Guanfacine

INDICATIONS AND USAGE Guanfacine tablets, USP are indicated in the management of hypertension. Guanfacine tablets, USP may be given alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

CLINICAL PHARMACOLOGY Guanfacine hydrochloride is an orally active antihypertensive agent whose principal mechanism of action appears to be stimulation of central α 2 -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 tablets. 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 Changes (mm Hg) from Baseline in Seated Systolic and Diastolic Blood Pressure for Patients Completing 4 Weeks to 8 Weeks of Treatment with Guanfacine Monotherapy * S/D = Systolic/diastolic blood pressure 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 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 mg, 1 mg, 2 mg, 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 mg, 2 mg, 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 Decreases (mm Hg) in Seated and Standing Blood Pressure for Patients Treated with Guanfacine in Combination with Chlorthalidone * S/D = Systolic/diastolic blood pressure Mean Change n = Placebo 63 0.5 mg 63 1 mg 64 2 mg 58 3 mg 59 SD * Seated -5/-7 -5/-6 -14/-13 -12/-13 -16/-13 SD Standing -3/-5 -5/-4 -11/-9 -9/-10 -15/-12 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 mg

DOSAGE AND ADMINISTRATION The recommended initial dose of guanfacine tablets when given alone or in combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize somnolence. If after 3 weeks to 4 weeks of therapy 1 mg does not give a satisfactory result, a dose of 2 mg may be given, although most of the effect of guanfacine tablets are seen at 1 mg (see CLINICAL PHARMACOLOGY ). Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day. The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2 days to 4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2 days to 4 days) without ill effects.

ADVERSE REACTIONS Adverse reactions noted with guanfacine hydrochloride are similar to those of other drugs of the central α 2 -adrenoreceptor agonist class: dry mouth, sedation (somnolence), weakness (asthenia), dizziness, constipation, and impotence. While the reactions are common, most are mild and tend to disappear on continued dosing. Skin rash with exfoliation has been reported in a few cases; although clear cause and effect relationships to guanfacine tablets could not be established, should a rash occur, guanfacine tablets should be discontinued and the patient monitored appropriately. In the dose-response monotherapy study described under CLINICAL PHARMACOLOGY , the frequency of the most commonly observed adverse reactions showed a dose relationship from 0.5 mg to 3 mg as follows: Adverse Reaction Placebo n = 59 0.5 mg n = 60 1 mg n = 61 2 mg n = 60 3 mg n = 59 Dry Mouth 0 % 10 % 10 % 42 % 54 % Somnolence 8 % 5 % 10 % 13 % 39 % Asthenia 0 % 2 % 3 % 7 % 3 % Dizziness 8 % 12 % 2 % 8 % 15 % Headache 8 % 13 % 7 % 5 % 3 % Impotence 0 % 0 % 0 % 7 % 3 % Constipation 0 % 2 % 0 % 5 % 15 % Fatigue 2 % 2 % 5 % 8 % 10 % The percent of patients who dropped out because of adverse reactions are shown below for each dosage group. Placebo 0.5 mg 1 mg 2 mg 3 mg Percent dropouts 0 % 2.0 % 5.0 % 13 % 32 % The most common reasons for dropouts among patients who received guanfacine were dry mouth, somnolence, dizziness, fatigue, weakness, and constipation. In the 12-week, placebo-controlled, dose-response study of guanfacine administered with 25 mg chlorthalidone at bedtime, the frequency of the most commonly observed adverse reactions showed a clear dose relationship from 0.5 mg to 3 mg as follows: Adverse Reaction Placebo n = 73 0.5 mg n = 72 1 mg n = 72 2 mg n = 72 3 mg n = 72 Dry Mouth 5 (7 %) 4 (5 %) 6 (8 %) 8 (11 %) 20 (28 %) Somnolence 1 (1 %) 3 (4 %) 0 (0 %) 1 (1 %) 10 (14 %) Asthenia 0 (0 %) 2 (3 %) 0 (0 %) 2 (2 %) 7 (10 %) Dizziness 2 (2 %) 1 (1 %) 3 (4 %) 6 (8 %) 3 (4 %) Headache 3 (4 %) 4 (3 %) 3 (4 %) 1 (1 %) 2 (2 %) Impotence 1 (1 %) 1 (0 %) 0 (0 %) 1 (1 %) 3 (4 %) Constipation 0 (0 %) 0 (0 %) 0 (0 %) 1 (1 %) 1 (1 %) Fatigue 3 (3 %) 2 (3 %) 2 (3 %) 5 (6 %) 3 (4 %) There were 41 premature terminations because of adverse reactions in this study. The percent of patients who dropped out and the dose at which the dropout occurred were as follows: Dose Placebo 0.5 mg 1 mg 2 mg 3 mg Percent dropouts 6.9 % 4.2 % 3.2 % 6.9 % 8.3 % Reasons for dropouts among patients who received guanfacine were: somnolence, headache, weakness, dry mouth, dizziness, impotence, insomnia, constipation, syncope, urinary incontinence, conjunctivitis, paresthesia, and dermatitis. In a second 12-week placebo-controlled combination therapy study in which the dose could be adjusted upward to 3 mg per day in 1-mg increments at 3-week intervals, i.e., a setting more similar to ordinary clinical use, the most commonly recorded reactions were: dry mouth, 47 %; constipation, 16 %; fatigue, 12 %; somnolence, 10 %; asthenia, 6 %; dizziness, 6 %; headache, 4 %; and insomnia, 4 %. Reasons for dropouts among patients who received guanfacine were: somnolence, dry mouth, dizziness, impotence, constipation, confusion, depression, and palpitations. In the clonidine/guanfacine comparison described in CLINICAL PHARMACOLOGY , the most common adverse reactions noted were as follows: Adverse Reactions Guanfacine (n = 279) Clonidine (n = 278) Dry Mouth 30 % 37 % Somnolence 21 % 35 % Dizziness 11 % 8 % Constipation 10 % 5 % Fatigue 9 % 8 % Headache 4 % 4 % Insomnia 4 % 3 % Adverse reactions occurring in 3 % or less of patients in the three controlled trials of guanfacine hydrochloride with a diuretic were: Cardiovascular- bradycardia, palpitations, substernal pain Gastrointestinal- abdominal pain, diarrhea, dyspepsia, dysphagia, nausea CNS- amnesia, confusion, depression, insomnia, libido decrease ENT disorders- rhinitis, taste perversion, tinnitus Eye disorders- conjunctivitis, i

CONTRAINDICATIONS Guanfacine tablets are contraindicated in patients with known hypersensitivity to guanfacine hydrochloride.