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Information on MINT-CLONIDINE (clonidine hydrochloride), its indications, clinical use, adverse effects, and drug interactions. It is essential for healthcare professionals and students studying pharmacology and therapeutics. the use of clonidine hydrochloride for hypertension, its cautions and warnings, and potential drug interactions.
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Pr
Clonidine Hydrochloride Tablets, USP
0.1 mg and 0.2 mg
Antihypertensive
Mint Pharmaceuticals Inc. 1093 Meyerside Drive, Unit # Mississauga, Ontario L5T 1J
Date of Preparation: March 8, 2017
Submission Control No: 184607
galactose intolerance e.g. galactosaemia. MINT-CLONIDINE tablets contain approximately 210 mg of lactose per maximum recommended daily dose (0.6 mg) and thus should not be used by patients with this condition.
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 MINT-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. 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 MINT-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, MINT-CLONIDINE (clonidine hydrochloride) should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease or chronic renal failure.
MINT-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, MINT-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.
MINT-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 MINT-CLONIDINE should receive periodic eye examinations.
Patients who wear contact lenses should be warned that treatment with MINT-CLONIDINE may cause decreased lacrimation (see ADVERSE REACTIONS: Eye disorder).
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 MINT-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 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
System Organ Class (SOC) Preferred MedDRA Term clonidine hydrochloride n = 640 % Psychiatric disorders Depression 1 Sleep disorder 5 Nervous system disorder Dizziness 15 Headache 1 Sedation 50 Vascular disorders Orthostatic hypotension 19. Gastrointestinal disorders Constipation 4 Dry mouth 44 Nausea 1. Salivary gland pain 2 Vomiting 1. Reproductive system and breast disorders
Erectile dysfunction 4
General disorders Fatigue 1
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
Proper name References Effect Clinical comment Tricyclic antidepressants or neuroleptics with alpha-receptor blocking properties
Briant RH et al, 1973 (48) Hui KK et al, 1983 (49) Fruncillo RJ et al, 1985 (50)
(See REFERENCES)
The antihypertensive effect of clonidine may be reduced or abolished and orthostatic regulation disturbances may be provoked or aggravated by concomitant administration. Amitriptyline in combination with clonidine hydrochloride enhances the manifestation of corneal lesions in rats (see PART II: TOXICOLOGY).
If clonidine hydrochloride and tricyclic antidepressants are administered as concurrent therapy, an increase in the dosage of clonidine hydrochloride may be necessary.
Substances with alpha 2 receptor blocking properties such as phentolamine
May abolish the alpha 2 - receptor mediated effects of clonidine in a dose- dependent manner. Appetite suppressants (with the exception of fenfluramine)
Concurrent use with 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.
Alcohol, barbiturates or other sedatives.
Clonidine hydrochloride may enhance the CNS- depressive effects Drugs which affect the metabolism, tissue uptake
Withdrawal of clonidine hydrochloride may result
Caution should be exercised in
Proper name References Effect Clinical comment or pressor effects of these amines (monoamine oxidase (MAO) inhibitors, tricyclic antidepressants and beta blocking agents, respectively).
in an excess of circulating catecholamines (see WARNINGS AND PRECAUTIONS).
concomitant use of these drugs.
Methylphenidate Popper CW, 1995 (52)
(See REFERENCES)
The concomitant use with clonidine has resulted in serious adverse reactions, including death, in children with attention- deficit/hyperactivity (ADHD).
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.
Dosing Considerations
Treatment of hypertension requires regular medical supervision.
The dose of MINT-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.
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.
Mechanism of Action
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 α 2 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.
For management of a suspected drug overdose, contact your regional Poison Control Centre immediately.
Pharmacokinetics
Absorption: The plasma level of clonidine hydrochloride peaks in approximately 1 to 3 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 μg.
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.
Drug Substance
Proper name: clonidine hydrochloride
Chemical name: 2-[(2,6-dichlorophenyl)imino]imidazolidinemonohydrochloride
Molecular formula and molecular mass: C 9 H 9 Cl 2 N 3 ·HCl, 266.55 g/mol
Structural formula:
Physicochemical properties: A white to almost white powder. It is soluble in water and alcohol, practically insoluble in acetone and ethyl acetate. The pH lies between 3.5 and 5.5 (50 mg/mL in water).
Comparative Bioavailability Studies
A Single-Dose, Double-Blinded, Crossover, Comparative Bioavailability Study of Clonidine Hydrochloride 1 x 0.2 mg Tablets (Mint Pharmaceuticals Inc.) and Novo-Clonidine 1 x 0.2 mg Tablets (Teva Canada Limited) in 18 Healthy Male and Female Volunteers under Fasting Conditions. The results are presented below.
SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA
Clonidine Hydrochloride (1 x 0.2mg) From measured data uncorrected for potency Geometric Mean Arithmetic Mean (CV %) Parameter Test*^ Reference†^ Geometric Means% Ratio of 90% Confidence Interval AUCT (ng•h/mL )
14 .4 (33.3)
100.3 97. 0 - 103.
AUCI (ng•h/mL )
4 15 .3 (36.0)
15 .2 (35.8)
100.6 97.0 - 104.
Cmax (ng/mL)
0.9 (20.5)
1.0 (20.4)
Tmax§ (h)
2.0 (0. 8 - 4.0) 1.3 (0. 8 - 5.0)
T½^ € (h)
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 μg% of clonidine) can be detected one hour after oral administration of a single dose of 390 μg. 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
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 10μg/kg/day for 4 weeks or 20 μg/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 epinephrine, 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 μg/kg of clonidine, either before or after ganglion blockade as well as after seven days of intramuscular administration of 20 μg/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
