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% 5% 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 to 3 mg as follows: adverse reactions 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 (0%) 1 (0%) 0 (0%) 1 (1%) 3 (4%) constipation 0 (0%) 1 (0%) 0 (0%) 1 (1%) 1 (1%) fatigue 3 (3%) 0 (0%) 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, iritis, vision disturbance • musculoskeletal: leg cramps, hypokinesia • respiratory: dyspnea • dermatologic: dermatitis, pruritus, purpura, sweating • urogenital: testicular disorder, urinary incontinence • other: malaise, paresthesia, paresis adverse reaction reports tend to decrease over time. in an open-label trial of one year’s duration, 580 hypertensive subjects were given guanfacine, titrated to achieve goal blood pressure, alone (51%), with diuretic (38%), with beta blocker (3%), with diuretic plus beta blocker (6%), or with diuretic plus vasodilator (2%). the mean daily dose of guanfacine reached was 4.7 mg. adverse reaction incidence of adverse reactions at any time during the study incidence of adverse reactions at end of one year n=580 n=580 dry mouth 60% 15% drowsiness 33% 6% dizziness 15% 1% constipation 14% 3% weakness 5% 1% headache 4% 0.2% insomnia 5% 0% there were 52 (8.9%) dropouts due to adverse effects in this 1-year trial. the causes were: dry mouth (n = 20), weakness (n = 12), constipation (n = 7), somnolence (n = 3), nausea (n = 3), orthostatic hypotension (n = 2), insomnia (n = 1), rash (n = 1), nightmares (n = 1), headache (n = 1) and depression (n = 1). postmarketing experience an open-label postmarketing study involving 21,718 patients was conducted to assess the safety of guanfacine hydrochloride 1 mg/day given at bedtime for 28 days. guanfacine was administered with or without other antihypertensive agents. adverse events reported in the postmarketing study at an incidence greater than 1% included dry mouth, dizziness, somnolence, fatigue, headache and nausea. the most commonly reported adverse events in this study were the same as those observed in controlled clinical trials. less frequent, possibly guanfacine-related events observed in the postmarketing study and/or reported spontaneously include: • body as a whole: asthenia, chest pain, edema, malaise, tremor • cardiovascular: bradycardia, palpitations, syncope, tachycardia • central nervous system: paresthesias, vertigo • eye disorders: blurred vision • gastrointestinal system: abdominal pain, constipation, diarrhea, dyspepsia • liver and biliary system: abnormal liver function tests • musculo-skeletal system: arthralgia, leg cramps, leg pain, myalgia • psychiatric: agitation, anxiety, confusion, depression, insomnia, nervousness • reproductive system, male: impotence • respiratory system: dyspnea • skin and appendages: alopecia, dermatitis, exfoliative dermatitis, pruritus, rash • special senses: alterations in taste • urinary system: nocturia, urinary frequency rare, serious disorders with no definitive cause and effect relationship to guanfacine have been reported spontaneously and/or in the postmarketing study. these events include acute renal failure, cardiac fibrillation, cerebrovascular accident, congestive heart failure, heart block, and myocardial infarction.

ed 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 to 8 weeks of treatment with guanfacine monotherapy mean change s/d* seate d n= (range) placebo 0.5 mg 1 mg 2 mg 3 mg 5 mg white patients black patients 11 to 30 8 to 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 decreases (mm hg) in seated and standing blood pressure for patients treated with guanfacine in combination with chlorthalidone 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 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. pharmacodynamics 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 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. pharmacokinetics 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, 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.