Physiotens®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PHYSIOTENS® (PHYSIOTENS®)

Composition:

Active substance: moxonidine;

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

Excipients: lactose monohydrate; povidone K25; crospovidone; magnesium stearate; tablet coating: hypromellose, aqueous dispersion of ethylcellulose 30%, macrogol 6000, talc, red iron oxide (E 172), titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

tablets of 0.2 mg – round convex tablets of light pink color with the imprint «0.2» on one side;

tablets of 0.3 mg – round convex tablets of pale red color with the imprint «0.3» on one side;

tablets of 0.4 mg – round convex tablets of dull red color with the imprint «0.4» on one side.

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

Pharmacological Properties

Pharmacodynamics

Moxonidine has been demonstrated to be 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 ventrolateral portion of the medulla oblongata—a region considered to be the center for regulation of peripheral sympathetic nervous system activity. Stimulation of imidazoline receptors leads to reduced sympathetic nervous system activity and a consequent decrease in arterial blood pressure.

Moxonidine differs from other sympatholytic antihypertensive agents by its relatively low affinity for known α2-adrenergic receptors compared to imidazoline receptors. Due to this selectivity, sedative effects and dry mouth occur infrequently 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 combining an angiotensin II antagonist (AIIA) with moxonidine in patients with arterial hypertension and left ventricular hypertrophy leads to enhanced regression of left ventricular hypertrophy compared to a free combination of a thiazide and a calcium channel blocker, at equivalent blood pressure reduction.

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

Pharmacokinetics

Absorption. After oral administration, moxonidine is rapidly (time to reach maximum plasma concentration (tmax) – approximately 1 hour) and almost completely absorbed from the upper gastrointestinal tract. Absolute bioavailability is approximately 88%, indicating minimal 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. In human plasma samples, only dehydrogenated moxonidine has been identified. 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 as unchanged compound and 13% as dehydrogenated moxonidine. Other minor metabolites in urine account for approximately 8% of the dose. Less than 1% is excreted in feces. The elimination half-life of moxonidine and its metabolite is approximately 2.5 hours and 5 hours, respectively.

Pharmacokinetics in patients with arterial hypertension. In patients with arterial hypertension, the pharmacokinetics of moxonidine do not differ significantly from those in healthy volunteers.

Pharmacokinetics in elderly patients. Age-related changes in pharmacokinetics have been observed, most likely due to reduced metabolic rate and/or slightly increased bioavailability in elderly patients. However, these pharmacokinetic differences are not considered clinically significant.

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

Pharmacokinetics in renal impairment. Elimination of moxonidine is largely dependent on creatinine clearance. In patients with moderate renal impairment (glomerular filtration rate – 30–60 mL/min), steady-state plasma concentration and terminal half-life are approximately 2 and 1.5 times higher, respectively, than in patients with arterial hypertension and normal renal function (glomerular filtration rate > 90 mL/min). In patients with severe renal impairment (glomerular filtration rate < 30 mL/min), steady-state plasma concentration and terminal 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 (glomerular filtration rate < 10 mL/min) undergoing hemodialysis, AUC and terminal half-life are 6 and 4 times higher, respectively, compared to patients with arterial hypertension and normal renal function. In patients with moderate renal impairment, maximum plasma concentration of moxonidine is only 1.5–2 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

Preclinical data reveal no special risk for humans based on standard studies of pharmacological safety, chronic toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity.

Animal studies revealed embryotoxic effects when administered at doses toxic to the maternal organism. Reproductive toxicity studies showed no effects on fertility or teratogenic potential. Embryotoxic effects were observed in rats at doses ≥ 9 mg/kg/day and in rabbits at doses > 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.

Moxonidine is contraindicated in:

• hypersensitivity to the active substance or to any component of the medicinal product;
• sinus node weakness syndrome;
• bradycardia (resting heart rate below 50 beats/min);
• second- or third-degree atrioventricular (AV) block;
• heart failure.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of moxonidine with other antihypertensive agents may result 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.

Moxonidine moderately enhances cognitive impairment in patients receiving lorazepam. Moxonidine may increase 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 have not shown any evidence of interaction. Oral bioavailability of glyburide (glibenclamide) 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 receiving moxonidine treatment. Therefore, a causal role of moxonidine in atrioventricular conduction delay cannot be entirely 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 ischemic heart disease or unstable angina, as experience with the use of the drug in such patients is limited.

Caution is recommended when using moxonidine in patients with renal impairment, as moxonidine is primarily excreted by the kidneys. In such patients, careful dose titration is recommended, 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 moxonidine is used in combination with a β-blocker and both drugs need to be discontinued, the β-blocker should be withdrawn first, followed by moxonidine a few days later.

To date, no rebound 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 medication.

Elderly patients may be more sensitive to the effects of antihypertensive agents. Therefore, treatment should be initiated at the lowest dose, and dose escalation should be performed cautiously 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 to humans is unknown. Moxonidine should not be used during pregnancy unless clearly necessary.

Breastfeeding.

Moxonidine passes into breast milk and therefore 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 phase of treatment, dose escalation, switching medications, and in combination with alcohol.

Method of Administration and Dosage

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.

Moxonidine may be taken independently of food intake, 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 provided the drug is well tolerated, 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 moxonidine is 0.2 mg daily. If necessary and provided the drug is well tolerated, the dose may be increased to 0.4 mg daily.

Hepatic Impairment

Studies in patients with hepatic impairment are lacking. Since moxonidine does not undergo 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 dose for adults.

The 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 two-week period.

Children

Moxonidine is not recommended for use in children and adolescents (under 18 years of age) due to insufficient data on safety and efficacy in this patient group.

Overdose

Symptoms of overdose

Even in individual cases of moxonidine overdose, including single doses as high as 19.6 mg, no fatal outcomes have been reported. 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 in consciousness and respiratory depression is recommended.

Following accidental ingestion of an unknown quantity of moxonidine (possibly 14 mg) by a two-year-old child, sedative effect, 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 hypotension, dopamine and plasma volume expanders are recommended to support hemodynamics. Atropine may be used in the presence of bradycardia.

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

Adverse Reactions

The most commonly observed adverse effects during moxonidine treatment include 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 trials in 886 patients treated with moxonidine, grouped by system organ classes and categorized by frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100).

Psychiatric disorders:
Common – insomnia;
Uncommon – restlessness.

Nervous system disorders:
Common – headache*, dizziness, vertigo, somnolence;
Uncommon – syncope*.

Ear and labyrinth disorders:
Uncommon – tinnitus.

Cardiac and vascular disorders:
Uncommon – bradycardia, hypotension* (including orthostatic hypotension).

Gastrointestinal disorders:
Very common – dry mouth;
Common – diarrhea, nausea, vomiting, dyspepsia.

Skin and subcutaneous tissue disorders:
Common – rash, pruritus;
Uncommon – angioneurotic edema.

Musculoskeletal and connective tissue disorders:
Common – back pain;
Uncommon – neck pain.

General disorders:
Common – asthenia;
Uncommon – edema.

* Frequency not increased compared to placebo.

Shelf Life

Tablets 0.2 mg – 2 years.
Tablets 0.3 mg and 0.4 mg – 3 years.

Storage Conditions

Tablets 0.2 mg: Store at temperatures not exceeding 25 °C, in a place inaccessible to children.
Tablets 0.3 mg and 0.4 mg: Store at temperatures not exceeding 30 °C, in a place inaccessible to children.

Packaging

Tablets 0.2 mg and 0.4 mg:
No. 14 (14 tablets in a blister, 1 blister per cardboard box);
No. 28 (14 tablets in a blister, 2 blisters per cardboard box, or 28 tablets in a single blister, 1 blister per cardboard box);
No. 98 (14 tablets in a blister, 7 blisters per cardboard box).

Tablets 0.3 mg:
No. 28 (14 tablets in a blister, 2 blisters per cardboard box, or 28 tablets in a single blister, 1 blister per cardboard box);
No. 98 (14 tablets in a blister, 7 blisters per cardboard box).

Prescription Status

Prescription only.

Manufacturer

Mylan Laboratories SAS, France.

Manufacturer's Address

Route de Belleville, Lieu dit Maillard, 01400, Chatillon-sur-Chalaronne, France.