Amderip Tablets

AMDERIP is indicated for the treatment of depression in adults (18 years and older).

Posology

Adults: Initially 75 mg to 150 mg daily in divided doses. Maintenance dose is 50 mg to 100 mg daily in divided doses.

Method of administration

Amitriptyline is for oral use. The tablets should be swallowed with water.

AMDERIP is contraindicated in:

• Patients with hypersensitivity to amitriptyline or to any of the excipients (see section 6.1).
• Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with MAOIs (see section 4.5).
• Concurrent use with linezolid.
• Concurrent use with antihypertensive medicines (see section 4.5).
• Recent myocardial infarction, dysrhythmias, particularly heart block to any degree, congestive heart failure, coronary artery insufficiency.
• Pregnancy and lactation (see section 4.6).
• Children under 18 years of age.
• Mania.
• Severe liver disease.

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

Anticholinergic effects

Peripheral anticholinergic adverse events such as dry mouth, constipation and urinary retention may occur. Patients may also experience pupillary dilatation, blurred vision and changes in visual accommodation. When anticholinergic effects are severe, AMDERIP should be discontinued or the dosage should be reduced.

Sedative effects

Drowsiness, excessive sedation, disorientation and agitation may be caused in certain patients. Insomnia and restlessness may also occur. Drowsiness is often experienced at the start of treatment with AMDERIP.

Cardiac disease

Special caution should be observed in patients suffering from cardiac disease, as tachycardia, cardiac dysrhythmias, orthostatic hypotension and other unwanted effects on blood pressure may occur. There may also be an increase in conduction disturbances and electrocardiographic abnormalities. Regular cardiological and electrocardiographic examination is advised. Elderly patients are particularly susceptible to orthostatic hypotension. There is an increased risk of ventricular dysrhythmias when AMDERIP is used with medicines which prolong the QT interval.

Endocrine effects

Endocrine effects include changes in libido, sexual dysfunction, gynaecomastia, breast enlargement and galactorrhoea. Changes in blood sugar concentrations may also occur and less frequently, hyponatraemia which may be due to the inappropriate secretion of antidiuretic hormone (ADH).

Manic depressive psychosis

Caution should be observed with patients suffering from manic depressive psychosis as a shift towards the manic phase may occur. Should the patient enter into a manic phase, amitriptyline should be discontinued.

Suicidal tendencies

Patients with a history of suicide-related events or those experiencing a significant degree of suicidal ideation prior to the start of treatment should receive careful monitoring during treatment, as they are known to be at greater risk of suicidal thoughts or attempts.

Direct acting sympathomimetic and anaesthetics

The pressor effects of the direct-acting sympathomimetic medicines, epinephrine (adrenaline) and norepinephrine (noradrenaline) are potentiated by AMDERIP. Anaesthetics containing these vasoconstrictors should be avoided as hypertensive reactions may occur. When possible, treatment should be discontinued several days before elective surgery. If emergency surgery is unavoidable, the anaesthetist should be informed that the patient is being treated with AMDERIP.

Tricyclic antidepressants

may counteract the antihypertensive effects of centrally acting antihypertensives.

Porphyria

AMDERIP should be used with caution in patients suffering from acute forms of porphyria.

Cautious use in certain conditions

AMDERIP should be used with caution in patients with a history of epilepsy, impaired liver function, cardiovascular disease, urinary retention, prostatic hypertrophy, hyperthyroidism, constipation, paralytic ileus and narrow angled glaucoma as these conditions may be aggravated by amitriptyline.

Skin conditions

AMDERIP should be withdrawn if allergic skin reactions appear.

Co-administration of certain medicines

AMDERIP may enhance the effects of central nervous system depressants such as alcohol, and barbiturates and anticholinergic medicines. Concomitant use should be avoided.

Electroconvulsive therapy

Unless essential, it is not advisable to combine AMDERIP and electroconvulsive therapy (ECT).

Hyponatraemia

Hyponatraemia may be due to inappropriate excretion of the antidiuretic hormone. Elderly patients are particularly susceptible to these adverse events and treatment should be initiated at lower than standard doses.

Lactose warning

AMDERIP contains lactose which may have an effect on the glycaemic control in patients with diabetes mellitus. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

After prolonged administration, abrupt cessation of treatment may produce withdrawal symptoms namely headache, malaise, insomnia or irritability.

Simultaneous administration of monoamine oxidase inhibitors (MAOIs) and AMDERIP may cause serotonin syndrome (a combination of symptoms such as hyperthermia, convulsions, myoclonus, confusion, agitation). A minimum of 14 days should elapse between discontinuation of a MAOI and starting AMDERIP, which should be introduced cautiously and dosage increased gradually (see section 4.3).

AMDERIP may counteract the antihypertensive effects of debrisoquine, bethanidine and clonidine (see section 4.3). There is an increased risk of hypertension on clonidine withdrawal. All antihypertensive therapy should be reviewed during treatment with AMDERIP.

Antibacterials: Concomitant use of AMDERIP and linezolid may result in CNS excitation and hypertension (see section 4.3). Plasma concentrations of amitriptyline may be reduced by rifampicin which reduces the antidepressant effect. Concomitant use of AMDERIP and reboxetine should be used with caution. The plasma concentrations of amitriptyline, found in AMDERIP, may be increased by selective serotonin reuptake inhibitors (SSRIs). Fluoxetine which is an SSRI, significantly inhibits cytochrome P450 II D6, which is involved in the metabolism of AMDERIP and therefore significantly decreases the metabolism of AMDERIP which results in increased plasma concentrations. Patients should be monitored for increased antidepressant plasma levels and toxicity when AMDERIP is used concurrently with fluoxetine. Dosage adjustments of AMDERIP and/or fluoxetine may be required.

Alpha 2 -adrenoceptor stimulants: Concomitant use of apraclonidine and brimonidine with AMDERIP should be avoided.

Analgesics: The risk of central nervous system (CNS) toxicity with AMDERIP is increased with tramadol. There is a possibility of increased sedation with opioid analgesics.

Anaesthetics: Concomitant therapy with AMDERIP and anaesthetics may increase the risk of dysrhythmias and hypotension. If surgery is necessary, the anaesthetist should be informed that the patient is being treated with AMDERIP.

Antidysrhythmics: Medicines which prolong the QT interval such as amiodarone, disopyramide, procainamide, propafenone and quinidine may increase the likelihood of ventricular dysrhythmias when taken with tricyclic antidepressants. Concomitant use with AMDERIP should be avoided. AMDERIP should not be given with sympathomimetic medicines such as epinephrine (adrenaline), isoprenaline, norepinephrine (noradrenaline), phenylephrine, and phenylpropanolamine due to hypertension and dysrhythmias. Methylphenidate may inhibit the metabolism of amitriptyline contained in AMDERIP and therefore increase the antidepressant effect of AMDERIP. AMDERIP may enhance the response to alcohol, barbiturates and other CNS depressants.

Concomitant use of disulfiram may inhibit the metabolism of amitriptyline. Concomitant use of AMDERIP and antiepileptics may lead to a lower convulsive threshold and seizures. Dosage adjustments may be necessary. Barbiturates and carbamazepine may reduce the antidepressant effect of AMDERIP.

Antifungals: Fluconazole may increase serum concentrations of amitriptyline found in AMDERIP.

Antihistamines: Increased sedative and anticholinergic effects may occur when antihistamines are used concurrently with AMDERIP.

Antivirals: The protease inhibitor, ritonavir, may increase the serum levels of amitriptyline, found in AMDERIP, whose metabolism is mediated through cytochrome P450 isoenzymes. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are used concomitantly.

Antipsychotics: Concomitant use of amitriptyline, which is found in AMDERIP, with pimozide and thioridazine may lead to an increased risk of ventricular dysrhythmias. Avoid concomitant use with pimozide and thioridazine. Concomitant use with antipsychotics may increase the plasma levels of amitriptyline and increase the anticholinergic effects of phenothiazines and possibly clozapine.

Beta-blockers: There is an increased risk of ventricular dysrhythmias when AMDERIP is taken with sotalol.

Calcium channel blockers: Verapamil and diltiazem may increase plasma concentrations of amitriptyline found in AMDERIP.

Diuretics: There is an increased risk of postural hypotension.

Dopaminergics: Concomitant use of AMDERIP and entacapone should be avoided. CNS toxicity has been reported with selegiline.

Muscle relaxants: Concomitant use of baclofen enhances the muscle relaxant effect.

Nitrates: Reduced effect of sublingual nitrates (due to dry mouth).

Estrogens and progestogens: Oral contraceptives antagonise the antidepressant effect of AMDERIP but adverse effects may be increased due to increased plasma concentrations of tricyclic antidepressants as per AMDERIP. Excessive anticholinergic effects may occur when AMDERIP is combined with anticholinergic medicines. Paralytic ileus, urinary retention or acute glaucoma may be precipitated in elderly patients. Cimetidine may reduce the hepatic metabolism of AMDERIP which may lead to increased plasma levels of amitriptyline. St. Johnu2019s Wort may reduce plasma concentrations of amitriptyline which is found in AMDERIP thus decreasing the antidepressant effect. Patients taking thyroid preparations may show an accelerated response to AMDERIP. Concomitant use of AMDERIP with thyroid hormones may precipitate cardiac dysrhythmias.

Pregnancy

Safety and efficacy of AMDERIP during pregnancy has not been established (see section 4.3). Only limited data are available regarding exposed pregnancies. Animal studies have shown reproductive toxicity.

Breastfeeding

Safety and efficacy of AMDERIP during lactation has not been established (see section 4.3). Mothers on AMDERIP should not breastfeed their babies (see section 4.3).

Fertility

Amitriptyline reduced the pregnancy rate in rats. No data on the effects of amitriptyline 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 for at least several days. 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 AMDERIP, patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that AMDERIP does not adversely affect their ability to do so (see section 4.8).

a. Summary of the safety profile

AMDERIP may induce adverse events similar to other tricyclic antidepressants. Some of the below mentioned adverse events 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

MedDRA system organ class Frequency Adverse reactions

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

Immune system disorders Less frequent Hypersensitivity reactions including skin rash, urticaria, photosensitization, 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 Increased appetite, weight gain, weight loss, anorexia

Psychiatric disorders Less frequent Confusional state, disorientation, agitation, insomnia, nightmares, delusions, hallucinations, mania or hypomania, excitement, anxiety, restlessness, disturbed concentration, behavioural changes, suicidal thoughts or behaviour

Nervous system disorders Frequent Drowsiness or excessive sedation Less frequent Dizziness, headache, peripheral neuropathy, numbness, paraesthesia, ataxia, tremors, coma, convulsions, altered EEG, extrapyramidal disorder including dysarthria (speech disorder), tardive dyskinesia and abnormal involuntary movements

Eye disorders Frequent Accommodation disorder, blurred vision, increased intra-ocular pressure Less frequent Mydriasis

Ear and labyrinth disorders Less frequent Tinnitus

Cardiac disorders Less frequent Tachycardia, palpitations, myocardial infarction, heart block, dysrhythmias, changes in atrioventricular conduction, nonspecific ECG changes

Vascular disorders Less frequent Hypotension, hypertension, postural hypotension, syncope, stroke

Gastrointestinal disorders Frequent Dry mouth, constipation Less frequent Diarrhoea, vomiting, nausea, paralytic ileus, epigastric distress, dysgeusia, metallic taste, stomatitis, parotid swelling, black tongue

Hepato-biliary disorders Less frequent Hepatitis (including hepatic impairment and cholestatic jaundice)

Skin and subcutaneous tissue disorders Less frequent Rash, alopecia

Musculoskeletal and connective tissue disorders Less frequent Increased risk of bone fractures

Renal and urinary disorders Frequent Urinary retention Less frequent Urinary frequency, urinary tract dilation

Reproductive system and breast disorders Less frequent Gynaecomastia, breast enlargement, galactorrhoea, testicular swelling, changes in libido, impotence, sexual dysfunction

General disorders and administration site conditions Frequent Hyperthermia Less frequent Fatigue, weakness, increased perspiration

AMDERIP should be used with caution in patients with a history of epilepsy, impaired liver function, urinary retention, prostatic hypertrophy, hyperthyroidism and narrow angled glaucoma as these conditions may be aggravated by AMDERIP. Peripheral anticholinergic adverse events notably dry mouth, constipation, urinary retention and pupillary dilatation with blurred vision and changes in visual accommodation, have been reported. When anticholinergic effects are severe, AMDERIP should be discontinued or reduced.

Overdosage and poisoning may be characterised by central nervous system depression or excitation, severe anticholinergic effects and cardiotoxicity. The signs and symptoms of an overdosage include: drowsiness, restlessness, ataxia, coma, stupor, cardiac dysrhythmias, pyrexia, palpitations, hypotension, tachycardia, convulsions and respiratory depression. Mixed poisoning with other central nervous system depressants is not uncommon. Treatment for overdosage is symptomatic and supportive.