Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Glenmark Pharmaceuticals Europe Limited, Laxmi House, 2B Draycott Avenue, Kenton, Middlesex, HA3 0BU, United Kingdom
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 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 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 in which case the treatment with nortriptyline should be discontinued.
Cross sensitivity between nortriptyline and other tricyclic antidepressants is a possibility.
Caution should be exercised when treating patients with advance liver disease.
Patients with cardiovascular disease 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. Great care is necessary if nortriptyline is administered to hyperthyroid patients or to those receiving thyroid medication, since cardiac arrhythmias may develop.
Cardiac arrhythmias are likely to occur with high dosage. They may also occur in patients with pre-existing heart disease taking normal dosage.
Cases of QT interval prolongation and arrhythmia have been reported during the post-marketing period. Caution is advised in patients with significant bradycardia, in patients with uncompensated heart failure, or in patients concurrently taking QT-prolonging drugs. Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) are known to be conditions increasing the proarrhythmic risk.
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 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 or symptoms suggestive of prostatic hypertrophy.
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).
Anaesthetics given during tricyclic antidepressant therapy may increase the risk of arrhythmias and hypotension. If possible, discontinue this medicinal product several days before surgery; if emergency surgery is unavoidable, the anaesthetist should be informed that the patient is being so treated (see section 4.5).
Nortriptyline should be used with caution in patients with urinary retention, pylorus stenosis or paralytic ileus.
Hyperpyrexia has been reported with tricyclic antidepressants when administered with anticholinergic or with neuroleptic medications, especially in hot weather.
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.)
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.
Nortriptyline 10mg Film-coated Tablets contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
MAOIs (non-selective as well as selective A (moclobemide) and B (selegiline)) - risk of “serotonin syndrome” (see section 4.3).
Nortriptyline should not be given with sympathomimetic agents such as adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine and phenylpropanolamine (e.g. as contained in local and general anaesthetics and nasal decongestants).
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 is advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants.
Tricyclic antidepressants may potentiate the effects of these medicinal products on the eye, central nervous system, bowel and bladder; concomitant use of these should be avoided due to an increased risk of paralytic ileus, hyperpyrexia, etc.
Drugs which prolong the QT-interval, including antiarrhytmics such as quinidine, the antihistamines astemizole and terfenadine, some antipsychotics (notably pimozide and sertindole), cisapride, halofantrine, and sotalol, may increase the likelihood of ventricular arrhythmias when taken with tricyclic antidepressants.
Use caution when using nortriptyline and methadone concomitantly due to a potential for additive effects on the QT interval and increased risk of serious cardiovascular effects.
Caution is also advised for co-administration of nortriptyline and diuretics inducing hypokalaemia (e.g. furosemide).
Thioridazine: Co-administration of nortriptyline and thioridazine (CYP2D6 substrate) should be avoided due to inhibition of thioridazine metabolism and consequently increased risk of cardiac side effects
Tramadol: Concomitant use of tramadol (a CYP2D6 substrate) and tricyclic antidepressants (TCAs), such as nortriptyline increases the risk for seizures and serotonin syndrome. Additionally, this combination can inhibit the metabolism of tramadol to the active metabolite and thereby increasing tramadol concentrations potentially causing opioid toxicity.
Antifungals such as fluconazole and terbinafine increase serum concentrations of tricyclics and accompanying toxicity. Syncope and torsade de pointes have occurred.
CNS depressants: Nortriptyline may enhance the sedative effects of alcohol, barbiturates and other CNS depressants.
Tricyclic antidepressants (TCA) including nortriptyline are primarily metabolised by various hepatic cytochrome P450 isozymes (e.g. CYP1A2, CYP2C, CYP2D6, CYP3A4).
CYP2D6 inhibitors: The CYP2D6 isozyme can be inhibited by a variety of medicinal products, e.g. neuroleptics, serotonin reuptake inhibitors, beta blockers, and antiarrhythmics. Examples of strong CYP2D6 inhibitors include bupropion, fluoxetine, paroxetine and quinidine. These drugs may produce substantial decreases in TCA metabolism and marked increases in plasma concentrations. Consider to monitor TCA plasma levels, whenever a TCA is to be co-administered with another medicinal product known to be an inhibitor of CYP2D6. Dose adjustment of nortriptyline may be necessary (see section 4.2).
Other Cytochrome P450 inhibitors: Cimetidine, methylphenidate and calcium-channel blockers (e.g. diltiazem and verapamil) may increase plasma levels of tricyclic antidepressants and accompanying toxicity.
Tricyclic antidepressants and neuroleptics mutually inhibit the metabolism of each other; this may lead to a lowered convulsion threshold, and seizures. It may be necessary to adjust the dosage of these drugs.
Cytochrome P450 inducers: Oral contraceptives, rifampicin, phenytoin, barbiturates, carbamazepine and St. John’s Wort (Hypericum perforatum) may increase the metabolism of tricyclic antidepressants and result in lowered plasma levels of tricyclic antidepressants and reduced antidepressant response.
In the presence of ethanol nortriptyline plasma concentrations were increased.
The CYP3A4 and CYP1A2 isozymes metabolise nortriptyline to a lesser extent. However, fluvoxamine (strong CYP1A2 inhibitor) was shown to increase nortriptyline plasma concentrations and this combination should be avoided. Clinically relevant interactions may be expected with concomitant use of nortriptyline and strong CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir.
Nortriptyline plasma concentration can be increased by valproic acid. Clinical monitoring is therefore recommended.
There is a moderate amount of data from the use of nortriptyline in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Therefore, the drug should not be administered to pregnant patients or women of childbearing age unless the potential benefits clearly outweigh any potential risk.
Following administration in the final weeks of pregnancy, neonatal withdrawal symptoms may occur including irritability, hypertonia, tremors, irregular breathing, weak suckling and possibly anticholinergic symptoms (urine retention, obstipation).
Nortriptyline is excreted in limited amounts in breastmilk (corresponding to 0.6%-1% of the maternal dose). Adverse effects for infants have not been reported thus far. Breastfeeding can be continued during nortriptyline therapy if the benefit of the mother outweighs the potential risk for the infant. Observation of the infant is advised, especially during the first four weeks after birth.
The reproductive toxicity of nortriptyline has not been investigated in animals. For its parent substance amitriptyline, association with an effect on fertility in rats, namely a lower pregnancy rate was observed. (see section 5.3).
Nortriptyline has moderate influence on the 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.
In the listing below the following convention is used:
MedDRA system organ class/preferred term: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Rare: Bone marrow depression, agranulocytosis, leucopenia, eosinophilia, thrombocytopenia
Not Known: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
Rare: Decreased appetite
Not Known: Changes of blood sugar levels
Very common: Aggression
Common: Confusional state, libido decreased, agitation
Uncommon: Hypomania, mania, anxiety, insomnia, nightmare
Rare: Delirium (in elderly patients), hallucination (in schizophrenic patients)
Not Known: *Suicidal ideation and suicidal behaviour, paranoia
Very common: Tremor, dizziness, headache
Common: Disturbance in attention, dysgeusia, paresthesia, ataxia
Uncommon: Convulsion
Rare: akathisia, dyskinesia
Not Known: Extrapyramidal disorder
Very common: Accommodation disorder
Common: Mydriasis
Very rare: Acute glaucoma
Uncommon: Tinnitus
Very common: Palpitations, tachycardia
Common: Atrioventricular block, bundle branch block
Uncommon: Collapse conditions, worsening of cardiac failure
Rare: Arrhythmia
Very rare: Cardiomyopathies, torsades de pointes
Not Known: hypersensitivity myocarditis
Common: Orthostatic hypotension
Uncommon: Hypertension
Not Known: Hyperthermia
Very common: Congested nose
Very rare: Allergic inflammation of the pulmonary alveoli and of the lung tissue, respectively (alveolitis, Löffler’s syndrome)
Very common: Dry mouth, constipation, nausea
Uncommon: Diarrhoea, vomiting, tongue oedema
Rare: Salivary gland enlargement, ileus paralytic
Uncommon: Hepatic impairment (e.g. cholestatic liver disease)
Rare: Jaundice
Not Known: Hepatitis
Very common: Hyperhidrosis
Uncommon: Rash, urticaria, face oedema
Rare: Alopecia, photosensitivity reaction
Uncommon: Urinary retention
Common: Micturition disorders
Common: Erectile dysfunction
Uncommon: Galactorrhoea
Rare: Gynaecomastia
Common: Fatigue, feeling thirst
Rare: Pyrexia
Very common: Weight increase
Common: Electrocardiogram abnormal, electrocardiogram QT prolonged, electrocardiogram QRS complex prolonged, hyponatremia.
Uncommon: Intraocular pressure increased.
Rare: Weight decreased.
Liver function test abnormal, blood alkaline phosphatase increased, transaminases increased.
=*== Cases of suicidal ideation and suicidal behaviours have been reported during nortriptyline therapy or early after treatment discontinuation (see section 4.4)
Abrupt cessation of treatment after prolonged therapy may produce nausea, headache and malaise.
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRs and TCAs. The mechanism leading to this risk is unknown.
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 the Yellow Card Scheme at www.mhra.gov.co.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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