Drug Interactions
The doses of DIXARIT used during clinical trials in menopausal flushing, 0.05 mg b.i.d., did not produce significant changes in blood pressure. Caution should, however, be exercised in patients receiving antihypertensive therapy because of the possibility of an additive effect. The reduction in blood pressure induced by clonidine can be further potentiated by concurrent administration of agents such as diuretics, vasodilators, beta-receptor blockers, calcium antagonists and ACE-inhibitors.
Concomitant use of β-receptor 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.
Orthostatic regulation disturbances may be provoked or aggravated by concomitant administration of tricyclic antidepressants or neuroleptics with alpha-receptor blocking properties.
Withdrawal of higher doses 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 inhibitors, tricyclic antidepressants and beta blocking agents, respectively).
If combined treatment with a β-blocker necessitates the interim interruption of antihypertensive therapy or even total discontinuation, the β-blocker must always be discontinued slowly first, reducing the dose gradually to avoid sympathetic hyperactivity. DIXARIT must then be reduced gradually over several days if previously given in high dosages.
If clonidine hydrochloride and tricyclic antidepressants are administered as concurrent therapy, the effect of clonidine hydrochloride may be reduced, thus necessitating an increase in the dosage of DIXARIT. Amitriptyline in combination with clonidine hydrochloride enhances the manifestation of corneal lesions in rats.
Clonidine hydrochloride may enhance the CNS-depressive effects of alcohol, barbiturates or other sedatives.
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.
Information for the Patient
Dixarit
Dosage and Administration
The recommended dose for the treatment of menopausal flushing is 0.05 mg of DIXARIT (clonidine hydrochloride) twice daily. If after two to four weeks there has been no remission, the treatment should be discontinued and the patient reassessed.
Attempts should be made to discontinue treatment at three to six month intervals for patient re-evaluation of menopausal symptoms.
The tablets should be swallowed whole with water.
If a dose of DIXARIT is missed, patients should take the dose as soon as possible and then return to their normal schedule.
Adverse Reactions
Most adverse reactions associated with the use of DIXARIT (clonidine hydrochloride) are mild and diminish with continued therapy.
Accumulated clinical and postmarketing data indicate that the most frequently occurring adverse reactions are dryness of mouth, sedation and reduction of blood pressure.
Occasionally, constipation, nausea and vomiting, headache, malaise, impotence, decreased libido, gynaecomastia, orthostatic symptoms, paresthesia of the extremities, Raynauds's phenomenon, pain in the parotid gland, dryness of the nasal mucosa and reduced lacrymal flow (caution: contact lens wearers) as well as skin reactions with symptoms such as rash, urticaria, pruritus, and alopecia have been observed.
In rare instances, sleep disturbances, nightmares, depression, perceptual disorders, hallucinations, confusion, disturbances of accommodation and transient elevations of blood sugar have been reported.
In very rare cases, pseudo-obstruction of the large bowel has been observed in predisposed patients.
Clonidine may cause or potentiate bradyarrhythmic conditions such as sinus bradycardia or atrioventricular-block.
Adverse events reported during treatment with DIXARIT include, fatigue, muscle or joint pain and cramps, drowsiness and dizziness. In addition, there have been isolated reports of accelerated rate of dental caries due to continual dry mouth, in patients receiving higher doses of clonidine hydrochloride.
Indications and Clinical Use
Safety and effectiveness in children has not been established.
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
The signs and symptoms of clonidine hydrochloride overdosage are due to generalised sympathetic depression and include pupillary constriction, hypotension, hypothermia, bradycardia, lethargy, irritability, weakness, somnolence, diminished or absent reflexes, vomiting and hypoventilation. With large overdoses, reversible cardiac conduction defects or arrhythmias, coma, apnea, 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, apnea, 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 ingestion 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 antidote to clonidine poisoning, with inconsistent results. If other efforts fail, these agents may provide some benefit in reversing the effects of clonidine.
Dosage Forms, Composition and Packaging
Each blue, sugar-coated, round, biconvex tablet contains: 0.025 mg of clonidine HCl. Nonmedicinal ingredients: Tablet core: CaHPO4, colloidal silica, FD&C Blue #2, lactose (fine), magnesium stearate, maize starch, polyvinylpyrrolidone and soluble starch. Sugar coating: carnauba wax, FD&C Blue #2, gum arabic, polyethylene glycol 6000, polyvinylpyrrolidone, sucrose, talc, titanium dioxide and white wax. Bottles of 100.
Warnings and Precautions
Clonidine and its metabolites are extensively excreted with urine. As a result, DIXARIT should be used with caution in patients with renal insufficiency. 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.
DIXARIT (clonidine hydrochloride) can have a hypotensive effect especially in high doses. In patients whose blood pressure decreases to an intolerable extent when taking DIXARIT, treatment should be discontinued.
It has been demonstrated that an excessive rise in blood pressure, should it occur on discontinuation of DIXARIT, can be reversed by resumption of clonidine hydrochloride therapy or by intravenous phentolamine.
An abrupt withdrawal of higher doses of clonidine hydrochloride is followed in some cases by an excess of circulating catecholamines. Therefore, caution should be exercised in concomitant use of drugs which affect the metabolism, tissue uptake or pressor effects of these amines (monoamine oxidase inhibitors, tricyclic antidepressants and beta-blocking agents).
DIXARIT (clonidine hydrochloride 0.025 mg) should not be confused with Catapres (clonidine hydrochloride 0.1 mg, 0.2 mg). Catapres is a higher dosage form of the same active ingredient, clonidine hydrochloride, and is used for treating hypertension. Catapres is available as white tablets of 0.1 mg and orange tablets containing 0.2 mg of clonidine. Caution should however be exercised in patients receiving antihypertensive therapy because of the possibility of an additive effect.
Patients who engage in potentially hazardous activities such as operating machinery or driving should be warned of the possible sedative effect of clonidine hydrochloride. Caution should be exercised in the concomitant administration of sedatives, tranquilizing drugs or alcohol.
Patients should be instructed not to discontinue therapy without consulting their physician. Following sudden discontinuation of DIXARIT after prolonged treatment with high doses, restlessness, palpitations, rapid rise in blood pressure, nervousness, tremor, headache or nausea have been reported. When discontinuing therapy with DIXARIT, the physician should reduce the dose gradually over 2-4 days.
A few instances of a condition resembling Raynaud's phenomenon have been reported with the higher doses of clonidine as used in the therapy of hypertension. Caution should be observed if patients with Raynaud's disease or thromboangiitis obliterans are to be treated with DIXARIT.
Safety and effectiveness in children has 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 hypertensive 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.
When rats were given clonidine hydrochloride alone in doses as low as one-third the maximum recommended daily human dose, some embryotoxicity was evident. There are, however, no adequate and well-controlled studies in pregnant women. Thus, use of clonidine hydrochloride in pregnancy is not recommended.
The use of DIXARIT during lactation is not recommended due to a lack of supporting information.
Because it can lower blood pressure at high doses, DIXARIT (clonidine hydrochloride) should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebral vascular disease, or chronic renal failure. DIXARIT 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, patients with heart failure or severe coronary heart disease.
Depending on the dose given, DIXARIT can lower the heart and pulse rate. In patients with diseases affecting the rhythmic and atrioventricular conduction system of the heart, arrhythmias have been observed after high doses.
DIXARIT should be monitored particularly carefully in patients with heart failure or severe coronary disease.
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.
Storage and Stability
The DIXARIT tablets should be stored at room temperature (15-30°C).
Action and Clinical Pharmacology
DIXARIT (clonidine hydrochloride) reduces the response of peripheral vessels to either vasoconstrictor or vasodilator stimuli. Clonidine hydrochloride, the active ingredient, is an α-adrenergic agonist which also has some α-adrenergic antagonist effects.
DIXARIT therapy has been shown to reduce the frequency, severity, and duration of flushing attacks associated with the menopausal syndrome. There is a gradual onset of therapeutic response, and a gradual return of symptoms on interruption of treatment.
DIXARIT will not correct or relieve other menopausal changes that are due to hormonal deficiencies.
Clonidine stimulates alpha-adrenoreceptors in the brain stem, resulting in reduced sympathetic outflow from the central nervous system and a decrease in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. Renal blood flow and glomerular filtration rate remain essentially unchanged.
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. The plasma level of clonidine peaks in approximately 3 to 5 hours and the plasma half-life from 12-16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Following oral administration about 40-60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver.
Acute studies with clonidine hydrochloride in humans have demonstrated a moderate reduction (15%-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 in peripheral resistance. During long-term therapy, cardiac output tends to return to controlled 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.
Clonidine acutely stimulates growth hormone release in both children and adults, but does not produce a chronic elevation of growth hormone with long-term use.
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 50% bound, this reflects an actual free plasma level.
Sixty-five percent (65%) of the orally administered drug is excreted in the urine and an estimated 22% in the feces. 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.
The blood pressure reduction due to higher doses of 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.
Contraindications
DIXARIT (clonidine hydrochloride) is contraindicated in patients with known hypersensitivity to the active substance or to any of the ingredients of the product. For a complete listing, see Dosage Forms, Composition and Packaging.
DIXARIT is contraindicated in patients with severe bradyarrhythmia resulting from either sick sinus syndrome or atrioventricular block of 2nd or 3rd degree; patients with sinus node function impairment.
