Included as part of the PRECAUTIONS section.
Treatment with KAPVAY can cause
dose related decreases in blood pressure and heart rate [see ADVERSE
REACTIONS]. Measure heart rate and blood pressure prior to initiation of
therapy, following dose increases, and periodically while on therapy. Titrate KAPVAY
slowly in patients with a history of hypotension, and those with underlying
conditions that may be worsened by hypotension and bradycardia; e.g., heart
block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular
disease, or chronic renal failure. In patients who have a history of syncope or
may have a condition that predisposes them to syncope, such as hypotension,
orthostatic hypotension, bradycardia, or dehydration advise patients to avoid
becoming dehydrated or overheated. Monitor blood pressure and heart rate, and
adjust dosages accordingly in patients treated concomitantly with
antihypertensives or other drugs that can reduce blood pressure or heart rate
or increase the risk of syncope.
Sedation And Somnolence
Somnolence and sedation were commonly reported adverse
reactions in clinical studies. In patients that completed 5 weeks of therapy in
a controlled, fixed dose pediatric monotherapy study, 31% of patients treated
with 0.4 mg/day and 38% treated with 0.2 mg/day versus 4% of placebo treated
patients reported somnolence as an adverse event. In patients that completed 5
weeks of therapy in a controlled flexible dose pediatric adjunctive to
stimulants study, 19% of patients treated with KAPVAY+stimulant versus 7%
treated with placebo+stimulant reported somnolence. Before using KAPVAY with
other centrally active depressants (such as phenothiazines, barbiturates, or
benzodiazepines), consider the potential for additive sedative effects. Caution
patients against operating heavy equipment or driving until they know how they
respond to treatment with KAPVAY. Advise patients to avoid use with alcohol.
Abrupt discontinuation of KAPVAY can cause rebound
hypertension. In adults with hypertension, sudden cessation of clonidine
hydrochloride extended-release formulation treatment in the 0.2 to 0.6 mg/day
range resulted in reports of headache, tachycardia, nausea, flushing, warm
feeling, brief lightheadedness, tightness in chest, and anxiety. In adults with
hypertension, sudden cessation of treatment with immediate-release clonidine
has, in some cases, resulted in symptoms such as nervousness, agitation, headache,
and tremor accompanied or followed by a rapid rise in blood pressure and
elevated catecholamine concentrations in the plasma.
No studies evaluating abrupt discontinuation of KAPVAY in
children with ADHD have been conducted; however, to minimize the risk of
rebound hypertension, gradually reduce the dose of KAPVAY in decrements of no
more than 0.1 mg every 3 to 7 days. Patients should be instructed not to
discontinue KAPVAY therapy without consulting their physician due to the
potential risk of withdrawal effects.
In patients who have developed localized contact
sensitization to clonidine transdermal system, continuation of clonidine
transdermal system or substitution of oral KAPVAY therapy may be associated
with the development of a generalized skin rash.
In patients who develop an allergic reaction from
clonidine transdermal system, substitution of oral KAPVAY may also elicit an
allergic reaction (including generalized rash, urticaria, or angioedema).
Cardiac Conduction Abnormalities
The sympatholytic action of clonidine may worsen sinus
node dysfunction and atrioventricular (AV) block, especially in patients taking
other sympatholytic drugs. There have been post-marketing reports of patients
with conduction abnormalities and/or taking other sympatholytic drugs who
developed severe bradycardia requiring IV atropine, IV isoproterenol, and
temporary cardiac pacing while taking clonidine. Titrate KAPVAY slowly and
monitor vital signs frequently in patients with cardiac conduction
abnormalities or patients concomitantly treated with other sympatholytic drugs.
Patient Counseling Information
Advise the patient to read the
FDA-approved Patient Labeling (PATIENT INFORMATION)
Dosage And Administration
Advise patients that KAPVAY
must be swallowed whole, never crushed, cut, or chewed, and may be taken with
or without food. When initiating treatment, provide dosage escalation
instructions [see DOSAGE AND ADMINISTRATION].
If patients miss a dose of
KAPVAY, advise them to skip the dose and take the next dose as scheduled and
not to take more than the prescribed total daily amount of KAPVAY in any
24-hour period [see DOSAGE AND ADMINISTRATION].
Advise patients who have a
history of syncope or may have a condition that predisposes them to syncope,
such as hypotension, orthostatic hypotension, bradycardia, or dehydration, to
avoid becoming dehydrated or overheated [see WARNINGS AND PRECAUTIONS].
Sedation And Somnolence
Instruct patients to use
caution when driving a car or operating hazardous machinery until they know how
they will respond to treatment with KAPVAY. Also advise patients to avoid the
use of KAPVAY with other centrally active depressants and with alcohol [see WARNINGS
Advise patients not to
discontinue KAPVAY abruptly [see WARNINGS AND PRECAUTIONS].
Advise patients to discontinue
KAPVAY and seek immediate medical attention if any signs or symptoms of a
hypersensitivity reaction occur, such as generalized rash, urticaria, or
angioedema [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis And Impairment Of Fertility
Clonidine HCl was not carcinogenic when administered in
the diet of rats (for up to 132 weeks) or mice (for up to 78 weeks) at doses of
up to 1620 (male rats), 2040 (female rats), or 2500 (mice) mcg/kg/day. These
doses are approximately 20, 25, and 15 times, respectively, the maximum
recommended human dose (MRHD) of 0.4 mg/day on a mg/m² basis.
There was no evidence of genotoxicity in the Ames test
for mutagenicity or mouse micronucleus test for clastogenicity.
Fertility of male or female rats was unaffected by
clonidine HCl doses as high as 150 mcg/kg/day (approximately 3 times the MRHD
on a mg/m² basis). In a separate experiment, fertility of female
rats appeared to be adversely affected at dose levels of 500 and 2000
mcg/kg/day (10 and 40 times the MRHD on a mg/ m² basis).
Use In Specific Populations
Pregnancy Category C
There are no adequate or
well-controlled studies with KAPVAY in pregnant women. In animal embryofetal
studies, increased resorptions were seen in rats and mice administered oral
clonidine hydrochloride from implantation through organogenesis at 10 and 5
times, respectively, the maximum recommended human dose (MRHD). No embryotoxic
or teratogenic effects were seen in rabbits administered oral clonidine hydrochloride
during organogenesis at doses up to 3 times the MRHD. KAPVAY should be used
during pregnancy only if the potential benefit justifies the potential risk to
Oral administration of
clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal
organogenesis at doses of up to 80 mcg/kg/day (approximately 3 times the oral
maximum recommended daily dose [MRHD] of 0.4 mg/day on a mg/m² basis)
produced no evidence of teratogenic or embryotoxic potential. In pregnant rats,
however, doses as low as 15 mcg/kg/day (1/3 the MRHD on a mg/m² basis)
were associated with increased resorptions in a study in which dams were
treated continuously from 2 months prior to mating and throughout gestation.
Increased resorptions were not associated with treatment at the same or at
higher dose levels (up to 3 times the MRHD) when treatment of the dams was
restricted to gestation days 6-15. Increases in resorptions were observed in
both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice,
respectively) or higher when the animals were treated on gestation days 1-14;
500 mcg/kg/day was the lowest dose employed in this study.
Clonidine hydrochloride is
present in human milk. The developmental and health benefits of breastfeeding
should be considered along with the mother's clinical need for KAPVAY and any
potential adverse effects on the breastfed child from KAPVAY or from the
underlying maternal condition. Exercise caution when KAPVAY is administered to
a nursing woman.
The safety and efficacy of KAPVAY in the treatment of
ADHD have been established in pediatric patients 6 to 17 years of age. Use of
KAPVAY in pediatric patients 6 to 17 years of age is supported by three
adequate and well-controlled studies; a short-term, placebo-controlled
monotherapy trial, a short-term adjunctive therapy trial and a longer-term
randomized monotherapy trial [see Clinical Studies]. Safety and efficacy
in pediatric patients below the age of 6 years has not been established.
Juvenile Animal Data A study was conducted in which young
rats were treated orally with clonidine hydrochloride from day 21 of age to
adulthood at doses of up to 300 mcg/kg/day, which is approximately 3 times the
maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m² basis.
A slight delay in onset of preputial separation (delayed sexual maturation) was
seen in males treated with the highest dose (with a no-effect dose of 100
mcg/kg/day, which is approximately equal to the MRHD), but there were no drug
effects on fertility or on other measures of sexual or neurobehavioral
The impact of renal impairment on the pharmacokinetics of
clonidine in children has not been assessed. The initial dosage of KAPVAY
should be based on degree of impairment. Monitor patients carefully for
hypotension and bradycardia, and titrate to higher doses cautiously. Since only
a minimal amount of clonidine is removed during routine hemodialysis, there is
no need to give supplemental KAPVAY following dialysis.