Doxazosin 2 MG Oral Tablet
Generic Name: DOXAZOSIN
Brand Name: Doxazosin
- Substance Name(s):
- DOXAZOSIN MESYLATE
WARNINGS
Syncope and “First-dose” Effect Doxazosin, like other alpha-adrenergic blocking agents, can cause marked hypotension, especially in the upright position, with syncope and other postural symptoms such as dizziness.
Marked orthostatic effects are most common with the first dose but can also occur when there is a dosage increase, or if therapy is interrupted for more than a few days.
To decrease the likelihood of excessive hypotension and syncope, it is essential that treatment be initiated with the 1 mg dose.
The 2 mg, 4 mg, and 8 mg tablets are not for initial therapy.
Dosage should then be adjusted slowly (see DOSAGE AND ADMINISTRATION) with evaluations and increases in dose every 2 weeks to the recommended dose.
Additional antihypertensive agents should be added with caution.
Patients being titrated with doxazosin should be cautioned to avoid situations where injury could result should syncope occur, during both the day and night.
In an early investigational study of the safety and tolerance of increasing daily doses of doxazosin in normotensives beginning at 1 mg/day, only two of six subjects could tolerate more than 2 mg/day without experiencing symptomatic postural hypotension.
In another study of 24 healthy normotensive male subjects receiving initial doses of 2 mg/day of doxazosin, seven (29%) of the subjects experienced symptomatic postural hypotension between 0.5 and 6 hours after the first dose, necessitating termination of the study.
In this study, two of the normotensive subjects experienced syncope.
Subsequent trials in hypertensive patients always began doxazosin dosing at 1 mg/day, resulting in a 4% incidence of postural side effects at 1 mg/day with no cases of syncope.
In multiple dose clinical trials in hypertension involving over 1,500 hypertensive patients with dose titration every 1 to 2 weeks, syncope was reported in 0.7% of patients.
None of these events occurred at the starting dose of 1 mg and 1.2% (8/664) occurred at 16 mg/day.
In placebo-controlled clinical trials in BPH, three out of 665 patients (0.5%) taking doxazosin reported syncope.
Two of the patients were taking 1 mg doxazosin, while one patient was taking 2 mg doxazosin when syncope occurred.
In the open-label, long-term extension follow-up of approximately 450 BPH patients, there were three reports of syncope (0.7%).
One patient was taking 2 mg, one patient was taking 8 mg and one patient was taking 12 mg when syncope occurred.
In a clinical pharmacology study, one subject receiving 2 mg experienced syncope.
If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary.
Priapism Rarely (probably less frequently than once in every several thousand patients), alpha1 antagonists, including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation).
Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition (see PRECAUTIONS: Information for Patients).
DRUG INTERACTIONS
Drug Interactions Most (98%) of plasma doxazosin is protein bound.
In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin.
There is no information on the effect of other highly plasma protein bound drugs on doxazosin binding.
Doxazosin has been administered without any evidence of an adverse drug interaction to patients receiving thiazide diuretics, beta-blocking agents, and nonsteroidal anti-inflammatory drugs.
In a placebo-controlled trial in normal volunteers, the administration of a single 1 mg dose of doxazosin on day one of a 4-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin (p = 0.006), and a slight but not statistically significant increase in mean Cmax and mean half-life of doxazosin.
The clinical significance of this increase in doxazosin AUC is unknown.
In clinical trials, doxazosin tablets have been administered to patients on a variety of concomitant medications; while no formal interaction studies have been conducted, no interactions were observed.
Doxazosin tablets have been used with the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine and codeine combinations, ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole, amoxicillin); 3) antihistamines (e.g., chlorpheniramine); 4) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, propranolol); 5) corticosteroids; 6) gastrointestinal agents (e.g., antacids); 7) hypoglycemics and endocrine drugs; 8) sedatives and tranquilizers (e.g., diazepam); 9) cold and flu remedies.
Concomitant administration of doxazosin tablets with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension (see DOSAGE AND ADMINISTRATION).
OVERDOSAGE
Experience with doxazosin overdosage is limited.
Two adolescents who each intentionally ingested 40 mg doxazosin with diclofenac or acetaminophen, were treated with gastric lavage with activated charcoal and made full recoveries.
A 2-year-old child who accidentally ingested 4 mg doxazosin was treated with gastric lavage and remained normotensive during the 5-hour emergency room observation period.
A 6-month-old child accidentally received a crushed 1 mg tablet of doxazosin and was reported to have been drowsy.
A 32-year-old female with chronic renal failure, epilepsy and depression intentionally ingested 60 mg doxazosin (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, alcohol and flurazepam developed hypotension which responded to fluid therapy.
The oral LD50 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
Doxazosin mesylate is a quinazoline compound that is a selective inhibitor of the alpha1 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 methanesulfonate.
The molecular formula for doxazosin mesylate is C23H25N5O5 • CH4O3S and the molecular weight is 547.6.
It has the following structure: Doxazosin mesylate 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, USP for oral administration, contain 1 mg, 2 mg, 4 mg or 8 mg of doxazosin as doxazosin mesylate, USP.
In addition, each tablet also contains the following inactive ingredients: anhydrous lactose, colloidal silicon, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate.
The 2 mg tablets also contain D&C Red No.
30 Aluminum Lake, the 4 mg tablets contain FD&C Blue No.
2 Aluminum Lake, and the 8 mg tablets contain D&C Red No.
30 Aluminum Lake and FD&C Blue No.
2 Aluminum Lake.
Structural Formula
HOW SUPPLIED
: 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 1 mg are available as white to off-white round tablets debossed with M over D9 on one side of the tablet and scored on the other side.
They are available as follows: Overbagged with 10 tablets per bag, NDC 55154-5468-0 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 The 4 mg are available as blue round tablets debossed with M over D11 on one side of the tablet and scored on the other side.
They are available as follows: Overbagged with 10 tablets per bag, NDC 55154-5469-0 Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature.] PHARMACIST: Dispense a Patient Information Leaflet with each prescription.
Repackaged By: Cardinal Health Zanesville, OH 43701
GERIATRIC USE
Geriatric Use The safety and effectiveness profile of doxazosin in BPH was similar in the elderly (age ≥ 65 years) and younger (age < 65 years) patients.
For Hypertension Clinical studies of doxazosin 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.
INDICATIONS AND USAGE
Benign Prostatic Hyperplasia (BPH) Doxazosin tablets are indicated for the treatment of both the urinary outflow obstruction and obstructive and irritative symptoms associated with BPH: obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning).
Doxazosin tablets may be used in all BPH patients whether hypertensive or normotensive.
In patients with hypertension and BPH, both conditions were effectively treated with doxazosin tablet monotherapy.
Doxazosin tablets provide rapid improvement in symptoms and urinary flow rate in 66% to 71% of patients.
Sustained improvements with doxazosin tablets were seen in patients treated for up to 14 weeks in double-blind studies and up to 2 years in open-label studies.
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 diuretics, beta-adrenergic blocking agents, calcium channel blockers or angiotensin-converting enzyme inhibitors.
PEDIATRIC USE
Pediatric Use The safety and effectiveness of doxazosin as an antihypertensive agent have not been established in children.
PREGNANCY
Pregnancy Teratogenic Effects.
Pregnancy Category C Studies in pregnant rabbits and rats at daily oral doses of up to 41 and 20 mg/kg, respectively (plasma drug concentrations 10 and 4 times human Cmax and AUC exposures with a 12 mg/day therapeutic dose), have revealed no evidence of harm to the fetus.
A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival.
There are no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, doxazosin should be used during pregnancy only if clearly needed.
Radioactivity was found to cross the placenta following oral administration of labeled doxazosin to pregnant rats.
Nonteratogenic Effects In peri-postnatal studies in rats, postnatal development at maternal doses of 40 or 50 mg/kg/day of doxazosin (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.
NUSRING MOTHERS
Nursing Mothers 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 concentration about 20 times greater than the maternal plasma concentration.
It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when doxazosin is administered to a nursing mother.
INFORMATION FOR PATIENTS
Information for Patients (See Patient Package Insert) Patients should be made aware 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.
They should be cautioned to avoid situations where injury could result should syncope occur during initiation of doxazosin therapy.
They should also be advised of the need to sit or lie down when symptoms of lowered blood pressure occur, although these symptoms are not always orthostatic, and to be careful when rising from a sitting or 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 doxazosin or any selective alpha1 adrenoceptor antagonist, requiring caution in people who must drive or operate heavy machinery.
Patients should be advised about the possibility of priapism as a result of treatment with alpha1 antagonists.
Patients should know that this adverse event is very rare.
If they experience priapism, it should be brought to immediate medical attention, for, if not treated promptly, it can lead to permanent erectile dysfunction (impotence).
DOSAGE AND ADMINISTRATION
DOSAGE MUST BE INDIVIDUALIZED.
The initial dosage of doxazosin tablets in patients with hypertension and/or BPH is 1 mg given once daily in the a.m.
or p.m.
This starting dose is intended to minimize the frequency of postural hypotension and first dose syncope associated with doxazosin tablets.
Postural effects are most likely to occur between 2 and 6 hours after a dose.
Therefore, blood pressure measurements should be taken during this time period after the first dose and with each increase in dose.
If doxazosin tablet administration is discontinued for several days, therapy should be restarted using the initial dosing regimen.
Concomitant administration of doxazosin tablets with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy should be initiated at the lowest dose in patients taking doxazosin tablets.
Benign Prostatic Hyperplasia 1 mg to 8 mg Once Daily The initial dosage of doxazosin tablets is 1 mg, given once daily in the a.m.
or p.m.
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 for BPH.
The recommended titration interval is 1 to 2 weeks.
Blood pressure should be evaluated routinely in these patients.
Hypertension 1 mg to 16 mg Once Daily The initial dosage of doxazosin tablets is 1 mg given once daily.
Depending on the individual patient’s standing blood pressure response (based on measurements taken at 2 to 6 hours post-dose and 24 hours post-dose), dosage may then be increased to 2 mg and thereafter if necessary to 4 mg, 8 mg and 16 mg to achieve the desired reduction in blood pressure.
Increases in dose beyond 4 mg increase 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.