Guanfacine Information
Guanfacine () Description
Guanfacine () hydrochloride is a centrally acting antihypertensive with α-adrenoceptor agonist properties in tablet form for oral administration.
The structural formula is:
The chemical name of Guanfacine () hydrochloride is N-amidino-2-(2,6-dichlorophenyl) acetamide hydrochloride and its molecular weight is 282.56.
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 or 2 mg of Guanfacine () and the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. In addition, the 2 mg tablets contain the following ingredient: FD&C Blue #1 Aluminum Lake.
Guanfacine () Clinical Pharmacology
Guanfacine () hydrochloride is an orally active antihypertensive agent whose principal mechanism of action appears to be stimulation of central α-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.
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.
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 ).
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.
Guanfacine () Indications And Usage
Guanfacine () tablets are indicated in the management of hypertension. Guanfacine () may be given alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.
Guanfacine () Contraindications
Guanfacine () hydrochloride is contraindicated in patients with known hypersensitivity to Guanfacine () hydrochloride.
Guanfacine () Precautions
The potential for increased sedation when Guanfacine () is given with other CNS-depressant drugs should be appreciated.
The administration of Guanfacine () concomitantly with a known microsomal enzyme inducer (phenobarbital or phenytoin) to two patients with renal impairment reportedly resulted in significant reductions in elimination half-life and plasma concentration. In such cases, therefore, more frequent dosing may be required to achieve or maintain the desired hypotensive response. Further, if Guanfacine () is to be discontinued in such patients, careful tapering of the dosage may be necessary in order to avoid rebound phenomena (see above).
Ten patients who were stabilized on oral anticoagulants were given Guanfacine () , 1 to 2 mg/day, for 4 weeks. No changes were observed in the degree of anticoagulation.
In several well-controlled studies, Guanfacine () was administered together with diuretics with no drug interactions reported. In the long-term safety studies, Guanfacine () was given concomitantly with many drugs without evidence of any interactions. The principal drugs given (number of patients in parentheses) were: cardiac glycosides (115), sedatives and hypnotics (103), coronary vasodilators (52), oral hypoglycemics (45), cough and cold preparations (45), NSAIDs (38), antihyperlipidemics (29), antigout drugs (24), oral contraceptives (18), bronchodilators (13), insulin (10), and beta blockers (10).
No carcinogenic effect was observed in studies of 78 weeks in mice at doses more than 150 times the maximum recommended human dose and 102 weeks in rats at doses more than 100 times the maximum recommended human dose. In a variety of test models, Guanfacine () was not mutagenic.
No adverse effects were observed in fertility studies in male and female rats.
Clinical studies of Guanfacine () did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy (see ).
Guanfacine () Adverse Reactions
Adverse reactions noted with Guanfacine () are similar to those of other drugs of the central α-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 () could not be established, should a rash occur, Guanfacine () should be discontinued and the patient monitored appropriately.
In the dose-response monotherapy study described under , the frequency of the most commonly observed adverse reactions showed a dose relationship from 0.5 to 3 mg as follows:
The percent of patients who dropped out because of adverse reactions are shown below for each dosage group.
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:
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:
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 , the most common adverse reactions noted were as follows:
Adverse reactions occurring in 3% or less of patients in the three controlled trials of Guanfacine () with a diuretic were:
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.
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).
Guanfacine () Drug Abuse And Dependence
No reported abuse or dependence has been associated with the administration of Guanfacine () .
Guanfacine () Overdosage
Drowsiness, lethargy, bradycardia and hypotension have been observed following overdose with Guanfacine () .
A 25-year-old female intentionally ingested 60 mg. She presented with severe drowsiness and bradycardia of 45 beats/minute. Gastric lavage was performed and an infusion of isoproterenol (0.8 mg in 12 hours) was administered. She recovered quickly and without sequelae.
A 28-year-old female who ingested 30 to 40 mg developed only lethargy, was treated with activated charcoal and a cathartic, was monitored for 24 hours, and was discharged in good health.
A 2-year-old male weighing 12 kg who ingested up to 4 mg of Guanfacine () developed lethargy. Gastric lavage (followed by activated charcoal and sorbitol slurry via NG tube) removed some tablet fragments within 2 hours after ingestion, and vital signs were normal.
During 24-hour observation in ICU, systolic pressure was 58 and heart rate 70 at 16 hours post-ingestion. No intervention was required, and the child was discharged fully recovered the next day.
Guanfacine () Dosage And Administration
The recommended initial dose of Guanfacine () (as the hydrochloride) when given alone or in combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize somnolence. If after 3 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 () is seen at 1 mg (see ). 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 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 to 4 days) without ill effects.
Guanfacine () How Supplied
Guanfacine () Tablets, USP equivalent to 1 or 2 mg of Guanfacine () are supplied as follows:
The 1 mg tablets are white, unscored, round tablets debossed with on one side and on the other side. They are available as follows:
NDC 0378-1160-01bottles of 100 tablets
The 2 mg tablets are blue, unscored, round tablets debossed with on one side and on the other side. They are available as follows:
NDC 0378-1190-01bottles of 100 tablets
Guanfacine ()
Guanfacine () Principal Display Panel - Carton
NDC: 55154-6218-4
Guanfacine () Tablets, USP
1 mg
100 Tablets
Each tablet contains Guanfacine () hydrochloride equivalent to 1 mg of Guanfacine () .
See product insert for usual dosage, prescribing information, precautions and warnings.
STORAGE: Store at Controlled Room Temperature 15°-30°C (59°-86°F).
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
RX ONLY
WARNING: This package is intended for institutional use only. This package is not child resistant. Keep this and all drugs out of the reach of children.
See window for lot number and expiration date.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505
Repackaged by: Cardinal Health
Zanesville, OH 43701
LUC40284290308
Guanfacine () Principal Display Panel - Pouch
Guanfacine ()
Tablet, USP
1 mg
