Anafranil 25mg Capsules

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Clomipramine hydrochloride
Available from:
Novartis Pharmaceuticals UK Ltd
ATC code:
N06AA; N06AA04
INN (International Name):
Clomipramine hydrochloride
Dosage:
25 milligram(s)
Pharmaceutical form:
Capsule
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Non-selective monoamine reuptake inhibitors; clomipramine
Authorization status:
Marketed
Authorization number:
PA0013/084/003
Authorization date:
1978-04-01

Package leaflet: Information for the user

ANAFRANIL

®

10mg capsules

ANAFRANIL

®

25mg capsules

ANAFRANIL

®

50mg capsules

Clomipramine hydrochloride

This medicine will be referred to as Anafranil in this leaflet.

Read all of this information carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if

their symptoms are the same as yours.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell

your doctor or pharmacist.

In this leaflet

1. What Anafranil is and what it is used for……………………………………………….......

2. What you need to know before you take

Anafranil…………………………………………………………………..

3. How to take Anafranil…………………………………………………………………........

4. Possible side effects………………………………………………………………………....

5. How to store Anafranil……………………………………………………………………...

6. Further information……………………………………………………………………….....

1

What Anafranil is and what it is used for

Anafranil contains a medicine called clomipramine hydrochloride. This belongs to a group of medicines called

“tricyclic

antidepressants”.

Anafranil

thought

work

either

increasing

amount

chemical

“messengers” in the brain or by making their effects last longer.

Anafranil is used to treat depression, obsessions and phobias (irrational fears). It is also used to treat muscular

weakness (cataplexy) associated with repeat attacks of extreme sleepiness (narcolepsy) in adults.

2

What you need to know before you take Anafranil

Do not take Anafranil if:

you are allergic (hypersensitive) to clomipramine or any of the other ingredients of Anafranil (listed in

Section 6 below)

you have ever had a rash or other allergic reaction to any other antidepressants

you have had a heart attack within the last 3 months

you have any serious heart disease

you have any serious liver disease

you have any other mental illness apart from depression, obsessions or phobias

you have glaucoma (increased eye pressure)

you have difficulty in passing urine

you are pregnant, might become pregnant or are breast-feeding

you are aged under 18

you are taking medicines for depression called monoamine oxidase inhibitors (MAOIs), or have taken

them within the last 3 weeks.

Do not take Anafranil if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist

before taking Anafranil.

Take special care with Anafranil

Check with your doctor or pharmacist before taking your medicine if:

you have epilepsy (fits)

you have an overactive thyroid gland

you have a tumour (cancer) of the adrenal gland (such as phaeochromocytoma or neuroblastoma)

you have low blood pressure

you wear contact lenses

you have had severe constipation for a long time

you find yourself thinking about suicide

you have had a head injury and suffered brain damage

you are going to have ECT (electroconvulsive therapy)

you have an irregular heart beat or other problems with your heart

you have been diagnosed as having a low level of potassium in your blood (hypokalemia)

you have schizophrenia or any other mental disorder

you are elderly

you have glaucoma(increased pressure in the eye)

you have liver or kidney disease

you have any blood disorder

you have difficulties in passing urine (e.g. due to diseases of the prostate)

you are easily faint

Information for families, and caregivers

You should monitor whether your depressed child/patient shows signs of behavioral changes such as unusually

anxiety, restlessness, sleeping problems, irritability, aggressiveness, over-excitedness or other unusual changes in

behavior, worsening of depression or thinking about suicide. You should report any such symptoms to the

patient's doctor, especially if they are severe, abrupt in onset, or were not part of the patient's presenting

symptoms before. You should evaluate the emergence of such symptoms on a day-to-day basis, especially early

during antidepressant treatment and when the dose is increased or decreased, since changes may be abrupt.

Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate

a need for very close monitoring and possibly changes in the medication.

Older people

Elderly patients generally need lower doses than young and middle-aged patients. Side effects are more likely to

occur in older patients. Your doctor will provide any special information about careful dosage and close

observation needed.

Children or adolescents

Anafranil should not be given to children or adolescents unless specifically prescribed by a doctor. Your doctor

will provide any special information about careful dosage and close observation needed.

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking Anafranil.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes

medicines obtained without a prescription, including herbal medicines. Anafranil interacts with a large number

of medicines.

In particular, do not take Anafranil if you are taking the following:

medicines for depression called monoamine oxidase inhibitors (MAOIs), or have taken them within the

last 3 weeks.

Do not take Anafranil if this applies to you. If you are not sure, talk to your doctor or pharmacist before taking

Anafranil.

Tell your doctor if you are taking any of the following:

other medicines for depression called SSRIs e.g. fluoxetine, fluvoxamine; tricyclic antidepressants e.g.

barbiturates, benzodiazepines

medicines for other mental illnesses such as schizophrenia or manic depression e.g. thioridazine, lithium

medicines for high blood pressure

medicines to treat heart disorders, particularly those used to treat an abnormal heart rhythm

anticoagulants (blood thinning tablets like warfarin)

medicines for Parkinson’s Disease

drugs which affect your liver (your doctor will know which these are). They include nicotine and

barbiturates

cold, flu or hayfever drugs such as antihistamines and decongestants

carbamazepine or phenytoin (for epilepsy)

cimetidine (for stomach problems)

methylphenidate (Ritalin) prescribed for children with ADHD

atropine or similar medicines (including eye drops)

estrogens (e.g. contraceptive pill or hormone replacement therapy)

a medicine called terbinafine (used orally to treat skin, hair or nail infections due to fungus)

drugs used to reduce fat in blood

grapefruit/grapefruit juice,

cranberry juice.

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking Anafranil.

Operations, tests and check-ups

Tell your doctor or dentist if you are planning to have an operation of any kind, as Anafranil may interact

with local or general anaesthetic.

Your doctor may want to do blood tests and check your heart and liver function while you are taking

Anafranil.

You should go to the dentist regularly if you take Anafranil for a long time. Anafranil can cause a dry

mouth which may increase the chance of tooth decay.

Taking Anafranil with food and alcohol

You should not drink alcohol during your treatment with Anafranil – it may affect you more than usual.

You can take Anafranil with or without food.

Pregnancy and breast-feeding

Do not take Anafranil if you are pregnant or might become pregnant. Do not take Anafranil if you are breast-

feeding.

Ask your doctor or pharmacist for advice before taking any medicine, if you are pregnant, might become

pregnant or are breast-feeding.

Driving and using machines

If you feel dizzy, tired or have blurred vision when you start to take Anafranil, do not drive or work with

machinery until this effect has worn off.

Important information about some of the ingredients of Anafranil

Anafranil capsules contain lactose (a type of sugar). If you have been told by your doctor that you cannot tolerate

or digest some sugars, talk to your doctor before taking this medicine.

Information for you, your family and caregivers

Information for you

If you are depressed or have anxiety disorders you can sometimes have thoughts of harming or killing yourself.

These may be increased when you first start taking antidepressants, since these medicines all take time to work,

usually about two weeks but sometimes longer.

You may be more likely to have these thoughts if:

if you have previously had thoughts about killing or harming yourself

if you are a young adult. Information from clinical trials has shown an increased risk of suicidal behaviour

in adults aged less than 25 years with psychiatric conditions who were treated with an antidepressant.

If you have thought of harming or killing yourself at any time, contact your doctor or go to a hospital straight

away. You may find it helpful to tell a relative or close friend that you are depressed or have an anxiety disorder,

and ask them to read this leaflet. You might ask them to tell you if they think your depression or anxiety is

getting worse, or if they are worried about changes in your behaviour.

Information for your family and caregivers

The patient should be monitored to see if they show signs of behavioural changes such as unusual anxiety,

restlessness,

sleeping

problems,

irritability,

aggressiveness,

over-excitedness

other

unusual

changes

behaviour, worsening of depression or thinking about suicide. Any such symptoms should be reported to the

patient’s doctor, especially if they are severe, start suddenly or were not part of the patient’s presenting

symptoms before. You should evaluate the emergence of such symptoms on a day to day basis, especially early

during anti-depressant treatment and when the dose is increased or decreased, since changes may be abrupt.

Symptoms such as these may be associated with an increased risk of suicidal thinking or behaviour and indicate

a need for very close monitoring and possible changes in medication.

3

How to take Anafranil

The doctor will tell you how much Anafranil to take and when to take it. Always follow the doctor’s instructions

carefully. The dose will be on the pharmacist’s label. Check the label carefully. If you are not sure, ask your

doctor or pharmacist.

Taking this medicine

Swallow your Anafranil capsules whole with a drink of water.

Keep taking your medicine until your doctor tells you to stop. Do not stop because you do not feel any

better. This medicine may take up to 4 weeks to work.

The medicine may be taken as one dose at night or as smaller doses at intervals during the day.

How much to take

The usual dosages for adults are as follows:

For depression: 10 mg to 150 mg daily. Severe cases may need even higher doses.

For obsessions and phobias: 10 mg to 150 mg daily.

For cataplexy: 10 mg to 75 mg daily.

If you are not sure how much Anafranil to take, ask your doctor or pharmacist.

The elderly

Elderly patients often need a lower dose because they are more likely to experience side effects. Your doctor will

tell you about this.

If you take more Anafranil than you should

If you or anyone else, accidently takes too much Anafranil, tell your doctor or go to your nearest hospital

casualty department immediately. Take your medicine pack with you so that people can see what you have taken.

If you forget to take Anafranil

If you miss a dose, take the next dose at the usual time. Then go on as before. DO NOT take a double dose.

If you stop taking Anafranil

Do not stop taking Anafranil suddenly because this may cause withdrawal side effects. If the decision is made by

your doctor to discontinue treatment, the dose you will receive will be cut down gradually to prevent the

development of withdrawal symptoms. You may get these side effects if you stop taking Anafranil suddenly:

feeling or being sick, stomach ache, diarrhoea, headache, difficulty sleeping, nervousness or anxiety. If you have

any further questions on the use of this product, ask your doctor or pharmacist.

4

Possible side effects

Like all medicines, Anafranil can cause side effects. The side effects are usually mild and disappear as treatment

continues.

Some side effects can be serious.

Stop taking Anafranil and tell your doctor immediately if you notice the following very rare symptoms:

Rash, changes in blood pressure, swelling and increased fluid in tissues, and increased heart rate, difficulty

with breathing and collapse. These may be signs of an allergic reaction.

A high temperature and sweating with rigid muscles and confusion or agitation, or if you experience jerky

muscle movements which you can’t control. These may be signs of a serious condition known as

neuroleptic malignant syndrome.

The side effects listed below have also been reported:

Very common (More than 1 in 10 people have experienced):

Increase in appetite and weight gain.

Headaches, dizziness, nausea, constipation, dry mouth, increased sweating, shaking hands, tremor, difficulty in

passing urine, problems with their eyes, feeling tired or sleepy, sexual disturbances, restlessness.

Common (Up to 1 in 10 people have experienced):

Loss of appetite, stomach upset, vomiting, diarrhoea, light headedness when standing up (due to low blood

pressure), increased anxiety, agitation, hot flushes, enlarged pupils, speech disturbances, yawning, feeling

confused, disorientated or over excited, sleep disturbances, nightmares, hallucinations or thought disturbances,

worsening of existing depression, impaired memory and concentration, aggressiveness, disturbances in heart

rhythm, increased sensitivity of the skin to sunlight, rash and itching, breast changes, numbness or tingling in the

arms and legs, muscle weakness, movement disorder, changes in liver function tests, taste disturbances,

tinnitus(ringing in the ears), swelling of the breasts and discharge of milk, irritability, feeling detached from a

situation (like watching it from afar).

Uncommon (Up to 1 in 100 people have experienced):

Mood changes including aggression, fits, movement disorders, increased blood pressure, irregular heart rhythm

and fever.

Very rare (Up to 1 in 10,000 people have experienced):

Glaucoma, hepatitis causing jaundice (yellowing of the skin or whites of the eyes), and light coloured urine,

urinary retention, oedema (generalised swelling), hair loss, blood disorders (which might result in persistent sore

throat, fever or frequent infections, unexplained bruising or bruising more easily).

Most of the side effects are mild and may wear off after a few days treatment. If they are severe or last

more than a few days, tell your doctor.

Also, if your medicine upsets you in any other way, tell your doctor.

Patients aged 50 years or older and taking medicines of this group are more likely to experience bone fractures.

Children and Adolescents

Anafranil should not be used in the treatment of depressive states, phobias or cataplexy associated with

narcolepsy in children and adults under the age of 18 years as long-term safety effects concerning growth,

maturation and cognitive and behavioural development of Anafranil in this age group have not yet been

demonstrated.

Also patients under 18 may have an increased risk of side effects such as suicidal thoughts, harming themselves

and hostility (predominantly aggression, oppositional behaviours and anger) when they take drugs like Anafranil.

Despite this, your doctor may prescribe Anafranil for patients under 18 because they decide that this is in their

best interests. If your doctor has prescribed Anafranil for you (or your child) and you want to discuss this, please

go back to your doctor.

You should inform your doctor if any of the symptoms listed above develop or worsen when patients under 18

are taking Anafranil.

Also reported (frequency not known)

Feeling of inner restlessness and a compelling need to be in constant motion, repetitive, involuntary, purposeless

movements, breakdown of muscle, increase in prolactin (a hormone) level in the blood, and serotonin syndrome

(syndrome caused due to increase in naturally occurring messenger, serotonin, in brain; manifested by symptoms

like agitation, confusion, diarrhoea, high temperature, increased blood pressure, excessive sweating and rapid

heartbeat), delayed or no ejaculation of semen if you are a male.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not

listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance, Earlsfort Terrace,

Dublin

Tel:

+353

6764971;

Fax:

+353

6762517.

Website:

www.hpra.ie;

E-mail:

medsafety@hpra.ie. By reporting side effects you can help provide more information on the safety of this

medicine.

5

How to store Anafranil

Keep out of the reach and sight of children.

Do not use Anafranil after the expiry date, which is stated on the label and carton after EXP. The expiry date

refers to the last day of that month.

The capsules should be protected from heat and moisture.

If your doctor tells you to stop taking Anafranil, please take any unused medicine back to your pharmacist to be

destroyed. Do not throw it away with your normal household water or waste. This will help to protect the

environment.

6

Further information

What Anafranil contains

The active substance is clomipramine hydrochloride

Anafranil

Capsules

available

three

strengths

containing

clomipramine

hydrochloride.

The other ingredients are lactose monohydrate, gelatin, magnesium stearate, titanium dioxide (E171), black iron

oxide (E172), red iron oxide (E172), yellow iron oxide (E172) and

Printing ink Opacode Brown which consists of, Shellac, black iron oxide (E172), red iron oxide (E172) and

yellow iron oxide (E172), ammonium hydroxide and propylene glycol (E1520)

or alternatively

Printing ink Opacode Brown which consists of titanium dioxide (E171), Shellac (E904), aluminium lakes:

yellow (E110), blue (E132) and red (E129), ammonia and propylene glycol

What Anafranil looks like and the contents of the pack

Anafranil 10mg capsules are opaque, hard gelatin capsules with a caramel top and a greyish yellow body.

Imprinted on both cap and body is the “GEIGY” logo. They come in packs containing 84 capsules.

Anafranil 25mg capsules are opaque, hard gelatin capsules with a caramel top and a brownish-orange body.

Imprinted on both cap and body is the “GEIGY” logo. They come in packs containing 84 capsules.

Anafranil 50mg capsules are opaque, hard gelatine capsules with a caramel top and a light grey body. Imprinted

on both cap and body is the “GEIGY” log. They come in packs containing 56 capsules.

Marketing Authorisation Holder and Manufacturer

Novartis Pharmaceuticals

UK Limited

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

Irish Office Address:

Novartis Ireland Limited

Beech House

Beech Hill Office Campus

Clonskeagh

Dublin 4

This leaflet was last revised in August 2014.

Copyright:

Novartis Pharmaceuticals UK Limited

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Anafranil 25mg Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 25mg clomipramine hydrochloride.

Also contains lactose monohydrate, 123.0mg per capsule

For a full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM

Hard capsules

Size No. 4, opaque hard gelatin capsules with a caramel cap and a brownish-orange body, imprinted with the ‘GEIGY’

logo and containing a white powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

In the management of endogenous depression including manic depression, periodic and involutional depression,

reactive and neurotic depression, obsessional and phobic states and as an adjunctive treatment of cataplexy associated

with narcolepsy.

4.2 Posology and method of administration

Before initiating treatment with Anafranil, hypokalemia should be treated (see 4.4 Special warnings and precautions for

use).

As a precaution against possible QTc prolongation and serotonergic toxicity, adherence to the recommended doses of

Anafranil is advised and any increase in dose should be made with caution if other serotonergic agents are co-

administered (see sections 4.4 Special Warnings and Precautions for use and 4.5 Interaction with other Medicinal

Products and other forms of Interaction).

The dosage should be adapted to the individual patient’s condition. The aim is to achieve an optimum effect while

keeping the doses as low as possible and increasing them cautiously. After a response has been obtained, maintenance

therapy should be continued at the optimum dose to avoid relapse. Patients with a history of recurrent depression

require maintenance treatment for a longer duration. Duration of maintenance treatment and need for further treatment

should be reviewed periodically.

Abrupt discontinuation of Anafranil therapy should be avoided because of possible withdrawal symptoms. Therefore,

dosage should be stopped gradually after regular use for long duration and the patient should be monitored carefully

when Anafranil therapy is discontinued.

Immediate release formulations (capsules) and sustained-release tablets can be used interchangeably in equivalent

doses.

Adults:

Depression:

The usual daily dosage is in the range of 30 to 75mg in single or divided doses. Initial dosage should be 10mg/day with

gradual increments to 30-150mg/day in divided doses or as a single dose at bedtime. Dosage may exceed the stated

range if necessary up to a maximum of 250mg.

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Obsessional/phobic states:

“The maintenance dosage of Anafranil is generally higher than that used in depression. It is recommended that the

dose be built up to 100-150mg Anafranil daily, according to the severity of the condition. This should be attained

gradually over a period of 2 weeks starting with 1 x 25mg Anafranil daily. In elderly patients and those sensitive to

tricyclic antidepressants a starting dose of 1 x 10mg Anafranil daily is recommended. Again where a higher dosage is

required the Sustained-release 75mg formulation may be preferable.”

Adjunctive treatment of cataplexy associated with narcolepsy:

Initially 10mg, increasing to 50mg daily. Control of cataplexy should be achieved within 24 hours of reaching optimal

dose.

Geriatric patients (aged 65 years and older)

Elderly patients generally show a stronger response to Anafranil than patients of intermediate age groups. Anafranil

should be used with caution in elderly patients and doses should be increased cautiously. Daily dose should generally

be low, initiated at the lowest level (10mg) with very slow cautious increments to 30-75mg daily.

Paediatric Patients

Anafranil is not recommended for use in children due to insufficient data on safety and/or efficacy” (See Section 4.4

Special Warnings and Precautions for use).

Renal imparment:

Anafranil should be given with caution in patients with renal impairment (see section 4.4 special warnings and

precautions for use and section 5 pharmacological properties).

Hepatic imparment:

Anafranil should be given with caution in patients with hepatic impairment (see section 4.4 special warnings and

precautions for use and section 5 pharmacological properties).

Anafranil prolonged-release tablets should be swallowed whole.

Anafranil can be administered with or without food.

4.3 Contraindications

Use in patients who are currently receiving, or have received within 3 weeks, monoamine oxidase inhibitors.

Use in patients in acute recovery phase of myocardial infarction.

Use in patients hypersensitive to dibenzazepines.

Use in patients with cardiac arrhythmias, particularly heartblock.

Use during lactation in women breast-feeding infants.

Use in mania, severe liver disease, narrow-angle glaucoma, and retention of urine.

Use in patients with congenital QT syndrome.

4.4 Special warnings and precautions for use

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This

risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of

treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the

risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which Anafranil is prescribed can also be associated with an increased risk of suicide-

related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions

observed when treating patients with major depressive disorder should therefore be observed when treating patients

with other psychiatric disorders.

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2

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to

commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive

careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in

adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared

to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early

treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor

for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice

immediately if these symptoms present.

Modifying the therapeutic regimen, including possibly discontinuing the medication, should be considered in these

patients, especially if these changes are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Prescriptions for Anafranil should be written for the smallest quantity of tablets or capsules consistent with good patient

management, in order to reduce the risk of overdose.

Other psychiatric effects

Many patients with panic disorder experience more marked anxiety at the start of treatment with Anafranil. This

paradoxical initial increase in anxiety is most pronounced during the first few days of treatment and generally subsides

within two weeks.

Activation of psychosis has occasionally been observed in patients with schizophrenia receiving tricyclic antidepressants.

Hypomanic or manic episodes have also been reported during a depressive phase in patients with cyclic affective

disorders receiving treatment with a tricyclic antidepressant. In such cases it may be necessary to reduce the dosage of

Anafranil or to withdraw it and administer an antipsychotic agent. After such episodes have subsided, low dose therapy

with Anafranil may be resumed if required.

In predisposed patients, tricyclic antidepressants may provoke pharmacogenic (delirious) psychoses, particularly at

night. These disappear within a few days of withdrawing the drug.

Cardiac and vascular disorders

Anafranil should be administered with particular caution in patients with cardiovascular disorders, especially those with

cardiovascular insufficiency, conduction disorders, (e.g. atrioventricular block grades I to III), or arrhythmias.

Monitoring of cardiac function and the ECG is indicated in such patients. There may be a risk of QTc prolongation and

Torsades de Pointes, particularly at supratherapeutic doses or supra-therapeutic plasma concentrations of clomipramine,

as occur in the case of co-medication with selective serotonin reuptake inhibitors (SSRIs) or serotonin and

noradrenergic reuptake inhibitors (SNaRIs). Therefore, concomitant administration of drugs that can cause

accumulation of clomipramine should be avoided equally, concomitant administration of drugs that can prolong the

QTc interval should be avoided (see sections 4.2 Posology and method of administration and 4.5. interactions with

other medicinal products and other forms of interaction). It is established that hypokalaemia is a risk-factor of QTc

prolongation and Torsades de pointes. Therefore, hypokalaemia should be treated before initiating treatment with

Anafranil and Anafranil should be used with caution when combined with SSRIs, SNaRIs or diuretics (see section 4.5)

Tricyclic antidepressants are known to lower the convulsion threshold and Anafranil should therefore be used with

extreme caution in patients with epilepsy and other predisposing factors, e.g. brain damage of varying aetiology,

concomitant use of neuroleptics, withdrawal from alcohol or drugs with anticonvulsive properties (e.g. benzodiazepines).

It appears that the occurrence of seizures is dose dependent, therefore the recommended total daily dose of Anafranil

should not be exceeded.

Caution is called for when giving tricyclic antidepressants to patients with severe hepatic disease and tumours of the

adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), in whom they may provoke hypertensive crises.

Concomitant treatment of Anafranil and electroconvulsive therapy should only be resorted to under careful supervision.

Elderly patients are particularly liable to experience adverse effects, especially agitation, confusion, and postural

hypotension.

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This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency

of glucose-galactose malabsorption should not use this medication.

Precautions

Before initiating treatment it is advisable to check the patient’s blood pressure, because individuals with hypotension or a

labile circulation may react to the drug with a fall in blood pressure.

White blood cell count

Although changes in the white blood cell count have been reported with Anafranil only in isolated cases, periodic blood

cell counts and monitoring for symptoms such as fever and sore throat are called for, particularly during the first few

months of therapy. They are also recommended during prolonged therapy.

It is advisable to monitor cardiac and hepatic function during long-term therapy with Anafranil. In patients with hepatic

and renal disease, periodic monitoring of the hepatic enzyme levels and renal function is recommended.

Anticholinergic effects

Because of its anticholinergic properties, Anafranil should be used with caution in patients with a history of increased

intra-ocular pressure, narrow angle glaucoma or urinary retention) e.g. diseases of the prostate).

Specific treatment populations

Caution is indicated in patients with hyperthyroidism or during concomitant treatment with thyroid preparations since

aggravation of unwanted cardiac effects may occur.

Caution should be exercised when using Anafranil in patients with severe renal disease.

In elderly patients, tricyclic antidepressants may provoke pharmacogenic (delirious) psychoses, particularly at

night. These disappear within a few days of withdrawing the drug.

Monitoring of cardiac function and the ECG is indicated in elderly patients.

An increase in dental caries has been reported during long-term treatment with tricyclic antidepressants. Regular dental

check-ups are therefore advisable during long-term treatment.

Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural

development are not available. Anafranil is not recommended for use in children due to insufficient data on safety and/or

efficacy”.

Caution is called for in patients with chronic constipation.

Tricyclic antidepressants may cause paralytic ileus,

particularly in the elderly and in bedridden patients.

Decreased lacrimation and accumulation of mucoid secretions due to the anticholinergic properties of trycyclic

antidepressants may cause damage to the corneal epithelium in patients with contact lenses.

Risk of suicide is inherent to severe depression and may persist until significant remission occurs. Patients posing a high

suicide risk require close initial supervision.

Anaesthesia

Before general or local anaesthesia, the anaesthetist should be aware that the patient has been receiving Anafranil and of

the possible interactions (see 4.5 Interaction with other medicaments and other forms of interaction).

Treatment discontinuation

Abrupt withdrawal should be avoided because of possible adverse reactions (see 4.8 Undesirable Effects). If the decision

has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that

abrupt discontinuation can be associated with certain symptoms (see section 4.8 Undesirable effects, for a description of

the risks of discontinuation of Anafranil).

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4.5 Interaction with other medicinal products and other forms of interaction

Adrenergic neurone blockers: Anafranil may diminish or abolish the antihypertensive effects of guanethidine,

betanidine, reserpine, clonidine and alpha-methyldopa. Patients requiring comedication for hypertension should

therefore be given antihypertensives of a different type (e.g. vasodilators, or beta-blockers).

Anticholinergic agents: Tricyclic antidepressants may potentiate the effects of these drugs (e.g. phenothiazine,

antiparkinsonian agents, antihistamines, atropine, biperiden) on the eye, central nervous system, bowel and bladder.

CNS depressants: Tricyclic antidepressants may potentiate the effects of alcohol and other central depressant

substances (e.g. barbiturates, benzodiazepines, or general anaesthetics).

Diuretics: Comedication of Anafranil with diuretics may lead to hypokalemia, which in turn increases the risk of QTc

prolongation and Torsades de Pointes. Hypokalaemia should therefore be treated prior to administration of Anafranil

(see 4.2 Posology and 4.4 Special warnings and precautions).

MAO inhibitors: Do not give Anafranil for at least 3 weeks after discontinuation of treatment with MAO inhibitors

(there is a risk of severe symptoms such as hypertensive crisis, hyperpyrexia and those consistent with Serotonin

Syndrome e.g. myoclonus, agitation, seizures, delirium and coma). The same applies when giving a MAO inhibitor

after previous treatment with Anafranil. In both instances the treatment should initially be given in small gradually

increasing doses and its effects monitored. There is evidence to suggest that Anafranil may be given as little as 24

hours after a reversible MAO-A inhibitor such as moclobemide, but the 3 week wash-out period must be observed if

the MAO-A inhibitor is used after Anafranil.

Selective serotonin reuptake inhibitors: Co-medication with SSRI’s may lead to additive effects on the serotonin

system, (see serotonergic agents).

Serotenergic Agents: Seretonin Syndrome can possible occur when clomipramine is administered with serotonergic co-

medications such as selective serotonin re-uptake inhibitors (SSRIs), serotonin and nonadrenergic reuptake inhibitors

SNaRI’s), tricyclic antidepressants –or lithium. For fluoxetine, a washout period of two to three weeks is advised

before and after treatment with fluoxetine.

Sympathomimetic drugs: Anafranil may potentiate the cardiovascular effects of adrenaline, ephedrine, isoprenaline,

noradrenaline, phenylephrine, and phenylpropanolamine (e.g. as contained in local and general anaesthetic preparations

and nasal decongestants).

Pharmacokinetic-related interactions: Anafranil (clomapramine) is predominantly eliminated through metabolism. The

primary route of metabolism is demethylation to form the active metabolite, N-desmethylclomipramine, followed by

hydroxylation and further conjugation of both N-desmethylclomipramine and the parent drug. Several cytochrome

P450’s are involved in the desmethylation, mainly CYP3A4, CYP2C19 and CYP1A2. Elimination of both active

components is by hydroxylation and its catalyzed by CYP2D6.

Concomitant administration of CYP2D6 inhibitors may lead to an increase in concentration of both active components,

up to

3 fold in patients with desbrinoquine/sparteine extensive metabolizer phenotype, converting them to poor-

metabolizer phenotype. Concomitant administration of CYP1A2, CYP2C19 and CYP3A4 inhibitors are expected to

increase clomipramine concerntrations and decrease N-desmethylclomipramine, thus not necessarily affecting the

overall pharmacology.

MAO inhibitors which are also potent CYP2D6 inhibitors in vivo, such as moclobemide, are contraindicated

for coadministration with clomipramine.

Antiarrhythmics (such as quinidine and propafenone), which are potent inhibitors of CYP2D6, should not be

used in combination with tricyclic antidepressants.

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SSRI’s, which are inhibitors of CYP2D6, such as fluoxetine, paroxetine or sertraline and of others including

CYP1A and CYP2C19 (e.g. Fluvoxamine) may also increase plasma concentrations of clomipramine, with

corresponding adverse

effects.

Steady-state

serum levels

clomipramine

increased

4 fold by co-

administration of fluvoxamine (N-desmethylclomipramine decreased

2 fold)

Comedication of

antipsychotics

(e.g.phenothiazines)

may result

in increased plasma levels

tricyclic

antidepressants,

a lowered convulsion threshold and seizures.

Combination with thioridazine may produce

severe cardiac arrhythmias.

Oral antifungal, terbinafine. Coadministration of Anafranil with terbinafine, a strong inhibitor of CYP2D6,

may result

in increased exposure and accumulation of clomipramine and its N-demethylated metabolite.

Therefore, dose adjustments of Anafranil may be necessary when coadministered with terbinafine.

Coadministration with the histamine

receptor

antagonist,

cimetidine (an inhibitor

several

P450

enzymes,

including

CYP2D6

CYP3A4),

increase

plasma

concentrations

tricyclic

antidepressants, whose dosage should therefore be reduced.

No interaction between chronic oral contraceptive use (15 or 30 mg ethinyl estradiol daily) and Anafranil

(25 mg daily)

has been documented.

Estrogens are not

known to be inhibitors of

CYP2D6,

the major

enzyme involved in clomipramine clearance and therefore,

no interaction is expected.

Although in a few

cases with high dose estrogen (50 mg daily) and the tricyclic antidepressant

imipramine,

increased side

effects and therapeutic response were noted, it is unclear as to the relevance of these cases to clomipramine

and lower dose estrogen regimens. Monitoring therapeutic response of tricyclic antidepressants at high dose

estrogen regimems (50 mg daily) is recommended and dose adjustments may be necessary.

Methylphenidate (e.g.

Ritalin) may also increase concentrations of tricyclic antidepressants by potentially

inhibiting their metabolism, and a dose reduction of tricyclic antidepressant may be necessary.

Concomitant

administration of valproate with clomipramine may cause inhibition of CYP2C and/or UGT

enzymes resulting in increased serum levels of clomipramine and desmethylclomipramine.

Concomitant administration of Anafranil with grapefruit, grapefruit juice or cranberry juice my increase the

plasma concentrations of clomipramine.

Some tricyclic antidepressants may potentiate the anticoagulant effect of coumarin drugs, such as warfarin,

and this may be through inhibition of their metabolism (CYP2C9).

There is no evidence for the ability of

clomipramine to inhibit the metabolism of anticoagulants, such as warfarin, however, careful monitoring of

plasma prothrombin has been advised for this class of drug.

Concomitant

administration of drugs known to induce cytochrome P450 enzymes,

particularly CYP3A4,

CYP2C19, and/or CYP1A2 may accelerate the metabolism and decrease the efficacy of Anafranil.

CYP3A and CYP2C inducers

such as

rifampicin or

anticonvulsants

(e.g.

barbiturates,

carbamazepine,

phenobarbital and phenytoin), may decrease clomipramine concentrations.

Known inducers of CYP1A2 (e.g. nicotine/components in cigarette smoke), decrease plasma concentrations

of tricyclic drugs.

In cigarette smokers,

clomipramine steady-state plasma concentrations were decreased 2

fold compared to non-smokers (no change in N-desmethylclomipramine).

Concomitant administration of ion exchange resins such as cholestyramine or colestipol may reduce the plasma

levels of clomipramine. Staggering the dosage of clomipramine and resins, such that the drug is administered at

least 2 h before or 4-6 h after the administration of resins, is recommended.

Concomitant administration of Anafranil with St. John’s wort during the treatment may decrease the plasma

concentrations of clomipramine.

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Clomipramine is also an in vitro (K

= 2.2µM) and in vivo inhibitor of CYP2D6 activity (sparteine oxidation) and

therefore, may cause increased concentrations of co-administered compounds that are primarily cleared by CYP2D6 in

extensive metabolizers.

4.6 Fertility, pregnancy and lactation

Women of child-bearing potential

There are no data supporting any special recommendations in women of child-bearing potential.

Pregnancy

There is limited amount of data from the use of Anafranil in pregnant women that indicates a potential to harm the

foetus or cause congenital malformation. Anafranil should be used during pregnancy only if the potential benefit

outweighs the potential risk to the foetus.

Neonates whose mothers had taken tricyclic antidepressants until delivery showed drug withdrawal symptoms, such as

dyspnoea, lethargy, colic, irritability, hypotension or hypertension, and tremor /convulsions, during the first few hours

or days. To avoid such symptoms, Anafranil should if possible be gradually withdrawn at least 7 weeks before the

calculated date of confinement.

Lactation

Since the active substance passes into breast milk, Anafranil should be gradually withdrawn or the infant weaned if the

patient is breast-feeding.

Fertility

No adverse effects on reproductive performance, including male and female fertility, were observed in rats at oral doses

up to 24 mg/kg.

No teratogenic effects were detected in mice, rats, and rabbits at doses up to 100, 50, and 60 mg/kg, respectively (see

section 5.3 Preclinical safety data).

4.7 Effects on ability to drive and use machines

Patients receiving Anafranil should be warned that blurred vision, and other nervous system and psychiatric related

disorders such as somnolence, disturbance in attention, confusion, disorientation, aggravation of depression, delirium

etc, have been observed. In the presence of such effects, patients should not drive or operate machinery or do anything

else which may require alertness or quick actions.

4.8 Undesirable effects

Unwanted effects are usually mild and transient, disappearing under continued treatment or with a reduction in the

dosage. They do not always correlate with plasma drug levels or dose. It is often difficult to distinguish certain

undesirable effects from symptoms of depression such as fatigue, sleep disturbances, agitation, anxiety, constipation,

and dry mouth.

If severe neurological or psychiatric reactions occur, Anafranil should be withdrawn.

Frequency estimates: Very common

10%, common

1% to <10%, uncommon

0.1% to <1%, rare

0.01% to

<0.1%, very rare <0.01%. The ADRs listed below are based on clinical trials as well as post marketing reports.

Blood and lymphatic system disorders

Very rare

leukopenia, agranulocytosis, thrombocytopenia, eosinophilia

Cardiac disorders

Common

sinus tachycardia, palpitations, orthostatic hypotension, clinically irrelevant ECG changes (e.g.

ST and T changes) in patients of normal cardiac status

Uncommon

arrhythmias, blood pressure increased

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Very rare

conduction disorders (e.g. widening of QRS complex, prolonged QT interval, PQ changes,

bundle-branch block, Torsade de Pointes, particularly in patients with hypokalaemia)

Ear and labyrinth disorders

Common

tinnitus

Endocrine disorders

Very rare

SIADH (inappropriate antidiuretic hormone secretion syndrome)

Eye disorders

Very common

accomodation disorder, vision blurred

Common

mydriasis

Very rare

glaucoma

Gastrointestinal disorder

Very common

nausea, dry mouth, constipation

Common

vomiting, gastrointestinal disorder, diarrhoea

General disorders and administration site conditions

Very common

fatigue

Very rare

oedema (local or generalised), alopecia, hyperpyrexia

Hepatobiliary disorders

Very rare

hepatitis with or without jaundice.

Immune system disorders

Very rare

systemic anaphylactic and anaphylactoid reactions including hypotension

Investigations

Very common

weight increased

Common

transaminases increased

Very rare

electroencephalogram abnormal

Metabolism and nutrition disorders

Very common

increased appetite

Common

decreased appetitie

Musculoskeletal and connective tissue disorders

Common

muscular weakness

Nervous system disorders

Very common

dizziness, tremor, headache, myoclonus, somnolence

Common

speech disorders, paraesthesia, hypertonia, dysgeusia, memory impairment, disturbance in

attention

Uncommon

convulsions, ataxia

Very rare

neuroleptic malignant syndrome

Psychiatric disorders

Very common

restlessness

Common

confusional state, disorientation, hallucinations (particularly in elderly patients and patients with

Parkinson’s disease), anxiety, agitation, sleep disorder, mania, hypomania, aggression,

depersonalisation, aggravation of depression,

insomnia, nightmares, delirium

Uncommon

activation of psychotic symptoms

Unknown

suicidal ideation* and suicidal behaviour*

* Cases of suicidal ideation and suicidal behaviours have been reported during clomipramine therapy or early after

treatment discontinuation (see section 4.4)

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Renal and urinary disorders

Very common

micturition disorder

Very rare

urinary retention

Reproductive system and breast disorders

Very common

libido disorder, erectile dysfunction

Common

galactorrhoea, breast enlargement

Respiratory, thoracic and mediastinal disorders

Common

yawning

Very rare

alveolitis (pneumonitis) with or without eosinophilia

Skin and subcutaneous tissue disorders

Very common

hyperhidrosis

Common

dermatitis allergic (skin rash, urticaria), photosensitivity reaction, pruritus

Very rare

purpura

Vascular disorders

Common

hot flush

Additional adverse drug reaction from port-marketing spontaneous reports

The following additional adverse drug reactions have been identified with Anafranil oral or IM/IV dosage forms based

on post-marketing spontaneous reports. Because these reactions are reported voluntarily from a population of uncertain

size, it is not always possible to reliably estimate their frequency.

Nervous system disorders

Frequency not known: Serotonin syndrome, extrapyramidal symptoms (including akathisia and tardive dyskinesia)

Musculoskeletal and connective tissue disorders

Frequency not known: Rhabdomyolysis (as a complication of neuroleptic malignant syndrome)

Reproductive system and breast disorders

Frequency not known: Ejaculation failure, Ejaculation delayed

Investigations

Frequency not known: Blood prolactin increased

Bone fractures

Epidemiological studies, mainly in patients 50 years of age and older, show an increased risk of bone fractures in

patients receiving SSRIs and TCAs. The mechanism leading to the risk is unknown.

Withdrawal symptoms

The following symptoms commonly occur after abrupt withdrawal or reduction of the dose: nausea, vomiting,

abdominal pain, diarrhoea, insomnia, headache, nervousness, and anxiety.

Geriatric population

Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric or cardiovascular effects. Their

ability to metabolise and eliminate drugs may be reduced, leading to a risk of elevated plasma concentrations at

therapeutic doses.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

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4.9 Overdose

The signs and symptoms of overdose with Anafranil are similar to those reported with other tricyclic antidepressants.

Cardiac abnormalities and neurological disturbances are the main complications. In children accidental ingestion of any

amount should be regarded as serious and potentially fatal.

Signs and symptoms

Symptoms generally appear within 4 hours of ingestion and reach maximum severity after 24 hours. Owing to delayed

absorption (anticholinergic effect), long half-fife, and enterohepatic recycling of the drug, the patient may be at risk for

up to 4-6 days.

The following signs and symptoms may be seen:

Central nervous system

Somnolence, stupor, coma, ataxia, restlessness, agitation, hyperrefexia, muscule rigidity and choreoathetosis,

convulsions. In addition, symptoms consistent with Seotonin Syndrome (e.g. hyperpyrexia, myoclonus, delirium and

coma) may be observed.

Cardiovascular system

Hypotension, tachycardia, arrhythmias, QTc prolongation and arrhythmias including Torsades de Pointes, conduction

disorders, shock, heart failure; in very rare cases cardiac arrest.

Respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, and oliguria or anuria may also occur.

Treatment

There is no specific antidote, and treatment is essentially symptomatic and supportive.

Anyone suspected of receiving an overdose of Anafranil, particularly children, should be hospitalised and kept under

close surveillance for at least 72 hours.

Perform gastric lavage or induce vomiting as soon as possible if the patient is alert. If the patient is not alert, secure the

airway with a cuffed endotracheal tube before beginning lavage, and do not induce vomiting. These measures are

recommended for up to 12 hours or ever longer after the overdose, since the anticholinergic effect of the drug may help

to reduce drug absorption.

Since it has been reported that phyotigmine may cause severe bradycardia, asystole, and seizures, it’s use is not

recommended in cases of overdosage with Anafranil. Haemodialysis or peritoneal dialysis are ineffective because of

the low plasma concentrations of clomipramine.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group

Tricyclic antidepressant, ATC code: N06A A04

Mechanism of action

The pharmacological action includes alpha-adrenolytic, anticholinergic, anti-histaminic and 5-HT receptor blocking

properties. The main property displayed by the compound is its ability to inhibit the neuronal re-uptake of noradrenaline

and 5-HT. Inhibition of the latter is the dominant component.

5.2 Pharmacokinetic properties

Absorption:

The active substance is completely absorbed following oral administration and intramuscular injection.

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The systemic bioavailability of unchanged clomipramine is reduced by 50% by hepatic "first-pass" metabolism to

desmethylclomipramine (an active metabolite). Following single dose administration 25 mg coated tablet and 75 mg

sustained release tablet, the mean maximum plasma concentration (Cmax) of clomipramine were 63.37 ± 12.71 ng/mL

(Tmax 4.83 ± 0.39 hr) and 32.55 ± 8.10 (Tmax 9.00 ± 1.81 hr), respectively. The dose of 75mg Anafranil daily

produces steady state concentrations of clomipramine ranging from about 20 to 175ng/ml. The steady state plasma

concentrations of he active metabolit N-desmethylclomipramine follow a similar pattern but are 40-85% higher than

those of clomipramine.

Distribution:

Clomipramine is 97.6% bound to plasma proteins. Clomipramine is extensively distributed throughout the body with

the apparent volume of distribution of about 12-17 L/kg bodyweight. Concentrations in cerebrospinal fluid are about

2% of the plasma concentration. Clomipramine passes into maternal milk in concentrations similar to those in plasma

and crosses the placenta.

Metabolism:

The primary route of clomipramine metabolism is demethylation to form the active metabolite, N-

desmethylclomipramine. N-desmethylclomipramine can be formed by several P450 enzymes, primary CYP3A4,

CYP2C19, and CYP1A2. Clomipramine and N-desmethylclomipramine are hydroxylated to form 8-

hydroxyclomipramine or 8-hydroxy-N-desmethylclomipramine. Clomipramine is also hydroxylated at the 2-position

and N-desmethylclomipramine can be further demethylated to form didesmethylclomipramine. The 2- and 8-hydroxy

metabolites are excreted primarily as glucuronides in the urine. Elimination of the active components, clomipramine

and N-desmethylclomipramine, by formation of 2-and 8-hydroxy clomipramine is catalysed by CYP2D6.

Elimination:

Oral clomipramine is eliminated from the blood with a mean half-life of 21 hours (range 12-36 h), and

desmethylclomipramine with a half-life of 36 hours.

About two-thirds of a single dose of clomipramine is excreted in the form of water-soluble conjugates in the urine, and

approximately one-third in the faeces. The quantity of unchanged clomipramine and desmethylclomipramine excreted

in the urine amounts to about 2% and 0.5% of the administered dose respectively.

Food effect

Food has no significant impact on the pharmacokinetics of clomipramine. A slight delay in the onset of absorption may

be observed with the administration of Anafranil with food.

Dose proportionality

The drug follows dose-proportionate pharmacokinetics over a dose range of 25 to 150 mg.

Effect of age

In elderly patients, clomipramine has relatively low clearance in comparison to younger adult patients. It is reported to

reach a therapeutic steady state at doses lower than that reported for middle-age patients. Clomipramine should be used

with caution in elderly patients.

Renal impairment

There are no specific reports describing the pharmacokinetic of the drug in patients with renal impairment. Although

the drug is excreted as inactive metabolites in the urine and faeces, the accumulation of inactive metabolites may

subsequently result in the accumulation of the parent drug and its active metabolite. In moderate and severe renal

impairment, it is recommended to monitor the patient during the treatment.

Hepatic impairment

Clomipramine is extensively metabolized in the liver by CYP2D6, CYP3A4, CYP2C19 and CYP1A2, hepatic

impairment may impact on its pharmacokinetics. In patients with liver impairment, clomipramine should be

administered with caution.

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Ethnic sensitivity

Although the impact of ethnic sensitivity and race on the pharmacokinetics of clomipramine has not been studied

extensively, the metabolism of clomipramine and its active metabolite is governed by genetic factors leading to poor

and extensive metabolism of the drug and its metabolite. The metabolism of clomipramine in Caucasians population

may not be extrapolated to Asians, in particular, Japanese and Chinese because of the pronounced differences of

metabolism of clomipramine between these two ethnic groups.

Sustained release formulation

Sustained release of clomipramine from Anafranil sustained release formulation provides a smoother pharmacokinetic

profile by maintaining therapeutic plasma concentrations over 24 hours. Maximum mean plasma concentrations are

reached within about 9 hours post-dose. Following administration of 75 mg clomipramine as sustained release

formulation, observed Cmax is half the maximum concentration levels reached after administration of 25 mg tablets

three times a day. Nevertheless, the total exposure remains unchanged. Following multiple administration of sustained

release formulation, Cmin and Cmax levels attained at steady state are within the therapeutic range. Sustained-release

tablets are bioequivalent with coated tablets and capsules.

5.3 Preclinical safety data

Repeat-dose toxicity

Phospholipidosis and testicular changes, commonly associated with tricyclic compounds, have been observed with

clomipramine hydrochloride at doses >10 fold greater than the maximum recommended human daily dose (MRHD).

Reproductive toxicity

No adverse effects on reproductive performance, including male and female fertility, were observed in rats at oral doses

up to 24 mg/kg.

No teratogenic effects were detected in mice, rats, and rabbits at doses up to 100, 50, and 60 mg/kg, respectively.

Mutagenicity

Various in vitro and in vivo mutagenicity tests were performed and did not reveal any mutagenic activity of

clomipramine hydrochloride.

Carcinogenicity

There was no evidence of carcinogenicity in mice and rats after 104 weeks of treatment with clomipramine

hydrochloride.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Gelatin

Magnesium stearate

Lactose monohydrate

Capsule

Titanium Dioxide (E171)

Iron oxide yellow (E172)

Iron oxide red (E172)

Gelatin

Iron oxide black (E172)

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Printing Ink

Printing ink Opacode Brown (ref. 03A2) which consists of: Shellac, black iron oxide (E172), red iron oxide (E172) and

yellow iron oxide (E172), ammonium hydroxide 28 % (E527) and propylene glycol (E1520)

and alternatively

Printing ink Opacode Brown (ref. 03A1) which consists of: titanium dioxide (E171), Shellac (E904), aluminium lakes:

yellow (E110), blue (E132) and red (E129), strong ammonia solution and propylene glycol

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30

C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

PVC/PVDC/Aluminium blister packs in cardboard cartons.

Pack sizes of 100 capsules and 84 capsules are available.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from

such medicinal product and other handling of the product

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Novartis Pharmaceuticals UK Limited

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

England

8 MARKETING AUTHORISATION NUMBER

PA0013/084/003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

01 April 1978

Date of last renewal:

01 April 2008

10 DATE OF REVISION OF THE TEXT

May 2015

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