Action And Clinical Pharmacology: Clonidine is an a-adrenergic agonist which also has some a-adrenergic antagonist effects. The antihypertensive effect of clonidine is thought to be due to central a2-adrenergic stimulation, which results in a decreased sympathetic outflow to the heart, kidneys, and peripheral vasculature and thus decreased peripheral vascular resistance, decreased systolic and diastolic blood pressure and decreased heart rate. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact and therefore orthostatic symptoms are mild and infrequent. Acute studies with clonidine 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.
Clonidine 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. 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.
Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines, but the exact relationship of these pharmacologic actions to the antihypertensive effect has not been fully elucidated.
Prolonged treatment with clonidine in animals causes a decrease in the responsiveness of the vascular smooth muscle to catecholamines and angiotensin. The change in vascular response may be of importance in explaining the chronic hypotensive effect in man.
Acute administration of clonidine stimulates the release of growth hormone in children and adults, but the drug does not produce sustained elevation of growth hormone during chronic administration.
Indications And Clinical Uses: The treatment of hypertension. It may be used alone or in combination with thiazide diuretics. Clonidine should normally be used in those patients in whom treatment with diuretic or beta-blocker was found ineffective or has been associated with unacceptable adverse effects.
Clonidine can also be tried as an initial agent in those patients in whom use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.
Contra-Indications: Hypersensitivity to clonidine or to any of the tablet excipients; patients with sinus node function impairment.
Manufacturers’ Warnings In Clinical States: Withdrawal: Patients should be instructed not to discontinue therapy without consulting their physician. A pronounced withdrawal reaction with symptoms suggesting sympathetic over-activity may develop within 12 to 48 hours when clonidine is discontinued. High serum levels of catecholamines have been found during such episodes (see Drug Interactions). When discontinuing clonidine therapy, the physician should reduce the dose gradually over 2 to 4 days to avoid a possible rapid rise in blood pressure and associated subjective symptoms such as nervousness, agitation, and headache. Rare instances of hypertensive encephalopathy and death have been recorded after abrupt cessation of clonidine therapy. A withdrawal reaction is most likely to occur in patients who have been receiving large doses (greater than 1.2 mg/kg) or in those who are continuing to receive a concomitant beta-blocker. If therapy is to be discontinued in patients receiving clonidine and a b-adrenergic blocking agent concomitantly, the b-blocker should be discontinued several days before clonidine therapy is discontinued.
It has been demonstrated that an excessive rise in blood pressure, should it occur, can be reversed by resumption of clonidine therapy or by i.v. phentolamine.
Perioperative Use: Administration of clonidine should be continued to within 4 hours of surgery and resumed as soon as possible thereafter. The blood pressure should be carefully monitored and appropriate measures instituted to control it as necessary.
Precautions: General: Because it lowers blood pressure, clonidine should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease or chronic renal failure.
Depending on the dose given, clonidine can lower the heart rate and pulse rate. In patients with diseases affecting the rhythmic and AV conduction system of the heart, arrhythmias have been observed after high doses.
Tolerance may develop in some patients, necessitating a re-evaluation of therapy. This usually consists of an increase in dosage or concomitant administration of a diuretic to enhance the hypotensive response to the drug.
Occupational Hazards: The dosage of clonidine should be increased gradually to minimize the sedative effect of the drug. This is of particular importance in those patients who operate automobiles and potentially dangerous machinery.
Patients with a known history of depression should be carefully supervised while under treatment with clonidine, as there have been occasional reports of further depressive episodes occurring in such patients.
In several studies clonidine produced a dose-dependent increase in the incidence and severity of spontaneously occurring retinal degeneration in albino rats treated for 6 months or longer. In view of this retinal degeneration, eye examinations were performed in 908 patients prior to the start of clonidine therapy, who were then examined periodically thereafter. In 353 of these 908 patients, examinations were performed for periods of 24 months or longer. Except for the dryness of the eyes, no drug-related abnormal ophthalmologic findings were recorded and clonidine did not alter retinal function as shown by specialized tests such as the electroretinogram and macular dazzle. It is recommended that as an integral part of their overall long-term care, patients treated with clonidine should receive periodic eye examinations.
As with any drug excreted primarily in the urine, smaller doses of the drug are often effective in treating patients with a degree of renal failure. In patients exhibiting renal failure, periodic determination of the BUN is indicated. If, in the physician’s opinion, a rising BUN is significant, the drug should be stopped.
A few instances of a condition resembling Raynaud’s phenomenon have been reported. Caution should therefore be observed if patients with Raynaud’s disease or thromboangiitis obliterans are to be treated with clonidine.
Pheochromocytoma: Clonidine is not indicated in pheochromocytoma. However, in contrast to guanethidine and reserpine the drug has no crisis-inducing properties, in this condition.
Clonidine does not affect the urinary VMA and catecholamine excretion significantly in patients with pheochromocytoma, so that no false positive or false negative results will occur during the administration of the drug.
Pregnancy: Reproduction studies performed in rabbits at doses up to approximately 3 times the maximum recommended daily human dose (MRDHD) of clonidine has revealed no evidence of teratogenic or embryotoxic potential in rabbits. When rats were given clonidine alone in doses as low as one-third the MRDHD, some embryotoxicity was evident.
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.
Careful monitoring of the mother and child is recommended. Clonidine passes the placenta barrier and may lower the heart rate of the fetus. Postpartum a transient rise in blood pressure in the newborn cannot be excluded. There is no adequate experience regarding the long-term effect of prenatal exposure.
Lactation: Since clonidine is distributed into breast milk, the drug should be used with caution in nursing women.
Children: Safety and effectiveness in children have not been established.
Drug Interactions: Along with diuretics, vasodilators and b-blockers have the ability to enhance the blood pressure lowering effect of clonidine.
Concomitant use of b-blockers and/or cardiac glycosides can further lower heart rate (bradycardia) or cause dysrhythmia (AV-block) in isolated cases.
If clonidine and tricyclic antidepressants are administered as concurrent therapy, the effect of clonidine may be reduced, thus necessitating an increase in the dosage of clonidine. Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats.
Depending upon the dose administered, tolazoline can reduce or neutralize the effect of clonidine, and therefore, is suitable as an antidote.
Concurrent use of appetite suppressants (with the exception of fenfluramine) and clonidine may decrease the hypotensive effects of clonidine. Concurrent use of fenfluramine and clonidine may increase the hypotensive effects of clonidine.
Sympathomimetic amines, indomethacin and possibly other nonsteroidal anti-inflammatory agents may reduce the antihypertensive effects of clonidine. The patient should be carefully monitored to confirm that the desired effect is being obtained.
Clonidine may enhance the CNS-depressive effects of alcohol, barbiturates or other sedatives.
Withdrawal of clonidine may result in an excess of circulating catecholamines (see Warnings). Therefore, caution should be exercised in concomitant use of drugs which affect the metabolism, tissue uptake or pressor effects of these amines (MAO inhibitors, tricyclic antidepressants and beta-blocking agents, respectively).
Adverse Reactions: Most adverse effects are mild and generally tend to diminish with continuation of therapy. The most common (which appear to be dose-related) are dry mouth (about 40%), drowsiness (about 33%), dizziness (about 16%), constipation and sedation (each in about 10%).
There have been isolated reports of continual dry mouth leading to an accelerated rate of dental caries, in patients receiving clonidine.
The most serious reactions have been reported upon abrupt discontinuation of the drug (see Warnings, Withdrawal).
The following less frequent adverse experiences have also been reported in patients receiving clonidine, but in many cases patients were receiving concomitant medication and a causal relationship has not been established.
Gastrointestinal: nausea and vomiting, about 5% of patients; anorexia and malaise, each about 1%; mild transient abnormalities in liver function tests, about 1%; rare reports of hepatitis; parotitis, rarely. In very rare cases pseudo-obstruction of the large bowel have been observed in predisposed patients.
Metabolic: weight gain, about 1% of patients; gynecomastia, about 0.1%, transient elevation of blood glucose or serum creatine phosphokinase, rarely.
CNS: nervousness and agitation, about 3% of patients, mental depression, about 1%; headache, about 1%; insomnia, about 0.5%. Vivid dreams or nightmares, other behavioral changes, restlessness, sleep disturbances, anxiety, visual and auditory hallucinations, perceptual disorders, confusion, disturbances of accommodation and delirium have been reported.
Cardiovascular: orthostatic symptoms, about 3% of patients; palpitations and tachycardia, bradycardia, each about 0.5%. Congestive heart failure and electrocardiographic abnormalities i.e., conduction disturbances 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.
Dermatologic: rash, about 1% of patients; pruritus, about 0.7%; hives, angioneurotic edema and urticaria, about 0.5%; alopecia, about 0.2%.
Genitourinary: decreased sexual activity, impotence and loss of libido, about 3% of patients; nocturia, about 1%; difficulty in micturition, about 0.2%; urinary retention, about 0.1%.
Other: weakness, about 10% of patients; fatigue, about 4%; discontinuation syndrome, about 1%; muscle or joint pain, about 0.6% and cramps of the lower limbs, about 0.3%. Dryness, burning of the eyes, blurred vision, dryness of the nasal mucosa, pallor, weakly positive Coombs’ test, increased sensitivity to alcohol and fever have been reported. Raynaud’s phenomenon has been reported rarely.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: The signs and symptoms of clonidine overdosage include hypotension, bradycardia, lethargy, irritability, weakness, somnolence, diminished or absent reflexes, miosis, vomiting and hypoventilation. With large overdoses, reversible cardiac induction defects or arrhythmias, apnea, seizures and transient hypertension have been reported. The oral LD50 of clonidine in rats was 465 mg/kg, and in mice 206 mg/kg.
In a patient who ingested 100 mg clonidine, plasma clonidine levels were 60 ng/mL (1 hour), 190 ng/mL (1.5 hours), 370 ng/mL (2 hours) and 120 ng/mL (5.5 and 6.5 hours). This patient developed hypertension followed by hypotension; bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment.
Clonidine overdosage usually responds to symptomatic treatment with careful cardiovascular monitoring. Gastric lavage is only worthwhile if it is guaranteed that part of the dose taken, which has not yet been absorbed, can be removed. Routine hemodialysis is of limited benefit since a maximum of 5% of circulating clonidine is removed.
I.V. tolazoline (an a-antagonist) and naloxone have each been used as antidotes to clonidine poisoning, with inconsistent results. If other efforts fail, these agents may provide some benefit in reversing the effects of clonidine.
Dosage And Administration: The dose must be adjusted according to the patient’s individual blood pressure response.
Initial Dose: 0.1 mg tablet twice daily (morning and bedtime). (Elderly patients may benefit from a lower initial dose.)
Maintenance Dose: After a period of 2 to 4 weeks, further increments of 0.1 mg/day may be necessary until the desired response is achieved. In those instances where it is not possible to have equal amounts of drug at each of the dosing intervals, taking the larger portion of the total daily dose at bedtime may minimize transient adjustment effect of dry mouth and drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 to 0.6 mg/day given in divided doses. Usually above 0.6 mg/day do not result in a further marked reduction in blood pressure.
Renal Insufficiency: Doses 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 during dialysis.
Discontinuation of Treatment: If clonidine is to be discontinued, reduce dosage gradually (see Warnings).
Availability And Storage: 0.1 mg: Each round, white, flat tablet with bevelled edges, the reverse side bearing the Ingelheim Tower, contains: clonidine HCl 0.1 mg. Nonmedicinal ingredients: colloidal silica, dibasic calcium phosphate, lactose (fine), maize starch, polyvinylpyrrolidone, soluble starch and stearic acid. Bottles of 100 and 500.
0.2 mg: Each round, orange, flat tablet with bevelled edges, one side scored with each half bearing the imprint , the reverse side bearing the Ingelheim Tower, contains: clonidine HCl 0.2 mg. Nonmedicinal ingredients: colloidal silica, dibasic calcium phosphate, FD&C Yellow #6, lactose (fine), maize starch, polyvinylpyrrolidone, soluble starch and stearic acid. Bottles of 100 and 500.
Store at controlled room temperature (15 to 30°C).
CATAPRES® Boehringer Ingelheim Clonidine HCl Antihypertensive