Guanfacine hydrochloride is a centrally acting antihypertensive
with α2-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.
Clinical Pharmacology
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 Changes (mm Hg) from Baseline in Seated Systolic and Diastolic
Blood Pressure for Patients Completing 4 to 8 Weeks of Treatment with Guanfacine
Monotherapy
*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
*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 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.
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.
Contraindications
Guanfacine hydrochloride is contraindicated in patients with
known hypersensitivity to guanfacine hydrochloride.
Precautions
General Like other antihypertensive agents, guanfacine should be used
with caution in patients with severe coronary insufficiency, recent myocardial
infarction, cerebrovascular disease or chronic renal or hepatic failure. Sedation 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. Rebound 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. Laboratory Tests In clinical trials, no clinically relevant laboratory test
abnormalities were identified as causally related to drug during short-term
treatment with guanfacine. Drug Interactions 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 Rebound above). Anticoagulants 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). Drug/Laboratory Test Interactions No laboratory test abnormalities related to the use of guanfacine
have been identified. Carcinogenesis, Mutagenesis, Impairment of
Fertility 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. PregnancyTeratogenic Effects. Pregnancy Category B 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. Labor and Delivery Guanfacine 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. Nursing Mothers It is not known whether guanfacine is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
guanfacine hydrochloride is administered to a nursing woman. Experiments with
rats have shown that guanfacine is excreted in the milk. Pediatric Use Safety and effectiveness in pediatric patients 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 HCl. Geriatric Use 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 CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Adverse Reactions
Adverse reactions noted with guanfacine are similar to those of
other drugs of the central α2-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 CLINICAL PHARMACOLOGY, the frequency of the most commonly
observed adverse reactions showed a dose relationship from 0.5 to 3 mg as
follows:
AdverseReaction
Placebon=59
0.5 mgn=60
1 mgn=61
2 mgn=60
3 mgn=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 to
3 mg as follows:
AdverseReaction
Placebon=73
0.5 mgn=72
1 mgn=72
2 mgn=72
3 mgn=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:
AdverseReactions
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 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.
AdverseReaction
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 (as the 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
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.
Drug Abuse And Dependence
No reported abuse or dependence has been associated with the
administration of guanfacine.
Overdosage
Signs and Symptoms 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. Treatment of Overdosage Gastric lavage and supportive therapy as appropriate. Guanfacine
is not dialyzable in clinically significant amounts (2.4%).
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 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 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.
How Supplied/storage And Handling
Guanfacine Tablets, USP equivalent to 2 mg of guanfacine are
supplied as follows: The 2 mg tablets are blue, unscored, round tablets debossed with M on one side and G5 on the other
side. They are available as follows:
Bottles of 30
NDC 54868-4876-0
Bottles of 60
NDC 54868-4876-1
Bottles of 100
NDC 54868-4876-2
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. Mylan Pharmaceuticals Inc.Morgantown, WV 26505
REV APRIL 2003GUAN:R4 Relabeling and Repackaging by:
Physician Total Care, Inc.Tulsa, OKÂ Â Â Â Â 74146
Principal Display Panel
Guanfacine Tablets, USP
2 mg
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