Contents

Clonidine HCl

Indication

Clonidine HCl (CATAPRES) is indicated in the treatment of hypertension. Clonidine HCl (CATAPRES) may be employed alone or concomitantly with other antihypertensive agents.For the treatment of hypertensive crisis, slow parenteral administration is especially suitable due to rapid onset of action.

Dosage / Direction For Use

Treatment of hypertension requires regular medical supervision.The dose of Clonidine HCl (CATAPRES) must be adjusted according to the patient’s individual blood pressure response.Tablets: As an initial daily dose in mild to moderate forms of hypertension, 75 mcg (or 100 mcg) to 150 mcg (or 200 mcg) twice daily are sufficient in most cases.After a period of 2-4 weeks the dose may be increased if necessary until the desired response is achieved.Usually doses above 600 mcg per day do not result in a further marked drop in blood pressure.In severe hypertension it might be necessary to increase the single dose further to 300 mcg; this could be repeated up to three times daily (900 mcg).Ampoules: Subcutaneous or i.m. injection of an ampoule containing 150 mcg Clonidine HCl (CATAPRES) should only be carried out in patients in a lying position.A dosage of 0.2 mcg/kg/minute is recommended for i.v. infusion. The rate of infusion should not exceed 0.5 mcg/kg/minute to avoid transient blood pressure increase. No more than 150 mcg should be used per infusion.If necessary, ampoules can be administered parenterally up to four times daily.This medicinal product contains less than 1 mmol sodium (23 mg) per ampoule, i.e. essentially ‘sodium-free’.Renal Insufficiency: Dosage must be adjusted: according to the individual antihypertensive response which can show high variability in patients with renal insufficiency; according to the degree of renal impairment.Careful monitoring is required. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

Overdosage

Symptoms: Clonidine has a wide therapeutic range. Manifestations of intoxication are due to generalised sympathetic depression and include pupillary constriction, lethargy, bradycardia, hypotension, hypothermia, somnolence including coma, respiratory depression including apnea. Paradoxic hypertension caused by stimulation of peripheral alpha1-receptors may occur.Treatment: Careful monitoring and symptomatic measures.

Administration

May be taken with or without food.

Contraindication

Clonidine HCl (CATAPRES) should not be used in patients with known hypersensitivity to the active ingredient or other components of the product, and in patients with severe bradyarrhythmia resulting from either sick sinus syndrome or AV block of 2nd or 3rd degree.In case of rare hereditary conditions that may be incompatible with an excipient of the product (please refer to Precautions) the use of the product is contraindicated.

Special Precaution

Clonidine HCl (CATAPRES) should be used with caution in patients with mild to moderate bradyarrhythmia such as low sinus rhythm, with disorders of cerebral or peripheral perfusion, depression, polyneuropathy and constipation.In hypertension caused by phaeochromocytoma no therapeutic effect of Clonidine HCl (CATAPRES) can be expected.Clonidine, the active ingredient of CATAPRES, and its metabolites are extensively excreted with the urine. Renal insufficiency requires particularly careful adjustment of dosage (see Dosage & Administration).As with other antihypertensive drugs, treatment with Clonidine HCl (CATAPRES) should be monitored particularly carefully in patients with heart failure or severe coronary heart disease.Patients should be instructed not to discontinue therapy without consulting their physician. Following sudden discontinuation of Clonidine HCl (CATAPRES) 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 Clonidine HCl (CATAPRES), the physician should reduce the dose gradually over 2-4 days.An excessive rise in blood pressure following discontinuation of Clonidine HCl (CATAPRES) therapy can be reversed by intravenous phentolamine or tolazoline (see Interactions).If long-term treatment with a beta-receptor blocker has to be interrupted, then the beta-receptor blocker should first be phased out gradually and then clonidine.Patients who wear contact lenses should be warned that treatment with Clonidine HCl (CATAPRES) may cause decreased lacrimation.The use and safety of clonidine in children and adolescents has little supporting evidence in randomized controlled trials and therefore can not be recommended for use in this population.In particular, when clonidine is used off-label concomitantly with methylphenidate in children with ADHS, serious adverse reactions, including death, have been observed. Therefore, clonidine in this combination is not recommended.Tablets 75 mcg or 150 mcg: This product contains 205.5 mg of Lactose per maximum recommended daily dose. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia should not take this medicine.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, sedation and accommodation disorder during treatment with Clonidine HCl (CATAPRES). Therefore, caution should be recommended when driving a car or operating machinery. If patients experience the previously mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

Adverse Reactions

Gynaecomastia; confusional state, delusional perception, depression, hallucination, decreased libido, nightmare, sleep disorder; dizziness, headache, paresthesia, sedation; accomodation disorder, decreased lacrimation; AV block, bradyarrhythmia, sinus bradycardia; orthostatic hypotension, Raynaud’s phenomenon; nasal dryness; colonic pseudo-obstruction, constipation, dry mouth, nausea, salivary gland pain, vomiting; alopecia, pruritus, rash, urticaria; erectile dysfunction; fatigue, malaise; blood glucose increase.

Drug Interaction

he reduction in blood pressure induced by clonidine can be further potentiated by concurrent administration of other hypotensive agents. This can be of therapeutic use in the case of other antihypertensive agents such as diuretics, vasodilators, beta-receptor blockers, calcium antagonist and ACE-inhibitors, but not alpha1-blocking agents.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.Substances with alpha2-receptor blocking properties such as phentolamine or tolazoline may abolish the alpha2-receptor mediated effects of clonidine in a dose-dependent manner.Concomitant administration of substances with a negative chronotropic or dromotropic effect such as beta-receptor blockers or digitalis glycosides can cause or potentiate bradycardic rhythm disturbances.It cannot be ruled out that concomitant administration of a beta-receptor blocker will cause or potentiate peripheral vascular disorders.The antihypertensive effect of clonidine may be reduced or abolished and orthostatic regulation disturbances may be provoked or aggravated by concomitant administration of tricyclic antidepressants or neuroleptics with alpha-receptor blocking properties.Based on observations in patients in a state of alcoholic delirium it has been suggested that high intravenous doses of clonidine may increase the arrhythmogenic potential (QT-prolongation, ventricular fibrillation) of high intravenous doses of haloperidol.Causal relationship and relevance for antihypertensive treatment have not been established.The effects of centrally depressant substances or alcohol can be potentiated by clonidine.

Storage

Store at temperatures not exceeding 30°C.

Description

1 tablet contains 75 or 150 mcg.1 ampoule of 1 mL contains 150 mcg.2,6-dichloro-N-2-imidazolidinylidenebenzenamine hydrochloride (=clonidine hydrochloride).Excipients: Tablets: Lactose monohydrate, calcium hydrogen phosphate anhydrous, maize starch dried, silica colloidal anhydrous, povidone, starch soluble, stearic acid.Ampoules: Sodium chloride, hydrochloric acid.

Action

Pharmacology: Clonidine acts primarily on the central nervous system, resulting in reduced sympathetic outflow and a decrease in peripheral resistance, renal vascular resistance, heart rate and blood pressure. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact and therefore orthostatic symptoms are mild and infrequent.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.Pharmacokinetics: Absorption and distribution: The pharmacokinetics of clonidine is dose-proportional in the range of 75-300 mcg. Clonidine, the active ingredient of CATAPRES, is well absorbed and undergoes a minor first pass effect.Peak plasma concentrations are reached within 1-3 h after oral administration. The plasma protein binding is 30-40 %.Clonidine is rapidly and extensively distributed into tissues, and crosses the blood-brain-barrier as well as the placental barrier. Clonidine is excreted in human milk. However, there is insufficient information on the effect on newborns.Metabolism and elimination: The terminal elimination half-life of clonidine has been found to range from 5 to 25.5 hours. It can be prolonged in patients with severely impaired renal function up to 41 hours.About 70% of the dose administered is excreted with the urine mainly in form of the unchanged parent drug (40-60 % of the dose). The main metabolite p-hydroxy-clonidine is pharmacologically inactive. Approximately 20% of the total amount is excreted with the faeces.The pharmacokinetics of clonidine is not influenced by food nor by the race of the patient.The antihypertensive effect is reached at plasma concentrations between about 0.2 and 2.0 ng/mL in patients with normal renal function.The hypotensive effect is attenuated or decreases with plasma concentrations above 2.0 ng/mL.Toxicology: Single dose toxicity studies were performed with clonidine in different animal species by oral and parenteral routes of administration. The approximative oral LD50 values were 70 mg/kg (mouse), 190 mg/kg (rat), > 15 mg/kg (dog), and 150 mg/kg in monkeys. Following subcutaneous injection, the LD50 values were > 3 mg/kg in dogs, 153 mg/kg in rats. After intravenous administration the lethal dose ranges were between 6 mg/kg (dog) and < 21 mg/kg (rat).Toxic trans-species signs of toxicity following exposure to clonidine were exophthalmus, ataxia and tremor, independently from the route of administration. At lethal doses, tonic-clonic convulsions occurred. In addition, excitement and aggressiveness alternating with sedation (mouse, rat, dog), salivation and tachypnea (dog) as well as hypothermia and apathy (monkey) were observed.In repeated oral dose toxicity studies up to 18 months clonidine was well tolerated at 0.1 mg/kg (rat), 0.03 mg/kg (dog) and 1.5 mg/kg (monkey). In a 13 week study in rats, the no adverse effect level (NOAEL) was 0.05 mg/kg following subcutaneous administration. After intravenous administration rabbits and dogs tolerated 0.01 mg/kg/day for 5 and 4 weeks, respectively. Higher dosages caused hyperactivity, aggression, reduced food consumption and body weight gain (rat), sedation (rabbit) or an increase in heart and liver weight accompanied by elevated serum GPT, alkaline phosphatase and alpha-globulin levels and focal liver necroses (dog).There were no signs of any teratogenic potential after oral administration in mouse and rat at 2.0 mg/kg and rabbit at 0.09 mg/kg or after s.c. (0.015 mg/kg, rat) and i.v. treatment (0.15 mg/kg, rabbit). In rats, increases in resorption rate were observed at oral dosage of > 0.015 mg/kg/day; however dependent on duration of dosing. Fertility in rats was not impaired up to 0.15 mg/kg. Doses up to 0.075 mg/kg did not affect the peri- and postnatal development of the progeny.There was no mutagenic potential in Ames and micronucleus assay in mice. Clonidine was not tumorigenic in a carcinogenicity assay in rats.No local irritating or sensitizing potential was found in guinea pigs and rabbits following i.v. and i.a. administrations.