NORTRILEN Film-coated tablet Ref.[51158] Active ingredients: Nortriptyline

Nortriptyline should not be administered together with MAOIs (see section 4.3 and section 4.5).

Cardiac arrhythmias are likely to occur with high dosage. They may also occur in patients with pre-existing heart disease taking normal dosage.

Nortriptyline should be used with caution in patients with convulsive disorders, urinary retention, prostatic hypertrophy, hyperthyroidism, paranoid symptomatology, and advanced hepatic or cardiovascular disease.

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.

Serotonin syndrome

Concomitant administration of tricyclic antidepressants including nortriptyline and other serotonergic agents such as MAO Inhibitors (see section 4.3) or buprenorphine may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

Great care is necessary if nortriptyline is administered to hyperthyroid patients or to those receiving thyroid medication, since cardiac arrhythmias may develop.

Elderly patients are particularly susceptible to orthostatic hypotension. However, nortriptyline is less inclined than other tricyclic antidepressants to cause orthostatic hypotension.

In manic-depressives, a shift towards the manic phase may occur; should the patient enter a manic phase nortriptyline should be discontinued. When nortriptyline is used for the depressive component of schizophrenia, psychotic symptoms may be aggravated. Nortriptyline should be used in combination with a neuroleptic.

In patients with the rare condition of shallow anterior chamber and narrow chamber angle attacks of acute glaucoma due to dilation of the pupil may be provoked.

Anaesthetics given during tri/tetracyclic antidepressant therapy may increase the risk of arrhythmias and hypotension. If possible, discontinue nortriptyline several days before surgery; if emergency surgery is unavoidable, the anaesthetist should be informed that the patient is being so treated.

As described for other psychotropics nortriptyline may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients; in addition the depressive illness itself may affect patients´ glucose balance.

Hyperpyrexia has been reported with tricyclic antidepressants when administered with anticholinergic or with neuroleptic medications, especially in hot weather.

After prolonged administration, abrupt cessation of therapy may produce withdrawal symptoms such as headache, malaise, insomnia and irritability. These symptoms are not indicative of addiction.

Paediatric population

Nortrilen is not recommended for use in children and adolescents due to lack of dataon efficacy and safety. Treatment with Nortrilen is associated with a risk of cardiovascular adverse events in all age groups.

Excipients

The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pharmacodynamic interactions

Contra-indicated combinations

MAOIs (non-selective as well as selective A (moclobemide) and B (selegiline)) – risk of “serotonin syndrome” (see section 4.3).

Inadvisable combinations

Sympathomimetic agents: Nortriptyline may potentiate the cardiovascular effects of adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, and phenylpropanolamine (e.g. as contained in local and general anaesthetics and nasal decongestants).

Adrenergic neurone blockers: Tricyclic antidepressants may counteract the antihypertensive effects of guanethidine, betanidine, reserpine, clonidine and methyldopa. It is advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants.

Anticholinergic agents: Tricyclic antidepressants may potentiate the effects of these drugs 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 antiarrhythmics 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.

Antifungals such as fluconazole and terbinafine increase serum concentrations of tricyclics and accompanying toxicity. Syncope and torsade de pointes have occurred.

Combinations requiring precautions for use

Serotonergic medicinal products such as buprenorphine, as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4)

CNS depressants: Nortriptyline may enhance the effects of alcohol, barbiturates and other CNS depressants.

Pharmacokinetic interactions

Influence of other medicinal products on the pharmacokinetics of tricyclic antidepressants

Tricyclic antidepressants including nortriptyline are metabolised by the hepatic cytochrome P450 isoenzyme CYP2D6. CYP2D6 is polymorphic in the population. The CYP2D6 isozyme can be inhibited by a variety of psychotropic and other drugs, e.g. neuroleptics, serotonin reuptake inhibitors except citalopram (which is a very weak inhibitor), betablockers, and newer antiarrhythmics. These drugs may produce substantial decreases in tricyclic metabolism and marked increases in plasma concentrations.

Barbiturates and other enzyme inducers may lower plasma levels of tricyclic antidepressants and reduce antidepressant response.

Cimetidine, methylphenidate and calcium-channel blockers increase plasma levels of tricyclics 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.

Antifungals such as terbinafine have been observed to increase serum levels of nortriptyline.

Nortriptyline plasma concentration can be increased by valproic acid. Clinical monitoring is therefore recommended.

Pregnancy

Nortriptyline should not be administered during pregnancy unless the expected benefit to the patient outweighs the theoretical risk to the foetus.

Using high dosages of TCAs in the third trimester may result in effects, including neurobehavioral disturbances, in the newborn infant.

Breast-feeding

As nortriptyline is found in breast milk in low concentrations it is not likely to affect the infant when therapeutic doses are used. The dose ingested by the infant is about 2% of the weight related maternal daily dose (in mg/kg).

Breast-feeding can be continued during nortriptyline therapy if considered of clinical importance but observation of the infant is recommended, particularly in the first 4 weeks after giving birth.

Fertility

No data on the effect of nortriptyline on animal and human fertility is available.

Nortriptyline is not a particularly sedative drug.

However, patients who are prescribed psychotropic medication may be expected to have some impairment in general attention and concentration and should be cautioned about their ability to drive or operate machinery.

Nortriptyline may induce side effects similar to other cyclic antidepressants. Some of the below mentioned side effects e.g. headache, tremor, disturbance in attention, dry mouth, constipation and decreased libido may also be symptoms of depression and usually attenuate when the depressive state improves.

In the listing below the following convention is used: MedDRA system organ class/preferred term: Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

^* Cases of suicidal ideation and suicidal behaviours have been reported during nortriptyline therapy or early after treatment discontinuation (see section 4.4).
^** This event has been reported for serotonergic medicinal products such as the therapeutic class of tricyclic antidepressants (see sections 4.4 and 4.5).

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: ADR Reporting, Website: www.medicinesauthority.gov.mt/adrportal.

Not applicable.