Kamiren

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Kamiren (Kamiren®)

Composition:

Active substance: doxazosin;

1 tablet contains 1 mg, 2 mg, or 4 mg of doxazosin in the form of doxazosin mesylate;

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

Pharmaceutical form. Tablets.

Main physicochemical properties:
1 mg tablets: white, slightly biconvex, round tablets with bevelled edges;

2 mg tablets: white, flat, round tablets with a bevelled edge and a score line on one side. The tablet can be divided into two equal parts;

4 mg tablets: white, flat, round tablets with a bevelled edge and a score line on one side. The tablet can be divided into two equal parts.

Pharmacotherapeutic group. Selective α1-adrenoreceptor antagonist.

ATC code C02CA04.

Pharmacological properties.

Pharmacodynamics.

Arterial hypertension

Administration of doxazosin to patients with arterial hypertension results in clinically significant reduction of arterial blood pressure due to decreased peripheral vascular resistance. This effect is associated with selective blockade of α1-adrenoceptors located in blood vessels. When administered once daily, the clinically significant antihypertensive effect of the drug persists for 24 hours. Maximum reduction in arterial blood pressure is usually observed within 2–6 hours after a single dose. In patients with arterial hypertension, arterial pressure remained similar in both supine and standing positions during treatment with doxazosin.

Unlike non-selective α1-adrenergic blockers, tolerance to doxazosin does not develop during prolonged therapy.

During long-term use of the drug, occasional increases in plasma renin activity and tachycardia have been observed.

Doxazosin has a favorable effect on blood lipids, significantly increasing the high-density lipoprotein to total cholesterol ratio and substantially reducing total triglyceride levels and total cholesterol. This gives it an advantage over diuretics and β-adrenergic blockers, which have negative effects on these parameters.

Given the established association between arterial hypertension and lipid metabolism disorders with ischemic heart disease, the beneficial effects of doxazosin on both arterial pressure and levels of atherogenic lipids contribute to a reduced risk of developing ischemic heart disease.

Treatment with doxazosin has been shown to reduce left ventricular hypertrophy, inhibit platelet aggregation, and increase tissue plasminogen activity. In addition, doxazosin improves insulin sensitivity in peripheral tissues in patients with impaired insulin sensitivity.

Doxazosin has virtually no adverse metabolic effects and can be used in patients with bronchial asthma, diabetes mellitus, left ventricular dysfunction, and keratosis.

In patients with arterial hypertension, treatment with doxazosin has been associated with improvement in erectile dysfunction. A lower incidence of new cases of erectile dysfunction has been recorded in patients taking doxazosin compared to those taking other antihypertensive agents.

Benign prostatic hyperplasia (BPH)

Administration of doxazosin to patients with symptoms of BPH leads to significant improvement in urodynamics and reduction in disease manifestations and symptoms. This effect of the drug is attributed to selective blockade of α1-adrenoceptors located in the smooth muscle stroma and capsule of the prostate gland, as well as in the bladder neck.

Doxazosin is a potent blocker of α1-adrenoceptor subtype IA, which constitutes approximately 70% of all receptor subtypes present in the prostate gland. This explains the drug's action in patients with BPH.

Doxazosin has demonstrated stable efficacy and safety during long-term treatment of patients with BPH (up to 48 months).

Pharmacokinetics.

Absorption.

After oral administration in therapeutic doses, Kamiren is well absorbed; drug concentration in blood reaches peak levels approximately 2 hours after intake.

Metabolism/elimination.

Elimination from plasma is biphasic, with a terminal half-life of 22 hours, allowing once-daily dosing. Doxazosin undergoes extensive biotransformation; less than 5% of the dose is excreted unchanged.

In patients with renal impairment, no significant pharmacokinetic differences have been observed compared to patients with normal renal function.

Limited data are available regarding patients with impaired liver function and regarding the influence of drugs capable of altering hepatic metabolism (e.g., cimetidine).

Since the drug is predominantly metabolized in the liver, doxazosin should be used with caution in patients with impaired liver function.

Approximately 98% of doxazosin is protein-bound in plasma.

Doxazosin is primarily metabolized via O-demethylation and hydroxylation pathways.

Clinical characteristics.

Indications.

Arterial hypertension

Kamiren is indicated for the treatment of arterial hypertension and can be used as a first-line agent for most patients with the aim of controlling blood pressure. For patients in whom adequate reduction of blood pressure cannot be achieved with a single antihypertensive agent, doxazosin may be used in combination with other medicinal products such as thiazide diuretics, β-blockers, calcium antagonists, or angiotensin-converting enzyme inhibitors.

Benign prostatic hyperplasia (BPH)

The drug is indicated for the relief of urinary flow obstruction and symptoms associated with BPH. Kamiren may be prescribed to patients with BPH both in the presence and absence of arterial hypertension.

Contraindications.

• Hypersensitivity to the active substance, quinazoline derivatives (e.g., prazosin, terazosin), or to any of the excipients of the drug.
• BPH with concomitant obstruction of the upper urinary tract, chronic urinary tract infections, and presence of bladder stones.
• Arterial hypotension (applies only to patients with BPH).
• History of orthostatic hypotension.
• 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.

Use with PDE-5 inhibitors (phosphodiesterase type 5)

Concomitant use of doxazosin with PDE-5 inhibitors should be performed with caution, as arterial hypotension symptoms may occur in some patients. Studies with extended-release formulations of doxazosin have not been conducted.

Other

Approximately 98% of doxazosin in plasma is protein-bound. In vitro studies using human plasma indicate that doxazosin has virtually no effect on the protein binding of digoxin, warfarin, phenytoin, and indomethacin.

Clinical experience indicates no negative interactions when doxazosin is used concomitantly with thiazide diuretics, furosemide, β-blockers, nonsteroidal anti-inflammatory drugs, antibiotics, oral hypoglycemic agents, diuretics, or anticoagulants. However, formal studies evaluating drug interactions are lacking.

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

According to a clinical study in healthy male volunteers, 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 the 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 levels of doxazosin compared to placebo.

Special precautions for use.

Orthostatic hypotension/syncope.

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, or less frequently as loss of consciousness (syncope), especially at the beginning of therapy.

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 doxazosin therapy.

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;
• Hyperdynamic heart failure;
• Right ventricular heart failure due to pulmonary artery thromboembolism or pericardial effusion;
• Left ventricular heart failure with low filling pressure.

Use in patients with 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 insufficiency, administration of the drug to this patient group is not recommended.

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) was observed during the procedure. Isolated cases of this adverse effect have also been reported with other α1-blockers; therefore, the possibility of this effect cannot be excluded for other drugs in this class. Since IFIS may lead to increased frequency of procedural complications during surgery, ophthalmic surgeons should be informed during preoperative preparation whether the patient is currently taking or has previously taken α1-adrenergic receptor blockers.

Concomitant use with PDE-5 inhibitors.

Doxazosin should be used with caution 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 while receiving α-blockers. Additionally, it is recommended to initiate PDE-5 inhibitor therapy with the lowest possible dose and to maintain a 6-hour interval between administration of doxazosin and PDE-5 inhibitors. Studies with extended-release formulations of doxazosin have not been conducted.

Special warnings regarding inactive ingredients.

The product contains lactose; therefore, patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this product.

Use during pregnancy or breastfeeding.

Due to the lack of adequate and well-controlled studies during pregnancy or breastfeeding, the safety of doxazosin in these patient groups 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 use at very high doses—approximately 300 times the maximum recommended human dose—led to reduced fetal lifespan.

Since clinical safety has not been studied, the use of the drug is contraindicated during breastfeeding. If doxazosin treatment is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving vehicles or operating machinery.

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

Dosage and Administration

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

Arterial Hypertension

The dosage range for doxazosin is 1–16 mg once daily. Therapy should be initiated at 1 mg once daily for 1–2 weeks to minimize the risk of potential postural hypotension and/or syncope. After 1–2 weeks, the dose may be increased to 2 mg once daily. If necessary, the daily dose may be sequentially increased at similar intervals to 4 mg, 8 mg, and 16 mg, with monitoring of the therapeutic response to achieve the desired reduction in blood pressure. The usual dose is 2–4 mg daily.

Benign Prostatic Hyperplasia (BPH)

The recommended initial dose of doxazosin is 1 mg once daily, to minimize the risk of postural hypotension and/or syncope. Depending on individual urodynamic parameters and BPH symptomatology, the dose may be increased to 2 mg and subsequently to 4 mg. The maximum recommended dose is 8 mg. The recommended dose escalation interval is 1–2 weeks. The usual recommended dose is 2–4 mg daily.

Use in Elderly Patients: the usual adult dose.

Use in Renal Impairment: the standard adult doses are recommended, as the pharmacokinetic parameters of the drug are not altered in renal impairment.

Kamiren is not removed from the body by hemodialysis.

Hepatic Impairment: currently, information regarding the use of the drug in patients with hepatic dysfunction and the effect of agents capable of altering hepatic metabolism (e.g., cimetidine) is limited. As with other drugs that are entirely metabolized by the liver, Kamiren should be administered with caution to patients with signs of hepatic dysfunction.

Children

Kamiren is not recommended for use in children, as the safety and efficacy of this drug have not been studied in pediatric populations.

Overdose

If overdose results in arterial hypotension, the patient should be immediately placed in a supine position with the head lowered. Other symptomatic measures may be applied if necessary. Due to the high degree of plasma protein binding of doxazosin, dialysis is ineffective.

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

Adverse reactions.

Arterial hypertension.

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

Benign prostatic hyperplasia.

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

Shelf life. 5 years.

Storage conditions.

The medicinal product does not require special storage conditions.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 2 or 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.