4.1. Therapeutic indications

a) The prophylactic management of migraine or recurrent vascular headache

b) The management of vasomotor conditions commonly associated with the menopause and characterised by flushing.

4.2. Posology and method of administration

Posology

Adults:

Initially 5 ml (50 micrograms) twice daily. If after two weeks there has been no remission, increase to 7.5 ml (75 micrograms) twice daily.

The duration of treatment depends upon the severity of the condition.

If symptoms continue to occur the patient should be informed that it may take 2 - 4 weeks until Clonidine hydrochloride is fully effective.

Elderly:

No specific information on the use of this product in the older people is available.

Clinical trials have included patients over 65 years and no adverse reactions specific to this age group have been reported.

Paediatric population:

There is insufficient evidence for the application of clonidine in children and adolescents younger than 18 years.

Therefore, the use of clonidine is not recommended in paediatric subjects under 18 years.

Patients with renal impairment:

Clonidine hydrochloride should be used with caution in patients with renal insufficiency. Careful monitoring of blood pressure is required.

Method of administration

For oral administration.

4.3. Contraindications

Clonidine hydrochloride should not be used in patients with severe bradyarrhythmia resulting from either sick-sinus syndrome or AV block of 2nd or 3rd degree, or in patients with known hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Clonidine hydrochloride should be used with caution in patients with cerebrovascular disease, coronary insufficiency, heart failure, occlusive peripheral vascular disorders such as Raynaud's disease, polyneuropathy, constipation or those with a history of depression.

At doses higher than those recommended above, clonidine is an effective antihypertensive agent. Caution should therefore be observed where antihypertensive agents are being used, as potentiation of the hypotensive effect may occur. Provided the recommended Clonidine hydrochloride dosage regimen is followed, no difficulty with hypotension should arise during the routine management of patients with either migraine or menopausal flushing.

Depending on the dose given, Clonidine hydrochloride can cause bradycardia. In patients with pre-existing cardiac conduction abnormalities, arrhythmias have been observed after high doses of Clonidine hydrochloride.

Patients with renal failure require extreme care (see section 4.2).

Patients should be instructed not to discontinue therapy without consulting their physician. Following sudden discontinuation of Clonidine hydrochloride after prolonged treatment with high doses, agitation, restlessness, palpitations, rapid rise in blood pressure, nervousness, tremor, headache or nausea have been reported. When discontinuing therapy with Clonidine hydrochloride, the physician should reduce the dose gradually over 2-4 days.

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

The use and the safety of clonidine in children and adolescents under 18 years have insufficient 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.

Excipients warnings

Benzoic acid: This medicine contains 3 mg benzoic acid in 5 ml oral solution.

Increase in bilirubinaemia following its displacement from albumin may increase neonatal jaundice which may develop into kernicterus (non-conjugated bilirubin deposits in the brain tissue).

4.5. Interaction with other medicinal products and other forms of interaction

Concurrent administration of antihypertensive agents, vasodilators or diuretics may lead to an increased hypotensive effect.

Substances with alpha2-receptor blocking properties, such as mirtazapine, may abolish the alpha2- receptor mediated effects of clonidine in a dose-dependent manner.

Concomitant use of beta-blockers and/or cardiac glycosides can cause bradycardia or dysrhythmia (AV-block) in isolated cases.

It cannot be ruled out that concomitant administration of a beta-receptor blocker will cause or potentiate peripheral vascular disorders.

If during combined treatment with a beta-blocker there is need to interrupt or discontinue antihypertensive therapy, the beta-blocker must always be discontinued slowly first (reducing the dose gradually to avoid sympathetic hyperactivity) and then the clonidine, which should also be reduced gradually over several days if previously given in high doses.

Orthostatic hypotension may be provoked or aggravated by concomitant administration of tricyclic antidepressants or neuroleptics with alpha-receptor blocking properties.

As the effects of clonidine can be antagonised by tricyclic anti-depressants, it may be necessary to adjust the dosage of Clonidine hydrochloride, if these agents are administered concurrently.

Although there is no experience from clinical trials, the effect of tranquillisers, hypnotics or alcohol could theoretically be potentiated by Clonidine hydrochloride.

4.6. Fertility, pregnancy and lactation

Pregnancy:

There are limited amount of data from the use of clonidine in pregnant women. As with all medicines, Clonidine hydrochloride should not be used in pregnancy, especially the first trimester, unless the expected benefit is thought to outweigh any possible risk to the foetus.

Careful monitoring of mother and child is recommended.

Clonidine passes the placental barrier and may lower the heart rate of the foetus. Postpartum a transient rise in blood pressure in the newborn cannot be excluded.

There is no adequate experience regarding the long term effects of prenatal exposure.

Non-clinical studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Breast-feeding:

Clonidine is excreted in human milk. However, there is insufficient information on the effect on newborns. The use of clonidine is therefore not recommended during breast feeding.

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.

4.7. 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. If patients experience the above-mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8. Undesirable effects

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:

Very common

≥ 1/10

Common

≥ 1/100 to <1/10

Uncommon

≥ 1/1,000 to <1/100

Rare

≥ 1/10,000 to <1/1,000

Very rare

<1/10,000

Not known

Cannot be estimated from the available data

System Organ Class

Frequency

Adverse events

Endocrine disorders

Rare

Gynaecomastia

Psychiatric disorders

Common

Depression, sleep disorder

Uncommon

Delusional perception, hallucination, nightmare

Not known

Confusional state, libido decreased

Nervous System disorders

Very common

Dizziness, sedation

Common

Headache

Uncommon

Paraesthesia

Eye disorder

Rare

Lacrimation decreased

Not known

Accommodation disorder

Cardiac disorders

Uncommon

Sinus bradycardia

Rare

Atrioventricular block

Not known

Bradyarrhythmia

Vascular disorders

Very common

Orthostatic hypotension

Uncommon

Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders

Rare

Nasal dryness

Gastrointestinal disorders

Very common

Dry mouth

Common

Constipation, nausea, salivary gland pain, vomiting

Rare

Colonic pseudo-obstruction

Skin and subcutaneous tissue disorders

Uncommon

Pruritus, rash, urticaria

Rare

Alopecia

Reproductive system and breast disorders

Common

Erectile dysfunction

General disorders and administration site conditions

Common

Fatigue

Uncommon

Malaise

Investigations

Rare

Blood glucose increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms:

Manifestations of intoxication are due to a generalised sympathetic depression and include pupillary constriction, somnolence including coma, hypotension, orthostatic hypotension, bradycardia, hypothermia, respiratory depression including apnoea, occasionally vomiting, very occasionally hypertension and dryness of the mouth.

Treatment:

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

Supportive care may include atropine sulfate 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.