Zytrip Tablets

ZYTRIP is indicated for:

• Treatment of endogenous depression.
• Adjunctive therapy for nocturnal enuresis in children over 6 years of age where organic pathology has been excluded.

Posology

Depression:

Initial: One tablet (25 mg) three times per day increasing gradually to 150 mg daily if necessary. Additional doses should be taken in the late afternoon or evening. Therapy may also be initiated with a single dose of 50 to 100 mg at night increased by 25 or 50 mg as necessary to a total of 150 mg daily. The antidepressant activity may be evident within three or four days or may take up to 30 days to develop adequately.

Maintenance: 50 to 100 mg daily. Treatment should be continued for at least three months before being gradually withdrawn. Hospitalised patients may be given doses of up to 200 mg daily and, occasionally, up to 300 mg daily.

Nocturnal enuresis:

Children 6 to 10 years: 10 to 20 mg at bedtime

Children 11 to 16 years: 25 to 50 mg at bedtime

Do not exceed the recommended dose.

Duration of treatment

Treatment should not be continued for longer than 3 months. When stopping treatment, amitriptyline should be withdrawn gradually.

Method of administration

ZYTRIP is for oral use. The tablets should be swallowed with water. Missed dose: Doctors should advise patients who forget to take ZYTRIP to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.

• hypersensitivity to amitriptyline hydrochloride, tricyclic antidepressants or to any of the ingredients of ZYTRIP
• the acute-phase after myocardial infarction and in patients with heart block
• history of myocardial infarction, dysrhythmias, congestive heart failure, coronary artery insufficiency
• for the treatment of depression in children
• patients receiving monoamine oxidase inhibitors or for at least 14 days after their discontinuation
• concurrent use with linezolid (see section 4.5)
• concurrent use with antihypertensive medicines (see section 4.5)
• pregnancy and lactation (see section 4.6)
• severe liver disease
• mania (see section 4.4).

ZYTRIP should at all times be kept out of the reach of children, as even small doses may be fatal to them.

Anticholinergic effects

Peripheral anticholinergic side effects, notably dry mouth, constipation, urinary retention and pupillary dilatation with blurred vision and changes in visual accommodation. When anticholinergic effects are severe, ZYTRIP should be discontinued or reduced.

Sedative effects

At the time of initiation of therapy, patients should be advised not to drive a motor vehicle, climb dangerous heights or operate dangerous machinery for at least several days. In these situations, impaired decision making could lead to accidents as drowsiness or excessive sedation may be caused in certain patients (see section 4.7). On the other hand, disorientation and agitation, insomnia and restlessness can also occur with normal doses. The risks of central nervous system depression are greater when administered together with other central nervous system depressants, e.g. alcohol, barbiturates.

Elderly patients

Elderly patients are more prone to all these effects, and therapy should be initiated at lower than standard doses in the elderly. Elderly patients are particularly susceptible to orthostatic hypotension. In elderly male patients suffering from prostatism, urinary retention may be precipitated.

Manic depressive psychosis

Caution should be exercised with patients suffering from a depressive phase of manic-depressive psychosis, as occasionally hypomania or mania can be precipitated in such patients. Withdraw ZYTRIP if the depression turns into a manic phase.

Cardiac disease

In patients suffering from cardiac disease, special caution should be observed because of the occasional problems of tachycardia, dysrhythmias orthostatic hypotension and other unwanted effects on blood pressure, aggravation of conduction disturbances and electrocardiographic abnormalities. Regular cardiological and electrocardiographic examination is advised. QT interval prolongation and dysrrhythmia can occur. Caution is advised in patients with significant bradycardia, in patients with uncompensated heart failure, or in patients concurrently taking QT-prolonging medicines. Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) are known to be conditions increasing the prodysrhythmic risk.

Endocrine effects

Endocrine effects include changes in libido, interference with sexual function, gynaecomastia and breast enlargement, and galactorrhoea. Changes in blood sugar concentrations may also occur and, less frequently, inappropriate secretion of antidiuretic hormone.

Cautious use in certain conditions

Great care is necessary if ZYTRIP is administered to patients with hyperthyroidism or to those receiving thyroid medication, since cardiac dysrhythmias may develop (see section 4.5). ZYTRIP should be used with caution in patients with convulsive disorders, urinary retention, prostatic hypertrophy, paranoid symptomatology and advanced hepatic or cardiovascular disease, pylorus stenosis, constipation or paralytic ileus as some of these conditions may be aggravated by ZYTRIP. 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. Narrow-angle glaucoma may be aggravated. Epilepsy may be aggravated. ZYTRIP should be used with caution in patients with a history of epilepsy, and in those with impaired liver function or phaeochromocytoma.

Hyponatraemia

Hyponatraemia (usually in the elderly and possibly due to inappropriate secretion of antidiuretic hormone) has been associated with all types of antidepressants such as ZYTRIP and should be considered in all patients who develop drowsiness, confusion or convulsions while taking ZYTRIP (an antidepressant).

• Analgesics: increased anticholinergic side-effects with nefopam; increased analgesia with morphine. Increased risk of CNS toxicity when tricyclics given with tramadol.
• Muscle relaxants: Tricyclics enhance muscle relaxant effect of baclofen.
• Nitrates: reduced effect of sublingual nitrates (owing to dry mouth).
• Contraindicated combinations: MAOIs (non-selective as well as selective A (moclobemide) and B (selegiline)) u2013 can potentiate the effects of tricyclic antidepressants such as ZYTRIP and hyperpyretic crises, severe convulsions, and fatalities have occurred. Also, an increased risk of developing u201cserotonin syndromeu201d (see section 4.3). Treatment with ZYTRIP should only commence after at least 14 days after the discontinuation of a monoamine oxidase inhibitor as severe hypertensive reactions and have been reported with concomitant use. Conversely, several days should elapse between withdrawing a tricyclic antidepressant such as ZYTRIP and starting a monoamine oxidase inhibitor.
• Concomitant use of ZYTRIP and linezolid may result in CNS excitation and hypertension (see section 4.3).
• Combinations that are not recommended: Sympathomimetic medicines: Amitriptyline may potentiate the cardiovascular effects of adrenaline (epinephrine), ephedrine, isoprenaline, noradrenaline (norepinephrine), phenylephrine, and phenylpropanolamine (e.g. as contained in local and general anaesthetics and nasal decongestants).
• Adrenergic neurone blockers: Tricyclic antidepressants including ZYTRIP may counteract the antihypertensive effects of centrally acting antihypertensives such as reserpine, clonidine and methyldopa. It is advisable to review all antihypertensive therapy during treatment with ZYTRIP. There is an increased risk of hypertension on clonidine withdrawal.
• Anticholinergic medicines: Tricyclic antidepressants, including ZYTRIP may potentiate the effects of these medicines 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, urinary retention or acute glaucoma (especially in elderly patients).
• Medicines which prolong the QT-interval including antidysrhythmics such as quinidine, amiodarone, disopyramide, procainamide and propafenone, the antihistamines astemizole and terfenadine, some antipsychotics (notably pimozide and sertindole), cisapride, halofantrine, and sotalol may increase the likelihood of ventricular dysrhythmias when taken with tricyclic antidepressants including ZYTRIP.
• Methadone: Use caution when using ZYTRIP and methadone concomitantly due to a potential for additive effects on the QT interval and increased risk of serious cardiovascular effects.
• Diuretics: Caution is also advised for co-administration of ZYTRIP and diuretics inducing hypokalaemia (e.g. furosemide) as there is an increased risk of postural hypotension.
• Thioridazine: Co-administration of ZYTRIP 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 ZYTRIP 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.
• Alpha 2 -adrenoceptor stimulants: Concomitant use of apraclonidine and brimonidine with ZYTRIP should be avoided.
• Disulfiram: Concomitant use of disulfiram may inhibit the metabolism of amitriptyline. Delirium has been reported in patients taking ZYTRIP with disulfiram.
• Dopaminergics: Concomitant use of ZYTRIP and entacapone should be avoided. CNS toxicity has also been reported with selegiline.

Combinations requiring precautions for use:

• CNS depressants: ZYTRIP may enhance the sedative effects of alcohol, barbiturates and other central nervous system (CNS) depressants and anticonvulsants (i.e. carbamazepine).
• Antihypertensives: The effects of bethanidine, debrisoquine, guanethidine and possibly of clonidine are reduced by tricyclic antidepressants.
• Norepinephrine reuptake inhibitors (NRI): Concomitant use of ZYTRIP and reboxetine should be used with caution.
• Anaesthetics: Concomitant therapy with ZYTRIP and anesthetics may increase the risk of dysrhythmias and hypotension. If surgery is necessary, the anaesthetist should be informed that a patient is being treated with ZYTRIP.
• Patients taking thyroid preparations may show an accelerated response to ZYTRIP. The use of ZYTRIP with thyroid hormones may precipitate cardiac dysrhythmias.

Pregnancy

ZYTRIP should not be taken during pregnancy. Safety in pregnancy and lactation has not been established u2013 only limited data is available. Animal studies have shown reproductive toxicity (see section 5.3).

Breastfeeding

ZYTRIP should not be taken during breastfeeding. Amitriptyline and its metabolites are excreted into breast milk (corresponding to 0,6 % - 1 % of the maternal dose). A risk to the breastfed child cannot be excluded.

Fertility

No data on the effects of amitriptyline (as in ZYTRIP) on human fertility are available.

At the time of initiation of therapy, patients should be advised not to drive a motor vehicle, climb dangerous heights or operate dangerous machinery. In these situations, impaired decision making could lead to accidents. Since adverse reactions such as drowsiness, dizziness and blurred vision have been reported in patients receiving ZYTRIP, patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that ZYTRIP does not adversely affect their ability to do so (see section 4.8).

a) Summary of the safety profile

Amitriptyline may induce side effects similar to other tricyclic antidepressants. Some of the 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.

b) Tabulated summary of adverse reactions

System Organ Class Frequency Side effects

Blood and lymphatic system disorders Less frequent Bone marrow depression including agranulocytosis, eosinophilia, leucopenia, thrombocytopenia, purpura

Immune system disorders Less frequent Allergic skin rash, urticaria, photosensitisation, oedema of face and tongue, angioedema

Endocrine disorders Less frequent Syndrome of inappropriate ADH secretion (SIADH), hyperglycaemia, hypoglycaemia, hyponatraemia

Metabolism and nutrition disorders Less frequent Frequency unknown Decreased appetite, increased appetite, weight gain, weight loss, anorexia

Elevation or lowering of blood sugar levels

Psychiatric disorders Frequent Less frequent Frequency unknown Aggression, confusional states, agitation

Hypomania or mania, anxiety, insomnia, nightmares, delirium (in elderly patients), hallucinations, suicidal ideation or behaviour, disorientation, excitement, restlessness, disturbed concentration, behavioural changes

Paranoia

Nervous system disorders Frequent Less frequent Somnolence, tremors, dizziness, headache, drowsiness or excessive sedation, speech disorders (dysarthria), disturbance in attention, dysgeusia, paraesthesia, ataxia

Convulsions, akathisia, polyneuropathy, peripheral neuropathy, numbness, incoordination, tremors, coma, epileptiform seizures, altered EEG, extrapyramidal disorder including abnormal involuntary movements and tardive dyskinesia, dysarthria

Eye disorders Frequent Less frequent Frequency unknown Accommodation disorder, mydriasis, blurred vision

Acute glaucoma

Dry eye

Ear and labyrinth disorders Less frequent Tinnitus

Cardiac disorders Frequent Less frequent Frequency unknown Palpitations, tachycardia, atrioventricular block, bundle branch block

Myocardial infarction, heart block, non-specific ECG changes and changes in AV-conduction, dysrhythmias, cardiomyopathies, torsades de pointes

Hypersensitivity myocarditis, sudden death, worsening of cardiac failure

Vascular disorders Frequent Less frequent Orthostatic hypotension, hypotension

Hypertension, syncope, stroke

Respiratory, thoracic and mediastinal disorders Frequent Less frequent Congested nose

Allergic inflammation of the pulmonary alveoli and of the lung tissue, respectively (alveolitis, Lu00f6ffler's syndrome)

Gastrointestinal disorders Frequent Less frequent Dry mouth, constipation, nausea, sour or metallic taste, gastric irritation

Diarrhoea, vomiting, tongue oedema, salivary gland enlargement, paralytic ileus, epigastric distress, dysgeusia, stomatitis, black tongue

Hepato-biliary disorders Less frequent Jaundice, hepatic impairment (e.g. cholestatic liver disease), hepatitis

Skin and subcutaneous tissue disorders Frequent Less frequent Frequency unknown Hyperhidrosis

Rash, urticaria, face oedema, alopecia, photosensitivity reaction

Pruritis

Musculoskeletal, connective tissue and bone disorders Frequency unknown Increased risk of bone fractures (class effect)

Renal and urinary disorders Frequent Less frequent Micturition disorders, urinary retention

Urinary tract dilation

Reproductive system and breast disorders Frequent Less frequent Erectile dysfunction, impotence, changes in libido, sexual dysfunction

Galactorrhoea, gynaecomastia, breast enlargement, testicular swelling

General disorders and administrative site conditions Frequent Less frequent Fatigue, feeling thirsty, hyperthermia

Pyrexia, weakness

Investigations Frequent Less frequent Abnormal electrocardiogram, electrocardiogram QT prolonged, electrocardiogram QRS complex prolonged, hyponatremia

Liver function test abnormal, blood alkaline phosphatase increased, transaminases increased

c) Description of selected adverse reactions

Withdrawal symptoms: The symptoms associated with withdrawal of tricyclic antidepressants such as ZYTRIP, particularly after prolonged administration, include gastrointestinal disturbances such as nausea; generalised somatic symptoms such as malaise, chills, headache, itching and increased perspiration; irritability, restlessness, anxiety and agitation; sleep disturbances (insomnia and vivid dreams); parkinsonism or akasthisia; hypomania or mania (reported rarely, occurring within 2-7 days of stopping chronic therapy with tricyclic antidepressants); cardiac dysrhythmias. These symptoms are not indicative of addiction. Withdrawal symptoms seem to be more common and more severe in children.

Adverse reactions such as withdrawal symptoms, respiratory depression and agitation have been reported in neonates whose mothers had taken tricyclic antidepressants in the last trimester of pregnancy.

d) Other special populations

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 (see section 4.8). The mechanism leading to this increased risk is unknown.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the online service for adverse drug reaction reporting by following the link: https://www.sahpra.org.za/Publications/Index/8. An email can be sent directly to the company, [email protected] to ensure safety of the product.

Ingestion of 750 mg or more by an adult may result in severe toxicity. The effects in overdose will be potentiated by simultaneous ingestion of alcohol and other psychotropic. There is considerably individual variability in response to overdose. Children are especially susceptible to cardiotoxicity, seizures and hyponatraemia. During awakening possibly again confusion, agitation and hallucinations and ataxia.

Signs and symptoms: Overdosage and poisoning may be characterised by central nervous system depression or excitation, severe anticholinergic effects and cardiotoxicity. The following symptoms and signs are characteristic of acute overdosage: drowsiness, restlessness, ataxia, stupor, coma, pyrexia, palpitations, tachycardia, cardiac arrhythmias and hypotension. Epileptiform seizures may occur. Marked antimuscarinic effects may occur, including dryness of the mouth, dilated pupils, tachycardia, urinary retention and intestinal stasis. Severe symptoms include unconsciousness, convulsions and myoclonus, hyperreflexia, hypotension and respiratory and cardiac depression, with life-threatening cardiac arrhythmias that may recur some days after apparent recovery.

Cardiac symptoms: Dysrhythmias (ventricular tachydysrhythmias, torsade de pointes, ventricular fibrillation). The ECG characteristically show prolonged PR interval, widening of the QRS-complex, QT prolongation, T-wave flattening or inversion, ST segment depression, and varying degrees of heart block progressing to cardiac standstill. Widening of the QRS-complex usually correlates well with the severity of the toxicity following acute overdoses.

Heart failure, hypotension, cardiogenic shock. Metabolic acidosis, hypokalemia, hyponatraemia.

Management of overdose: Treatment is symptomatic and supportive.