APO-AMITRIPTYLINE

Main information

  • Trade name:
  • APO-AMITRIPTYLINE 25 amitriptyline hydrochloride 25mg tablet bottle pack
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • APO-AMITRIPTYLINE 25 amitriptyline hydrochloride 25mg tablet bottle pack
    Australia
  • Language:
  • English

Other information

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization number:
  • 215363
  • Last update:
  • 09-10-2017

Public Assessment Report

Public Summary

Summary for ARTG Entry:

215363

APO-AMITRIPTYLINE 25 amitriptyline hydrochloride 25mg tablet bottle pack

ARTG entry for

Medicine Registered

Sponsor

Apotex Pty Ltd

Postal Address

PO Box 280,NORTH RYDE BC, NSW, 1670

Australia

ARTG Start Date

22/08/2014

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. APO-AMITRIPTYLINE 25 amitriptyline hydrochloride 25mg tablet bottle pack

Product Type

Single Medicine Product

Effective date

26/05/2016

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

For the treatment of major depression. Amitriptyline 50 mg tablets are indicated only for the maintenance treatment of major depression ,Nocturnal

enuresis where organic pathology has been excluded.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Bottle

HDPE

12 Months

Store below 25

degrees Celsius

Neither child resistant

closure nor restricted

flow insert

Not recorded

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

Components

1. APO-AMITRIPTYLINE 25 amitriptyline hydrochloride 25mg tablet bottle pack

Dosage Form

Tablet

Route of Administration

Oral

Visual Identification

Yellow colour, circular, biconvex, film coated tablets with 'IA' over '25'

debossed on one side and plain on the other side

Active Ingredients

amitriptyline hydrochloride

25 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 26.11.2017 at 08:56:49 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics

Product Information – Australia

APO-Amitriptyline Tablets

Page 1

APO-Amitriptyline 10 Tablets

APO-Amitriptyline 25 Tablets

APO-Amitriptyline 50 Tablets

NAME OF THE MEDICINE

Amitriptyline hydrochloride

Active Ingredient

Chemical Name:

3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-

dimethylpropylamine hydrochloride

Structural Formula:

Molecular Formula:

N.HCl

Molecular Weight:

313.9

CAS Registry Number:

549-18-8

DESCRIPTION

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. pKa of amitriptyline hydrochloride is 9.4.

Each tablet contains amitriptyline hydrochloride as the active ingredient. In addition, each tablet

contains the following inactive ingredients: lactose, microcrystalline cellulose, crospovidone, maize

starch, colloidalanhydrous silica, purified talc, magnesium stearate, hypromellose, titanium dioxide,

macrogol 6000, brilliant blue FCF aluminium lake (10mg only), quinoline yellow aluminium lake (25mg

only), sunset yellow FCF aluminium lake and indigo carmine aluminium lake (50mg only).

PHARMACOLOGY

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.

Product Information – Australia

APO-Amitriptyline Tablets

Page 2

However, amitriptyline does have anticholinergic properties and medicines of this group, such as

belladonna, have been used in the treatment of enuresis.

Pharmacokinetics

Amitriptyline is readily absorbed from the gastrointestinal tract, with peak plasma concentrations

occurring within approximately 6 hours of oral administration.

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 approximately 96% bound to plasma proteins.

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.

Amitriptyline is excreted in the urine, mainly in the form of metabolites, either free or as glucuronide

and sulphate 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.

INDICATIONS

treatment

of major

depression.

Amitriptyline

tablets

indicated

only

maintenance treatment of major depression (see Precautions).

Nocturnal enuresis where organic pathology has been excluded.

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 Precautions, Use in Pregnancy and Use in Lactation.

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APO-Amitriptyline Tablets

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PRECAUTIONS

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

seek

medical

advice

immediately

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.

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APO-Amitriptyline Tablets

Page 4

Table 1

Age Range

Drug-Placebo Difference in Number of Cases of

Suicidality per 1000 Patients Treated

Drug-Related Increases

<18

14 additional cases

18-24

5 additional cases

Drug-Related Decreases

25-64

1 fewer case

65

6 fewer cases

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

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

major

depressive

disorder

other

condition

(psychiatric

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 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.

Product Information – Australia

APO-Amitriptyline Tablets

Page 5

When

amitriptyline

hydrochloride

used

treat

depressive

component

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 hydrochloride, 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 Interactions with other medicines).

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 hydrochloride and other

antidepressant medicines should

undertaken only

with

due recognition

of the possibility

potentiation and with a thorough knowledge of the pharmacology of both medicines. There has been

evidence

potentiation

when

patients

receiving

amitriptyline

hydrochloride

were

changed

immediately to protriptyline or vice versa.

Elective Surgery

Discontinue the medicine several days before elective surgery if possible.

Impairment of Motor Co-ordination

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 Pregnancy (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.

Use in Lactation

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.

Use in Children and Adolescents (<18 years)

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APO-Amitriptyline Tablets

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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.

Carcinogenicity

Long-term carcinogenicity studies in rodents have not been performed with amitriptyline. Genotoxicity

studies have not been performed with amitriptyline. Accumulated data from up to 19 years follow-up in

approximately 2,00 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.

Genotoxicity

Genotoxicity studies have not been performed with amitriptyline.

INTERACTIONS WITH OTHER MEDICINES

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 Contraindications).

Concurrent

fluoxetine

tricyclic

antidepressants

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

fluoxetine

concurrently

should

observed

closely

adverse

effects

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 hydrochloride

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

with

neuroleptic

medicines,

particularly

during

weather.

Concurrent

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, eg. 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 P 450 2D6, they may vary in the extent of inhibition.

Cimetidine

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Page 7

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).

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 (ie.

levodopa) or which may be absorbed to a greater extent because of the increased time available for

absorption (ie. anticoagulants).

ADVERSE 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.

Cardiovascular

Hypotension, syncope, hypertension, tachycardia, palpitations, myocardial infarction, arrhythmias,

heart block, stroke, nonspecific ECG changes and changes in AV conduction.

Central nervous system and neuromuscular

Confusional

states,

disturbed

concentration,

disorientation,

delusions,

hallucinations,

excitement,

anxiety, restlessness, insomnia, drowsiness, nightmares; numbness, tingling, paraesthesiae of the

extremities, peripheral neuropathy, incoordination, ataxia, tremors, coma, seizures, alteration in EEG

patterns, extrapyramidal symptoms includingabnormal voluntary movements and tardive dyskinesia;

dysarthria, tinnitus. thrombocytopenia

Anticholinergic

mouth,

blurred

vision,

disturbance

accommodation,

constipation,

paralytic

ileus,

urinary

retention, dilatation of urinary tract, increased intraocular pressure, hyperpyrexia.

Allergic

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Skin rash, urticaria, pruritus, photosensitisation, oedema of face and tongue.

Haematological

Bone marrow depression including agranulocytosis, leucopenia, eosinophilia, purpura,

Gastrointestinal

Nausea, epigastric distress, vomiting, anorexia, stomatitis, peculiar taste, diarrhoea, parotid swelling,

black tongue, rarely hepatitis (including altered liver function and jaundice).

Endocrine

Testicular swelling and gynaecomastia in the male, breast enlargement and galactorrhoea in the

female, increased or decreased libido, impotence, elevation or

lowering of blood sugar levels,

syndrome of inappropriate ADH (antidiuretic hormone) secretion.

Other

Dizziness, weakness, fatigue, headache, weight gain or loss, oedema, increased perspiration, urinary

frequency, mydriasis, drowsiness, alopecia.

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,

dream

sleep

disturbance.

These

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.

DOSAGE AND 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.

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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

tolerate

higher

doses.

required

daily

dose

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 recommended in the treatment of enuresis are low compared with those

used

treatment

depression,

even

allowing

differences

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.

OVERDOSAGE

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

High

doses

cause

temporary

confusion,

disturbed

concentration,

transient

visual

hallucinations. Overdosage may cause drowsiness, hypothermia, tachycardia and other arrhythmic

abnormalities, such as bundle branch block, ECG evidence of impaired conduction, congestive heart

failure, dilated pupils, convulsions, severe hypotension, stupor, coma and polyradiculoneuropathy.

Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators

of tricyclic antidepressant toxicity. Other symptoms may be agitation, hyperactive reflexes, muscle

rigidity, vomiting, hyperpyrexia, or any of those listed under Adverse 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.

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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.

In cases of overdosage, it is advisable to contact the Poisons Information Centre on 131126

(Australia) for recommendation on the management and treatment of overdosage.

PRESENTATION AND STORAGE CONDITIONS

APO-Amitriptyline tablets are intended for oral administration.

10mg tablet:

Blue colour, circular, biconvex, film coated tablets with “IA” over “10” debossed on one side and plain

on the other side.

Blister (PVC/Alu) pack of 20, 50 and 100 tablets (AUST R 215351).

Bottle (HDPE) pack of 100 tablets (AUST R 215370)

25mg tablet:

Yellow colour, circular, biconvex, film coated tablets with “IA” over “25” debossed on one side and

plain on the other side.

Blister (PVC/Alu) pack of 20, 50 and 100 tablets (AUST R 215380).

Bottle (HDPE) pack of 100 tablets (AUST R 215363)

50mg tablet:

Brown colour, circular, biconvex, film coated tablets with “IA” over “50” debossed on one side and

plain on the other side

Blister (PVC/Alu) pack of 20, 50 and 100 tablets (AUST R 215367).

Bottle (HDPE) pack of 100 tablets (AUST R 215390)

100 tablets pack size is for dispensing only. Not all strengths, pack types and/or pack sizes may be

available.

Storage

Store below 25ºC.

NAME AND ADDRESS OF THE SPONSOR

Apotex Pty Ltd

16 Giffnock Avenue

Macquarie Park NSW 2113

APO- and APOTEX- are registered trademarks of Apotex Inc.

POISON SCHEDULE OF THE MEDICINE

S4 – Prescription Only Medicine.

Date of first inclusion in the Australian Register of Therapeutic Goods (the ARTG): 22

August

2014

9-11-2018

First Choice Vapor recalls Unflavoured 100 mg Nicotine Base E-Liquids

First Choice Vapor recalls Unflavoured 100 mg Nicotine Base E-Liquids

These vaping products do not meet requirements of the Consumer Chemicals and Containers Regulations, 2001 (CCCR, 2001) under the Canada Consumer Product Safety Act.

Health Canada

4-6-2018

Hospira Issues a Voluntary Nationwide Recall for Two Lots of Naloxone Hydrochloride Injection, USP, in the Carpuject™ Syringe System due to the Potential Presence of Particulate Matter

Hospira Issues a Voluntary Nationwide Recall for Two Lots of Naloxone Hydrochloride Injection, USP, in the Carpuject™ Syringe System due to the Potential Presence of Particulate Matter

Hospira, Inc., a Pfizer company, is voluntarily recalling lots 72680LL and 76510LL of Naloxone Hydrochloride Injection, USP, 0.4 mg/mL, 1 mL in 2.5 mL, Carpuject Single-use cartridge syringe system (NDC 0409-1782-69), to the hospital/institution level due to the potential presence of embedded and loose particulate matter on the syringe plunger.

FDA - U.S. Food and Drug Administration

4-6-2018

Naloxone Hydrochloride Injection, USP, 0.4 mg/mL, 1 mL in 2.5 mL in the Carpuject™ Single-use Cartridge Syringe System   by Hospira: Recall - Due to the Potential Presence of Particulate Matter

Naloxone Hydrochloride Injection, USP, 0.4 mg/mL, 1 mL in 2.5 mL in the Carpuject™ Single-use Cartridge Syringe System by Hospira: Recall - Due to the Potential Presence of Particulate Matter

The patient has a low likelihood of experiencing adverse events ranging from local irritation, allergic reactions, phlebitis, end-organ granuloma, tissue ischemia, pulmonary emboli, pulmonary dysfunction, pulmonary infarction, and toxicity.

FDA - U.S. Food and Drug Administration

13-11-2018

EU/3/17/1836 (Zogenix GmbH)

EU/3/17/1836 (Zogenix GmbH)

EU/3/17/1836 (Active substance: Fenfluramine hydrochloride) - Transfer of orphan designation - Commission Decision (2018)7576 of Tue, 13 Nov 2018 European Medicines Agency (EMA) procedure number: EMA/OD/233/16/T/01

Europe -DG Health and Food Safety

13-11-2018

EU/3/13/1219 (Zogenix GmbH)

EU/3/13/1219 (Zogenix GmbH)

EU/3/13/1219 (Active substance: Fenfluramine hydrochloride) - Transfer of orphan designation - Commission Decision (2018)7575 of Tue, 13 Nov 2018 European Medicines Agency (EMA) procedure number: EMA/OD/140/13/T/01

Europe -DG Health and Food Safety

1-11-2018

Dexdomitor (Orion Corporation)

Dexdomitor (Orion Corporation)

Dexdomitor (Active substance: dexmedetomidine hydrochloride) - Centralised - Yearly update - Commission Decision (2018)7380 of Thu, 01 Nov 2018

Europe -DG Health and Food Safety

31-10-2018

Evista (Daiichi Sankyo Europe GmbH)

Evista (Daiichi Sankyo Europe GmbH)

Evista (Active substance: Raloxifene hydrochloride) - Centralised - Yearly update - Commission Decision (2018)7342 of Wed, 31 Oct 2018

Europe -DG Health and Food Safety

26-9-2018

Sileo (Orion Corporation)

Sileo (Orion Corporation)

Sileo (Active substance: Dexmedetomidine hydrochloride) - Centralised - Yearly update - Commission Decision (2018)6325 of Wed, 26 Sep 2018

Europe -DG Health and Food Safety

10-9-2018

Silapo (STADA Arzneimittel AG)

Silapo (STADA Arzneimittel AG)

Silapo (Active substance: epoetin zeta) - Centralised - Yearly update - Commission Decision (2018)5944 of Mon, 10 Sep 2018

Europe -DG Health and Food Safety

10-8-2018

Brinavess (Correvio)

Brinavess (Correvio)

Brinavess (Active substance: vernakalant hydrochloride) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)5523 of Fri, 10 Aug 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/1215/T/31

Europe -DG Health and Food Safety

30-7-2018

Segluromet (Merck Sharp and Dohme B.V.)

Segluromet (Merck Sharp and Dohme B.V.)

Segluromet (Active substance: ertugliflozin / metformin hydrochloride) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)5103 of Mon, 30 Jul 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/4314/T/2

Europe -DG Health and Food Safety

30-7-2018

Ceplene (Noventia Pharma Srl)

Ceplene (Noventia Pharma Srl)

Ceplene (Active substance: Histamine dihydrochloride) - Centralised - Renewal - Commission Decision (2018)5116 of Mon, 30 Jul 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/796/R/36

Europe -DG Health and Food Safety

23-7-2018

Optruma (Eli Lilly Nederland B.V.)

Optruma (Eli Lilly Nederland B.V.)

Optruma (Active substance: Raloxifene hydrochloride) - Centralised - Yearly update - Commission Decision (2018)4893 of Mon, 23 Jul 2018

Europe -DG Health and Food Safety

12-7-2018

Econor (Elanco Europe Ltd)

Econor (Elanco Europe Ltd)

Econor (Active substance: Valnemulin hydrochloride) - Centralised - Yearly update - Commission Decision (2018)4580 of Thu, 12 Jul 2018

Europe -DG Health and Food Safety

11-7-2018

Ariclaim (Eli Lilly Nederland B.V.)

Ariclaim (Eli Lilly Nederland B.V.)

Ariclaim (Active substance: duloxetine hydrochloride) - Centralised - Withdrawal - Commission Decision (2018)4515 of Wed, 11 Jul 2018

Europe -DG Health and Food Safety

5-7-2018

Scientific guideline:  Draft pegylated liposomal doxorubicin hydrochloride concentrate for solution 2 mg/ml product-specific bioequivalence guidance, draft: consultation open

Scientific guideline: Draft pegylated liposomal doxorubicin hydrochloride concentrate for solution 2 mg/ml product-specific bioequivalence guidance, draft: consultation open

This document provides product-specific guidance on the demonstration of the bioequivalence of pegylated liposomal doxorubicin hydrochloride concentrate for solution 2 mg/ml.

Europe - EMA - European Medicines Agency

3-7-2018

Efficib (Merck Sharp and Dohme B.V.)

Efficib (Merck Sharp and Dohme B.V.)

Efficib (Active substance: sitagliptin / metformin hydrochloride) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018) 4254 of Tue, 03 Jul 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/896/T/90

Europe -DG Health and Food Safety

3-7-2018

Ristfor (Merck Sharp and Dohme B.V.)

Ristfor (Merck Sharp and Dohme B.V.)

Ristfor (Active substance: sitagliptin / metformin hydrochloride) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018) 4249 of Tue, 03 Jul 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/1235/T/77

Europe -DG Health and Food Safety

3-7-2018

Velmetia (Merck Sharp and Dohme B.V.)

Velmetia (Merck Sharp and Dohme B.V.)

Velmetia (Active substance: sitagliptin / metformin hydrochloride) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018) 4252 of Tue, 03 Jul 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/862/T/93

Europe -DG Health and Food Safety

3-7-2018

Janumet (Merck Sharp and Dohme B.V.)

Janumet (Merck Sharp and Dohme B.V.)

Janumet (Active substance: sitagliptin / metformin hydrochloride) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018) 4251 of Tue, 03 Jul 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/861/T/90

Europe -DG Health and Food Safety

29-6-2018

EU/3/18/2028 (BioCryst UK Ltd)

EU/3/18/2028 (BioCryst UK Ltd)

EU/3/18/2028 (Active substance: (R)-1-(3-(aminomethyl) phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide dihydrochloride) - Orphan designation - Commission Decision (2018)4173 of Fri, 29 Jun 2018 European Medicines Agency (EMA) procedure number: EMA/OD/003/18

Europe -DG Health and Food Safety

14-6-2018

Kuvan (BioMarin International Limited)

Kuvan (BioMarin International Limited)

Kuvan (Active substance: sapropterin dihydrochloride) - Centralised - Yearly update - Commission Decision (2018)3859 of Thu, 14 Jun 2018

Europe -DG Health and Food Safety

12-6-2018

EU/3/10/811 (Celgene Europe B.V.)

EU/3/10/811 (Celgene Europe B.V.)

EU/3/10/811 (Active substance: N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino] benzenesulfonamide dihydrochloride monohydrate) - Transfer of orphan designation - Commission Decision (2018)3809 of Tue, 12 Jun 2018 European Medicines Agency (EMA) procedure number: EMA/OD/092/10/T/03

Europe -DG Health and Food Safety

12-6-2018

EU/3/10/810 (Celgene Europe B.V.)

EU/3/10/810 (Celgene Europe B.V.)

EU/3/10/810 (Active substance: N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino] benzenesulfonamide dihydrochloride monohydrate) - Transfer of orphan designation - Commission Decision (2018)3808 of Tue, 12 Jun 2018 European Medicines Agency (EMA) procedure number: EMA/OD/084/10/T/03

Europe -DG Health and Food Safety

12-6-2018

EU/3/10/794 (Celgene Europe B.V.)

EU/3/10/794 (Celgene Europe B.V.)

EU/3/10/794 (Active substance: N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino] benzenesulfonamide dihydrochloride monohydrate) - Transfer of orphan designation - Commission Decision (2018)3803 of Tue, 12 Jun 2018 European Medicines Agency (EMA) procedure number: EMA/OD/069/10/T/03

Europe -DG Health and Food Safety

12-6-2018

EU/3/11/888 (Gilead Sciences Ireland UC)

EU/3/11/888 (Gilead Sciences Ireland UC)

EU/3/11/888 (Active substance: N-(cyanomethyl)-4-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzamide, dihydrochloride salt) - Transfer of orphan designation - Commission Decision (2018)3802 of Tue, 12 Jun 2018 European Medicines Agency (EMA) procedure number: EMA/OD/152/10/T/03

Europe -DG Health and Food Safety

12-6-2018

EU/3/11/887 (Gilead Sciences Ireland UC)

EU/3/11/887 (Gilead Sciences Ireland UC)

EU/3/11/887 (Active substance: N-(cyanomethyl)-4-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzamide, dihydrochloride salt) - Transfer of orphan designation - Commission Decision (2018)3801 of Tue, 12 Jun 2018 European Medicines Agency (EMA) procedure number: EMA/OD/020/11/T/03

Europe -DG Health and Food Safety

12-6-2018

EU/3/11/886 (Gilead Sciences Ireland UC)

EU/3/11/886 (Gilead Sciences Ireland UC)

EU/3/11/886 (Active substance: N-(cyanomethyl)-4-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzamide, dihydrochloride salt) - Transfer of orphan designation - Commission Decision (2018)3799 of Tue, 12 Jun 2018 European Medicines Agency (EMA) procedure number: EMA/OD/019/11/T/03

Europe -DG Health and Food Safety

30-5-2018

Eviplera (Gilead Sciences Ireland UC)

Eviplera (Gilead Sciences Ireland UC)

Eviplera (Active substance: emtricitabine / rilpivirine (as hydrochloride) / tenofovir disoproxil (as fumarate)) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)3453 of Wed, 30 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/2312/T/91

Europe -DG Health and Food Safety

30-5-2018

Vokanamet (Janssen-Cilag International NV)

Vokanamet (Janssen-Cilag International NV)

Vokanamet (Active substance: canagliflozin / metformin hydrochloride) - Centralised - Yearly update - Commission Decision (2018)3463 of Wed, 30 May 2018

Europe -DG Health and Food Safety

29-5-2018

EU/3/18/2017 (Spedding Research Solutions SAS)

EU/3/18/2017 (Spedding Research Solutions SAS)

EU/3/18/2017 (Active substance: Ambroxol hydrochloride) - Orphan designation - Commission Decision (2018)3384 of Tue, 29 May 2018 European Medicines Agency (EMA) procedure number: EMA/OD/236/17

Europe -DG Health and Food Safety

24-5-2018

Velmetia (Merck Sharp and Dohme Limited)

Velmetia (Merck Sharp and Dohme Limited)

Velmetia (Active substance: sitagliptin / metformin hydrochloride) - PSUSA - Modification - Commission Decision (2018)3261 of Thu, 24 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/PSUSA/2003/201708

Europe -DG Health and Food Safety

24-5-2018

Ristfor (Merck Sharp and Dohme Limited)

Ristfor (Merck Sharp and Dohme Limited)

Ristfor (Active substance: sitagliptin / metformin hydrochloride) - PSUSA - Modification - Commission Decision (2018)3262 of Thu, 24 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/PSUSA/2003/201708

Europe -DG Health and Food Safety

24-5-2018

Janumet (Merck Sharp and Dohme Limited)

Janumet (Merck Sharp and Dohme Limited)

Janumet (Active substance: sitagliptin / metformin hydrochloride) - PSUSA - Modification - Commission Decision (2018)3260 of Thu, 24 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/PSUSA/2003/201708

Europe -DG Health and Food Safety

24-5-2018

Efficib (Merck Sharp and Dohme Limited)

Efficib (Merck Sharp and Dohme Limited)

Efficib (Active substance: sitagliptin / metformin hydrochloride) - PSUSA - Modification - Commission Decision (2018)3276 of Thu, 24 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/PSUSA/2003/201708

Europe -DG Health and Food Safety

21-5-2018

EU/3/14/1353 (Lupin Europe GmbH)

EU/3/14/1353 (Lupin Europe GmbH)

EU/3/14/1353 (Active substance: Mexiletine hydrochloride) - Transfer of orphan designation - Commission Decision (2018)3134 of Mon, 21 May 2018 European Medicines Agency (EMA) procedure number: EMA/OD/074/14/T/03

Europe -DG Health and Food Safety