myocardial necrosis or fibrosis was displayed by Sprague-Dawley rats after 6 months of dietary administration at concentrations calculated to provide 80 mg doxazosin/kg/day, and after 12 months of dietary administration at concentrations calculated to provide 40 mg doxazosin/kg/day.

Myocardial fibrosis was observed in both rats and mice treated in the same manner with 40 mg doxazosin/kg/day for 18 months. No cardiotoxicity was observed at lower doses (up to 10 or 20 mg/kg/day, depending on the study) in either species.

These lesions were not observed after 12 months of oral dosing in dogs and Wistar rats at maximum doses of 20 and 100 mg/kg/day, respectively. There is no evidence that similar lesions occur in humans.

Drug Interactions

Doxazosin is highly (98%) bound to plasma protein. In vitro data in human plasma indicates that doxazosin mesylate has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin.

Doxazosin mesylate has been administered to patients receiving thiazide diuretics, beta-adrenergic blocking agents and non-steroidal anti-inflammatory drugs. No unexpected interactions were reported. An additive hypotensive effect was observed when doxazosin mesylate was co-administered with thiazide diuretics and beta-adrenergic blocking agents. There is limited experience with doxazosin mesylate in combination with ACE inhibitors or calcium channel blockers.

Digoxin

Serum digoxin concentrations were not affected by treatment with doxazosin.

Cimetidine

In a randomized, open-label, placebo-controlled, cross-over study in 22 healthy male subjects, the single co-administration of 1 mg doxazosin with 400 mg b.i.d. cimetidine resulted in a 10% increase in mean AUC of doxazosin (p = 0.006), and a slight but not statistically significant increase in mean C_max and mean half-life of doxazosin. The effect of further administration of cimetidine has not been studied.

PDE-5 Inhibitors

Symptomatic hypotension has been reported during the concomitant use of PDE-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) and doxazosin mesylate (see WARNINGS).

ADVERSE REACTIONS

Hypertension

Doxazosin mesylate has been administered to approximately 4,000 patients in clinical trials of whom 1,679 patients were included in controlled trials. The most serious adverse event occurring in the controlled clinical trials was syncope occurring in 0.7% of patients and resulting in a discontinuation rate of 0.2%.

The most frequent adverse events in controlled clinical trials were: headache (16.5%), fatigue/malaise (14.8%), dizziness (14.6%), postural dizziness (8.7%) and edema (6.6%). Discontinuation of doxazosin mesylate due to adverse events was required in 7% of patients.

Adverse events which occurred with an incidence of ≥ 1% in the controlled clinical trials in patients with mild to moderate essential hypertension were as shown in the following table.

The following other adverse events occurred in hypertensive patients with an incidence of < 1% in controlled clinical trials (n=1679): postural hypotension, arrhythmia, syncope, pruritus, arthralgia, agitation, flushing, tremor, paroniria, tinnitus, vomiting, epistaxis, sinusitis, bronchospasm/bronchitis, urinary incontinence, urinary disorder, face edema, weight increase, general edema, angina pectoris, peripheral ischemia, hypotension, paresis, twitching, migraine, amnesia, movement disorders, emotional lability, abnormal thinking, depersonalization, pallor, hypertonia, ataxia, thirst, gout, hypokalemia, lymphadenopathy, purpura, breast pain, alopecia, dry skin, eczema, taste perversion, photophobia, abnormal lacrimation, increased appetite,

anorexia, fecal incontinence, coughing, pharyngitis, hot flushes, back pain, infection, fever/rigors and muscle weakness.

Benign Prostatic Hyperplasia

Doxazosin mesylate has been administered once daily to 665 both hypertensive and normotensive patients with BPH in controlled clinical trials. The most serious adverse event occurring in the controlled trials was syncope (0.5%).

The most frequent adverse events in controlled trials were dizziness (15.6%), headache (9.8%) and fatigue (8%).

Discontinuation rate of doxazosin mesylate due to adverse events was 9%.

Adverse events which occurred with an incidence of ≥ 1% in the controlled clinical trials in normotensive or hypertensive patients with BPH were as shown in the following table.

* Placebo-controlled clinical trials; treated with doxazosin from 1-203 days.

** Open label extension of 3 placebo controlled clinical trials; treated for up to 50 months.

The following other adverse events occurred in normotensive or hypertensive patients with BPH with an incidence of <1% in short-term controlled clinical trials (n=665): tachycardia, angina, syncope, postural hypotension, pruritus, rash, myalgia, paresthesia, flushing, conjunctivitis, tinnitus, decreased libido, depression, nervousness, flatulence, rhinitis, epistaxis, carcinoma, dysuria, asthenia, influenza like symptoms, viral infection, fever, weight increase, malaise, myocardial infarction, bradycardia, sudden death, pallor, hyperglycemia, gout, lymphadenopathy, prostatic disorder, ejaculation failure, epididymitis, dry skin, genital pruritus, urticaria, maculopapular rash, erythematous rash, aggravated psoriasis, eczema, hypoesthesia, hypertonia, leg cramps, confusion, speech disorder, ataxia, abnormal thinking, depersonalization, paroniria, emotional lability, impaired concentration, amnesia, earache, taste perversion, eye pain, visual field defect, cataract, melena, constipation, vomiting, gingivitis, increased appetite, coughing, bronchospasm, bronchitis, upper respiratory tract infection, sinusitis, pneumonia, urinary retention, micturition disorder, abnormal urine, renal pain, urinary incontinence, cystitis, arthritis, tendon disorder, arthalgia, hernia, rigors, hot flushes, allergy, sepsis, fungal infection, hematuria and subarachnoid hemorrhage.

The following other adverse events occurred in normotensive or hypertensive patients with BPH with an incidence of <1% in long-term controlled clinical trials (n=450): convulsions,

encephalopathy, hypokinesia, migraine, fever, malaise, rigor, enlarged abdomen, allergic reaction/allergy, weight increase, nervousness, amnesia, anxiety, depersonalization, impaired concentration, abnormal thinking, flatulence, melena, vomiting, rectal hemorrhage, abnormal semen, tooth disorder, increased appetite, diverticulitis, esophagitis, gastric ulcer, tenesmus, tongue disorder, tooth hypoplasia, syncope, aneurysm, cardiac failure, abnormal ECG, hypertension, epistaxis, pharyngitis, rhinitis, bronchitis, pulmonary carcinoma, epididymitis, perineal pain, cystitis, dysuria, polyuria, urinary incontinence, oliguria, abnormal urine, increased sweating, seborrhea, maculopapular rash, skin disorder, nail disorder, photosensitivity reaction, pruritus, skin hypertrophy, urticaria, conjunctivitis, diplopia, eye abnormality, eye pain, myopia, visual field defect, myalgia, arthritis, polymyalgia rheumatica, atrial fibrillation, tachycardia, extra systoles, angina pectoris, myocardial ischemia, flushing, dry mouth, aggravated hypertension, sexual dysfunction, purpura, deafness, earache, cerebrovascular disorder/accident, intermittent claudication, carcinoma, herpes simplex, herpes zoster, fungal infection, otitis media, dehydration, hyperglycemia, hyperuricemia, cholelithiasis, SGOT increase, SGPT increase and breast neoplasm.

Data from long-term (up to 50 months), open BPH studies (n=450) indicate higher rates of dizziness in younger hypertensive (27%) and normotensive (22%) patients, impotence in younger hypertensive (8%) patients, and discontinuation rates in patients due to adverse events (16.7%) compared to data from short-term placebo-controlled BPH studies (n=665).

Uncontrolled Trials and Post-Marketing Experience

The following additional adverse events have also been reported in patients with essential hypertension and in normotensive or hypertensive patients with BPH: parosmia, renal calculus, priapism, ejaculation disorders such as retrograde ejaculation, jaundice, cholestasis and hepatitis. Intraoperative Floppy Iris Syndrome (see PRECAUTIONS, Ophthalmologic) and gynecomastia.

Laboratory Abnormalities

No clinically relevant adverse effects were noted on serum potassium, serum glucose, uric acid, blood urea nitrogen or creatinine. Decreases in white blood cells, neutrophils, platelets (see WARNINGS), hemoglobin and hematocrit have been reported. Abnormal liver function tests have occurred.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

No data are available regarding overdosage with doxazosin mesylate in humans.

Should administration of MYLAN-DOXAZOSIN (doxazosin mesylate) 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, shock should first be treated with volume expanders. If necessary, vasopressors should be used. Renal function should be monitored and supported as needed. As doxazosin mesylate is highly protein bound, dialysis may not be of benefit.

DOSAGE AND ADMINISTRATION

Dosage must be individualized. Doxazosin may be administered either in the morning or in the evening.

The absorption of MYLAN-DOXAZOSIN is not affected by food.

When MYLAN-DOXAZOSIN (doxazosin mesylate) is being added to existing antihypertensive therapy, the patient should be carefully monitored for the occurrence of hypotension (see WARNINGS – Syncope and “First Dose” Effect). If a diuretic or other antihypertensive agent is being added to a MYLAN-DOXAZOSIN regimen, reducing the dose of MYLAN-DOXAZOSIN and retitration, with careful monitoring, may be necessary.

If MYLAN-DOXAZOSIN administration is discontinued for several days, or longer, therapy should be reinstituted using the initial dosing regimen.

Hypertension - 1-16 mg Once Daily

The initial dose of MYLAN-DOXAZOSIN in patients with hypertension is 1 mg given once daily and this dose should not be exceeded. This starting dose is intended to minimize postural hypotensive effects. The maximum reduction in blood pressure normally occurs between 2 and 6 hours after a dose.

The dose may be slowly increased to achieve the desired blood pressure response. The usual dose range is 1 to 8 mg once daily. The maximum recommended daily dose is 16 mg once daily.

Increases in dose beyond 4 mg increased the likelihood of excessive postural effects including syncope, postural dizziness/vertigo and postural hypotension. At a titrated dose of 16 mg once daily, the frequency of postural effects is about 12% compared to 3% for placebo.

Benign Prostatic Hyperplasia: 1-8 mg Once Daily

The initial dosage of MYLAN-DOXAZOSIN is 1 mg given once daily (see WARNINGS – Syncope and “First Dose” Effect). Depending on the individual patient's urodynamics and BPH

symptomatology, dosage may then be increased to 2 mg and thereafter to 4 mg and 8 mg once daily, the maximum recommended dose. The recommended titration interval is 1-2 weeks. Blood pressure should be evaluated routinely in these patients.

MYLAN-DOXAZOSIN should be discontinued if the drug has been increased to the maximum tolerated dose and improvement in urinary flowmetry is less than 25%, or if doxazosin side effects are more bothersome than BPH symptoms, or if the patient develops a urinary complication secondary to BPH while on doxazosin therapy.

OVERDOSAGE

PHARMACEUTICAL INFORMATION

Drug Substance

Structure:

Proper/Common Name: Doxazosin Mesylate

Chemical Name: 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxin-2yl)carbonyl] piperazine monomethanesulfonate

Other Names: 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxy quinazolinemesylate

Molecular Formula: C₂₄H₂₉N₅O₈S

Molecular Weight: 547.57 g/mol

Description: A white to off-white crystalline powder.

Solubilities: Freely soluble in dimethylsulfoxide and slightly soluble in methanol.

Melting Range: 270.0°C - 280.0°C

Composition

MYLAN-DOXAZOSIN is formulated as white tablets containing doxazosin mesylate equivalent to 1 mg, 2 mg, and 4 mg of doxazosin.

O

O

N

O

N

N

N OCH ₃

OCH ₃

NH ₂

CH₃SO₃H

Non-Medicinal Ingredients: sodium lauryl sulfate, anhydrous lactose, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.

Stability and Storage Recommendations

MYLAN-DOXAZOSIN (doxazosin mesylate) tablets 1 mg, 2 mg and 4 mg should be stored at room temperature between 15°C and 30°C.

AVAILABILITY OF DOSAGE FORMS

MYLAN-DOXAZOSIN (doxazosin mesylate) is available as white tablets containing doxazosin mesylate equivalent to 1 mg, 2 mg or 4 mg of doxazosin. Each strength is available in bottles of 100 tablets.

MYLAN-DOXAZOSIN 1 mg tablets are white, round, biconvex tablets, debossed “DX1” on one side and “G” on the other side.

MYLAN-DOXAZOSIN 2 mg tablets are white, capsule-shaped tablets, debossed “DX” scoreline “2” on one side and “G” on the other side.

MYLAN-DOXAZOSIN 4 mg tablets are white, diamond-shaped tablets, debossed “DX” scoreline “4” on one side and “G” on the other side.

PHARMACOLOGY

Animal Pharmacology - In Vivo

In anaesthetized cats, doxazosin caused adrenaline reversal and was more effective in antagonizing pressor responses to phenylephrine (ED₅₀=0.06 mg/kg, i.v.) than to noradrenaline, (ED₅₀ < 10 mg/kg, i.v.) indicating selective effect on post-junctional alpha₁- as opposed to alpha₂-adrenoceptors. This was confirmed by the lack of effect of doxazosin on the alpha₂-mediated pressor responses induced by alpha-methylnor-adrenaline. The lack of effect of doxazosin on pre-junctional alpha₂-adrenoceptors was confirmed in anaesthetized dogs.

Animal Pharmacology - In Vitro

In the perfused isolated rabbit ear artery and in the rabbit pulmonary artery rings, doxazosin had a selective effect on post-synaptic alpha₁-adrenoceptors. The superfused rabbit pulmonary artery preparation was used to show that doxazosin is highly selective (pre-synaptic activity EC₂₀=2 x 10^-5 M vs post-synaptic activity EC₂₀=2.4 x 10^-8 M); for the post- as opposed to the pre-junctional alpha receptors in this tissue.

Miscellaneous Actions

At high doses, doxazosin increased both alcohol and pentobarbitone sleeping time in mice and may possess mild CNS sedative activity per se, increased basal gastric acid secretion and gastrointestinal motility in rats, and had antidiuretic activity in normotensive rats and dogs.

Human Pharmacology

Hypertension

A comparison of the blood pressure lowering effect of doxazosin mesylate in patients 65 years and over (n=204), and those below 65 years (n=1,344) show similar falls in blood pressure. The changes in standing systolic/diastolic pressures were -15/-l2 mm Hg for the elderly and -13/-11 mm Hg for the under 65 years groups, respectively.

Pharmacokinetic studies at steady state in hypertensive patients given doxazosin doses of 2-16 mg once daily showed linear kinetics and dose proportionality. In two studies, following the administration of 2 mg orally once daily, the mean accumulation ratios (steady state AUC vs first dose AUC) were 1.2 and 1.7.

Benign Prostatic Hyperplasia (BPH)

In three placebo-controlled studies of 14-16 weeks’ duration obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning) of BPH were evaluated at each visit by patient-assessed symptom questionnaires. The bothersomeness of symptoms was measured with a modified Boyarsky questionnaire. Symptom severity/frequency was assessed using a modified Boyarsky questionnaire or an AUA-based questionnaire. Uroflowmetric evaluations were performed at times of peak (2-6 hours post-dose) and/or trough (24 hours post-dose) plasma concentrations of doxazosin mesylate.

The results from the three placebo-controlled studies (N=609) showing significant efficacy with 4 mg and 8 mg doxazosin are summarized in Table 2. In all three studies, doxazosin mesylate resulted in statistically significant relief of obstructive and irritative symptoms compared to placebo. Statistically significant improvements of 2.3-3.3 mL/sec in maximum flow rate were seen with doxazosin mesylate in Studies 1 and 2, compared to 0.1-0.7 mL/sec with placebo.

Table 2

In one fixed dose study (Study 2) doxazosin mesylate therapy (4-8 mg, once daily) resulted in a significant and sustained improvement in maximum urinary flow rate of 2.3-3.3 mL/sec (Table

1. 2) compared to placebo (0.1 mL/sec). In this study, the only study in which weekly evaluations were made, significant improvement with doxazosin mesylate vs placebo was seen after one week. The proportion of patients who responded with a maximum flow rate improvement of ≥3 mL/sec was significantly larger with doxazosin mesylate (34-42%) than placebo (13-17%). A significantly greater improvement was also seen in average flow rate with doxazosin mesylate (1.5 mL/sec) than with placebo (0.2 mL/sec).

The onset and time course of symptom relief and increased urinary flow from study 1 are illustrated in Figure 1.

Figure 1

In BPH patients (n=450) treated for up to 4 years in open-label studies, doxazosin mesylate therapy resulted in significant improvement above baseline in urinary flow rates and BPH symptoms. The significant effects of doxazosin mesylate were maintained over the entire treatment period, as shown in Figure 2.

Figure 2

Although blockade of α₁-adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, doxazosin mesylate treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect (Table 3). The proportion of normotensive patients with a sitting systolic blood pressure less than 90 mm Hg and/or diastolic blood pressure less than 60 mm Hg at any time during treatment with doxazosin mesylate 1-8 mg once daily was 6.7% and not statistically significantly different from that with placebo (5%).

Table 3 Mean Changes in Blood Pressure from Baseline to the Mean of the Final Efficacy

Phase in Normotensive (Diastolic BP < 90 mm Hg) in All Double-Blind, Placebo Controlled U.S. Studies.

* p ≤ 0.05 compared to placebo

TOXICOLOGY

Acute Toxicology

After oral administration of the drug, the animals displayed vulval opening (females), ptosis and prostration, with the signs lasting up to two days depending on dose level. The 3 deaths which occurred were between days 2 and 5.

Toxicology

Mutagenicity studies revealed no drug or metabolite related effects at either chromosomal or subchromosomal levels.

Carcinogenicity

Chronic dietary administration (up to 24 months) of doxazosin mesylate at maximally tolerated concentrations (highest dose 40 mg/kg/day) revealed no evidence of carcinogenicity in rats. Doxazosin was also administered for up to 18 months in the diet of mice, at doses up to 40 mg/kg/day, with no evidence of carcinogenicity observed. This mouse study however, was compromised by the failure to use a maximally tolerated dose of doxazosin. A subsequent 24-

month dietary study of doxazosin mesylate, at maximally tolerated concentrations (highest dose 120 mg/kg/day), showed no carcinogenic effect in mice. The highest doses evaluated in the rat and mouse studies are associated with AUCs (a measure of systemic exposure) that are 8 times and 4 times, respectively, the human AUC at a dose of 16 mg/day.

Studies in rats showed reduced fertility in males treated with doxazosin at oral doses of 20 (but not 5 or 10) mg/kg/day, about 4 times the AUC exposures obtained with a 12 mg/day human dose. This effect was reversible within two weeks of drug withdrawal.

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Product Monograph for Cardura-1 mg, 2 mg & 4 mg, Pfizer Canada Inc., Date of Revision: September 18, 2012, Control #: 156309