Nortriptyline 10mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Nortriptyline hydrochloride
Available from:
Macleods Pharma UK Ltd
ATC code:
N06AA10
INN (International Name):
Nortriptyline hydrochloride
Dosage:
10mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 07040200; GTIN: 18901463139568

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Nortriptyline All Strengths Tablets PIL - UK

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Profile

Antidepressants may not make you feel better for the first two

weeks or more of treatment, so keep taking Nortriptyline Tablets

until your doctor tells you to stop. Do not stop these tablets

without discussing it with your doctor first.

Do not suddenly stop taking the tablets. Your doctor will tell you

how to cut them down gradually.

If you take more Nortriptyline Tablets than you should

Do not take more tablets than your doctor tells you to. If you ever

take too many, or if a child has taken any nortriptyline, go to the

nearest hospital casualty department or tell your doctor at once. An

overdose can be very dangerous.

If you forget to take Nortriptyline Tablets

If you forget to take a dose, take it as soon as you remember. If it is

almost time for your next dose do not take a double dose to make

up for a forgotten dose, just carry on as before. If you have missed

several doses, discuss this with your doctor.

If you stop taking Nortriptyline Tablets

If you stop taking Nortriptyline Tablets abruptly after prolonged

therapy, you may have withdrawal symptoms, including not being

able to sleep, headache, nausea, irritability and sweating.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although

not everybody gets them. If any of the side effects gets

serious, or if you notice any side effects not listed in this

leaflet, please tell your doctor or pharmacist.

All medicines can cause allergic reactions, although serious allergic

reactions are very rare.

Tell your doctor straight away if you get any sudden

wheeziness, difficulty in breathing, swelling of the eyelids,

face or lips, rash or itching, especially affecting your whole

body.

Tell your doctor or pharmacist immediately if you

experience any of the following serious side effects:

sudden chest pain which may spread to the neck or arm, with a

shortness of breath and a clammy feeling (these may be signs of

a heart attack)

sudden collapse, numbness or weakness in the arms or legs,

headache, dizziness and confusion, disturbances in vision,

difficulty swallowing, slurred, mixed up or loss of speech (these

may be signs of a stroke)

bruising, bleeding, pallor or persistent sore throat and fever.

These symptoms can be the first signs that your blood or

bone marrow may be affected. Effects on the blood could be a

decrease in the number of red cells (which carry oxygen around

the body), white cells (which help to fight infection) and platelets

(which help with clotting).

persistent constipation with a swollen stomach, fever and

vomiting. These symptoms may be due to parts of the intestine

becoming paralysed.

inflammation of the liver, yellowing of your skin or whites of your

eyes, dark urine, pale stools, tiredness, fever, nausea, weakness,

drowsiness and abdominal pain, with test results showing

abnormal liver function

thoughts of harming or killing yourself at any time (see section

The following side effects have also been reported:

fast or irregular heartbeat (palpitations)

abnormal heart rhythm

swelling of the ankles, feet or legs (oedema)

confusion (especially in the elderly) with seeing or hearing things

(hallucinations)

not knowing where you are (disorientation)

false beliefs (delusions)

anxiety, restlessness, agitation

not sleeping (insomnia)

nightmares

panic

long-lasting abnormal mood

worsening of mental illness

numbness, tingling, pins and needles in the hands or feet

co-ordination problems

tremors

abnormal movements

fits (seizures)

altered brainwave (EEG) patterns

ringing in the ears (tinnitus)

dry mouth

rarely, inflamed glands under the tongue or inflammation of the

gums (gingivitis)

blurred vision, difficulty in focusing, dilated pupils

unable to urinate or delayed urination

rash

itching

light sensitivity

fever

reaction to other similar drugs

feeling sick (nausea) and being sick (vomiting)

not eating (anorexia)

indigestion

diarrhoea

constipation

peculiar taste

inflamed mouth

abdominal cramps

black tongue

development of breasts in men, breast enlargement and milk

production in women

increased or decreased sex drive

failure to have an erection (impotence)

swollen testicles

altered blood sugar levels

weight gain or loss

sweating

flushing

urinating often and at night

sleepiness

dizziness

weakness

tiredness

headache

swollen glands

hair loss (alopecia)

an increased risk of bone fractures has been observed in

patients taking this type of medicine.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse.

This includes any possible side effects not listed in this leaflet. You

can also report side effects directly via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow

Card in the Google Play or Apple App Store.

By reporting side effects you can help provide more information on

the safety of this medicine.

5.

How to store Nortriptyline Tablets

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date, which is stated

on the label and carton. The expiry date refers to the last day of

that month.

Do not store above 25°C. Store in the original container. Keep

the container tightly closed.

Do not throw away any medicines via wastewater or household

waste. Ask your pharmacist how to throw away medicines

you no longer use. These measures will help protect the

environment.

6.

Contents of the pack and other information

What Nortriptyline Tablets contain

The name of this medicine is Nortriptyline 10mg or 25mg Tablets.

The active substance in your tablet is nortriptyline hydrochloride.

Each tablet contains 10mg or 25mg of nortriptyline (as the

hydrochloride) respectively. Other ingredients include lactose

monohydrate, maize starch and magnesium stearate.

What Nortriptyline Tablets look like and contents of the

pack

Nortriptyline 10 mg Tablets are white to off white, round, biconvex,

uncoated tablets, debossed ‘NO’ on one side and ‘10’ on other side.

Nortriptyline 25 mg Tablets are white to off white, round, biconvex,

uncoated tablets, debossed ‘NO’ on one side and ‘25’ on other side.

Nortriptyline 10mg & 25mg Tablets are packed in a white HDPE

bottle, with a white polypropylene child resistant cap and tamper

evident film, containing 100 tablets.

Marketing Authorisation Holder and Manufacturer

Accord, Barnstaple, EX32 8NS, UK

This leaflet was last revised in November 2019.

BBBA6898

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Nortriptyline 10mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains nortriptyline hydrochloride equivalent to nortriptyline 10mg

Excipient with known effect

The tablet also contains lactose monohydrate.

For full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM

Tablet

White to off-white round biconvex tablets, debossed ‘NO’ on one side and

‘10’ on the other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Nortriptyline is indicated for the treatment of Major Depressive Episodes.

4.2

Posology and method of administration

Posology

Adults: The usual adult dose is 25mg three or four times daily. Dosage should begin

at a low level (50mg once daily or 25mg 2-3 times daily). If necessary, dose could be

gradually increased in 25mg increments no more rapidly than every other day to be

added to the morning dose. When doses above 100mg daily are administered,

monitoring of plasma levels of nortriptyline should be considered and maintained in

the optimum range of 50 to 150ng/ml. Doses above 150mg per day are not

recommended.

Lower than usual dosages are recommended for elderly patients. Lower dosages are

also recommended for outpatients than for hospitalised patients who will be under

close supervision. The physician should initiate dosage at a low level and increase it

gradually, noting carefully the clinical response and any evidence of intolerance.

Following remission, maintenance medication may be required for a longer period of

time. The maintenance dose should be the same as the optimal therapeutic dose.

If a patient develops minor side-effects, the dosage should be reduced. The drug

should be discontinued promptly if adverse effects of a serious nature or allergic

manifestations occur.

Elderly: 30 to 50mg/day in divided doses. Dosage should begin at a low level (10 –

20 mg daily) and be increased as required to the maximum dose of 50mg. If it is

considered necessary to use higher dosing in an elderly patient an ECG should be

checked and plasma levels of nortriptyline should be monitored.

Adolescent patients: The use of nortriptyline in children and adolescents to treat

depression is not recommended due to lack of evidence regarding its safety and

efficacy.

Plasma levels: Optimal responses to nortriptyline have been associated with plasma

concentrations of 50 to 150ng/ml. Higher concentrations may be associated with more

adverse experiences. Plasma concentrations are difficult to measure, and physicians

should consult the laboratory professional staff.

Many antidepressants (tricyclic antidepressants, including nortriptyline, selective

serotonin re-uptake inhibitors and others) are metabolised by the hepatic cytochrome

P450 isoenzyme P450IID6. Three to ten per cent of the population have reduced

isoenzyme activity ('poor metabolisers') and may have higher than expected plasma

concentrations at usual doses. The percentage of 'poor metabolisers' in a population is

also affected by its ethnic origin.

Older patients have been reported to have higher plasma concentrations of the active

nortriptyline metabolite 10-hydroxynortriptyline. In one case, this was associated

with apparent cardiotoxicity, despite the fact that nortriptyline concentrations were

within the 'therapeutic range'. Clinical findings should predominate over plasma

concentrations as primary determinants of dosage changes.

A lower or less frequent dose should be considered in patients with hepatic

impairment, concurrent diseases, or who are taking multiple medications (see “4.4

Special Warnings and Precautions for Use” and “4.5 interactions with other

Medicinal products and other forms of Interaction”)

Renal failure does not affect the kinetics of nortriptyline.

Duration of treatment: The antidepressive effect usually sets in after 2-4 weeks.

Treatment with antidepressants is symptomatic and should therefore be continued for

a sufficient period of time, usually 6 months or longer to prevent recurrence.

Discontinuation: Treatment should be discontinued gradually, otherwise withdrawal

symptoms as headache, sleep disturbances, irritability and malaise could develop.

These symptoms are not indicative of addiction

Method of administration

For oral administration

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in

section 6.1

Recent myocardial infarction, any degree of heart block or other cardiac

arrhythmias

Severe liver disease

Mania

Nortriptyline is contraindicated for the nursing mother.

Please also refer to section 4.5.

4.4

Special warnings and precautions for use

Paediatric population

Use in children and adolescents under the age of 18

Nortriptyline should not be used in the treatment of depression in children and

adolescents under the age of 18 years. Studies in depression of this age group did not

show a beneficial effect for class of tricyclic antidepressants. Studies with other

classes of antidepressants (SSRI’s and SNRI’s) have shown risk of suicidality, self-

harm and hostility to be related to these compounds. This risk cannot be excluded

with nortriptyline. In addition, nortriptyline is associated with a risk of cardiovascular

adverse events in all age groups. Furthermore, long-term safety data in children and

adolescents concerning growth, maturation and cognitive and behavioural

development are not available (see also section 4.8 Undesirable effects and Section

4.9 Overdose.)

Warnings: As improvement may not occur during the initial weeks of therapy,

patients, especially those posing a high suicidal risk, should be closely monitored

during this period.

Suicide/suicidal thoughts or clinical worsening.

Depression is associated with an increased risk of suicidal thoughts, self harm and

suicide (suicide-related events). This risk persists until significant remission occurs.

As improvement may not occur during the first few weeks or more of treatment,

patients should be closely monitored until such improvement occurs. It is general

clinical experience that the risk of suicide may increase in the early stages of

recovery.

Patients with a history of suicide-related events, or those exhibiting a significant

degree of suicidal ideation prior to commencement of treatment are known to be at

greater risk of suicidal thoughts or suicide attempts, and should receive careful

monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of

antidepressant drugs in adult patients with psychiatric disorders showed an increased

risk of suicidal behaviour with antidepressants compared to placebo in patients less

than 25 years old.

Close supervision of patients and in particular those at high risk should accompany

drug therapy especially in early treatment and following dose changes. Patients (and

caregivers of patients) should be alerted about the need to monitor for any clinical

worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to

seek medical advice immediately if these symptoms present.

Withdrawal symptoms, including insomnia, irritability, nausea, headache and

excessive perspiration, may occur on abrupt cessation of therapy.

The use of nortriptyline in schizophrenic patients may result in an exacerbation of the

psychosis or may activate latent schizophrenic symptoms. If administered to

overactive or agitated patients, increased anxiety and agitation may occur. In manic-

depressive patients, nortriptyline may cause symptoms of the manic phase to emerge.

Cross sensitivity between nortriptyline and other tricyclic antidepressants is a

possibility.

Caution should be exercised when treating patients with advanced liver disease.

Patients with cardiovascular disease or hypotension should be given nortriptyline only

under close supervision because of the tendency of the drug to produce sinus

tachycardia and to prolong the conduction time. Myocardial infarction, arrhythmia

and strokes have occurred. Arrhythmias and hypotension can occur in patients

without prior risk, especially when high doses are prescribed. Therefore patients who

receive high doses should be followed up for arrhythmias and hypotension

Great care is necessary if nortriptyline is administered to hyperthyroid patients or to

those receiving thyroid medication, since cardiac arrhythmias may develop.

The use of nortriptyline should be avoided, if possible, in patients with a history of

epilepsy. If it is used, however, the patients should be observed carefully at the

beginning of treatment, for nortriptyline is known to lower the convulsive threshold.

The elderly are particularly liable to experience adverse reactions, especially

agitation, confusion, other anti-cholinergic reactions and postural hypotension.

Troublesome hostility in a patient may be aroused by the use of nortriptyline.

If possible, the use of nortriptyline should be avoided in patients with narrow angle

glaucoma, raised intra-ocular pressure or symptoms suggestive of urinary retention or

prostatic hypertrophy.

The possibility of a suicide attempt by a depressed patient remains after the initiation

of treatment. This possibility should be considered in relation to the quantity of drug

dispensed at any one time.

When it is essential, nortriptyline may be administered with electroconvulsive

therapy, although the hazards may be increased.

Both elevation and lowering of blood sugar levels have been reported. Significant

hypoglycaemia was reported in a Type II diabetic patient maintained on

chlorpropamide (250mg/day), after the addition of nortriptyline (125mg/day).

Adjustment of anti-diabetic therapy may, therefore, be necessary.

In patients developing throat pain, fever and flu symptoms during the first 10 weeks

of treatment, it is recommended that a FBC is taken to exclude agranulocytosis.

Hyperpyrexia has been reported during treatment with tricyclic antidepressants

together with anticholinergic or with neuroleptics, especially during hot weather.

The tablets contain lactose monohydrate. Patients with rare hereditary diseases such

as galactose intolerance, Lapp lactose deficiency, or glucose-galactose malabsorption

should not use this medication

4.5

Interaction with other medicinal products and other forms of interaction

Drug interactions:

Under no circumstances should nortriptyline be given concurrently with, or within

two weeks of cessation of, therapy with monoamine oxidase inhibitors. Hyperpyretic

crises, severe convulsions and fatalities have occurred when similar tricyclic

antidepressants were used in such combinations.

Nortriptyline should not be given with sympathomimetic agents such as adrenaline,

ephedrine, isoprenaline, noradrenaline, phenylephrine and phenylpropanolamine.

Nortriptyline may decrease the antihypertensive effect of guanethidine, debrisoquine,

bethanidine, methyldopa and possibly clonidine. Concurrent administration of

reserpine has been shown to produce a 'stimulating' effect in some depressed patients.

It would be advisable to review all antihypertensive therapy during treatment with

tricyclic antidepressants.

Barbiturates may increase the rate of metabolism of nortriptyline.

Anaesthetics given during tricyclic antidepressant therapy may increase the risk of

arrhythmias and hypotension. If surgery is necessary, the drug should be

discontinued, if possible, for several days prior to the procedure, or the anaesthetist

should be informed if the patient is still receiving therapy.

Tricyclic antidepressants may potentiate the CNS depressant effect of alcohol.

The potentiating effect of excessive consumption of alcohol may lead to increased

suicidal attempts or overdosage, especially in patients with histories of emotional

disturbances or suicidal ideation.

Steady-state serum concentrations of the tricyclic antidepressants are reported to

fluctuate significantly as cimetidine is either added to or deleted from the drug

regimen. Higher than expected steady-state serum concentrations of the tricyclic

antidepressant have been observed when therapy is initiated in patients already taking

cimetidine. A decrease may occur when cimetidine therapy is discontinued.

Because nortriptyline's metabolism (like other tricyclic and SSRI antidepressants)

involves the hepatic cytochrome P450IID6 isoenzyme system, concomitant therapy

with drugs also metabolised by this system may lead to drug interactions. Lower

doses than are usually prescribed for either the tricyclic antidepressant or the other

drug may therefore be required.

Greater than two-fold increases in previously stable plasma levels of nortriptyline

have occurred when fluoxetine was administered concomitantly. Fluoxetine and its

active metabolite, norfluoxetine, have long half-lives (4-16 days for norfluoxetine).

Concomitant therapy with other drugs that are metabolised by this isoenzyme,

including other antidepressants, phenothiazines, carbamazepine, propafenone,

flecainide and encainide, or that inhibit this enzyme (e.g. quinidine), should be

approached with caution.

The combination of nortriptyline with medications that increase the QT interval: such

as quinidine, antihistamines such as astemizole and terfenadine, some antipsychotics

(mainly pimozide and sertindole), cisapride, halofrantine, and sotalolcan increase the

risk for ventricular arrhythmias in combination with TCA’s. TCAs have some

characteristics of class I anti-arrhythmics. Caution is warranted in combination with

antiarrhythmics from this class, with beta-receptor blockers and with calcium

antagonists (especially verampanil) due to a potentiating effect on the AV-conduction

time and negative inotropic effects. In combination with class I anti-arrhythmias and

loop and thiazide diuretics attention should be paid to potential inhibitory effect on

the QT time due to potassium loss.

Antifungal medication such as fluconazol and terbinafine increase the serum

concentration of tricyclic antidepressants and the associated toxicity. Syncope and

Torsade de Pointes have been reported.

In combination with levothyroxine antidepressants can give rise to hyperthyroidism

and Levothyroxine may strengthen the antidepressant effect

The metabolism of levodopa in the intestine may be accelerated, possibly through

delay of peristalsis.

TCAs may increase the risk of seizure in patients using tramadol.

The “serotonin syndrome” (changes in cognition, behaviour, function of the

autonomic nervous system and neuromuscular activity) have been reported when

nortriptyline is administered together with serotonin enhancing medications.

Supervision and adjustment of dosage may be required when nortriptyline is used

with other anticholinergic drugs due to an increased risk of ileus, delirium and

hyperpyrexia.

Nortriptyline plasma concentration can be increased by valproic acid. Clinical

monitoring is therefore recommended.

4.6

Fertility, pregnancy and lactation

Pregnancy:

The safety of nortriptyline for use during pregnancy has not been established, nor is

there evidence from animal studies that it is free from hazard; therefore the drug

should not be administered to pregnant patients or women of childbearing age unless

the potential benefits clearly outweigh any potential risk.

Breast-feeding:

See section 4.3.

4.7

Effects on ability to drive and use machines

Nortriptyline may impair the mental and/or physical abilities required for the

performance of hazardous tasks, such as operating machinery or driving a car;

therefore the patient should be warned accordingly.

4.8

Undesirable effects

Included in the following list are a few adverse reactions that have not been reported

with this specific drug. However, the pharmacological similarities among the tricyclic

antidepressant drugs require that each of the reactions be considered when

nortriptyline is administered.

Cardiovascular: Hypotension, hypertension, tachycardia, palpitation, myocardial

infarction, arrhythmias, heart block, stroke.

Psychiatric: Confusional states (especially in the elderly) with hallucinations,

disorientation, delusions; anxiety, restlessness, agitation; insomnia, panic, nightmares;

hypomania; exacerbation of psychosis. Cases of suicidal ideation and suicidal

behaviours have been reported during nortriptyline therapy or early treatment

discontinuation (see section 4.4).

Neurological: Numbness, tingling, paraesthesia of extremities; inco ordination, ataxia,

tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alteration of

EEG patterns; tinnitus.

Anticholinergic: Dry mouth and, rarely, associated sublingual adenitis or gingivitis;

blurred vision, disturbance of accommodation, mydriasis; constipation, paralytic

ileus; urinary retention, delayed micturition, dilation of the urinary tract.

Allergic: Rash, petechiae, urticaria, itching, photosensitisation (avoid excessive

exposure to sunlight); oedema (general or of face and tongue), drug fever, cross-

sensitivity with other tricyclic drugs.

Haematological: Bone-marrow depression, including agranulocytosis; aplastic

anaemia; eosinophilia; purpura; thrombocytopenia.

Gastro-intestinal: Nausea and vomiting, anorexia, epigastric distress, diarrhoea;

peculiar taste, stomatitis, abdominal cramps, black tongue, constipation, paralytic

ileus.

Endocrine: Gynaecomastia in the male; breast enlargement and galactorrhoea in the

female; increased or decreased libido, impotence; testicular swelling; elevation or

depression of blood sugar levels; syndrome of inappropriate secretion of antidiuretic

hormone.

Other: Jaundice (simulating obstructive); altered liver function, hepatitis and liver

necrosis; weight gain or loss; sweating; flushing; urinary frequency, nocturia;

drowsiness, dizziness, weakness, fatigue; headache; parotid swelling; alopecia.

Withdrawal symptoms: Though these are not indicative of addiction, abrupt cessation

of treatment after prolonged therapy may produce nausea, headache and malaise.

Class effects: Epidemiological studies, mainly conducted in patients 50 years of age

and older, show an increased risk of bone fractures in patients receiving SSRIs and

TCAs. The mechanism leading to this risk is unknown.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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

via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

or search for

MHRA Yellow Card in the Google Play or Apple App Store.

4.9

Overdose

Individual differences in metabolism may lead to symptoms and signs of overdose

even after relatively modest excess ingestion, irrespective of age.

Signs and symptoms: Of patients who are alive at presentation, mortality of 0-15%

has been reported. Symptoms may begin within several hours and may include

blurred vision, confusion, restlessness, dizziness, hypothermia, hyperthermia,

agitation, vomiting, hyperactive reflexes, dilated pupils, fever, rapid heart rate,

decreased bowel sounds, dry mouth, inability to void, myoclonic jerks, seizures,

respiratory depression, myoglobinuric renal failure, nystagmus, ataxia, dysarthria,

choreoathetosis, coma, hypotension and cardiac arrhythmias. Cardiac conduction may

be slowed, with prolongation of QRS complex and QT intervals, right bundle branch

and AV block, ventricular tachyarrhythmias (including Torsade de pointes and

fibrillation) and death. Prolongation of QRS duration to more than 100msec is

predictive of more severe toxicity. The absence of sinus tachycardia does not ensure a

benign course. Hypotension may be caused by vasodilatation, central and peripheral

alpha-adrenergic blockade and cardiac depression. In a healthy young person,

prolonged resuscitation may be effective; one patient survived 5 hours of cardiac

massage.

Treatment: Symptomatic and supportive therapy is recommended. Early transfer to a

hospital with an intensive care unit is recommended. Activated charcoal may be more

effective than emesis or lavage to reduce absorption, although combination therapy

may be appropriate depending on the time since ingestion.

Ventricular arrhythmias, especially when accompanied by lengthened QRS intervals,

may respond to alkalinisation by hyperventilation or administration of sodium

bicarbonate or the rapid infusion of hypertonic sodium chloride (100-200mmol)..

Serum electrolytes should be monitored and managed. Refractory arrhythmias may

respond to propranolol, bretylium or lignocaine (usually 1-1.5mg/kg iv followed by

1-3mg/min). Quinidine and procainamide usually should not be used because they

may exacerbate arrhythmias and conduction already slowed by the overdose.

Seizures or agitation may respond to diazepam. Phenytoin may treat seizures and

cardiac rhythm disturbances. Physostigmine may antagonise atrial tachycardia, gut

immotility, myoclonic jerks and somnolence. The effects of physostigmine may be

short-lived.

Diuresis and dialysis have little effect. Haemoperfusion is unproven. Monitoring

should continue, at least until the QRS duration is normal.

Doses as low of 50mg (especially in children) may lead to clinically significant

symptoms. Cardiotoxicity and convulsions are commoner in children and

toxicological advice is recommended in all cases.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Nortriptyline is a tricyclic antidepressant with actions and uses similar to these of

Amitriplyline. It is the principal active metabolite of Amitriplyline. Nortriptyline

itself is a stronger inhibitor of pre-synaptic noradrenaline reuptake than of serotonin,

and is less anticholinergic than amitriptyline whilst having stronger antihistaminergic

effects.

Nortriptyline has prolonged half-life hence once daily dosage regimens are suitable,

usually given at night.

5.2

Pharmacokinetic properties

Absorption:

Oral administration results in maximum plasma concentrations in approximately 5

hours (Tmax = 5.5 ±1.9 hours; range 4.0-8.8 hours). The mean oral bioavailability is

51% (Fabs = 0.51±0.05; range 0.46-0.59).

Distribution:

The apparent volume of distribution (Vd)ß, estimated after intravenous administration

is 1633 ± 268 l; range 1460 to 2030 (21 ± 4 l / kg). Plasma protein binding is

approximately 93%. Nortriptyline crosses the placental barrier.

Metabolism:

The metabolism of nortriptyline is by demethylation and hydroxylation followed by

conjugation with glucuronic acid. The metabolism is subject to genetic polymorphism

(CYP2D6). The main active metabolite is 10-hydroxynortriptyline, which exists in a

cis and a trans form, the trans form is dominant. N demethylnortriptyline is also

formed to some extent. The metabolites have the same profile as nortiptyline but are

weaker. Trans 10-hydroxynortriptyline is more potent than the cis form. 10-

hydroxynortriptyline dominates in the plasma but most of the metabolites are

conjugated.

Elimination:

The elimination half-life (t ½ ß) after oral nortriptyline administration is

approximately 26 hours (25.5 ± 7.9 hours; range 16-38 hours). The mean systemic

clearance (Cls) is 30.6 ± 6.9 l / h; ranging from 18.6 to 39.6 l / hour.

Excretion is mainly via the urine. The renal elimination of unchanged nortriptyline is

insignificant (about 2%).

In lactating mothers nortriptyline is excreted in small quantities into breast milk. The

concentration ratio of milk / plasma concentration in women is 1:2. The estimated

daily infant exposure is on average equivalent to 2% of the maternal weight-related

dose of nortriptyline (mg/kg). Steady state plasma levels of nortriptyline for most

patients are reached within one week.

In elderly patients, longer half-lives and reduced oral clearance (CLO) values due to

reduced metabolic rate have been shown.

Moderate to severe liver disease may reduce hepatic clearance resulting in higher

plasma levels.

Renal failure has no significant effect on nortriptyline kinetics.

Pharmacokinetic / pharmacodynamic relationship

The therapeutic plasma concentration in endogenous depression is 50-140 ng / ml (~

190-530 nmol / l). Levels above 170-200 ng/ml are associated with an increased risk

of cardiac conduction disturbance in terms of a prolonged QRS complex or an AV

block.

5.3

Preclinical safety data

Malformations have been observed in animal reproduction studies, in particular

cranial malformations and encephalocele

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Lactose monohydrate

Maize Starch

Magnesium stearate

6.2

Incompatibilities

None Stated.

6.3

Shelf life

48 months.

6.4

Special precautions for storage

Do not store above 25

C. Store in original container. Keep the container

tightly closed.

Public Assessment Report

Mutual Recognition Procedure

Nortriptyline 10mg Tablets

Nortriptyline 25mg Tablets

(Nortriptyline hydrochloride)

UK/H/4130/001-2/MR

UK Licence No: PL 20620/0018-9

NRIM Limited

UKPAR Nortriptyline 10mg and 25mg Tablets

UK/H/4130/001-2/MR

2

NORTRIPTYLINE 10MG TABLETS

NORTRIPTYLINE 25MG TABLETS

LAY SUMMARY

On 1

May 2009, the UK granted NRIM Limited Marketing Authorisations (licences) for the

medicinal products Nortriptyline 10mg and 25mg Tablets.

Based on the review of the data on quality, safety and efficacy, Germany, Italy, the

Netherlands, Spain considered that the applications for Nortriptyline 10mg and 25mg Tablets

could be approved.

Nortriptyline 10mg and 25mg Tablets contain the active ingredient nortriptyline

hydrochloride, a tricyclic antidepressant.

These are prescription only medicines (POM) to treat major depression.

No new or unexpected safety concerns arose from these applications and it was, therefore,

judged that the benefits of taking Nortriptyline 10 and 25mg Tablets outweigh the risks,

hence these Marketing Authorisations have been granted.

UKPAR Nortriptyline 10mg and 25mg Tablets

UK/H/4130/001-2/MR

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NORTRIPTYLINE 10MG TABLETS

NORTRIPTYLINE 25MG TABLETS

TABLE OF CONTENTS

Module 1: Information about the procedure

Page 4

Module 2: Summary of Product Characteristics

Page 5

Module 3: Product Information Leaflets

Page 21

Module 4: Labelling

Page 23

Module 5: Scientific Discussion

Page 25

1 Introduction

2 Quality aspects

3 Non-clinical aspects

4 Clinical aspects

5 Overall conclusions

Module 6:

Steps taken after initial procedure

Not applicable

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Module 1

Product Names

Nortriptyline 10mg Tablets

Nortriptyline 25mg Tablets

Type of Application

Generic application, Article 10(1)

Active Substance

Nortriptyline hydrochloride

Pharmaceutical Form

Tablets

Strengths

10mg

25mg

MA Holder

NRIM Limited

Unit 15 Moorcroft,

Harlington Road,

Hillingdon,

UB8 3HD

Reference Member

State (RMS)

Concerned Member

States (CMS)

Germany (DE), Italy (IT), the Netherlands (NL) and Spain (ES)

Procedure Numbers

UK/H/4130/001/MR

UK/H/4130/002/MR

End of Procedure

Day 90 – 24

January 2011

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Module 2

Summary of Product Characteristics

1

NAME OF THE MEDICINAL PRODUCT

Nortriptyline 10mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains nortriptyline hydrochloride equivalent to nortriptyline 10mg

The tablet also contains lactose monohydrate.

For full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM

Tablet

White to off-white round biconvex tablets plain on both sides.

4

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

Nortriptyline is indicated for the treatment of Major Depressive Episodes.

4.2

POSOLOGY AND METHOD OF ADMINISTRATION

For oral administration

Adults:

The usual adult dose is 25mg three or four times daily. Dosage should begin at a low level

(50mg once daily or 25mg 2-3 times daily). If necessary, dose could be gradually increased in 25mg

increments no more than rapidly than every other day to be added to the morning dose. When doses

above 100mg daily are administered, monitoring of plasma levels of nortriptyline should be considered

and maintained in the optimum range of 50 to 150ng/ml. Doses above 150mg per day are not

recommended.

Lower than usual dosages are recommended for elderly patients. Lower dosages are also recommended

for outpatients than for hospitalised patients who will be under close supervision. The physician should

initiate dosage at a low level and increase it gradually, noting carefully the clinical response and any

evidence of intolerance. Following remission, maintenance medication may be required for a longer

period of time. The maintenance dose should be the same as the optimal therapeutic dose.

If a patient develops minor side-effects, the dosage should be reduced. The drug should be discontinued

promptly if adverse effects of a serious nature or allergic manifestations occur.

Elderly:

30 to 50mg/day in divided doses. Dosage should begin at a low level (10 – 20 mg daily) and

be increased as required to the maximum dose of 50mg. If it is considered necessary to use higher

dosing in an elderly patient an ECG should be checked and plasma levels of nortriptyline should be

monitored.

Adolescent patients:

The use of nortriptyline in children and adolescents to treat depression is not

recommended due to lack of evidence regarding its safety and efficacy.

Plasma levels: Optimal responses to nortriptyline have been associated with plasma concentrations of

50 to 150ng/ml. Higher concentrations may be associated with more adverse experiences. Plasma

concentrations are difficult to measure, and physicians should consult the laboratory professional staff.

Many antidepressants (tricyclic antidepressants, including nortriptyline, selective serotonin re-uptake

inhibitors and others) are metabolised by the hepatic cytochrome P450 isoenzyme P450IID6. Three to

ten per cent of the population have reduced isoenzyme activity ('poor metabolisers') and may have

higher than expected plasma concentrations at usual doses. The percentage of 'poor metabolisers' in a

population is also affected by its ethnic origin.

Older patients have been reported to have higher plasma concentrations of the active nortriptyline

metabolite 10-hydroxynortriptyline. In one case, this was associated with apparent cardiotoxicity,

despite the fact that nortriptyline concentrations were within the 'therapeutic range'. Clinical findings

should predominate over plasma concentrations as primary determinants of dosage changes.

A lower or less frequent dose should be considered in patients with hepatic impairment, concurrent

diseases, or who are taking multiple medications (see “4.4 Special Warnings and Precautions for Use”

and “4.5 interactions with other Medicinal products and other forms of Interaction”)

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Renal failure does not affect the kinetics of nortriptyline.

Duration of treatment:

The antidepressive effect usually sets in after 2-4 weeks. Treatment with

antidepressants is symptomatic and should therefore be continued for a sufficient period of time,

usually 6 months or longer to prevent recurrence.

Discontinuation:

Treatment should be discontinued gradually, otherwise withdrawal symptoms as

headache, sleep disturbances, irritability and malaise could develop. These symptoms are not indicative

of addiction

4.3

CONTRAINDICATIONS

Hypersensitivity to nortriptyline

Recent myocardial infarction, any degree of heart block or other cardiac arrhythmias

As for all tricyclic antidepressants, nortriptyline should not be administered

to patients

who are treated with monoamine oxidase inhibitors (MAOi; e.g., phenelzine, tranylcypromine,

etc.). Concomitant use of nortriptyline and a MAOi might cause serotonin syndrome (a syndrome

that can include symptoms such as agitation, confusion, tremor, myoclonia en hyperthermia).

Nortriptyline therapy can begin 14 days after the termination of a MAOi, and 1 day after the

termination of the reversible MAOi moclobemide. Treatment with MAOIs can begin 14 days after

the terminations of treatment with nortriptyline (see section 4.5).

Please also refer to 'Drug interactions' section.

4.4

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Use in children and adolescents under the age of 18

Nortriptyline should not be used in the treatment of depression in children and adolescents under the

age of 18 years. Studies in depression of this age group did not show a beneficial effect for class of

tricyclic antidepressants. Studies with other classes of antidepressants (SSRI’s and SNRI’s) have

shown risk of suicidality, self-harm and hostility to be related to these compounds. This risk cannot be

excluded with nortriptyline. In addition, nortriptyline is associated with a risk of cardiovascular adverse

events in all age groups. Furthermore, long-term safety data in children and adolescents concerning

growth, maturation and cognitive and behavioural development are not available (see also section 4.8

Undesirable effects and Section 4.9 Overdose.)

Warnings:

As improvement may not occur during the initial weeks of therapy, patients, especially

those posing a high suicidal risk, should be closely monitored during this period.

Suicide/suicidal thoughts or clinical worsening.

Depression is associated with an increased risk of

suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant

remission occurs. As improvement may not occur during the first few weeks or more of treatment,

patients should be closely monitored until such improvement occurs. It is general clinical experience

that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal

ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or

suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of

placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders

showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients

less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy

especially in early treatment and following dose changes. Patients (and caregivers of patients) should

be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and

unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Withdrawal symptoms, including insomnia, irritability, nausea, headache and excessive perspiration,

may occur on abrupt cessation of therapy.

The use of nortriptyline in schizophrenic patients may result in an exacerbation of the psychosis or may

activate latent schizophrenic symptoms. If administered to overactive or agitated patients, increased

anxiety and agitation may occur. In manic-depressive patients, nortriptyline may cause symptoms of

the manic phase to emerge.

Cross sensitivity between nortriptyline and other tricyclic antidepressants is a possibility.

Caution should be exercised when treating patients with advanced liver disease.

Patients with cardiovascular disease or hypotension should be given nortriptyline only under close

supervision because of the tendency of the drug to produce sinus tachycardia and to prolong the

conduction time. Myocardial infarction, arrhythmia and strokes have occurred. Arrhythmias and

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hypotension can occur in patients without prior risk, especially when high doses are prescribed.

Therefore patients who receive high doses should be followed up for arrhythmia’s and hypotension

Great care is necessary if nortriptyline is administered to hyperthyroid patients or to those receiving

thyroid medication, since cardiac arrhythmias may develop.

The use of nortriptyline should be avoided, if possible, in patients with a history of epilepsy. If it is

used, however, the patients should be observed carefully at the beginning of treatment, for nortriptyline

is known to lower the convulsive threshold.

The elderly are particularly liable to experience adverse reactions, especially agitation, confusion, other

anti-cholinergic reactions and postural hypotension.

Troublesome hostility in a patient may be aroused by the use of nortriptyline.

If possible, the use of nortriptyline should be avoided in patients with narrow angle glaucoma, raised

intra-ocular pressure or symptoms suggestive of urinary retention or prostatic hypertrophy.

The possibility of a suicide attempt by a depressed patient remains after the initiation of treatment. This

possibility should be considered in relation to the quantity of drug dispensed at any one time.

When it is essential, nortriptyline may be administered with electroconvulsive therapy, although the

hazards may be increased.

Both elevation and lowering of blood sugar levels have been reported. Significant hypoglycaemia was

reported in a Type II diabetic patient maintained on chlorpropamide (250mg/day), after the addition of

nortriptyline (125mg/day).

Adjustment of anti-diabetic therapy may, therefore, be necessary.

In patients developing throat pain, fever and flu symptoms during the first 10 weeks of treatment, it is

recommended that a FBC is taken to exclude agranulocytosis.

Hyperpyrexia has been reported during treatment with tricyclic antidepressants together with

anticholinergic or with neuroleptics, especially during hot weather.

The tablets contain lactose monohydrate. Patients with rare hereditary diseases such as galactose

intolerance, Lapp lactose deficiency, or glucose-galactose malabsorbtion should not use this medication

4.5

INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF

INTERACTION

Drug interactions: Under no circumstances should nortriptyline be given concurrently with, or within

two weeks of cessation of, therapy with monoamine oxidase inhibitors. Hyperpyretic crises, severe

convulsions and fatalities have occurred when similar tricyclic antidepressants were used in such

combinations.

Nortriptyline should not be given with sympathomimetic agents such as adrenaline, ephedrine,

isoprenaline, noradrenaline, phenylephrine and phenylpropanolamine.

Nortriptyline may decrease the antihypertensive effect of guanethidine, debrisoquine, bethanidine,

methyldopa and possibly clonidine. Concurrent administration of reserpine has been shown to produce

a 'stimulating' effect in some depressed patients. It would be advisable to review all antihypertensive

therapy during treatment with tricyclic antidepressants.

Barbiturates may increase the rate of metabolism of nortriptyline.

Anaesthetics given during tricyclic antidepressant therapy may increase the risk of arrhythmias and

hypotension. If surgery is necessary, the drug should be discontinued, if possible, for several days prior

to the procedure, or the anaesthetist should be informed if the patient is still receiving therapy.

Tricyclic antidepressants may potentiate the CNS depressant effect of alcohol.

The potentiating effect of excessive consumption of alcohol may lead to increased suicidal attempts or

overdosage, especially in patients with histories of emotional disturbances or suicidal ideation.

Steady-state serum concentrations of the tricyclic antidepressants are reported to fluctuate significantly

as cimetidine is either added to or deleted from the drug regimen. Higher than expected steady-state

serum concentrations of the tricyclic antidepressant have been observed when therapy is initiated in

patients already taking cimetidine. A decrease may occur when cimetidine therapy is discontinued.

Because nortriptyline's metabolism (like other tricyclic and SSRI antidepressants) involves the hepatic

cytochrome P450IID6 isoenzyme system, concomitant therapy with drugs also metabolised by this

system may lead to drug interactions. Lower doses than are usually prescribed for either the tricyclic

antidepressant or the other drug may therefore be required.

Greater than two-fold increases in previously stable plasma levels of nortriptyline have occurred when

fluoxetine was administered concomitantly. Fluoxetine and its active metabolite, norfluoxetine, have

long half-lives (4-16 days for norfluoxetine).

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Concomitant therapy with other drugs that are metabolised by this isoenzyme, including other

antidepressants, phenothiazines, carbamazepine, propafenone, flecainide and encainide, or that inhibit

this enzyme (e.g. quinidine), should be approached with caution.

The combination of nortriptyline with medications that increase the QT interval: such as quinidine,

antihistamines such as astemizole and terfenadine, some antipsychotics (mainly pimozide and

sertindole), cisapride, halofrantine, and sotalolcan increase the risk for ventricular arrhythmia’s in

combination with TCA’s. TCAs have some characteristics of class I anti-arrhythmics. Caution is

warranted in combination with antiarrhythmics from this class, with beta-receptor blockers and with

calcium antagonists (especially verampanil) due to a potentiating effect on the AV-conduction time and

negative inotropic effects. In combination with class I anti-arrhythmias and loop and thiazide diuretics

attention should be paid to potential inhibitory effect on the QT time due to potassium loss.

Antifungal medication such as fluconazol and terbinafine increase the serum concentration of tricyclic

antidepressants and the associated toxicity. Syncope and Torsade de Pointes have been reported.

In combination with levothyroxine antidepressants can give rise to hyperthyroidism and Levothyroxine

may strengthen the antidepressant effect

The metabolism of levodopa in the intestine may be accelerated, possibly through delay of peristalsis.

TCAs may increase the risk of seizure in patients using tramadol.

The “serotonin syndrome” (changes in cognition, behaviour, function of the autonomic nervous system

and neuromuscular activity) have been reported when nortriptyline is administered together with

serotonin enhancing medications.

Supervision and adjustment of dosage may be required when nortriptyline is used with other

anticholinergic drugs due to an increased risk of ileus, delirium and hyperpyrexia.

4.6

PREGNANCY AND LACTATION

Usage in pregnancy:

A moderate amount of data in pregnant women indicate no malformative or

feto/neonatal toxicity. Animal studies have shown reproductive toxicity (see section 5.3). Nortriptyline

should only be used when strictly indicated.

The kinetics of nortriptyline changes during pregnancy, especially during the 2

and 3

trimesters.

Therefore serum levels should be monitored and the dose should be adjusted if needed. After chronic

use and administration near term neonatal withdrawal symptoms (irritability, hypertonism, tremors,

irregular breathing, weak suckling) and anticholinergic symptoms (urine retention, constipation) may

occur.

Usage in Lactation:

Nortriptyline is excreted in limited amounts. The relative infant dose is low and

serum levels have been reported as low or undetectable. Adverse effects on the suckling infant have not

been reported to date. Nortiptyline can be used during lactation if the expected benefit for the mother

outweighs the potential risk to the infant.”

4.7

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Nortriptyline may impair the mental and/or physical abilities required for the performance of hazardous

tasks, such as operating machinery or driving a car; therefore the patient should be warned accordingly.

4.8

UNDESIRABLE EFFECTS

Included in the following list are a few adverse reactions that have not been reported with this specific

drug. However, the pharmacological similarities among the tricyclic antidepressant drugs require that

each of the reactions be considered when nortriptyline is administered.

The following definitions are usually used to evaluate side effects:

Very common: More than 1 out of 10 patients

Common:

More than 1 but less than 10 out of 100 patients

Uncommon:

More than 1 but less than 10 out of 1,000 patients

Rare:

More than 1 but less than 10 out of 10,000 patients

Very rare:

Less than 1 out of 10,000 patients.

Examinations:

Common

: weight increase, abnormal ECG, QT prolongation, QRS complex prolongation

Uncommon

: increased intraocular pressure

Rare

: weight loss, abnormal liver function, increased blood alkaline phosphatase, increased

transaminase

Very rare

: changes in blood sugar levels

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Cardiovascular:

Very common

: palpitation, irregular or heavy heart beats and tachycardia

Common

: artroventicular block, bundle branch block , high or low blood pressure

Rare

: arrhythmias

Very rare

: peripheral oedema

Blood and Lymphatic disorders:

Rare

: bone marrow depression, agranulocytosis, leucopenia, eosinophilia, thrombocytopenia

Nervous system disorders:

Very common

: dizziness, headache

Common

: concentration disorders, taste disorders, paraethesia, ataxia, strange body movements and

tremors.

Uncommon

: convulsion, numbness

Rare

: clumsiness

Very rare

: Alterations in brain function (including perhaps seizures)

Eye disorders:

Very common

: accommodation disorder including blurred vision

Common

: mydriasis

Vestibular and ear disorders:

Uncommon

: tinnitus

Gastrointestinal disorders:

Very common

: dry mouth, constipation

Uncommon

: diarrhoea, nausea, vomiting, tongue oedema

Rare

: increased salivary glands, paralytic ileus, loss of appetite, diarrhoea, and stomach cramps

Kidney and urinary tract disorders:

Uncommon

: problems urinating (increased or decreased) and urinary retention

Skin and subcutaneous disorders:

Very common

: sweating, flushing

Uncommon

: rash, urticaria, facial oedema

Rare

: alopecia, light sensitivity

Endocrine disorders:

Unknown

: SIADH

Nutritional and metabolic disorders:

Rare

: decreased appetite, weight gain or loss

Vascular diseases:

Very common

: orthostatic hypotension

Uncommon

: hypertension

General and application site disorders:

Common

: weakness and fatigue,

Rare

: fever, peculiar taste, mouth or gum problems,

Liver and bile disorders

Rare

: Jaundice

Unknown

: cholestasis

Reproductive system and breast disorders:

Common

: erection disorders

Rare

: gynaecomastia, changes in sexual performance may also rarely occur.

Very rare

: galactorrhoea, swelling of testicles

Psychiatric disorders:

Common

: confusion, decreased libido

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Uncommon

: hypomania, mania, anxiety, insomnia (especially on sudden withdrawal), changes in sleep

patterns (including nightmares)

Rare

: confusional states / delirium (especially in older patients), hallucinations (in patients with

schizophrenia), irritability

Unknown Cases of suicidal ideation and suicidal behaviours have been reported during nortriptyline

therapy or early treatment discontinuation (see Section 4.4). Agitation, restlessness, aggressive

outbursts, delusions, orgasm disorders in women, increased libido, disorientation

Withdrawal symptoms:

Though these are not indicative of addiction, abrupt cessation of treatment after

prolonged therapy may produce nausea, headache and malaise.

Class effects: Epidemiological studies, mainly conducted in patients 50 years of age and older, show an

increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this

risk is unknown

.

4.9

OVERDOSE

Individual differences in metabolism may lead to symptoms and signs of overdose even after relatively

modest excess ingestion, irrespective of age.

Signs and symptoms:

Of patients who are alive at presentation, mortality of 0-15% has been reported.

Symptoms may begin within several hours and may include blurred vision, confusion, restlessness,

dizziness, hypothermia, hyperthermia, agitation, vomiting, hyperactive reflexes, dilated pupils, fever,

rapid heart rate, decreased bowel sounds, dry mouth, inability to void, myoclonic jerks, seizures,

respiratory depression, myoglobinuric renal failure, nystagmus, ataxia, dysarthria, choreoathetosis,

coma, hypotension and cardiac arrhythmias. Cardiac conduction may be slowed, with prolongation of

QRS complex and QT intervals, right bundle branch and AV block, ventricular tachyarrhythmias

(including Torsade de pointes and fibrillation) and death. Prolongation of QRS duration to more than

100msec is predictive of more severe toxicity. The absence of sinus tachycardia does not ensure a

benign course. Hypotension may be caused by vasodilatation, central and peripheral alpha-adrenergic

blockade and cardiac depression. In a healthy young person, prolonged resuscitation may be effective;

one patient survived 5 hours of cardiac massage.

Treatment:

Symptomatic and supportive therapy is recommended. Early transfer to a hospital with an

intensive care unit is recommended. Activated charcoal may be more effective than emesis or lavage to

reduce absorption, although combination therapy may be appropriate depending on the time since

ingestion.

Ventricular arrhythmias, especially when accompanied by lengthened QRS intervals, may respond to

alkalinisation by hyperventilation or administration of sodium bicarbonate or the rapid infusion of

hypertonic sodium chloride (100-200mmol).. Serum electrolytes should be monitored and managed.

Refractory arrhythmias may respond to propranolol, bretylium or lignocaine (usually 1-1.5mg/kg iv

followed by 1-3mg/min). Quinidine and procainamide usually should not be used because they may

exacerbate arrhythmias and conduction already slowed by the overdose.

Seizures or agitation may respond to diazepam. Phenytoin may treat seizures and cardiac rhythm

disturbances. Physostigmine may antagonise atrial tachycardia, gut immotility, myoclonic jerks and

somnolence. The effects of physostigmine may be short-lived.

Diuresis and dialysis have little effect. Haemoperfusion is unproven. Monitoring should continue, at

least until the QRS duration is normal.

Doses as low of 50mg (especially in children) may lead to clinically significant symptoms.

Cardiotoxicity and convulsions are commoner in children and toxicological advice is recommended in

all cases.

5

PHARMACOLOGICAL PROPERTIES

5.1

PHARMACODYNAMIC PROPERTIES

Nortriptyline is a tricyclic antidepressant with actions and uses similar to these of Amitriplyline. It is

the principal active metabolite of Amitriplyline. Nortriptyline itself is a stronger inhibitor of pre-

synaptic noradrenaline reuptake than of serotonin, and is less anticholinergic than amitriptyline whilst

having stronger antihistaminergic effects.

Nortriptyline has prolonged half-life hence once daily dosage regimens are suitable, usually given at

night.

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