Consumer medicine information

Entrip

Amitriptyline hydrochloride

BRAND INFORMATION

Brand name

Entrip

Active ingredient

Amitriptyline hydrochloride

Schedule

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about ENTRIP.

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

All medicines have benefits and risks. Your doctor has weighed the risks of you taking ENTRIP against the benefits they expect it will have for you.

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

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

WHAT ENTRIP IS USED FOR

ENTRIP is used to treat depression.

ENTRIP 10 mg and 25 mg tablets can be used at any stage in the treatment of depression. However, the highest strength ENTRIP 50 mg, is approved only for the maintenance treatment of depression (after your symptoms have improved).

ENTRIP belongs to a group of medicines called tricyclic antidepressants (TCAs). TCA medicines work by correcting the imbalance of certain chemicals in the brain. These chemicals, called amines, are involved in controlling mood. By correcting this imbalance, TCAs can help relieve the symptoms of depression.

ENTRIP can also be used to treat bed-wetting, provided that there is no physical cause for the problem (e.g. problems with the bladder).

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

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

ENTRIP is available only with a doctor's prescription.

BEFORE YOU TAKE ENTRIP

When you must not take it

Do not take ENTRIP if you are allergic to medicines containing amitriptyline (e.g. Tryptanol) or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include skin rash, itching or hives; swelling of the face or tongue which may cause difficulty swallowing or breathing; increased sensitivity of the skin to the sun.

Do not take ENTRIP if you have recently had a heart attack. Taking ENTRIP could make your condition worse.

Do not take ENTRIP if you are taking, or have taken within the last 14 days another medicine for depression called a monoamine oxidase inhibitor (MAOI). Taking ENTRIP 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 severe convulsions. Your doctor will tell you when it is safe to start taking ENTRIP after stopping the MAOI.

Ask your doctor or pharmacist if you are unsure if you are taking, or have been taking a MAOI. MAOIs are medicines used to treat depression and symptoms of Parkinson's disease. Examples of MAOIs are phenelzine (Nardil), tranylcypromine (Parnate), moclobemide (eg. Aurorix, Arima) and selegiline (Eldepryl, Selgene).

Do not take ENTRIP if you are taking cisapride (Prepulsid), a medicine used to treat stomach reflux. Combining ENTRIP with cisapride may cause serious side effects such as an abnormal heart rhythm.

Do not take ENTRIP if you are breastfeeding. ENTRIP passes into breast milk and may harm your baby.

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

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

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

Before you start to take it

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

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

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

heart or blood vessel problems
liver problems
glaucoma, a condition characterised by an increased pressure in the eye
urinary problems such as difficulty in passing urine
thyroid problems
seizures or fits
any mental illness other than depression, for example schizophrenia.

Tell your doctor if you plan to undergo any type of surgery or if you are undergoing electroshock therapy.

If you have not told your doctor about any of the above, tell him/her before you start taking ENTRIP.

Taking other medicines

Do not take ENTRIP if you are taking:

cisapride (Prepulsid), a medicine used to treat stomach reflux
any monoamine oxidase inhibitor (MAOI) such as:
- phenelzine (Nardil) and tranylcypromine (Parnate), moclobemide (eg. Aurorix, Arima), used to treat depression
- selegiline (Eldepryl, Selgene), used to treat symptoms of Parkinson's disease.
Wait at least 14 days after stopping your MAOI before starting ENTRIP.

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

Tell your doctor if you are taking or have recently taken any other medicines, such as valproic acid.

Some medicines may be affected by ENTRIP or may affect how well ENTRIP works. These include:

selective serotonin reuptake inhibitors (SSRIs), a group of medicines used to treat depression and other mental illnesses, such as fluoxetine (eg. Prozac, Lovan), sertraline (eg. Zoloft) and paroxetine (eg. Aropax, Paxtine)
some medicines used to treat high blood pressure
anticholinergics, found in some medicines used to relieve stomach cramps; travel sickness; hayfever and allergies; cough and colds
medicines used to treat mental disorders such as schizophrenia
quinidine (Kinidin) and flecainide (Tambocor, Flecatab), medicines used to control an irregular heart beat
cimetidine (eg. Tagamet, Magicul), a medicine used to treat reflux and ulcers
sleeping tablets/sedatives, anti-anxiety medicines
medicines for epilepsy
thyroid medicines
disulfiram (eg. Antabuse), a medicine used to deter alcohol consumption
tramadol (eg. Tramal), a medicine used to relieve pain.

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

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

HOW TO TAKE ENTRIP

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.

Your doctor will decide the right dose for you.

Depression
ENTRIP is usually started at a low dose and then, if necessary, increased depending on how your symptoms improve and how well you tolerate it. For depression, the usual starting dose is 75 mg to 150 mg per day in divided doses.

For people being treated in hospital for their depression, the usual starting dose is 100 mg to 200 mg per day.

For the elderly, lower doses are recommended, as ENTRIP may not be well tolerated in this age group. Your doctor may then reduce your dose to 50 mg to 100 mg per day when your depressive symptoms have improved, depending on your response to ENTRIP.

Bed-wetting
Keep ENTRIP out of the reach of children.

Do not give your child more ENTRIP than what is recommended by your doctor.

The doses recommended for bed-wetting are lower than the doses used to treat depression and usually depend on the person's age and weight.

How to take it

Swallow the tablets whole with a glass of water.

When to take it

ENTRIP can be taken with or without food.

ENTRIP can be taken as a single dose (eg. at bedtime) or as divided doses (eg. three times a day). Your doctor will advise you.

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

How long to take it for

Depression
Keep taking ENTRIP for as long as your doctor recommends.

The length of treatment will depend on how quickly your symptoms improve.

Most medicines for depression take time to work, so do not be discouraged if you do not feel better right away. Some people notice an improvement in their depressive symptoms after 3 or 4 days. However, it may take up to 4 weeks to feel the full benefits of ENTRIP.

Even when you feel well, your doctor may ask you to continue taking ENTRIP for 3 months or longer to make sure that the benefits last.

Bed-wetting
Most children respond to treatment in the first few days. However, continued treatment is usually required to maintain the response until bed-wetting ends.

If you forget to take it

If you take one dose a day (at bedtime):

If you forget to take ENTRIP before going to bed and wake up late in the night or early in the morning, do not take the missed dose until you have checked with your doctor. You may have difficulty waking up or experience drowsiness in the morning or during the day, if you take ENTRIP at these times.

If you take more than one dose a day:

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

Do not try to make up the dose you missed by taking a double dose.

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

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

If you take too much (overdose)

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

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much ENTRIP, you may feel drowsy, cold, very dizzy or have a fast or irregular heart beat.

You may also have fits, difficulty breathing or lose consciousness.

Keep ENTRIP out of the reach of children. Children are much more sensitive than adults to medicines such as ENTRIP. An accidental overdose is especially dangerous in children.

WHILE YOU ARE TAKING ENTRIP

Things you must do

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

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

worsening of your depression
thoughts or talk of death or suicide
thoughts or talk of self-harm or harm to others
any recent attempts of self-harm
increase in aggressive behaviour, irritability or any other unusual changes in behaviour or mood.

All mentions of suicide or violence must be taken seriously.

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

Keep all of your appointments with your doctor so that your progress can be checked.

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

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

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

If you plan to have surgery, including dental surgery, tell your doctor or dentist that you are taking ENTRIP. Your doctor may ask you to temporarily stop taking ENTRIP a few days before elective surgery.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Things you must not do

Do not drive or operate machinery until you know how ENTRIP affects you. ENTRIP may reduce your alertness, cause drowsiness or dizziness in some people. If you experience any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

For the same reasons, children should not ride a bike, climb trees or do anything else that could be dangerous if they are drowsy.

Do not stop taking ENTRIP, or lower the dose, without checking with your doctor.

Do not let yourself run out of your medicine over weekends or during holidays.

Stopping ENTRIP suddenly may make you feel sick (nauseous), have headaches or feel generally unwell.

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

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

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

Things to be careful of

Be careful drinking alcohol while taking ENTRIP. Combining ENTRIP with alcohol can make you more drowsy or dizzy. Your doctor may suggest you avoid alcohol while being treated for depression.

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

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

SIDE EFFECTS

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

ENTRIP helps most people, 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.

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 the following and they worry you:

dry mouth, altered sense of taste
nausea (feeling sick), vomiting
diarrhoea, constipation
blurred vision, difficulty in focussing
drowsiness, tiredness, headache
dizziness, lightheadedness
increased sweating
weight gain or loss
changes in sex drive

The above list includes the milder side effects of ENTRIP.

Tell your doctor as soon as possible if you notice any of the following:

fast or irregular heart beats
larger breast than normal (in men and women)
tingling or numbness of the hands or feet
uncontrolled movements, including trembling and shaking of the hands and fingers, twisting movements of the body, shuffling walk and stiffness of the arms and legs
difficulty in passing urine
signs of frequent infections such as fever, chills, sore throat or mouth ulcers
yellowing of the eyes or skin (jaundice)
unusual bruising or bleeding
feeling anxious, restless or confused
abnormal ideas, hallucinations
sudden switch of mood to one of excitement, overactivity, talkativeness and uninhibited behaviour.

The above side effects are serious and may require medical attention.

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

skin rash, itching, hives; swelling of the face or tongue; severe sunburn, blistering or swelling of the skin
fainting or collapse
chest pain
seizures or fits

The above side effects are very serious and may require urgent medical attention or even hospitalisation.

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

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

AFTER TAKING ENTRIP

Storage

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

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

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

Do not leave ENTRIP in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

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

PRODUCT DESCRIPTION

What it looks like

ENTRIP is available in three strengths:

ENTRIP 10 mg: round blue coloured biconvex tablets debossed AM on one side and 10 on the other side.

ENTRIP 25 mg: round yellow coloured biconvex tablets debossed AM on one side and 25 on the other side.

ENTRIP 50 mg: round brown coloured biconvex tablets debossed AM on one side and 50 on the other side.

ENTRIP is available in blister and bottle packs of various pack sizes.

Not all pack sizes may be marketed.

Ingredients

The active ingredient in ENTRIP is amitriptyline hydrochloride.

Each ENTRIP tablet contains 10 mg, 25 mg or 50 mg of amitriptyline hydrochloride.

ENTRIP tablets also contain the following inactive ingredients:

lactose monohydrate
microcrystalline cellulose
maize starch
croscarmellose sodium
colloidal anhydrous silica
purified talc
magnesium stearate
hypromellose
Macrogol 6000

The tablet coating contains:

OPADRY II complete film coating system

85F99075 BLUE
[ARTG 109882 for 10 mg]
85F92349 YELLOW
[ARTG 109879 for 25 mg]
85F565015 BROWN
[ARTG 109885 for 50 mg].

Tablet contains sugars as lactose.

Sponsor

Arrow Pharma Pty Ltd
15-17 Chapel Street
Cremorne Victoria 3121

Australian registration number:

ENTRIP 10 mg - AUST R 232152
ENTRIP 25 mg - AUST R 232154
ENTRIP 50 mg - AUST R 232156

This leaflet was prepared on November 2021.

Published by MIMS January 2022

BRAND INFORMATION

Brand name

Entrip

Active ingredient

Amitriptyline hydrochloride

Schedule

1 Name of Medicine

Amitriptyline hydrochloride.

2 Qualitative and Quantitative Composition

Entrip tablets contain 10 mg, 25 mg or 50 mg of amitriptyline hydrochloride.

Excipients with known effect.

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

3 Pharmaceutical Form

Entrip 10 mg tablet.

Round blue coloured biconvex tablets debossed AM on one side and 10 on the other side.

Entrip 25 mg tablet.

Round yellow coloured biconvex tablets debossed AM on one side and 25 on the other side.

Entrip 50 mg tablet.

Round brown coloured biconvex tablets debossed AM on one side and 50 on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of major depression. Entrip 50 mg tablets are indicated only for the maintenance treatment of major depression (see Section 4.4 Special Warnings and Precautions for Use).
Nocturnal enuresis where organic pathology has been excluded.

4.2 Dose and Method of Administration

Depression.

Dosage considerations.

Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance.

Initial dosage for outpatient adults.

75 mg a day in divided doses is usually satisfactory. If necessary, this may be increased to a total of 150 mg a day. Increases are made preferably in the late afternoon and/or bedtime doses. The sedative effect is usually rapidly apparent. The antidepressant activity may be evident within three or four days or may take up to 30 days to develop adequately.
Alternative methods for initiating therapy in outpatients are: begin therapy with 50 to 100 mg preferably in the evening or at bedtime; this may be increased by 25 to 50 mg as necessary to a total of 150 mg per day.

Dosage for hospitalised patients.

100 mg a day may be required initially. This can be increased gradually to 200 mg a day if necessary. A small number of hospitalised patients may need as much as 300 mg per day.

Dosage for elderly patients.

In general, lower dosages are recommended for these patients. 50 mg daily may be satisfactory in those elderly patients who may not tolerate higher doses. The required daily dose may be administered either in divided doses or as a single dose preferably in the evening or at bedtime.

Maintenance dosage.

Usually from 50 to 100 mg per day. For maintenance therapy, the total daily dosage may be given in a single dose preferably in the evening or at bedtime. When satisfactory improvement has been reached, dosage should be reduced to the lowest amount that will maintain relief of symptoms. It is appropriate to continue maintenance therapy 3 months or longer to lessen the possibility of relapse.

Enuresis.

A dose of 10 mg at bedtime has been found effective in children under 6 years of age. In older children, the dosage should be increased as necessary according to weight and age. Children 6 to 10 years of age may receive 10 to 20 mg per day. In the age group from 11 to 16, a dose of 25 to 50 mg at bedtime may be required.
Most patients respond in the first few days of therapy. In those who do respond, the tendency is for increasing, continued improvement as the period of treatment is extended. Continued treatment is usually required to maintain the response until control is established.
The doses of amitriptyline hydrochloride recommended in the treatment of enuresis are low compared with those used in the treatment of depression, even allowing for differences in age and weight. This recommended dose must not be exceeded. This medication should be kept out of reach of children.

Plasma levels.

Because of the wide variation in the absorption and distribution of tricyclic antidepressants in body fluids, it is difficult to directly correlate plasma levels and therapeutic effect. However, determination of plasma levels may be useful in identifying patients who appear to have toxic effects and may have excessively high levels, or those in whom lack of absorption or non-compliance is suspected. Adjustments in dosage should be made according to the patient's clinical response and not on the basis of plasma levels.

4.3 Contraindications

Amitriptyline is contraindicated in patients who have shown prior hypersensitivity to it.

Monoamine oxidase inhibitors (MAOIs).

Amitriptyline should not be given concurrently with monoamine oxidase inhibitors, including selegiline. The combination of amitriptyline with a monoamine oxidase inhibitor has caused severe convulsions, hyperpyretic crises and death. When it is desired to substitute amitriptyline for a monoamine oxidase inhibitor, a minimum of 14 days should be allowed to elapse after the latter is discontinued. Amitriptyline should then be initiated cautiously with gradual increase in dosage until optimum response is achieved.

Cisapride.

Amitriptyline is contraindicated in patients taking cisapride due to the possibility of adverse cardiac interactions including prolongation of the QT interval, cardiac arrhythmias and conduction system disturbances.

Myocardial infarction.

Amitriptyline is not recommended for use during the acute recovery phase following myocardial infarction.
See Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation.

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, both adult and paediatric, may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviour (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.
Pooled analyses of short-term placebo controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behaviour (suicidality) in children, adolescents and young adults (ages 18-24) with major depressive disorder and other psychiatric disorders. Short-term studies did not show an increase in risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
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 analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).
The pooled analyses of placebo controlled trials in adults with major depressive disorder or other psychiatric disorders included a total of 295 short-term trials (average duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. Absolute risk of suicidality varied across the different indications, with the highest incidence in major depressive disorder. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e. beyond several months. However, there is substantial evidence from placebo controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
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 non-psychiatric. 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, adolescents and young adults (ages 18-24) being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or non-psychiatric) 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 amitriptyline should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Amitriptyline hydrochloride 50 mg tablets.

The 50 mg tablets are indicated only for the maintenance treatment of major depression. The 50 mg tablets should not be used in acutely ill patients where there is a risk of suicide. There is an increased risk of completed suicide by overdose with the 50 mg tablet compared with the 25 mg tablet.
To prevent accidental overdose and the potentially fatal consequences, patients should be made aware of the unusual toxicity of tricyclic antidepressants and the need to maintain strict control over the tablets as well as the need to store them out of reach of children.

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 detailed psychiatric history, including a family history of suicide, bipolar disorder and depression.

Seizures.

Amitriptyline should be used with caution in patients with a history of seizures.

Central nervous disorders.

The possibility of suicide in depressed patients remains during treatment. Patients should not have access to large quantities of this medicine during treatment.
When amitriptyline is used to treat the depressive component of schizophrenia, psychotic symptoms may be aggravated. Likewise, in manic depressive psychosis, depressed patients may experience a shift toward the manic phase. Paranoid delusions, with or without associated hostility, may be exaggerated. In any of these circumstances, it may be advisable to reduce the dose of amitriptyline or to use a major tranquillising medicine, such as perphenazine, concurrently.

Glaucoma and urinary retention.

Due to its atropine-like action, amitriptyline should be used with caution in patients with a history of urinary retention, or with narrow angle glaucoma or increased intraocular pressure. In patients with narrow angle glaucoma, even average doses precipitate an attack.

Cardiovascular disorders.

Patients with cardiovascular disorders should be watched closely. Tricyclic antidepressant medicines, including amitriptyline, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia, and prolongation of the conduction time. Myocardial infarction and stroke have been reported with medicines of this class.

Endocrine disorders.

Close supervision is required when amitriptyline is given to hyperthyroid patients or those receiving thyroid medication (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Other antidepressant medicines.

The addition of other antidepressant medicines generally does not result in any additional therapeutic benefit. Untoward reactions have been reported after the combined use of antidepressant agents having varying modes of activity. Therefore, combined use of amitriptyline and other antidepressant medicines should be undertaken only with due recognition of the possibility of potentiation and with a thorough knowledge of the pharmacology of both medicines. There has been no evidence of potentiation when patients receiving amitriptyline were changed immediately to protriptyline or vice versa.
See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Elective surgery.

Discontinue the medicine several days before elective surgery if possible.

Impairment of motor coordination.

Amitriptyline may impair alertness in some patients; operation of motor vehicles and other activities made hazardous by diminished alertness should be avoided.

Use in hepatic impairment.

In the presence of hepatic disease, amitriptyline should be used cautiously.

Use in renal impairment.

Due to its atropine-like action, amitriptyline should be used with caution in patients with a history of urinary retention.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

The safety and efficacy of amitriptyline for the treatment of depression or other psychiatric disorders in children and adolescents aged less than 18 years has not been satisfactorily established. Amitriptyline should not be used in this age group for the treatment of depression.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Other antidepressant medicines.

A potentially lethal interaction can occur between monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants. It is advisable to discontinue the MAOI for at least 2 weeks before taking amitriptyline (see Section 4.3 Contraindications).
Concurrent use of fluoxetine and tricyclic antidepressants has produced increased plasma concentrations of the tricyclic antidepressants. Some clinicians recommend dosage reductions for tricyclic antidepressants of about 50% if used concurrently with fluoxetine. Any patient receiving amitriptyline and fluoxetine concurrently should be observed closely for adverse effects and consideration should be given to monitoring the plasma levels of the tricyclic antidepressant with dosage reduction where necessary.
There have been no reports of untoward events when patients receiving amitriptyline were changed immediately to protriptyline or vice versa.

Guanethidine.

Amitriptyline may block the antihypertensive action of guanethidine or similarly acting compounds.

Anticholinergic agents/ sympathomimetic medicines.

When amitriptyline is given with anticholinergic agents or sympathomimetic medicines, including adrenaline combined with local anaesthetics, close supervision and careful adjustment of dosage are required. Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic type medicines.

Anticholinergic agents/ neuroleptic medicines.

Hyperpyrexia has been reported when tricyclic antidepressants are administered with anticholinergic agents or with neuroleptic medicines, particularly during hot weather. Concurrent use of phenothiazines and tricyclic antidepressants have the potential to elevate plasma levels of both agents. The sedative and anticholinergic effects may be prolonged and the risk of seizures and neuroleptic malignant syndrome increased.

Medicines metabolised by cytochrome P450 2D6.

Concomitant use of tricyclic antidepressants with medicines that can inhibit cytochrome P450 2D6 (e.g. quinidine; cimetidine) and those that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the type 1C antiarrhythmics, e.g. flecainide) may require lower doses than usually prescribed for either the tricyclic antidepressant or the other medicine. Whenever one of these other medicines is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. While all the selective serotonin reuptake inhibitors (SSRIs), e.g. fluoxetine, sertraline and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition.
Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants, thereby delaying elimination and increasing steady-state concentrations of these medicines.

Central nervous system depressants.

Amitriptyline may enhance the response to alcohol and the effects of barbiturates and other CNS depressants.

Disulfiram.

Delirium has been reported with concurrent administration of amitriptyline and disulfiram.

Electroshock therapy.

Concurrent administration of amitriptyline and electroshock therapy may increase the hazards of therapy. Such treatment should be limited to patients for whom it is essential.

Antithyroid medicines.

Concurrent use may increase the risk of agranulocytosis.

Thyroid hormones.

Concurrent use with tricyclic antidepressants may increase the therapeutic and toxic effects of both medications. Toxic effects include cardiac arrhythmias and CNS stimulation.

Analgesics.

Tricyclic antidepressants may enhance the seizure risk in patients taking tramadol.

Selective serotonin reuptake inhibitors (SSRIs).

The "serotonin syndrome" (alterations in cognition, behaviour, autonomic nervous system function, and neuromuscular activity) has been reported with amitriptyline when given concomitantly with other serotonin enhancing medicines including selective serotonin reuptake inhibitors (SSRIs).

Sodium valproate.

Amitriptyline plasma concentration can be increased by sodium valproate. Clinical monitoring is therefore recommended.

Other medicines.

Because tricyclic antidepressants may delay gastric emptying and decrease intestinal motility, careful dosage monitoring is essential with any medicine that may be subject to gastric inactivation (i.e. levodopa) or which may be absorbed to a greater extent because of the increased time available for absorption (i.e. anticoagulants).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
Withdrawal symptoms in newborn infants have been reported with prolonged maternal use of this class of medicines. 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.
There are no well controlled studies in pregnant women; therefore, in administering amitriptyline to pregnant women or women who may become pregnant, the potential benefits must be weighed against the possible hazards to mother and child.
Amitriptyline is detectable in breast milk. Because of the potential for serious adverse effects in infants from amitriptyline, a decision should be made whether to discontinue nursing or discontinue the medicine.

4.7 Effects on Ability to Drive and Use Machines

Amitriptyline may cause drowsiness, impair alertness in some patients and increase the effects of alcohol. Patients should be instructed not to drive a motor vehicle, operate machinery and/or undertake activities that may be hazardous by diminished alertness if they are affected by amitriptyline.

4.8 Adverse Effects (Undesirable Effects)

Note.

Included are a few adverse effects which have not been reported with this specific medicine. However, pharmacological similarities among the tricyclic antidepressants require that each of the effects be considered when amitriptyline is administered.
Very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Metabolism and nutrition disorders.

Rare: decreased appetite.
Frequency not known: elevation or lowering of blood sugar levels, increased appetite, anorexia.

Cardiac disorders.

Very common: tachycardia, palpitations.
Common: atrioventricular block, bundle branch block.
Uncommon: collapse conditions, worsening of cardiac failure.
Rare: arrhythmias.
Very rare: cardiomyopathies, torsades de pointes.
Frequency not known: hypersensitivity myocarditis, myocardial infarction.

Vascular disorders.

Very common: orthostatic hypotension.
Uncommon: hypertension.
Frequency not known: hyperthermia, stroke, syncope.

Nervous system and neuromuscular disorders.

Very common: somnolence, tremors, dizziness, headache, drowsiness, speech disorders (dysarthria).
Common: disturbance in attention, dysgeusia, paraesthesia (of the extremities), ataxia.
Uncommon: convulsions.
Very rare: akathisia, polyneuropathy.
Frequency not known: weakness, disturbed concentration disorder, disorientation, delusions, excitement, restlessness, numbness, tingling, peripheral neuropathy, incoordination, coma, seizures, alteration in EEG patterns, extrapyramidal disorder including abnormal voluntary movements and tardive dyskinesia.

Psychiatric disorders.

Very common: aggression.
Common: confusional states, decrease libido, agitation.
Uncommon: hypomania, mania, anxiety, insomnia, nightmares.
Rare: delirium (in elderly patients), hallucinations, suicidal thoughts or behaviour.*
Frequency not known: Paranoia.
*Case reports of suicidal thoughts or behaviour were reported during the treatment with or just after conclusion of the treatment with amitriptyline (see Section 4.4 Special Warnings and Precautions for Use).

Skin and subcutaneous tissue disorders.

Very common: hyperhidrosis.
Uncommon: rash, urticaria, pruritus, oedema of face and tongue.
Rare: alopecia, photosensitisation.

Blood and lymphatic system disorders.

Rare: bone marrow depression including agranulocytosis, leucopenia, eosinophilia, purpura and thrombocytopenia.

Respiratory, thoracic and mediastinal disorders.

Very common: congested nose.
Very rare: allergic inflammation of the pulmonary alveoli and of the lung tissue, respectively (alveolitis, Loffler's syndrome).

Gastrointestinal disorders.

Very common: dry mouth, constipation, nausea.
Uncommon: diarrhoea, vomiting.
Rare: parotid swelling (salivary gland enlargement), paralytic ileus.
Frequency not known: epigastric distress, stomatitis, peculiar taste, black tongue.

Hepatobiliary disorders.

Rare: jaundice, hepatitis.
Uncommon: hepatic impairment (e.g. cholestatic liver disease).

Eye disorders.

Very common: disturbance of accommodation.
Common: mydriasis.
Very rare: acute glaucoma.
Frequency not known: blurred vision, dry eye.

Ear and labyrinth disorders.

Uncommon: tinnitus.

Renal and urinary disorders.

Common: micturition disorders, erectile dysfunction.
Uncommon: urinary retention.
Frequency not known: urinary frequency, dilatation of urinary tract, syndrome of inappropriate ADH (antidiuretic hormone) secretion.

Reproductive system and breast disorders.

Common: erectile dysfunction.
Uncommon: galactorrhoea.
Rare: gynaecomastia.
Frequency not known: testicular swelling, breast enlargement, increased or decreased libido, interference with sexual function including impotence.

General disorders and administration site conditions.

Common: fatigue, feeling thirst, oedema, increased perspiration, drowsiness, hyperpyrexia.
Rare: pyrexia.

Investigations.

Very common: weight gain.
Common: nonspecific ECG changes and changes in AV conduction, electrocardiogram QT prolonged, electrocardiogram QRS complex prolonged, hyponatremia.
Uncommon: increased intraocular pressure.
Rare: weight loss, liver function test abnormal, blood alkaline phosphatase increased, transaminases increased.

Serotonin syndrome.

The “serotonin syndrome” (alterations in cognition, behaviour, autonomic nervous system function, and neuromuscular activity) has been reported with amitriptyline when given concomitantly with other serotonin enhancing medicines.

Withdrawal symptoms.

Abrupt cessation of treatment after prolonged administration may produce nausea, headache and malaise. Gradual dosage reduction has been reported to produce, within two weeks, transient symptoms including irritability, restlessness, and dream and sleep disturbance. These are not indicative of addiction. Rare instances have been reported of mania or hypomania occurring within 2 to 7 days following cessation of chronic therapy with tricyclic antidepressants.

In enuresis.

The doses of amitriptyline recommended in the treatment of enuresis are low compared with those used in the treatment of depression, even allowing for differences in age and weight. Consequently, side effects are less frequent than when the medicine is used in treating depression. The most common side effects are drowsiness and anticholinergic effects.

Causal relationship unknown.

A lupus-like syndrome (migratory arthritis, positive ANA and rheumatoid factor) has been reported rarely; however, a causal relationship to therapy with amitriptyline could not be established.

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

Deaths by deliberate or accidental overdosage have occurred with this class of medicine.
There has been a report of fatal dysrhythmia occurring as late as 56 hours after amitriptyline overdose.

Symptoms.

Anticholinergic symptoms.

Mydriasis, tachycardia, urinary retention, dry mucus membranes, reduced bowel motility. Convulsions. Fever. Sudden occurrence of CNS depression. Lowered consciousness progressing into coma. Respiratory depression. Hyperreflexia (hyperactive reflexes) may be present with extensor plantar reflexes. Hypothermia may occur.

Cardiac symptoms.

Arrhythmic (ventricular tachyarrhythmias, torsade de pointes, ventricular fibrillation) and other abnormalities such as bundle branch block, ECG evidence of impaired conduction, congestive heart failure.
The ECG characteristically show prolonged PR interval, widening of the QRS-complex, QT prolongation, T-wave flattening or inversion, ST segment depression, and varying degrees of heart block progressing to cardiac standstill. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Widening of the QRS-complex usually correlates well with the severity of the toxicity following acute overdoses. Hypotension, cardiogenic shock. Metabolic acidosis, hypokalemia, hyponatraemia.
High doses may cause temporary confusion, disturbed concentration, or transient visual hallucinations. Overdosage may cause drowsiness, hypothermia, dilated pupils, stupor and polyradiculoneuropathy. Other symptoms may be agitation, muscle rigidity, vomiting, hyperpyrexia or any of those listed, see Section 4.8 Adverse Effects (Undesirable Effects).

Treatment.

All patients suspected of having taken an overdosage should be admitted to a hospital as soon as possible. Treatment is symptomatic and supportive. 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, one the airway is protected. An ECG should be taken and close monitoring of cardiac function instituted if there is any sign of abnormality. Maintain an open airway and adequate fluid intake; regulate body temperature.
Standard measures should be used to manage circulatory shock and metabolic acidosis. Cardiac arrhythmias have been treated with propranolol. Should cardiac failure occur, the use of digitalis should be considered. Close monitoring of cardiac function for not less than five days is advisable.
Anticonvulsants may be given to control convulsions. Amitriptyline increases the CNS depressant action but not the anticonvulsant action of barbiturates; therefore, an inhalation anaesthetic or diazepam is recommended for control of convulsions.
Dialysis is of no value because of low plasma concentrations of the medicine.
Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Amitriptyline is a tricyclic antidepressant with sedative properties.

Mechanism of action.

The mechanism of action of amitriptyline in man is not known. It is not a monoamine oxidase inhibitor and it does not act primarily by stimulation of the central nervous system. In broad clinical use, amitriptyline has been found to be well tolerated.
Amitriptyline inhibits the membrane pump mechanism responsible for uptake of noradrenaline and serotonin in adrenergic and serotonergic neurons. Pharmacologically, this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating its transmitting activity. This interference with the uptake of noradrenaline and/or serotonin is believed by some to underlie the antidepressant activity of amitriptyline.
Amitriptyline has also been found to be effective in the treatment of enuresis in some cases where organic pathology has been excluded. The mode of action of amitriptyline in enuresis is not known. However, amitriptyline does have anticholinergic properties and medicines of this group, such as belladonna, have been used in the treatment of enuresis.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Amitriptyline is readily absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within approximately 6 hours of oral administration.

Distribution.

Amitriptyline is approximately 96% bound to plasma proteins.

Metabolism.

Amitriptyline undergoes extensive metabolism in the liver, primarily through N-demethylation, to nortriptyline. Paths of metabolism of both amitriptyline and nortriptyline include hydroxylation and N-oxidation.

Excretion.

The mean apparent elimination half-life for amitriptyline was reported by one source to be 22.4 hours; the mean half-life of its active metabolite, nortriptyline was 26 hours.
Amitriptyline is excreted in the urine, mainly in the form of metabolites, either free or as glucuronide and sulfate conjugates. Very little unchanged medicine is excreted in the urine. From one-third to one-half of an oral radioactive dose is excreted in the urine within 24 hours of administration.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies have not been performed with amitriptyline.

Carcinogenicity.

Long-term carcinogenicity studies in rodents have not been performed with amitriptyline.
Accumulated data from up to 19 years follow-up in approximately 200 patients showed no statistically significant association between treatment with amitriptyline and the incidence of cancers. Clinical experience over 30 years has produced no evidence of an altered carcinogenic risk.

6 Pharmaceutical Particulars

6.1 List of Excipients

Entrip tablets contain the following inactive excipients: lactose monohydrate, microcrystalline cellulose, maize starch, croscarmellose sodium, colloidal anhydrous silica, purified talc, magnesium stearate, hypromellose and Macrogol 6000. The tablet film coating contains Opadry II complete film coating system 85F99075 Blue (ARTG 109882 for 10 mg), 85F92349 Yellow (ARTG 109879 for 25 mg) or 85F565015 Brown (ARTG 109885 for 50 mg).

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. Protect from light.

6.5 Nature and Contents of Container

Entrip 10 mg tablet.

Available in PVC/PVDC/Al blister packs of 50 and 100 tablets; and HDPE bottles of 50, 250 and 1000 tablets.

Entrip 25 mg tablet.

Available in PVC/PVDC/Al blister packs of 10, 50, 90, 100 and 1000 tablets; and HDPE bottles of 50, 250 and 1000 tablets.

Entrip 50 mg tablet.

Available in PVC/PVDC/Al blister packs of 10, 50, 100 and 1000 tablets; and HDPE bottles of 50, 250 and 1000 tablets.
Not all pack sizes may be marketed.

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

Amitriptyline hydrochloride occurs as colourless crystals or a white or almost white powder; odourless or almost odourless; taste, bitter and burning, followed by a sensation of numbness. It is soluble in 1 part of water, in 1.5 parts of ethanol (96%), in 1.2 parts of chloroform and in 1 part of methanol. It is practically insoluble in ether.
The chemical name: 3-(10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ylidene)- N,N-dimethylpropylamine hydrochloride.
Empirical formula: C₂₀H₂₃N.HCl.
Molecular weight: 313.9.

Chemical structure.

Its structural formula is:

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