Prescription Drug Name:

CLONIDINE HYDROCHLORIDE – clonidine hydrochloride tablet

ID:

5dcbeb73-e8a4-42ee-a2f8-68f2b4cc7aff

Code:

34391-3

DESCRIPTION


id: d6d5436a-53fb-4aeb-a06d-efa7b731fd4a
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

Clonidine hydrochloride is a centrally acting alpha-agonist
hypotensive agent available as tablets for oral administration in three dosage
strengths: 0.1 mg, 0.2 mg and 0.3 mg. The 0.1 mg tablet is equivalent to 0.087
mg of the free base. Clonidine hydrochloride is an imidazoline derivative and exists as a
mesomeric compound. The chemical name is 2-(2,6-dichlorophenylamino)-2-
imidazoline hydrochloride. The following is the structural formula: Clonidine hydrochloride is an odorless, bitter, white, crystalline substance
soluble in water and alcohol. Each tablet for oral administration contains ammonium chloride, colloidal
silicon dioxide, croscarmellose sodium (Type A), magnesium stearate,
microcrystalline cellulose, sodium lauryl sulfate.

CLINICAL PHARMACOLOGY


id: 2e003bd7-cfe7-4820-8519-42afbb491746
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

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. Clonidine hydrochloride acts relatively rapidly.
The patient’s blood pressure declines within 30 to 60 minutes after an oral
dose, the maximum decrease occurring within 2 to 4 hours. Renal blood flow and
glomerular filtration rate remain essentially unchanged. Normal postural
reflexes are intact; therefore, orthostatic symptoms are mild and
infrequent. Acute studies with clonidine hydrochloride in humans have demonstrated a
moderate reduction (15% to 20%) of cardiac output in the supine position with no
change in the peripheral resistance: at a 45° 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
response 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 growth hormone release in both children and
adults, but does not produce a chronic elevation of growth hormone with
long-term use.

Pharmacokinetics The plasma level of clonidine peaks in approximately 3 to 5 hours
and the plasma half-life ranges from 12 to 16 hours. The half-life increases up
to 41 hours in patients with severe impairment of renal function. Following oral
administration about 40 to 60% of the absorbed dose is recovered in the urine as
unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the
liver.

INDICATIONS AND USAGE


id: 9f55ff04-4855-4870-8966-a475c41920ae
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

Clonidine hydrochloride is indicated in the treatment of
hypertension. Clonidine hydrochloride may be employed alone or concomitantly
with other antihypertensive agents.

CONTRAINDICATIONS


id: bd374fd8-5262-4a33-a4cc-ba7fe3d9eb2f
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Clonidine hydrochloride tablets should not be used in patients
with known hypersensitivity to clonidine (see PRECAUTIONS).

WARNINGS


id: 767ab7b0-02f1-40c9-b950-2ed15652f60b
displayName: WARNINGS SECTION
FDA Article Code: 34071-1

Withdrawal Patients should be instructed not to discontinue therapy without
consulting their physician. Sudden cessation of clonidine treatment 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. 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 clonidine
hydrochloride, 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 clonidine
hydrochloride 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 clonidine hydrochloride. Because children commonly have gastrointestinal illnesses
that lead to vomiting, they may be particularly susceptible to hypertensive
episodes resulting from abrupt inability to take medication.

PRECAUTIONS


id: 4693da7f-edad-4ec1-bf82-505ee246ea88
displayName: PRECAUTIONS SECTION
FDA Article Code: 42232-9

General In patients who have developed localized contact sensitization to
transdermal clonidine, substitution of oral clonidine hydrochloride therapy may
be associated with the development of a generalized skin rash. In patients who develop an allergic reaction to transdermal clonidine,
substitution of oral clonidine hydrochloride may also elicit an allergic
reaction (including generalized rash, urticaria, or angioedema). Clonidine hydrochloride should be used with caution in patients with severe
coronary insufficiency, conduction disturbances, recent myocardial infarction,
cerebrovascular disease or chronic renal failure.

Perioperative Use Administration of clonidine hydrochloride should be continued to
within four hours of surgery and resumed as soon as possible thereafter. Blood
pressure should be carefully monitored during surgery and additional measures to
control blood pressure should be available if required.

Information for Patients Patients should be cautioned against interruption of clonidine
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.

Drug Interactions Clonidine may potentiate the CNS-depressive effects of alcohol,
barbiturates or other sedatives. If a patient receiving clonidine hydrochloride
is also taking tricyclic antidepressants, the hypotensive effect of clonidine
may be reduced, necessitating an increase in the clonidine dosage. Due to a 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 ophthalmological 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 or 70
times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD
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 doses as high as
150 mcg/kg (about 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/m2 basis).

Usage in Pregnancy

Teratogenic Effects

Pregnancy Category CReproduction studies performed in rabbits at doses up to
approximately 3 times the oral maximum recommended daily human dose (MRDHD) of
clonidine hydrochloride produced no evidence of 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/m2 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 or at higher dose levels (up to 3 times the oral MRDHD)
when dams were treated on gestation days 6 to 15. Increases in resorptions 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/m2 basis) in mice and rats
treated on gestation days 1 to 14 (lowest dose employed in that 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 hydrochloride is excreted in human milk, caution
should be exercised when clonidine hydrochloride is administered to a nursing
woman.

Pediatric Use Safety and effectiveness in pediatric patients below the age of
twelve have not been established (see Warnings on
Withdrawal).

ADVERSE REACTIONS


id: 1677b699-1313-4771-aeea-a35dd924cd49
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

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 clonidine hydrochloride, but in many cases patients were
receiving concomitant medication and 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 1,000.
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 atrioventricular 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 1,000. Other behavioral changes, vivid dreams or nightmares, restlessness,
anxiety, visual and auditory hallucinations and delirium have rarely been
reported. Dermatological: Rash, about 1 in 100 patients;
pruritus, about 7 in 1,000; hives, angioneurotic edema and urticaria, about 5 in
1,000; alopecia, about 2 in 1,000. 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 1,000; urinary retention, about 1 in
1,000. Hematologic: Thrombocytopenia, rarely. Metabolic: Weight gain, about 1 in 100 patients;
gynecomastia, about 1 in 1,000; transient elevation of blood glucose or serum
creatine phosphokinase, rarely. Musculoskeletal: Muscle or joint pain, about 6 in
1,000 and leg cramps, about 3 in 1,000. Oro-otolaryngeal: Dryness of the nasal mucosa was
rarely reported. Ophthalmological: Dryness of eyes, burning of the
eyes, and blurred vision were reported.

OVERDOSAGE


id: f21e6071-12a0-4bfa-add2-0599d93d4ca5
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

Hypertension may develop early and may be followed by
hypotension, bradycardia, respiratory depression, hypothermia, drowsiness,
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. There is no specific antidote for clonidine overdosage. Clonidine overdosage
may result in the rapid development of CNS depression; therefore, induction of
vomiting with ipecac syrup is not recommended. Gastric lavage may be indicated
following recent and/or large ingestions. Administration of activated charcoal
and/or a 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


id: 776d8cb2-bceb-4743-a88c-07c6f5ee8f34
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Adults The dose of clonidine hydrochloride must be adjusted according to
the patient’s individual blood pressure response. The following is a general
guide to its administration.

Initial Dose 0.1 mg tablet twice daily (morning and bedtime). Elderly patients
may benefit from a lower initial dose.

Maintenance Dose Further increments of 0.1 mg per day may be made at weekly
intervals if necessary until the desired response is achieved. Taking the larger
portion of the oral daily dose at bedtime may minimize transient adjustment
effects of dry mouth and drowsiness. The therapeutic doses most commonly
employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses.
Studies have indicated that 2.4 mg is the maximum effective daily dose, but
doses as high as this have rarely been employed.

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.

HOW SUPPLIED


id: ff1e9794-0325-409e-9dcc-abaa436ffe55
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Clonidine hydrochloride tablets, USP are available containing 0.2 mg of clonidine hydrochloride, USP. The 0.2 mg tablets are white, round scored tablets debossed with MYLAN 186. They are available as follows:

Bottles of 15 – NDC 16590-267-15
Bottles of 30 – NDC 16590-267-30
Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]
 Protect from light. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 REVISED FEBRUARY 2008
CLON:R14 Relabeling and Repackaging by:
STAT Rx USA LLC
Gainesville, GA 30501

PACKAGE LABEL – CLONIDINE 0.2 MG TABLETS


id: d226cdd8-46b4-49fc-a92e-1c477387b3e8
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4