Teva-Doxazosin Product Monograph

ACTIONS AND CLINICAL PHARMACOLOGY

The mechanism of action of doxazosin mesylate is selective blockade of α₁ subtype of post-synaptic, post-junctional α-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 ≥ 65 years old and < 65 years old.

During controlled clinical studies, predominantly normocholesterolemic patients receiving doxazosin mesylate had small but statistically significant reductions in total serum cholesterol (2.7%) and low-density lipoprotein (LDL) cholesterol (4.3%), and increase in the high-density lipoprotein (HDL)/total cholesterol ratio (4.3%) relative to placebo. No significant changes were observed in HDL 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 - 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 >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 2 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 ≤ 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 2 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 cross-over 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 primarily metabolized, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. Doxazosin is extensively metabolized in the liver. In vitro studies suggest that the primary pathway for elimination is via CYP 3A4; however, CYP 2D6 and CYP 2C9 metabolic pathways are also involved for elimination, but to a lesser extent (see PRECAUTIONS, Drug Interactions). 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 single dose, randomized, blinded, two-way, crossover bioavailability study was performed to compare the rate and extent of absorption and bioequivalence of Teva-Doxazosin 1 mg Tablets with Cardura-1™ 1 mg Tablets in fasting volunteers. The pharmacokinetic mean plasma data calculated for the two products are tabulated below:

^* Teva-Doxazosin 1 mg Tablets (Teva Canada Limited, Canada)

^⊥ Cardura-1™ manufactured by Astra Pharma Inc., Mississauga, ON, Canada.

^§ Expressed as the arithmetic means (CV %) only

INDICATIONS AND CLINICAL USE

Hypertension

TEVA-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.

TEVA-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)

TEVA-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 (≤4 years). TEVA-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

TEVA-DOXAZOSIN is contraindicated in:

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see PHARMACEUTICAL INFORMATION, Composition section of the product monograph.
• Patients with a known sensitivity to other quinazolines (e.g. prazosin, terazosin).
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption because lactose is a non-medicinal ingredient in TEVA-DOXAZOSIN.

WARNINGS

Syncope and "First Dose" Effect

TEVA-DOXAZOSIN (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 - 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 TEVA-DOXAZOSIN, 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 TEVA-DOXAZOSIN.

Orthostatic Hypotension

While syncope is the most severe orthostatic effect of TEVA-DOXAZOSIN, other symptoms of lowered blood pressure such as dizziness, light-headedness or vertigo can occur. These were common in clinical trials in hypertension, occurring in ≤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 (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 ≤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, light-headedness 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 doxazosin mesylate, 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 TEVA-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

TEVA-DOXAZOSIN (doxazosin mesylate) 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 TEVA-DOXAZOSIN therapy to rule out the presence of carcinoma of the prostate.

TEVA-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 α₁ blockers. As IFIS may lead to increased procedural complications during the operation, current or past use of α 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 TEVA-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

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

• Chronic fibrous or granulomatous prostatitis,
• Chronic urinary retention,
• Gross hematuria,
• High residual urine (>200 mL),
• History of pelvic irradiation,
• History of prior prostatic surgery,
• Hydronephrosis,
• Peak urine flow of ≤5 mL/sec,
• Presence of calculi in urinary bladder,
• Presence of carcinoma of the prostate
• Presence of large median lobe of prostate,
• Presence of neurogenic bladder dysfunction (diabetes mellitus, parkinsonism, uninhibited neurogenic bladder, etc.),
• Presence of prostatic calculi,
• Recent history of epididymitis,
• Urethral stricture,

Doxazosin should also not be prescribed to patients having experienced within the past 6 months:

• A myocardial infarction,
• Transient ischemic attacks,
• Cerebrovascular accident

Use in Pregnancy

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

TEVA-DOXAZOSIN crosses the placental barrier.

Animal data: Studies in pregnant rabbits and rats at daily oral doses of ≤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

Animal data: Studies in lactating rats given a single oral dose of 1 mg/kg of [2-¹⁴C]-doxazosin indicate that doxazosin accumulates in rat breast milk with a maximum of concentration about 20 times greater than the maternal plasma concentration.

A single case report demonstrated transfer of doxazosin into human breast milk. Caution should be exercised when TEVA-DOXAZOSIN is administered to a nursing mother and in general, nursing should be interrupted.

Use in Children

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

Use in Elderly

TEVA-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 (≤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).

CYP3A4 Inhibitors

In vitro studies suggest that doxazosin is a substrate of CYP 3A4. Caution should be exercised when concomitantly administering doxazosin with a strong CYP 3A4 inhibitor, such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole (see ACTIONS AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

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 (AE) 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 AEs 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 AEs was required in 7% of patients.

AEs 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.

Table 1 – Incidence of Adverse Events ≥ 1% in the controlled clinical trials in patients with mild to moderate essential hypertension

Less Common Clinical Trial Adverse Drug Reactions (<1%)

The following other AEs occurred in hypertensive patients with an incidence of <1% in controlled clinical trials (n=1679):

Blood and Lymphatic Disorders: lymphadenopathy

Cardiac Disorders: angina pectoris, arrhythmia

Ear and Labyrinth Disorders: tinnitus

Eye Disorders: abnormal lacrimation, photophobia

Gastrointestinal Disorders: fecal incontinence, vomiting

General Disorders and Administration Site Conditions: face edema, fever/rigors, general edema, thirst

Infections and infestations: infection

Metabolism and Nutrition Disorders: anorexia, gout, hypokalemia, increased appetite, weight increase

Musculoskeletal and Connective Tissue Disorders: arthralgia, back pain, muscle weakness, twitching

Nervous System Disorders: amnesia, ataxia, depersonalization, hypertonia, migraine, movement disorders, paresis, syncope, tremor

Psychiatric Disorders: abnormal thinking, agitation, emotional lability, paroniria

Renal and Urinary Disorders: urinary disorder, urinary incontinence

Reproductive System and Breast Disorder: breast pain

Respiratory, Thoracic and Mediastinal Disorders: bronchospasm/bronchitis, coughing, epistaxis, pharyngitis, sinusitis

Skin and Subcutaneous Tissue Disorders: alopecia, dry skin, eczema, pallor, pruritus, purpura

Special Senses: taste perversion

Vascular Disorders: flushing, hot flushes, hypotension, peripheral ischemia, postural hypotension

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 AEs occurring in the controlled trials was syncope (0.5%).

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

Discontinuation rate of doxazosin mesylate due to AEs was 9%.

AEs 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.

Table 2 – Incidence of Adverse Events of ≥ 1% in the controlled clinical trials in normotensive or hypertensive patients with BPH

* 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.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Short-term controlled clinical trials:

The following other AEs occurred in normotensive or hypertensive patients with BPH with an incidence of <1% in short-term controlled clinical trials (n=665):

Blood and Lymphatic Disorders: lymphadenopathy

Cardiac Disorders: angina, bradycardia, myocardial infarction, tachycardia

Ear and Labyrinth Disorders: earache, tinnitus

Eye Disorders: cataract, conjunctivitis, eye pain, visual field defect

Gastrointestinal Disorders: constipation, flatulence, gingivitis, melena, vomiting

General Disorders and Administration Site Conditions: allergy, asthenia, fever, influenza like symptoms, malaise, rigors, sudden death

Infections and infestations: fungal infection, sepsis, upper respiratory tract infection, viral infection

Metabolism and Nutrition Disorders: gout, hyperglycemia, increased appetite, weight increase

Musculoskeletal and Connective Tissue Disorders: arthralgia, arthritis, hernia, leg cramps, myalgia, tendon disorder

Neoplasms Benign, Malignant and Unspecified: carcinoma

Nervous System Disorders: amnesia, ataxia, depersonalization, hypertonia, hypoesthesia, paresthesia, speech disorder, syncope

Psychiatric Disorders: abnormal thinking, confusion, decreased libido, depression, emotional lability, impaired concentration, nervousness, paroniria

Renal and Urinary Disorders: abnormal urine, cystitis, dysuria, hematuria, micturition disorder, renal pain, urinary incontinence, urinary retention

Reproductive System and Breast Disorder: ejaculation failure, epididymitis, genital pruritus, prostatic disorder

Respiratory, Thoracic and Mediastinal Disorders: bronchitis, bronchospasm, coughing, epistaxis, pneumonia, rhinitis, sinusitis

Skin and Subcutaneous Tissue Disorders: aggravated psoriasis, dry skin, eczema, erythematous rash, maculopapular rash, pallor, pruritus, rash, urticaria

Special Senses: taste perversion

Vascular Disorders: flushing, hot flushes, postural hypotension, subarachnoid haemorrhage

Long-term controlled clinical trials:

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

Cardiac Disorders: abnormal ECG, angina pectoris, atrial fibrillation, cardiac failure, extra systoles, myocardial ischemia, tachycardia

Ear and Labyrinth Disorders: deafness, earache, otitis media

Eye Disorders: conjunctivitis, diplopia, eye abnormality, eye pain, myopia, visual field defect

Gastrointestinal Disorders: diverticulitis, dry mouth, enlarged abdomen, esophagitis, flatulence, gastric ulcer, melena, rectal haemorrhage, tenesmus, tongue disorder, tooth disorder, tooth hypoplasia, vomiting

General Disorders and Administration Site Conditions: allergic reaction/allergy, fever, malaise, rigor

Hepatobiliary Disorders: cholelithiasis

Infections and Infestations: fungal infection, herpes simplex, herpes zoster

Metabolism and Nutrition Disorders: dehydration, hyperglycemia, hyperuricemia, increased appetite, SGOT increase, SGPT increase, weight increase

Musculoskeletal and Connective Tissue Disorders: arthritis, myalgia, polymyalgia rheumatica

Neoplasms Benign, Malignant and Unspecified: breast neoplasm, carcinoma, pulmonary carcinoma

Nervous System Disorders: amnesia, convulsions, depersonalization, encephalopathy, hypokinesia, migraine, syncope

Psychiatric Disorders: abnormal thinking, anxiety, impaired concentration, nervousness

Renal and Urinary Disorders: abnormal urine, cystitis, dysuria, oliguria, polyuria, urinary incontinence

Reproductive System and Breast Disorder: abnormal semen, epididymitis, perineal pain, sexual dysfunction

Respiratory, Thoracic and Mediastinal Disorders: bronchitis, epistaxis, pharyngitis, rhinitis

Skin and Subcutaneous Tissue Disorders: increased sweating, maculopapular rash, nail disorder, photosensitivity reaction, pruritus, purpura, seborrhea, skin disorder, skin hypertrophy, urticaria

Vascular Disorders: aggravated hypertension, aneurysm, cerebrovascular disorder/accident, flushing, hypertension, intermittent claudication

Data from long-term (≤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 AEs (16.7%) compared to data from short-term placebo-controlled BPH studies (n=665).

Uncontrolled Trials and Post-Marketing Experience

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

Laboratory Abnormalities

No clinically relevant adverse effects were noted on serum potassium, serum glucose, uric acid, blood urea nitrogen (BUN) 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 TEVA-DOXAZOSIN (doxazosin mesylate) in humans.

Should administration of TEVA-DOXAZOSIN 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 the evening.

The absorption of TEVA-DOXAZOSIN (doxazosin mesylate) is not affected by food.

When TEVA-DOXAZOSIN 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 TEVA-DOXAZOSIN regimen, reducing the dose of TEVA-DOXAZOSIN and retitration with careful monitoring may be necessary.

If TEVA-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 TEVA-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 - 6 hours after a dose.

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

Increases in dose >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 TEVA-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.

Doxazosin should be discontinued if the drug has been increased to the maximum tolerated dose and improvement in urinary flowmetry is <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

Common Name: Doxazosin mesylate

Chemical Name: 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl)piperazine methanesulfonate

Structural Formula:

N N CH₃O CH₃O NH₂ N N O O O CH₃SO₃H.

Molecular Formula: C₂₃H₂₅N₅O₅·CH₄O₃S

Molecular Weight: 547.6

Description: Doxazosin mesylate is a white to off-white crystalline solid of uniform appearance. It is freely soluble in dimethylsulphoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, and water (0.8% w/v at 25°C), and very slightly soluble in acetone and methylene chloride. The pKa of the doxazosin moiety is 6.93 at 25°C and the melting point of doxazosin mesylate is 273.7°C.

Composition:

TEVA-DOXAZOSIN (doxazosin mesylate) Tablets are formulated to contain doxazosin mesylate equivalent to 1, 2 and 4 mg of doxazosin.

The following excipients are used in the manufacture of TEVA-DOXAZOSIN Tablets: microcrystalline cellulose, lactose, pregelatinized starch, sodium starch glycolate, magnesium stearate, and sodium lauryl sulphate.

STABILITY AND STORAGE RECOMMENDATIONS

TEVA-DOXAZOSIN (doxazosin mesylate) Tablets are packaged in white high density polyethylene bottles and are stored at controlled room temperature between 15° to 30°C.

AVAILABILITY

TEVA-DOXAZOSIN (doxazosin mesylate) tablets are available as:

1 mg: white round, scored tablet, engraved with N/N on scored side and C01 on the other.

2 mg: white, capsule-shaped, scored tablet, engraved 2 “N’s” and a vertical scoreline on one side and 2 on the unscored side.

4 mg: white, modified diamond-shaped, scored tablet, engraved 2 “N’s” and a vertical scoreline on one side and 4 on the unscored side.

Available in white high density polyethylene bottles of 100, 500 and 1000 tablets.

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 α₁- as opposed to α₂-adrenoceptors. This was confirmed by the lack of effect of doxazosin on the α₂-mediated pressor responses induced by α-methylnoradrenaline. The lack of effect of doxazosin on prejunctional α₂-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 α₁-adrenoceptors. The superfused rabbit pulmonary artery preparation was used to show that doxazosin is highly selective (pre-synaptic activity EC₂₀=2 x 10^-5M vs post-synaptic activity EC₂₀=2.4 x 10^-8M); for the post-as opposed to the pre-junctional α 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 old (n=204), and those <65 years old (n=1,344) show similar falls in blood pressure. The changes in standing systolic/diastolic pressures were -15/-12 mm Hg for the patients ≥65 years old and -13/-11 mm Hg for the patients <65 years old.

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 3. 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 3: Summary of effectiveness data in placebo controlled trials.

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 3) 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 1 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 ≤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 4). The proportion of normotensive patients with a sitting systolic blood pressure <90 mm Hg and/or diastolic blood pressure <60 mm Hg at any time during treatment with doxazosin mesylate 1-8 mg once daily was 6.7% and not significantly different from that with placebo (5%).

Table 4: 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 ≤2 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 (≤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 ≤18 months in the diet of mice at doses ≤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 8x and 4x, 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 4x the AUC exposures obtained with a 12 mg/day human dose. This effect was reversible within 2 weeks of drug withdrawal.

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