SUMMARY OF PRODUCT CHARATERISTICS
I.N.N. : Rilmenidine
HYPERIUM 1 mg, tablets 2. COMPOSITION
Rilmenidine (I.N.N.) dihydrogenphosphate ….1.544 mg
amount equivalent to rilmenidine base…………1 mg
Excipients q.s. for one tablet.
3. PHARMACEUTICAL FORM
Tablet 4. CLINICAL DATA
4.1. THERAPEUTIC INDICATIONS
4.2. DOSAGE AND METHOD OF ADMINISTRATION
The recommended dosage is 1 tablet per day as a single morning administration.
If results are not adequate after one month of treatment, the dosage may be increased to 2
tablets per day, given in divided doses (1 tablet morning and evening) before meals.
As a result of its good clinical and biological acceptability, HYPERIUM may be administered
to both elderly and diabetic hypertensive patients.
In patients with renal insufficiency, no dosage adjustment is necessary in principle when the
creatinine clearance is greater than 15 ml/min.
Treatment may be continued indefinitely.
This medicine MUST NEVER BE used in the following cases:
- hypersensitivity to one of the ingredients - severe depression, - severe renal insufficiency (creatinine clearance < 15 ml/min), - in combination with sultopride.
This medicine SHOULD NOT GENERALLY be used in the following cases: in combination with:
- alcohol, - beta-blockers used in heart failure (bisoprolol, carvedilol, metoprolol) (See Section 4.5
Interactions with other medicinal products and other forms of interactions).
4.4. WARNINGS AND SPECIAL PRECAUTIONS FOR USE
Therapy should never be interrupted suddenly, the dosage should be reduced gradually.
As with all antihypertensive agents, regular medical monitoring is required when HYPERIUM
is administered to patients with a recent history of cardiovascular disease (stroke, myocardial
Alcohol consumption should be avoided during treatment.
In patients with renal insufficiency, no dosage adjustment is necessary if creatinine clearance
is greater than 15 ml/min.
In the absence of documented experiments in this area, HYPERIUM is not recommended for
prescription to children.
4.5. INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER
FORMS OF INTERACTION
Increased risk of ventricular arrhythmias, particularly torsades de pointes.
Alcohol increases the sedative effect of these substances. Impaired vigilance may render driving of vehicles and use of machinery dangerous. Alcoholic beverages and medicines containing alcohol should be avoided.
+ Beta-blockers used in heart failure (bisoprolol, carvedilol, metoprolol)
Central reduction of sympathetic tone and vasodilator effect of centrally acting antihypertensive agents that may be harmful in patients with heart failure undergoing treatment with beta-blockers and vasodilators.
Combinations requiring cautions for use
Increased antihypertensive effect; blood pressure must be monitored and the dosage of the antihypertensive agent adjusted if necessary.
Marked increase in blood pressure in the event of abrupt discontinuation of treatment with the central antihypertensive agent.
Avoid abrupt discontinuation of the central antihypertensive agent. Clinical monitoring is required.
+ Medicines that induce torsades de pointes (except sultopride):
- class Ia antiarrhythmic agents (quinidine, hydroquinidine, disopyramide);
- class III antiarrhythmic agents (amiodarone, dofetilide, ibutilide, sotalol);
- certain neuroleptics: phenothiazines (chlorpromazine, levomepromazine,
thioridazine), benzamides (amisulpride, sulpiride, tiapride),
butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide);
- other drugs: bepridil, cisapride, diphemanil, erythromycin IV, halofantrine,
mizolastine, moxifloxacin, pentamidine, spiramycin IV, vincamine IV.
Increased risk of ventricular arrhythmias, particularly torsades de pointes. Clinical and electrocardiographic monitoring.
Combinations to be taken into consideration
Potentiation of hypotensive effect. Increased risk of orthostatic hypotension.
+ Corticosteroids, tetracosactide (systemic route) (except hydrocortisone used as
replacement therapy in Addison’s disease)
Reduced antihypertensive effect (water/sodium retention through corticosteroids)
+ Neuroleptics, imipramine antidepressants
Increased antihypertensive effect and risk of orthostatic hypotension (cumulative effect).
+ Other CNS depressants: morphine derivatives (analgesics, antitussive agents
and replacement treatments), benzodiazepines, anxiolytics other than
benzodiazepines, hypnotics, neuroleptics, sedative H1 histamine antagonists,
sedative antidepressants (amitriptyline, doxepine, mianserine, mirtazapine,
trimipramine), other centrally acting antihypertensive agents, baclofen,
thalidomide, pizotifen, indoramin.
Increased central depression. Impaired vigilance may render driving vehicles and operation of machinery dangerous.
4.6. PREGNANCY AND BREAST-FEEDING
- Pregnancy : as with all new molecules, administration of HYPERIUM should be avoided
in pregnant women, although no teratogenic or embryotoxic effects have been observed in animal studies.
- Lactation :
HYPERIUM is excreted in breast milk, its use is therefore not recommended
4.7. EFFECTS ON THE ABILITY TO DRIVE MOTOR VEHICLES OR OPERATE
Double-blind placebo controlled studies have not shown HYPERIUM to have any effect on
alertness at therapeutic doses (1or 2 daily administrations of 1 mg). If these doses are
exceeded or if HYPERIUM is associated with other drugs capable of reducing alertness,
vehicle drivers or machine operators should be warned of the possibility of drowsiness. 4.8. SIDE-EFFECTS
At the dose of 1 mg in a single daily administration, during controlled studies, the incidence of
undesirable effects was comparable to that observed with placebo.
At a dose of 2 mg of HYPERIUM daily, the controlled comparative studies versus clonidine
at a dose of 0.15 to 0.30 mg/day or alphamethyldopa at a dose of 500 to 1000 mg/day showed
that the incidence of undesirable effects was significantly lower than that observed with
clonidine or alphamethyldopa.
Incidence estimate: Very common: (≥1/10), Common (≥1/100, <1/10), Uncommon (≥1/1 000,
<1/100), Rare (≥1/10 000, <1/1 000), Very Rare: (< 1/10 0000)
Nervous system disorders
Skin and subcutaneous tissue disorders
Common: pruritus, rash
Reproductive system and breast disorders
Common: sexual dysfunction
Common: gastralgia, dry mouth, diarrhoea, constipation
Common: muscle cramps
Common: anxiety, depression, insomnia
Common: cold in the extremities, oedema
Uncommon: hot flushes, orthostatic hypotension
Common: asthenia, fatigue on effort
No cases of massive absorption have been reported. Likely symptoms in such an eventuality
would be marked hypotension and lowered alertness. In addition to gastric lavage,
sympathomimetic agents may also be required. HYPERIUM is only slightly dialysable.
5. PHARMACOLOGICAL PROPERTIES
5.1 PHARMACODYNAMIC PROPERTIES
- HYPERIUM, an oxazoline compound with anti-hypertensive properties acts on both
medullary and peripheral vasomotor structures. HYPERIUM shows greater selectivity for "imidazoline" receptors than for cerebral alpha-2-adrenergic receptors, distinguishing it from reference alpha-2-agonists.
- HYPERIUM exerts dose-dependent antihypertensive effect in the congenitally
hypertensive rat. Its effects are not associated with the central neuropharmacological effects usually seen with alpha 2 agonists, except at doses higher than the antihypertensive dose in animals. In particular, the sedative effect appears to be considerably less marked.
- This dissociation between the antihypertensive activity and neuropharmacological effects
has been confirmed in man. HYPERIUM exerts a dose-dependent antihypertensive activity on the systolic and diastolic blood pressure in both the erect and supine positions. At therapeutic doses (1mg per day as a single administration or 2 mg per day in divided doses), double- blind studies versus placebo and reference product have demonstrated the antihypertensive efficacy of
HYPERIUM in mild to moderate hypertension. This efficacy is maintained throughout the 24-hour period and on exercise. These results have been confirmed over the long-term, without the development of tolerance. With the dose of 1 mg per day, double-blind placebo controlled studies have shown that HYPERIUM does not affect tests of alertness. The incidence of side-effects (drowsiness, dryness of the mouth, constipation) was no different than that seen with placebo. With the dose of 2 mg per day, double-blind studies versus a reference alpha-2-agonist administered at an equihypotensive dose demonstrated that the incidence of side-effects, and the severity of these effects were significantly lower with HYPERIUM.
- At therapeutic doses, HYPERIUM has no effect on cardiac function, does not cause salt
and water retention and does not disturb metabolic equilibrium :
HYPERIUM continues to exert significant antihypertensive activity 24 hours after administration, with a reduction in total peripheral resistance, but no change in cardiac output. Indices of contractility and cardiac electrophysiology are not affected.
HYPERIUM does not cause postural hypotension (particularly in the elderly) and does not interfere with the physiological increase in heart rate on exercise.
HYPERIUM does not induce any changes in renal blood flow, glomerular filtration rate or filtration fraction, and does not affect kidney function.
HYPERIUM spares glucose metabolism (including that of diabetic subjects, whether insulin or non-insulin dependent), and does not affect lipid metabolism.
5.2. PHARMACOKINETICS PROPERTIES
- is rapid : the peak plasma concentration (3.5 ng/ml) is reached 1.5 to 2 hours following
absorption of a single dose of 1 mg of HYPERIUM ;
- is complete : the absolute bioavailability is 100 %, there is no hepatic first-pass effect ; - is consistent : interindividual variation is not marked, and concomitant food consumption
does not affect the bioavailability. There is no variation in absorption levels at the recommended therapeutic doses.
: protein binding is less than 10%. The volume of distribution is 5 l/kg. Metabolism
: HYPERIUM is only very slightly metabolised. The metabolites are found in
trace amounts in the urine and result from the hydrolysis or oxidation of the oxazoline ring.
These metabolites are devoid of alpha 2 agonist activity.
: HYPERIUM is essentially eliminated by the kidney : 65 % of the dose
administered is excreted unchanged in the urine. Renal clearance represents two thirds of total
The elimination half-life is 8 hours. This is not affected by the dose administered nor by
repeated administration. The pharmacological duration of action is longer, significant
antihypertensive activity being maintained to 24 h after administration in hypertensive patients
treated with a dose of 1 mg per day.
Repeated administration : Steady state is attained at 3 days ; study of plasma levels has shown
that they remain stable over 10 days.
Long-term monitoring of plasma levels in hypertensive patients (treatment for 2 years) has
established that plasma levels of HYPERIUM remain stable.
In elderly subjects : pharmacokinetic studies in elderly patients (over 70 years old) have
demonstrated an elimination half-life of 12 hours.
In subjects with hepatic insufficiency : the elimination half-life is 11 hours.
In subjects with renal insufficiency : as a result of the essentially renal elimination of the drug,
a reduction in the rate of elimination is observed proportional to the severity of the renal
insufficiency. In patients with severe renal insufficiency (creatinine clearance less than
15 ml/min), the elimination half-life is approximately 35 hours.
5.3 PRECLINICAL SAFETY DATA
6. PHARMACEUTICAL DATA
6.3 SPECIAL STORAGE PRECAUTIONS
ARTICLE IN PRESS The Journal of Emergency Medicine, Vol. xx, No. x, pp. xxx, 2009Copyright © 2009 Published by Elsevier Inc. doi:10.1016/j.jemermed.2008.06.029 Original Contributions EFFICACY AND COST COMPARISONS OF BRONCHODILATATOR ADMINISTRATION BETWEEN METERED DOSE INHALERS WITH DISPOSABLE SPACERS AND NEBULIZERS FOR ACUTE ASTHMA IN AN INNER-CITY ADULT POPULATION Su
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