Moxonidin-pharmak

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MOXONIDINE-FARMAK (MOXONIDINE-FARMAK)

Composition:

Active substance: moxonidine;

1 tablet contains moxonidine 0.2 mg or 0.3 mg or 0.4 mg;

Excipients: lactose monohydrate, povidone, anhydrous lactose, crospovidone, magnesium stearate;

Coating of the tablet: hypromellose, titanium dioxide (E 171), macrogol, red iron oxide (E 172), yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

0.2 mg – film-coated tablets, round-shaped, biconvex, pink in colour.

0.3 mg – film-coated tablets, elongated shape, biconvex, pink in colour, with a groove on both sides (the groove is intended to facilitate swallowing and is not intended for dividing the tablet into two equal doses).

0.4 mg – film-coated tablets, round-shaped, biconvex, pink in colour, with a groove on one side (the groove is intended to facilitate swallowing and is not intended for dividing the tablet into two equal doses).

Pharmacotherapeutic group. Antihypertensive medicinal products. Imidazoline receptor agonists. ATC code C02AC05.

Pharmacological properties

Pharmacodynamics

Moxonidine is an effective antihypertensive agent. Available experimental data indicate that the central nervous system (CNS) is the site of moxonidine's antihypertensive action. Moxonidine is a selective agonist of imidazoline receptors. These imidazoline-sensitive receptors are concentrated in the rostral part of the ventrolateral region of the medulla oblongata – an area considered to be the center for regulation of the peripheral sympathetic nervous system. Stimulation of imidazoline receptors leads to reduced sympathetic nervous system activity and decreased arterial blood pressure.

Moxonidine differs from other sympatholytic antihypertensive agents by its relatively low affinity for known α₂-adrenoceptors compared to imidazoline receptors. Due to this property, sedative effects and dry mouth occur rarely with moxonidine use.

In humans, moxonidine administration results in reduced peripheral vascular resistance and subsequent lowering of arterial blood pressure. The antihypertensive effect of moxonidine has been demonstrated in double-blind, placebo-controlled, randomized studies. Published data indicate that in patients with arterial hypertension and left ventricular hypertrophy, combining an angiotensin II antagonist (AIIA) with moxonidine, while achieving comparable blood pressure reduction, led to enhanced regression of left ventricular hypertrophy compared to a free combination of a thiazide and a calcium channel blocker.

In therapeutic studies lasting 2 months, moxonidine increased insulin sensitivity index by 21 % compared to placebo in patients with moderate arterial hypertension, obesity, and insulin resistance.

Pharmacokinetics

Absorption. After oral administration, moxonidine is rapidly (time to maximum plasma concentration – approximately 1 hour) and almost completely absorbed from the upper gastrointestinal tract. Absolute bioavailability is approximately 88 %, indicating absence of significant first-pass metabolism in the liver. Concomitant food intake does not affect the pharmacokinetics of moxonidine.

Distribution. Plasma protein binding, determined in vitro, is approximately 7.2 %.

Biological transformation. Only dehydrogenated moxonidine has been identified in human plasma samples. The pharmacodynamic activity of dehydrogenated moxonidine is approximately 1/10 that of moxonidine.

Elimination. Within a 24-hour period, 78 % of the total dose of moxonidine is excreted in urine unchanged and 13 % as dehydrogenated moxonidine. Other minor metabolites in urine account for approximately 8 % of the dose. Less than 1 % of the dose is excreted in feces. The elimination half-life of moxonidine and its metabolite is approximately 2.5 hours and 5 hours, respectively.

In patients with arterial hypertension, the pharmacokinetics of moxonidine did not differ significantly from that in healthy volunteers.

In elderly patients, changes in pharmacokinetics have been observed, most likely due to reduced metabolism and/or slightly increased bioavailability. However, these changes are not considered clinically significant.

Since moxonidine is not recommended for use in children, pharmacokinetic studies have not been conducted in this subpopulation.

Moxonidine elimination is largely dependent on creatinine clearance. In patients with moderate renal impairment (glomerular filtration rate (GFR) – 30–60 mL/min), steady-state plasma concentration and elimination half-life are approximately 2 and 1.5 times higher, respectively, than in patients with normal renal function (GFR > 90 mL/min). In patients with severe renal impairment (GFR < 30 mL/min), steady-state plasma concentration and elimination half-life are approximately 3 times higher. No accumulation of moxonidine was observed in these patients after repeated administration. In patients with end-stage renal disease (GFR < 10 mL/min) undergoing hemodialysis, AUC in plasma and elimination half-life are approximately 6 and 4 times higher, respectively, compared to hypertensive patients with normal renal function. In patients with moderate renal impairment, maximum plasma concentration of moxonidine is only 1.5 to 2 times higher.

Based on the above data, the dose of moxonidine in patients with renal impairment should be individually adjusted. Moxonidine is only minimally removed during hemodialysis.

Preclinical safety data

Standard pharmacological safety, chronic toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity studies revealed no special risk for humans in preclinical data.

Animal studies revealed toxic effects on embryonic development when administered at doses toxic to the maternal organism. Reproductive toxicity studies showed no effect on fertility or teratogenic potential. Toxic effects on embryonic development were observed in rats at doses ≥ 9 mg/kg/day and in rabbits at doses above 0.7 mg/kg/day. In peri- and postnatal developmental studies in rats, effects on development and viability were observed at doses ≥ 3 mg/kg/day.

Clinical characteristics.

Indications.

Arterial hypertension.

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product.

Sick sinus syndrome.

Bradycardia (resting heart rate below 50 beats/min).

Second- and third-degree atrioventricular (AV) block.

Heart failure.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of the medicinal product with other antihypertensive agents results in an additive effect.

Since tricyclic antidepressants may reduce the effectiveness of centrally acting antihypertensive agents, concomitant administration of these drugs with moxonidine is not recommended.

Moxonidine may enhance the sedative effect of tricyclic antidepressants (concomitant use should be avoided), tranquilizers, alcohol, sedatives, and hypnotics.

The medicinal product moderately increases cognitive impairment in patients receiving lorazepam. Moxonidine may enhance the sedative effect of benzodiazepines when used concomitantly.

Moxonidine is eliminated via tubular secretion. Interactions with other agents that are also eliminated by tubular secretion cannot be excluded. However, studies with digoxin and hydrochlorothiazide did not reveal any evidence of interaction. Oral bioavailability of glyburide was reduced by 11%.

Special precautions for use

During the post-marketing period, cases of atrioventricular block of varying severity have been reported in patients treated with moxonidine. Therefore, a causal role of moxonidine in delaying atrioventricular conduction cannot be completely excluded. Hence, caution is recommended when treating patients predisposed to developing atrioventricular block.

Moxonidine should be used with particular caution in patients with first-degree atrioventricular block to avoid bradycardia. Moxonidine is contraindicated in patients with higher-degree atrioventricular block (see section "Contraindications").

Moxonidine should be used cautiously in patients with severe coronary heart disease or unstable angina, as experience with the use of this drug in such patients is limited.

Caution is recommended when using moxonidine in patients with impaired renal function, as moxonidine is primarily excreted by the kidneys. Careful dose titration is recommended in these patients, especially at the beginning of therapy. Treatment should be initiated at a dose of 0.2 mg once daily; the dose may be increased up to a maximum of 0.4 mg once daily in patients with moderate renal impairment (GFR > 30 ml/min but < 60 ml/min) and up to a maximum of 0.3 mg once daily in patients with severe renal impairment (GFR < 30 ml/min), if clinically indicated and the drug is well tolerated.

If the medicinal product Moxonidin-Farmak is used in combination with a β-adrenoblocker and both drugs need to be discontinued, the β-adrenoblocker should be withdrawn first, followed by Moxonidin-Farmak several days later.

To date, no withdrawal effects on blood pressure have been observed after discontinuation of moxonidine. However, abrupt cessation of moxonidine therapy is not recommended; instead, the dose should be gradually reduced over a two-week period.

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

Elderly patients may be more sensitive to the effects of antihypertensive agents; therefore, treatment in such patients should be initiated at the lowest dose, with cautious dose escalation to avoid serious adverse reactions.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on the use of moxonidine in pregnant women. Animal studies have shown embryotoxic effects (see section "Pharmacological properties / Preclinical safety data"). The potential risk in humans is unknown. Moxonidine should not be used during pregnancy unless clearly necessary.

Breastfeeding period.

Moxonidine passes into breast milk; therefore, it should not be used during breastfeeding. If moxonidine therapy is considered absolutely necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of the drug on the ability to drive or operate machinery have not been conducted.

Treatment of arterial hypertension with this medicinal product requires regular medical supervision. Various adverse reactions reported in individual cases (e.g., dizziness, somnolence) may impair reaction ability to such an extent that the ability to drive, operate machinery, or work without safety equipment may be compromised. This is particularly relevant during the initial treatment period, dose escalation, drug substitution, and concomitant alcohol use.

Dosage and Administration

The standard initial dose of moxonidine is 0.2 mg once daily. The maximum single dose is 0.4 mg. The maximum daily dose is 0.6 mg, administered in two divided doses. The dose should be individually adjusted according to the patient's response.

Moxonidin-Farmak may be taken independently of food intake, swallowed with a small amount of liquid.

Renal Impairment

For patients with moderate or severe renal impairment, the initial dose of moxonidine is 0.2 mg daily. If necessary and in case of good tolerability, the dose may be increased to 0.4 mg daily in patients with moderate renal impairment and to 0.3 mg daily in patients with severe renal impairment (see section "Special Warnings and Precautions for Use").

For patients undergoing hemodialysis, the initial dose of Moxonidin-Farmak is 0.2 mg daily. If necessary and in case of good tolerability, the dose may be increased to 0.4 mg daily.

Hepatic Impairment

Studies in patients with hepatic impairment are lacking. Since moxonidine is not subject to significant hepatic metabolism, a major impact on pharmacokinetics is not expected. Therefore, the recommended dose for patients with mild to moderate hepatic impairment corresponds to the usual recommended adult dose.

Duration of treatment is not limited.

Although rebound hypertension (withdrawal effect) has not been observed in a limited number of studies following abrupt discontinuation of moxonidine, abrupt cessation of moxonidine therapy (if necessary) is not recommended, as is generally the case with all antihypertensive agents. The dose of moxonidine should be gradually reduced over a period of two weeks.

Children

Moxonidin-Farmak is not recommended for use in children and adolescents (under 18 years of age) due to insufficient data on safety and efficacy in this population.

Overdose

Symptoms of Overdose

Even single doses of moxonidine as high as 19.6 mg have not resulted in fatal outcomes in isolated cases. Signs and symptoms of overdose include headache, sedative effect, drowsiness, arterial hypotension, dizziness, asthenia, bradycardia, dry mouth, vomiting, fatigue, and upper abdominal pain. In cases of severe overdose, careful monitoring for disturbances of consciousness and respiratory depression is recommended.

Following accidental ingestion of an unknown amount of moxonidine (possibly 14 mg) by a two-year-old child, sedation, coma, arterial hypotension, miosis, and dyspnea were observed. Gastric lavage, glucose infusion, controlled ventilation, and immobilization led to complete resolution of symptoms within 11 hours.

Based on animal studies with high doses of the drug, additional expected effects may include orthostatic dysregulation, transient hypertension, tachycardia, and hyperglycemia.

Management of Overdose

No specific antidotes are known. In case of arterial hypotension, dopamine and plasma substitutes are recommended to support hemodynamics. Atropine may be administered in case of bradycardia.

Alpha-adrenergic antagonists may reduce or eliminate paradoxical hypertensive effects of moxonidine overdose.

Adverse reactions

The most common adverse reactions associated with the use of moxonidine are dry mouth, dizziness, asthenia, and somnolence. These symptoms often diminish after the first few weeks of treatment.

Below is a list of adverse reactions observed during placebo-controlled clinical studies in 886 patients treated with moxonidine, grouped by system organ classes and categorized by frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100).

* Frequency is not increased compared to placebo.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging to protect from light at a temperature not exceeding 30 °C. Keep out of reach and sight of children.

Packaging. 10 tablets per blister, 3 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer. Saneca Pharmaceuticals AT.

Manufacturer's address and location of operations.

Nitrianska 100, 920 27 Glogovec, Slovak Republic.

Marketing Authorization Holder. JSC "Farmak".

Address of the Marketing Authorization Holder. 63 Kyrylivska Street, Kyiv, 04080, Ukraine.