GUANFACINE HYDROCHLORIDE- guanfacine hydrochloride tablet
A-S Medication Solutions
Guanfacine hydrochloride, USP is a centrally acting antihypertensive with α2 -adrenoceptor agonist properties in tablet form for oral administration.
The chemical name of guanfacine hydrochloride, USP is N-amidino-2-(2,6-dichlorophenyl) acetamide hydrochloride and its molecular weight is 282.55. Its structural formula is:
Guanfacine hydrochloride, USP is a white or almost white crystalline powder; sparingly soluble in water and alcohol and slightly soluble in acetone.
Each tablet contains 1.15 mg or 2.30 mg of guanfacine hydrochloride, USP equivalent to 1 mg or 2 mg of guanfacine respectively for oral administration. 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.
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 PatientsBlack Patients||11 to 308 to 28||-1/-5-3/-5||-6/-80/-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 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
|Mean Change n =||Placebo 63||0.5 mg 63||1 mg 64||2 mg 58||3 mg 59|
|S/D* SeatedS/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 mg and 3 mg (see ADVERSE REACTIONS).
In a second 12-week placebo-controlled study of 1 mg, 2 mg 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 mg 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 hours 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 hours (range 10 hours to 30 hours). Younger patients tend to have shorter elimination half-lives (13 hours to 14 hourrs) 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.
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 tablets are contraindicated in patients with known hypersensitivity to guanfacine hydrochloride.
Like other antihypertensive agents, guanfacine hydrochloride should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, or chronic renal or hepatic failure.
Guanfacine, like other orally active central α2 -adrenergic agonists, causes sedation or drowsiness, especially when beginning therapy. These symptoms are dose-related (see ADVERSE REACTIONS). When guanfacine is used with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered.
Abrupt cessation of therapy with orally active central α2 -adrenergic agonists may be associated with increases (from depressed on-therapy levels) in plasma and urinary catecholamines, symptoms of “nervousness and anxiety” and, less commonly, increases in blood pressure to levels significantly greater than those prior to therapy.
Information for Patients
Patients who receive guanfacine should be advised to exercise caution when operating dangerous machinery or driving motor vehicles until it is determined that they do not become drowsy or dizzy from the medication. Patients should be warned that their tolerance for alcohol and other CNS depressants may be diminished. Patients should be advised not to discontinue therapy abruptly.
In clinical trials, no clinically relevant laboratory test abnormalities were identified as causally related to drug during short-term treatment with guanfacine hydrochloride.
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 Reboundabove).
Ten patients who were stabilized on oral anticoagulants were given guanfacine, 1 mg/day 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).
Drug/Laboratory Test Interactions
No laboratory test abnormalities related to the use of guanfacine hydrochloride have been identified.
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.
Administration of guanfacine to rats at 70 times the maximum recommended human dose and to rabbits at 20 times the maximum recommended human dose resulted in no evidence of harm to the fetus. Higher doses (100 and 200 times the maximum recommended human dose in rabbits and rats respectively) were associated with reduced fetal survival and maternal toxicity. Rat experiments have shown that guanfacine crosses the placenta.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Guanfacine hydrochloride is not recommended in the treatment of acute hypertension associated with toxemia of pregnancy. There is no information available on the effects of guanfacine on the course of labor and delivery.
It is not known whether guanfacine hydrochloride is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when guanfacine is administered to a nursing woman. Experiments with rats have shown that guanfacine is excreted in the milk.
Safety and effectiveness in children under 12 years of age have not been demonstrated. Therefore, the use of guanfacine in this age group is not recommended. There have been spontaneous postmarketing reports of mania and aggressive behavioral changes in pediatric patients with attention-deficit hyperactivity disorder (ADHD) receiving guanfacine. The reported cases were from a single center. All patients had medical or family risk factors for bipolar disorder. All patients recovered upon discontinuation of guanfacine hydrochloride. Hallucinations have been reported in pediatric patients receiving guanfacine for treatment of attention-deficit hyperactivity disorder.
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