CLONIDINA CLORIDRATO

Clonidine is an imidazole derivate that acts as an agonist of alpha-2 adrenoceptors.

This activity is useful for the treatment of hypertension, severe pain, and ADHD. 8, 15, 9, 10, 11 Clonidine was granted FDA approval on 3 September 1974.

Clonidine tablets, oral solution and transdermal systems are indicated for the treatment of hypertension alone or in combination with other medications. 8, 9, 15 A clonidine injection is indicated for use with opiates in the treatment of severe cancer pain where opiates alone are insufficient.

An extended-release tablet of clonidine is indicated for the treatment of ADHD, either alone or in combination with other medications.

Clonidine is also used for the diagnosis of pheochromocytoma, 3 treatment of nicotine dependance, 4 and opiate withdrawal.

Additionally, clonidine is also indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as a monotherapy or as an adjunctive therapy to central nervous system (CNS) stimulant medications in pediatric patients 6 years of age and older. 13,

Clonidine functions through agonism of alpha-2 adrenoceptors which have effects such as lowering blood pressure, sedation, and hyperpolarization of nerves.

It has a long duration of action as it is given twice daily and the therapeutic window is between 0.1 mg and 2.4 mg daily. 8, 9, 10, 11.

Alpha-2B adrenergic receptor Agonist Alpha-2C adrenergic receptor Agonist Alpha-2A adrenergic receptor Agonist.

Clonidine reaches maximum concentration in 60-90 minutes after oral administration. 2, 6 Race and fasting status do not influence pharmacokinetics of clonidine.

A 100 µg oral clonidine tablet reaches a C max of 400.72pg/mL with an AUC of 5606.78h*pg/mL and a bioavailability of 55-87%.

The volume of distribution of clonidine has been reported as 1.7-2.5 L/kg 2, 2.9 L/kg 9, or 2.1±0.4 L/kg 10 depending on the source.

The metabolism of clonidine is poorly understood.

The main reaction in clonidine metabolism is the 4-hydroxylation of clonidine by CYP2D6, CYP1A2, CYP3A4, CYP1A1, and CYP3A5.

Clonidine is <50% metabolized in the liver to inactive metabolites. 2, 8, 9, 10, 11 Hover over products below to view reaction partners Clonidine 4-Hydroxyclonidine.

Approximately 50% of a clonidine dose is excreted in the urine as the unchanged drug and 20% is eliminated in the feces. 2, 8.

The elimination half life after epidural administration is 30 minutes but otherwise can range from 6-23h.

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LD is 126 mg/kg in rats.

TDLO is 70 µg/kg in children, 126 µg/kg in women, and 69 µg/kg in men.

Symptoms of overdose include hypertension followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased reflexes, weakness, irritability, and miosis. 8, 9, 10, 11 Severe overdoses can cause reversible cardiac conduction defects or dysrhythmias, apnea, coma, and seizures. 8, 9, 10, 11 Induction of vomiting is not recommended due to CNS depression but gastric lavage or activated charcoal may be useful in recent ingestion. 8, 9, 10, 11 Dialysis is also unlikely to be beneficial. 8, 9, 10, 11 Overdose can be treated with supportive measures such as atropine sulfate for bradycardia, intravenous fluids or vasopressors for hypotension, vasodilators for hypertension, naloxone for respiratory depression, and blood pressure monitoring. 8, 9, 10, 11.

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 tablets, the physician should reduce the dose gradually over to 4 days to avoid withdrawal symptomatology.

An excessive rise in blood pressure following discontinuation of clonidine hydrochloride tablets 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 tablets.

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.

Clonidine hydrochloride tablets should not be used in patients with known hypersensitivity to clonidine.

The dose of clonidine hydrochloride tablets must be adjusted according to the patient’s individual blood pressure response.

The following is a general guide to its administration.

Dose: 0.1 mg tablet twice daily (morning and bedtime).

Elderly patients may benefit from a lower initial 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.

Patients with renal impairment may benefit from a lower initial dose.

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.

For questions regarding this product, call Teva at 1-888-838-2872.

Clonidine hydrochloride tablets, USP are supplied as follows: 0.1 mg — Each orange, round tablet imprinted with R and on one side and bisect on the other side contains 0.1 mg of clonidine hydrochloride, USP and is supplied in NDC: 70518-4342-00 NDC: 70518-4342-01 PACKAGING: 30 in 1 BOTTLE PLASTIC PACKAGING: 30 in 1 BLISTER PACK Dispense in a tight, light-resistant container as defined in the USP.

Store at 25°C (77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) .

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Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of clonidine hydrochloride tablets 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 2 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 to 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 2 basis) in mice and rats treated on gestation days to 14 (lowest dose employed in the study was 500 mcg/kg).

No adequate, well-controlled studies have been conducted in pregnant women.

Clonidine crosses the placental barrier.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

As clonidine hydrochloride is excreted in human milk, caution should be exercised when clonidine hydrochloride tablets are administered to a nursing woman.

Safety and effectiveness in pediatric patients have not been established in adequate and well-controlled trials See WARNINGS, Withdrawal.