Source: Medicines Authority (MT) Revision Year: 2021 Publisher: Les Laboratoires Servier, 50, rue Carnot, 92284 Suresnes cedex, France
Pharmacotherapeutic group: Antihypertensive drug
ATC code: C02AC
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 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.
Protein binding is less than 10%. The volume of distribution is 5 l/kg.
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 clearance.
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.
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 halflife is approximately 35 hours.
The maximum non-lethal dose administered to rodents was about 4000 to 5500 times the human therapeutic oral dose. Intoxication symptoms were essentially signs affecting the central nervous system, as convulsions and were dose related and most notable at lethal or near lethal doses.
Tests of the effect of rilmenidine on fertility, reproduction as well as peri- and postnatal behavior in young rats showed no signs of damages with excessive doses (2.5 to 5 mg/kg orally).
Repeated dose toxicity studies in rodents, dog and monkey revealed no consistent evidence of impaired function of the excretory organs or frank pathological damage to any organ at doses up to 1 mg/kg/day or 30 times the human therapeutic oral dose. Hyperium presents no embryotoxic/teratogenic risk at doses equivalent to 250 times the human therapeutic oral dose.
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