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.
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.
Tenex (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 Tenex (guanfacine hydrochloride) is
excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when Tenex is administered to a nursing
woman. Experiments with rats have shown that guanfacine is excreted in
the milk.
Tenex (guanfacine hydrochloride) is a centrally acting antihypertensive with α2-adrenoceptor agonist properties in tablet form for oral administration.
The chemical name of Tenex (guanfacine hydrochloride) is N-amidino- 2-(2,6-dichlorophenyl) acetamide hydrochloride and its molecular weight is 282.56. Its structural formula is:
Guanfacine hydrochloride is a white to off-white powder; sparingly soluble in water and alcohol and slightly soluble in acetone. The tablets contain the following inactive ingredients:
1 mg—FD&C Red 40 aluminum lake, lactose, microcrystalline cellulose, povidone, stearic acid.
Tenex (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 Tenex. 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/DS/D = Systolic/diastolic
blood pressure Seated
n = (range)
Placebo
0.5 mg
1 mg
2 mg
3 mg
5 mg
White Patients
11–30
-1/-5
-6/-8
-8/-9
-12/-11
-15/-12
-18/-16
Black Patients
8–28
-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, 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 =
Placebo63
0.5 mg63
1 mg64
2 mg58
3 mg59
SDS/D = Systolic/diastolic blood
pressure 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 and 3 mg (see ADVERSE REACTIONS).
In a second 12-week placebo-controlled study of 1, 2 or 3 mg of Tenex
(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.
Tenex (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 Tenex 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 - 30 hr). Younger
patients tend to have shorter elimination half-lives (13 - 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 -
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 1.0,
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
Tenex (guanfacine hydrochloride) is indicated in the
management of hypertension. Tenex may be given alone or in combination
with other antihypertensive agents, especially thiazide-type
diuretics.
Contraindications
Tenex is contraindicated in patients with known hypersensitivity to
guanfacine hydrochloride.
Precautions
General Like other antihypertensive agents, Tenex (guanfacine hydrochloride)
should be used with caution in patients with severe coronary insufficiency,
recent myocardial infarction, cerebrovascular disease, or chronic renal or
hepatic failure. Sedation Tenex, 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 Tenex 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 Tenex 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 Tenex (guanfancine hydrochloride).
Drug Interactions
The potential for increased sedation when Tenex 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 - 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, Tenex 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 Tenex
(guanfacine hydrochloride) 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.
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.
Pregnancy Section
Labor and Delivery
Tenex (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.
Nursing Mothers
It is not known whether Tenex (guanfacine hydrochloride) is
excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when Tenex is administered to a nursing
woman. Experiments with rats have shown that guanfacine is excreted in
the milk.
Use In Specific Populations Section
Pediatric Use
Safety and effectiveness in children under 12 years of age have not been demonstrated. Therefore, the use of Tenex 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 Tenex. 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. Hallucinations have been reported in pediatric patients receiving Tenex for treatment of attention-deficit hyperactivity disorder.
Geriatric Use
Clinical studies of Tenex 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 Tenex (guanfacine hydrochloride) 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 Tenex could not be established, should
a rash occur, Tenex 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 Tenex (guanfacine hydrochloride) 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 Tenex (guanfacine hydrochloride) 1 mg/day
given at bedtime for 28 days. Tenex 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 Tenex-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 Tenex 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 Tenex (guanfacine hdyrochloride).
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 - 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 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 Tenex (guanfacine 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 Tenex 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 - 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 - 4 days) without ill
effects.
How Supplied
Tenex® (guanfacine hydrochloride) Tablets are available in the following dosing strengths (expressed in equivalent amounts of guanfacine):
1 mg—light pink, diamond-shaped tablet embossed with a 1 and engraved RP on one side and engraved TENEX on the other side in bottles of 100 (NDC 67857-705-01) and 500 (NDC 67857-705-05).
2 mg—yellow, diamond-shaped tablet, one side engraved TENEX, other side engraved 2 with RP below it in bottles of 100 (NDC 67857-706-01).
Store at controlled temperature, between 20ଌ and 25°C (68°F and 77°F).
Manufactured by:PATHEON, Puerto Rico, Inc.Manati, Puerto Rico 00674, USA
Revised: May 2013
Package Label.principal Display Panel
NDC-67857-706-01 100 Tablets
TENEX®
(Guanfancine HCL)
equivalent to2 mg guanfancine
Rx only
PROMIUS PHARMA
Package Label.principal Display Panel
NDC-67857-705-05 500 Tablets
TENEX®
(Guanfancine HCL)
equivalent to1 mg guanfancine
Rx only
PROMIUS PHARMA
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