Catapres

The reduction in blood pressure induced by clonidine can be further potentiated by concurrent administration of other anti-hypertensive agents such as diuretics, vasodilators, β blockers, calcium antagonists and ACE-inhibitors, but not α₁-blocking agents.

Concomitant use of β-blockers and/or cardiac glycosides can further lower heart rate (bradycardia) or cause dysrhythmia (atrioventricular block) in isolated cases.

It cannot be ruled out that concomitant administration of a beta-receptor blocker will cause or potentiate peripheral vascular disorders.

The antihypertensive effect of clonidine may be reduced or abolished and orthostatic regulation disturbances may be provoked or aggravated by concomitant administration of tricyclic antidepressants or neuroleptics with alpha-receptor blocking properties.

If clonidine hydrochloride and tricyclic antidepressants are administered as concurrent therapy, an increase in the dosage of CATAPRES may be necessary. Amitriptyline in combination with clonidine hydrochloride enhances the manifestation of corneal lesions in rats.

Substances with alpha₂ receptor blocking properties such as phenolamine or tolazoline may abolish the alpha₂-receptor mediated effects of clonidine in a dose-dependent manner. Therefore, depending upon the dose administered, tolazoline is suitable as an antidote.

Concurrent use of appetite suppressants (with the exception of fenfluramine) and clonidine hydrochloride may decrease the hypotensive effects of clonidine hydrochloride. Concurrent use of fenfluramine and clonidine hydrochloride may increase the hypotensive effects of clonidine hydrochloride.

Sympathomimetic amines, indomethacin and possibly other non-steroidal anti-inflammatory agents may reduce the antihypertensive effects of clonidine hydrochloride. Substances which raise blood pressure or induce a Na⁺ and water retaining effect such as non steroidal anti- inflammatory agents can reduce the therapeutic effect of clonidine. The patient should be carefully monitored to confirm that the desired effect is being obtained.

Clonidine hydrochloride may enhance the CNS-depressive effects of alcohol, barbiturates or other sedatives.

Withdrawal of clonidine hydrochloride may result in an excess of circulating catecholamines (see Warnings and Precautions). Therefore, caution should be exercised in concomitant use of drugs which affect the metabolism, tissue uptake or pressor effects of these amines (monoamine oxidase (MAO) inhibitors, tricyclic antidepressants and beta blocking agents, respectively).

The concomitant use of clonidine with methylphenidate has resulted in serious adverse reactions, including death, in children with attention-deficit/hyperactivity (ADHD).

Elderly patients may benefit from a lower initial dose.

Treatment of hypertension requires regular medical supervision.

The dose of CATAPRES (clonidine hydrochloride) must be adjusted according to the patient's individual blood pressure response.

The safety and efficacy of clonidine have not been established in children.

Dosage instructions for patients with impaired hepatic function have not been established.

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

Maintenance Dose: After a period of 2-4 weeks, further increments of 0.1 mg per 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 mg to 0.6 mg per day given in divided doses. Usually doses above 0.6 mg per day do not result in a further marked reduction in blood pressure.

Discontinuation of Treatment: If CATAPRES (clonidine hydrochloride) is to be discontinued, reduce dosage gradually (see Warnings and Precautions).

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.

The tablets should be swallowed whole with water.

If a dose of CATAPRES is missed, patients should take the dose as soon as possible and then return to their normal schedule.

decreased sexual activity, erectile dysfunction about 3% of patients.

accommodation disorder, lacrimation decreased (caution: contact lens wearers).

rash, about 1 % of patients; pruritus, about 0.7%; urticaria, about 0.5%; and alopecia, about 0.2%.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The following less frequent adverse reactions have been reported in patients receiving clonidine hydrochloride.

orthostatic hypotension, about 3% of patients, Raynaud's phenomenon has been reported rarely.

fatigue, about 4%, malaise, about 1%.

bradyarrhythmia, about 0.5%. Rare cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

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%).

The most serious reactions have been reported upon abrupt discontinuation of the drug (see Warnings and Precautions).

weakness, about 10% of patients; dryness, burning of the eyes.

The following adverse events have been reported during therapy with Catapres: anorexia (about 1%); mild transient abnormalities in liver function tests (about 1%); weight gain (about 1%); nervousness and agitation (each about 3%); insomnia (about 0.5%); palpitations and tachycardia (each about 0.5%); angioneurotic edema (about 0.5%); nocturia (about 1%); difficulty in micturition (about 0.2%); urinary retention (about 0.1%); discontinuation syndrome (about 1%); muscle or joint pain (about 0.6%) and cramps of the lower limbs (about 0.3%).

Behavioural changes; restlessness; anxiety; delirium; blurred vision; pallor; weakly positive Coombs' test; increased sensitivity to alcohol and fever have also been reported.

Rarely: hepatitis, parotitis; transient elevation of serum creatine phosphokinase; congestive heart failure and electro cardiographic abnormalities i.e. conduction disturbances and arrhythmias have been reported.

Also, there have been isolated reports of continual dry mouth leading to an accelerated rate of dental caries, in patients receiving clonidine hydrochloride.

nasal dryness.

gynecomastia, about 0.1%.

headache, about 1%, dizziness, paresthesia, sedation.

blood glucose increased rarely.

confusional state, delusional perception, depression, about 1%; hallucinations, libido decreased, nightmares, sleep disorder.

nausea and vomiting, about 5% of patients; colonic pseudo-obstruction, constipation, dry mouth, salivary gland pain.

Safety and effectiveness in children have not been established.

Each round, orange, flat tablet with bevelled edges, one side scored with each half bearing the imprint O2C, 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, maize starch, polyvinylpyrrolidone, soluble starch and stearic acid. Bottles of 100.

Each round, white, flat tablet with bevelled edges, one side scored with each half bearing the imprint O1C, the reverse side bearing the Ingelheim Tower, contains: clonidine HCl 0.1 mg. Nonmedicinal ingredients: colloidal silica, dibasic calcium phosphate, lactose, maize starch (dried), polyvinylpyrrolidone, soluble starch and stearic acid. Bottles of 100.

Clonidine and its metabolites are extensively excreted with the urine. Renal insufficiency requires particularly careful adjustment of dosage.

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 or insufficiency, periodic determination of the BUN is indicated. If, in the physician's opinion, a rising BUN is significant, the drug should be stopped.

Administration of CATAPRES should be continued to within four 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.

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.

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 CATAPRES (clonidine hydrochloride) 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, restlessness, palpitations, tremor, nausea and headache. Rare instances of hypertensive encephalopathy and death have been recorded after abrupt cessation of CATAPRES therapy. A withdrawal reaction is most likely to occur in patients who have been receiving large doses (greater than 1.2 mg/day) or in those who are continuing to receive a concomitant beta-blocker. If therapy is to be discontinued in patients receiving clonidine and a β adrenergic blocking agent concomitantly, the β blocker should be first phased out gradually 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 CATAPRES therapy or by intravenous phentolamine.

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 vanilmandelic acid (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.

CATAPRES tablets contain up to 216.1 mg of lactose per maximum recommended daily dose (0.6 mg). Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia should not take this medicine.

Safety and effectiveness in children have not been established.

In several studies clonidine hydrochloride produced a dose-dependent increase in the incidence and severity of spontaneously occurring retinal degeneration in albino rats treated for six months or longer. In view of this retinal degeneration, eye examinations were performed in 908 patients prior to the start of clonidine hydrochloride 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 hydrochloride 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 CATAPRES should receive periodic eye examinations.

Patients who wear contact lenses should be warned that treatment with CATAPRES may cause decreased lacrimation (see Adverse Reactions).

Reproduction studies performed in rabbits at doses up to approximately 3 times the maximum recommended daily human dose (MRDHD) of clonidine hydrochloride has revealed no evidence of teratogenic or embryotoxic potential in rabbits. When rats were given clonidine hydrochloride 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 hydrochloride passes the placenta barrier and may lower the heart rate of the fetus. A postpartum transient rise in blood pressure in the newborn cannot be excluded. There is no adequate experience regarding the long-term effect of prenatal exposure.

The use of CATAPRES during lactation is not recommended due to a lack of supporting information.

Because it lowers blood pressure, CATAPRES (clonidine hydrochloride) should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease or chronic renal failure.

CATAPRES should be used with caution in patients with mild to moderate bradyarrhythmia such as low sinus rhythm, with disorders of cerebral or peripheral perfusion, polyneuropathy, and constipation, and in patients with heart failure or severe coronary heart disease.

The dosage of clonidine hydrochloride 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.

Depending on the dose given, CATAPRES can lower the heart rate and pulse rate. In patients with diseases affecting the rhythmic and atrioventricular (AV) conduction system of the heart, arrhythmias have been observed after high doses.

CATAPRES should be monitored particularly carefully in patients with heart failure or severe coronary disease.

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.

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.

Clonidine is 50% bound to plasma proteins.

The plasma level of CATAPRES peaks in approximately 3 to 5 hours. In humans, a significant plasma level (0.20 µg% of clonidine) can be detected one hour after oral administration of a single dose of 390 mg.

Clonidine hydrochloride is an α adrenergic agonist which also has some α adrenergic antagonist effects. The antihypertensive effect of clonidine hydrochloride is thought to be due to central α₂ 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 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.

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 hydrochloride 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.

Following oral administration about 40-60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours.

The plasma half-life ranges from 12 to 16 hours, but the half-life increases up to 41 hours in patients with severe impairment of renal function. In humans, 65% of the orally administered drug is excreted in the urine, and an estimated 22% in the faeces.

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.

About 50% of the absorbed dose is metabolized in the liver. Four different metabolites have been detected in humans.

CATAPRES (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.

In man, the blood pressure reduction due to clonidine does not cause significant alterations in renal blood flow in the supine position. In the erect position, a consistent decrease in renal vascular resistance is seen.