Cardura

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARDURAÒ (CARDURAÒ)

Composition:

Active substance: doxazosin;

1 mg tablets: 1 tablet contains 1.213 mg of doxazosin mesylate, equivalent to 1 mg of doxazosin;

2 mg tablets: 1 tablet contains 2.43 mg of doxazosin mesylate, equivalent to 2 mg of doxazosin;

4 mg tablets: 1 tablet contains 4.85 mg of doxazosin mesylate, equivalent to 4 mg of doxazosin;

Excipients: lactose monohydrate; magnesium stearate; microcrystalline cellulose; sodium lauryl sulfate; sodium starch glycolate (type A).

Pharmaceutical form. Tablets.

Main physicochemical properties:

• 1 mg tablets – white, round, biconvex tablets, marked with the code «CN 1» on one side and the «Pfizer» logo on the other;
• 2 mg tablets – white, oblong, biconvex tablets, with a break line and marked with the code «CN 2» on one side and the «Pfizer» logo on the other;
• 4 mg tablets – white, rhomboid-shaped, biconvex tablets, with a break line and marked with the code «CN 4» on one side and the «Pfizer» logo on the other.

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 a reduction in systemic arterial pressure. Cardura® is intended for oral administration once daily to patients with essential arterial hypertension.

Pharmacodynamic effects.

Cardura® has been shown not to cause undesirable metabolic effects and can therefore be used in patients with diabetes mellitus, gout, or insulin resistance.

Cardura® may also be prescribed to patients with bronchial asthma, left ventricular hypertrophy, and elderly patients. The use of the drug contributes to a reduction in left ventricular hypertrophy, inhibits platelet aggregation, and enhances tissue plasminogen activator activity. Furthermore, treatment with Cardura® improves insulin sensitivity in patients with impaired insulin sensitivity.

Long-term studies have also demonstrated that, in addition to its antihypertensive effect, treatment with Cardura® 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 both arterial hypertension and hyperlipidemia.

The use of Cardura® in patients with symptomatic benign prostatic hyperplasia (BPH) leads to significant improvement in urodynamics and symptom relief. 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 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 and is primarily excreted in feces.

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

After oral administration of doxazosin, plasma concentrations of metabolites are low. The plasma concentration of the most active metabolite (6'-hydroxy) in humans is 40 times lower than the plasma concentration of the parent compound, indicating that the antihypertensive effect of the drug is predominantly 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. In a clinical study involving 12 patients with moderate hepatic dysfunction, single-dose administration of doxazosin resulted in a 43% increase in AUC and a 40% reduction in apparent oral clearance. As with other drugs that are completely metabolized by the liver, doxazosin should be used with particular caution in patients with evidence of hepatic impairment.

Doxazosin is extensively metabolized in the liver. In vitro studies indicate that this is primarily mediated by the CYP3A4 enzyme, and to a lesser extent by CYP2D6 and CYP2C9.

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-adrenergic 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 can be prescribed to patients with BPH both in the presence and absence of arterial hypertension.

Contraindications.

Use of Cardura® 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 listed in the section "Composition";
• 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;
• patients with 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 (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 (digoxin, phenytoin, warfarin, or indomethacin).

In clinical practice, 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.

In vitro studies indicate that doxazosin is a substrate of cytochrome P450 3A4 (CYP3A4). Caution should be exercised when prescribing doxazosin concomitantly with strong inhibitors of CYP3A4, such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole (see section "Pharmacological properties").

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

According to results from an open, randomized, placebo-controlled clinical study involving 22 healthy male volunteers, single 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 elimination half-life 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.

Initiation of therapy. As a consequence of α-adrenoreceptor blocker action, orthostatic hypotension may develop, manifesting as dizziness and weakness or, 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 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 how to act if such symptoms occur. Patients should also be warned to avoid situations where injury may occur due to possible dizziness or weakness at the beginning of treatment with Cardura®.

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 caused by aortic or mitral stenosis;
• Hyperkinetic 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, Cardura® 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.

Concomitant use with PDE-5 inhibitors.

Doxazosin should be used with caution when administered concomitantly with phosphodiesterase-5 (PDE-5) inhibitors (e.g., sildenafil, tadalafil, and vardenafil), since both medicinal products cause vasodilation and thus may lead to symptomatic hypotension in some patients. To reduce the risk of orthostatic hypotension, initiation of therapy with PDE-5 inhibitors is recommended only if the patient has stable hemodynamics while receiving α-blockers. Additionally, 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 phosphodiesterase-5 inhibitors. Studies with doxazosin in sustained-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) has been observed during the procedure. Isolated cases of this adverse effect have also been reported with other α1-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 or previously taking α1-adrenoreceptor blockers prior to surgery.

Priapism.

During the post-marketing period, reports of prolonged erection and priapism have been received with the use of α1-blockers, including doxazosin. If an erection lasts longer than 4 hours, the patient should seek immediate medical attention. If priapism is not treated promptly, penile tissue damage 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.

Information on excipients.

Patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is essentially sodium-free.

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 Cardura® during pregnancy has not been established. Therefore, the drug should be used only if the potential benefits of treatment, in the physician’s opinion, 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.

Studies in lactating rats given a single oral dose of radiolabeled doxazosin showed that doxazosin accumulates in rat milk, with peak concentrations in milk approximately 20 times higher than plasma concentrations in the mother.

Human data are very limited, but it has been demonstrated that excretion of doxazosin into human breast milk is minimal (the relative infant dose is less than 1%). The risk to the newborn or infant cannot be excluded; therefore, doxazosin should be used only if, in the physician’s opinion, the potential benefit outweighs the potential risk.

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

Cardura® can be taken either in the morning or in the evening.

The medication is administered orally.

Arterial Hypertension.

The drug should be taken 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 with doses 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 Cardura® 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 impaired renal function.

Cardura® is not eliminated from the body by hemodialysis.

Patients with Hepatic Impairment.

Currently, information regarding the use of the drug in patients with hepatic impairment and the influence of agents that may alter hepatic metabolism (e.g., cimetidine) is limited. As with other drugs that are completely metabolized by the liver, Cardura® should be administered with caution in patients showing signs of hepatic dysfunction (see sections "Special Precautions" and "Pharmacokinetics").

Children.

The safety and efficacy of Cardura® in children have not been studied.

Overdose.

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

If symptomatic treatment is insufficient, plasma expanders should be used first-line for the treatment of shock. If necessary, vasoconstrictor agents may then be administered. 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.

Arterial hypertension.

In clinical trials involving patients with arterial hypertension, the most commonly occurring adverse reactions were of a postural type (rarely accompanied by loss of consciousness), or non-specific adverse reactions.

Benign prostatic hyperplasia (BPH).

According to data from controlled clinical studies, patients with BPH experienced the same adverse reaction profile as patients with arterial hypertension.

The following classification is used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated based on available data).

Infections and infestations.

Common: respiratory tract infections, urinary tract infections.

Blood and lymphatic system disorders.

Very rare: leukopenia, thrombocytopenia.

Immune system disorders.

Uncommon: allergic reactions.

Metabolism and nutrition disorders.

Uncommon: gout, increased appetite, loss of appetite.

Psychiatric disorders.

Uncommon: agitation, depression, anxiety, insomnia, nervousness.

Nervous system disorders.

Common: somnolence, dizziness, headache.

Uncommon: stroke, hypesthesia, syncope, tremor.

Very rare: orthostatic dizziness, paraesthesia.

Eye disorders.

Very rare: blurred vision.

Frequency not known: Intraoperative Floppy Iris Syndrome (IFIS) (see section "Special precautions").

Ear and labyrinth disorders.

Common: vertigo.

Uncommon: tinnitus.

Cardiac disorders.

Common: palpitations, tachycardia.

Uncommon: angina pectoris, myocardial infarction.

Very rare: bradycardia, cardiac arrhythmias.

Vascular disorders.

Common: hypotension, orthostatic hypotension.

Very rare: flushing.

Respiratory, thoracic and mediastinal disorders.

Common: bronchitis, cough, dyspnoea, rhinitis.

Uncommon: epistaxis.

Very rare: bronchospasm.

Gastrointestinal disorders.

Common: abdominal pain, dyspepsia, dry mouth, nausea.

Uncommon: constipation, flatulence, vomiting, gastroenteritis, diarrhoea.

Hepatobiliary disorders.

Uncommon: liver function test abnormalities.

Very rare: cholestasis, hepatitis, jaundice.

Skin and subcutaneous tissue disorders.

Common: pruritus.

Uncommon: skin rash.

Very rare: urticaria, alopecia, purpura.

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: dysuria, frequent urination, haematuria.

Rare: polyuria.

Very rare: increased diuresis, urinary disorders, nocturia.

Reproductive system and breast disorders.

Uncommon: impotence.

Very rare: gynaecomastia, priapism.

Frequency not known: retrograde ejaculation.

General disorders and administration site conditions.

Common: asthenia, chest pain, influenza-like symptoms, peripheral oedema.

Uncommon: body pain, facial swelling.

Very rare: increased fatigue, malaise.

Investigations.

Uncommon: weight gain.

Reporting suspected adverse reactions.

After marketing authorization, it is important to report suspected adverse reactions. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any adverse reactions via the national reporting system.

Shelf life. 5 years.

Storage conditions. Store in a place inaccessible to children, at a temperature not exceeding 30 °C.

Packaging. 10 tablets per blister pack, 3 blister packs per cardboard box.

Prescription category. Prescription only.

Manufacturer. Pfizer Manufacturing Deutschland GmbH.

Manufacturer's address.
Mooswaldallee 1, 79090 Freiburg Im Breisgau, Germany.