For the treatment of primary forms of arterial hypertension or arterial hypertension with no recognisable cause (essential hypertension).

 

Moxonidine should be dosed on an individual basis. The therapeutic daily dose is usually between 0.2 mg moxonidine and 0.4 mg moxonidine.

 

Treatment should be started at the lowest dose of moxonidine, i.e. 0.2 mg moxonidine per day, corresponding to1 film-coated tablet of Physiotens 0.2 mg in the morning.

 

If the effect is inadequate, the dose should be increased after 3 weeks at the earliest to 0.4 mg moxonidine per day, corresponding to 2 film-coated tablets of Physiotens 0.2 mg in the morning or 1 film-coated tablet of Physiotens 0.2 mg twice daily (1 film-coated tablet in the morning, 1 film-coated tablet in the evening).

 

If a higher daily dose is indicated, Physiotens 0.3 mg and Physiotens 0.4 mg are available to simplify usage.

 

A single dose of 0.4 mg moxonidine and a daily dose of 0.6 mg moxonidine should not be exceeded.

 

Impaired kidney function:

In patients with moderately impaired kidney function (GFR higher than 30 ml/min but less than 60 ml/min), a single dose of 0.2 mg moxonidine and a daily dose of 0.4 mg moxonidine should not be exceeded.

 

In haemodialysis patients, the initial dose is 0.2 mg daily. If necessary and it is well tolerated, in patients with moderately impaired kidney function the dose can be increased to 0.4 mg daily and in patients with severe kidney impairment to 0.3 mg daily (see section 4.4).

 

Impaired liver function:

So far there are no studies on patients with impaired liver function. As moxonidine is not liable to extensive liver metabolism, no substantial effect on pharmacokinetics is expected. Therefore the recommended dose for patients with mild to moderate liver damage corresponds to the normal dose recommendation for adults.

 

Children and Adolescents:

Because of the lack of data on safety and efficacy, the use of moxonidine in children and adolescents under 18 years of age is not recommended.

 

Method of Administration

 

The film-coated tablets should preferably be taken with sufficient fluid. They may be taken with or without food.

 

No time limit on duration of use is envisaged.

 

Although in a limited number of studies, following sudden discontinuation of moxonidine, no counter-regulation of blood pressure (rebound effect) was noted, it is not recommended - as is usual with all antihypertensives - that the treatment with moxonidine is ended abruptly in case this is necessary. Moxonidine should be discontinued by reducing it over a period of 2 weeks.

Moxonidine should not be used in the case of: • sick sinus syndrome • 2nd and 3rd degree atrioventricularblock • resting bradycardia below 50 beats a minute • cardiac insufficiency • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

After market launch, cases of AV block of varying degree have been reported in patients treated with moxonidine. Because of these case reports, a contributory role of moxonidine in delayed atrioventricular conduction cannot be ruled out. Caution is therefore advisable in the treatment of patients in whom a tendency to develop an AV block is possible.

 

If moxonidine is used in patients with 1^st degree atrioventricularblock, care must be taken in particular to avoid bradycardia. Moxonidine should not be used in cases of AV block of a higher degree (see section 4.3).

 

When using moxonidine in patients with severe coronary artery disease or unstable angina pectoris, special care is required, as there is only limited experience with this patient population.

 

When using moxonidine in patients with kidney damage, caution is advisable since moxonidine is eliminated primarily through the kidneys. In these patients, especially at the start of therapy, care should be exercised when increasing the dose. The dose should be started at 0.2 mg daily and in patients with moderately impaired kidney function (GFR > 30 ml/min but < 60 ml/min) can be increased to a maximum of 0.4 mg daily and in patients with severely impaired kidney function (GFR < 30 ml/min) to 0.3 mg daily, if this is indicated clinically and is well tolerated.

 

If moxonidine is used with a beta-blocker and both therapies have to be terminated, the beta-blocker should be stopped first and then the moxonidine a few days later.

 

So far no rebound effect on blood pressure has been noted after stopping moxonidine therapy. However, abrupt termination of treatment with moxonidine is not advisable; it is better to reduce the dose gradually over a period of two weeks.

 

Patients with the rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take Physiotens.

 

Older people may be more sensitive to the effect of antihypertensives. Therefore the therapy should be started at the lowest dose and the dose should be carefully increased in order to avoid serious secondary reactions.

Co-administration of other antihypertensives increases the hypotensive effect of moxonidine.

As tricyclic antidepressantscan reduce the effect of centrally acting antihypertensives, concomitant administration of tricyclic antidepressantswith moxonidine is not recommended.

Moxonidine can potentiate the sedative effect of tricyclic antidepressants (co-prescribing should be avoided), tranquillisers, alcohol, sedatives and hypnotics.

Moxonidine moderately increases loss of cognitive performance in test subjects who received lorazepam. Moxonidine can increase the sedative effect of benzodiazepines when administered at the same time.

Moxonidine is eliminated by tubular secretion. Interaction with other substanceseliminated by tubular secretion cannot be ruled out. However, studies with digoxin and hydrochlorothiazide did not reveal any evidence of interactions. Oral bioavailability of glibenclamide was reduced by 11%.

Pregnancy:

There are no adequate data on the use of moxonidine in pregnant women. Studies on animals have revealed embryotoxic effects (see section 5.3). The potential risk for humans is unknown. Moxonidine should be used in pregnancy only if clearly necessary.

Breast-feeding:

Moxonidine is excreted in breast milk and should therefore not be used when breastfeeding. If therapy with moxonidine is considered essential, weaning is necessary.

No studies on the effects on the ability to drive and use machines have been carried out.

 

The treatment of arterial hypertension with this medicinal product requires regular medical supervision. Because of various reactions that occur in individual cases (e.g. dizziness, drowsiness), responsiveness can be changed to such an extent that the ability to drive, use machines or work without secure support is affected. This applies even more so at the start of treatment, if the dose is increased or the medication changed, and during interaction with alcohol.

The undesirable effects most commonly reported when taking moxonidine include dry mouth, dizziness, asthenia and somnolence. These effects normally diminish after the first few weeks of treatment.

 

Undesirable effects according to system organ class: Class (The following undesirable effects were noted in placebo-controlled clinical trials with n=866 patients who received moxonidine and at the following frequencies):

 

 

 

 

System organ class according to MedRA	Very common ( can occur in more than 1 in 10 patients treated)	Common (can occur in  up to 1 in 10 patients treated)	Uncommon (can occur in up to 1 in 100 patients treated)
Cardiac disorders			Bradycardia
Ear and labyrinth disorders			Tinnitus
Nervous system disorders		Headache*, dizziness/vertigo, somnolence	Syncope*
Vascular disorders			Hypotension* (including orthostatic hypotension)
Gastrointestinal disorders	Dry mouth	Diarrhoea, nausea/vomiting/dyspepsia
Skin and subcutaneous tissue disorders		Erythema, pruritus	Angioedema
Reproductive system and breast disorders
General disorders and administration site conditions		Asthenia	Oedema
Musculoskeletal and connective tissue disorders		Back pain	Neck pain
Psychiatric disorders		Insomnia	Nervousness

* The frequency was not increased compared with placebo.

 

Reporting of suspected undesirable effects.

The reporting of suspected undesirable effects after authorisation is of great importance. It enables continuous monitoring of the medicinal product’s risk-benefit ratio. Healthcare professionals are asked to report every suspected case of an undesirable effect 

To report any side effect(s):

- National Pharmacovigilance Center (NPC)

o    Fax: +966-11-205-7662

o    SFDA Call Center: 19999

o    E-mail: npc.drug@sfda.gov.sa

o    Website: https://ade.sfda.gov.sa

However, in some cases acute doses of up to 19.6 mg were taken without a fatal development. The reported signs and symptoms of overdose are: headache, sedation, somnolence, hypotension, dizziness, asthenia, bradycardia, dry mouth, vomiting, fatigue and upper abdominal pain. In the case of a heavy overdose, close monitoring is recommended, particularly for disorders of consciousness and respiratory depression.

 

In the case of a 2-year old child who had accidentally ingested an unknown quantity of moxonidine (potentially 14 mg), sedation, coma, hypotension, miosis and dyspnoea occurred. Gastrolavage, a glucose infusion, controlled respiration and immobilisation led to complete remission of the symptoms within 11 hours.

 

On the basis of animal trials at high doses, the following symptoms are also possible: orthostatic dysregulation, paradoxical hypertension, tachycardia and hyperglycaemia.

 

Treatment of intoxication:

A specific antidote is not known. If there is a fall in blood pressure, circulatory support, for example with administration of fluid and dopamine, may be indicated. Bradycardia can be treated with atropine.

 

α-receptor antagonists can reduce or annul the paradoxical hypertensive effect of moxonidine overdose.

Pharmacotherapeutic group: Imidazoline receptor agonist, moxonidine

ATC code: C02AC05

 

In various animal models, moxonidine proved to be a highly effective antihypertensive. The available data from experimental studies clearly show that the site of action for the antihypertensive effect of moxonidine is the central nervous system (CNS). It has been established that moxonidine in the brain stem binds selectively to I₁-imidazoline receptors. These imidazoline receptors are concentrated in the rostral ventrolateral medulla, an area of decisive significance in central control of the peripheral sympathetic nervous system. The binding of moxonidine to the I₁-imidazoline receptor has an inhibiting effect on the activity of the sympathetic nerves (demonstrated in sympathetic nerve endings of the heart, internal organs and kidneys). In humans, through a reduction in the sympathetic nerve activity, moxonidine leads to a reduction in systemic vascular resistance and consequently to a lowering of arterial blood pressure. The effects of moxonidine on mortality and cardiovascular morbidity during treatment of essential hypertension are currently unknown.

Moxonidine differs from other available centrally acting antihypertensives in a lesser affinity for central alpha-2 receptors compared with I₁-imidazoline receptors; the undesirable effects of fatigue and dry mouth are attributed to the interaction with alpha-2 receptors. Because of the high selectivity for imidazoline receptors, undesirable effects such as sedation and dry mouth resulting from the interaction with alpha-2 receptors - the most commonly occurring undesirable effects of centrally acting antihypertensives - are clearly less pronounced.

Published data prove that in hypertensive patients with left ventricular hypertrophy (LVH) who have had an angiotensin-II-antagonist (AIIA) administered together with moxonidine to lower blood pressure, improved LVH reduction is achieved compared with the free combination of a thiazide and a calcium channel blocker.

In a two-month clinical study, moxonidine, in comparison with placebo, improved the insulin-sensitivity index of overweight and insulin-resistant patients with moderate hypertension by 21%.

Absorption:

Following oral administration, moxonidine is quickly and almost completely absorbed into the upper gastrointestinal tract (t_max approx. 1 hour), it does not undergo any first-pass metabolism and is therefore 88% bioavailable. Ingestion of food has no effect on the pharmacokinetics of moxonidine.

 

Distribution:

The maximum moxonidine plasma levels are reached 30 to 180 minutes after administration of the film-coated tablets.

Following in vitro measurements, human plasma protein binding to moxonidine is only about 7.2% (Vd_ss = 1.8 +/- 0.4 l/kg).

 

Biotransformation:

Moxonidine is metabolised up to 10 - 20%, in fact mainly to 4,5-dehydromoxonidine and through opening of the imidazoline ring to guanidine derivative. 4,5-dehydro-moxonidine shows only 1/10 and guanidine derivative less than 1/100 of the hypotensive efficacy of moxonidine.

 

Elimination:

Moxonidine and its metabolites are eliminated almost exclusively by the kidneys. Over 90% of the applied activity dose is eliminated by the kidneys in the first 24 hours after administration; in comparison, only about 1% through faeces. Cumulative renal elimination of unchanged moxonidine in the process amounts to approximately 50-75%.

The mean plasma elimination half-life of moxonidine is 2.2 to 2.3 hours; the renal elimination half-life is 2.6 to 2.8 hours.

It has been shown that under moxonidine, in spite of the renal elimination, no accumulation occurs either with repeated application or with impaired kidney function.

 

Pharmacokinetics in hypertensive patients:

In hypertensive patients, no relevant changes were noted in the pharmacokinetics compared with healthy test subjects.

 

Pharmacokinetics in elderly patients:

The slight difference in the pharmacokinetic properties of moxonidine in healthy older patients and young adults has so far proven to be clinically irrelevant. As moxonidine does not have a tendency to accumulate, no dose adjustment is necessary, if kidney function is normal.

 

Pharmacokinetics in children:

So far no pharmacokinetic studies have been carried out on children.

 

Pharmacokinetics in patients with impaired kidney function:

There is a significant correlation between moxonidine elimination and creatinine clearance. In patients with impaired kidney function, the dose has to be adjusted to individual requirements.

In patients with moderately impaired kidney function (GFR 30-60 ml/min), the AUC is increased by 85%, clearance is reduced by 52% and steady-state plasma concentration and terminal half-life are increased approximately 2-fold or 1.5-fold compared with hypertensive patients with normal kidney function (GFR > 90 ml/min). The maximum moxonidine plasma concentrations are increased by only 1.5 to 2-fold.

 

In patients with severe kidney damage (GFR < 30 ml/min), steady-state plasma concentrations and terminal half-life are approximately three times higher. In these patients, no unexpected drug accumulation was noted after multi-dosing. In kidney patients in the terminal stage (GFR < 10 ml/min) who undergo haemodialysis, AUC and terminal half-life are increased 6-fold or 4-fold compared with hypertensive patients with normal kidney function.

 

Moxonidine is eliminated to a lesser extent through haemodialysis

Based on the conventional studies on safety pharmacology, chronic toxicity, reproductive toxicity, genotoxicity and carcinogenic potential, the preclinical data do not indicate any particular risk for humans.

 

Experimental studies on animals have shown embryotoxic effects at maternally toxic doses.

 

Reproductive studies did not reveal any impaired fertility or teratogenic effects.

 

Embryotoxic effects were observed in rats in the dose range above 3 mg/kg of body weight daily and in rabbits above 0.7 mg/kg of body weight daily.

 

In a peri- and post-natal study on rats, development and viability of the young were impaired at doses above 1 mg/kg of body weight daily.

 

Carcinogenicity studies on rats at doses up to 3.6 mg/kg of body weight daily and on mice up to 7.5 mg/kg of body weight daily revealed no evidence of a carcinogenic risk through moxonidine.

Tablet core:

Crospovidone Type A (Ph. Eur.)

Lactose monohydrate

Magnesium stearate (Ph. Eur.) [vegetable]

Povidone (K25)

 

Film-coating:

Red iron oxide (E172)

Ethylcellulose

Hypromellose

Macrogol 6000

Talc

Titanium dioxide (E171)

Not applicable.

3 years

Do not store above 30°

PVC aluminium blister pack or PVC/PVDC aluminium blister pack

 

Original packagings with:

- 28 film-coated tablets

- 98 film-coated tablets

Not all pack sizes may be marketed

 

No special requirements.