SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Moxonidine 400 microgram film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 400 microgram moxonidine.

Excipient with known effect: 94.5mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

Appearance: Round, dark pink tablet, approximately 6 mm in diameter.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Mild to moderate essential hypertension.

4.2    Posology and method of administration

Adults

Treatment must be instituted with the lowest dosage of moxonidine. This means a daily dose of 200 microgram moxonidine in the morning. If the therapeutic effect is insufficient, the dose can be increased after three weeks to 400 microgram. 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 600 microgram given divided in the morning and evening.

A single dose of 400 microgram moxonidine and a daily dose of 600 microgram moxonidine should not be exceeded.

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

Moxonidine should not be given to children and adolescents under 16 years of age as insufficient therapeutic data are available for this.

Elderly:

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

Renal impairment:

Patients with moderately impaired renal function (GFR > 30 ml/min but < 60 ml/min), should start the treatment with a dose of 200 microgram daily and the daily dose could be increased to a maximum of 400 microgram daily, if clinically indicated and well tolerate. Patients with severely impaired renal function (GFR < 30 ml/min) may also start the treatment with 200micrograms daily but they may increase the daily dose to a maximum of 300 micrograms, if clinically indicated and well tolerated.

Hepatic impairment:

No studies are available in patients with impaired hepatic function. However, as moxonidine lacks extensive hepatic metabolism no major influence on the pharmacokinetics may be expected and dosage recommendation is the same for patients with hepatic impairment as for adults.

The treatment should not be stopped abruptly, but withdrawn over a period of two weeks (see also section 4.4).

4.3. Contraindications

Moxonidine is contraindicated in patients with:

•    hypersensitivity to moxonidine or to any of the excipients

•    sick sinus syndrome

•    bradycardia (resting HR < 50 beats/minute)

•    AV-block 2nd or 3rd degree

•    cardiac insufficiency (see section 4.4)

4.4 Special warnings and precautions for use

Cases of varying degrees of AV block have been reported in the postmarketing setting in patients undergoing moxonidine treatment. Based on these case reports, the causative role of moxonidine 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 moxonidine is used in patients with 1st degree AV block special care should be exercised to avoid bradycardia.

Moxonidine must not be used in higher degree AV blocks (see section 4.3).

When moxonidine 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.

Caution is advised in the administration of moxonidine to patients with renal impairment as moxonidine is excreted primarily via kidney. In these patients careful titration of the dose is recommended, especially at the start of therapy. Dosing should be initiated with 200micrograms daily and can be increased to a maximum of 400micrograms 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 moxonidine is used in combination with a P-blocker and both treatments have to be discontinued, the P-blocker should be discontinued first, and then moxonidine after a few days.

So far, no rebound-effect has been observed on the blood pressure after discontinuing the treatment with moxonidine. However, an abrupt discontinuance of the moxonidine treatment is not advisable; instead the dose should be reduced 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.

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

Tolazoline can reduce the effect of moxonidine dose-dependently.

4.5    Interaction with other medicinal products and other forms of interaction

Concomitant administration moxonidine and other antihypertensive agents result in an additive effect.

Since tricyclic antidepressants may reduce the effectiveness of centrally acting antihypertensive agents, it is not recommended that tricyclic antidepressants be co-administered with moxonidine.

Moxonidine can potentiate the effect of tricyclic anti-depressants (avoid coprescribing), tranquillisers, alcohol, sedatives and hypnotics.

Moxonidine moderately augmented the impaired performance in cognitive functions in subjects receiving lorazepam. Moxonidine may enhance the sedative effect of benzodiazepines when administered concomitantly. Moxonidine is eliminated by tubular secretion. Interactions with other drugs eliminated by tubular secretion cannot be excluded.

4.6    Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Moxonidine in pregnant women. Studies in animals have shown no reproductive toxicity at high doses (see 5.3). The potential risk for humans is unknown. Moxonidine should not be used during pregnancy unless clearly necessary.

Breastfeeding

Moxonidine is excreted into breast milk. Therefore, Moxonidine should not be used while breast feeding. If therapy with Moxonidine is clearly necessary, breast feeding should be stopped.

4.7    Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, drowsiness and dizziness have been reported. This should be taken into account when performing these tasks.

4.8    Undesirable effects

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

MedDRA system organ class	very common (>1/10)	common (>1/100, <1/10)	uncommon (>1/1,000, <1/100)	very rare
Cardiac disorders			Bradycardia
Ear and Labyrinth disorders			Tinnitus
Eye disorders		Dry itching or burning sensation of the eye
Gastrointestinal disorders	Dry mouth	Nausea, diarrhoea, constipation, vomiting, dyspepsia and other gastrointestinal disorders
General disorders and administration site conditions		Asthenia	Oedema, leg weakness, fluid retention, anorexia, parotid pain

Hepatobiliary disorders				Hepatic reactions (hepatitis, cholestasis)
Musculoskeletal and connective tissue disorders		Back pain	Neck pain
Nervous system disorders	Drowsiness	Sleep disturbances, somnolence, headache, dizziness/vertigo	Sedation, syncope
Psychiatric disorders		Altered thought processes, insomnia	Depression, anxiety, nervousness
Renal and urinary disorders			Urinary retention or incontinence
Reproductive system and breast disorders			Gynaecomasty, impotence and loss of libido
Skin and subcutaneous tissue disorders		Rash/pruritus	Allergic skin reactions, angioedema
Vascular disorders		Vasodilatation	Hypotension, orthostatic hypotension, paraesthesia of extremities, Raynaud’s syndrome, peripheral circulation disorders

*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; website: www.mhra.gov.uk/yellowcard

4.9. Overdose

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. 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

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.

a-Receptor antagonists may diminish or abolish the paradoxal hypertensive effects of a moxonidine overdose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antihypertensives, antiadrenergic agents, centrally acting ATC code: C02AC05

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

In the brain stem, moxonidine binds selectively to ^-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.

Moxonidine differs from other centrally acting hypertensives in the fact that it has only a weak affinity for the central a₂-adrenergic receptors compared to the affinity for ^-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 moxonidine on mortality and cardiovascular morbidity are currently unknown.

5.2 Pharmacokinetic properties

Absorption

Moxonidine 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 moxonidine.

There is no first-pass metabolism and bioavailability is 88 %.

Distribution

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

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

Elimination

Moxonidine 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 moxonidine 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.

In patients with moderately impaired renal function (GFR 30 - 60 ml/min), the AUC increased by 85% and the clearance reduced by 52%. The dose must be adapted in these patients so that the maximum daily dose is not more than 400 microgram and the maximum single dose is 200 microgram.

In patients with severely impaired renal function (GFR < 30 ml) the clearance is reduced by 68 % and the elimination half live is prolonged up to 7 hours.

Pharmacokinetics in children

No pharmacokinetic studies in children have been performed.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of repeated toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies revealed no effects on fertility and no teratogenic potential. Embryotoxic effects were seen in rats at dosages above 3 mg/kg/d and in rabbits as dosages above 0.7 mg/kg/d. In a perinatal and postnatal study in rats the development as well as the viability of the offspring was affected in dosages above 1mg/kg/d.

6.1    List of excipients

Tablet core: lactose monohydrate crospovidone povidone K25 magnesium stearate

Film-coating:

Hypromellose titanium dioxide (E171) macrogol 400 red iron oxide (E172)

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years

6.4    Special precautions for storage

Do not store above 30°C.

6.5    Nature and contents of container

PVC/PVDC/Al blister pack with 10, 20, 28, 30, 50, 98, 100, 400 (20 x 20, 10 x 40, as hospital pack sizes only) film-coated tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements for disposal.

MARKETING AUTHORISATION HOLDER

Actavis UK Limited (Trading style: Actavis)

Whiddon Valley

Barnstaple

N. Devon EX32 8NS

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00142/0618

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

First authorisation: 21 July 2004 05/08/2008

10 DATE OF REVISION OF THE TEXT

23/10/2013