Consumer medicine information

Tofranil

Imipramine hydrochloride

BRAND INFORMATION

Brand name

Tofranil

Active ingredient

Imipramine hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tofranil.

What is in this leaflet

This leaflet answers some common questions about Tofranil. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you or your child taking this medicine against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What Tofranil is used for

Tofranil is used to treat:

  1. Depression that is longer lasting and/or more severe than the "low moods" that everyone has from time to time due to the stress of everyday life. It 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 feeling guilty over nothing.
  2. Bed-wetting in people from the age of 5 years onwards if there is no physical cause for the problem (i.e. there is nothing wrong with the bladder itself).

Tofranil belongs to a group of medicines called tricyclic antidepressants (TCAs).

Tofranil corrects this chemical imbalance and may help relieve the symptoms of depression.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another purpose.

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

Before you take Tofranil

When you must not take it

Do not take Tofranil if you have ever had an allergic reaction after taking:

  • imipramine (the active ingredient in Tofranil)
  • any of the other ingredients listed at the end of this leaflet
  • any other tricyclic antidepressant.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not start taking Tofranil if you are already taking another medicine called a monoamine-oxidase inhibitor (MAOI) or you have been taking it within the past 2 weeks. Taking this medicine together with a MAOI may cause a serious reaction (a condition called serotonin syndrome) with a sudden increase in body temperature, extremely high blood pressure, seizures (fits), hyperactivity, increase in muscle tone or stiffness of muscle and coma or death. Your doctor will know when it is safe to start Tofranil after the MAOI has been stopped.

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

Do not take Tofranil if you are recovering from a recent heart attack. It may make your condition worse.

Do not take Tofranil if you are under 18 years of age for the treatment of depression or other psychiatric disorders. There is not enough information to recommend the use of this medicine to treat depression or other psychiatric disorders in children under 18 years of age.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

In that case, return it to your pharmacist.

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

Before you start to take it

Tell your doctor if you have any of the following health problems/medical conditions:

  • heart problems, especially an irregular heartbeat
  • increased pressure in the eye from any cause (e.g. glaucoma)
  • difficulty in passing urine (water), due to prostate trouble or any other cause
  • seizures (fits)
  • severe liver or kidney disease
  • mental disorders other than depression
  • problems with blood pressure (either too high or too low)
  • blood disorders
  • thyroid problems
  • chronic constipation
  • a tumour of the adrenal gland.
  • depression or other conditions that are treated with antidepressants.

The use of these medicines such as imipramine, selective serotonin reuptake inhibitors (SSRIs) and noradrenaline reuptake inhibitors together with Tofranil can lead to serotonin syndrome, a potentially life-threatening condition. Symptoms may include confusion, agitation, mood changes, diarrhoea, chills, increased body temperature, sweating, changes in blood pressures, nausea, vomiting, involuntary muscle jerk, overresponsive bodily reflexes, involuntary shaking or movement in one or more parts of body, difficult movement coordination, disturbances in mental abilities and coma. Your doctor may not want you to take this medicine or may want to take special precautions if you have any of the above conditions.

Tell your doctor if you are pregnant or intend to become pregnant. 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.

Tell your doctor if you are breastfeeding or plan to breastfeed. Breastfeeding is not recommended while you are taking Tofranil. The active ingredient passes into the breast milk and could affect your baby.

Tell your doctor if you smoke. Nicotine can affect the amount of Tofranil that is in your body. Sudden changes in your usual smoking habits can also change the effects of Tofranil.

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.

Tell your doctor if you have an intolerance to lactose or sucrose. This medicine contains lactose and sucrose.

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 and Tofranil may interfere with each other. These include:

  • MAOI medicines. You must not take Tofranil together with a MAOI (see "When you must not take it")
  • medicines for high blood pressure or heart problems
  • medicines to help you sleep or calm you down
  • other medicines for depression called SSRIs (e.g. fluoxetine and paroxetine)
  • medicines for other mental disorders
  • medicines for seizures (fits)
  • medicines to prevent blood clots (e.g. warfarin)
  • some medicines for colds or allergies, including some nose drops
  • anticholinergic medicines, which are used to relieve stomach cramps, spasms and travel sickness
  • medicines for thyroid problems
  • cimetidine, a medicine for stomach ulcers
  • sulfamethoxazole and trimethoprim, medicines used to treat bacterial infections
  • terbinafine, a medicine to treat fungal infections
  • medicines for Parkinson's disease
  • oestrogens (e.g. birth control pills, hormone replacement therapy)
  • nicotine in medicines used to help you quit smoking, such as nicotine patches or chewing gum
  • methylphenidate (Ritalin)
  • disulfiram, a medicine for alcoholism.

These medicines may be affected by Tofranil or they may affect how well it works. 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 on medicines to be careful with or avoid while you are taking Tofranil.

If you have not told your doctor about any of these things, tell them before you take Tofranil.

How to take Tofranil

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 label, ask your doctor or pharmacist for help.

How much to take

For depression, treatment is usually started with a low dose (e.g. up to 75 mg each day). The dose can be increased slowly over the first week up to 150 to 200 mg each day.

If your symptoms are very severe, up to 300 mg each day may be prescribed.

Some people will need higher doses than others because each person's body chemistry is different.

Once you are feeling better, your doctor may be able to slowly reduce the dose, usually down to 50 to 100 mg each day.

For bed-wetting, the usual dose for children aged 5-8 years is 20 to 30 mg each day. For children aged 9-12 years the dose is 25 to 50 mg each day, and for children aged over 12 years, the dose is up to 75 mg each day.

The higher doses are usually used if bed-wetting does not improve after a week of treatment at a lower dose.

If you are older than 65 years, your doctor will probably start with a low dose (e.g. 10 mg each day) to help avoid side effects. The dose is gradually increased over about ten days to 30 to 50 mg each day and kept at that dose for the rest of your treatment.

When to take it

For depression, take the tablets in 2 or 3 doses spread over the day unless your doctor advises you otherwise. If the tablets make you sleepy, your doctor may suggest that you take one dose at night to help you sleep well.

For bed-wetting, take the tablets as a single dose after the evening meal unless your doctor advises you otherwise. If bed-wetting tends to happen early in the night, your doctor may advise you to take part of the dose earlier (e.g. at 4 p.m.).

How to take it

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

How long to take it

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

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

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

Continue taking it until your doctor tells you to stop.

For bed-wetting, the treatment is usually continued for 1 to 3 months.

If you forget to take it

If you normally take the tablets 2 or 3 times a day and 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 it as soon as you remember, and then go back to taking the tablets as you would normally.

If you normally take the tablets only at bedtime and you miss a dose, do not take the missed dose the next morning until you check with your doctor. The medicine may cause some side effects during the day if you take the whole dose in the morning.

Do not take a double dose to make up for the one that 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 (Overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much Tofranil. Do this even if there are no signs of discomfort or poisoning.

Keep the telephone numbers for these places handy.

In children, accidental ingestion of any amount should be regarded as serious and potentially fatal. If you take too much Tofranil, you may feel sleepy, unresponsive, coma, impaired balance or coordination, restless or agitated, dilated pupils, overresponsive bodily reflexes, less wakeful or aware and symptoms of serotonin syndrome (refer section 4.4). You may also have stiffness or unusual muscle movements, fever, sweating, vomiting, difficulty breathing, a drop in blood pressure/shock, fast or irregular heartbeat, heart disorder including heart failure and cardiac arrest, bluish discoloration of the skin, unable to breath during sleep, fits or other symptoms including dry mouth, constipation, and low urine output.

If you are not sure what to do, contact your doctor or pharmacist.

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

While you are taking Tofranil

Things you must do

If you become pregnant while taking Tofranil, tell your doctor immediately. Your doctor can discuss with you the risks of using it while you are pregnant.

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 you are being treated for depression, be sure to discuss with your doctor any problems you may have and how you feel, especially any feelings of severe sadness or bursts of unusual energy or anger. This will help your doctor to determine the best treatment for you.

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.

Contact your doctor immediately if you or someone you know develop any of the following symptoms at any time during treatment with Tofranil:

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

Symptoms such as these may be associated with an increased risk of suicidal thinking and behaviour and must be taken seriously. Talk to your doctor or mental health professional if you have thoughts or talk about death or suicide; or thoughts or talk about self-harm or doing harm to others.

Before having any surgery or emergency treatment, even a minor procedure, tell the doctor or dentist in charge that you are taking Tofranil or have been taking it within the last two weeks or so. If possible, this medicine should be stopped before surgery to avoid unnecessary side effects.

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

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

Do not take any other medicines, whether they require a prescription or not, without first telling your doctor.

Tell any other doctor, dentist or pharmacist who treats you that you are taking Tofranil.

Things you must not do

Do not stop taking Tofranil or change the dose without first checking with your doctor. Do not let yourself run out of medicine over the weekend or on holidays. 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, abdominal pain, chills, pain that affects bones, muscles and nerves, inability to sleep, irritability, tiredness, anxiety and nervousness. If possible, your doctor will gradually reduce the amount you take each day before stopping the medicine completely.

Do not take Tofranil to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours or if they have the same condition as you.

Things to be careful of

You must tell your doctor if you are pregnant or are intending to become pregnant. There have been reports of some congenital abnormalities or an increase in pre-term delivery associated with taking antidepressants in pregnancy.

Some infants, exposed to antidepressants late in the third trimester, have shown drug withdrawal symptoms such as difficulty of breathing, sluggish, colic irritability, low or high blood pressure, and tremor or spasms. To avoid such symptoms, Tofranil should, if possible, be gradually withdrawn at least 7 weeks before the calculated date of confinement.

Your doctor will discuss the possible risks and benefits of taking Tofranil during pregnancy.

Be careful driving, operating machinery or doing jobs that require you to be alert while you are taking Tofranil until you know how it affects you. Children should take care when doing things like riding bicycles or climbing trees.

This medicine may cause tiredness, dizziness, drowsiness or blurred vision in some people.

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 Tofranil. This medicine can increase the drowsiness caused by alcohol and by medicines that affect your nervous system.

If this medicine makes you feel lightheaded, be careful when getting up from a sitting or lying position. You can usually prevent these symptoms by getting up slowly and flexing leg muscles and toes to get the blood flowing. When getting out of bed, dangle your legs over the side for a minute or two before standing up.

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

After you have stopped taking Tofranil, you should still be careful for 1 or 2 weeks since some 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 Tofranil.

Tofranil helps most people with depression, but it may have unwanted side effects in some people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the 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.

Tofranil can cause confusion or disorientation, especially in older people. Your family or carer should be aware of this. Special care may be needed.

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

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of these side effects and they worry you:

  • drowsiness, dizziness, blurred vision or difficulty focussing your eyes, especially when treatment is started or the dose is increased
  • palpitations
  • rash, hives
  • light-headedness, especially when you get up too quickly from a sitting or lying position
  • dry mouth
  • altered sense of taste
  • problems with urinating (passing water)
  • dry or sticky eyes
  • constipation or diarrhoea
  • sweating or hot flushes
  • weight gain
  • tired feeling
  • feeling of unrest or anxiety
  • hallucinations, feeling very confused
  • euphoria (strong feeling of happiness)
  • disturbed sleep
  • aggression
  • suicidal thinking and behaviour
  • mood swings
  • prickly skin
  • nausea (feeling sick), vomiting, loss of appetite or weight loss
  • headache
  • reduced sexual desire
  • hairloss
  • dark skin (hyperpigmentation)
  • swelling (generalised or local)
  • excessive breast tissue growth (Hypertrophy breast)
  • milky nipple discharge unrelated to the normal milk production (galactorrhoea)
  • abnormal liver function test.

These are the more common side effects of Tofranil.

An increased risk of bone fracture has been observed in patients over 50 years of age taking this type of medicine.

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

  • signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other part of the body; shortness of breath, wheezing or troubled breathing
  • pink or red skin rash with blotchy blisters, scaly patches (photosensitivity reactions)
  • high fever, agitation, confusion, trembling and abrupt contractions of muscles
  • constant "flu-like" symptoms (chills, fever, sore throat, aching joints, swollen glands, tiredness or lack of energy)
  • unusual bleeding or bruising
  • reduction in some blood cells (recurring infections)
  • pain in the stomach or abdomen that is severe or doesn't go away
  • fast or irregular heart beat (pounding, racing, skipping beats)
  • heart failure
  • muscle numbness, tingling or spasms
  • stoke (trouble walking, speaking and understanding, as well as paralysis or numbness of the face, arm or leg.)
  • uncontrolled, involuntary and jerky movements, including tremors and shaking of the hands, arms or legs
  • weakness or loss of balance
  • severe dizziness or drowsiness
  • fainting spells or seizures (fits)
  • difficulty in speaking or slurred speech
  • unusually high energy, irritability or outbursts of anger
  • confusion or hallucinations (seeing, hearing or feeling things that are not there)
  • frequent passing of large amounts of urine
  • yellow colour to the skin or eyes
  • eye pain
  • high or unstable blood sugar levels
  • abnormal Electrocardiogram (ECG)

Sudden deaths have occurred in patients taking this medicine.

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

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

Other side effects not listed here may happen in some people. Tell your doctor if you notice anything else that is making you feel unwell.

Ask your doctor or pharmacist if you don’t understand anything in this list.

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

After using Tofranil

Storage

Keep your tablets in their container until it is time to take them. If you take the tablets out of their container they may not keep well.

Store Tofranil in a cool dry place where the temperature stays below 30°C. Protect from moisture.

Do not store this or any other medicine in the bathroom or near a sink. Do not leave it in the car or on windowsills. Heat and dampness can destroy some medicines.

Keep the tablets where children cannot reach them. A locked cupboard at least 1½ metres above the ground is a good place to store medicines.

Disposal

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

Product Description

What it looks like

Tofranil 10 tablets - red-brown, triangular-shaped, convex sugar-coated tablets

Blister pack of 50 tablets.

Tofranil 25 tablets - reddish-brown, round, biconvex sugar-coated tablets

Blister pack of 50 tablets.

Ingredients

Tofranil tablets contain either 10 mg or 25 mg of imipramine hydrochloride as the active ingredient.

They also contain:

  • colloidal anhydrous silica
  • glycerol
  • lactose monohydrate
  • magnesium stearate
  • maize starch
  • stearic acid
  • purified talc
  • hypromellose
  • microcrystalline cellulose
  • macrogol 8000
  • povidone
  • copovidone
  • sucrose
  • titanium dioxide
  • iron oxide red
  • carnauba wax (Tofranil 25 mg tablets only)

Sponsor

Tofranil tablets are supplied in Australia by:

Amdipharm Mercury (Australia) Pty Ltd
Level 9, 76 Berry Street, North
Sydney NSW 2060

Date of preparation

06 September 2022

Australian registration numbers

Tofranil 10 AUST R 11064

Tofranil 25 AUST R 60673

Amdipharm Mercury (Australia) Pty Ltd is licensed to use the trademark Tofranil

Published by MIMS October 2023

BRAND INFORMATION

Brand name

Tofranil

Active ingredient

Imipramine hydrochloride

Schedule

S4

 

1 Name of Medicine

Imipramine hydrochloride.

2 Qualitative and Quantitative Composition

Tofranil 10 tablets contain 10 mg imipramine hydrochloride.
Tofranil 25 tablets contain 25 mg imipramine hydrochloride.

Excipients with known effect.

Lactose and sugars.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tofranil 10.

The tablets are red-brown, triangular-shaped, convex, sugar coated tablets.

Tofranil 25.

The tablets are reddish-brown, round, biconvex, sugar coated tablets.

4 Clinical Particulars

4.1 Therapeutic Indications

Major depression.
Nocturnal enuresis (from the age of 5 years onwards and provided the possibility of organic causes has first been excluded).

4.2 Dose and Method of Administration

General.

The dosage should be determined individually and adapted to the patient's condition. In principle, every effort must be made to achieve an optimum effect while keeping the dose as low as possible and increasing the dosage cautiously, particularly when treating elderly patients, who generally show a more marked response to Tofranil than patients belonging to intermediate age groups.
During treatment with Tofranil, patients must be kept under close surveillance with respect to the efficacy and tolerability of the medication.

Major depression.

Treatment in ambulatory patients.

Initiate treatment with 25 mg up to three times daily. Raise the daily dosage stepwise to 150 to 200 mg. This dosage should be reached by the end of the first week and adhered to until a clear cut improvement has occurred. The subsequent maintenance dose, which must be individually determined by cautiously reducing the dosage, usually amounts to 50 to 100 mg daily.

Treatment in hospitalised patients.

Initiate treatment with 25 mg three times a day. Raise the daily dosage stepwise by 25 mg until a dose of 200 mg has been reached, and adhere to this dose until the depressive condition has improved. In severe cases the dose may be increased to 100 mg three times a day. Once a distinct improvement has set in, the subsequent daily maintenance dose should be determined according to the patient's individual requirements (generally 100 mg).

Paediatric use.

The safety and efficacy of Tofranil for the treatment of depression or other psychiatric disorders in children and adolescents aged less than 18 years has not been satisfactorily established. Tofranil should not be used in this age group for the treatment of depression or other psychiatric disorders (see Section 4.4 Special Warnings and Precautions for Use).

Use in the elderly.

Start treatment with 1 tablet of 10 mg daily. Gradually raise the dosage to an optimum level of 30 to 50 mg daily, which should be reached after about 10 days and then adhered to until the end of treatment.

Nocturnal enuresis.

Children 5 years and over only. The initial daily dose is:

5 to 8 years of age.

2 or 3 tablets of 10 mg.

9 to 12 years of age.

1 to 2 tablets of 25 mg.

Older children.

1 to 3 tablets of 25 mg.
The higher doses apply to those cases which do not respond fully to treatment within one week. The tablets should be given in a single dose after the evening meal, although children who wet their beds early in the night should be given part of the dose beforehand (at 4 pm). Once the desired response has been achieved the treatment should be continued (for 1 to 3 months), reducing the dose stepwise to the maintenance dose.
A daily dosage of 2.5 mg/kg should not be exceeded in children. The safety and efficacy of imipramine as temporary adjunctive treatment for nocturnal enuresis in children less than 5 years of age have not been established.

4.3 Contraindications

Known hypersensitivity to imipramine or any of the excipients in the tablets.
Cross sensitivity to tricyclic antidepressants of the dibenzazepine group.
Concomitant use with a MAO inhibitor, or within 14 days before or after treatment with an irreversible MAO inhibitor, or within 14 days before moclobemide, a reversible MAO inhibitor (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Acute and recovery stages of myocardial infarction.
Subjects under 18 years of age for the treatment of depression or other psychiatric disorders.

4.4 Special Warnings and Precautions for Use

Clinical worsening and suicide risk.

The risk of suicide is inherent in depression and may persist until significant remission occurs. This risk must be considered in all depressed patients.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset or was not part of the patient's presenting symptoms. Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/ behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Patients with co-morbid 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 (selective serotonin reuptake inhibitors (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 Tofranil should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Caution in the following circumstances.

Caution is called for when employing tricyclic antidepressants in patients with:
Cardiovascular diseases, cardiac disease and in elderly patients, considering the tachycardiac and hypotensive effects of this class of products. Cardiovascular insufficiency, conduction disorders, atrioventricular block (grades I to III), and arrhythmias. Monitoring of cardiovascular function and the ECG is required in such patients, especially in the elderly. Myocardial infarction, precipitation of congestive cardiac failure, stroke and sudden death have been reported with drugs of this class.
Isolated cases of QTc prolongation and very rare cases of ventricular tachycardia and sudden unexplained death have occurred at supra-therapeutic doses of Tofranil which have primarily occurred in conjunction with overdose, but also in a few reports of comedication that itself can lead to a prolonged QTc interval (e.g. thioridazine). Concomitant administration of medicines that can provoke prolonged QT syndrome/Torsades de pointes should be avoided.
A history of increased intraocular pressure, narrow angle glaucoma.
Disorders of micturition due to an impeded flow of urine (e.g. in diseases of the prostate).
A low convulsion threshold (e.g. due to brain damage of varying aetiology, epilepsy, concomitant use of other drugs such as neuroleptics that may lower the seizure threshold, and withdrawal from alcohol or drugs with anticonvulsive properties, e.g. benzodiazepines). The occurrence of seizures seems to be dose dependent. Therefore the recommended total daily dose of Tofranil should not be exceeded. In case of seizures, the treatment should be discontinued.
Tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma), in whom the drug may provoke hypertensive crises.
Hyperthyroidism, or concomitant treatment with thyroid preparations, since aggravation of unwanted cardiac effects can generally be expected to occur owing to the anticholinergic action.
Chronic constipation, as tricyclic antidepressants may cause paralytic ileus, particularly in elderly and in bedridden patients.
Higher sensitivity to orthostatic hypotension, sedation and possible prostatic hypertrophy in elderly patients.
A daily dose of 2.5 mg/kg of imipramine should not be exceeded in children owing to possible cardiotoxic effects (see Section 4.2 Dose and Method of Administration).
Concomitant use of Tofranil and electroconvulsive therapy should only be undertaken under careful supervision.
Many patients with panic disorder experience intensified anxiety symptoms at the start of the treatment with antidepressants. This paradoxical initial increase in anxiety is most pronounced during the first few days of treatment and generally subsides within two weeks.
Tofranil may cause anxiety, feelings of unrest, and hyperexcitation in agitated patients and psychosis may be activated in schizophrenic patients.

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 an 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.
Hypomanic or manic episodes have also been reported during a depressive phase in patients with bipolar affective disorders receiving treatment with a tricyclic antidepressant. In such cases it is necessary to reduce the dosage or to withdraw Tofranil.
Exacerbation of psychotic states has been observed occasionally in schizophrenic patients receiving tricyclic antidepressants.
In predisposed and elderly patients, particularly at night, Tofranil may provoke pharmacogenic (delirious) psychosis, which disappears without treatment within a few days of withdrawing the drug.
Specific mood improvement often occurs after symptoms such as insomnia or anxiety have improved. This is to be considered prior to making any decision about whether treatment should be continued or adjusting the effective dose.

Treatment discontinuation.

Abrupt withdrawal should be avoided because of possible adverse reactions. If the decision has been made to discontinue treatment, medication should be tapered, with recognition that abrupt discontinuation can be associated with certain symptoms [see Section 4.8 Adverse Effects (Undesirable Effects)].

Patient monitoring.

Before starting treatment it is advisable to check the patient's blood pressure, because individuals with hypotension or a labile circulation may react to the drug with a fall in blood pressure. Monitoring the plasma concentration may be indicated in patients at risk of overdose (elderly patients, patients with concomitant cardiac, hepatic or renal disease), resistance to treatment and presenting marked adverse effects, or those on multiple medications.
The blood count should be monitored during treatment with Tofranil (especially if the patient develops fever, sore throat or other symptoms such as are associated with influenzal infections), 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.
Treatment with tricyclic antidepressants can lead to an increased incidence of dental caries. Regular dental check-ups are therefore advisable during long term treatment.
Decreased lacrimation and accumulation of mucoid secretions may cause damage to the corneal epithelium in patients with contact lenses.

Other.

Before elective surgery, Tofranil should be discontinued for as long as the clinical situation will allow. Before general or local anaesthesia, the anaesthetist should be aware that the patient has been receiving Tofranil (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Serotonin syndrome.

Due to the risk of serotonin toxicity, it is advisable to follow the dosage suggested. In cases when imipramine, selective serotonin uptake inhibitors (SSRIs) and noradrenaline reuptake inhibitors are used concomitantly with tricyclic antidepressants or with any other serotonin medicines, serotonin syndrome symptoms may occur with symptoms such as behavioural disorders (confusional state, hypomania, agitation), autonomic nervous system disorders (diarrhoea, chills, hyperpyrexia, sweating, blood pressures alterations, nausea, vomiting) and changes in the neuromuscular functions (myoclonus, hyperreflexia, tremors, difficult movement coordination), delirium and coma.

Paediatric use.

The safety and efficacy of Tofranil for the treatment of depression or other psychiatric disorders in children and adolescents aged less than 18 years has not been satisfactorily established. Tofranil should not be used in this age group for the treatment of depression or other psychiatric disorders. There are no long-term safety data available in children and adolescents regarding growth, maturation and cognitive and behavioural development.

Animal toxicology.

Acute.

Oral LD50 ranges are as follows: rat - 355 to 682 mg/kg; dog - 100 to 215 mg/kg.
Depending on the dosage in both species, toxic signs proceeded progressively from depression, irregular respiration and ataxia to convulsions and death.

Lactose monohydrate and sucrose.

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

Use in hepatic impairment.

Severe hepatic or renal diseases. In case of patients with hepatic impairment, it is appropriate to periodically check hepatic function values. In patients with known liver disease or a history of liver disease, periodic monitoring of hepatic enzyme levels is recommended (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in renal impairment.

It is also recommended that patients with known renal impairment be monitored.
See Section 4.2 Dose and Method of Administration.

Use in the elderly.

See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.

Paediatric use.

See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

MAO-inhibitors.

If Tofranil is to be used after treatment with a MAO inhibitor, it is absolutely essential that an interval of at least 14 days should elapse before starting therapy; otherwise severe interactions may occur (e.g. hyperactivity, hypertensive crisis, hyperpyrexia, spasticity, convulsions, coma or death). The same precaution should be taken when administering a MAO inhibitor after previous treatment with Tofranil. In either instance, medication with Tofranil or with the MAO inhibitor should be started cautiously and the dosage slowly raised stepwise until the optimum response is obtained (see Section 4.3 Contraindications).
There is evidence to suggest that Tofranil 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 Tofranil has been used. Patients should be monitored for symptoms suggestive of serotonergic syndrome (serotonin syndrome).

Antihypertensive agents.

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

Sympathomimetic amines.

The cardiovascular effects of sympathomimetic agents, such as adrenaline (epinephrine), noradrenaline (norepinephrine), isoprenaline, ephedrine, phenylephrine and amfetamine may be potentiated by tricyclic antidepressants. This includes sympathomimetic amines in nose drops or in local anaesthetic preparations.

Alcohol and other central nervous system depressants.

Tricyclic antidepressants may also increase the effect of alcohol and central depressant drugs (e.g. barbiturates, benzodiazepines, hypnotics, sedatives, anxiolytics or general anaesthetics).

Anticholinergic agents.

When tricyclic antidepressants are given in combination with anticholinergics, including those used to treat Parkinson's disease, 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.

Antiarrhythmic agents.

Tricyclic antidepressants should not be employed in combination with antiarrhythmic agents of the quinidine type.

Selective serotonin reuptake inhibitors.

Co-medication may lead to additive effects on the serotonergic system. SSRIs such as fluoxetine and paroxetine are strong inhibitors of CYP2D6. Fluvoxamine is a strong inhibitor of CYP1A2. Therefore, the use of imipramine with these SSRIs may increase plasma concentrations of imipramine with corresponding adverse effects, mainly on the cardiovascular system. An adjustment of the dosage of imipramine may be necessary.

Liver enzyme inducers.

Substances which activate the hepatic mono-oxygenase enzyme system (e.g. barbiturates, phenytoin, carbamazepine, nicotine, oral contraceptives) may accelerate the metabolism of imipramine and lower the plasma concentration of tricyclic antidepressants and so reduce their effect. In addition, concomitant administration of a tricyclic antidepressant with phenytoin or carbamazepine may lead to elevated serum phenytoin or carbamazepine concentrations. If necessary, the doses of the drugs should be adjusted accordingly. Drugs like phenothiazines, haloperidol and cimetidine may delay elimination of imipramine increasing its plasma concentration. Imipramine binding with plasma protein may be reduced by drugs like phenytoin due to the competition.

Neuroleptic agents.

Neuroleptic agents (e.g. phenothiazines) may increase the plasma concentration of imipramine, a lowered convulsion threshold and seizures. Combination with thioridazine may produce severe cardiac arrhythmias.

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 may be necessary to lower the dosage of imipramine if administered concomitantly with disulfiram.

Anticoagulants.

Tricyclic antidepressants may potentiate the anticoagulant effect of coumarin drugs due to their inhibition of hepatic metabolism. Careful monitoring of plasma prothrombin is therefore advised.

Cimetidine.

Since cimetidine raises the plasma concentration of imipramine, the dosage of imipramine should be reduced if the two drugs are administered concurrently; by contrast, ranitidine does not alter the kinetics of imipramine.

Methylphenidate.

Methylphenidate may raise the plasma concentration of tricyclics and so intensify their antidepressant effect.

Oestrogens.

If administered concomitantly with oestrogens, the dose of imipramine should be reduced, since steroid hormones inhibit the metabolism of imipramine and at the same time cause increased adverse effects.

Oral antifungals.

The concomitant administration of imipramine and terbinafine, a potent inhibitor of CYP2D6, may cause an increased exposure and accumulation of imipramine and desipramine. Therefore, dose adjustments may be necessary when imipramine is coadministered with terbinafine.

Drugs inducing prolonged QT.

Prolonged QTc and induction of tachycardia and Torsades de pointes may result from the combined administration of imipramine with medicines prolonging QTc (e.g. thioridazine, cisapride, cotrimoxazole). Coadministration of imipramine with these medicines should be avoided.

Calcium channel blockers.

Verapamil and diltiazem may increase plasma levels of imipramine.

Beta-blockers.

Labetalol and propranolol increase plasma concentrations of imipramine.

Thyroid preparations.

Potential worsening of the cardiac undesirable effect.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible.
Experience with Tofranil in pregnancy is limited. Since there have been isolated reports of a possible connection between the use of Tofranil and adverse effects on the fetus, treatment with Tofranil should be avoided during pregnancy, and only considered if the benefits expected justify the potential risk for the fetus.
Epidemiological studies have suggested an increased risk of congenital abnormalities associated with use of antidepressants in pregnancy and the use of antidepressants in pregnancy may be associated with an increase in pre-term delivery.
Babies whose mothers had taken Tofranil up until delivery showed symptoms, such as dyspnoea, lethargy, colic, irritability, hypotension or hypertension, tremor or spasms, during the first month of life. To avoid such symptoms, Tofranil should, if possible, be gradually withdrawn at least 7 weeks before the calculated date of confinement.
 Imipramine and desmethylimipramine pass into human milk in small quantities. Since nothing is known about the clinical relevance of this finding to the infant, babies should be weaned or the medication gradually withdrawn.

4.7 Effects on Ability to Drive and Use Machines

Tofranil may cause fatigue, blurred vision, somnolence and other central nervous symptoms [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 reactions do not always correlate with plasma drug levels or dose. If severe neurological or psychiatric reactions occur, Tofranil should be withdrawn. Elderly patients are particularly susceptible to anticholinergic, neurological, psychiatric and cardiovascular effects.
Reporting frequencies are described as follows. Very common: ≥ 10%; common: ≥ 1 - < 10%; uncommon: ≥ 0.1 - < 1%; rare: ≥ 0.01 - < 0.1%; very rare: < 0.01%.

Blood and lymphatic system disorders.

Very rare: bone marrow depression including leucopenia, agranulocytosis, eosinophilia, thrombocytopenia, lymphadenitis.

Immune system disorders.

Very rare: anaphylactic reaction.

Endocrine disorders.

Very rare: inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders.

Very common: weight increased.
Common: anorexia.
Very rare: weight decreased.

Psychiatric disorders.

Common: restlessness, euphoria, confusion, delirium, hallucinations, anxiety, agitation, mania, hypomania, libido disorder, sleep disorder, disorientation.
Rare: psychotic disorder.
Very rare: aggression.
Not known: suicide ideation and suicidal behaviours.

Nervous system disorders.

Very common: tremor.
Common: dizziness, headache, sedation, somnolence, paraesthesias.
Rare: convulsions.
Very rare: myoclonus, extrapyramidal disorder, ataxia, speech disorders, progressive stroke.
Not known: dysgeusia.

Eye disorders.

Common: blurred vision, disorders of visual accommodation, lacrimation decreased.
Very rare: mydriasis, glaucoma.

Ear and labyrinth disorders.

Very rare: tinnitus.

Cardiac disorders.

Very common: sinus tachycardia.
Common: arrhythmias, palpitations, conduction disorders (e.g. widening of QRS complex, bundle branch block, PR changes).
Very rare: cardiac failure, QT interval prolongation, ventricular arrhythmia, ventricular tachycardia, ventricular fibrillation, torsades de pointes.

Vascular disorders.

Very common: hot flushes, orthostatic hypotension.
Very rare: vasospasm, blood pressure increase, stroke.

Respiratory, thoracic and mediastinal disorders.

Very rare: alveolitis allergic (with or without eosinophilia).

Gastrointestinal disorders.

Very common: dry mouth, constipation.
Common: nausea, vomiting, diarrhoea.
Very rare: ileus paralytic, stomatitis, abdominal disorders, tongue ulceration, dental caries.

Hepatobiliary disorders.

Very rare: hepatitis (with or without jaundice), acute hepatitis, hepatic necrosis.

Skin and subcutaneous tissue disorders.

Very common: hyperhidrosis.
Common: dermatitis allergic, contact (skin rash), urticaria.
Very rare: pruritus, purpura, petechiae, photosensitivity reactions, alopecia, skin hyperpigmentation.

Renal and urinary disorders.

Common: micturition disorder.
Very rare: urinary retention.

Reproductive system and breast disorders.

Very rare: hypertrophy breast, galactorrhoea.

General disorders and administration site conditions.

Common: fatigue.
Very rare: asthenia, oedema (localised or generalised), pyrexia, sudden death.

Investigations.

Very common: electrocardiogram abnormalities (e.g. ST and T wave changes).
Common: liver function test abnormal.
Very rare: blood glucose increased, blood glucose decreased, electroencephalogram abnormal, blood pressure increased.

Withdrawal symptoms.

Common: although not indicative of addiction, withdrawal symptoms follow abrupt discontinuation of treatment or reduction of the dose: nausea, vomiting, abdominal pain, diarrhoea, chills, sweating, musculoskeletal pain, insomnia, headache, nervousness irritability, malaise and anxiety. It is advisable to reduce imipramine dose gradually when the treatment is no more necessary (see Section 4.4 Special Warnings and Precautions for Use).

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.
With the class of tricyclic antidepressants the following adverse reactions have been observed: dyskinesia and serotonin syndrome.

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

The signs and symptoms of overdose with Tofranil are similar to those reported with other tricyclic antidepressants. Cardiac abnormalities and neurological disturbances are the main alterations. In children, accidental ingestion of any amount should be regarded as serious and potentially fatal.

Signs and symptoms.

The first signs and symptoms of poisoning with tricyclic antidepressants generally appear rapidly and take the form of severe anticholinergic reactions, which set in about ½ to 2 hours after the drug has been taken.
The severity of poisoning with tricyclic antidepressants depends 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.

Drowsiness, stupor, coma, ataxia, restlessness, agitation, mydriasis, enhanced reflexes, muscular rigidity with athetoid and choreiform movements, convulsions, consciousness, clouding and serotonin syndrome.

Cardiovascular.

Arrhythmia, tachycardia, conduction disorders, hypotension, shock, heart failure; in very rare cases, cardiac arrest.

Respiratory system.

Respiratory depression, cyanosis, apnoea.

Other.

Vomiting, dry mouth, constipation, fever, sweating and oliguria or anuria may occur.
Isolated cases of QT prolongation, torsades de pointes and death have been reported in overdose.

Treatment.

There is no specific antidote and treatment is essentially symptomatic and supportive.
Where the drug has been taken by mouth, activated charcoal should be administered. Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
Anyone suspected of receiving an overdose of Tofranil, particularly children, should be hospitalised and kept under close surveillance for at least 72 hours. Severe poisoning with tricyclic drugs requires immediate hospitalisation and continuous cardiovascular monitoring for at least 48 hours.
In all patients with ECG abnormalities, cardiac function should be kept under close observation well 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 in cases of bradycardia, heart block not responding to alkalinisation or treatment with isoprenaline.
Low potassium values and acidosis should be corrected.
In convulsions: diazepam should be given i.v. Other anticonvulsants may be required.
Dialysis and haemodialysis are of no use.
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.

Imipramine is a tricyclic antidepressant with a multivalent spectrum of pharmacological action, which includes alpha-adrenolytic, anti-histaminic, anticholinergic, and 5-HT-receptor blocking properties. However, the therapeutic activity of imipramine is believed to be based mainly on its ability to inhibit the neuronal re-uptake of noradrenaline (norepinephrine) (NA) and serotonin (5-HT).
Imipramine belongs to the category of so called mixed re-uptake blockers, i.e. it has been shown to inhibit the re-uptake of NA and 5-HT to approximately the same extent in the rat brain.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Imipramine is well absorbed following oral administration. During its first passage through the liver, orally administered imipramine becomes partly converted to desmethylimipramine, which also exhibits antidepressant activity.
During oral administration of 50 mg 3 times daily for 10 days, the mean steady state plasma concentrations of imipramine and desmethylimipramine (on day 7 in four healthy male volunteers) were 33 to 85 nanogram/mL and 43 to 109 nanogram/mL respectively. Owing to lower clearance from the plasma, resulting in greater systemic availability, elderly patients require lower doses of imipramine than patients in intermediate age groups.

Distribution.

Protein binding: mean 86%; distribution volume: mean 21 L/kg; plasma half-life: mean approximately 20 hours.

Excretion.

Approximately 80% is excreted in the urine and 20% in the faeces, chiefly in the form of inactive metabolites.

5.3 Preclinical Safety Data

Genotoxicity.

The overall evaluation may be summarised as follows:

Oral.

Independent studies in three species (rat, mouse and rabbit) revealed that when Tofranil is administered orally in doses up to approximately two and a half times the maximum human dose in the first two species and up to 25 times the maximum human dose in the third species, the drug is essentially free from teratogenic potential. In the three species studied only one instance of fetal abnormality occurred (in the rabbit) and in that study there was likewise an abnormality in the control group. However, evidence does exist from the rat studies that some systemic and embryotoxic potential is demonstrable. This is manifested by reduced litter size, a slight increase in the stillborn rate and a reduction in the mean birth weight.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tofranil contains colloidal anhydrous silica, glycerol, lactose monohydrate, magnesium stearate, maize starch, stearic acid, purified talc, hypromellose, povidone, copovidone, titanium dioxide, microcrystalline cellulose, macrogol 8000, sucrose, iron oxide red and carnauba wax (Tofranil 25 mg tablets only).

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C and protected from moisture.

6.5 Nature and Contents of Container

Tofranil 10.

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

Tofranil 25.

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

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


Molecular formula: C19H24N2.HCl.
Molecular weight: 316.9.
Chemical name (imipramine hydrochloride): 5-(3-Dimethylamino-propyl)-10, 11-dihydro-5H-dibenz[b,f]azepine hydrochloride.
Imipramine hydrochloride is a white to yellowish powder. It is freely soluble in water, methanol, and ethanol; soluble in acetone; slightly soluble in ethyl acetate; and practically insoluble in ether and petroleum ether.

CAS number.

113-52-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes