GUANFACINE HYDROCHLORIDE — guanfacine hydrochloride tablet
Full Prescribing Information
Guanfacine hydrochloride is a centrally acting antihypertensive with α2 -adrenoceptor agonist properties in tablet form for oral administration.
The chemical name of guanfacine hydrochloride is N-amidino-2-(2,6-dichlorophenyl) acetamide hydrochloride and its molecular weight is 282.56. Its structural formula is:
Guanfacine hydrochloride is a white to off-white powder; sparingly soluble in water and alcohol and slightly soluble in acetone.
Each tablet, for oral administration, contains guanfacine hydrochloride equivalent to 1 mg or 2 mg guanfacine. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, and stearic acid.
Guanfacine hydrochloride is an orally active antihypertensive agent whose principal mechanism of action appears to be stimulation of central α2 -adrenergic receptors. By stimulating these receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate.
The dose-response relationship for blood pressure and adverse effects of guanfacine given once a day as monotherapy has been evaluated in patients with mild to moderate hypertension. In this study, patients were randomized to placebo or to 0.5 mg, 1 mg, 2 mg, 3 mg or 5 mg of guanfacine. Results are shown in the following table. A useful effect was not observed overall until doses of 2 mg were reached, although responses in white patients were seen at 1 mg; 24-hour effectiveness of 1 mg to 3 mg doses was documented using 24-hour ambulatory monitoring. While the 5 mg dose added an increment of effectiveness, it caused an unacceptable increase in adverse reactions.
|d Mean Change S/D* Seate||n= (range)||Placebo||0.5 mg||1 mg||2 mg||3 mg||5 mg|
|White Patients Black Patients||11 – 30 8 — 28||-1/-5 -3/-5||-6/-8 0/-2||-8/-9 -3/-5||-12/-11 -7/-7||-15/-12 -8/-9||-18/-16 -19/-15|
|* S/D = Systolic/diastolic blood pressure|
Controlled clinical trials in patients with mild to moderate hypertension who were receiving a thiazide-type diuretic have defined the dose-response relationship for blood pressure response and adverse reactions of guanfacine given at bedtime and have shown that the blood pressure response to guanfacine can persist for 24 hours after a single dose. In the 12-week placebo-controlled dose-response study, patients were randomized to placebo or to doses of 0.5, 1, 2 and 3 mg of guanfacine, in addition to 25 mg chlorthalidone, each given at bedtime. The observed mean changes from baseline, tabulated below, indicate the similarity of response for placebo and the 0.5 mg dose. Doses of 1, 2 and 3 mg resulted in decreased blood pressure in the sitting position with no real differences among the three doses. In the standing position, there was some increase in response with dose.
|Mean Change n =||Placebo 63||0.5 mg 63||1 mg 64||2 mg 58||3 mg 59|
|S/D* Seated S/D* Standing||-5/-7 -3/-5||-5/-6 -5/-4||-14/-13 -11/-9||-12/-13 -9/-10||-16/-13 -15/-12|
|* S/D = Systolic/diastolic blood pressure|
While most of the effectiveness of guanfacine in combination (and as monotherapy in white patients) was present at 1 mg, adverse reactions at this dose were not clearly distinguishable from those associated with placebo. Adverse reactions were clearly present at 2 and 3 mg (see ). ADVERSE REACTIONS
In a second 12-week placebo-controlled study of 1, 2 or 3 mg of guanfacine administered with 25 mg chlorthalidone once daily, a significant decrease in blood pressure was maintained for a full 24 hours after dosing. While there was no significant difference between the 12- and 24-hour blood pressure readings, the fall in blood pressure at 24 hours was numerically smaller, suggesting possible escape of blood pressure in some patients and the need for individualization of therapy.
In a double-blind, randomized trial, either guanfacine or clonidine was given at recommended doses with 25 mg chlorthalidone for 24 weeks and then abruptly discontinued. Results showed equal degrees of blood pressure reduction with the two drugs and there was no tendency for blood pressures to increase despite maintenance of the same daily dose of the two drugs. Signs and symptoms of rebound phenomena were infrequent upon discontinuation of either drug. Abrupt withdrawal of clonidine produced a rapid return of diastolic and especially, systolic blood pressure to approximately pre-treatment levels, with occasional values significantly greater than baseline, whereas guanfacine withdrawal produced a more gradual increase to pre-treatment levels, but also with occasional values significantly greater than baseline.
Hemodynamic studies in man showed that the decrease in blood pressure observed after singledose or long-term oral treatment with guanfacine was accompanied by a significant decrease in peripheral resistance and a slight reduction in heart rate (5 beats/min). Cardiac output under conditions of rest or exercise was not altered by guanfacine.
Guanfacine lowered elevated plasma renin activity and plasma catecholamine levels in hypertensive patients, but this does not correlate with individual blood-pressure responses.
Growth hormone secretion was stimulated with single oral doses of 2 and 4 mg of guanfacine. Long-term use of guanfacine had no effect on growth hormone levels.
Guanfacine had no effect on plasma aldosterone. A slight but insignificant decrease in plasma volume occurred after one month of guanfacine therapy. There were no changes in mean body weight or electrolytes.
Relative to an intravenous dose of 3 mg, the absolute oral bioavailability of guanfacine is about 80%. Peak plasma concentrations occur from 1 to 4 hours with an average of 2.6 hours after single oral doses or at steady state.
The area under the concentration-time curve (AUC) increases linearly with the dose.
In individuals with normal renal function, the average elimination half-life is approximately 17 hr (range 10 to 30 hr). Younger patients tend to have shorter elimination half-lives (13 to 14 hr) while older patients tend to have half-lives at the upper end of the range. Steady state blood levels were attained within 4 days in most subjects.
In individuals with normal renal function, guanfacine and its metabolites are excreted primarily in the urine. Approximately 50% (40 to 75%) of the dose is eliminated in the urine as unchanged drug; the remainder is eliminated mostly as conjugates of metabolites produced by oxidative metabolism of the aromatic ring.
The guanfacine-to-creatinine clearance ratio is greater than 1.0, which would suggest that tubular secretion of drug occurs.
The drug is approximately 70% bound to plasma proteins, independent of drug concentration.
The whole body volume of distribution is high (a mean of 6.3 L/kg), which suggests a high distribution of drug to the tissues.
The clearance of guanfacine in patients with varying degrees of renal insufficiency is reduced, but plasma levels of drug are only slightly increased compared to patients with normal renal function. When prescribing for patients with renal impairment, the low end of the dosing range should be used. Patients on dialysis also can be given usual doses of guanfacine hydrochloride as the drug is poorly dialyzed.
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