Consumer medicine information

Placil

Clomipramine hydrochloride

BRAND INFORMATION

Brand name

Placil

Active ingredient

Clomipramine hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Placil.

SUMMARY CMI

PLACIL®

Consumer Medicine Information (CMI) summary

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

1. Why am I taking PLACIL?

PLACIL contains the active ingredient clomipramine hydrochloride. PLACIL is used to treat: depression that is longer-lasting and/or more severe than the typical "low moods" that everyone experiences 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 taking PLACIL? in the full CMI.

2. What should I know before I take PLACIL?

Do not take if you have ever had an allergic reaction to PLACIL 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 take PLACIL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with PLACIL 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 take PLACIL?

  • 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 take PLACIL? in the full CMI.

5. What should I know while taking PLACIL?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using PLACIL.
  • 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.
  • 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 or lower the dose without checking with your doctor.
  • 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 PLACIL affects you.
  • PLACIL may cause tiredness, dizziness, drowsiness or blurred vision in some people.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • PLACIL 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 below 25°C.

For more information, see Section 5. What should I know while taking PLACIL? 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 PLACIL. All medicines 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

PLACIL®

Active ingredient: clomipramine hydrochloride

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I taking PLACIL?

PLACIL contains the active ingredient clomipramine hydrochloride. PLACIL belongs to a group of medicines called tricyclic antidepressants. These medicines are thought to work by their action on brain chemicals called amines.

PLACIL is used to treat:

  1. depression that is longer-lasting and/or more severe than the typical "low moods" that everyone experiences 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 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 PLACIL has been prescribed for you.

Your doctor may have prescribed PLACIL for another reason.

2. What should I know before I take PLACIL?

Warnings

Do not take PLACIL if:

  • you are allergic to clomipramine, or any other tricyclic antidepressant, or any ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include:
    - rash, itching or hives on the skin
    - swelling of the face, lips, tongue or other parts of the body
    - difficulty in swallowing
    - wheezing or shortness of breath
    Always check the ingredients to make sure you can take this medicine.
  • PLACIL is not approved for use in children or adolescents below 18 years of age for the treatment of depression or other psychiatric disorders.
    The safe use and effectiveness of PLACIL in treating the above conditions, for this age group, has not been established.
  • you are already taking another medicine called monoamineoxidase inhibitor (MAOI) or have been taking it within the past 2 weeks.
    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.
  • you are recovering from a recent heart attack or you have 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 may make your condition worse.
  • the expiry date (EXP) printed on the pack has passed or if the packaging is torn or shows signs of tampering.
    If you take this medicine after the expiry date has passed, it may not work as well.
    In this case, return it to your pharmacist.

Check with your doctor if you have:

  • heart or blood vessel problems including an irregular heart beat, coronary heart disease, angina (chest pain)
  • 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 problems or any other cause
  • epilepsy or seizures (fits)
  • liver or kidney problems
  • a low level of potassium in your blood (called hypokalaemia)
  • any mental disorder other than the one being treated (e.g. schizophrenia, mania, bipolar disorders)
  • problems with blood pressure (either too high or too low)
  • a blood disorder
  • overactive thyroid
  • chronic constipation
  • Parkinson's disease
  • a tumour of the adrenal gland
  • lactose or galactose intolerance (PLACIL tablets contain sugars as lactose monohydrate)
  • take any medicines for any other condition

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

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.

PLACIL 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 PLACIL 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 PLACIL in the 7 weeks before giving birth.

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

Breastfeeding is not recommended while you are taking PLACIL. The active ingredient passes into breast milk and may 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 PLACIL and affect how 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). You must not take PLACIL together with a MAOI (see Section 2. What should I know before I take PLACIL?)
    - 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)
  • medicines for high blood pressure or heart problems
  • medicines to help you sleep or calm you down
  • some medicines for anxiety
  • medicines for other mental disorders
  • medicines for seizures (fits) or epilepsy, such as carbamazepine (Teril, Tegretol) or phenytoin (Dilantin)
  • medicines to prevent blood clots such as warfarin (Coumadin, Marevan)
  • diuretic medicines, also called fluid or water tablets
  • some medicines for colds or allergies, including antihistamines and some nose drops, hayfever or travel sickness
  • anticholinergic medicines, which are used to relieve stomach cramps, spasms and travel sickness, e.g. hyoscine (Buscopan), mebeverine (Colofac)
  • medicines for thyroid problems
  • cimetidine (Tagamet, Magicul), a medicine used to treat reflux and stomach ulcers
  • certain medicines for Parkinson's disease such as biperiden (Akineton), benztropine (Cogentin)
  • oestrogens (e.g. birth control pills, hormone replacement therapy)
  • nicotine in medicines used to help you quit smoking such as nicotine gum, patches lozenges or inhalers
  • methylphenidate (Ritalin®, Attenta) a medicine used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy
  • 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 PLACIL.

4. How do I 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 described 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 accompanying 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.

When to take PLACIL

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

How to take PLACIL

  • 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.

How long to take PLACIL for

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

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.

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

If you forget to take PLACIL

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 PLACIL

If you think that you or anyone else has taken too much PLACIL, urgent medical attention may be needed.

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26) for advice, 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 PLACIL, 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. You may lose consciousness.

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

5. What should I know while taking PLACIL?

Things you should do

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

Do not stop taking your tablets until you have spoken to your doctor. Your doctor can discuss with you the risks of taking it while you are pregnant.

Call your doctor or a mental health professional straight away or go to the nearest hospital for treatment if you or someone you know develop any of the following:

  • thoughts or talk about suicide or dying
  • thoughts or talk of self-harm or harm to others
  • attempts of self-harm or to commit suicide
  • new or worsening depression
  • new or worsening anxiety
  • feeling very agitated or restless
  • panic attacks
  • new or worsening irritability
  • difficulty sleeping (insomnia)
  • acting on dangerous impulses
  • an extreme increase in activity and talking
  • acting aggressive, being angry, or violent
  • 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.

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.

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 PLACIL.

Remind any doctor, dentist or pharmacist you visit that you are taking PLACIL.

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

Your doctor may ask you to stop taking PLACIL a few days before elective surgery to avoid unnecessary side effects.

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.

If this medicine causes your mouth to feel dry and this problem doesn't go away after 2 weeks, 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.

Things you should not do

  • Do not stop taking this medicine suddenly.
  • Do not stop taking PLACIL or lower 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 they have the same condition as you.
  • 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 pan relivers, sleeping tablets or antihistamines (medicines for colds or allergies such as hay fever) while you are taking PLACIL.
  • PLACIL 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.

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.

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 sunscreen. Do not use a sunlamp.

PLACIL makes some people more sensitive than usual to sunlight. Wear protective clothing and use SPF 30+ sunscreen.

Smoking

Tell your doctor if you smoke.

Nicotine can affect the amount of PLACIL that is in your body. Changes in your usual smoking habits can also change the effects of PLACIL.

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.

Elderly

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.

Driving or using machines

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

PLACIL may cause tiredness, dizziness, drowsiness, lightheadedness or blurred vision in some people.

If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Combining alcohol with PLACIL can make you more drowsy, dizzy or lightheaded. Your doctor may suggest you avoid alcohol while being treated with 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.

Looking after your medicine

  • Keep your medicine in the original container until it is time to take a dose.
  • Store below 25°C.

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

Store it in a cool dry place 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.

Heat and dampness can destroy some medicines.

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 take this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not take this medicine after the expiry date.

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 PLACIL.

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.

PLACIL 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 from 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.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal-related:
  • constipation
  • increased appetite and weight
  • gain
  • decreased appetite
  • nausea (feeling sick), vomiting, diarrhoea
  • poor appetite or weight loss
Reproductive system-related:
  • reduced sexual desire or difficulty in reaching orgasm
  • swelling of the breasts or discharge of milk
  • swelling of the testicles
  • delayed or no ejaculation of semen if you are a male
Psychological:
  • tired feeling and mental dullness
  • feeling of unrest or anxiety
  • disturbed sleep or nightmares
  • change in sense of taste
  • confusion, hallucinations
  • loss of memory or reduced concentration
Nervous system-related:
  • drowsiness, dizziness, blurred vision or difficulty focusing 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.
  • a compelling need to be in constant motion
  • repetitive, involuntary, purposeless movements
  • shakiness or trembling
  • muscle spasms
  • headache
  • sweating or hot flushes
Kidney-related:
  • difficulty urinating (passing water) or frequently passing of large amounts of urine
Other:
  • dry mouth
  • dry or sticky eyes if you wear contact lenses
  • sores in the mouth or on the tongue
  • increased sensitivity to the sun
  • ringing in the ears
  • hair loss
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
Psychological:
  • 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
  • confusion or hallucinations (seeing, hearing or feeling things that are not there)
  • unusually high energy, irritability or outbursts of anger
  • mood swings alternating from one of excitement, overactivity and uninhibited behaviour to a depressed mood.
Infection-related:
  • constant flu-like symptoms (fever, chills, sore throat or swollen glands, tiredness or lack of energy)
  • eye pain
Liver-related:
  • 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
Gastrointestinal-related:
  • pain in the stomach or abdomen that is severe or doesn't go away
Blood-related:
  • bruising or bleeding more easily than usual
Call your doctor straight away.
The above list includes serious side effects that require medical attention.

Very serious side effects

Very serious side effectsWhat to do
  • signs of allergic reaction such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other part of the body; difficulty swallowing; shortness of breath, wheezing or troubled breathing
  • fast or irregular heart beat (pounding, racing, skipping beats) or chest pain
  • fainting spells or seizures (fits)
  • 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
  • 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)
See your doctor immediately or go to the Emergency at your nearest hospital if you notice any of the following.
These are very serious side effects. You may need urgent medical attention or hospitalisation.

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 PLACIL contains

Active ingredient
(main ingredient)		clomipramine hydrochloride 25 mg
Other ingredients
(inactive ingredients)		lactose monohydrate
maize starch
povidone
sodium starch glycollate
magnesium stearate
purified talc
Instacoat Universal White (A05G15138) ARTG PI No: 144681
Potential allergenssugar as lactose
sulfites

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

What PLACIL looks like

PLACIL 25 mg is a white, biconvex tablet, marked "Cl 25" on one side and "G" on the other; supplied in packs of 50 tablets (AUST R 143879).

Who distributes PLACIL

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

This leaflet was prepared in July 2024.

PLACIL® is a Viatris company trade mark

PLACIL_cmi\Jul24/00

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Placil

Active ingredient

Clomipramine hydrochloride

Schedule

S4

 

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.

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 General precautions above) 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.
Chronic constipation, as tricyclic antidepressants may cause paralytic ileus, particularly in elderly and bedridden patients.
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.
Also see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects), Geriatric population; Section 5.2 Pharmacokinetic Properties, Absorption.

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.

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).

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.

Summary Table of Changes