GUANFACINE HYDROCHLORIDE — guanfacine tablet
Unichem Pharmaceuticals (USA), Inc.
The chemical name of guanfacine hydrochloride is N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride and its molecular weight is 282.55. Its structural formula is:
The tablets contain the following inactive ingredients:
1 mg — colloidal silicon dioxide, corn starch, lactose monohydrate and stearic acid.
2 mg — colloidal silicon dioxide, corn starch, FD & C Blue No. 1 aluminum lake, lactose monohydrate and stearic acid.
FDA approved dissolution test specifications differ from USP.
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 hydrochloride. 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.
|Mean Change S/D* Seated||n = (range)||Placebo||0.5 mg||1 mg||2 mg||3 mg||5 mg|
|White Patients||11 to 30||-1/-5||-6/-8||-8/-9||-12/-11||-15/-12||-18/-16|
|Black Patients||8 to 28||-3/-5||0/-2||-3/-5||-7/-7||-8/-9||-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 = 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 hydrochloride administered with 25 mg of 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 pretreatment levels, with occasional values significantly greater than baseline, whereas guanfacine withdrawal produced a more gradual increase to pretreatment levels, but also with occasional values significantly greater than baseline.
Hemodynamic studies in man showed that the decrease in blood pressure observed after single-dose 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 hydrochloride 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 hydrochloride 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.
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