Clonidine (Sivem Pharmaceuticals, 0.1 mg, 0.2 mg) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

CLONIDINE (clonidine hydrochloride) is indicated for 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.

Pediatrics (< 18 years of age):

Safety and effectiveness in children have not been established.

CONTRAINDICATIONS

CLONIDINE is contraindicated in patients with severe bradyarrhythmia resulting from either sick sinus syndrome or atrioventricular (AV) block of 2nd or 3rd degree; patients with sinus node function impairment.

Patients who are hypersensitive to this drug or to any ingredients in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

CLONIDINE is also contraindicated in patients with the rare hereditary condition of galactose intolerance e.g. galactosaemia. CLONIDINE tablets contain approximately 450.18 mg of lactose monohydrate per maximum recommended daily dose (0.6 mg) and thus should not be used by patients with this condition.

WARNINGS AND PRECAUTIONS

General

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 (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 clonidine hydrochloride 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.

An excessive rise in blood pressure following discontinuation of CLONIDINE therapy can be reversed 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.

Pediatrics (< 18 years of age):

Safety and effectiveness in children have not been established and therefore cannot be recommended for use in this population.

Carcinogenesis and Mutagenesis

See PART II: TOXICOLOGY section.

Cardiovascular

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

CLONIDINE 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 (see WARNINGS AND PRECAUTIONS: Effects on ability to drive and use machines).

Depending on the dose given, CLONIDINE 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.

CLONIDINE 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.

Dependence/Tolerance

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.

Ophthalmologic

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 (see PART II: TOXICOLOGY). 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 CLONIDINE should receive periodic eye examinations.

Patients who wear contact lenses should be warned that treatment with CLONIDINE may cause decreased lacrimation (see ADVERSE REACTIONS: Eye disorder).

Peri-Operative Considerations

Administration of CLONIDINE 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.

Psychiatric

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.

Renal

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.

Special Populations

Pregnant Women: 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 (see PART II: TOXICOLOGY).

There are, however, limited amount of data from the use of clonidine 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 placental 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.

Nursing Women: Clonidine is excreted in human milk. However, there is insufficient information on the effect on newborns. The use of CLONIDINE is therefore not recommended during breast feeding.

Pediatrics (< 18 years of age): Safety and effectiveness in children have not been established and therefore cannot be recommended for use in this population.

Fertility

No clinical studies on the effect on human fertility have been conducted with clonidine. Non-clinical studies with clonidine indicate no direct or indirect harmful effects with respect to the fertility index (see PART II: TOXICOLOGY).

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as dizziness, and accommodation disorder during treatment with CLONIDINE. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Most adverse reactions associated with the use of clonidine hydrochloride are mild and generally tend to diminish with continuation of therapy. The most common are sedation (about 50%), dry mouth (about 44%), orthostatic hypotension (about 19%) and dizziness (about 15%).

The most serious reactions have been reported upon abrupt discontinuation of the drug (see WARNINGS AND PRECAUTIONS - Withdrawal). The potentially serious adverse drug reactions are the following:

Psychiatric disorders: confusional state, depression, hallucination

Nervous system disorders: dizziness, sedation

Cardiac disorders: atrioventricular block, bradyarrhythmia, sinus bradycardia. Vascular disorders: orthostatic hypotension, Raynaud’s phenomenon

Gastrointestinal disorders: colonic pseudo-obstruction

The above-mentioned serious adverse drug reactions could result in clinical intervention.

Clinical Trial Adverse Drug Reactions

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 information from this section is based on 22 clinical studies, which were published between 1968 and 1985. The studies comprised of 640 patients, which have been treated with clonidine hydrochloride.

Table 1: Adverse events occurring in ≥ 1 % of the clonidine hydrochloride patients in placebo-controlled clinical trials

Most adverse reactions associated with the use of clonidine hydrochloride are mild and generally tend to diminish with continuation of therapy.

Less Common Clinical Trial Adverse Drug Reactions

In addition, the following potentially important events occurred in less than 1% of patients receiving clonidine hydrochloride:

Cardiac disorders:

atrioventricular block, bradyarrhythmia, sinus bradycardia

Endocrine disorders:

gynaecomastia

Eye disorder:

accommodation disorder, lacrimation decreased

Gastrointestinal disorders:

colonic pseudo-obstruction, accelerated rate of dental caries

General disorders and administration site conditions: Malaise

Nervous system disorders:

paraesthesia

Psychiatric disorders:

confusional state, delusional perception, hallucination, libido decreased, nightmare

Respiratory, thoracic and mediastinal disorders: nasal dryness

Skin and subcutaneous tissue disorders:

Alopecia, pruritus, rash, urticaria

Vascular disorders:

Raynaud's phenomenon

Abnormal Hematologic and Clinical Chemistry Findings

Investigations: blood glucose increased

DRUG INTERACTIONS

Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction.

Proper name

Clinical comment Other anti-hypertensive agents such as diuretics, vasodilators, β blockers, calcium antagonists and ACE-inhibitors, but not α₁ -blocking agents

β -blockers and/or cardiac glycosides

Beta-receptor blocker

Proper name

Clinical comment

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 clonidine hydrochloride may be necessary.

Substances with alpha₂ receptor blocking properties such as phentolamine

Appetite suppressants (with the exception of fenfluramine)

Sympathomimetic amines, indomethacin and possibly other non- steroidal anti-

inflammatory agents

The patient should be carefully monitored to confirm that the desired effect is being obtained.

Alcohol, barbiturates or other sedatives.

Drugs which affect the

metabolism, tissue uptake or pressor effects of these amines (monoamine oxidase (MAO) inhibitors, tricyclic

antidepressants and beta blocking agents, respectively).

Caution should be exercised in concomitant use of these drugs.

Methylphenidate

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbs have not been established.

Drug-Laboratory Test Interactions

In rare cases, an increase in blood glucose has occurred in clinical studies.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Treatment of hypertension requires regular medical supervision.

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

Recommended Dose and Dosage Adjustment

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 CLONIDINE (clonidine hydrochloride) is to be discontinued, reduce dosage gradually (see WARNINGS AND PRECAUTIONS).

Missed Dose

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

Administration

The tablets should be swallowed whole with water.

Use in Elderly

Elderly patients may benefit from a lower initial dose.

Use in Impaired Renal Function

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.

Use in Impaired Hepatic Function

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

Use in Children

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

OVERDOSAGE

The signs and symptoms of clonidine hydrochloride overdosage include generalised sympathetic depression and include pupillary constriction, hypotension, hypothermia, bradycardia, lethargy, irritability, weakness, somnolence including coma, diminished or absent reflexes, vomiting and hypoventilation. With large overdoses, reversible cardiac induction defects or arrhythmias, coma, respiratory depression including apnoea, seizures and transient hypertension have been reported.

In a patient who ingested 100 mg clonidine hydrochloride, plasma clonidine levels were 60 ng/mL (one hour), 190 ng/mL (1.5 hours), 370 ng/mL (two hours) and 120 ng/mL (5.5 and 6.5 hours). This patient developed hypertension followed by hypotension, bradycardia, apnoea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment.

Clonidine overdosage usually responds to symptomatic treatment, volume expansion for hypotension and careful cardiovascular monitoring. Gastric lavage, followed by administration of activated charcoal if a large dose has been taken, can be initiated within two hours of ingestions if the airway can be protected. Routine hemodialysis is of limited benefit since a maximum of 5% of circulating clonidine is removed.

Intravenous naloxone has been used as antidotes to clonidine poisoning, with inconsistent results.

If other efforts fail, this agent may provide some benefit in reversing the effects of clonidine.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Clonidine hydrochloride is α andrenergic 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.

Pharmacodynamics

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.

Pharmacokinetics

Absorption: The plasma level of clonidine hydrochloride peaks in approximately 1 to 3 hours. In humans, a significant plasma level (0.20 mcg% of clonidine) can be detected one hour after oral administration of a single dose of 390 mcg.

Distribution: Clonidine is 30-40% bound to plasma proteins.

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

Excretion: Following oral administration about 40-60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. Clonidine is excreted in human milk. However, there is insufficient information on the effect in newborns.

The terminal elimination half-life ranges from 5 to 25.5 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.

Special Populations and Conditions

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.

STORAGE AND STABILITY

Store between 15°C - 30°C. Protect from moisture.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms

CLONIDINE (clonidine hydrochloride) is available as:

0.1 mg tablets: White to off white, round, flat faced bevel edged tablet, with breakline on one side and debossed with ‘L’ on one side of breakline and ‘84’ on another side of breakline; tablet is plain on other side. 0.2 mg tablets: Orange colored, round, flat faced bevel edged tablet, with breakline on one side and debossed with ‘L’ on one side of breakline and ‘792’ on another side of breakline; tablet is plain on other side.

Composition

The CLONIDINE 0.1 mg tablets contain, in addition to clonidine hydrochloride, the following non-medicinal ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate.

The CLONIDINE 0.2 mg tablets contain, in addition to clonidine hydrochloride, the following non-medicinal ingredients: FD&C Yellow #6 lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate.

Packaging

CLONIDINE 0.1mg and 0.2 mg tablets are supplied in bottles of 100 tablets.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: clonidine hydrochloride

Chemical name: 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride

Molecular formula and molecular mass: C₉H₉N₃C1₂·HCl, 266.55 g/mol

Structural formula:

Physicochemical properties: A white, odorless, bitter, crystalline powder. It is soluble in water and alcohol, practically insoluble in chloroform and ether. The pH of a 5% aqueous solution lies between 3.5 and 5.5.

CLINICAL TRIALS

Comparative Bioavailability Studies

A randomized, two-way, single-dose, crossover comparative bioavailability study of CLONIDINE 0.2 mg tablets (Sivem Pharmaceuticals ULC) with TEVA-CLONIDINE^® 0.2 mg tablets (Teva Canada Limited) was conducted in healthy, adult, male subjects under fasting conditions. Comparative bioavailability data from the 18 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Clonidine

(1 x 0.2 mg)

Geometric Mean

Arithmetic Mean (CV %)

¹CLONIDINE (clonidine hydrochloride) tablets, 0.2 mg (Sivem Pharmaceuticals ULC) ²TEVA-CLONIDINE^® (clonidine hydrochloride) tablets, 0.2 mg (Teva Canada Limited) ³Expressed as the median (range) only

⁴Expressed as the arithmetic mean (CV%) only

DETAILED PHARMACOLOGY

Pharmacokinetics

Clonidine is well absorbed from the intestine in all species examined. In the dog, plasma levels can be detected one hour after administration of an oral dose of 0.52 mg/kg, and maximum plasma levels are reached after 4-8 hours. In man, a significant plasma level (0.20 mcg% of clonidine) can be detected one hour after oral administration of a single dose of 390 mcg. Since clonidine is approximately 30-40% bound, this reflects an actual free plasma level. Peak plasma levels in man and monkey occur after three hours, and decline with a half-life of 5 to 25.5 hours.

Elimination decreases after 24 hours, and is completed only after five days.

In rats, clonidine hydrochloride tissue levels are distinctly above blood levels. They show similar distribution patterns over heart, liver, lung, spleen, testes, brain, adrenal gland, fat and muscle after either oral or i.v. administration. The highest concentration of clonidine hydrochloride after oral administration is found in the kidneys and the gastrointestinal tract, but only very small amounts can be detected in these organs 48 hours after administration. There is a high concentration of clonidine in the lacrimal and parotid glands (40 times higher than the blood level).

The cerebrospinal fluid contains only half the plasma concentration of clonidine, which might be interpreted as an expression of affinity for brain tissue. The overall brain distribution suggests a greater affinity for noradrenergic than for other aminergic cell systems.

An enterohepatic circulation of clonidine has been described in the rat. Up to 24% of an oral dose is excreted in the bile, within the first 24-28 hours.

A large proportion (90-95%) of the given dose is metabolized in dogs and monkeys, whereas in humans clonidine is less extensively metabolized. In dogs, after 48 hours up to 80% of the administered radioactive clonidine is excreted in the urine, and up to 18% in the faeces. In man, 65% of the orally administered drug is excreted in the urine, and an estimated 22% in the faeces.

Fifty-eight percent of the activity in human urine at 24 hours and 44% at 48 hours is unchanged clonidine. Four different metabolites have been detected in man.

Effects on the Cardiovascular System

Clonidine has two opposing actions on the cardiovascular system. As an alpha-sympathomimetic it constricts blood vessels but, as it seems devoid of beta-stimulant action, it does not directly influence the heart. The very potent inhibitory action on central spontaneous sympathetic activity tends to reduce the peripheral resistance and to decrease cardiac output. In addition, a vagal component appears to be involved, since phentolamine or reserpine abolish the effect on blood pressure but only decrease the bradycardia produced by clonidine, while atropine decreases the hypotension and bradycardia.

Clonidine has neither a ganglionic nor a postganglionic blocking action; it is free of alpha- and beta-adrenergic blocking actions; it does not act on vagal receptors, and it does not interfere with the catecholamine content of the various tissues.

Intravenous doses (1-100 pg/kg) of clonidine given to animals of different species, either intact or in various experimental preparations, exert a biphasic cardiovascular effect: (a) an initial very brief rise of the blood pressure is followed by (b) a sustained fall.

(a) The brief vasopressor effect shows the following characteristics:

(1) it is not prevented by pretreatment with reserpine;

(2) it is abolished by pretreatment with phentolamine;

(3) it is reduced by cocaine;

(4) it is still elicited in the spinal, decerebrated, decapitated, pithed,

immunosympathectomized, bivagotomized, stellate ganglionectomized and debuffered animal; and

(5) it is accompanied by bradycardia.

In addition, clonidine causes direct vasoconstriction in isolated organs. In experiments with isolated smooth muscles of rabbits (non-pregnant uterus, small intestine and blood vessels of the ear), clonidine appears to compete with adrenaline and causes an adrenaline-like effect.

Contrary to the initial vasopressor effect of guanethidine and bretylium, clonidine does not interfere with the synthesis, storage, or release of catecholamines from the nerve endings. Clonidine is less depressant than guanethidine upon reflex blood pressure responses, as shown by the conservation of the normal diving reflex in ducks and by the absence of effect on the blood pressure response to vertical tilting in dogs. However, clonidine markedly enhances the pressure-induced reflex bradycardia in dogs (total heart-lung bypass); this effect is abolished by stellate ganglionectomy and bivagotomy.

Bradycardia is seen with 5 mg/kg i.v. in experimental animals, but total denervation of the heart abolishes any bradycardic response to doses as high as 1 mg/kg. In very high doses it has been shown, however, that clonidine is depressant directly upon the myocardium.

(b) The long-lasting, slow-recovering depressor phase of clonidine is clearly dose-dependent and shows the following characteristics:

(1) it is inhibited by pretreatment with reserpine or phentolamine; (2) it is absent in the spinal, pithed or decapitated animal;

(3) it is elicited by injection of minute quantities (even 1/100 of the intravenous dose) administered directly into the central nervous system (intracisternal, intrahypothalamic or intraventricular injection, or infusion into the vertebral arteries) and

(4) It is also accompanied by bradycardia which persists throughout the entire blood pressure response to clonidine.

Clonidine reduces the cardiac output in dogs and rabbits. Apparently, this is not due to a direct negative inotropic effect upon the cardiac muscle or to a local action on the pacemaker region, nor does it arise as a reflex response to a change in blood pressure. It is apparently due to a reduction in the sympathetic drive to the heart or to the systemic venodilatation caused by the drug. No change is seen in this cardiac response after vagotomy.

Clonidine decreases the neuronal traffic in the sympathetic nervous system or at least changes the pattern of sympathetic discharges, inhibiting centrally the bulbar sympathetic cardio-accelerator and vasoconstrictor mechanisms. In different animal species the impulse traffic in the renal, phrenic, cervical, splanchnic, and cardiac sympathetic nerves (pre- or postganglionic) rapidly decreases after clonidine and finally disappears. Clonidine does not reduce the discharges in all the sympathetic nerves to the same extent, the cardiac nerve being less affected. This effect is dose-dependent, lasts as long as the hypotension and the bradycardia and is not influenced by vagotomy nor by suppression of afferent input from the peripheral chemo- and baroreceptors.

The depression of the sympathetic activity is more effective on the spontaneous discharges than on reflexly or centrally evoked discharges, especially if submaximal or supramaximal stimulation at low frequencies is used. An adrenergic block is not the reason for the decrease in the sympathetic tone since low doses of clonidine potentiate and prolong the blood pressure effect of adrenaline and prolong the responses to noradrenaline.

The biphasic change in arterial blood pressure is accompanied by a corresponding sharp increase and then a fall in total peripheral resistance. The significant reduction in the total peripheral resistance obtained in unanaesthetized rabbits by single intravenous injections of clonidine is unaffected even when the effects of the autonomic nervous system are blocked by pretreatment with phenoxybenzamine, propranolol and atropine. This indicates that clonidine may have a direct peripheral vasodilator action in addition to its effect on the CNS and its peripheral sympathomimetic effect, especially when the level of resting sympathetic activity is low. In dogs there is a decreased skin and skeletal muscle blood flow during the transient pressor phase, but the coronary blood flow is increased, indicating either a lesser degree of vasoconstriction relative to that in other vascular fields, or vasodilatation.

The depressor phase usually shows an increase in the circulatory capacity. There is a corresponding change in the regional distribution of blood in the peripheral circulation; the vascular resistance in the cutaneous and skeletal beds decreases, whereas the cerebral, pulmonary, renal and splanchnic vascular fields show variable responses. A fall in the calculated coronary vascular resistance has been demonstrated in the dog heart-lung bypass preparation with separate coronary and systemic perfused circulation, even when the heart rate was maintained constant.

Effects on Vascular Reactivity

Administration of oral clonidine to cats at a dose of 10 mcg/kg/day for 4 weeks or 20 mcg/kg/day for seven days resulted in a reduction in vascular response to either vasoconstrictor or vasodilator stimuli. The vasoactive drugs administered under general anesthesia were epinehrine, norepinephrine, isoprenaline and angiotensin.

Reduced vascular reactivity to angiotensin, norepinephrine and vasopresin administered intravenously was observed in conscious rats. These effects were also seen after single intramuscular doses of 1, 3, or 10 mcg/kg of clonidine, either before or after ganglion blockade as well as after seven days of intramuscular administration of 20 mcg/kg of clonidine.

Effects on the Kidney, Renal Hemodynamics and Sodium Balance

In acute studies clonidine given intravenously or by infusion into the renal artery diminishes the renal blood flow and reduces the excretion of sodium in dogs. However, the intravenous or intraperitoneal administration of clonidine to rats enhances the diuresis and produces a dose-dependent increase in the excretion of inorganic ions, their relative composition being quite uniform.

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.

In animals, acute administration of the drug causes a dose-related increase in renal vascular resistance without any change in glomerular filtration rate. There is correlation between these effects and increased tubular reabsorption of sodium.

Clinically, there may be some sodium retention and slight weight gain during the initial three to four days of therapy. Thereafter the sodium is re-excreted and weight goes down during continued administration of the drug. These transient changes in sodium balance are rarely of clinical significance and are not seen at all if clonidine is given concomitantly with a diuretic.

Effects on the Central Nervous System

In acute experiments a dose-dependent sedative action has been demonstrated in cats and dogs receiving i.v. clonidine. In rats there is a reduction of exploratory behaviour and inhibition of pain-induced aggression in doses smaller than or equal to those effective in producing hypotension.

Mice have shown exophthalmos, horripilation and intense tremors at 1-5 mg/kg and marked aggressivity at 10 mg/kg, followed by sedation and reduction of spontaneous mobility. The conditioned avoidance behaviour of guinea pigs and rats is inhibited by clonidine, and the young chicken suffers a loss of the righting reflex. Very small doses (0.02 mcg/kg) induce sleep in young chickens. The depth and the duration of sleep (either behavioural or barbital- or chloral-induced) are potentiated by clonidine in rat, mouse and cat. Given i.v., clonidine produces in rabbits a typical resting EEG. The cat EEG shows synchronization, slower waves and a decrease of faster waves.

In mice the drug has an analgesic action, as these animals do not take up their usual defence and escape reaction. A local anaesthetic action has been observed at very high doses. Clonidine closely resembles the typical local anaesthetic procaine, as shown by electrophysiological studies of intracellular action potentials and membrane resistance and firing threshold of the crayfish stretch receptor. The local anaesthetic effect of clonidine appears to be much more potent than the effect produced by tetracaine on the rabbit cornea.

Effect on Salivation and Gastric Secretion

Clonidine greatly reduces the conditioned salivation in dogs, but has no effect upon the salivation produced either by pilocarpine or by stimulation of the chorda tympani. The most likely action of the drug is upon central nervous centers controlling salivation, and not by a peripheral effect. Given intravenously, clonidine inhibits the gastric secretion and reduces its acidity in rats, thus giving protection against stress- and reserpine-induced ulcers and gastric haemorrhage, but it is ineffective against histamine- and serotonin-provoked ulcers.

Metabolic effects

Intravenous administration of clonidine increases the pool, life and turnover of body glucose in the rat, and decreases glucose oxidation. There is no change in muscle glycogen, but liver glycogen is lowered. A dose-dependent hyperglycemia has been described in cats receiving clonidine (infusion of 10 pg/kg into the vertebral arteries provokes a 30% higher level than control), but this effect is less marked in adrenalectomized animals.

Rabbits show hyperglycemia with very high doses only. Normal and fasting rats also show increased plasma glucose levels after clonidine given by different routes. Clonidine does not affect the plasma level of free fatty acids, but with very high doses has increased the plasma renin level in rats.

Although single large doses of clonidine impair glucose handling, presumably because of the transient adrenergic effects described above, no effects on glucose metabolism are seen during the long term clinical use of the drug.

TOXICOLOGY

Acute Toxicity

The oral LD₅₀ of clonidine in rats was 465 mg/kg, and in mice 206 mg/kg.

The LD₅₀ in 24 hours when given intravenously to mice is 17.6 mg/kg; the LD₅₀ during a 14-day observation period following a single oral dose is over 30 mg/kg in dogs.

Long term Toxicity

Subacute (12-13 weeks) and chronic (26-78 weeks) toxicity studies have not shown any increased morbidity or mortality due to a cumulative effect or possible organ damage. No abnormality has been recorded in blood, urine or internal organs after subacute dosages. In rats there is a clear dose-related lag in weight gain, and sedation with a brief hyperactive phase immediately following the administration of the drug. Dogs show a dose-related restriction of growth; female dogs in subacute i.v. toxicity studies were anovulatory with high daily doses

(0.5 mg/kg.). Glycosuria has been found in rabbits receiving 1 mg/kg daily for 30 days. No significant drug-induced pathological or histological change in the circulatory and parenchymatous organs of the rat or in the endocrine organs of mice and rabbits have been observed.

Ophthalmologic Toxicity

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 6 months or longer. Tissue distribution studies in dogs and monkeys revealed that clonidine hydrochloride was concentrated in the choroid of the eye.

In rats, clonidine hydrochloride in combination with amitriptyline produced corneal lesions within 5 days.

Tolerance

Tolerance to clonidine has not been demonstrated in either dogs or in rats, as shown by two exactly measurable parameters (mydriasis and bradycardia).

Carcinogenesis, Mutagenesis, Impairment of Fertility

In one 32-week (fixed concentration) dietary administration study in rats, clonidine hydrochloride administered at 32 to 46 times the maximum recommended daily human dose was unassociated with evidence of carcinogenic potential. Fertility of male or female rats was unaffected by clonidine hydrochloride doses as high as 150 mcg/kg or about 3 times the maximum recommended daily human dose (MRDHD). Fertility of female rats did, however, appear to be affected (in another experiment) at dose levels of 500 to 2000 mcg/kg or 10 to 40 times the MRDHD.

Teratogenicity

Reproduction studies performed in rabbits at doses up to approximately 3 times the maximum recommended daily human dose (MRDHD) of clonidine hydrochloride have revealed no evidence of teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 the MRDHD 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 MRDHD) when dams were treated on days 6-15 of gestation. Increased resorptions were observed at much higher levels (40 times the MRDHD) in rats and mice treated on days 1-14 of gestation (lowest dose employed in that study was 500 mcg/kg).

REFERENCES

1. 1.

   Arndts D, Doevendans J, Kirsten R, Heintz B. NEW ASPECTS OF THE

   PHARMACOKINETICS AND PHARMACODYNAMICS OF CLONIDINE IN MAN. Eur J Clin Pharmacol 1983;24:21-30.

2. 2. Anavekar SN, Jarrott B, Toscano M, Louis WJ. Pharmacokinetic and pharmacodynamic studies of oral clonidine in normotensive subjects. Eur J Clin Pharmacol 1982;23:1-5.
3. 3.

   Baer L et al. Suppression of renin and aldosterone by clonidine. Ann Intern Med 1971;

   74:830.

4. 4. Boutroy MJ, Gisonna CR, Legagneur M. Clonidine: placental transfer and neonatal adaption. Early Hum Dev 1988; 17:275-286.
5. 5. Boutroy MJ, Gisonna C, Legagneur M, Vert P. Hypertensive crisis in infants born to clonidine treated mothers. 5th World Cong on the International Society for the Study of Hypertension in Pregnancy 1987. Clin Exp Hypertens (B) 1987;6:261.
6. 6.

   Campese VM, Massry SG. Effects of acute and chronic treatment with clonidine. Chest

   1983 ;83(Suppl):380-383.

7. 7. Cohen IM, O’Connor DT, Preston RA, Stone RA. Reduced renovascular resistance by clonidine. Clin Pharmacol Ther 1979; 26:572-577.
8. 8. Conolly ME, (ed). Catapres in Hypertension. Butterworths: London, 1970.
9. 9.

   Davidov M, et al. The antihypertensive effects of an imidazoline compound. Clin

   Pharmacol Ther 1967;8(Nov.-Dec:810-816.

10. 10.

    Delbruck 0 von. Results of toxicological and teratological animal experiments with 2-

    (2,6-dichlorophenylamino )-2-imidazoline hydrochloride. ArzneimittelForsch 1966; 16: 1 053-55.

11. 11.

    Elizur A, Liberson Z. An acute psychotic episode at the beginning of clonidine therapy.

    Prog Neuropsychopharmacol 1980;4:211-213.

12. 12. Ferder L, Inserra F, Medina F. Safety aspects of long-term antihypertensive therapy (10 years) with clonidine. Sat Symp on Neurotransmission and Neuromodulation, Heidelberg 11th Sci Mtg of the International Society of Hypertension, Heidelber 4 Sep 1986. J Cardiovasc Pharmacol 1987;10 (Suppl 12):S104-S108.
13. 13. Fillastre JP, Dubois D, Brunelle P. Plasma half-life of 1 4C-clonidine in normal and uraemic patients. Round Table Mtg, Inst of Cardiovascular Research, Milan 24-25 Nov 1973. In: Aspetti Moderni del Trattamento dell’lpertensione arteriosa. Ed. Zanchetti, A.; Enrico, M. - Florence: Boehringer Ingelheim, 1973 P81-85 1973.
14. 14. Fogari R, Corradi L. Interaction of clonidine and beta blocking agents in the treatment of essential hypertension. lnt Symp on Clonidine in Hypertension, Geneva 14-16 Jun 1984. In: Low Dose Oral and Transdermal Therapy of Hypertension Ed. Weber, MA.; Drayer, J.I.M., Kolloch, R-Darmstadt: Steinkopff Verlag, 1985.- P118-121,1985.
15. 15. Frisk-Holmberg M. The effectiveness of clonidine as an antihypertensive in a two-dose regimen. Acta Med Scand 1980;207:43-45.
16. 16. Gavrilovich L, et al. The value of Catapres and diuretics in the treatment of acute and chronic hypertension. Clin Res 1969; 17(i):16.
17. 17.

    Gifford RW. Clonidine in the management of mild hypertension in twenty-two patients.

    Cleveland Clinic Foundation. 1 969;36: 173-82.

18. 18.

    Graubner W, Wolf M. Critical reflections about the mechanism of action of 2-(2,6-dichlorophenylamino )-2-imidazoline hydrochloride. Arzneimittel-\ Forsch 1966; 16:

    1055-58.

19. 19. Hartikainen-Sorri AL, Heikkinen JE, Koivisto M. Pharmacokinetics of clonidine during pregnancy and nursing. Obstet Gynecol 1 987;69:598-600.
20. 20.

    Hoobler SW, Sagastume E. Clonidine hydrochloride in the treatment of hypertension.

    Am J Cardiol 1971;28:67-73.

21. 21.

    Hossmann V, Specht T. Clonidine in depressed kidney function. Clonidine Workshop,

    Essen 3-4 Dec 1982. In: Central Blood-Pressure Regulation: the Role of Alpha-2 Receptor Stimulation. Ed. Hayduk, K., Bock, K.D., Darmstadt: Steinkopff Verlag, 1 983-p1 01-112,1983.

22. 22. Hutchison JC, et al. The use of clonidine hydrochloride in ambulatory hypertensive patients. Angiology 1 971 ;22:647-58.
23. 23. Izzo JL, Santarosa RP, Larrabee PS, Smith RJ, Kallay MC. Increased plasma norepinephrine and sympathetic nervous activity in essential hypertensive and uremic humans: effects of clonidine. Sat Symp on Neurotransmission and Neuromodulation, Heidelberg 11th Sci Mtg of the International Society of Hypertension, Heidelberg 4 Sep 1986. J Cardiovasc Pharmacol 1987;10-(Suppl 12):S225-299.
24. 24.

    Khan A, et al. qlonidine (Catapres): a new antihypertensive agent. Curr Ther Res 1970;

    12(1): 10-18.

25. 25.

    Kobinger W, Walland A. Investigations into the mechanism of the hypotensive effect of

    2-(2,6-dichlorophenylamino) -2- imidazoline-HCI. Europ J Pharmacol 1 967;2:1 55-62.

26. 26.

    Lowenthal DT. PHARMACOKINETICS OF CLONIDINE. J Cardiovasc Pharmacol

    1980;2:S29-S37.

27. 27.

    McRaven DR, et al. The effect of clonidine on hemodynamics in hypertensive patients.

    Am Heart J 1978;81 (4):482-9.

28. 28. MacGregor TR, Relihan GL, Keirns JJ. Pharmacokinetics of oral sustained release clonidine in humans. Arzneimittelforschung 1985;35 :440-446.
29. 29.

    Mroczek W, et al. Comparison of clonidine and methyldopa in hypertensive patients.

    Clin Pharmacol Ther 1971; 13:147-8.

30. 30. Nayler WG, et al. Effect of the hypotensive drug St-i 55 (Catapres) on the heart and peripheral circulatin. J Pharmacol Exp Ther 1968;164:45-9.
31. 31.

    Onesti G, et al. Pharmacodynamic effects of a new antihypertensive drug, Catapres (St-i

    1. 55) Circulation 1969;39:2 19-28.
32. 32.

    Onesti G, et al. Antihypertensive effect of clonidine. Suppl II to Circulation 28 and 29.

    1971:11-53-11-69.

33. 33.

    Parsons WB, Morledge JH. Antihypertensive effect of a new imidazoline compound

    (clonidine) and chlorthalidone, individually and in combination. Am J Cardiol. 1970;26:258-61.

34. 34. Paul RR, Bansal K, Sharma PL, Wahi PL. Double blind cross over clinical trial of clonidine hydrochloride versus placebo in hypertensive patients. J Assoc Physicians India 1975;23:667-671.
35. 35. Putzeys MR, Hoobler SW. Comparison of clonidine and methyldopa on blood pressure and side effects in hypertensive patients. Am Heart J 1972;83(4):464-68.
36. 36. Schwartz AB. Clonidine: a new potent antihypertensive agent. Drug Ther 1971;1 :39-41.
37. 37. Smet G, et al. Clinical observations on a new antihypertensive drug, 2-(2, 6-dichlorophenylamino)-2-imidazoline hydrochloride. Am Heart J 1969;77 (4) :47 3-78.
38. 38. Sung PK, et al. Effects of clonidine and chlorthalidone on blood pressure and glucose tolerance in hypertensive patients. Curr Ther Res 1971; 13(5):280-85.
39. 39.

    Thomson P. et al. Studies on the mechanism of divergent actions of a new

    antihypertensive compound during acute and chronic administration to man. Clin Res 1969;i7: 104.

40. 40. Todesco 5, Huber W, Romagnoli GF, Gambari PF, Guardini R, Borsatti A. Effects of clonidine therapy on exchangeable sodium and renal hemodynamics in essential hyptertension. Arzneimittelforschung 1974; 24:348-351. (74-0191).
41. 41. Toubes DB, et al. Hypotensive effects of clonidine and chlorthalidone: Controlled clinical trial of drugs administered singly and in combination. Am Heart J 1971 ;82(3):312-18.
42. 42. Wing LMH, Reid JL, Davies DS, Neill EAM, Tippett P, Dollery CT. Pharmacokinetic and concentration-effect relationships of clonidine in essential hypertension. Eur J Clin Pharmacol 1977;12:463-469.
43. 43. Yeh BK, et al. Antihypertensive effect of clonidine: Its use alone and in combination with hydrochlorthiazide and guanethidine in the treatment of hypertension. Arch Intern Med 1971; 127:233-37.
44. 44.

    Lowenthal DT. Pharmacokinetics of Clonidine. J Cardiovasc Pharmacol 1980;2:S29-

    S37.

45. 45.

    Frisk-Holmberg M. Effect of clonidine at steady state on blood pressure in

    spontaneously hypertensive rats. Interaction of various alpha-adrenoceptor anatagonists. Acta Physiol Scand 1984, 120: 37-42.

46. 46. Andrejak M, Fournier A, Coevoet B, et al. Suppression de l’effet antihypertenseur de la clonidine par la prise simultanée d’un antidépresseur tricyclique. Probléme pratique du traitement d’un hypertendu déprimé. Nouv Presse Med 1977;6:2603.
47. 47. Lacomblez L, Warot D, Bouche P, et al. Suppression de l’effet antihypertenseur de la clonidine par la clomipramine. Rev Med Interne 1988;9:291-293.
48. 48.

    Briant RH, Reid JL, Dollery CT. Interaction between clonidine and desipramine in man.

    Br Med J 1973;1:522-523.

49. 49.

    49. Hui KK. Hypertensive crisis induced by interaction of clonidine with imipramine.

    Geriatr Soc 1983;31(3):164-165.

50. 50. Fruncillo RJ, Gibons WJ, Vlasses PH et al. Severe hypotension associated with concurrent clonidine and antipsychotic medication. Am J Psychiatry 1985;142:274.
51. 51. Radack KL, Deck CC, Bloomfield SS. Ibuprofen interferes with the efficacy of antihypertensive drugs: A randomized double-blind placebo-controlled trial of ibuprofen compared with acetaminophen. Ann Int Med 1987, 107:628-635.
52. 52. Popper CW. Combining methylphenidate and clonidine: pharmacologic questions and news reports about sudden death. J Child Adolesc Psychopharmacol 5 (3), 157 – 166 (1995).
53. 53.

    Catapres® Product Monograph by Boehringer Ingelheim (Canada) Ltd. Control Number

    154435. Date of Revision: June 21, 2012.

54. 54.

    Teva Canada Limited. Product Monograph: ^Pr TEVA-CLONIDINE. Control No:

    171843. Date of Revision: April 25, 2014.