This information is intended for use by health professionals

1. Name of the medicinal product

Nortriptyline 25 mg Capsules

2. Qualitative and quantitative composition

Nortriptyline 25 mg Capsules:

Each capsule contains Nortriptyline Hydrochloride EP equivalent to 25mg nortriptyline base.

Excipient(s) with known effect

Lactose

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Capsule, hard.

Hard gelatin capsules with a white, opaque body, yellow opaque cap and a hard gelatin capsule with white to off-white powder fill. The capsules are imprinted with “APO 25”.

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, e.g. 10mg three or four times daily, and be increased as required.

Alternatively, the total daily dose may be given once a day, usually given at night. When doses above 100 mg daily are administered, plasma levels of nortriptyline should be monitored and maintained in the optimum range of 50 to 150ng/ml. Doses above 150 mg 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 at the lowest dose that will maintain remission. 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 50 mg/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. 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.

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.

Cytochrome P450 isoenzyme CYP2D6 and poor metabolisers

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.

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.

Paediatric population

Nortriptyline should not be used in children and adolescents aged less than 18 years, as safety and efficacy have not been established (see section 4.4).

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.

- Concomitant treatment with MAOIs (monoamine oxidase inhibitors) is contraindicated (see section 4.5).

Simultaneous administration of nortriptyline and MAOIs may cause serotonin syndrome (a combination of symptoms, possibly including agitation, confusion, tremor, myoclonus and hyperthermia).

Treatment with nortriptyline may be instituted 14 days after discontinuation of irreversible non-selective MAOIs and minimum one day after discontinuation of the reversible moclobemide. Treatment with MAOIs may be introduced 14 days after discontinuation of nortriptyline.

- Recent myocardial infarction, any degree of heart block or disorders of cardiac rhythm and coronary artery insufficiency

4.4 Special warnings and precautions for use

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 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.

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

QT interval prolongation

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 proarrythmic risk.

Anaesthetics given during tri/tetracyclic 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.

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

Elderly patients are particularly susceptible to orthostatic hypotension.

This medical product should be used with caution in patients with convulsive disorders, urinary retention, prostatic hypertrophy, hyperthyroidism, paranoid symptomatology and advanced hepatic or cardiovascular disease, pylorus stenosis and paralytic ileus.

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.

Suicide/suicidal thoughts

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.

In manic-depressives, a shift towards the manic phase may occur; should the patient enter a manic phase amitriptyline should be discontinued.

As described for other psychotropics, amitriptyline 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.

Amitriptyline should be used with caution in patients receiving SSRIs (see sections 4.2 and 4.5).

Paediatric population

Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are not available (see section 4.2).

Excipients

The pellets in the capsule contain lactose.

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

4.5 Interaction with other medicinal products and other forms of interaction

Potential for amitriptyline to affect other medicinal products

Contraindicated combinations

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

Combinations that are not recommended

Sympathomimetic agents: Amitriptyline 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 centrally acting antihypertensives such as 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.

Use caution when using amitriptyline 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 amitriptyline and diuretics inducing hypokalaemia (e.g. furosemide)

Thioridazine: Co-administration of amitriptyline 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 amitriptyline 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.

Combinations requiring precautions for use

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

Potential of other medicinal products to affect amitriptyline

Tricyclic antidepressants (TCA) including amitriptyline are primarily metabolised by the hepatic cytochrome P450 isozymes CYP2D6 and CYP2C19, which are polymorphic in the population. Other isozymes involved in the metabolism of amitriptyline are CYP3A4, CYP1A2 and CYP2C9.

CYP2D6 inhibitors: The CYP2D6 isozyme can be inhibited by a variety of drugs, 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 drug known to be an inhibitor of CYP2D6. Dose adjustment of amitriptyline 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. Antifungals such as fluconazole (CYP2C9 inhibitor) and terbinafine (CYP2D6 inhibitor) have been observed to increase serum levels of amitriptyline and nortriptyline.

The CYP3A4 and CYP1A2 isozymes metabolise amitriptyline to a lesser extent. However, fluvoxamine (strong CYP1A2 inhibitor) was shown to increase amitriptyline plasma concentrations and this combination should be avoided. Clinically relevant interactions may be expected with concomitant use of amitriptyline and strong CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir.

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 amitriptyline free plasma concentrations and nortriptyline concentrations were increased.

4.6 Fertility, pregnancy and lactation

Pregnancy

Nortriptyline is the principal active metabolite of amitriptyline. For amitriptyline only limited clinical data are available regarding exposed pregnancies.

Animal studies have shown reproductive toxicity (see section 5.3).

Amitriptyline is not recommended during pregnancy unless clearly necessary and only after careful consideration of the risk/benefit.

During chronic use and after administration in the final weeks of pregnancy, neonatal withdrawal symptoms can occur. This may include irritability, hypertonia , tremor, irregular breathing, poor drinking and loud crying and possibly anticholinergic symptoms (urinary retention, constipation).

Breast-feeding

Nortriptyline is the principal active metabolite of amitriptyline. Amitriptyline and its metabolites are excreted into breast milk (corresponding to 0.6 % - 1 % of the maternal dose). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast- feeding or to discontinue/abstain from the therapy of this medicinal product taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

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 reduced pregnancy rate was observed (see section 5.3).

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

Amitriptyline may induce side effects similar to other tricyclic antidepressants. Some of the below mentioned side effects e.g. headache, tremor, disturbance in attention, 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).

MedDRA SOC

Frequency

Preferred Term

Blood and lymphatic system disorders

Rare

Bone marrow depression, agranulocytosis, leucopenia, eosinophilia, thrombocytopenia.

Endocrine Disorders

Not known

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

Metabolism and nutrition disorders

Rare

Decreased appetite

Not Known

Changes of blood sugar levels

Psychiatric disorders

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 behavior, Paranoia.

Nervous system disorders

Very common

Tremor, dizziness, headache.

Common

Disturbance in attention, dysgeusia. paresthesia, ataxia.

Uncommon

Convulsion.

Rare

Akathisia, dyskinesia.

Not known

Extrapyramidal disorder.

Eye disorders

Very common

Accommodation disorder.

Common

Mydriasis.

Very rare

Acute glaucoma.

Ear and labyrinth disorders

Uncommon

Tinnitus.

Cardiac disorders

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.

Vascular disorders

Common

Orthostatic hypotension.

Uncommon

Hypertension.

Not known

Hyperthermia.

Respiratory, thoracic, and mediastinal disorders

Very common

Congested nose.

Very rare

Allergic inflammation of the pulmonary alveoli and of the lung tissue, respectively (alveolitis, Löffler's syndrome).

Gastrointestinal disorders

Very common

Dry mouth, constipation, nausea.

Uncommon

Diarrhoea, vomiting, tongue oedema.

Rare

Salivary gland enlargement, ileus paralytic.

Hepatobiliary disorders

Uncommon

Hepatic impairment (e.g. cholestatic liver disease).

Rare

Jaundice.

Not known

Hepatitis.

Skin and subcutaneous tissue disorders

Very common

Hyperhidrosis.

Uncommon

Rash, urticaria, face oedema.

Rare

Alopecia, photosensitivity reaction.

Renal and urinary disorders

Common

Micturition disorders.

Uncommon

Urinary retention.

Reproductive system and breast disorders

Common

Erectile dysfunction.

Uncommon

Galactorrhoea.

Rare

Gynaecomastia.

General disorders and administration site conditions

Common

Fatigue, feeling thirst.

Rare

Pyrexia.

Investigations

Very common

Weight increased.

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).

Withdrawal Symptoms:

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 continues 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; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Signs and symptoms: 50mg of a tricyclic antidepressant can be an overdose in a child. 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 l00msec 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. Activated charcoal may be more effective than emesis or lavage to reduce absorption. Ventricular arrhythmias, especially when accompanied by lengthened QRS intervals, may respond to alkalinisation by hyperventilation or administration of sodium bicarbonate. Serum electrolytes should be monitored and managed. Refractory arrhythmias may respond to propranolol, bretylium or lignocaine. Quinidine and procainamide usually should not be used because they may exacerbate arrhythmias and conduction already slowed by the overdose.

Seizures 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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antidepressants, ATC code: N06AA10

Nortriptyline is a tricyclic antidepressant with actions and uses similar to these of Amitriptyline. It is the principal active metabolite of Amitriptyline.

5.2 Pharmacokinetic properties

Parts of metabolism of Nortriptyline include hydroxylation (possibly to active metabolites). N-oxidation and conjugation with glucuronic acid. Nortriptyline is widely distributed throughout the body and is extensively bound to plasma and tissue protein. Plasma concentrations of Nortriptyline vary very widely between individuals and no simple correlation with therapeutic response has been established.

5.3 Preclinical safety data

Nortriptyline is the principal active metabolite of amitriptyline. Amitriptyline inhibited ion channels, which are responsible for cardiac repolarization (hERG channels), in the upper micromolar range of therapeutic plasma concentrations. Therefore, amitriptyline may increase the risk for cardiac arrhythmia (see section 4.4).

The genotoxic potential of amitriptyline has been investigated in various in vitro and in vivo studies. Although these investigations revealed partially contradictory results, particularly a potential to induce chromosome aberrations cannot be excluded. Long-term carcinogenicity studies have not been performed.

In reproductive studies teratogenic effects were not observed in mice, rats, or rabbits when amitriptyline was given orally at doses of 2-40 mg/kg/day (up to 13 times the maximum recommended human amitriptyline dose of 150 mg/day or 3 mg/kg/day for a 50-kg patient). However, literature data suggested a risk for malformations and delays in ossification of mice, hamsters, rats and rabbits at 9 33 times the maximum recommended dose. There was a possible association with an effect on fertility in rats, namely a lower pregnancy rate. The reason for the effect on fertility is unknown.

6. Pharmaceutical particulars
6.1 List of excipients

Stearic Acid,

Lactose Monohydrate,

Maize Starch

Talc

Capsule shell:

White/Yellow shell:

Titanium dioxide (E171),

Yellow iron oxide(E172)

Gelatin.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

Do not use this medicine after the expiry date which is stated on blister or carton after EXP. That expiry date refers to the last day of that month

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

High density polyethylene bottles closed with polypropylene caps containing 100 capsules.

Aluminium/aluminium blister strips containing 100 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Kent Pharmaceuticals Limited,

DCC Vital, Westminster Indistrial Estate, Repton Road, Measham,

Swadlincote,

Derbyshire,

DE12 7DT,

United Kingdom

8. Marketing authorisation number(s)

PL 08215/0110

9. Date of first authorisation/renewal of the authorisation

08 Oct 2019

10. Date of revision of the text

08Oct2019