Doxazosin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOXAZOSIN

Composition:

Active substance: doxazosin;

1 tablet contains doxazosin mesylate equivalent to doxazosin 1 mg, or 2 mg, or 4 mg;

Excipients: microcrystalline cellulose; lactose monohydrate; maize starch; calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white-colored, biconvex tablets.

Pharmacotherapeutic group. Antihypertensive agents. Antiadrenergic agents with peripheral mechanism of action. α-Adrenoreceptor blockers. ATC code C02CA04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Doxazosin is a potent and selective antagonist of postsynaptic α1-adrenoceptors. Blockade of these receptors leads to reduction in systemic arterial pressure. Doxazosin is intended for once-daily oral administration to patients with essential arterial hypertension.

Pharmacodynamic effects.

It has been demonstrated that doxazosin does not cause undesirable metabolic effects and can be used in patients with diabetes mellitus, gout, or insulin resistance.

Doxazosin can also be prescribed to patients with bronchial asthma, left ventricular hypertrophy, and elderly patients. The use of the drug contributes to reduction of left ventricular hypertrophy, inhibits platelet aggregation, and enhances tissue plasminogen activator activity. In addition, doxazosin treatment increases insulin sensitivity in patients with impaired insulin sensitivity.

It has also been reported that, in addition to its antihypertensive effect, doxazosin administration causes a moderate reduction in plasma concentrations of total cholesterol, low-density lipoproteins, and triglycerides. Therefore, this drug may be particularly beneficial for patients with arterial hypertension and hyperlipidemia.

Administration of doxazosin to patients with symptomatic benign prostatic hyperplasia (BPH) leads to significant improvement in urodynamics and reduction of symptoms. The effect of the drug in BPH is believed to be achieved through selective blockade of α1-adrenoceptors located in the smooth muscle stroma and capsule of the prostate gland, as well as in the bladder neck.

Pharmacokinetics.

Absorption. After oral administration in humans (young men or elderly individuals of either gender), doxazosin is rapidly absorbed with a bioavailability of approximately two-thirds of the administered dose.

Biotransformation/Elimination. Approximately 98% of doxazosin is bound to plasma proteins. Doxazosin has been shown to be extensively metabolized in humans and in experimental animals and is primarily eliminated via feces.

The mean elimination half-life (T½) of the drug in plasma is 22 hours, allowing once-daily dosing.

After oral administration of doxazosin, plasma concentrations of metabolites are low. The plasma concentration of the most active metabolite, 6'-hydroxydoxazosin, is 40 times lower than the plasma concentration of the parent compound, indicating that the antihypertensive effect of the drug is primarily due to doxazosin itself.

Currently, there are only limited data available on the use of the drug in patients with impaired hepatic function and on the effects of drugs capable of altering hepatic metabolism (e.g., cimetidine). As with other drugs that are completely metabolized by the liver, doxazosin should be used with particular caution in patients with signs of hepatic dysfunction.

Clinical characteristics.

Indications.

Arterial hypertension. The drug is indicated for the treatment of arterial hypertension and for most patients it can be used as monotherapy to control blood pressure. In cases where monotherapy is ineffective, the drug may be used in combination with thiazide diuretics, β-adrenergic blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors for the treatment of arterial hypertension.

Benign prostatic hyperplasia (BPH). The drug is indicated for the treatment of urinary obstruction and symptoms associated with benign prostatic hyperplasia (BPH). The drug can be prescribed to patients with BPH both in the presence and absence of arterial hypertension.

Contraindications. Hypersensitivity to the active substance or to quinazoline derivatives (e.g., prazosin, terazosin, doxazosin) or to any of the excipients listed in the section "Composition"; history of orthostatic hypotension; BPH with concomitant upper urinary tract obstruction, chronic urinary tract infections, and presence of bladder stones; during breastfeeding (only when used for the treatment of arterial hypertension (see section "Use in pregnancy or breastfeeding")); arterial hypotension (applies only to patients with BPH). Doxazosin as monotherapy is contraindicated in patients with bladder distension or anuria with or without progressive renal insufficiency.

Interaction with other medicinal products and other forms of interaction.

Phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil). Concomitant use of doxazosin with PDE-5 inhibitors may cause symptomatic hypotension in some patients. Studies with extended-release formulations of doxazosin have not been conducted.

Doxazosin is highly bound to plasma proteins (98%). In vitro studies using human plasma indicate that the drug does not affect the protein binding of tested drugs (digoxin, phenytoin, warfarin, or indomethacin).

No adverse interactions have been observed with concomitant use of doxazosin and thiazide diuretics, furosemide, β-adrenergic blockers, nonsteroidal anti-inflammatory drugs, antibiotics, oral hypoglycemic agents, uricosuric agents, or anticoagulants. However, formal studies evaluating drug interactions are lacking.

Doxazosin potentiates the hypotensive effect of other α-adrenergic blockers as well as other antihypertensive agents.

Data indicate that single-dose administration of doxazosin 1 mg on the first day of a four-day course of oral cimetidine (400 mg twice daily) resulted in a 10% increase in the mean AUC of doxazosin, without causing any statistically significant changes in mean Cmax or mean T½ of doxazosin. This 10% increase in mean AUC of doxazosin during cimetidine administration falls within the range of inter-individual variability (27%) of mean AUC values of doxazosin compared to placebo.

Special precautions for use.

Orthostatic hypotension/syncope. At the beginning of therapy. As with other α-adrenoreceptor blockers, orthostatic hypotension occurs in a very small percentage of patients receiving doxazosin, manifesting as dizziness and weakness, or less frequently as loss of consciousness (syncope), particularly at the start of treatment. Therefore, blood pressure should be monitored at the beginning of therapy in order to minimize possible postural effects.

When prescribing therapy with any effective α-adrenoreceptor blocker, patients should be informed how to avoid symptoms of orthostatic hypotension and what to do if such symptoms occur. Patients should also be warned to avoid situations where there is a risk of injury, considering the possibility of dizziness or weakness at the beginning of doxazosin therapy.

Use in acute cardiac conditions. As with other vasodilating antihypertensive agents, doxazosin should be used with caution in patients with the following acute cardiac conditions:

• pulmonary edema due to aortic or mitral stenosis;
• hypersystolic heart failure;
• right ventricular heart failure due to pulmonary artery thromboembolism or pericardial effusion;
• left ventricular heart failure with low filling pressure.

Use in hepatic impairment. As with other drugs that are completely metabolized by the liver, doxazosin should be administered with particular caution to patients with signs of hepatic dysfunction. Due to the lack of clinical experience with the use of the drug in patients with severe hepatic impairment, its use in this patient population is not recommended.

Concomitant use with PDE-5 inhibitors. Doxazosin should be used with caution when administered together with phosphodiesterase-5 (PDE-5) inhibitors (e.g., sildenafil, tadalafil, vardenafil), as these medicinal products cause vasodilation and may therefore lead to symptomatic hypotension in some patients. To reduce the risk of orthostatic hypotension, it is recommended to initiate therapy with PDE-5 inhibitors only if the patient has stable hemodynamics on α-blocker therapy. Furthermore, it is recommended to initiate PDE-5 inhibitor therapy at the lowest possible dose and to maintain a 6-hour interval between administration of doxazosin and PDE-5 inhibitors.

Use in patients undergoing cataract surgery. In some patients who were taking tamsulosin at the time of cataract surgery or prior to surgery, intraoperative floppy iris syndrome (IFIS – a variant of the small pupil syndrome) has been observed during the procedure. Isolated cases of this adverse effect have also been reported with other α1-adrenoreceptor blockers, so the possibility of this effect occurring with other drugs in this class cannot be excluded. Since IFIS may lead to an increased frequency of procedural complications during surgery, ophthalmic surgeons should be informed whether the patient is currently taking or has previously taken α1-adrenoreceptor blockers prior to surgery.

Priapism. There have been reports of prolonged erection and priapism. In case of an erection lasting more than 4 hours, the patient should seek immediate medical help. If priapism is not treated immediately, damage to penile tissue may occur, which can lead to permanent loss of potency.

Screening for prostate cancer. Prostate carcinoma causes many of the symptoms associated with BPH, and these two conditions may coexist. Therefore, the presence of prostate carcinoma should be ruled out before initiating doxazosin therapy for BPH-related symptoms.

The product contains lactose. If the patient has been diagnosed with an intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

Use during pregnancy or breastfeeding.

Patients with arterial hypertension.

Pregnancy.

Due to the lack of adequate and well-controlled studies on the use of the drug in pregnant women, the safety of doxazosin during pregnancy has not been established. Therefore, the drug should be used only when the potential benefits of treatment, in the physician's opinion, outweigh the potential risks. Although data from animal studies indicate that the drug does not exhibit teratogenic effects, its use at very high doses—approximately 300 times the maximum recommended human dose—resulted in reduced fetal lifespan.

Breastfeeding.

Doxazosin is contraindicated during breastfeeding, as animal studies have shown that doxazosin accumulates in the milk of lactating rats, and because there are no data on the excretion of doxazosin into human breast milk. If treatment with doxazosin is necessary, breastfeeding should be discontinued.

Patients with BPH.

The information in this section does not apply to patients with BPH.

Ability to affect reaction speed when driving or operating machinery.

The ability to drive or operate machinery may be impaired, especially at the beginning of treatment.

Method of Administration and Dosage

Doxazosin can be taken either in the morning or in the evening.

The drug is administered orally.

Arterial hypertension. The drug should be administered once daily. The initial dose is 1 mg to minimize the risk of orthostatic hypotension and/or syncope. After 1–2 weeks of initial therapy, the dose may be increased to 2 mg, and then, if necessary, to 4 mg. Most patients respond to treatment with a dose of 4 mg or lower. If needed, the dose may be further increased to 8 mg or up to the maximum recommended dose of 16 mg.

Benign prostatic hyperplasia (BPH). The recommended initial dose of doxazosin is 1 mg once daily to minimize the risk of orthostatic hypotension and/or syncope. Depending on individual urodynamic characteristics and BPH symptoms, the dose may be increased to 2 mg, then to 4 mg, and up to the maximum recommended dose of 8 mg. The recommended dose titration interval is 1–2 weeks. The usual recommended dose is 2–4 mg daily.

Elderly patients should receive the standard adult doses.

Patients with renal impairment should receive the standard adult doses, as the pharmacokinetic parameters of the drug are not altered by renal dysfunction.

Doxazosin is not eliminated from the body by hemodialysis.

Patients with hepatic impairment. Currently, information regarding the use of the drug in patients with hepatic dysfunction and regarding the effect of drugs capable of altering hepatic metabolism (e.g., cimetidine) is limited. As with other drugs that are extensively metabolized by the liver, doxazosin should be administered with caution to patients showing signs of hepatic dysfunction.

Children.

The safety and efficacy of the drug in children have not been studied.

Overdose.

If an overdose results in arterial hypotension, the patient should be immediately placed in a supine position with the head lowered. In individual cases, other symptomatic measures may be applied.

If symptomatic measures are insufficient, plasma expanders should be primarily used to treat shock. Subsequently, vasoconstrictors should be administered if necessary. Renal function should be monitored, and supportive measures applied as needed.

Hemodialysis is not indicated, as doxazosin is highly bound to plasma proteins.

Side effects.

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

Blood and lymphatic system disorders: leukopenia, thrombocytopenia.

Immune system disorders: allergic reactions.

Metabolism and nutrition disorders: gout, increased appetite, loss of appetite.

Psychiatric disorders: agitation, depression, anxiety, insomnia, nervousness.

Nervous system disorders: drowsiness, dizziness, headache, stroke, hypesthesia, syncope, tremor, orthostatic dizziness, paresthesia.

Eye disorders: blurred vision, intraoperative floppy iris syndrome.

Ear and labyrinth disorders: vertigo, tinnitus.

Cardiac disorders: palpitations, tachycardia, angina pectoris, myocardial infarction, bradycardia, cardiac arrhythmias.

Vascular disorders: arterial hypotension, orthostatic arterial hypotension, flushing.

Respiratory, thoracic and mediastinal disorders: bronchitis, cough, dyspnea, rhinitis, epistaxis, exacerbation of existing bronchospasm.

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

Hepatobiliary disorders: liver function test abnormalities, cholestasis, hepatitis, jaundice.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, alopecia, purpura.

Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, muscle spasms, muscle weakness.

Renal and urinary disorders: cystitis, urinary incontinence, dysuria, frequent urination, hematuria, polyuria, increased diuresis, urinary disorders, nocturia.

Reproductive system and breast disorders: impotence, gynecomastia, priapism, retrograde ejaculation.

General disorders and administration site conditions: asthenia, chest pain, influenza-like symptoms, peripheral edema, body pain, facial swelling, increased fatigue, malaise.

Investigations: weight gain.

Shelf life. 5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. Tablets 1 mg № 30 in bottles or containers in a box; № 10×3 in blisters in a box; tablets 2 mg or 4 mg № 10×2 in blisters in a box.

Prescription category. Prescription only.

Manufacturer.

Limited Liability Company "Experimental Plant "GNCLS" or

Limited Liability Company "FARMEKS GROUP", or

LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business.

Ukraine, 61057, Kharkiv region, city of Kharkiv, Vorobiova Street, building 8.

(Limited Liability Company "Experimental Plant "GNCLS")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, building 100.

(Limited Liability Company "FARMEKS GROUP")

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, building 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA")