Moxonidin

Moxonidin is indicated in adults for treatment of mild to moderate essential hypertension.

Moxonidinidine is indicated in adults for treatment of mild to moderate essential hypertension.

Posology

Adults

Treatment must be instituted with the lowest dosage of Moxonidin. This means a daily dose of 0.2 mg Moxonidin in the morning. If the therapeutic effect is insufficient, the dose can be increased after three weeks to 0.4 mg. This dose can be given as a single dose (to be taken in the morning) or as a divided daily dose (morning and evening). If the results are still insufficient after a further three weeks, the dosage can be increased further to a maximum of 0.6 mg given divided in the morning and evening. A single dose of 0.4 mg Moxonidin and a daily dose of 0.6 mg Moxonidin should not be exceeded.

Special populations

Elderly

Provided that renal function is not impaired, dosage recommendation is the same as for adults.

Paediatric population

Moxonidin should not be given to children and adolescents under 18 years of age as insufficient safety and therapeutic data are available for this.

Method of administration

As concomitant ingestion of food does not affect the pharmacokinetics of Moxonidin, Moxonidin can be taken before, during or after meals. The tablets should be taken with sufficient fluid.

Posology

Adults

Treatment must be instituted with the lowest dosage of Moxonidinidine. This means a daily dose of 0.2 mg Moxonidinidine in the morning. If the therapeutic effect is insufficient, the dose can be increased after three weeks to 0.4 mg. This dose can be given as a single dose (to be taken in the morning) or as a divided daily dose (morning and evening). If the results are still insufficient after a further three weeks, the dosage can be increased further to a maximum of 0.6 mg given divided in the morning and evening. A single dose of 0.4 mg Moxonidinidine and a daily dose of 0.6 mg Moxonidinidine should not be exceeded.

Special populations

Elderly

Provided that renal function is not impaired, dosage recommendation is the same as for adults.

Paediatric population

Moxonidinidine should not be given to children and adolescents under 18 years of age as insufficient safety and therapeutic data are available for this.

Method of administration

As concomitant ingestion of food does not affect the pharmacokinetics of Moxonidinidine, Moxonidinidine can be taken before, during or after meals. The tablets should be taken with sufficient fluid.

Moxonidin is contraindicated in patients with:

- sick sinus syndrome

- bradycardia (resting HR <50 beats/minute)

- 2nd or 3rd degree atrioventricular block

- cardiac insufficiency

Moxonidinidine is contraindicated in patients with:

- sick sinus syndrome

- bradycardia (resting HR <50 beats/minute)

- 2nd or 3rd degree atrioventricular block

- cardiac insufficiency

Cases of varying degrees of AV block have been reported in the post-marketing setting in patients undergoing Moxonidin treatment. Based on these case reports, the causative role of Moxonidin in delaying atrioventricular conduction cannot be completely ruled out. Therefore, caution is recommended when treating patients with a possible predisposition to developing an AV block.

When Moxonidin is used in patients with 1^st degree AV block special care should be exercised to avoid bradycardia. Moxonidin must not be used in higher degree AV blocks.

When Moxonidin is used in patients with severe coronary artery disease or unstable angina pectoris special care should be exercised due to the fact that there is limited experience in this patient population.

Due to lack of clinical evidence supporting safe use in patients with co-existing moderate cardiac insufficiency, Moxonidin should be administered with caution in these patients.

Caution is advised in the administration of Moxonidin to patients with renal impairment as Moxonidin is excreted primarily via the kidneys. In these patients careful titration of the dose is recommended, especially at the start of therapy. Dosing should be initiated with 0.2 mg daily and can be increased to a maximum of 0.4 mg daily for patients with moderate renal impairment (GFR>30 ml/min but < 60 ml/min) and to a maximum of 0.3 mg daily for patients with severe renal impairment (GFR<30 ml/min) if clinically indicated and well tolerated.

If Moxonidin is used in combination with a β-blocker, and both treatments have to be discontinued the β-blocker should be discontinued first, and, then Moxonidin after a few days.

So far, no rebound effect on blood pressure has been observed after the discontinuation of treatment with Moxonidin. However, it is advisable not to stop taking Moxonidin abruptly, but to reduce it gradually over a period of two weeks.

The elderly population may be more susceptible to the CV effects of blood pressure lowering drugs. Therefore therapy should be started with the lowest dose and dose increments should be introduced with caution to prevent the serious consequences these reactions may lead to.

Moxonidin contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Cases of varying degrees of AV block have been reported in the post-marketing setting in patients undergoing Moxonidinidine treatment. Based on these case reports, the causative role of Moxonidinidine in delaying atrioventricular conduction cannot be completely ruled out. Therefore, caution is recommended when treating patients with a possible predisposition to developing an AV block.

When Moxonidinidine is used in patients with 1^st degree AV block special care should be exercised to avoid bradycardia. Moxonidinidine must not be used in higher degree AV blocks.

When Moxonidinidine is used in patients with severe coronary artery disease or unstable angina pectoris special care should be exercised due to the fact that there is limited experience in this patient population.

Due to lack of clinical evidence supporting safe use in patients with co-existing moderate cardiac insufficiency, Moxonidinidine should be administered with caution in these patients.

Caution is advised in the administration of Moxonidinidine to patients with renal impairment as Moxonidinidine is excreted primarily via the kidneys. In these patients careful titration of the dose is recommended, especially at the start of therapy. Dosing should be initiated with 0.2 mg daily and can be increased to a maximum of 0.4 mg daily for patients with moderate renal impairment (GFR>30 ml/min but < 60 ml/min) and to a maximum of 0.3 mg daily for patients with severe renal impairment (GFR<30 ml/min) if clinically indicated and well tolerated.

If Moxonidinidine is used in combination with a β-blocker, and both treatments have to be discontinued the β-blocker should be discontinued first, and, then Moxonidinidine after a few days.

So far, no rebound effect on blood pressure has been observed after the discontinuation of treatment with Moxonidinidine. However, it is advisable not to stop taking Moxonidinidine abruptly, but to reduce it gradually over a period of two weeks.

The elderly population may be more susceptible to the CV effects of blood pressure lowering drugs. Therefore therapy should be started with the lowest dose and dose increments should be introduced with caution to prevent the serious consequences these reactions may lead to.

Moxonidinidine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Most frequent side effects reported by those taking Moxonidin include dry mouth, dizziness, asthenia and somnolence. These symptoms often decrease after the first few weeks of treatment. Undesirable Effects by System Organ Class (observed during placebo-controlled clinical trials with n=886 patients exposed to Moxonidin resulted in frequencies below):

*there was no increase in frequency compared to placebo

*there was no increase in frequency compared to placebo

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Most frequent side effects reported by those taking Moxonidinidine include dry mouth, dizziness, asthenia and somnolence. These symptoms often decrease after the first few weeks of treatment. Undesirable Effects by System Organ Class (observed during placebo-controlled clinical trials with n=886 patients exposed to Moxonidinidine resulted in frequencies below):

*there was no increase in frequency compared to placebo

*there was no increase in frequency compared to placebo

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Symptoms of overdose

In the few cases of overdose that have been reported, a dose of 19.6 mg was ingested acutely without fatality. Signs and symptoms reported included: headache, sedation, somnolence, hypotension, dizziness, asthenia, bradycardia, dry mouth, vomiting, fatigue and upper abdominal pain. Based on the pharmacodynamic properties of Moxonidin, the following reactions may be expected in adults: headache, sedation, somnolence, hypotension, orthostatic dysregulation, dizziness, asthenia, bradycardia, dry mouth, fatigue and upper abdominal pain. In rare cases, emesis and a transient paradoxical increase in blood pressure can occur. In case of a severe overdose close monitoring of especially consciousness disturbances and respiratory depression is recommended.

In addition, based on a few high dose studies in animals, transient hypertension, tachycardia and hyperglycaemia may also occur.

Treatment of overdose

In the case of a severe overdose, in particular the observation of disorders of consciousness and respiratory depression is advisable. Treatment consists of absorption-reducing measures such as gastric lavage (if shortly after ingestion), administration of activated charcoal and laxatives, and otherwise is symptomatic.

No specific antidote is known.

In case of hypotension, circulatory support such as fluids and dopamine administration may be considered. Bradycardia may be treated with atropine. Alpha-receptor antagonists may diminish or abolish the paradoxical hypertensive effects of a Moxonidin overdose.

Paediatric population

The following case of inadvertent overdose in a 2-year old child has been described:

The child ingested an unknown quantity of Moxonidin. The maximum dose that could have been taken was 14 mg. The child exhibited the following symptoms: Sedation, coma hypotension, miosis and dyspnoea. Gastric lavage, glucose infusions, mechanical ventilation and rest resulted in the symptoms completely disappearing over the course of 11 hours.

Symptoms of overdose

In the few cases of overdose that have been reported, a dose of 19.6 mg was ingested acutely without fatality. Signs and symptoms reported included: headache, sedation, somnolence, hypotension, dizziness, asthenia, bradycardia, dry mouth, vomiting, fatigue and upper abdominal pain. Based on the pharmacodynamic properties of Moxonidinidine, the following reactions may be expected in adults: headache, sedation, somnolence, hypotension, orthostatic dysregulation, dizziness, asthenia, bradycardia, dry mouth, fatigue and upper abdominal pain. In rare cases, emesis and a transient paradoxical increase in blood pressure can occur. In case of a severe overdose close monitoring of especially consciousness disturbances and respiratory depression is recommended.

In addition, based on a few high dose studies in animals, transient hypertension, tachycardia and hyperglycaemia may also occur.

Treatment of overdose

In the case of a severe overdose, in particular the observation of disorders of consciousness and respiratory depression is advisable. Treatment consists of absorption-reducing measures such as gastric lavage (if shortly after ingestion), administration of activated charcoal and laxatives, and otherwise is symptomatic.

No specific antidote is known.

In case of hypotension, circulatory support such as fluids and dopamine administration may be considered. Bradycardia may be treated with atropine. Alpha-receptor antagonists may diminish or abolish the paradoxical hypertensive effects of a Moxonidinidine overdose.

Paediatric population

The following case of inadvertent overdose in a 2-year old child has been described:

The child ingested an unknown quantity of Moxonidinidine. The maximum dose that could have been taken was 14 mg. The child exhibited the following symptoms: Sedation, coma hypotension, miosis and dyspnoea. Gastric lavage, glucose infusions, mechanical ventilation and rest resulted in the symptoms completely disappearing over the course of 11 hours.

Pharmacotherapeutic group: Antihypertensives, antiadrenergic agents, centrally acting

ATC code: C02AC05

In various animal models it has been shown that Moxonidin has a strongly hypotensive effect. Available experimental data indicate that the site of action of Moxonidin is located in the central nervous system (CNS).

In the brain stem, Moxonidin binds selectively to I₁-imidazoline receptors. These imidazoline-sensitive receptors are predominantly found in the rostral ventrolateral medulla, an area which plays an important role in central control of the sympathetic nervous system. The effect of this interaction with these I₁-imidazoline receptors appears to be a reduction in the activity of the sympathetic nerves. This has been demonstrated for cardiac, splanchnic and renal sympathetic nerves.

Moxonidin differs from other centrally acting antihypertensives in the fact that it has only a weak affinity for the central α₂-adrenergic receptors compared to the affinity for I₁-imidazoline receptors. Alpha₂-adrenergic receptors are considered to be the intermediate pathway that causes sedation and dry mouth, the most commonly observed undesirable effects of centrally acting antihypertensives.

Mean systolic and diastolic blood pressure is reduced both at rest and during exercise. The effects of Moxonidin on mortality and cardiovascular morbidity are currently unknown.

In humans, Moxonidin leads to a reduction of systemic vascular resistance and consequently in arterial blood pressure.

Pharmacotherapeutic group: Antihypertensives, antiadrenergic agents, centrally acting

ATC code: C02AC05

In various animal models it has been shown that Moxonidinidine has a strongly hypotensive effect. Available experimental data indicate that the site of action of Moxonidinidine is located in the central nervous system (CNS).

In the brain stem, Moxonidinidine binds selectively to I₁-imidazoline receptors. These imidazoline-sensitive receptors are predominantly found in the rostral ventrolateral medulla, an area which plays an important role in central control of the sympathetic nervous system. The effect of this interaction with these I₁-imidazoline receptors appears to be a reduction in the activity of the sympathetic nerves. This has been demonstrated for cardiac, splanchnic and renal sympathetic nerves.

Moxonidinidine differs from other centrally acting antihypertensives in the fact that it has only a weak affinity for the central α₂-adrenergic receptors compared to the affinity for I₁-imidazoline receptors. Alpha₂-adrenergic receptors are considered to be the intermediate pathway that causes sedation and dry mouth, the most commonly observed undesirable effects of centrally acting antihypertensives.

Mean systolic and diastolic blood pressure is reduced both at rest and during exercise. The effects of Moxonidinidine on mortality and cardiovascular morbidity are currently unknown.

In humans, Moxonidinidine leads to a reduction of systemic vascular resistance and consequently in arterial blood pressure.

Absorption

Moxonidin is rapidly absorbed after oral administration. In humans, approximately 90% of an oral dose is absorbed. Ingestion of food has no effect on the pharmacokinetics of Moxonidin. There is no first-pass metabolism and bioavailability is 88 %.

Distribution

Only about 7% of Moxonidin is bound to human plasma proteins (Vd_ss = 1.8 ± 0.4 l/kg). Peak plasma levels of Moxonidin are reached 30-180 minutes after administration of a film-coated tablet.

Biotransformation

Moxonidin is 10-20% metabolised, predominantly to 4,5-dehydroMoxonidin and to an aminomethanamidine derivative by opening of the imidazoline ring. The hypotensive effect of 4,5-dehydroMoxonidin is only 1/10, and that of the aminomethanamidine derivative less than 1/100, of that of Moxonidin.

Elimination

Moxonidin and its metabolites are almost entirely eliminated via the kidney. More than 90% of the dose is eliminated in the first 24 hours via the kidney, while approximately 1% is eliminated in the faeces. The cumulative excretion of unchanged Moxonidin is approximately 50-75%. The mean plasma elimination half-life is 2.2-2.3 hours and the renal half-life 2.6-2.8 hours.

Characteristics in patients with renal impairment

In patients with moderately impaired renal function (GFR 30 - 60 ml/min), the AUC increased by 85% and the clearance decreased by 52%. In such patients the hypotensive effect of Moxonidin should be closely monitored, especially at the start of treatment. The dose must be adapted in these patients so that the maximum daily dose is not more than 0.4 mg and the maximum single dose is 0.2 mg.

In patients with severely impaired renal function (GFR < 30 ml/min) the clearance is reduced by 68 % and the elimination half live is prolonged up to 7 hours. In these patients Moxonidin dosing should be initiated with 0.2 mg daily and can be increased to a maximum of 0.3 mg daily, if clinically indicated and well tolerated. In such patients the hypotensive effect of Moxonidin should be closely monitored, especially at the start of treatment.

Paediatric population

No pharmacokinetic studies in children have been performed.

Absorption

Moxonidinidine is rapidly absorbed after oral administration. In humans, approximately 90% of an oral dose is absorbed. Ingestion of food has no effect on the pharmacokinetics of Moxonidinidine. There is no first-pass metabolism and bioavailability is 88 %.

Distribution

Only about 7% of Moxonidinidine is bound to human plasma proteins (Vd_ss = 1.8 ± 0.4 l/kg). Peak plasma levels of Moxonidinidine are reached 30-180 minutes after administration of a film-coated tablet.

Biotransformation

Moxonidinidine is 10-20% metabolised, predominantly to 4,5-dehydroMoxonidinidine and to an aminomethanamidine derivative by opening of the imidazoline ring. The hypotensive effect of 4,5-dehydroMoxonidinidine is only 1/10, and that of the aminomethanamidine derivative less than 1/100, of that of Moxonidinidine.

Elimination

Moxonidinidine and its metabolites are almost entirely eliminated via the kidney. More than 90% of the dose is eliminated in the first 24 hours via the kidney, while approximately 1% is eliminated in the faeces. The cumulative excretion of unchanged Moxonidinidine is approximately 50-75%. The mean plasma elimination half-life is 2.2-2.3 hours and the renal half-life 2.6-2.8 hours.

Characteristics in patients with renal impairment

In patients with moderately impaired renal function (GFR 30 - 60 ml/min), the AUC increased by 85% and the clearance decreased by 52%. In such patients the hypotensive effect of Moxonidinidine should be closely monitored, especially at the start of treatment. The dose must be adapted in these patients so that the maximum daily dose is not more than 0.4 mg and the maximum single dose is 0.2 mg.

In patients with severely impaired renal function (GFR < 30 ml/min) the clearance is reduced by 68 % and the elimination half live is prolonged up to 7 hours. In these patients Moxonidinidine dosing should be initiated with 0.2 mg daily and can be increased to a maximum of 0.3 mg daily, if clinically indicated and well tolerated. In such patients the hypotensive effect of Moxonidinidine should be closely monitored, especially at the start of treatment.

Paediatric population

No pharmacokinetic studies in children have been performed.