Vascular Stabilizer for the Treatment of Menopausal Flushing
Action And Clinical Pharmacology: Clonidine reduces the response of peripheral vessels to either vasoconstrictor or vasodilator stimuli. Clonidine, the active ingredient, is an a-adrenergic agonist which also has some a-adrenergic antagonist effects.
Clonidine 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.
Clonidine will not correct or relieve other menopausal changes that are due to hormonal deficiencies.
Clonidine stimulates a-adrenoreceptors in the brain stem, resulting in reduced sympathetic outflow from the CNS and a decrease in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. Renal blood flow and glomerular filtration rate remain essentially unchanged.
Pharmacokinetics: Clonidine acts relatively rapidly. The patient’s blood pressure declines within 30 to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4 hours. The plasma level of clonidine peaks in approximately 3 to 5 hours and the plasma half-life from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Following oral administration about 40 to 60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver.
Acute studies with clonidine in humans have demonstrated a moderate reduction (15 to 20%) of cardiac output in the supine position with no change in the peripheral resistance, at a 45Â° 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.
Indications And Clinical Uses: The relief of menopausal flushing in patients for whom hormonal replacement therapy is either unnecessary or not desirable.
Contra-Indications: Hypersensitivity to clonidine or to any of the tablet excipients; patients with sinus node function impairment.
Manufacturers’ Warnings In Clinical States: Clonidine can have a hypotensive effect especially in high doses. In patients whose blood pressure decreases to an intolerable extent when taking clonidine, treatment should be discontinued.
It has been demonstrated that an excessive rise in blood pressure, should it occur on discontinuation of clonidine, can be reversed by resumption of clonidine therapy or by i.v. phentolamine.
An abrupt withdrawal of higher doses of clonidine is followed in some cases by an excess of circulating catecholamines. Therefore, caution should be excercised in concomitant use of drugs which affect the metabolism, tissue uptake or pressor effects of these amines (MAO inhibitors, tricyclic antidepressants and beta-blocking agents).
Precautions: General: Dixarit should not be confused with Catapres. 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.
Because it can lower blood pressure at high doses, clonidine should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebral vascular disease, or chronic renal failure.
Depending on the dose given, clonidine can lower the heart and pulse rate. In patients with diseases affecting the rhythmic and AV conduction system of the heart, arrhythmias have been observed after high doses.
Occupational Hazards: Patients who engage in potentially hazardous activities such as operating machinery or driving should be warned of the possible sedative effect of clonidine. Caution should be exercised in the concomitant administration of sedatives, tranquilizing drugs or alcohol.
Patients with a known history of depression should be carefully supervised while under treatment with clonidine as there have been occasional reports of further depressive episodes occurring in such patients.
In several studies clonidine produced a dose-dependent increase in the incidence and severity of spontaneously occurring retinal degeneration in albino rats treated for 6 months or longer. In view of this retinal degeneration, eye examinations were performed in 908 hypertensive patients prior to the start of clonidine therapy, who were then examined periodically thereafter. In 353 of these 908 patients, examinations were performed for periods of 24 months or longer. Except for the dryness of the eyes, no drug-related abnormal ophthalmologic findings were recorded and clonidine did not alter retinal function as shown by specialized tests such as the electroretinogram and macular dazzle.
As with any drug excreted primarily in the urine, smaller doses of the drug are often effective in treating patients with a degree of renal failure. In patients exhibiting renal failure, periodic determination of the BUN is indicated. If, in the physician’s opinion, a rising BUN is significant, the drug should be stopped.
A few instances of a condition resembling Raynaud’s phenomenon have been reported 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 clonidine.
Pregnancy: When rats were given clonidine 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 in pregnancy is not recommended.
Lactation: Since clonidine is distributed into breast milk, the drug should be used with caution in nursing women.
Children: Safety and effectiveness in children has not been established.
Drug Interactions: The doses of clonidine 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.
Concomitant use of b-receptor blockers and/or cardiac glycosides can further lower heart rate (bradycardia) or cause dysrhythmia (AV block) in isolated cases.
Withdrawal of higher doses of clonidine may result in an excess of circulating catecholamines (see Warnings). Therefore, caution should be exercised in concomitant use of drugs which affect the metabolism, tissue uptake or pressor effects of these amines (MAO inhibitors, tricyclic antidepressants and beta-blocking agents, respectively).
If combined treatment with a b-blocker necessitates the interim interruption of antihypertensive therapy or even total discontinuation, the b-blocker must always be discontinued slowly first, reducing the dose gradually to avoid sympathetic hyperactivity. Clonidine must then be reduced gradually over several days if previously given in high dosages.
If clonidine and tricyclic antidepressants are administered as concurrent therapy, the effect of clonidine may be reduced, thus necessitating an increase in the dosage of clonidine. Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats.
Clonidine may enhance the CNS-depressive effects of alcohol, barbiturates and other sedatives.
Depending upon the dose administered, tolazoline can reduce or neutralize the effect of clonidine, and therefore, is suitable as an antidote.
Adverse Reactions: Clonidine is generally well tolerated. In controlled clinical studies, sedation and other CNS side effects were comparable to those occurring during the placebo period. Dry mouth was encountered in a low proportion of patients treated with the drug. Both dry mouth and fatigue occur particularly during the initial phase of treatment and may be expected to diminish as treatment continues. Muscle or joint pain and cramps of the lower limbs have also been reported during treatment with clonidine. The side effects of treatment with clonidine are to a high degree dose dependent.
When high doses of clonidine were used in treatment of hypertension, the most common reactions observed are dry mouth, drowsiness, dizziness, constipation and sedation. These effects generally tend to diminish with continuation of therapy.
There have been isolated reports of continual dry mouth leading to an accelerated rate of dental caries, in patients receiving higher doses of clonidine.
Symptoms And Treatment Of Overdose: Symptoms: The signs and symptoms of clonidine overdosage include hypotension, bradycardia, lethargy, irritability, weakness, somnolence, diminished or absent reflexes, miosis, vomiting and hypoventilation. With large overdoses, reversible cardiac conduction defects or arrhythmias, apnea, seizures and transient hypertension have been reported. The oral LD50 of clonidine in rats was 465 mg/kg, and in mice 206 mg/kg.
In a patient who ingested 100 mg clonidine, plasma clonidine levels were 60 ng/mL (1 hour), 190 ng/mL (1.5 hours), 370 ng/mL (2 hours) and 120 ng/mL (5.5 and 6.5 hours). This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment.
Treatment: Clonidine overdosage usually responds to symptomatic treatment with careful cardiovascular monitoring. Gastric lavage is only worthwhile if it is guaranteed that part of the dose taken, which has not yet been absorbed, can be removed. Routine hemodialysis is of limited benefit since a maximum of 5% of circulating clonidine is removed.
I.V. tolazoline (an a-antagonist) and naloxone have each been used as antidotes to clonidine poisoning, with inconsistent results. If other efforts fail, these agents may provide some benefit in reversing the effects of clonidine.
Dosage And Administration: The recommended dose for the treatment of menopausal flushing is 0.05 mg twice daily. If after 2 to 4 weeks there has been no remission the treatment should be discontinued and the patient reassessed.
Attempts should be made to discontinue treatment at 3- to 6-month intervals for patient re-evaluation of menopausal symptoms.
Availability And Storage: 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. Energy: 1.01 kJ (0.24 kcal). Bottles of 100. Store at controlled room temperature (15 to 30°C).
DIXARIT® Boehringer Ingelheim Clonidine HCl Vascular Stabilizer for the Treatment of Menopausal Flushing