Moxonidine 300 Microgram Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Moxonidine 300 Microgram Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 0.3 mg moxonidine.
Excipient: lactose monohydrate.
For a full list of excipients, see 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Appearance: All tablets are round, approximately 6 mm in diameter.
The 0.2 mg tablet is light pink.
The 0.3 mg tablet is pink.
The 0.4 mg tablet is dark pink.
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 0.2 mg moxonidine 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 Moxonidine and a daily dose of 0.6 mg 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:
In patients with moderately impaired renal function (GFR > 30 ml/min but < 60 ml/min), the single dose should be not more than 0.2 mg and the daily dose not more than 0.4 mg moxonidine. In patients with severely impaired renal function (GFR < 30 ml/min) moxonidine is contraindicated (see 4.3).
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 mild to moderate hepatic impairment as for adults. In patients with severe hepatic diseases moxonidine is contraindicated (see 4.3).
The treatment should not be stopped abruptly, but withdrawn over a period of two weeks (see also section 4.4).
4.3 Contraindications
- hypersensitivity to moxonidine or to any of the excipients
- sick sinus syndrome or sino-atrial block
- bradycardia (below 50 beats/minute at rest)
- severely impaired renal function (GFR < 30 ml/min, serum creatinine concentration >
160 ^mol/l)
- history of angioneurotic oedema
- 2nd or 3rd degree atrioventricular block
- malignant arrhythmia
- heart failure
- severe coronary artery disease or unstable angina pectoris
- severe hepatic disease
4.4 Special warnings and precautions for use
Moxonidine should not be used because of lack of therapeutic experience in cases of:
- intermittent claudication
- Raynaud’s disease
- Parkinson’s disease
- epileptic disorders
- glaucoma
- depression
- pregnancy or lactation (see also 4.6)
- children and adolescents below 16 years of age
In patients with moderately impaired renal function (GRF > 30 ml/min but <
60 ml/min, serum creatinine concentration > 105 pmol/l but < 160 pmol/l), the hypotensive effect of Moxonidine should be monitored closely, in particular during the beginning of treatment. In these patients a careful dose titration is necessary.
No rebound effect of blood pressure has been observed to date after the discontinuation of treatment with moxonidine. However, it is advisable not to stop taking moxonidine abruptly, but withdrawing it gradually over a period of two weeks. See also section 4.2.
If moxonidine is used in combination with a P-blocker, in case of discontinuing treatment the P-blocker should be stopped first and moxonidine not until a few days afterwards to avoid an increased blood pressure counter regulation.
Extreme caution is advised when moxonidine is given to patients with severe cerebrovascular insufficiency, recent myocardial infarction or peripheral circulatory disorders.
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
See also sections 4.2 and 4.5.
4.5 Interaction with other medicinal products and other forms of interaction
Co-administration of other antihypertensives increases the hypotensive effect of moxonidine.
Moxonidine can potentiate the effect of tricyclic anti-depressants (avoid coprescribing), tranquillisers, alcohol, sedatives and hypnotics. The sedative effect of benzodiazepines can be potentiated by concurrent administration of moxonidine. Moxonidine slightly decreased cognitive functions in patients when co-administrated with lorazepam.
Moxonidine is eliminated by tubular secretion. Interactions with other drugs eliminated by tubular secretion (e.g. digitalis, insulin, sulfonylurea, nitrate derived, anti-rheumatism agents, hypolipemic agents, allopurinol, colchicine, probenecide, anti-ulcerous agents, thyroid extracts) cannot be excluded. Tolazodine can reduce the effect of moxonidine dose-dependently.
4.6 Pregnancy and lactation
Pregnancy
There are no adequate data from the use of Moxonidine in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Moxonidine should not be used during pregnancy unless clearly necessary.
Lactation
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
Especially at the beginning of treatment dry mouth, headache, asthenia and dizziness have been described very commonly. The frequency and intensity usually decrease after repeated administration.
|
very common (>1/10) |
common (>1/100, <1/10) |
uncommon (>1/1,000, <1/100) |
very rare (<1/10,000, including isolated reports) | |
|
Psychiatric disorders |
altered thought processes |
depression, anxiety | ||
|
nervous system disorders |
drowsiness, headache, dizziness, somnolence |
sleep disturbances |
sedation | |
|
gastro intestinal disorders |
nausea, constipation and other gastrointestinal disorders | |||
|
general disorders |
dry mouth |
asthenia |
oedema of different location, leg weakness, angioedema, syncope, fluid retention, anorexia, parotid pain | |
|
Renal and urinary disorders |
urinary retention or incontinence | |||
|
Skin and subcutaneous tissue disorders |
allergic skin reactions | |||
|
Hepato-biliary disorders |
hepatic reactions (hepatitis, cholestasis) | |||
|
Eye disorders |
dry itching or burning sensation of the eye | |||
|
Vascular disorders |
vasodilatation |
hypotension, orthostatic hypotension, paraesthesia of extremities, Raynaud’s syndrome, peripheral circulation disorders | ||
|
Endocrine disorders |
gynaecomasty, impotence and loss of libido |
4.9 Overdose
The following case of inadvertent overdose in a 2-year old child has been described:
The child ingested an unknown quantity of moxonidine. 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.
Based on the pharmacodynamic properties of Moxonidine, the following reactions may be expected in adults: sedation, hypotension, orthostatic dysregulation, bradycardia, dry mouth. In rare cases, emesis and a paradoxical increase in blood pressure can occur.
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. Besides general supportive measures (intravenous fluids, catecholamines) Phentolamine (a2-blocker) may, depending on the dose, reverse part of the symptoms of moxonidine overdose. In case of severe bradycardia, atropine is recommended.
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 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 Ii-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 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 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 (Vdss = 1.8 ± 0.4 l/kg). Peak plasma levels of moxonidine are reached 30-180 minutes after administration of a film-coated tablet.
Metabolism
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.
Excretion
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 0.4 mg and the maximum single dose is 0.2 mg.
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. In these patients moxonidine is contraindicated (see 4.3).
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 at 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 1 mg/kg/d.
6 PHARMACEUTICAL PARTICULARS
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
2 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, 60, 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.
7 MARKETING AUTHORISATION HOLDER
Sandoz Limited Frimley Business Park,
Frimley,
Camberley,
Surrey,
GU16 7SR.
United Kingdom
8
MARKETING AUTHORISATION NUMBER(S)
PL 04416/1288
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DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
05/08/2008
10
DATE OF REVISION OF THE TEXT
18/03/2011