Consumer medicine information

Anafranil

Clomipramine hydrochloride

BRAND INFORMATION

Brand name

Anafranil

Active ingredient

Clomipramine hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Anafranil.

SUMMARY CMI

Anafranil®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Anafranil®?

Anafranil® contains the active ingredient clomipramine hydrochloride. Anafranil® is used to treat: depression that is longer lasting and/or more severe than the "low moods" that everyone has from time to time due to the stress of everyday life; obsessive-compulsive disorders (OCD) and phobias in adults; and, muscle weakness in people with a sleep disorder called narcolepsy.

For more information, see Section 1. Why am I using Anafranil®? in the full CMI.

2. What should I know before I use Anafranil®?

Do not use if you have ever had an allergic reaction to Anafranil® or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Anafranil®? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Anafranil® and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Anafranil®?

  • The dose, frequency and length of treatment will be determined by your doctor. Follow all directions given to you by your doctor or pharmacist carefully.
  • Swallow the tablets with a full glass of water.

More instructions can be found in Section 4. How do I use Anafranil®? in the full CMI.

5. What should I know while using Anafranil®?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Anafranil®.
  • Tell your doctor immediately if you become pregnant.
  • Call your doctor straight away if you or someone you know has thoughts about or attempts to commit suicide.
  • Call your doctor straight away if you or someone you know develops new or worse depression/anxiety, panic attacks, difficulty sleeping, or other unusual changes in behaviour or mood, for example: being angry or violent, acting on dangerous impulses, extreme increase in activity and talking.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not let yourself run out of medicine over the weekend or on holidays.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Anafranil® affects you.
  • Anafranil® may cause tiredness, dizziness, drowsiness or blurred vision in some people.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • Anafranil® can increase the drowsiness caused by alcohol.
Looking after your medicine
  • Keep your medicine in the original container until it is time to take a dose.
  • Store it in a cool dry place at room temperature.

For more information, see Section 5. What should I know while using Anafranil®? in the full CMI.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Anafranil®.

All medicines can have side effects. Sometimes they are serious, but most of the time they are not. You may need medical treatment if you get some of the side effects.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Anafranil®

Active ingredient(s): clomipramine hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using Anafranil®. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Anafranil®.

Where to find information in this leaflet:

1. Why am I using Anafranil®?
2. What should I know before I use Anafranil®?
3. What if I am taking other medicines?
4. How do I use Anafranil®?
5. What should I know while using Anafranil®?
6. Are there any side effects?
7. Product details

1. Why am I using Anafranil®?

Anafranil® contains the active ingredient clomipramine hydrochloride. Anafranil® belongs to a group of medicines called tricyclic antidepressants.

Anafranil® is used to treat:

  1. depression that is longer lasting and/or more severe than the "low moods" that everyone has from time to time due to the stress of everyday life.
Depression is thought to be caused by a chemical imbalance in parts of the brain. This imbalance affects your whole body and can cause emotional and physical symptoms such as feeling low in spirit, loss of interest in activities, being unable to enjoy life, poor appetite or overeating, disturbed sleep, loss of sex drive, lack of energy and feelings of guilt.
  1. obsessive-compulsive disorders (OCD) and phobias in adults.
  2. muscle weakness in people with a sleep disorder called narcolepsy.

The symptoms of these disorders vary from person to person. Your doctor can provide you with more information.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another purpose.

2. What should I know before I use Anafranil®?

Warnings

Do not use Anafranil® if:

  • you are allergic to clomipramine, any other tricyclic antidepressant, or any of the ingredients listed at the end of this leaflet.
  • you are under 18 years of age.
  • Always check the ingredients to make sure you can use this medicine.
    Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.
  • Do not start taking Anafranil® if you are already taking another medicine called a monoamineoxidase inhibitor (MAOI) or you have been taking it within the past 2 weeks.
    Taking Anafranil® together with a MAOI may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and seizures (fits). Your doctor will know when it is safe to start Anafranil® after the MAOI has been stopped.
  • Do not take Anafranil® if you are recovering from a recent heart attack.
    It may make your condition worse.
  • Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.
    In that case, return it to your pharmacist.

Check with your doctor if you have:

  • an irregular heart beat or other problems with your heart
  • an inherited heart problem called congenital long QT syndrome
  • increased pressure in the eye from any cause (e.g. glaucoma)
  • difficulty in passing urine (water), due to prostate trouble or any other cause
  • seizures (fits)
  • severe liver or kidney disease
  • a low level of potassium in your blood (called hypokalaemia)
  • a mental disorder other than the one being treated (e.g. schizophrenia, mania)
  • problems with blood pressure (either too high or too low)
  • a blood disorder
  • a thyroid problem
  • chronic constipation
  • Parkinson's disease
  • a tumour of the adrenal gland
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Anafranil should not be taken if you are pregnant unless your doctor has told you to do so. This medicine may affect your baby if you take it while you are pregnant, especially during the last 7 weeks of pregnancy. Your baby may have some side effects from the medicine during the first month after birth. Newborn infants whose mothers had taken this medicine up until delivery may show symptoms such as shortness of breath, abnormal bluish discoloration of the skin and mucous membranes, lethargy, feeding difficulties, colic, irritability, convulsions, tremor, overactive muscle tone, poor muscle tone or spasms, during the first hours or days of life. If there is a need to take Anafranil when you are pregnant, your doctor will discuss the risks and benefits to you and the unborn baby. Your doctor may also recommend gradually stopping Anafranil in the 7 weeks before giving birth.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Breast-feeding is not recommended while you are taking Anafranil®. The active ingredient passes into the breast milk and could affect your baby.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Anafranil® and affect how it works. These include:

  • MAOI medicines. You must not take Anafranil® together with a MAOI (see Section 2. What should I know before I use Anafranil®?)
  • medicines for high blood pressure or heart problems
  • medicines to help you sleep or calm you down
  • other medicines for depression called SSRIs or SNaRIs (e.g. fluoxetine, paroxetine, sertraline, fluvoxamine)
  • medicines for other mental disorders
  • medicines for seizures (fits)
  • medicines to prevent blood clots (e.g. warfarin)
  • diuretic medicines, also called fluid or water tablets
  • some medicines for colds or allergies, including antihistamines and some nose drops
  • anticholinergic medicines, which are used to relieve stomach cramps, spasms and travel sickness
  • medicines for thyroid problems
  • cimetidine, a medicine for stomach ulcers
  • medicines for Parkinson's disease
  • oestrogens (e.g. birth control pills, hormone replacement therapy)
  • nicotine in medicines used to help you quit smoking, such as nicotine patches or chewing gum
  • methylphenidate (Ritalin®)
  • disulfiram, a medicine for alcoholism
  • rifampicin, an antibiotic
  • terbinafine, a medicine used to treat skin, hair or nail infections due to fungus
  • medicines used to reduce fat in blood
  • grapefruit/grapefruit juice or cranberry juice.

You may need to take different amounts of your medicines or you may need to take different medicines. Your doctor and pharmacist have more information.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Anafranil®.

4. How do I use Anafranil®?

How much to take

  • For depression, obsessive-compulsive disorders and phobias, treatment is usually started with a low dose of 2 or 3 tablets (50 to 75 mg) each day. The dose can be raised slowly up to 4 to 6 tablets each day. Some people will need higher doses than others because each person's body chemistry is different. Once you are feeling better, your doctor may be able to slowly reduce the dose, usually down to 2 to 4 tablets each day.
  • For muscle weakness accompanying narcolepsy, the dose is usually from 1 to 3 tablets (25 to 75 mg) each day.
  • If you are older than 65 years, your doctor will probably start with a low dose (e.g. 1 tablet each day) to help avoid side effects. The dose is gradually increased over about ten days to 2 to 3 tablets each day and kept at that dose for the rest of your treatment.
  • Follow the instructions provided and use Anafranil® until your doctor tells you to stop.

When to take Anafranil®

  • Take the tablets in 2 or 3 doses spread over the day unless your doctor advises you otherwise.
  • If you have narcolepsy and you have trouble sleeping at night, take the last dose before evening to avoid making your insomnia worse.

How to take Anafranil®

  • Swallow the tablets with a full glass of water. If your stomach is upset after taking the tablets, take them with a meal or after a snack.

How long to take Anafranil®

Take this medicine until your doctor tells you to stop treatment.

The length of treatment will depend on your condition and on how well the medicine works.

For depression, the length of treatment will depend on how quickly your symptoms improve. This type of medicine takes time to work, so don't be discouraged if you don't feel better right away. Some of your symptoms may improve in 1 or 2 weeks but it can take up to 4 to 6 weeks to feel any real improvement. Even when you feel well, you will usually have to take Anafranil® for several months or even longer to make sure the benefits will last.

Do not stop taking Anafranil® suddenly as you could suffer possible withdrawal symptoms.

If you forget to use Anafranil®

If it is almost time for your next dose (e.g. within 2 or 3 hours), skip the dose you missed and take your next dose when you are meant to.

Otherwise, take the dose as soon as you remember, and then go back to taking the tablets as you would normally.

Do not take a double dose to make up for the dose you missed.

This may increase the chance of you getting an unwanted side effect.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much Anafranil®

If you think that you have used too much Anafranil®, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

If you take too much Anafranil®, you may feel sleepy, restless or agitated. You may have stiffness or unusual muscle movements, fever, sweating, vomiting, difficulty breathing, a drop in blood pressure, fast or irregular heartbeat, fits or other symptoms.

Children are much more sensitive than adults to tricyclic antidepressants. An accidental overdose is especially dangerous.

5. What should I know while using Anafranil®?

Things you should do

If you become pregnant while taking Anafranil®, tell your doctor immediately.

Your doctor can discuss with you the risks of taking it while you are pregnant.

Call your doctor straight away if you or someone you know develop any of the following:

  • thoughts about suicide or dying
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling very agitated or restless
  • panic attacks
  • difficulty sleeping (insomnia)
  • new or worse irritability
  • acting aggressive, being angry, or violent
  • acting on dangerous impulses
  • an extreme increase in activity and talking
  • other unusual changes in behaviour or mood

Symptoms such as these may be associated with an increased risk of suicidal thinking and behaviour and must be taken seriously.

Before having any surgery or emergency treatment, even a minor procedure, tell the doctor or dentist in charge that you are taking Anafranil® or have been taking it within the last two weeks or so.

If possible, this medicine should be stopped before surgery to avoid unnecessary side effects.

If this medicine causes your mouth to feel dry and this problem doesn't go away, tell your doctor or dentist. Be sure to have regular dental checkups.

Continuing dryness of the mouth may increase the chance of gum disease or cavities. You can relieve dry mouth by frequent sips of water, sucking sugarless lollies or chewing sugarless gum.

If you wear contact lenses and find that your eyes are dry, sticky or irritated, tell your doctor.

These side effects could damage your eyes.

Be sure to keep all of your doctor's appointments so that your progress can be checked.

Your doctor may want to take some blood tests and check your heart and blood pressure from time to time.

This helps to prevent unwanted side effects.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Anafranil®.

Remind any doctor, dentist or pharmacist you visit that you are using Anafranil®.

Things you should not do

  • Do not stop using this medicine suddenly.
  • Do not stop taking Anafranil® or change the dose without first checking with your doctor.
  • Do not let yourself run out of medicine over the weekend or on holidays.
  • Do not give this medicine to anyone else, even if their condition seems similar to yours.
  • Do not use it to treat any other complaints unless your doctor tells you to.

If you stop taking this medicine suddenly, your condition may worsen or you may have unwanted side effects such as headache, nausea (feeling sick), vomiting, diarrhoea and nervousness. If possible, your doctor will gradually reduce the amount you take each day before stopping the medicine completely.

Taking pain relievers, sleeping tablets or antihistamines

  • Be careful when taking pain relievers, sleeping tablets or antihistamines (medicines for colds or allergies such as hay fever) while you are taking Anafranil®.
  • Anafranil® can increase the drowsiness caused by medicines that affect your nervous system.

Lightheadedness

If this medicine makes you feel lightheaded, be careful when getting up from a sitting or lying position.

You can usually prevent these symptoms by getting up slowly and flexing leg muscles and toes to get the blood flowing. When getting out of bed, dangle your legs over the side for a minute or two before standing up.

Exposure to sunlight or sunlamps

Be careful to stay out of direct sunlight as much as possible until you find out if your skin is more sensitive than usual. Wear protective clothing and use a sunscreen. Do not use a sunlamp.

This medicine makes some people more sensitive to sunlight.

After you have stopped taking Anafranil®, you should still be careful for 1 or 2 weeks since some of the effects of the medicine will still be in your body.

Smoking

Tell your doctor if you smoke.

Nicotine can affect the amount of Anafranil® that is in your body. Sudden changes in your usual smoking habits can also change the effects of Anafranil®.

Lactose intolerance

Tell your doctor if you are lactose intolerant.

This medicine contains lactose.

Allergies

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Your doctor will want to know if you are prone to allergies.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Anafranil® affects you.

Anafranil® may cause tiredness, dizziness, drowsiness or blurred vision in some people.

Drinking alcohol

Tell your doctor if you drink alcohol.

Anafranil® can increase the drowsiness caused by alcohol.

Looking after your medicine

  • Keep your medicine in the original container until it is time to take a dose.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place at room temperature away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

A locked cupboard at least one-and a-half metres above the ground is a good place to store medicines.

When to discard your medicine

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine you have left over.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

If you are over 65 years old, you should be especially careful while taking this medicine. Report any side effects promptly to your doctor.

As people grow older, they are more likely to get side effects from medicines.

Anafranil® can cause confusion or disorientation, especially in older people or those with Parkinson's disease. Your family or carer should be aware of this. Special care may be needed.

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

Patients with pre-existing heart conditions and the elderly should be monitored for heart health, as they are at an increased risk of heart attack, stroke and sudden death.

Less serious side effects

Less serious side effectsWhat to do
  • drowsiness, dizziness, blurred vision or difficulty focussing your eyes, especially when treatment is started or the dose is increased.
  • lightheadedness, especially when you get up too quickly from a sitting or lying position.
  • dry mouth
  • difficulty urinating (passing water)
  • dry or sticky eyes if you wear contact lenses
  • constipation
  • sweating or hot flushes
  • increased appetite and weight gain
  • decreased appetite
  • tired feeling and mental dullness
  • feeling of unrest or anxiety
  • a compelling need to be in constant motion
  • repetitive, involuntary, purposeless movements
  • disturbed sleep or nightmares
  • shakiness or trembling
  • nausea (feeling sick), vomiting, diarrhoea
  • poor appetite or weight loss
  • sores in the mouth or on the tongue
  • headache
  • reduced sexual desire or difficulty in reaching orgasm
  • swelling of the breasts or discharge of milk
  • swelling of the testicles
  • increased sensitivity to the sun
  • ringing in the ears
  • hair loss
  • change in sense of taste
  • delayed or no ejaculation of semen if you are a male
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other part of the body; shortness of breath, wheezing or troubled breathing
  • constant "flu-like" symptoms (chills, fever, sore throat, aching joints, swollen glands, tiredness or lack of energy)
  • unusual bleeding or bruising
  • pain in the stomach or abdomen that is severe or doesn't go away
  • fast or irregular heart beat (pounding, racing, skipping beats)
  • muscle numbness, tingling or spasms
  • weakness or loss of balance
  • severe dizziness or drowsiness
  • fainting spells or seizures (fits)
  • difficulty in speaking or slurred speech
  • unusually high energy, irritability or outbursts of anger
  • confusion or hallucinations (seeing, hearing or feeling things that are not there)
  • frequent passing of large amounts of urine
  • yellow colour to the skin or eyes
  • eye pain
  • symptoms like agitation, confusion, diarrhoea, high temperature, increased blood pressure, excessive sweating and rapid heartbeat (syndrome caused due to increase in naturally occurring messenger, serotonin)
  • a sudden increase in body temperature, extremely high blood pressure and severe convulsions especially in conjunction with fast heart rate and sweating. This may be due to a very rare condition called neuroleptic malignant syndrome, which has been reported with various antipsychotic medicines.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Anafranil® contains

Active ingredient
(main ingredient)		Clomipramine hydrochloride
Other ingredients
(inactive ingredients)		Colloidal anhydrous silica
Glycerol
Lactose monohydrate
Magnesium stearate
Maize starch
Stearic acid
Purified talc
Hypromellose
Copovidone
Microcrystalline cellulose
Macrogol 8000
Povidone
Sucrose
Titanium dioxide
Iron oxide yellow

Do not take this medicine if you are allergic to any of these ingredients.

This medicine does not contain gluten, tartrazine or any other azo dyes.

What Anafranil® looks like

Anafranil® 25 mg tablets are round, pale yellow, sugar-coated tablets; supplied in packs of 50 tablets.

AUST R 10987

Who distributes Anafranil®

Pharmaco (Australia) Ltd
Level 13
465 Victoria Avenue
Chatswood NSW 2067
AUSTRALIA
Phone: 1800 201 564

This leaflet was prepared in March 2023.

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Anafranil

Active ingredient

Clomipramine hydrochloride

Schedule

S4

 

1 Name of Medicine

Clomipramine hydrochloride.

2 Qualitative and Quantitative Composition

Each tablet contains 25 mg clomipramine hydrochloride.

Excipients with known effect.

Sugars as lactose and sucrose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet.
Anafranil tablets are light yellow, round and biconvex and sugar-coated.

4 Clinical Particulars

4.1 Therapeutic Indications

Major depression.
Obsessive compulsive disorders and phobias in adults.
Cataplexy associated with narcolepsy.

4.2 Dose and Method of Administration

General.

The dosage should be determined individually and adapted to the patient's condition. Doses should be kept as low as possible and increased cautiously. Note that the plasma concentrations of the drug and active metabolite do not stabilise for 7 to 14 days after commencing treatment and after a dosage change.
During treatment, the efficacy and tolerability of Anafranil must be judged by keeping the patients under close surveillance.

Depression, obsessive compulsive disorders and phobias.

Start treatment with one tablet of 25 mg 2 or 3 times daily. Raise the daily dosage stepwise, e.g. 25 mg every few days (depending on how the medication is tolerated) to 4 to 6 tablets of 25 mg. Once a distinct improvement has set in, adjust the daily dosage to a maintenance level averaging 2 to 4 tablets of 25 mg.

Cataplexy accompanying narcolepsy.

Anafranil should be given orally in a daily dose of 25 to 75 mg. Nocturnal medication should only be given in cases where Anafranil does not appear to exacerbate insomnia.

Elderly patients.

Elderly patients generally show a more marked response to Anafranil than patients belonging to intermediate age groups. Anafranil should be used with caution in elderly and doses should be increased cautiously. Start treatment with one tablet of 25 mg daily. Gradually raise the dosage to an optimum level of 50 to 75 mg daily, which should be reached after about 10 days and then adhered to until the end of treatment.

4.3 Contraindications

Known hypersensitivity to clomipramine and any of the excipients in the tablets.
Cross sensitivity to tricyclic antidepressants of the dibenzazepine group.
Concomitant use with a MAO inhibitor, or within 14 days before or after treatment with an irreversible MAO inhibitor, or within 14 days before moclobemide, a reversible MAO inhibitor. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions regarding moclobemide.
Acute and recovery stages of myocardial infarction.
Congenital long QT syndrome.

4.4 Special Warnings and Precautions for Use

Clinical worsening and suicide risk.

The risk of suicide is inherent in depression and may persist until significant remission occurs. This risk must be considered in all depressed patients.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms. Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/ behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Patients with comorbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Patients with a history of suicide related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are at greater risk of suicidal thoughts or suicidal attempts and should receive careful monitoring during treatment.
Pooled analyses of 24 short-term (4-16 weeks), placebo controlled trials of nine antidepressant medicines (SSRIs and others) in 4400 children and adolescents with major depressive disorder (16 trials), obsessive compulsive disorder (4 trials), or other psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4%, compared with 2% of patients given placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder trials, but there were signals of risk arising from trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medicines in the pooled analysis included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).
Pooled analysis of short-term studies of antidepressant medications have also shown an increased risk of suicidal thinking and behaviour, known as suicidality, in young adults ages 18 to 24 during initial treatment (generally the first one to two months). Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years; there was a reduction with antidepressants compared to placebo in adults aged 65 years and older.
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
Families and caregivers of children and adolescents being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or nonpsychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour and other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
Prescriptions for Anafranil should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Caution in the following circumstances.

Caution is called for when employing tricyclic antidepressants in patients with:
Cardiovascular disorders, especially those with cardiovascular insufficiency, conduction disorders (atrioventricular block grades I to III), or arrhythmias. Monitoring of cardiac function and the ECG is required in such patients, especially in the elderly. Myocardial infarction, precipitation of congestive cardiac failure, stroke and sudden death have been reported with drugs of this class.
A history of increased intraocular pressure, narrow angle glaucoma.
Disorders of micturition due to an impeded flow of urine (e.g. in diseases of the prostate).
A low convulsion threshold (e.g. due to brain damage of varying aetiology, epilepsy, concomitant use of other drugs, such as neuroleptics that may lower the seizure threshold, and withdrawal from alcohol or drugs with anticonvulsive properties, e.g. benzodiazepines). The occurrence of seizures seems to be dose dependent. The recommended daily dose of Anafranil should, therefore, not be exceeded.
Severe hepatic or renal diseases.
Tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), in whom the drug may provoke hypertensive crises.
Hyperthyroidism, or concomitant treatment with thyroid preparations, since aggravation of unwanted cardiac effects can generally be expected to occur owing to the anticholinergic action.
Chronic constipation, as tricyclic antidepressants may cause paralytic ileus, particularly in elderly and in bedridden patients.

QTc prolongation.

There may be a risk of QTc prolongation and torsades de pointes, particularly at supratherapeutic doses or supratherapeutic plasma concentrations of clomipramine, as occur in the case of comedication 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 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Equally, concomitant administration of drugs that can prolong the QTc interval should be avoided. It is established that hypokalaemia is a risk factor for QTc prolongation and torsades de pointes. Therefore, hypokalaemia should be treated before initiating treatment with Anafranil. Anafranil should be used with caution when combined with diuretics (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Serotonin syndrome.

Due to the risk of serotonergic toxicity, it is advisable to adhere to recommended doses of clomipramine. Serotonin syndrome, with symptoms, such as hyperpyrexia, myoclonus, agitation, seizures, delirium and coma, can possibly occur when clomipramine is coadministered with serotonergic medications such as SSRIs, SNaRIs, tricyclic antidepressants or lithium. For fluoxetine, a washout period of two to three weeks is advised before and after treatment with fluoxetine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Electroconvulsive therapy.

Concomitant use of tricyclic antidepressants and electroconvulsive therapy should only be undertaken under careful supervision as there is minimal clinical experience with this combination.

Central nervous system effects.

Many patients with panic disorder experience intensified anxiety symptoms at the start of the 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.
Owing to their activating effect, tricyclic antidepressants may cause anxiety, feelings of unrest and hyperexcitation in agitated patients and patients with accompanying schizophrenic symptoms. Activation of psychosis has occasionally been observed in patients with schizophrenia receiving tricyclic antidepressants.
In predisposed and elderly patients, particularly at night, tricyclic antidepressants may provoke drug induced (delirious) psychoses, which disappear without treatment within a few days of withdrawing the drug.

Treatment discontinuation.

Abrupt discontinuation of Anafranil therapy should be avoided because of possible withdrawal symptoms (see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, dosage should be stopped gradually after regular use for long duration and the patient should be monitored carefully when Anafranil therapy is discontinued.

Patient monitoring.

Before initiating treatment with Anafranil, pre-existing hypokalaemia should be treated.
Before starting 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.
The blood count should be monitored during treatment with Anafranil (especially if the patient develops fever, sore throat or other symptoms which are associated with influenza infection), since isolated cases of agranulocytosis have been associated with the use of tricyclic antidepressants. This is particularly called for during the first few months of therapy and during prolonged treatment.
In patients with hepatic and renal disease or a history of liver disease, periodic monitoring of the hepatic enzyme levels and renal function is recommended (see Section 4.8 Adverse Effects (Undesirable Effects)).

Dental effects.

Treatment with tricyclic antidepressants can lead to an increased incidence of dental caries.

Effects on the eye.

Decreased lacrimation and accumulation of mucoid secretions may cause damage to the corneal epithelium in patients with contact lenses.

Anaesthesia.

Before general or local anaesthesia, the anaesthetist should be notified that the patient has been receiving Anafranil (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Bipolar disorder and activation of mania/ hypomania.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed that treating such an episode with antidepressant alone can increase the likelihood of precipitation of a mixed/ manic episode in patients at risk of bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression.

Lactose and sucrose.

Anafranil tablets contain lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, severe lactase deficiency, sucrase-isomaltase insufficiency or glucose-galactose malabsorption should not take Anafranil tablets.

Use in hepatic and renal impairment.

Caution is called for when employing tricyclic antidepressants in patients with hepatic or renal impairment (see Section 4.4 Special Warnings and Precautions for Use).

Use in the elderly.

Elderly patients generally show a more marked response to Anafranil than patients belonging to intermediate age groups (see Section 4.2 Dose and Method of Administration, Elderly patients).

Use in children and adolescents (< 18 years).

The safety and efficacy of Anafranil for the treatment of depression or other psychiatric disorders in children and adolescents aged less than 18 years has not been satisfactorily established. Anafranil should not be used in this age group for the treatment of depression or other psychiatric disorders. Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are not available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions resulting in a contraindication.

MAO inhibitors.

These agents, which are also potent CYP2D6 inhibitors in vivo, such as moclobemide, are contraindicated for coadministration with clomipramine.
If Anafranil is to be used after treatment with a MAO inhibitor, it is absolutely essential that an interval of at least 14 days should elapse before starting therapy, otherwise severe interactions may occur (e.g. hyperactivity, hypertensive crisis, hyperpyrexia, spasticity, convulsions, coma or death), including those consistent with serotonin syndrome (see Section 4.4 Special Warnings and Precautions for Use). The same precaution should be taken when administering a MAO inhibitor after previous treatment with Anafranil. In either instance, medication with Anafranil or with the MAO inhibitor should be started cautiously and the dosage raised stepwise until the optimum response is obtained (see Section 4.3 Contraindications).
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 two week washout period must be observed if the MAO-A inhibitor is given after Anafranil has been used. Patients should be monitored for symptoms suggestive of serotoninergic syndrome (serotonin syndrome).

Interactions resulting in a concomitant use not recommended.

Antiarrhythmic agents.

Antiarrhythmics (such as quinidine and propafenone) which are potent inhibitors of CYP2D6, should not be used in combination with tricyclic antidepressants.

Diuretics.

Comedication of Anafranil with diuretics may lead to hypokalaemia, which in turn increases the risk of QTc prolongation and torsades de pointes. Therefore, hypokalaemia should be treated prior to administration of Anafranil (see Section 4.4 Special Warnings and Precautions for Use).

Selective serotonin reuptake inhibitors (SSRI).

SSRIs which are inhibitors of CYP2D6, such as fluoxetine, paroxetine or sertraline, and of others including CYP1A2 and CYP2C19 (e.g. fluvoxamine) may also increase plasma concentrations of clomipramine with corresponding adverse effects. Steady-state serum levels of clomipramine increased ~ 4-fold by coadministration of fluvoxamine and N-desmethylclomipramine decreased ~ 2-fold. For fluoxetine, a washout period of two to three weeks is advised before and after treatment with fluoxetine.

Serotonergic agents.

Serotonin syndrome can possibly occur when clomipramine is coadministered with serotonergic medications such as serotonin reuptake inhibitors (SSRIs), serotonin and noradrenergic reuptake inhibitors (SNaRIs), tricyclic antidepressants or lithium (see Section 4.4 Special Warnings and Precautions for Use).

Interactions resulting in increased effect of Anafranil.

Concomitant administration of CYP2D6 inhibitors may lead to an increase in concentration of both active components, up to ~3-fold in patients with a debrisoquine/ sparteine extensive metaboliser phenotype, converting them to a poor metaboliser phenotype. Concomitant administration of CYP1A2, CYP2C19 and CYP3A4 inhibitors is expected to increase clomipramine concentrations and decrease N-desmethylclomipramine, thus not necessarily affecting the overall pharmacology.

Terbinafine.

Coadministration of Anafranil with oral antifungal terbinafine, a strong inhibitor of CYP2D6, may result in increased exposure and accumulation of clomipramine and its N-demethylated metabolite. Therefore, dose adjustments may be necessary when coadministered with terbinafine.

Cimetidine.

Since cimetidine is an inhibitor of several P450 enzymes, including CYP2D6 and CYP3A4, and raises the plasma concentration of tricyclic antidepressants, the dosage of the tricyclic agent should be reduced if the two drugs are administered concurrently.

Oral contraceptives.

No interaction between chronic oral contraceptive use (15 or 30 microgram ethinyloestradiol daily) and Anafranil (25 mg daily) has been documented. Oestrogens 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 oestrogen (50 microgram 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 oestrogen regimens. Monitoring therapeutic response of tricyclic antidepressants at high dose oestrogen regimens (50 microgram daily) is recommended and dose adjustments may be necessary.

Antipsychotics.

Comedication of antipsychotics (e.g. phenothiazines) may result in an increase in the plasma concentration of tricyclic antidepressant agents, a lowered convulsion threshold and seizures. Combination with thioridazine may produce severe cardiac arrhythmias.

Methylphenidate.

By potentially inhibiting their metabolism, methylphenidate may cause the plasma concentration of tricyclic antidepressants to rise and so intensify their antidepressant effect. A dose reduction of the tricyclic antidepressant may be necessary.

Benzodiazepines.

It might be necessary to lower the dosage of the tricyclic antidepressant if administered concomitantly with alprazolam. No such effects are known to occur in combination with diazepam.

Disulfiram.

It might be necessary to lower the dosage of the tricyclic antidepressant if used concomitantly with disulfiram.

Valproate.

Concomitant administration of valproate with clomipramine may cause inhibition of CYP2C and/or UGT enzymes resulting in increased serum levels of clomipramine and desmethylclomipramine. Caution is therefore required when prescribing Anafranil to patients taking this medicine.

Grapefruit, grapefruit juice, or cranberry juice.

Concomitant administration of Anafranil with grapefruit, grapefruit juice, or cranberry juice may increase the plasma concentrations of clomipramine. Caution is therefore required when prescribing Anafranil to patients taking these products.

Interactions resulting in decreased effect of Anafranil.

Rifampicin and anticonvulsants.

CYP3A and CYP2C inducers, such as rifampicin or anticonvulsants (e.g. barbiturates, carbamazepine, phenobarbital and phenytoin), may decrease clomipramine concentrations as concomitant administration of drugs known to induce cytochrome P450 enzymes, particularly CYP3A4, CYP2C19 may accelerate the metabolism and decrease the efficacy of Anafranil.

Cigarette smoking.

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 nonsmokers (no change in N-desmethylclomipramine).

Colestipol and colestyramine.

Concomitant administration of ion exchange resins such as colestyramine or colestipol may reduce the plasma levels of clomipramine. Caution is therefore required when prescribing Anafranil to patients taking these medicines.

St John's wort.

Concomitant administration of St John's wort may reduce the plasma levels of clomipramine. Caution is therefore required when prescribing Anafranil to patients taking St John's wort.

Interactions affecting other drugs.

Anticholinergic agents.

When tricyclic antidepressants are given in combination with anticholinergics, including those used to treat Parkinson's disease, antihistamines, atropine, biperiden or neuroleptics such as phenothiazines with an anticholinergic action, hyperexcitation states or delirium may occur, as well as attacks of glaucoma, urinary retention or paralytic ileus.

Antihypertensive agents.

Since tricyclic antidepressants may reduce or abolish the antihypertensive effect of clonidine, guanethidine, bethanidine, reserpine and methyldopa, antihypertensive agents with a different mode of action (e.g. beta-blockers) should be used if necessary.

Alcohol and other central nervous system depressants.

Tricyclic antidepressants may also increase the effect of alcohol and other central depressant substances (e.g. barbiturates, benzodiazepines or general anaesthetics).

Sympathomimetic amines.

The cardiovascular effects of sympathomimetic agents such as adrenaline, noradrenaline and amphetamine may be potentiated by tricyclic antidepressants. This includes sympathomimetic amines in nose drops or in local anaesthetic preparations.

Anticoagulants.

Some tricyclic antidepressants may potentiate the anticoagulant effect of coumarin drugs such as warfarin, which may be due to inhibition of their hepatic 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 is advised.
Clomipramine is also an in vitro (Ki = 2.2 microM) and in vivo inhibitor of CYP2D6 activity (sparteine oxidation) and, therefore, may cause increased concentrations of coadministered compounds that are primarily cleared by CYP2D6 in extensive metabolisers.

Anticonvulsants.

Concomitant administration of a tricyclic antidepressant with phenytoin or carbamazepine may lead to elevated serum phenytoin or carbamazepine concentrations. If necessary, the doses of the drugs should be adjusted accordingly.

Pharmacokinetic related interactions.

Clomipramine is predominately 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 P450s are involved in the demethylation, mainly CYP3A4, CYP2C19 and CYP1A2. Elimination of both active components is by hydroxylation and this is catalysed by CYP2D6 (see Section 5.2 Pharmacokinetic Properties, Metabolism).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
Tricyclic antidepressants have not been shown to be associated with an increased incidence of birth defects. However, there is evidence of interference with central monoamine neurotransmission in rats. Care should be taken that there are sound indications for the use of these antidepressants in pregnancy. Experience with Anafranil in pregnancy is limited. Since there have been isolated reports of a possible connection between the use of Anafranil and adverse effects (developmental disorders) on the fetus, treatment with Anafranil should be avoided during pregnancy and only considered if the benefits expected justify the potential risk for the fetus.
Newborn infants whose mothers had taken Anafranil up until delivery showed symptoms, such as dyspnoea, cyanosis, lethargy, feeding difficulties, colic, irritability, convulsions, tremor, hypertonia, hypotonia or spasms during the first hours or days of life. To guard against such symptoms, Anafranil should be gradually withdrawn, if at all possible, at least 7 weeks before the calculated date of confinement.
 As clomipramine passes into human milk, babies should be weaned or the medication gradually withdrawn.

4.7 Effects on Ability to Drive and Use Machines

Anafranil may cause blurred vision, drowsiness and other nervous system and psychiatric related disorders such as somnolence, disturbance in attention, confusion, disorientation, aggravation of depression, delirium, etc. (see Section 4.8 Adverse Effects (Undesirable Effects)) which may impair the patient's reactions. Patients must, therefore, be warned against engaging in activities that require quick reactions, such as driving motor vehicles and operating machines. Patients should also be warned that alcohol or other drugs may potentiate these effects (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.
Adverse reactions do not always correlate with plasma drug levels or dose. If severe neurological or psychiatric reactions occur, Anafranil should be withdrawn.
Reporting frequencies are described as follows. Very common: ≥ 10%; common: ≥ 1 - < 10%; uncommon: ≥ 0.1 - < 1%; rare: ≥ 0.01 - < 0.1%; very rare: < 0.01%.

Blood and lymphatic system disorders.

Very rare: leucopoenia, agranulocytosis, thrombocytopenia, eosinophilia. One case of pancytopenia has been reported.

Cardiac disorders.

Common: orthostatic hypotension, sinus tachycardia, clinically irrelevant ECG changes (e.g. T and ST-wave changes) in patients of normal cardiac status, palpitations.
Uncommon: arrhythmias, blood pressure increased.
Very rare: conduction disorders (e.g. widening of QRS complex, prolonged PR and QTc (QT/RR) intervals, bundle branch block, torsades de pointes, particularly in patients with hypokalaemia), cardiomyopathy, congestive cardiac failure, myocardial infarction, stroke and sudden death.

Ear and labyrinth disorders.

Common: tinnitus.

Endocrine disorders.

Very rare: SIADH (inappropriate antidiuretic hormone secretion syndrome).

Eye disorders.

Very common: accommodation disorder, vision blurred.
Common: mydriasis.
Very rare: glaucoma.

Gastrointestinal disorders.

Very common: nausea, dry mouth, constipation.
Common: vomiting, abdominal disorders, diarrhoea, anorexia.
Very rare: paralytic ileus.

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, acute hepatitis, hepatic necrosis.

Immune system disorders.

Very rare: anaphylactic and anaphylactoid reactions including hypotension.

Investigations.

Very common: weight increased.
Common: transaminases increased, alkaline phosphatase increased.
Very rare: electroencephalogram abnormal.

Metabolism and nutrition disorders.

Very common: increased appetite.
Common: decreased appetite.

Musculoskeletal and connective tissue disorders.

Common: muscular weakness.

Nervous system disorders.

Very common: drowsiness, dizziness, tremor, headache, myoclonus, somnolence, increased appetite.
Common: speech disorders, paraesthesia, muscle hypertonia, dysgeusia, memory impairment, disturbance in attention.
Uncommon: convulsions, ataxia.
Very rare: peripheral neuropathy, 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 disorders, mania, hypomania, aggression, depersonalisation, insomnia, nightmares, aggravation of depression, delirium.
Uncommon: activation of psychotic symptoms.

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 allergic (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.

Withdrawal symptoms.

Common. Although not indicative of addiction, withdrawal symptoms follow abrupt discontinuation of treatment or reduction of the dose: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, anxiety, dizziness and worsening of psychiatric status.

Bone fractures.

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and tricyclic antidepressants. The mechanism leading to this risk is unknown.

Geriatric population.

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

Additional adverse drug reactions from postmarketing spontaneous reports.

The following additional adverse drug reactions have been identified with Anafranil based on postmarketing 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.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
Since children react much more sensitively than adults to acute overdosages of tricyclics, and since fatalities have been reported, every effort should be made to avoid an overdosage (see Section 6.4 Special Precautions for Storage, Safety note concerning children) which, if it does occur, should be treated with extreme care.

Signs and symptoms.

The first signs and symptoms of poisoning with tricyclic antidepressants generally take the form of severe anticholinergic reactions, which set in about ½ to 2 hours after the drug has been taken. Owing to delayed absorption (anticholinergic effect), long half-life and enterohepatic recycling of the drug, the patient may be at risk for up to 4-6 days.
The severity of poisoning with tricyclic antidepressants may depend on various factors, such as the amount of the drug absorbed, the time elapsing between its ingestion and the start of treatment and the patient's age.
The following signs and symptoms may be encountered.

Central nervous system.

Somnolence, stupor, coma, ataxia, restlessness, agitation, mydriasis, hyper-reflexia, muscle rigidity, athetoid and choreoathetosis, convulsions. In addition, symptoms consistent with the serotonin syndrome (e.g. hyperpyrexia, myoclonus, delirium and coma) may be observed.

Cardiovascular system.

Arrhythmias (including torsades de pointes), tachycardia, QTc prolongation, conduction disorders, hypotension, shock, heart failure; in very rare cases, cardiac arrest.

Respiratory system.

Respiratory depression, apnoea, cyanosis.

Other.

Vomiting, fever, sweating and oliguria or anuria may occur.

Treatment.

There is no specific antidote and treatment is essentially symptomatic and supportive.
Where the drug has been taken by mouth, activated charcoal should be administered.
Anyone suspected of receiving an overdose of Anafranil, particularly children, should be hospitalised and kept under close surveillance for at least 72 hours. Severe poisoning with tricyclic drugs requires immediate hospitalisation and continuous cardiovascular monitoring for at least 48 hours.
In all patients with ECG abnormalities, cardiac function should be kept under close observation for at least another 72 hours, even after the ECG tracings have reverted to normal, because relapses may occur.
The following measures should be taken in cases of overdosage.
In respiratory failure, intubation and artificial respiration.
In severe hypotension, place the patient in an appropriate position and give a plasma expander.
Cardiac arrhythmias must be treated according to the requirements of the case.
Implantation of a cardiac pacemaker should be considered.
Low serum potassium and acidosis should be corrected.
In convulsions, diazepam should be given i.v. Other anticonvulsants may be required.
Dialysis and haemodialysis are of no use.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Clomipramine is a tricyclic antidepressant. It inhibits the neuronal reuptake of noradrenaline (NA) and serotonin (5HT) released in the synaptic cleft, inhibition of 5HT uptake being the dominant component of this activity. Clomipramine also has a wide spectrum of pharmacological action, including α1-adrenolytic, anticholinergic, antihistaminic and antiserotonergic (5HT-receptor blocking) properties.

5.2 Pharmacokinetic Properties

Absorption.

The active substance is completely absorbed following oral administration, but due to extensive hepatic first-pass metabolism to the active metabolite N-desmethylclomipramine, less than 50% of a dose reaches the systemic circulation unchanged.
During oral administration of constant daily doses of Anafranil, the steady-state plasma concentrations of clomipramine show wide variations between patients. The standard dose recommended for treatment of depression (i.e. 75 mg administered as Anafranil 25 mg t.i.d.) produced steady-state concentrations ranging from 31 to 186 nanogram/mL. This scatter reflects differences in the drug's distribution volume and clearance between individuals. Variations in concentration in any one patient are much less than those between patients.
The steady-state concentrations of the active metabolite N-desmethylclomipramine follow a similar pattern. On average, they reach 68 to 334 nanogram/mL at a dose of 75 mg Anafranil per day.
Owing to lower plasma clearance of clomipramine, elderly patients require smaller doses of Anafranil than patients in intermediate age groups.

Distribution.

Clomipramine is highly (97.6%) bound to serum proteins. Its distribution and elimination follow two compartment kinetics, with a beta-phase half-life of 21 hours (range 12 to 36 hours). The principal metabolite, N-desmethylclomipramine, has a beta-phase half-life in the range of 13 to 25 hours.
In the cerebrospinal fluid the concentration is equivalent to about 2% of the plasma concentration.
The distribution volume of unchanged clomipramine is approximately 12 L/kg bodyweight.

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, primarily CYP3A4, CYP2C19 and CYP1A2. Clomipramine and N-desmethylclomipramine are hydroxylated to form 8-hydroxyclomipramine or 8-hydroxy- N-desmethylclomipramine. The activity of the 8-hydroxy metabolites are not defined in vivo. 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-hydroxyclomipramine is catalysed by CYP2D6.

Excretion.

Two-thirds of a single dose of clomipramine is excreted in the form of water soluble conjugates in the urine and about one-third in the faeces. The quantity of unchanged clomipramine and N-desmethylclomipramine excreted in the urine amounts in each instance to less than 1% of the dose administered.

5.3 Preclinical Safety Data

Carcinogenicity/ mutagenicity/ reproduction toxicity studies.

According to the experimental data available, Anafranil has no mutagenic, carcinogenic or teratogenic effects. However, Anafranil has been shown to be embryotoxic in the mouse and rat at the lowest dose tested, which was 4 times the maximum recommended human dose on a bodyweight basis.

6 Pharmaceutical Particulars

6.1 List of Excipients

Anafranil tablets are sugar coated and contain 25 mg of clomipramine with the excipients: colloidal anhydrous silica, glycerol, lactose monohydrate, magnesium stearate, maize starch, stearic acid, purified talc, hypromellose, copovidone and titanium dioxide. In addition the sugar coating contains microcrystalline cellulose, povidone, macrogol 8000, sucrose and the dye, iron oxide yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Protect from moisture.

Safety note concerning children.

Patients should be advised to keep Anafranil out of reach of children.

6.5 Nature and Contents of Container

PVC/PE/PVDC/Al blister packs of 50 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Clomipramine is the 3-chloro derivative of imipramine. It is a white crystalline powder, soluble in water, slightly soluble in ethyl alcohol and insoluble in diethyl ether.

Chemical structure.


3-chloro-5- [3-(dimethylamino) -propyl] -10,11-dihydro -5H-dibenz[b,f]azepine hydrochloride (clomipramine hydrochloride).
Empirical formula: C19H23N2Cl.HCl.
Molecular weight: 351.3.

CAS number.

17321-77-6.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

Summary Table of Changes