Doxazosin 1 MG Oral Tablet
DRUG INTERACTIONS
7 • Strong cytochrome P450 (CYP) 3A inhibitors may increase exposure to doxazosin and increased risk of hypotension ( 7.1 ) • Concomitant administration of doxazosin tablets with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension.
( 7.2 ) 7.1 CYP3A Inhibitors In vitro studies suggest that doxazosin is a substrate of CYP3A4.
Strong CYP3A inhibitors may increase exposure to doxazosin.
Monitor blood pressure and for symptoms of hypotension when doxazosin tablets are used concomitantly with strong CYP3A inhibitors [see Clinical Pharmacology (12.3) ] .
7.2 Phosphodiesterase-5 (PDE-5) Inhibitors Concomitant administration of doxazosin tablets with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension.
Monitor blood pressure and for symptoms of hypotension [see Warnings and Precautions (5.1) ] .
OVERDOSAGE
10 Experience with doxazosin tablets overdosage is limited.
Two adolescents, who each intentionally ingested 40 mg doxazosin tablets with diclofenac or acetaminophen, were treated with gastric lavage with activated charcoal and made full recoveries.
A two-year-old child who accidently ingested 4 mg doxazosin tablets was treated with gastric lavage and remained normotensive during the five-hour emergency room observation period.
A six-month-old child accidentally received a crushed 1 mg tablet of doxazosin tablets and was reported to have been drowsy.
A 32-year-old female with chronic renal failure, epilepsy, and depression intentionally ingested 60 mg doxazosin tablets (blood level = 0.9 mcg/mL; normal values in hypertensives = 0.02 mcg/mL); death was attributed to a grand mal seizure resulting from hypotension.
A 39-year-old female who ingested 70 mg doxazosin tablets, alcohol, and Dalmane ® (flurazepam) developed hypotension which responded to fluid therapy.
The oral LD 50 of doxazosin is greater than 1000 mg/kg in mice and rats.
The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid.
As doxazosin is highly protein bound, dialysis would not be indicated.
DESCRIPTION
11 Doxazosin tablets, USP are a quinazoline compound that is a selective inhibitor of the alpha 1 subtype of alpha-adrenergic receptors.
The chemical name of doxazosin mesylate is 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine monomethanesulfonate.
The molecular formula for doxazosin mesylate is C 23 H 25 N 5 O 5 • CH 4 O 3 S and the molecular weight is 547.6.
It has the following structure: Doxazosin mesylate, USP is freely soluble in dimethylsulfoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, and water (0.8% at 25°C), and very slightly soluble in acetone and methylene chloride.
Doxazosin tablets are available as colored tablets for oral use and contain 1 mg (white to off-white), 2 mg (pink), 4 mg (blue) and 8 mg (purple) of doxazosin as the free base.
The inactive ingredients for all tablets are: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate (potato).
The 2 mg tablets also contain D&C Red No.
30 Aluminum Lake, the 4 mg tablets also contain FD&C Blue No.
2 Aluminum Lake, and the 8 mg tablets also contain D&C Red No.
30 Aluminum Lake and FD&C Blue No.
2 Aluminum Lake.
Doxazosin Structural Formula
CLINICAL STUDIES
14 14.1 Benign Prostatic Hyperplasia (BPH) The efficacy of doxazosin tablets was evaluated extensively in over 900 patients with BPH in double-blind, placebo-controlled trials.
Doxazosin tablets treatment was superior to placebo in improving patient symptoms and urinary flow rate.
Significant relief with doxazosin tablets was seen as early as one week into the treatment regimen, with doxazosin tablets-treated patients (N = 173) showing a significant (p < 0.01) increase in maximum flow rate of 0.8 mL/sec compared to a decrease of 0.5 mL/sec in the placebo group (N = 41).
In long-term studies, improvement was maintained for up to 2 years of treatment.
In 66% to 71% of patients, improvements above baseline were seen in both symptoms and maximum urinary flow rate.
In three placebo-controlled studies of 14 to 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 to 6 hours post-dose) and/or trough (24 hours post-dose) plasma concentrations of doxazosin tablets.
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 tablets resulted in statistically significant relief of obstructive and irritative symptoms compared to placebo.
Statistically significant improvements of 2.3 mL/sec to 3.3 mL/sec in maximum flow rate were seen with doxazosin tablets in Studies 1 and 2, compared to 0.1 mL/sec to 0.7 mL/sec with placebo.
In one fixed-dose study (Study 2), doxazosin tablets therapy (4 mg to 8 mg, once daily) resulted in a significant and sustained improvement in maximum urinary flow rate of 2.3 mL/sec to 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 tablets versus 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 tablets (34% to 42%) than placebo (13% to 17%).
A significantly greater improvement was also seen in average flow rate with doxazosin tablets (1.6 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.
Table 3.
Summary of Effectiveness Data in Placebo-Controlled Trials Figure 1 – Study 1 14.2 Hypertension In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive patients per treatment group, doxazosin, at doses of 1 mg to 16 mg given once daily, lowered blood pressure at 24 hours by about 10/8 mmHg compared to placebo in the standing position and about 9/5 mmHg in the supine position.
Peak blood pressure effects (1 to 6 hours) were larger by about 50% to 75% (i.e., trough values were about 55% to 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.
In the same patient population, patients receiving doxazosin tablets gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients.
Table 4.
Mean Changes in Blood Pressure from Baseline to the Mean of the Final Efficacy Phase in Normotensives (Diastolic BP < 90 mmHg) in Two Double-blind, Placebo-controlled U.S.
Studies with Doxazosin Tablets 1 mg to 8 mg once daily PLACEBO (N = 85) DOXAZOSIN TABLETS (N = 183) Sitting BP (mmHg) Baseline Change Baseline Change Systolic 128.4 –1.4 128.8 –4.9 p ≤ 0.05 compared to placebo Diastolic 79.2 –1.2 79.6 –2.4 Standing BP (mmHg) Baseline Change Baseline Change Systolic 128.5 –0.6 128.5 –5.3 Diastolic 80.5 –0.7 80.4 –2.6
HOW SUPPLIED
16 /STORAGE AND HANDLING Doxazosin Tablets, USP are available as tablets for oral administration.
Each tablet contains doxazosin mesylate, USP equivalent to 1 mg, 2 mg or 4 mg of doxazosin.
The 2 mg are available as pink round tablets debossed with M over D10 on one side of the tablet and scored on the other side.
They are available as follows: Overbagged with 10 tablets per bag, NDC 55154-5659-0 Recommended Storage: Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature.] PHARMACIST: Dispense a Patient Information Leaflet with each prescription.
GERIATRIC USE
8.5 Geriatric Use Benign Prostatic Hyperplasia (BPH) The safety and effectiveness profile of doxazosin tablets was similar in the elderly (age ≥ 65 years) and younger (age < 65 years) patients.
Hypertension Clinical studies of doxazosin tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
DOSAGE FORMS AND STRENGTHS
3 Doxazosin Tablets, USP are available containing doxazosin mesylate, USP equivalent to 1 mg, 2 mg, 4 mg or 8 mg of doxazosin.
• The 1 mg tablets are white to off-white, round tablets debossed with M over D9 on one side of the tablet and scored on the other side.
• The 2 mg tablets are pink, round tablets debossed with M over D10 on one side of the tablet and scored on the other side.
• The 4 mg tablets are blue, round tablets debossed with M over D11 on one side of the tablet and scored on the other side.
• The 8 mg tablets are purple, round tablets debossed with M over D12 on one side of the tablet and scored on the other side.
• Tablets: 1 mg, 2 mg, 4 mg, 8 mg.
MECHANISM OF ACTION
12.1 Mechanism of Action Benign Prostatic Hyperplasia (BPH) The symptoms associated with benign prostatic hyperplasia (BPH), such as urinary frequency, nocturia, weak stream, hesitancy, and incomplete emptying are related to two components, anatomical (static) and functional (dynamic).
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 the alpha 1 adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and bladder neck.
Blockade of the alpha 1 receptor decreases urethral resistance and may relieve the obstruction and BPH symptoms and improve urine flow.
Hypertension The mechanism of action of doxazosin tablets is selective blockade of the alpha 1 (postjunctional) subtype of adrenergic receptors.
Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an alpha 1 agonist) and the systolic pressor effect of norepinephrine.
Doxazosin and prazosin have similar abilities to antagonize phenylephrine.
The antihypertensive effect of doxazosin tablets results from a decrease in systemic vascular resistance.
The parent compound doxazosin is primarily responsible for the antihypertensive activity.
The low plasma concentrations of known active and inactive metabolites of doxazosin (2-piperazinyl, 6′- and 7′-hydroxy and 6- and 7-O-desmethyl compounds) compared to parent drug indicate that the contribution of even the most potent compound (6′-hydroxy) to the antihypertensive effect of doxazosin in man is probably small.
The 6′- and 7′-hydroxy metabolites have demonstrated antioxidant properties at concentrations of 5 µM, in vitro .
INDICATIONS AND USAGE
1 Doxazosin tablets are an alpha 1 adrenergic antagonist indicated for : • Signs and symptoms of Benign Prostatic Hyperplasia (BPH) • Treatment of Hypertension 1.1 Benign Prostatic Hyperplasia (BPH) Doxazosin tablets are indicated for the treatment of the signs and symptoms of BPH.
1.2 Hypertension Doxazosin tablets are indicated for the treatment of hypertension, to lower blood pressure.
Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.
These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including this drug.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.
Many patients will require more than one drug to achieve blood pressure goals.
For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.
The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.
Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).
These considerations may guide selection of therapy.
Doxazosin tablets may be used alone or in combination with other antihypertensives.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of doxazosin tablets have not been established in children.
PREGNANCY
8.1 Pregnancy Risk Summary The limited available data with doxazosin tablets in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage.
However, untreated hypertension during pregnancy can result in increased maternal risks [see Clinical Considerations ] .
In animal reproduction studies, no adverse developmental effects were observed when doxazosin was orally administered to pregnant rabbits and rats during the period of organogenesis at doses of up to 41 mg/kg and 20 mg/kg, respectively (exposures in rabbits and rats were 10 and 4 times, respectively, the human AUC exposures with a 12 mg/day therapeutic dose).
A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival [see Data ] .
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage).
Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.
Data Animal Data Radioactivity was found to cross the placenta following oral administration of labelled doxazosin to pregnant rats.
Studies in pregnant rabbits and rats at daily oral doses of up to 41 mg/kg and 20 mg/kg, respectively (plasma drug concentrations of 10 and 4 times, respectively, the human AUC exposures with a 12 mg/day therapeutic dose), have revealed no evidence of adverse developmental effects.
A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival.
In peri- and postnatal studies in rats, postnatal development at maternal doses of 40 mg/kg/day or 50 mg/kg/day of doxazosin (about 8 times human AUC exposure with a 12 mg/day therapeutic dose) was delayed, as evidenced by slower body weight gain and slightly later appearance of anatomical features and reflexes.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Postural hypotension with or without syncope may occur.
( 5.1 ) • Risk of Intraoperative Floppy Iris Syndrome during cataract surgery.
( 5.2 ) • Screen for the presence of prostate cancer prior to treatment for BPH and at regular intervals afterwards.
( 5.3 ) 5.1 Postural Hypotension Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of doxazosin tablets.
However, infrequently, symptomatic postural hypotension has also been reported later than a few hours after dosing.
As with other alpha-blockers, there is a potential for syncope, especially after the initial dose or after an increase in dosage strength.
Advise patient how to avoid symptoms resulting from postural hypotension and what measures to take should they develop.
Concomitant administration of doxazosin tablets with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension.
5.2 Cataract Surgery Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha 1 blockers.
This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions.
The patient’s surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances.
There does not appear to be a benefit of stopping alpha 1 blocker therapy prior to cataract surgery.
5.3 Prostate Cancer Carcinoma of the prostate causes many of the symptoms associated with BPH and the two disorders frequently co-exist.
Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with doxazosin tablets for the treatment of BPH.
5.4 Priapism Alpha 1 antagonists, including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation).
This condition can lead to permanent impotence if not promptly treated.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ).
Postural Hypotension: Advise patients of the possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, and urged to avoid driving or hazardous tasks for 24 hours after the first dose, after a dosage increase, and after interruption of therapy when treatment is resumed.
Advise patients to report symptoms to their healthcare provider.
Priapism: Advise patients of the possibility of priapism and to seek immediate medical attention if symptoms occur.
DOSAGE AND ADMINISTRATION
2 • For the treatment of BPH: Initiate therapy at 1 mg once daily.
Dose maybe titrated at 1 to 2 week intervals, up to 8 mg once daily.
( 2.2 ) • For the treatment of hypertension: Initiate therapy at 1 mg once daily.
Dose may be titrated as needed, up to 16 mg once daily.
( 2.3 ) 2.1 Dosing Information Following the initial dose and with each dose increase of doxazosin tablets, monitor blood pressure for at least 6 hours following administration.
If doxazosin tablets administration is discontinued for several days, therapy should be restarted using the initial dosing regimen.
2.2 Benign Prostatic Hyperplasia The recommended initial dosage of doxazosin tablets is 1 mg given once daily either in the morning or evening.
Depending on the individual patient’s urodynamics and BPH symptomatology, the dose may be titrated at 1 to 2 week intervals to 2 mg, and thereafter to 4 mg and 8 mg once daily.
The maximum recommended dose for BPH is 8 mg once daily.
Routinely monitor blood pressure in these patients.
2.3 Hypertension The initial dosage of doxazosin tablets is 1 mg given once daily.
Daily dosage may be doubled up 16 mg once daily, as needed, to achieve the desired reduction in blood pressure.