Boehringer Ingelheim Limited

Catapres Ampoules 150 micrograms in 1 ml Solution for Injection

Each 1 ml ampoule contains clonidine hydrochloride 150 micrograms.

For a full list of excipients, see section 6.1.

Solution for injection

Clear, colourless solution.

Catapres is indicated for the treatment of hypertensive crises.

Adults, including the elderly:

In hypertensive crises 150 to 300 micrograms (1 to 2 ampoules) should be given by slow intravenous injection. This dose may be repeated up to a maximum of 750 micrograms (5 ampoules) in a 24 hour period.

Patients undergoing anaesthesia should continue their Catapres treatment before, during and after anaesthesia using oral or intravenous administration according to individual circumstances.

Intravenous injection of Catapres should be given slowly over 10 – 15 minutes to avoid a possible transient pressor effect.

Catapres injection solution is compatible with 0.9% sodium chloride solution and with 5% dextrose solution.

Children:

Not recommended. Please refer to section 4.4 Special Warnings and Precautions for Use.

Catapres should not be used in children (please refer to section 4.4 Special Warnings and Precautions for Use) or 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 2^nd or 3^rd degree.

Clonidine should only be used with caution in patients with depression or a history thereof, with Raynaud's disease, or other peripheral vascular occlusive disease. The product should only be used with caution in patients with cerebrovascular or coronary insufficiency. Catapres should be used with caution in patients with mild to moderate bradyarrhythmia such as low sinus rhythm, and with polyneuropathy or constipation.

As with other antihypertensive drugs, treatment with Catapres should be monitored particularly carefully in patients with heart failure.

In hypertension caused by phaeochromocytoma, no therapeutic effect of Catapres can be expected.

Clonidine, the active ingredient of Catapres, and its metabolites are extensively excreted with the urine. Dosage must be adjusted to the individual antihypertensive response, which can show high variability in patients with renal insufficiency; careful monitoring is required. Since only a minimal amount of clonidine is removed during routine haemodialysis, there is no need to give supplemental clonidine following dialysis.

Patients who wear contact lenses should be warned that treatment with Catapres may cause decreased lacrimation.

The use and the safety of clonidine in children and adolescents has little supporting evidence in randomized controlled trials and therefore cannot be recommended for use in this population.

Serious adverse events, including sudden death have been reported in concomitant use with methylphenidate. The safety of using methylphenidate in combination with clonidine has not been systematically evaluated.

The 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 antagonists and ACE-inhibitors, but the effect of alpha₁-blockers is unpredictable.

The antihypertensive effect of clonidine may be reduced or abolished and orthostatic hypotension may be provoked or aggravated by concomitant administration of tricyclic antidepressants or neuroleptics with alpha-receptor blocking properties.

Substances, which raise blood pressure or induce a sodium ion (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 mirtazapine, 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 disorder.

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.

This product should only be used in pregnancy if considered necessary by the physician.

Clonidine passes the placental barrier and may lower the heart rate of the foetus. Post partum a transient rise in blood pressure in the new-born cannot be excluded.

The use of Catapres during lactation is not recommended due to a lack of supporting information.

This product may cause drowsiness. Patients who are affected should not drive or operate machinery.

Most adverse effects are mild and tend to diminish with continued therapy.

Adverse events have been ranked under headings of frequency using the following convention:

Endocrine disorders:

Psychiatric disorders:

Nervous system disorders:

Eye disorders:

Cardiac disorders:

Vascular disorders:

Respiratory, thoracic and mediastinal disorders:

Gastrointestinal disorders:

Skin and subcutaneous tissue disorders:

Reproductive system and breast disorders:

General disorders and administration site conditions:

Investigations:

Fluid retention and abnormal liver function tests have been reported occasionally. Two cases of hepatitis have also been reported.

Symptoms:

Manifestations of intoxication are due to a generalised sympathetic depression and include pupillary constriction, lethargy, bradycardia, hypotension, hypothermia, somnolence including coma and respiratory depression including apnoea. Paradoxical hypertension caused by stimulation of peripheral alpha₁- receptors may occur. Transient hypertension may be seen if the total dose is over 10 mg.

Treatment:

There is no specific antidote for clonidine overdose. Administration of activated charcoal should be performed where appropriate.

Supportive care may include atropine sulphate for symptomatic bradycardia, and intravenous fluids and/or inotropic sympathomimetic agents for hypotension. Severe persistent hypertension may require correction with alpha-adrenoceptor blocking drugs.

Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression

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 haemodynamic response to exercise.

The pharmacokinetics of clonidine is dose-proportional in the range of 100-600 micrograms. Clonidine, the active ingredient of Catapres, is well absorbed and no first pass effect exists. It is rapidly and extensively distributed into tissues and crosses the blood-brain barrier as well as the placental barrier. The plasma protein binding is 30-40%.

The mean plasma half life of clonidine is about 13 hours ranging between 10 and 20 hours. The half-life does not depend on the sex or race of the patient but can be prolonged in patients with severely impaired renal function up to 41 hours.

About 70% of the dose administered is excreted in the urine mainly in the form of the unchanged parent drug (40-60%). The main metabolite p-hydroxy-clonidine is pharmacologically inactive. Approximately 20% of the total amount is excreted in the faeces.

The antihypertensive effect is reached at plasma concentrations between about 0.2 and 1.5ng/ml in patients with normal excretory function. A further rise in the plasma levels will not enhance the antihypertensive effect.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Sodium chloride

Water for injections

Hydrochloric acid

None known.

Unopened: 5 years.

Once opened, use immediately and discard any unused contents.

Do not store above 30^oC.

Keep the ampoules in the outer carton.

1 ml colourless glass (Ph. Eur. Type I) ampoules, marketed in packs of 5.

For single use only. Discard any unused contents.

Boehringer Ingelheim Ltd.

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

United Kingdom

PA 7/14/3

Date of first authorisation: 01 April 1979

Date of last renewal: 01 November 2005

November 2009