Doxazosin-kv

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOXAZOSIN-KV (DOXAZOSIN-KV)

Composition:

Active substance: doxazosin;

1 tablet contains 2 mg or 4 mg of doxazosin (as doxazosin mesylate);

Excipients: lactose monohydrate, microcrystalline cellulose, corn starch, sodium starch glycolate (type A), sodium lauryl sulfate, magnesium stearate, stearic acid.

Pharmaceutical form. Tablets.

Main physicochemical properties:

for 2 mg tablets: flat cylindrical tablets, bevelled, white or almost white;

for 4 mg tablets: flat cylindrical tablets, bevelled and scored, white or almost white.

Pharmacotherapeutic group. Agents acting on the cardiovascular system. 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 a reduction in systemic arterial pressure. The medication Doxazosin-KV 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.

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

It has also been reported that, in addition to its antihypertensive effect, the use of doxazosin leads to a moderate reduction in plasma concentrations of total cholesterol, low-density lipoproteins, and triglycerides. Therefore, this medication may be particularly effective in patients with arterial hypertension and hyperlipidemia.

Administration of Doxazosin-KV to patients with symptomatic benign prostatic hyperplasia (BPH) results in significant improvement in urodynamics and reduction in symptom severity. The effect of the medication 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 males or elderly patients of either sex), 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 studied, and is primarily excreted in feces.

The mean elimination half-life of the drug from plasma is 22 hours, allowing for once-daily dosing.

After oral administration of Doxazosin-KV, plasma concentrations of drug 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, data on the use of the drug in patients with impaired liver function and on the influence of drugs capable of altering hepatic metabolism (e.g., cimetidine) are limited. It is known that in patients with moderate hepatic dysfunction, single-dose administration of doxazosin resulted in a 43% increase in AUC and a 40% decrease in apparent oral clearance. As with other drugs that are entirely metabolized by the liver, Doxazosin-KV should be administered with particular caution to patients showing signs of hepatic impairment.

Clinical characteristics.

Indications.

Arterial hypertension.

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

Benign prostatic hyperplasia (BPH).

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

Contraindications.

The use of Doxazosin-KV is contraindicated in the following patient groups:

• patients with hypersensitivity to the active substance or to quinazoline derivatives (e.g., prazosin, terazosin, doxazosin) or to any of the excipients;
• patients with a history of orthostatic hypotension;
• patients with BPH and concomitant upper urinary tract obstruction, chronic urinary tract infections, or presence of bladder stones;
• during breastfeeding (only when used for the treatment of arterial hypertension; see section "Use during pregnancy or breastfeeding");
• patients with arterial hypotension (applies only to patients with BPH).

Doxazosin as monotherapy is contraindicated in patients with bladder overdistension or anuria with or without progressive renal insufficiency.

Interaction with other medicinal products and other forms of interaction.

Phosphodiesterase-5 (PDE-5) inhibitors (e.g., sildenafil, tadalafil, vardenafil)

Concomitant use of doxazosin with PDE-5 inhibitors may cause symptomatic hypotension in some patients (see section "Special precautions for use"). 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 (e.g., digoxin, phenytoin, warfarin, or indomethacin).

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

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

It has been reported 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 mean AUC of doxazosin, without causing any statistically significant changes in mean Cmax or mean elimination half-life of doxazosin. This 10% increase in mean AUC of doxazosin during cimetidine coadministration 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.

Initiation of therapy. As with other α-adrenergic receptor blockers, orthostatic hypotension occurred in a very small percentage of patients treated with this drug, manifesting as dizziness and weakness, and less frequently as loss of consciousness (syncope), particularly at the beginning of therapy (see section "Dosage and administration"). Therefore, blood pressure should be monitored at the start of therapy to minimize possible postural effects.

When prescribing therapy with any effective α-adrenergic receptor blocker, patients should be informed how to avoid symptoms of orthostatic hypotension and how to act if such symptoms occur. Patients should also be warned about the need to avoid situations where there is a risk of injury, considering the possibility of dizziness or weakness at the beginning of treatment with Doxazosin-KV.

Use in acute cardiac conditions.

Like 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;
• hyperkinetic heart failure;
• right ventricular heart failure caused by 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-KV should be administered with particular caution to patients with signs of hepatic dysfunction (see section "Dosage and administration"). Due to the lack of clinical experience with the use of the drug in patients with severe hepatic insufficiency, administration of the drug to this patient group is not recommended.

Use with PDE-5 inhibitors.

Doxazosin should be used with caution when co-administered with PDE-5 inhibitors (e.g., sildenafil, tadalafil, and vardenafil), as these medicinal products cause vasodilation and may therefore lead to symptomatic arterial 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 while receiving α-blockers. Furthermore, it is recommended to initiate therapy with PDE-5 inhibitors at the lowest possible dose and to maintain a 6-hour interval between administration of doxazosin and PDE-5 inhibitors. Studies with doxazosin in prolonged-release formulations have not been conducted.

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 small pupil syndrome) was observed during the procedure. Isolated cases of this adverse effect have also been reported with other α1-adrenergic blockers; therefore, 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-adrenergic blockers prior to surgery.

Priapism.

Cases of prolonged erection and priapism have been reported during treatment with α1-blockers, including doxazosin. If an erection lasts longer than 4 hours, the patient should seek immediate medical help. If priapism is not treated promptly, damage to penile tissue may occur, potentially leading to irreversible 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 therapy with doxazosin for BPH-related symptoms.

This medication should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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-KV during pregnancy has not been established. Therefore, the drug should be used only when, in the physician’s opinion, the potential benefits of treatment outweigh the potential risks. Although the drug did not show teratogenic effects in animal studies, its administration at very high doses—approximately 300 times the maximum recommended human dose—resulted in reduced fetal lifespan.

Breastfeeding. Doxazosin is contraindicated during breastfeeding due to the lack of data on the excretion of doxazosin into breast milk. Alternatively, if doxazosin therapy 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-KV can be taken either in the morning or in the evening.

The medication 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 (see section "Special Precautions"). 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 at a dose of 4 mg or lower. If needed, the dose may be further increased up to 8 mg or to the maximum recommended dose of 16 mg.

Benign Prostatic Hyperplasia (BPH)

The recommended initial dose of Doxazosin-KV is 1 mg once daily to minimize the risk of orthostatic hypotension and/or syncope (see section "Special Precautions"). 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

Standard adult doses should be used.

Patients with Renal Impairment

Standard adult doses should be used, as the pharmacokinetic parameters of the drug are not altered in patients with renal impairment.

Doxazosin-KV is not eliminated from the body by hemodialysis.

Patients with Hepatic Impairment

Information regarding the use of the drug in patients with hepatic impairment and the influence of agents capable of altering hepatic metabolism (e.g., cimetidine) is limited. As with other drugs that are entirely metabolized by the liver, Doxazosin-KV should be administered with caution to patients showing signs of hepatic dysfunction (see sections "Pharmacokinetics" and "Special Precautions").

Children

The safety and efficacy of Doxazosin-KV in children have not been established.

Overdose

Symptoms
If overdose results in arterial hypotension, the patient should be placed immediately in a supine position with the head lowered. Additional symptomatic measures may be required in individual cases.

Treatment
If symptomatic measures are insufficient, plasma expanders should be administered first-line for shock treatment. If necessary, vasoconstrictor agents should then be used. Renal function should be monitored, and supportive measures applied as needed.

Hemodialysis is not indicated, as Doxazosin-KV is highly bound to plasma proteins.

Side effects.

Arterial hypertension.

In patients with arterial hypertension, postural side effects (which rarely included loss of consciousness) or non-specific side effects were most commonly observed.

Benign prostatic hyperplasia (BPH).

In patients with BPH, the side effect profile was the same as in patients with arterial hypertension.

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: excitement, depression, anxiety, insomnia, nervousness.

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

Eye disorders: blurred vision, intraoperative floppy iris syndrome (IFIS).

Ear and labyrinth disorders: vertigo, tinnitus.

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

Vascular disorders: hypotension, orthostatic hypotension, flushing.

Respiratory, thoracic and mediastinal disorders: bronchitis, cough, dyspnea, rhinitis, epistaxis, worsening of pre-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, skin 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, urinary frequency, hematuria, polyuria, increased diuresis, micturition 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 increase.

Reporting of side effects.

If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in the package leaflet of the medicinal product. Reporting side effects can help provide more information on the safety of this medicinal product.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C.

Keep out of the reach of children.

Packaging. 10 tablets in a blister; 3 blisters in a carton.

Prescription category. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and place of business.

38 Kopilivska St., Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua.