Moxonidine 400 Microgram Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Moxonidine 400 microgram Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 400mcg moxonidine.
Also includes lactose.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Appearance: All tablets are round, approximately 6 mm in diameter.
The 400 microgram 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 200mcg moxonidine in the morning. If the therapeutic effect is insufficient, the dose can be increased after three weeks to 400mcg. 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 600mcg given divided in the morning and evening. A single dose of 400mcg moxonidine and a daily dose of 600mcg 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 > 30ml/min but <60ml/min), the single dose should be not more than 200mcg and the daily dose not more than 400mcg moxonidine. In patients with severely impaired renal function (GFR < 30ml/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The treatment should not be stopped abruptly, but withdrawn over a period of two weeks (see also section 4.4).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
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 and 3 rd degree
• Cardiac Insufficiency (see section 4.4)
4.4 Special warnings and precautions for use
When moxonidine is used in patients with 1st degree AV block special care should be exercised to avoid bradycardia.
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.
Due to lack of clinical evidence supporting safe use in patients with moderate cardiac insufficiency, moxonidine should be administered with caution in these patients
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 0.2 mg daily and can be increased to a maximum of 0.4 mg daily if clinically indicated and well tolerated.
If moxonidine is used in combination with a P-blocker, in case of discontinuing treatment the P-blocker should be stopped 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.
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 coadministered 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 excreted through tubular secretion. Interactions with other agents that are excreted through tubular secretion cannot be excluded. Tolazoline 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 embryo-toxicological effects(see section 5.3). The potential risk for humans is unknown. Moxonidine should not be used during pregnancy unless clearly necessary.
Lactation:
Moxonidine is excreted into breast milk and should therefore not be used during breast feeding. If therapy with moxonidine is considered absolutely necessary, the breast feeding shall be stopped.
Effects on ability to drive and use machines
4.7
No studies on the effects on the ability to drive and use machines have been performed. Somnolence and dizziness have been reported. This should be borne in mind 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 of treatment. 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 |
|
Cardiac disorders |
Bradycardia | ||
|
Ear and labyrinth disorders |
Tinnitus | ||
|
Nervous system disorders |
Drowsiness |
Headache*, Dizziness / Vertigo, Somnolence, |
Syncope * |
|
Vascular disorders |
Vasodilatation |
Hypotension* (including orthostatic) paraesthesia of extremities, peripheral circulation disorders | |
|
Gastrointestinal disorders |
Dry mouth |
Diarrhoea, Nausea / Vomiting / Dyspepsia* | |
|
Skin and subcutaneous tissue disorders |
Rash/Pruritus |
Angioedema | |
|
General disorders and administration site reactions |
Asthenia |
Oedema, leg weakness, fluid retention, anorexia, parotid pain | |
|
Eye disorders |
Dry itching or burning sensation |
|
of the eye | |||
|
Musculoskeletal and connective tissue disorders |
Back pain |
Neck pain | |
|
Psychiatric disorders |
Insomnia, altered thought processes |
Nervousness, anxiety | |
|
Endocrine disorders |
Gynaecomasty, impotence and loss of libido |
*there was no increase in frequency compared to placebo
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.
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.
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.
Treatment consists of absorption-reducing measures such as gastric lavage (if shortly after ingestion), administration of activated charcoal and laxatives, and otherwise is symptomatic.
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 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 - 60ml/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 400mcg and the maximum single dose is 200mcg.
In patients with severely impaired renal function (GFR < 30ml) 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. Embryonic effects were seen in rats at dosages above 3mg/kg/d and in rabbits at dosages above 0.7mg/kg/d. In 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 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, 56, 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
TEVA UK Limited Brampton Road Hampden Park Eastbourne BN22 9AG
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/0598
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10/03/2004 / 05/08/2008 01/12/2011