Doxazosin Zentiva (Tablets) Instructions for Use

Marketing Authorization Holder

Zentiva, k.s. (Czech Republic)

ATC Code

C02CA04 (Doxazosin)

Active Substance

Doxazosin (Rec.INN registered by WHO)

Dosage Forms

	Doxazosin Zentiva	Tablets 1 mg: 15 or 30 pcs.
		Tablets 2 mg: 10, 30, 60 or 90 pcs.
		Tablets 4 mg: 30, 60, 90 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat, with an engraving “ZX 1” on one side.

Excipients : lactose – 40 mg, granulated microcrystalline cellulose – 31.267 mg, microcrystalline cellulose – 45 mg, sodium carboxymethyl starch (type A) – 1.2 mg, colloidal anhydrous silicon dioxide – 0.12 mg, sodium lauryl sulfate – 0.12 mg, magnesium stearate – 1.08 mg.

15 pcs. – blisters (1) – cardboard packs.
15 pcs. – blisters (2) – cardboard packs.

Tablets white or almost white, oblong, biconvex, with an engraving “ZX 2” and a score line for division on one side.

Excipients : lactose – 40 mg, granulated microcrystalline cellulose – 45 mg, microcrystalline cellulose – 30.055 mg, sodium carboxymethyl starch (type A) – 1.2 mg, colloidal anhydrous silicon dioxide – 0.12 mg, sodium lauryl sulfate – 0.12 mg, magnesium stearate – 1.08 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Tablets white or almost white, oblong, biconvex, with an engraving “ZX 4” and a score line for division on one side.

Excipients : lactose – 80 mg, granulated microcrystalline cellulose – 90 mg, microcrystalline cellulose – 60.11 mg, sodium carboxymethyl starch (type A) – 2.4 mg, colloidal anhydrous silicon dioxide – 0.24 mg, sodium lauryl sulfate – 0.24 mg, magnesium stearate – 2.16 mg.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Alpha₁-adrenergic blocker. Antihypertensive agent. Agent used for urination disorders in benign prostatic hyperplasia

Pharmacotherapeutic Group

Alpha1-adrenergic blocker

Pharmacological Action

Benign prostatic hyperplasia

Prescribing doxazosin to patients with symptoms of benign prostatic hyperplasia (BPH) leads to a significant improvement in urodynamic parameters and a reduction in the manifestations of disease symptoms. This action of the drug is associated with the selective blockade of α₁-adrenergic receptors located in the muscular stroma and capsule of the prostate gland, and the bladder neck.

It has been proven that Doxazosin is an effective blocker of the 1A subtype of α₁-adrenergic receptors, which constitute approximately 70% of all α₁-adrenergic receptor subtypes present in the prostate gland. This explains its action in patients with BPH.

The treatment effect of doxazosin and its safety have been proven with long-term use of the drug (more than 48 months).

Arterial hypertension

The use of doxazosin in patients with arterial hypertension leads to a significant decrease in blood pressure due to a reduction in total peripheral vascular resistance. The occurrence of this effect is associated with the selective blockade of α₁-adrenergic receptors located in blood vessels. When the drug is taken once a day, a clinically significant antihypertensive effect persists for 24 hours; blood pressure decreases gradually; the maximum effect is usually observed 2-6 hours after oral administration.

Unlike non-selective α₁-adrenergic blockers, tolerance to the drug does not develop with long-term treatment. During maintenance therapy, increased plasma renin activity and tachycardia are uncommon.

Doxazosin has a beneficial effect on the blood lipid profile, significantly increasing the ratio of high-density lipoproteins to total cholesterol (atherogenic index) and significantly reducing the content of triglycerides and total cholesterol.

Given the established relationship between arterial hypertension, lipid profile, and coronary heart disease (CHD), the normalization of blood pressure and lipid concentrations while taking doxazosin leads to a reduction in the risk of developing CHD. It was observed that treatment with doxazosin led to the regression of left ventricular hypertrophy, inhibition of platelet aggregation, and enhancement of tissue plasminogen activator activity. Furthermore, it has been established that Doxazosin increases insulin sensitivity in patients with impaired glucose tolerance. Doxazosin does not have adverse effects on metabolism and can be used in patients with bronchial asthma, diabetes mellitus, left ventricular failure, and gout.

In controlled clinical trials conducted in patients with arterial hypertension, treatment with doxazosin was accompanied by a lower incidence of erectile dysfunction.

Pharmacokinetics

Absorption and distribution

After oral administration, Doxazosin is well absorbed from the gastrointestinal tract (80-90%). C_max in blood plasma is reached 1-2 hours after administration.

Up to 98% is bound to plasma proteins. Bioavailability is 69-70% (presystemic metabolism).

Metabolism and excretion

Doxazosin undergoes significant biotransformation in the liver; metabolites do not possess pharmacological activity.

Elimination of the drug from plasma is biphasic, with a terminal T_1/2 of 22 hours. Most of the orally administered doxazosin is excreted as inactive metabolites through the intestines; less than 5% of the administered dose is excreted unchanged.

Pharmacokinetics in special clinical cases

In patients with impaired liver function, as well as when taking drugs that can alter hepatic metabolism, the biotransformation process of the drug may be impaired.

A study of pharmacokinetics in elderly patients and in patients with kidney diseases did not reveal significant pharmacokinetic differences.

Indications

• Benign prostatic hyperplasia;
• Arterial hypertension (as part of combination therapy).

ICD codes

Dosage Regimen

The drug Doxazosin Zentiva is prescribed orally regardless of meals and can be taken either in the morning or in the evening. The tablet should be swallowed without chewing, with a sufficient amount of water.

Benign prostatic hyperplasia

The recommended initial dose of Doxazosin Zentiva is 1 mg once a day to minimize the possibility of developing postural hypotension and/or syncope (fainting). Depending on the individual characteristics of urodynamic parameters and the presence of BPH symptoms, the dose can be increased to 2 mg, then to 4 mg, and up to the maximum recommended dose of 8 mg. The recommended interval for dose increase is 1-2 weeks. The usual recommended maintenance dose is 2-4 mg once a day.

Arterial hypertension

The dose ranges from 1 mg/day to 16 mg/day. It is recommended to start treatment with 1 mg once a day for 1 or 2 weeks to minimize the possibility of developing postural hypotension and/or syncope (fainting) (“first-dose” phenomenon). After the first dose, the patient’s blood pressure should be monitored for 6-8 hours. This is required due to the possibility of the “first-dose” phenomenon, especially pronounced against the background of previous diuretic use.

Over the next 1 or 2 weeks, the dose may be increased to 2 mg once a day.

To achieve the desired reduction in blood pressure, if necessary, the daily dose should be increased gradually, maintaining uniform intervals up to 4 mg, 8 mg, and up to the maximum of 16 mg, depending on the severity of the patient’s response to the drug. The usual dose is 2-4 mg once a day.

If a diuretic or another antihypertensive agent is added to the therapy, the dose of Doxazosin Zentiva should be adjusted according to the patient’s condition with further titration under medical supervision.

If therapy with Doxazosin Zentiva has been interrupted for several days, resumption of the drug should start with the initial dose.

In elderly patients, dose adjustment is not required.

The pharmacokinetics of doxazosin in patients with renal insufficiency do not change, and the drug itself does not worsen existing renal dysfunction, so it is used in usual doses in such patients.

In patients with hepatic insufficiency, the drug should be used with caution.

The use of Doxazosin Zentiva is contraindicated in children and adolescents under 18 years of age due to the lack of sufficient data on efficacy and safety.

Adverse Reactions

Adverse reactions are divided by system-organ classes in accordance with the Medical Dictionary for Regulatory Activities (MedDRA) classification. The WHO classification was used to indicate the frequency of adverse effects: very common (≥10%); common (≥1% and <10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%); unknown frequency (it is not possible to determine the frequency of the adverse effect from the available data).

Infections and infestations: common – respiratory tract infections, urinary tract infections.

Blood and lymphatic system disorders: very rare – thrombocytopenia, leukopenia.

Immune system disorders: uncommon – allergic drug reactions; very rare – anaphylactic reactions.

Metabolism and nutrition disorders: uncommon – anorexia, increased appetite, weight gain, gout.

Psychiatric disorders: uncommon – agitation, restlessness, insomnia, anxiety, depression.

Nervous system disorders: common – drowsiness, headache, dizziness; uncommon – hypoesthesia, tremor, syncope, cerebrovascular accident; very rare – paresthesia.

Eye disorders: very rare – blurred vision; unknown frequency – intraoperative floppy iris syndrome (a variant of small pupil syndrome).

Ear and labyrinth disorders: common – vertigo; uncommon – tinnitus.

Cardiac disorders: common – palpitations, tachycardia; uncommon – angina pectoris, myocardial infarction; very rare – bradycardia, arrhythmia.

Vascular disorders: common – marked decrease in blood pressure, postural hypotension; very rare – flushing.

Respiratory, thoracic and mediastinal disorders: common – dyspnea, rhinitis, cough, bronchitis; uncommon – epistaxis; very rare – bronchospasm.

Gastrointestinal disorders: common – abdominal pain, dyspepsia, dry mouth, nausea; uncommon – flatulence, diarrhea, constipation, vomiting, gastroenteritis.

Hepatobiliary disorders: very rare – cholestasis, hepatitis, jaundice.

Investigations: very rare – increased liver transaminase activity.

Skin and subcutaneous tissue disorders: common – pruritus; uncommon – skin rash; very rare – purpura, alopecia, urticaria.

Musculoskeletal and connective tissue disorders: common – back pain, myalgia; uncommon – arthralgia; rare – muscle spasms, muscle weakness.

Renal and urinary disorders: common – cystitis, urinary incontinence; uncommon – increased frequency of urination, dysuria, hematuria; rare – polyuria; very rare – nocturia, increased daily diuresis.

Reproductive system and breast disorders: uncommon – erectile dysfunction; very rare – gynecomastia, priapism; unknown frequency – retrograde ejaculation.

General disorders and administration site conditions: common – asthenia, peripheral edema, chest pain, flu-like syndrome; uncommon – facial edema, pain of various localizations; very rare – fatigue, malaise.

Contraindications

• Severe hepatic insufficiency (lack of experience of use in this category of patients);
• Urinary tract infections;
• Anuria;
• Progressive renal failure;
• Arterial hypotension with orthostatic disorders (including in history);
• Hypotension (applies only to the indication benign prostatic hyperplasia);
• Concomitant obstruction of the upper urinary tract;
• Chronic urinary tract infections;
• Bladder stones;
• Obstructive disorders of the gastrointestinal tract;
• Esophageal obstruction;
• Reduction in the diameter of the lumen of the gastrointestinal tract of any degree;
• Lactose intolerance, lactase deficiency or glucose-galactose malabsorption (due to the presence of lactose in the composition);
• Age under 18 years;
• Breastfeeding period (for the treatment of arterial hypertension);
• Hypersensitivity to quinazoline derivatives (e.g., prazosin, terazosin, doxazosin), or to any of the excipients of the drug.

As monotherapy

• Patients with bladder overflow;
• Anuria with or without progressive renal failure.

With caution the drug should be used in pulmonary edema caused by mitral valve stenosis or aortic stenosis; heart failure with high cardiac output; right ventricular failure due to pulmonary embolism or exudative pericarditis; left ventricular failure with low filling pressure; cerebrovascular accidents; in elderly patients; simultaneous use with PDE-5 inhibitors (risk of symptomatic arterial hypotension); in hepatic insufficiency; during pregnancy; during cataract surgery.

Use in Pregnancy and Lactation

Although experiments in animals did not reveal a teratogenic effect of the drug, when used in exceptionally high doses, a decrease in fetal survival was observed. These doses were approximately 300 times higher than the maximum recommended doses for humans.

Due to the lack of adequate, well-controlled studies in pregnant women, the safety of the drug during pregnancy has not been established. In this regard, the drug can be prescribed during pregnancy only in cases where the intended benefit to the mother outweighs the potential risk to the fetus.

Doxazosin is contraindicated during breastfeeding, as experimental studies in animals have shown that Doxazosin accumulates in the milk of lactating rats. There is no information on the excretion of the drug into breast milk.

If it is necessary to use the drug, breastfeeding should be discontinued.

Use in Hepatic Impairment

Caution should be exercised when prescribing Doxazosin Zentiva, as well as other drugs that undergo complete biotransformation in the liver, to patients with impaired liver function, avoiding the prescription of maximum doses. The use of Doxazosin Zentiva is not recommended in patients with severe hepatic insufficiency due to the lack of sufficient experience of use.

Use in Renal Impairment

The pharmacokinetics of doxazosin in patients with renal insufficiency do not change, and the drug itself does not worsen existing renal dysfunction, so it is used in usual doses in such patients.

Pediatric Use

The use of Doxazosin Zentiva is contraindicated in children under 18 years of age due to the lack of sufficient data on efficacy and safety.

Geriatric Use

In elderly patients, dose adjustment is not required, but the drug should be used with caution due to the possibility of developing orthostatic hypotension. With age, the risk of dizziness, visual disturbances, and fainting increases.

Special Precautions

As with treatment with any alpha₁-adrenergic blockers, especially at the beginning of therapy, treatment with Doxazosin Zentiva may cause postural hypotension in a very small percentage of patients, manifested by dizziness and weakness or loss of consciousness (syncope). Before starting treatment with Doxazosin Zentiva, the patient should be warned about how to avoid the symptoms of postural hypotension; in particular, it is necessary to refrain from rapid changes in body position. At the beginning of treatment with Doxazosin Zentiva, the patient should be advised to exercise caution in case of weakness or dizziness.

Doxazosin Zentiva should be used with caution in elderly patients due to the possibility of developing orthostatic hypotension. With age, the risk of dizziness, visual disturbances, and fainting increases. The patient should be informed about the increased risk of orthostatic hypotension when consuming alcohol, prolonged standing or exercising, as well as in hot weather.

Benign prostatic hyperplasia (BPH)

Before starting therapy for BPH, it is necessary to exclude malignant neoplasm of the prostate gland. In patients with BPH, the drug can be prescribed both in the presence of arterial hypertension and with normal blood pressure levels. When using the drug in patients with BPH with normal blood pressure, changes in the latter are insignificant. At the same time, the use of Doxazosin Zentiva in patients with a combination of arterial hypertension and BPH is possible as monotherapy.

Doxazosin does not affect the concentration of prostate-specific antigen (PSA) in blood plasma.

Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (a variant of small pupil syndrome) has been observed in some patients undergoing cataract surgery who are receiving or have previously received treatment with alpha₁-blockers.

Since Intraoperative Floppy Iris Syndrome can increase the rate of complications during surgical interventions, the operating surgeon must be informed that alpha₁-blockers are being taken currently or were taken in the past prior to surgery.

Concomitant use with PDE-5 inhibitors

Caution should be exercised when using doxazosin concomitantly with PDE-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil), as both drugs have vasodilatory effects and may lead to symptomatic arterial hypotension in some patients.

To reduce the risk of orthostatic hypotension, treatment with PDE-5 inhibitors should be initiated only after the patient’s hemodynamics have stabilized on alpha-blocker therapy.

Furthermore, treatment with PDE-5 inhibitors should be started at the lowest possible dose and a 6-hour interval from the doxazosin intake should be maintained.

No studies have been conducted with prolonged-release doxazosin preparations.

Hepatic impairment

Caution should be exercised when prescribing Doxazosin ZENTIVA, as well as other medicines that undergo complete biotransformation in the liver, to patients with impaired liver function, avoiding the use of maximum doses.

The use of Doxazosin ZENTIVA is not recommended in patients with severe hepatic insufficiency due to a lack of sufficient experience with its use.

The product contains lactose. It is contraindicated in patients with hereditary lactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Effect on ability to drive and operate machinery

Since drowsiness, dizziness, and fainting may occur from the nervous system during treatment with Doxazosin ZENTIVA, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms: pronounced decrease in blood pressure, sometimes accompanied by fainting.

Treatment: if signs of overdose appear, gastric lavage should be performed and activated charcoal administered; the patient should be placed in a horizontal position with the head down and legs elevated.

It is necessary to consult a doctor urgently.

Symptomatic therapy is carried out.

Since Doxazosin is highly bound to plasma proteins, hemodialysis is not effective.

Drug Interactions

Concomitant use of Doxazosin ZENTIVA with PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) may lead to symptomatic arterial hypotension in some patients.

It is not recommended to take Doxazosin ZENTIVA simultaneously with other α₁-adrenergic receptor blockers.

Doxazosin ZENTIVA enhances the hypotensive effect of other antihypertensive drugs.

Doxazosin is highly bound to plasma proteins (98%). Data from in vitro studies have shown that Doxazosin does not affect the protein binding of the following drugs: digoxin, phenytoin, warfarin, or indomethacin.

No undesirable drug interactions were observed in clinical studies with thiazide diuretics, furosemide, beta-blockers, NSAIDs, antibiotics, oral hypoglycemic agents, uric acid excretion agents, and anticoagulants.

No adverse interaction was noted with the simultaneous use of doxazosin and slow calcium channel blockers and ACE inhibitors.

When used concomitantly with inducers of microsomal oxidation in the liver, an increase in the effectiveness of doxazosin is possible; with inhibitors – a decrease.

Estrogens and sympathomimetic agents may reduce the hypotensive effect of doxazosin.

By eliminating the alpha-adrenostimulating effects of adrenaline, Doxazosin can lead to tachycardia and arterial hypotension.

In an open, randomized, placebo-controlled study in 22 healthy male volunteers, administration of a single dose of doxazosin 1 mg/day on the first day of a four-day regimen of cimetidine (400 mg orally twice daily) led to a 10% increase in the mean AUC of doxazosin without statistically significant changes in the mean C_max and T_1/2 of doxazosin.

The 10% increase in the mean AUC for doxazosin with cimetidine is within the value of the interindividual variability (27%) of the mean AUC for doxazosin with placebo.

Storage Conditions

The product should be stored in a place protected from light, out of the reach of children, at a temperature of 10-25°C (50-77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The product is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.