Doxazosin

C02C - Antiadrenergic agents, peripherally acting ATC C02CA04 Small molecule approved 1990 Oral Natural product

JFDA label: Prosta Tab

Mechanism of Action

Hypertension: Competitively inhibits postsynaptic alpha1-adrenergic receptors which results in vasodilation of veins and arterioles and a decrease in total peripheral resistance and blood pressure; ~50% as potent on a weight by weight basis as prazosin. BPH: Competitively inhibits postsynaptic alpha1-adrenergic receptors in prostatic stromal and bladder neck tissues. This reduces the sympathetic tone-induced urethral stricture causing BPH symptoms.

Indications

Approved

Benign prostatic hyperplasia
Hypertension (immediate release only)

Off-label

Pediatric hypertension
Ureteral calculi (distal)

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption Absolute
Hypersensitivity to doxazosin, other quinazolines (eg, prazosin, terazosin), or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (3)

Common Edema · hypotension · orthostatic hypotension, vertigo, pain, anxiety, ataxia, hypertonia, insomnia, movement disorder, myasthenia

Renal and urinary disorders (3)

Common Polyuria · Urinary incontinence · urinary tract infection

Metabolism and nutrition disorders (1)

Common Sexual disorder

Gastrointestinal disorders (4)

Common Abdominal pain · dyspepsia · nausea · xerostomia

Musculoskeletal and connective tissue disorders (5)

Common arthralgia · arthritis · muscle cramps · myalgia · Weakness

Eye disorders (1)

Common Visual disturbance

Ear and labyrinth disorders (1)

Common Tinnitus

Other (4)

Very Common Central nervous system: Dizziness · fatigue · headache · malaise

Respiratory, thoracic and mediastinal disorders (4)

Common dyspnea · epistaxis · Respiratory tract infection · rhinitis

Dosing

Source: Lexicomp

BPH: Oral: Immediate release: Initial: 1 mg once daily; may titrate (by doubling the daily dose [eg, to 2 mg, then 4 mg, then 8 mg]) at 1- to 2-week intervals up to 8 mg once daily based on patient response and tolerability (maximum: 8 mg/day). Reinitiation of therapy: If therapy is discontinued for several days, restart at 1 mg dose and titrate using initial dosing regimen. Extended release: 4 mg once daily; may titrate based on response and tolerability every 3 to 4 weeks to 8 mg once daily (maximum: 8 mg/day). Reinitiation of therapy: If therapy is discontinued for several days, restart at 4 mg dose and titrate using initial dosing regimen. Note: Conversion to extended release from immediate release: Omit final evening dose of immediate release prior to starting morning dosing with extended release product; initiate extended release product using 4 mg once daily. Hypertension: Oral: Immediate release: Initial: 1 mg once daily; may titrate by doubling the daily dosage up to 16 mg once daily based on blood pressure response; usual dosage range (ASH/ISH [Weber 2014]): 1 to 2 mg once daily; Maximum: 16 mg/day. Reinitiation of therapy: If therapy is discontinued for several days, restart at 1 mg dose and titrate using initial dosing regimen. Ureteral calculi (distal) expulsion (off-label use): Oral: Immediate release: 4 mg once daily in evening (Gurbuz 2011; Resorlu 2011). Note: Patients with stones >10 mm were excluded from studies.

(For additional information see "Doxazosin: Pediatric drug information") Hypertension (off-label use): Children and Adolescents 1 to 17 years: Oral: Immediate release: Initial: 1 mg once daily; maximum: 4 mg/day (NHBPEP 2004)

Refer to adult dosing. In the management of hypertension, consider lower initial doses (eg, immediate release: 0.5 mg once daily) and titrate to response (Aronow 2011)

There are no dosage adjustments provided in the manufacturer’s labeling (however, limited data suggest renal impairment does not significantly alter pharmacokinetic parameters).

Mild to moderate impairment (Child-Pugh class A or B): There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Severe impairment (Child-Pugh class C): Use is not recommended.

Warnings & Precautions

Source: Lexicomp

Allergic reactions

May occur, including skin rash, urticaria, pruritus, angioedema, and respiratory symptoms.

CNS depression

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

Floppy iris syndrome

Intraoperative floppy iris syndrome has been observed in cataract surgery patients who were on or were previously treated with alpha1-blockers; there appears to be no benefit in discontinuing alpha-blocker therapy prior to surgery. May require modifications to surgical technique.

Hematologic effect

Decreases in white blood cells (WBC) and neutrophil count have been reported; WBC and neutrophils returned to normal after discontinuation.

Orthostatic hypotension/syncope

May cause orthostatic hypotension and syncope within a few hours after dosing, but may occur later; anticipate a similar effect if therapy is interrupted for a few days, if dosage is increased, or if another antihypertensive drug, PDE-5 inhibitor, or nitrates are introduced. Use with caution in patients with symptomatic orthostatic hypotension.

Priapism

Priapism has been associated with use (rarely); seek immediate medical assistance for erections lasting longer than 4 hours. Disease-related concerns:

Cardiovascular disease

Use with caution in patients with heart failure, angina pectoris, or recent acute myocardial infarction (within the last 6 months). If symptoms of angina pectoris appear or worsen, discontinue use. In a scientific statement from the American Heart Association, doxazosin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: moderate) (AHA [Page 2016]).

Hepatic impairment

Use with caution in patients with mild to moderate impairment (Child-Pugh class A and B); monitor blood pressure and for symptoms of hypotension. Not recommended in severe impairment (Child-Pugh class C) (extensively metabolized).

Prostate cancer

Rule out prostatic carcinoma before beginning therapy (many symptoms of BPH and prostate cancer are similar). Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Extended release

Consists of drug within a nondeformable matrix; following drug release/absorption, the matrix/shell is expelled in the stool. The use of nondeformable products in patients with known stricture/narrowing of the GI tract has been associated with symptoms of obstruction. Use caution in patients with increased GI retention (eg, chronic constipation) as doxazosin exposure may be increased. Other warning/precautions:

Appropriate use

Extended release: Not indicated for use in women or for the treatment of hypertension.

Pregnancy & Lactation

Pregnancy

Adverse events were observed in some animal reproduction studies. Doxazosin crosses the placenta (Versmissen 2016). Untreated chronic maternal hypertension is associated with adverse events in the fetus, infant, and mother. If treatment for hypertension during pregnancy is needed, other agents are generally preferred (ACOG, 2013).

Lactation

Doxazosin is present in breast milk. Information is available from a single case report following a maternal dose of doxazosin 4 mg every 24 hours for 2 doses. Milk samples were obtained at various intervals over 24 hours, beginning ~17 hours after the first dose. Maternal serum samples were obtained at nearly the same times, beginning ~1 hour later. The highest serum and milk concentrations of doxazosin were observed ~1 hour after the dose. Using the highest milk concentration (4.15 mcg/L), the

Monitoring

Clinical pearl	Blood pressure routinely and for at least 6 hours after initial dose and with each dose increase (standing and sitting/supine); monitor patients with mild-to-moderate impairment for symptoms of hypotension.

Chemistry & Properties

Formula	C23H25N5O5
Molecular weight	451.48 g/mol
IUPAC name	[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl)methanone
CAS	74191-85-8
PubChem CID	3157
InChIKey	`RUZYUOTYCVRMRZ-UHFFFAOYSA-N`
logP	1.72 (XLogP 2.5)
Polar surface area	112.27 Å²
H-bond acceptors / donors	9 / 1
Drug-likeness (QED)	0.63
Lipinski violations	0

SMILES

COc1cc2nc(N3CCN(C(=O)C4COc5ccccc5O4)CC3)nc(N)c2cc1OC

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Substrate	—
CYP2C9	Inhibitor	—
CYP2C9	Substrate	—
CYP2D6	Substrate	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)NTCP (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (56, DDInter)

Interacting drug	Severity	Management
Aldesleukin	moderate
Alimemazine	moderate
Amifostine	moderate
Betamethasone	moderate
Brimonidine (ophthalmic)	moderate
Brimonidine (topical)	moderate
Budesonide	moderate
Bupropion	moderate
Canagliflozin	moderate
Ceritinib	moderate
Clarithromycin	moderate
Cobicistat	moderate
Codeine	moderate
Corticotropin	moderate
Dapagliflozin	moderate
Deflazacort	moderate
Dexamethasone	moderate
Diphenhydramine	moderate
Doxepin	moderate
Doxepin (topical)	moderate
Dronabinol	moderate
Empagliflozin	moderate
Epoprostenol	moderate
Ertugliflozin	moderate
Ethanol	moderate
Fludrocortisone	moderate
Hydrocodone	moderate
Hydrocortisone	moderate
Idelalisib	moderate
Iloprost	moderate
Ketoconazole	moderate
Larotrectinib	moderate
Mepyramine	moderate
Methdilazine	moderate
Methylprednisolone	moderate
Minoxidil (topical)	moderate
Morphine	moderate
Nabilone	moderate
Nitrous acid	moderate
Olopatadine (nasal)	moderate

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Registered Products (21)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Prosta Tab	Tablet 1 mg	20 tab pack varies	Al Hilal Drug Store	4.670
Prosta Tab	Tablet 2 mg	20 tab	Khoury Drug Store	4.700
Prosta Tab	Tablet 4 mg	20 tab pack varies	Khoury Drug Store	5.160
Alphapress 1	Tablet 1 mg	20 tab	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	5.260
Alphapress Tablets	Tablet as mesilate 4 mg	20 tab	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	5.260
Alphapress Tablets	Tablet (as Mesylate) 2 mg	20 tab	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	5.260
Cardox	Tablet 1 mg	20 tab pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	5.260
Cardox	Tablet as Mesylate 4 mg	20 tab pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	5.260
Curcard	Tablet 1 mg	20 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	5.260
CARDURA TABS	Tablet 1 mg	20 tab	Khoury Drug Store	5.610
CARDURA TABS	Tablet 4 mg	20 tab	Khoury Drug Store	5.610
Curcard Tablets	Tablet 4 mg	20 tab pack varies	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	6.550
Alphapress	Tablet 8 mg	20 tab	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	6.590
Prosta Tab	Tablet 1 mg	30 tab pack varies	Al Hilal Drug Store	7.000
Cardura XL	Tablet 4 mg	28 tab	Sabbagh Drug Store	7.260
Prosta Tab	Tablet 4 mg	30 tab pack varies	Khoury Drug Store	7.740
Cardox	Tablet as Mesylate 4 mg	30 tab pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	7.890
Cardox	Tablet 1 mg	30 tab pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	7.890
Cardura XL	Tablet 8 mg	28 tab	Sabbagh Drug Store	11.540
Prosta Tab	Tablet 4 mg	1000 tab pack varies	Khoury Drug Store	219.290
Curcard Tablets	Tablet 4 mg	1000 tab pack varies	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	278.380