Physiotens^® (Tablets) Instructions for Use

ATC Code

C02AC05 (Moxonidine)

Active Substance

Moxonidine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Selective imidazoline receptor agonist. Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive agents; centrally-acting antiadrenergic agents; imidazoline receptor agonists

Pharmacological Action

Moxonidine is an antihypertensive agent with a central mechanism of action. In the brainstem structures (rostral ventrolateral medulla), Moxonidine selectively stimulates imidazoline-sensitive receptors, which are involved in the tonic and reflex regulation of the sympathetic nervous system. Stimulation of imidazoline receptors reduces peripheral sympathetic activity and blood pressure.

Moxonidine differs from other sympatholytic antihypertensive agents by its lower affinity for α₂-adrenergic receptors, which explains the lower likelihood of sedative effects and dry mouth.

The use of moxonidine leads to a decrease in systemic vascular resistance and blood pressure. The antihypertensive effect of moxonidine has been confirmed in double-blind, placebo-controlled, randomized studies.

Results from a clinical study involving 42 patients with arterial hypertension and left ventricular hypertrophy (LVH) demonstrated that, with a similar reduction in blood pressure, the use of a combination of angiotensin II receptor antagonists with moxonidine allowed for a greater reduction in LVH compared to a free combination of a thiazide diuretic and a slow calcium channel blocker (15% vs. 11%; p<0.05).

Moxonidine improves the insulin sensitivity index by 21% (compared to placebo) in patients with obesity, insulin resistance, and moderate arterial hypertension.

Pharmacokinetics

Absorption

After oral administration, Moxonidine is rapidly and almost completely absorbed in the upper gastrointestinal tract. The absolute bioavailability is approximately 88%, indicating the absence of a significant first-pass effect through the liver.

The time to reach C_max is about 1 hour. Food intake does not affect the pharmacokinetics of the drug.

Distribution

Plasma protein binding is 7.2%.

Metabolism

The main metabolite of moxonidine is dehydrogenated Moxonidine. The pharmacodynamic activity of dehydrogenated moxonidine is about 10% compared to moxonidine.

Excretion

The T_1/2 of moxonidine and the metabolite is 2.5 and 5 hours, respectively. Within 24 hours, more than 90% of moxonidine is excreted by the kidneys (about 78% unchanged and 13% as dehydro-moxonidine; other metabolites in urine do not exceed 8% of the administered dose). Less than 1% of the dose is excreted via the intestines.

Pharmacokinetics in Special Clinical Situations

Patients with arterial hypertension: Compared to healthy volunteers, no changes in the pharmacokinetics of moxonidine were noted in patients with arterial hypertension.

Elderly patients: Clinically insignificant changes in the pharmacokinetic parameters of moxonidine were noted in elderly patients, probably due to a decrease in the intensity of its metabolism and/or slightly higher bioavailability.

Patients with renal impairment: The excretion of moxonidine significantly correlates with creatinine clearance. In patients with moderate renal impairment (creatinine clearance 30-60 ml/min), steady-state plasma concentrations and terminal T_1/2 are approximately 2 and 1.5 times higher, respectively, than in individuals with normal renal function (creatinine clearance >90 ml/min). In patients with severe renal impairment (creatinine clearance <30 ml/min), steady-state plasma concentrations and terminal T_1/2 are 3 times higher than in patients with normal renal function. Administration of multiple doses of moxonidine leads to predictable accumulation in patients with moderate and severe renal impairment. In patients with end-stage renal disease (creatinine clearance <10 ml/min) undergoing hemodialysis, steady-state plasma concentrations and terminal T_1/2 are 6 and 4 times higher, respectively, than in patients with normal renal function. In patients with moderate renal impairment, the C_max of moxonidine in plasma is 1.5-2 times higher. In patients with impaired renal function, the dose should be selected individually. Moxonidine is insignificantly removed during hemodialysis.

Children: Moxonidine is not recommended for use in patients under 18 years of age; therefore, pharmacokinetic studies have not been conducted in this group.

Indications

For use in adults aged 18 years and older

• Arterial hypertension.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally, regardless of meals.

In most cases, the initial dose of Physiotens^® is 0.2 mg/day. The maximum single dose is 0.4 mg. The maximum daily dose, which should be divided into 2 doses, is 0.6 mg.

Individual adjustment of the daily dose is necessary depending on the patient’s tolerance to the therapy.

Dose adjustment for patients with hepatic impairment is not required.

The initial dose for patients on hemodialysis is 0.2 mg/day. If necessary and well tolerated, the daily dose can be increased to a maximum of 0.4 mg.

Patients with renal impairment are recommended to have a careful dose selection, especially at the beginning of treatment. The initial dose should be 0.2 mg/day. If necessary and well tolerated, the daily dose of the drug can be increased to a maximum of 0.4 mg for patients with moderate renal impairment (creatinine clearance greater than 30 ml/min but less than 60 ml/min) and 0.3 mg for patients with severe renal impairment (creatinine clearance less than 30 ml/min).

If it is necessary to use moxonidine at a dose of 0.3 mg/day, medicinal products from other manufacturers in a dosage of 0.3 mg should be prescribed.

Safety and efficacy in children aged 0 to 18 years have not been established. Data are not available.

Adverse Reactions

The most frequent adverse reactions in patients taking Moxonidine are: headache*, dizziness, drowsiness, insomnia, dry mouth, diarrhea, nausea, vomiting, dyspepsia, skin rash, itching, back pain, asthenia. These symptoms often decrease after the first weeks of therapy.

Adverse reactions are grouped by system-organ class with an indication of their frequency of occurrence: very common (≥ 1/10); common (≥1/100 but <1/10); uncommon (≥ 1/1000 but <1/100), rare (≥ 1/10000 but < 1/1000), very rare (< 1/10000), frequency unknown (cannot be estimated from the available data).

Nervous system disorders: common – headache*, dizziness (vertigo), drowsiness, insomnia; uncommon – syncope*, increased excitability.

Ear and labyrinth disorders: uncommon – tinnitus.

Cardiac disorders uncommon – bradycardia.

Vascular disorders uncommon – marked decrease in blood pressure, orthostatic hypotension*.

Gastrointestinal disorders very common – dry mouth; common – diarrhea, nausea, vomiting, dyspepsia.

Skin and subcutaneous tissue disorders: common – skin rash, itching; uncommon – angioedema.

Musculoskeletal and connective tissue disorders: common – back pain; uncommon – neck pain.

General disorders common – asthenia; uncommon – peripheral edema.

* – frequency comparable to placebo.

Reporting of Suspected Adverse Reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to the active substance and other components of the drug;
• History of angioedema;
• Sick sinus syndrome or sinoatrial block;
• Severe bradycardia (resting heart rate less than 50 beats/min);
• Second- or third-degree AV block;
• Acute and chronic heart failure (NYHA functional class III and IV);
• Severe hepatic impairment;
• Breastfeeding period;
• Age under 18 years (due to lack of safety and efficacy data);

With caution

• First-degree AV block (risk of bradycardia);
• Coronary artery disease (including ischemic heart disease, unstable angina, early post-infarction period);
• Peripheral circulatory disorders (including intermittent claudication, Raynaud’s syndrome);
• Epilepsy;
• Parkinson’s disease;
• Depression;
• Glaucoma;
• Moderate renal impairment (creatinine clearance 30-60 ml/min, serum creatinine 105-160 µmol/l);
• Hepatic impairment;
• Pregnancy.

Use in Pregnancy and Lactation

Pregnancy

Clinical data on the use of Physiotens^® in pregnant women are not available.

Animal studies have established the embryotoxic effect of the drug.

Physiotens^® should be prescribed to pregnant women only after a careful assessment of the risk-benefit ratio, when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

Moxonidine passes into breast milk, so it should not be prescribed during breastfeeding. If it is necessary to use the drug Physiotens^® during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Dose adjustment for patients with hepatic impairment is not required.

Use in Renal Impairment

Patients with renal impairment are recommended to have a careful dose selection, especially at the beginning of treatment. If necessary and well tolerated, the daily dose of the drug can be increased to a maximum of 0.4 mg for patients with moderate renal impairment (creatinine clearance greater than 30-60 ml/min) and 0.3 mg for patients with severe renal impairment (creatinine clearance <30 ml/min).

Pediatric Use

The use of the drug is contraindicated in patients under 18 years of age (due to lack of safety and efficacy data).

Geriatric Use

Clinically insignificant changes in the pharmacokinetic parameters of moxonidine were noted in elderly patients, probably due to a decrease in the intensity of its metabolism and/or slightly higher bioavailability.

Special Precautions

Regular blood pressure monitoring is necessary during treatment.

Post-marketing surveillance has recorded cases of AV block of varying severity in patients taking Moxonidine. A connection between the use of Physiotens^® and slowing of AV conduction cannot be completely excluded. Thus, caution is recommended when treating patients with a probable predisposition to developing AV block.

If it is necessary to discontinue concurrently taken beta-blockers and Physiotens^®, beta-blockers should be discontinued first, and only after a few days – Physiotens^®.

Currently, there is no confirmation that discontinuation of Physiotens^® leads to an increase in blood pressure. However, it is not recommended to stop taking Physiotens^® abruptly; instead, the drug dose should be gradually reduced over 2 weeks.

Elderly patients

Elderly patients may have an increased risk of cardiovascular complications due to the use of antihypertensive drugs, so therapy with Physiotens^® should be started at the minimum dose.

Excipients

The drug Physiotens^® contains lactose monohydrate. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Effect on ability to drive vehicles and operate machinery

Studies on the effect of the drug on the ability to drive a car and operate other machinery have not been conducted. There are reports of drowsiness and dizziness during treatment with moxonidine, which should be taken into account by patients engaged in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Overdose

There are reports of several cases of non-fatal overdose when doses up to 19.6 mg were taken at one time.

Symptoms headache, sedative effect, drowsiness, marked decrease in blood pressure, dizziness, asthenia, bradycardia, dry mouth, vomiting, fatigue, epigastric pain, respiratory depression, and impaired consciousness. In addition, a short-term increase in blood pressure, tachycardia, and hyperglycemia are also possible, as shown in several studies of high doses in animals.

Treatment There is no specific antidote. In case of a marked decrease in blood pressure, restoration of circulating blood volume by fluid administration and dopamine (injection) may be required. Bradycardia can be stopped with atropine (injection). In severe cases of overdose, it is recommended to carefully monitor consciousness disorders and prevent respiratory depression. Alpha-adrenergic receptor antagonists may reduce or eliminate paradoxical hypertensive effects in moxonidine overdose.

Drug Interactions

Concomitant use of moxonidine with other antihypertensive drugs leads to an additive effect.

Beta-blockers enhance bradycardia, the severity of negative inotropic and dromotropic effects.

Tricyclic antidepressants may reduce the effectiveness of centrally acting antihypertensive agents, so their use together with moxonidine is not recommended.

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

Moxonidine is able to moderately improve impaired cognitive functions in patients receiving lorazepam.

Moxonidine may enhance the sedative effect of benzodiazepine derivatives when administered simultaneously.

Moxonidine is excreted by tubular secretion. Therefore, its interaction with other drugs excreted by tubular secretion cannot be excluded.

Studies with digoxin and hydrochlorothiazide did not reveal evidence of interaction.

The oral bioavailability of glibenclamide was reduced by 11% when used with moxonidine.

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Storage Conditions

For the 0.2 mg dosage (when manufactured at all sites), for the 0.4 mg dosage (when manufactured at JSC VEROPHARM, Russia) – store at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

For the 0.4 mg dosage (when manufactured at JSC Nobel Almaty Pharmaceutical Factory, Kazakhstan, Mylan Laboratories SAS, France) – store at a temperature not exceeding 30°C (86°F). Shelf life – 3 years.

The drug should be stored out of the reach of children.

Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.