Consumer medicine information

Placil

Clomipramine hydrochloride

BRAND INFORMATION

Brand name

Placil

Active ingredient

Clomipramine hydrochloride

Schedule

What is in this leaflet

This leaflet answers some common questions about PLACIL.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking PLACIL against the benefits expected for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Please read this leaflet carefully and keep it with your medicine. You may need to read it again.

What PLACIL is used for

PLACIL is used to treat:

depression
obsessive-compulsive disorders and phobias in adults
muscle weakness in people with a sleep disorder called narcolepsy.

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.

PLACIL belongs to a group of medicines called tricyclic antidepressants. These medicines are thought to work by their action on brain chemicals called amines.

Ask your doctor if you have any questions about why PLACIL has been prescribed for you. Your doctor may have prescribed PLACIL for another reason.

PLACIL is not approved for use in children and adolescents below 18 years of age for the treatment of depression and other psychiatric disorders. The safe use and effectiveness of PLACIL in treating the above conditions, for this age group, has not been established.

PLACIL is available only with a doctor's prescription.

Before you take PLACIL

When you must not take it

Do not take PLACIL if you are allergic to:

medicines containing clomipramine or any other tricyclic antidepressant
any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include skin rash, itching or hives; swelling of the face, lips or tongue, difficulty in swallowing; wheezing or shortness of breath.

Do not take PLACIL if you are taking, or have taken within the last 14 days, another medicine for depression called a monoamine oxidase inhibitor (MAOI). Taking PLACIL together with a MAOI or taking it too soon after stopping a MAOI may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and seizures (fits). Your doctor will tell you when it is safe to start taking PLACIL after stopping the MAOI.

Ask your doctor or pharmacist if you are not sure if you have been taking one of these medicines.

Do not take PLACIL if you have:

recently had a heart attack
congenital long QT syndrome - people with this inherited heart condition have electrical disturbances in the heart, which may cause sudden, extremely rapid heart rates.

Taking PLACIL could make your condition worse.

Do not take PLACIL if the expiry date (EXP) printed on the pack has passed. If you take this medicine after the expiry date has passed, it may not work as well.

Do not take PLACIL if the packaging shows signs of tampering or if the tablets do not look right.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

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

Tell your doctor if you are pregnant or plan to become pregnant. There have been reports of some babies experiencing complications immediately after delivery. Your doctor will discuss the possible risks and benefits of taking PLACIL during pregnancy.

Tell your doctor if you smoke. Nicotine in cigarette smoke can affect the amount of PLACIL that is in your body. Changes in your usual smoking habits can also change the effects of PLACIL.

Tell your doctor if you are breastfeeding or wish to breastfeed. Breastfeeding is not recommended while taking PLACIL. The active ingredient passes into breast milk and may affect your baby.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

heart or blood vessel problems including coronary heart disease, angina (chest pain), abnormal heart beat, or congenital long QT syndrome
liver or kidney problems
high or low blood pressure
glaucoma, a condition characterised by an increased pressure in the eye
difficulty in passing urine, due to prostate problems or any other cause
overactive thyroid
any mental illness other than the one being treated (e.g. mania, bipolar disorders, schizophrenia)
Parkinson's disease
epilepsy or (seizures) fits
tumour of the adrenal gland
chronic constipation
hypokalaemia, or low potassium levels in the blood
lactose or galactose intolerance
(PLACIL tablets contain sugars as lactose monohydrate).

If you have not told your doctor about any of the above, tell them before you start PLACIL.

Taking other medicines

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

Some medicines may be affected by PLACIL, or may affect how well it works. These include:

other medicines for depression such as:
- MAOIs, such as phenelzine (e.g. Nardil), tranylcypromine (e.g. Parnate) and moclobemide (e.g. Aurorix, Arima) (see "When you must not take it" section)
- SSRIs and SNRIs, such as fluoxetine (e.g. Prozac, Lovan), paroxetine (e.g. Aropax, Paxtine), sertraline (e.g. Zoloft), fluvoxamine (e.g. Luvox, Movox), and nefazodone (Serzone)
sleeping tablets or sedatives
some medicines for anxiety
other medicines for mental illness
some medicines for high blood pressure or irregular heart beats
certain cough and cold preparations including nose drops
antihistamines, medicines for allergy, hayfever or travel sickness
medicines to relieve gut cramps or spasms, e.g. hyoscine (Buscopan), mebeverine (Colofac)
certain medicines for Parkinson's disease such as biperiden (Akineton), benztropine (Cogentin)
medicines for epilepsy, such as carbamazepine (Teril, Tegretol) or phenytoin (Dilantin)
medicines to prevent blood clots, such as warfarin (Coumadin, Marevan)
cimetidine (Tagamet, Magicul), a medicine used to treat reflux and ulcers
methylphenidate (Ritalin, Attenta), a medicine used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy
medicines containing estrogen such as birth control pills and hormone replacement therapy
nicotine in medicines used to help you quit smoking, such as nicotine gum, patches, lozenges or inhalers
diuretics, also called fluid tablets
disulfiram, a medicine used to deter alcohol consumption
medicines for thyroid problems
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.

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking PLACIL.

How to take PLACIL

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack, ask your doctor or pharmacist.

How much to take

The dose varies from person to person.

Take PLACIL exactly as directed by your doctor. Your doctor will tell you how many tablets you need to take each day and when to take them. The dose may depend on your age, your condition and whether or not you are taking any other medicines.

PLACIL is usually started using low doses. Your doctor may gradually increase this dose depending on how you respond to this medicine.

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 increased slowly up to 4 to 6 tablets (100 to 150 mg) 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. The usual adult maintenance dose is between 2 to 4 tablets (50 to 100 mg) each day.

For muscle weakness in people with narcolepsy, the dose is usually from 1 to 3 tablets (25 to 75 mg) each day.

If you are older than 65 years old, your doctor will probably start with a low dose (e.g 1 tablet a day (25 mg)) to help avoid side effects. The dose is gradually increased over about ten days to 2 to 3 tablets (50 to 75 mg) each day and kept at that dose for the rest of your treatment.

How to take it

Swallow the tablets with a glass of water.

PLACIL can be taken with or without food.

If your stomach is upset after taking the tablets, take them with a meal or after a snack.

When to take it

The tablets are usually taken in 2 to 3 doses spaced throughout the day, unless your doctor advises you otherwise.

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

If you have narcolepsy and you have trouble sleeping at night, take the last dose before the evening to avoid making your insomnia worse.

If you forget to take it

If it is almost time for your next dose (e.g. within 2 or 3 hours), skip the dose you missed and take the next one 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 are not sure what to do, check with your doctor or pharmacist.

How long to take it

Keep taking PLACIL for as long as your doctor recommends. The length of treatment will depend on your condition and how you respond to PLACIL.

Most medicines of this type take time to work, so do not be discouraged if you do not feel better right away.

Some of your symptoms may improve in 1 or 2 weeks, but it can take up to 4 or 6 weeks to feel the full benefit of PLACIL. Even when you feel well, you will usually have to take PLACIL for several months or longer, to make sure that the benefits last.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital; if you think you or anyone else may have taken too much PLACIL.

Do this even if there are no signs of discomfort or poisoning.

Keep the telephone numbers for these places handy. You may need urgent medical attention.

If you take too much PLACIL, you may feel sleepy, restless or agitated, stiff or have unusual muscle movements. You may also vomit, sweat, have a fever, fits, have an irregular heartbeat, drop in blood pressure or have difficulty breathing. You may lose consciousness.

Keep PLACIL out of the reach of children. Children are much more sensitive than adults to tricyclic antidepressants such as PLACIL. An accidental overdose is especially dangerous.

While you are taking PLACIL

Things you must do

Tell your doctor immediately if you have any suicidal thoughts or other mental/mood changes. Occasionally, the symptoms of depression or other psychiatric conditions may include thoughts of harming yourself or committing suicide. These symptoms may continue or get worse during the first one to two months of treatment until the full antidepressant effect of the medicine becomes apparent. This is more likely to occur in young adults under 25 years of age.

Contact your doctor or a mental health professional right away or go to the nearest hospital for treatment if you or someone you know is showing any of the following warning signs of suicide:

new or worsening depression
new or worsening anxiety
feeling very agitated or restless
panic attacks
thoughts or talk of death or suicide
thoughts or talk of self-harm or harm to others
any recent attempts of self-harm or suicide
increase in aggressive behaviour, irritability or any other unusual changes in behaviour or mood.
new or worsening irritability
difficulty sleeping (insomnia)
acting on dangerous impulses
an extreme increase in activity and talking.

All mentions of suicide or violence must be taken seriously.

Keep all of your appointments with your doctor 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 prevent unwanted side effects.

Tell your doctor immediately if you become pregnant while taking PLACIL. Do not stop taking your tablets until you have spoken to your doctor.

Before starting any new medicine, tell your doctor or pharmacist that you are taking PLACIL.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking PLACIL.

If you plan to have any surgery, including dental surgery or minor surgery, tell your doctor, anaesthetist or dentist that you are taking PLACIL.

Your doctor may ask you to stop taking PLACIL a few days before elective surgery. Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel the tablets are not helping your condition.

Things you must not do

Do not stop taking PLACIL or lower the dose without checking with your doctor. Do not let yourself run out of medicine over weekends or holidays. Suddenly stopping PLACIL may cause nervousness, vomiting, diarrhoea, headache and nausea. It can also worsen your condition.

Your doctor will tell you how to gradually reduce the amount of PLACIL you are taking before stopping completely.

Do not use PLACIL to treat any other conditions unless your doctor tells you to.

Do not give PLACIL to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how PLACIL affects you. PLACIL may cause drowsiness, blurred vision, dizziness or lightheadness in some people. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when drinking alcohol or taking pain relievers, sleeping tablets or antihistamines (medicines for colds or allergies such as hay fever) while you are taking PLACIL. Combining alcohol with PLACIL can make you more drowsy, dizzy or lightheaded. Your doctor may suggest you avoid alcohol while being treated with PLACIL.

Be careful getting up from a sitting or lying position. Dizziness, lightheadedness or fainting may occur, especially when you get up quickly. Getting up slowly may help.

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.

Be careful to stay out of direct sunlight as much as possible until you find out if your skin is more sensitive than usual. PLACIL may cause your skin to be more sensitive than usual to sunlight. Wear protective clothing and use SPF 30+ sunscreen.

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.

Tell your doctor or dentist if your mouth continues to feel dry for more than 2 weeks. PLACIL may cause dry mouth. This can be relieved by frequent sips of water, sucking sugarless lollies or chewing sugarless gum. However, continuing dryness of the mouth may increase the chance of dental disease, including tooth decay and gum disease.

Families and carers should be aware that special care might be needed when elderly patients take PLACIL. They may become confused and are more likely to experience side effects when taking PLACIL.

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

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking PLACIL. Like all other medicines, PLACIL may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

If you are over 65 years of age, you may have an increased chance of getting side effects. Report any side effects promptly to your doctor. PLACIL can cause confusion or disorientation, especially in older people or those with Parkinson's disease. Your family or carer may be needed.

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

Ask your doctor or pharmacist any questions you may have.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Tell your doctor if you notice any of the following and they worry you:

dryness of the mouth
sweating, hot flushes
feeling sick (nausea), vomiting, diarrhoea
changes in taste
change in appetite, weight gain or weight loss
constipation
blurred vision, difficulty focussing eyes, especially when treatment is started or dose is increased.
Lightheadedness, especially when you get up too quickly from a sitting or lying down position.
dizziness, shakiness, muscle spasms
drowsiness, tiredness
headache, loss of memory or reduced concentration, mental dullness
restlessness, anxiety
confusion, hallucinations
difficulty in passing urine or frequent passing of large amounts of urine
changes in sex drive, or difficulty reaching orgasm or delayed or no ejaculation of semen if you are a male
ringing in the ears
increased sensitivity to the sun
change in sense of taste.
dry or sticky eyes if you wear contact lenses
compelling need to be in constant motion
repetitive, involuntary, purposeless movements
disturbed sleep or nightmares
sores in the mouth or tongue
swelling of the breast or discharge of milk
swelling of testicles
hair loss

Tell your doctor immediately if you notice any of the following:

any numbness, weakness or tingling of the arms or legs
unsteadiness when walking or difficulty coordinating your movements
weakness or loss of balance
difficulty in speaking or slurred speech
severe drowsiness or dizziness.
signs of frequent infections such as fever, chills, sore throat or swollen glands (constant flu-like symptoms)
bruising or bleeding more easily than usual
eye pain
signs of liver disease such as nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine
abnormal ideas or hallucinations
mood swings alternating from one of excitement, overactivity and uninhibited behaviour to a depressed mood.
pain in the stomach or abdomen that is severe or doesn't go away.

The above list includes serious side effects that require medical attention.

See your doctor immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following:

fainting, collapse
fast, irregular or pounding heart beat, chest pain
fits or seizures
a sudden increase in body temperature, extremely high blood pressure and severe convulsions
signs of an allergic reaction such as skin rash, itching or hives, swelling of the face, lips or tongue, difficulty in swallowing, wheezing or shortness of breath.
symptoms like agitation, confusion, diarrhoea, high temperature, increased blood pressure, excessive sweating and rapid heartbeat (a syndrome due to an increase in naturally occurring messenger, serotonin)

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything that is making you feel unwell.

This is not a complete list of all possible side effects.

Other side effects not listed above may also occur in some patients.

After using PLACIL

Storage

Keep PLACIL where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store PLACIL or any other medicine in the bathroom or near a sink.

Do not leave PLACIL in the car or on windowsills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking PLACIL, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

PLACIL is a white, biconvex tablet, marked "Cl 25" on one side and "G" on the other.

Each pack contains 50 tablets.

Ingredients

The active ingredient in PLACIL is clomipramine hydrochloride. Each PLACIL tablet contains 25 mg of clomipramine hydrochloride.

The tablets also contain:

lactose monohydrate
maize starch
povidone
sodium starch glycollate
magnesium stearate
purified talc
Instacoat Universal White (A05G15138) ARTG PI No: 144681.

PLACIL tablets contain sugar as lactose and trace quantities of sulfites.

Sponsor

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

Australian registration number:
AUST R 143879

This leaflet was prepared on
May 2023.

PLACIL® is a Viatris company trade mark

PLACIL_cmi\May23/00

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Placil

Active ingredient

Clomipramine hydrochloride

Schedule

1 Name of Medicine

Clomipramine hydrochloride.

2 Qualitative and Quantitative Composition

Each tablet contains 25 mg of clomipramine hydrochloride.

Excipients with known effect.

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

3 Pharmaceutical Form

Clomipramine hydrochloride 25 mg tablet: white, film coated, biconvex tablets marked "Cl 25" on one side and "G" on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of major depression, obsessive-compulsive disorders and phobias in adults, and cataplexy associated with narcolepsy.

4.2 Dose and Method of Administration

General.

The dosage and mode of administration should be determined individually and adapted to the patient's condition. Doses should be kept as low as possible and increased cautiously, particularly when treating elderly patients. These patients generally show a more marked response to Placil than patients in intermediate age groups. 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.
The efficacy and tolerability of Placil during treatment must be judged by keeping the patient under close surveillance.

Depression, obsessive-compulsive disorders and phobias.

Commence treatment with 25 mg (one tablet) two or three times daily. Increase the daily dosage stepwise, e.g. 25 mg every few days (depending on how the medication is tolerated) to 100 to 150 mg (four to six tablets). Once a distinct improvement has set in, adjust the daily dosage to a maintenance level averaging 50 to 100 mg (two to four tablets).

Cataplexy accompanying narcolepsy.

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

Elderly patients.

Elderly patients generally show a more marked response to Placil than patients belonging to intermediate age groups. Placil should be used with caution in elderly and doses should be increased cautiously. Start treatment with 25 mg (one tablet) daily. Gradually increase the dosage over about ten days to an optimum level of 50 to 75 mg daily. This dose should then be adhered to until the end of treatment.

4.3 Contraindications

Known hypersensitivity to clomipramine or any of the excipients of the tablets.
Cross sensitivity to tricyclic antidepressants of the dibenzazepine group.
Concomitant use with a monoamine oxidase (MAO) inhibitor, or within 14 days before or after treatment with an irreversible MAO inhibitors (MAOIs), or within 14 days before moclobemide (a reversible MAOI), 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 associated with psychiatric disorders.

The risk of suicide attempt 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 to 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 Placil should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

General precautions.

Caution is called for when employing tricyclic antidepressants in patients with the following conditions or in the following circumstances.
Cardiovascular disorders especially those who have a history of conduction disorders (see below) and in elderly patients. Cardiovascular insufficiency, atrioventricular block (grades I to III) and arrhythmias. Monitoring of cardiovascular function and ECG is called for in such cases, especially in the elderly. Myocardial infarction, precipitation of congestive cardiac failure, stroke and sudden death have been associated with medicines 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 seizure threshold, withdrawal from alcohol or drugs with anticonvulsive properties, e.g. benzodiazepines). Clinical trials with clomipramine in the USA have shown a clear relationship between the size of the dose and the occurrence of seizures. The recommended daily dose of Placil should, therefore, not be exceeded.
Severe hepatic or renal diseases.
Tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), in whom the medicine may provoke hypertensive crises.
Hyperthyroidism or when Placil is used concomitantly with thyroid preparations. Due to the anticholinergic action of clomipramine aggravation of unwanted cardiac effects can generally be expected to occur in these patients.
Chronic constipation, as tricyclic antidepressants may cause paralytic ileus, particularly in elderly and 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 co-medication with selective serotonin reuptake inhibitors (SSRIs) or serotonin and noradrenergic reuptake inhibitors (SNRIs). Therefore, concomitant administration of medicines 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 medicines 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 Placil. Placil 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 increased 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, SNRIs, 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 (CNS) effects.

Many patients with panic disorder experience intensified anxiety symptoms at the start of the treatment with Placil. 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.
Tricyclic antidepressants may provoke delirious psychoses in predisposed and elderly patients, particularly at night. These disappear without treatment within a few days of withdrawing the medicine.
In patients with bipolar affective disorders, a swing from depression to hypomania or mania is possible. It may be necessary, in such cases, to withdraw Placil and administer medicines to control the mania. After such episodes have subsided, low dose therapy with Placil may be resumed if required.

Anaesthetics.

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

Treatment discontinuation.

Abrupt withdrawal should be avoided because of possible adverse reactions (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 Placil therapy is discontinued.

Patient monitoring.

Before initiating treatment, with Placil, 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 medicine with a fall in blood pressure.
The blood count should be monitored during treatment with Placil (especially if the patient develops fever, sore throat or other flu-like symptoms), 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 known liver disease or a history of liver disease; or known renal impairment, periodic monitoring is recommended (see Section 4.8 Adverse Effects (Undesirable Effects)). It is also advisable to monitor hepatic and renal function during long-term therapy with tricyclic antidepressants.

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.

Lactose.

Placil tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption should not take Placil tablets.

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.

Use in hepatic impairment.

Caution is called for when employing tricyclic antidepressants in patients with severe hepatic diseases.
In patients with known liver disease or a history of liver disease, periodic monitoring is recommended (see Section 4.8 Adverse Effects (Undesirable Effects)). It is also advisable to monitor hepatic function during long term therapy with tricyclic antidepressants.

Use in renal impairment.

Caution is called for when employing tricyclic antidepressants in patients with severe renal diseases.
In patients with known renal impairment, periodic monitoring is recommended (see Section 4.8 Adverse Effects (Undesirable Effects)). It is also advisable to monitor renal function during long term therapy with tricyclic antidepressants.

Use in the elderly.

Paediatric use.

The safety and efficacy of Placil for the treatment of depression or other psychiatric disorders in children and adolescents aged less than 18 years has not been satisfactorily established. Placil 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.

Safety note concerning children.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions resulting in a contraindication.

Monoamine oxidase inhibitors (MAOIs).

These agents, which are also potent CYP2D6 inhibitors in vivo, such as moclobemide, are contraindicated for co-administration with clomipramine.
If Placil is to be used after treatment with a MAOI, 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 MAOI after previous treatment with Placil (see Section 4.3 Contraindications). In either instance, medication with Placil or with the MAOI should be started cautiously and the dosage raised stepwise until the optimum response is obtained.
There is evidence to suggest that clomipramine 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 clomipramine 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.

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

Diuretics.

Co-medication of clomipramine 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 Placil (see Section 4.4 Special Warnings and Precautions for Use).

Selective serotonin reuptake inhibitors (SSRIs).

SSRIs which are inhibitors of CYP2D6, such as fluoxetine, paroxetine, 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 SSRIs, SNRIs, tricyclic antidepressants or lithium (see Section 4.4 Special Warnings and Precautions for Use).

Interactions resulting in increased effect of Placil.

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.

Co-administration of Placil 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 co-administered with terbinafine.

Cimetidine.

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

Oral contraceptives.

No interaction between chronic oral contraceptive use (15 or 30 microgram ethinylestradiol daily) and clomipramine (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 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 estrogen regimens. Monitoring therapeutic response of tricyclic antidepressants at high dose estrogen regimens (50 microgram daily) is recommended and dose adjustments may be necessary.

Antipsychotics.

Co-medication 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 administered 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 Placil to patients taking this medicine.

Grapefruit, grapefruit juice, or cranberry juice.

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

Interactions resulting in decreased effect of Placil.

Rifampicin and anticonvulsants.

CYP3A and CYP2C inducers, such as rifampicin or anticonvulsants (e.g. carbamazepine, phenytoin and barbiturates including phenobarbitone), may decrease clomipramine concentrations as concomitant administration of medicines known to induce cytochrome P450 enzymes, particularly CYP3A4, CYP2C19 and CYP1A2, may accelerate the metabolism and decrease the efficacy of clomipramine.

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 cholestyramine.

Concomitant administration of ion exchange resins such as cholestyramine or colestipol may reduce the plasma levels of clomipramine. Caution is therefore required when prescribing Placil 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 Placil 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.

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

Alcohol and other CNS depressants.

Tricyclic antidepressants may also increase the effects 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 (epinephrine), noradrenaline (norepinephrine) and amphetamine may be potentiated by tricyclic antidepressants. This includes nose drops and local anaesthetics containing sympathomimetics.

Anticoagulants.

Some tricyclic antidepressants may potentiate the anticoagulant effect of coumarin medicines 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 co-administered 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 medicines 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).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

According to the experimental data available, clomipramine has no mutagenic, carcinogenic or teratogenic effects. However, clomipramine has been shown to be embryotoxic in the mouse and rat at the lowest dose tested (four times the maximum recommended human dose on a bodyweight basis).
(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 clomipramine in pregnancy is limited. There have been isolated reports of a possible connection between the use of clomipramine and adverse effects (developmental disorders) on the foetus, therefore treatment with Placil should be avoided during pregnancy and only considered if the benefits expected justify the potential risk for the foetus.
Withdrawal symptoms in newborn infants have been reported with prolonged maternal use of this class of medicines. Newborn infants whose mothers had taken Placil 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, Placil should be gradually withdrawn if at all possible, at least seven weeks before the calculated date of confinement.
As clomipramine passes into human milk, infants should be weaned or the medication gradually withdrawn.

4.7 Effects on Ability to Drive and Use Machines

Placil may cause blurred vision, drowsiness and other central 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)

Adverse effects do not always correlate with dose or plasma drug levels.
If severe neurological or psychiatric reactions occur, Placil should be withdrawn.
Reporting frequencies are described as follows: very common: ≥ 10%; common: ≥ 1 to < 10%; uncommon: ≥ 0.1 to < 1%; rare: ≥ 0.01% to < 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 and clinically irrelevant ECG changes (e.g. T- and ST-wave changes) in patients of normal cardiac status, palpitations.
Uncommon: arrhythmias, increased blood pressure.
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 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 post-marketing spontaneous reports.

The following additional adverse drug reactions have been identified with Placil 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.

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.

4.9 Overdose

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, which if it does occur, should be treated with extreme care (see Section 4.4 Special Warnings and Precautions for Use, Safety note concerning children).

Signs and symptoms.

The first signs and symptoms of poisoning with tricyclic antidepressants generally take the form of severe anticholinergic reactions, which appear about 1/2 to 2 hours after the medicine has been taken. Owing to the delayed absorption (anticholinergic effect), long half-life and enterohepatic recycling of the drug, the patient may be at risk for up to 4 to 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, hyperreflexia, muscular rigidity, athetoid and choreoathetosis, convulsions. In addition, symptoms consistent with 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 medicine has been taken by mouth, activated charcoal should be administered.
Anyone suspected of receiving an overdose of Placil, particularly children, should be hospitalised and kept under close surveillance for at least 72 hours. Severe poisoning with tricyclic medicines 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 intravenously. Other anticonvulsants may be required.
Dialysis and haemodialysis are of no use.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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

Clinical trials.

No data available. See Section 4.4 Special Warnings and Precautions for Use, Clinical worsening and suicide risk associated with psychiatric disorders for pooled analysis of antidepressant medicine trials.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, the active substance is completely absorbed 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 clomipramine, the steady-state plasma concentrations of clomipramine show wide variations between patients.
Administration of the standard dose recommended for treatment of depression, i.e. 25 mg of clomipramine orally three times daily, 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 clomipramine 75 mg/day.
The plasma clearance of clomipramine in elderly patients is lower than in patients in intermediate age groups. As a result elderly patients require smaller doses of Placil.

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). N-desmethylclomipramine, the principle metabolite, has a beta-phase half-life in the range of 13 to 25 hours.
The concentration in the cerebrospinal fluid 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-hydroxy clomipramine is catalysed by CYP2D6.

Excretion.

Two-thirds of a single dose of clomipramine is excreted in the urine as the water soluble conjugates of clomipramine or its metabolites. About one-third is excreted in the faeces. Unchanged clomipramine and N-desmethylclomipramine in the urine each amount for less than 1% of the dose administered.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets also contain the following excipients: lactose monohydrate, maize starch, povidone, sodium starch glycollate, magnesium stearate, purified talc and Instacoat Universal White (A05G15138) (ARTG PI No. 144681).

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 25°C.

Safety note concerning children.

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

6.5 Nature and Contents of Container

Container type: PVC/Al blister pack. Pack size: 50 tablets.

Australian register of therapeutic goods (ARTG).

AUST R 143879 - Placil Clomipramine hydrochloride 25 mg tablet.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

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

Chemical structure.

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

CAS number.

17321-77-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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Clomipramine hydrochloride

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Placil 25 mg Tablets