CLONIDINE HCL
DESCRIPTION
Catapres (clonidine) is a transdermal system providing continuous
systemic delivery of clonidine for 7 days at an approximately constant rate.
Clonidine is a centrally acting alpha- agonist hypotensive agent. It is an
imidazoline derivative with the chemical name 2, 6-dichloro- N-2-
imidazolidinylidenebenzenamine.
ACTIONS/CLINICAL PHARMACOLOGY:
Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action
results in reduced sympathetic outflow from the central nervous system and in
decreases in peripheral resistance, renal vascular resistance, heart rate, and
blood pressure. Renal blood flow and glomerular filtration rate remain
essentially unchanged. Normal postural reflexes are instant; therefore,
orthostatic symptoms are mild and infrequent.
Acute studies with clonidine hydrochloride in humans have demonstrated a
moderate reduction (15-20%) of cardiac output in the supine position with no
change in peripheral resistance, at a 45deg tilt there is a smaller reduction in
cardiac output and a decrease of peripheral resistance.
During long-term therapy, cardiac output tends to return to control values,
while peripheral resistance remains decreased. Slowing of the pulse rate has
been observed in most patients given clonidine, but the drug does not alter
normal hemodynamic responses to exercise.
Tolerance to the antihypertensive effect may develop in some patients,
necessitating a reevaluation of therapy.
Other studies in patients have provided evidence of a reduction in plasma renin
activity and in the excretion of aldosterone and catecholamines. The exact
relationship of these pharmacologic actions to the antihypertensive effect of
clonidine has not been fully elucidated.
Clonidine acutely stimulates the release of growth hormone in children as well
as adults but does not produce a chronic elevation of growth hormone with long-
term use.
PHARMACOKINETICS The plasma half-life of clonidine is 12.7 +/- 7 hours.
Following oral administration, about 40-60% of the absorbed dose is recovered in
the urine as unchanged drug within 24 hours. The remainder of the absorbed dose
is metabolized in the liver.
INDICATIONS AND USAGE:
Catapres (clonidine) is indicated in the treatment of hypertension. It
may be employed alone or concomitantly with other antihypertensive agents.
CONTRAINDICATIONS:
Catapres (clonidine) should not be used in patients with known
hypersensitivity to clonidine or to any other component of the therapeutic
system.
WARNINGS:
WITHDRAWAL Patients should be instructed not to discontinue therapy without
consulting their physician. Sudden cessation of clonidine treatment has, in some
cases, resulted in subjective symptoms such as nervousness, agitation, headache,
and confusion accompanied or followed by a rapid rise in blood pressure and
elevated catecholamine concentrations in the plasma. The likelihood of such
reactions to discontinuation of clonidine therapy appears to be greater after
administration of higher doses or continuation of concomitant beta-blocker
treatment and special caution is therefore advised in these situations. Rare
instances of hypertensive encephalopathy, cerebrovascular accidents and death
have been reported after clonidine withdrawal. When discontinuing therapy with
Catapres, the physician should reduce the dose gradually over 2 to 4 days to
avoid withdrawal symptomatology.
An excessive rise in blood pressure following discontinuation of Catapres
therapy can be reversed by administration of oral clonidine hydrochloride or by
intravenous phentolamine. If therapy is to be discontinued in patients receiving
a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn
several days before the gradual discontinuation of Catapres.
PRECAUTIONS:
GENERAL In patients who have developed localized contact sensitization to
Catapres (clonidine) continuation of Catapres or substitution of oral
clonidine hydrochloride therapy may be associated with development of a
generalized skin rash.
In patients who develop an allergic reaction to Catapres, substitution of
oral clonidine hydrochloride may also elicit an allergic reaction (including
generalized rash, urticaria, or angioedema).
Catapres should be used with caution in patients with severe coronary
insufficiency, conduction disturbances, recent myocardial infarction,
cerebrovascular disease, or chronic renal failure.
In rare instances, loss of blood pressure control has been reported in patients
using Catapres according to the instructions for use.
PERIOPERATIVE USE Catapres therapy should not be interrupted during the
surgical period. Blood pressure should be carefully monitored during surgery and
additional measures to control blood pressure should be available if required.
Physicians considering starting Catapres therapy during the perioperative
period must be aware that therapeutic plasma clonidine levels are not achieved
until 2 to 3 days after initial application of Catapres (see DOSAGE AND
ADMINISTRATION)).
DEFIBRILLATION OR CARDIOVERSION The transdermal clonidine systems should be
removed before attempting defibrillation or cardioversion because of the
potential for altered electrical conductivity which may increase the risk of
arcing, a phenomenon associated with the use of defibrillators.
INFORMATION FOR PATIENTS Patients should be cautioned against interruption of
Catapres therapy without their physician's advice.
Patients who engage in potentially hazardous activities, such as operating
machinery or driving, should be advised of a possible sedative effect of
clonidine. They should also be informed that this sedative effect may be
increased by concomitant use of alcohol, barbiturates, or other sedating drugs.
Patients should be instructed to consult their physicians promptly about the
possible need to remove the patch if they observe moderate to severe localized
erythema and/or vesicle formation at the site of application or generalized skin
rash.
If a patient experiences isolated, mild localized skin irritation before
completing 7 days of use, the system may be removed and replaced with a new
system applied to a fresh skin site.
If the system should begin to loosen from the skin after application, the
patient should be instructed to place the adhesive overlay directly over the
system to ensure adhesion during its 7-day use.
Used Catapres patches contain a substantial amount of their initial drug
content which may be harmful to infants and children if accidentally applied or
ingested. THEREFORE, PATIENTS SHOULD BE CAUTIONED TO KEEP BOTH USED AND UNUSED
CATAPRES PATCHES OUT OF THE REACH OF CHILDREN. After use, Catapres
should be folded in half with the adhesive sides together and discarded away
from children's reach.
Instructions for use, storage and disposal of the system are provided at the end
of this monograph. These instructions also are included in each box of Catapres-
TTS.
DRUG INTERACTIONS: Clonidine may potentiate the CNS-depressive effects of
alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine
is also taking tricyclic antidepressants, the hypotensive effect of clonidine
may be reduced, necessitating an increase in the clonidine dose.
potential for additive effects such as bradycardia and AV block, caution is
warranted in patients receiving clonidine concomitantly with agents known to
affect sinus node function or AV nodal conduction e.g., digitalis, calcium
channel blockers and beta-blockers.
Amitriptyline in combination with clonidine enhances the manifestation of
corneal lesions in rats (see TOXICOLOGY).
TOXICOLOGY In several studies with oral clonidine hydrochloride, a dose-
dependent increase in the incidence and severity of spontaneous retinal
degeneration was seen in albino rats treated for six months or longer. Tissue
distribution studies in dogs and monkeys showed a concentration of clonidine in
the choroid.
In view of the retinal degeneration seen in rats, eye examinations were
performed during clinical trials in 908 patients before, and periodically after,
the start of clonidine therapy. In 353 of these 908 patients, the eye
examinations were carried out over periods of 24 months or longer. Except for
some dryness of the eyes, no drug- related abnormal ophthalmologic findings were
recorded and, according to specialized tests such as electroretinography and
macular dazzle, retinal function was unchanged.
In combination with amitriptyline, clonidine hydrochloride administration led to
the development of corneal lesions in rats within 5 days.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Chronic dietary
administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78
weeks) dosed, respectively, at up to 46 to 70 times the maximum recommended
daily human dose (MRDHD) as mg/kg (9 or 6 times the MRDHD on a mg/m(squared)
basis). There was no evidence of genotoxicity in the Ames test for mutagenicity
or mouse micronucleus test for clastogenicity.
Fertility of male and female rats was unaffected by clonidine doses as high as
150 mcg/kg (approximately 3 times the MRDHD). In a separate experiment,
fertility of female rats appeared to be affected at dose levels of 500 to 2000
mcg/kg (10 to 40 times the oral MRDHD on a mg/kg basis; 2 to 8 times the MRDHD
on a mg/m(squared) basis.)
PREGNANCY TERATOGENIC EFFECTS PREGNANCY CATEGORY C. Reproduction studies
performed in rabbits at doses up to approximately 3 times the oral maximum
recommended daily human dose (MRDHD) of Catapres (clonidine) produced no
evidence of a teratogenic or embryotoxic potential in rabbits. In rats, however,
doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m(squared) basis) of
clonidine were associated with increased resorptions in a study in which dams
were treated continuously from 2 months prior to mating. Increased resorptions
were not associated with treatment at the same time or at higher dose levels (up
to 3 times the oral MRDHD) when the dams were treated on gestation days 6-15.
Increases in resorption were observed at much higher dose levels (40 times the
oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m(squared) basis) in
mice and rats treated on gestation days 1-14 (lowest dose employed in the study
was 500 mcg/kg).
No adequate, well-controlled studies have been conducted 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.
NURSING MOTHERS As clonidine is excreted in human milk, caution should be
exercised when Catapres is administered to a nursing woman.
PEDIATRIC USE Safety and effectiveness in pediatric patients below the age of
12 have not been established. (See Warnings on Withdrawal).)
DRUG INTERACTIONS:
DRUG INTERACTIONS: Clonidine may potentiate the CNS-depressive effects of
alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine
is also taking tricyclic antidepressants, the hypotensive effect of clonidine
may be reduced, necessitating an increase in the clonidine dose.
potential for additive effects such as bradycardia and AV block, caution is
warranted in patients receiving clonidine concomitantly with agents known to
affect sinus node function or AV nodal conduction e.g., digitalis, calcium
channel blockers and beta-blockers.
Amitriptyline in combination with clonidine enhances the manifestation of
corneal lesions in rats (see TOXICOLOGY).
TOXICOLOGY In several studies with oral clonidine hydrochloride, a dose-
dependent increase in the incidence and severity of spontaneous retinal
degeneration was seen in albino rats treated for six months or longer. Tissue
distribution studies in dogs and monkeys showed a concentration of clonidine in
the choroid.
In view of the retinal degeneration seen in rats, eye examinations were
performed during clinical trials in 908 patients before, and periodically after,
the start of clonidine therapy. In 353 of these 908 patients, the eye
examinations were carried out over periods of 24 months or longer. Except for
some dryness of the eyes, no drug- related abnormal ophthalmologic findings were
recorded and, according to specialized tests such as electroretinography and
macular dazzle, retinal function was unchanged.
In combination with amitriptyline, clonidine hydrochloride administration led to
the development of corneal lesions in rats within 5 days.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
CLINICAL TRIAL EXPERIENCE WITH CATAPRES Most systemic adverse effects
during Catapres therapy have been mild and have tended to diminish with
continued therapy. In a 3-month multiclinic trial of Catapres in 101
hypertensive patients, the systemic adverse reactions were, dry mouth (25
patients) and drowsiness (12) fatigue (6), headache (5), lethargy and sedation
(3 each), insomnia, dizziness, impotence/sexual dysfunction, dry throat (2 each)
and constipation, nausea, change in taste and nervousness (1 each).
In the previously mentioned 3-month controlled clinical trial, as well as other
uncontrolled clinical trials, the most frequent adverse reactions were
dermatologic and are described below.
In the 3-month trial, 51 of the 101 patients had localized skin reactions such
as erythema (26 patients) and/or pruritus, particularly after using an adhesive
overlay throughout the 7-day dosage interval. Allergic contact sensitization to
Catapres was observed in 5 patients. Other skin reactions were localized
vesiculation (7 patients), hyperpigmentation (5), edema (3), excoriation (3),
burning (3), papules (1), throbbing (1), blanching (1), and a generalized
macular rash (1).
In additional clinical experience, contact dermatitis resulting in treatment
discontinuation was observed in 128 of 673 patients (about 19 in 100) after a
mean duration of treatment of 37 weeks. The incidence of contact dermatitis was
about 34 in 100 among white women, about 18 in 100 in white men, about 14 in 100
in black women, and approximately 8 in 100 in black men. Analysis of skin
reaction data showed that the risk of having to discontinue Catapres
treatment because of contact dermatitis was greatest between treatment weeks 6
and 26, although sensitivity may develop either earlier or later in treatment.
In a large-scale clinical acceptability and safety study by 451 physicians in a
total of 3539 patients, other allergic reactions were recorded for which a
causal relationship to Catapres was not established: maculopapular rash (10
cases); urticaria (2 cases); and angioedema of the face (2 cases), which also
affected the tongue in one of the patients.
MARKETING EXPERIENCE WITH CATAPRES Other adverse effects reported since the
drug has been marketed are listed below by body system. In this setting, an
incidence or causal relationship cannot always be accurately determined.
However, none of the events listed below occurred in a frequency greater than
0.5%.
BODY AS A WHOLE Fever, malaise, weakness, pallor, and withdrawal syndrome.
CARDIOVASCULAR Congestive heart failure; cerebrovascular accident;
electrocardiographic abnormalities (i.e., bradycardia, sick sinus syndrome
disturbances and arrhythmias); chest pain; orthostatic symptoms; syncope,
increases in blood pressure; sinus bradycardia and atrioventricular block with
and without the use of concomitant digitalis; Raynaud's phenomenon; tachycardia;
bradycardia; and palpitations.
CENTRAL AND PERIPHERAL NERVOUS SYSTEM/PSYCHIATRIC Delirium, mental depression,
visual and auditory hallucinations, localized numbness, vivid dreams or
nightmares, restlessness, anxiety, agitation, irritability, other behavioral
changes, and drowsiness.
DERMATOLOGIC Angioneurotic edema, localized or generalized rash, hives,
urticaria, contact dermatitis, pruritus, alopecia, and localized hypo- or
hyperpigmentation.
GASTROINTESTINAL Anorexia and vomiting.
GENITOURINARY Difficult micturition, loss of libido, and decreased sexual
activity.
METABOLIC Gynecomastia or breast enlargement and weight gain.
MUSCULOSKELETAL Muscle or joint pain, and leg cramps.
OPHTHALMOLOGIC Blurred vision, burning of the eyes and dryness of the eyes.
ADVERSE EVENTS ASSOCIATED WITH ORAL CATAPARES THERAPY Most adverse effects are
mild and tend to diminish with continued therapy. The most frequent (which
appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients;
drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and
sedation, each about 10 in 100. The following less frequent adverse experiences
have also been reported in patients receiving Catapres(R) (clonidine
hydrochloride), but in many cases patients were receiving concomitant medication
and a causal relationship has not been established.
BODY AS A WHOLE Weakness, about 10 in 100 patients; fatigue, about 4 in 100;
headache and withdrawal syndrome, each about 1 in 100. Also reported were
pallor, a weakly positive Coombs' test, increased sensitivity to alcohol, and
fever.
CARDIOVASCULAR Orthostatic symptoms, about 3 in 100 patients; palpitations and
tachycardia; and bradycardia, each about 5 in 1000. Syncope, Raynaud's
phenomenon, congestive heart failure, and electrocardiographic abnormalities
(i.e., sinus node arrest, functional bradycardia, high- degree AV block and
arrhythmias) have been reported rarely. Rare cases of sinus bradycardia and AV
block have been reported, both with and without the use of concomitant
digitalis.
CENTRAL NERVOUS SYSTEM Nervousness and agitation, about 3 in 100 patients;
mental depression, about 1 in 100; and insomnia, about 5 in 1000. Other
behavioral changes, vivid dreams or nightmares, restlessness, anxiety, visual
and auditory hallucinations and delirium have rarely been reported.
DERMATOLOGIC Rash, about 1 in 100 patients; pruritus, about 7 in 1000; hives,
angioneurotic edema and urticaria, about 5 in 1000; alopecia, about 2 in 1000.
GASTROINTESTINAL Nausea and vomiting, about 5 in 100 patients; anorexia and
malaise, each about 1 in 100; mild transient abnormalities in liver function
tests, about 1 in 100; hepatitis; parotitis; constipation; pseudo- obstruction;
and abdominal pain, rarely.
GENITOURINARY Decreased sexual activity, impotence and loss of libido, about 3
in 100 patients; nocturia, about 1 in 100; difficulty in micturition, about 2 in
1000; urinary retention, about 1 in 1000.
HEMATOLOGIC Thrombocytopenia, rarely.
METABOLIC Weight gain, about 1 in 100 patients; gynecomastia, about 1 in 1000;
transient elevation of blood glucose or serum creatinine phosphokinase, rarely.
MUSCULOSKELETAL Muscle or joint pain, about 6 in 1000; and leg cramps, about 3
in 1000.
ORO-OTOLARYNGEAL Dryness of the nasal mucosa was rarely reported.
OPHTHALMOLOGIC Dryness of the eyes, burning of the eyes and blurred vision were
reported.
OVERDOSAGE:
Hypertension may develop early and may be followed by hypotension, bradycardia,
respiratory depression, hypothermia, drowsines, decreased or absent reflexes,
weakness, irritability and miosis. The frequency of CNS depression may be higher
in children than adults. Large overdoses may result in reversible cardiac
conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms
of overdose generally occur within 30 minutes to two hours after exposure. As
little as 0.1 mg of clonidine has produced signs of toxicity in children.
If symptoms of poisoning occur following dermal exposure, remove all Catapres-
TTS systems. After their removal, the plasma clonidine levels will persist for
about 8 hours, then decline slowly over a period of several days. Rare cases of
Catapres poisoning due to accidental or deliberate mouthing or ingestion of
the patch have been reported, many of them involving children.
There is no specific antidote for clonidine overdosage. Ipecac syrup-induced
vomiting and gastric lavage would not be expected to remove significant amounts
of clonidine following dermal exposure. If the patch is ingested, whole bowel
irrigation may be considered and the administration of activated charcoal and/or
cathartic may be beneficial. Supportive care may include atropine sulfate for
bradycardia, intravenous fluids and/or vasopressor agents for hypotension and
vasodilators for hypertension. Naloxone may be a useful adjunct for the
management of clonidine-induced respiratory depression, hypotension and/or coma;
blood pressure should be monitored since the administration of naloxone has
occasionally resulted in paradoxical hypertension. Tolazoline administration has
yielded inconsistent results and is not recommended as first-line therapy.
Dialysis is not likely to significantly enhance the elimination of clonidine.
The largest overdose reported to date, involved a 28-year-old male who ingested
100 mg of clonidine hydrochloride powder. This patient developed hypertension
followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and
premature ventricular contractions. The patient fully recovered after intensive
treatment. Plasma clonidine levels were 60 ng/mL after 1 hour, 190 ng/mL after
1.5 hours, 370 ng/mL after 2 hours, and 120 ng/mL after 5.5 and 6.5 hours. In
mice and rats, the oral LD50 of clonidine is 206 and 465 mg/kg, respectively.
DOSAGE AND ADMINISTRATION:
Apply Catapres (clonidine) once every 7 days to a hairless area of intact
skin on the upper outer arm or chest. Each new application of Catapres
should be on a different skin site from the previous location. If the system
loosens during 7-day wearing, the adhesive overlay should be applied directly
over the system to ensure good adhesion. There have been rare reports of the
need for patch changes prior to 7 days to maintain blood pressure control.
To initiate therapy, Catapres dosage should be titrated according to
individual therapeutic requirements, starting with Catapres-1. If after one
or two weeks the desired reduction in blood pressure is not achieved, increase
the dosage by adding another Catapres-1 or changing to a larger system. An
increase in dosage above two Catapres-3 is usually not associated with
additional efficacy.
When substituting Catapres for oral clonidine or for other antihypertensive
drugs, physicians should be aware that the antihypertensive effect of Catapres-
TTS may not commence until 2-3 days after initial application. Therefore,
gradual reduction of prior drug dosage is advised. Some or all previous
antihypertensive treatment may have to be continued, particularly in patients
with more severe forms of hypertension.
RENAL IMPAIRMENT Dosage must be adjusted according to the degree of impairment,
and patients should be carefully monitored. Since only a minimal amount of
clonidine is removed during routine hemodialysis, there is no need to give
supplemental clonidine following dialysis.
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