Cardiac arrhythmias and severe hypotension may occur at high doses. They may also occur at normal doses in patients with pre-existing heart disease.

QT Prolongation
Cases of QT prolongation and arrhythmias have been reported post-marketing. Caution is advised in patients with significant bradycardia, uncontrolled heart failure, or concomitantly taking drugs that prolong the QT interval. Electrolyte disturbances (hypokalemia, hyperkalemia, hypomagnesemia) are known to increase proarrhythmic risk.

Anesthetics administered concomitantly with tri/tetracyclic antidepressants may increase the risk of arrhythmias and hypotension. If possible, discontinue this medication several days before surgery; if emergency surgery is required, the anesthesiologist should be informed that the patient is taking this type of medication.

Extreme caution is necessary if amitriptyline is administered to patients with hyperthyroidism or those receiving medications for thyroid disorders because cardiac arrhythmias may occur.

Elderly patients are particularly prone to orthostatic hypotension.

This drug should be used with caution in patients with the following conditions: seizures, urinary retention, prostatic hypertrophy, hyperthyroidism, paranoid symptoms and advanced liver or cardiovascular disease, pyloric stenosis and paralytic ileus.

In patients with the rare disease characterized by a narrow anterior chamber and a closed iridocorneal angle, acute glaucoma attacks may occur, due to pupil dilation.

Suicide/suicidal ideation
Depression is associated with an increased risk of suicidal ideation, self-harm, and suicide (suicide-related behavior). This risk persists until significant remission occurs. Because clinical improvement may not occur for several weeks of treatment, patients should be closely monitored until such improvement occurs. Clinical experience shows that the risk of suicide may increase in the early stages of recovery.
Patients with a history of suicidal behavior, or those expressing significant suicidal ideation before starting treatment, are at greater risk of developing suicidal ideation or suicide-related behavior and should be closely monitored during treatment. A meta-analysis of placebo - controlled clinical trials of antidepressant use in adults with psychiatric disorders showed an increased risk of suicidal behavior in patients under 25 years of age treated with antidepressants compared to those receiving placebo.
Close monitoring of patients, particularly those at high risk, should accompany drug treatment, particularly at the start of treatment and during dose changes. Patients (and their caregivers) should be warned about the need to monitor for clinical worsening, suicidal ideation/behavior, and any abnormal changes in behavior and to seek immediate medical advice if these symptoms occur.

In bipolar patients, a transition to the manic phase may occur; if the patient enters the manic phase, amitriptyline should be stopped.

Serotonin syndrome
Concomitant administration of tricyclic antidepressants such as amitriptyline and other serotonergic agents such as MAOIs (see section 4.3), tramadol or buprenorphine may cause serotonin syndrome, a potentially life-threatening condition (see section 4.5).
If concomitant treatment with other serotonergic agents, excluding MAOIs (see section 4.3), is judged clinically appropriate, careful observation of the patient is recommended, particularly during treatment initiation and after 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 should be considered depending on the severity of symptoms.

Severe Skin Reactions
Severe cutaneous adverse reactions (SCARs), including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), which can be life-threatening or fatal, have been reported with amitriptyline treatment. Most of these reactions occurred within 2 to 6 weeks.
Patients should be informed of the signs and symptoms at the time of prescribing and closely monitored for skin reactions.
If signs and symptoms suggestive of these reactions occur, Redomex should be discontinued immediately, Redomex treatment should not be restarted in the patient under any circumstances, and alternative treatment should be considered (if appropriate).

As reported for other psychotropic drugs, amitriptyline may alter glycemic and insulin responses, necessitating adjustment of antidiabetic therapy in diabetics; in addition, depressive illness itself may affect the patient's glycemic control.

Hyperpyrexia has been reported with tricyclic antidepressants when given with anticholinergics or neuroleptics, particularly in hot weather.

After prolonged administration, abrupt discontinuation of treatment may result in 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).

Nocturnal enuresis
An ECG should be performed before initiating amitriptyline therapy to exclude long QT syndrome.
Amitriptyline should not be used in combination with an anticholinergic agent for the treatment of enuresis.
Suicidal thoughts and behaviors may also occur early in the course of antidepressant therapy for conditions other than depression; therefore, the same precautions should be taken in these patients as in patients being treated for depression.

Paediatric population
No data are available on long-term safety in children and adolescents with regard to growth, maturation and cognitive and behavioural development (see section 4.2).

Excipients
The tablets contain lactose and sodium.

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

This medicine contains less than 1 mmol (23 mg) sodium per tablet, that is to say essentially 'sodium-free'.

Risk of amitriptyline affecting other drugs

Contraindicated associations

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

Non-recommended associations

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

Adrenergic neuron blocking agents  : Tricyclic antidepressants may counteract the antihypertensive effects of centrally acting antihypertensives such as guanethidine, betanidine, reserpine, clonidine, and methyldopa. It is recommended that all antihypertensive medications be reviewed 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 drugs should be avoided due to an increased risk of paralytic ileus, hyperpyrexia, etc.

Drugs that prolong the QT interval , including antiarrhythmics such as quinidine, the antihistamines astemizole and terfenadine, certain antipsychotics (including pimozide and sertindole), cisapride, halofantrine, and sotalol, may increase the risk of ventricular arrhythmia when taken with tricyclic antidepressants.
They should be used with caution during concomitant use of amitriptyline and methadone due to a risk of additive effects on the QT interval and an increased risk of serious cardiovascular effects.
Caution is also advised when co-administering amitriptyline with diuretics that induce hypokalemia (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 of seizures and serotonin syndrome. In addition, this combination may inhibit the metabolism of tramadol to its active metabolite.

Antifungals  : Antifungals such as fluconazole (CYP2C9 inhibitor) and terbinafine (CYP2D6 inhibitor) have been observed to increase serum levels of amitriptyline and nortriptyline and their associated toxicity. Syncope and torsades de pointes have been observed.

Associations requiring precautions for use

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

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

Risk of other drugs affecting amitriptyline

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

CYP2D6 inhibitors  : CYP2D6 may be inhibited by various medicinal products, e.g., neuroleptics, serotonin reuptake inhibitors, beta-blockers, and antiarrhythmics. Bupropion, fluoxetine, paroxetine, and quinidine are examples of potent CYP2D6 inhibitors. These medicinal products may markedly slow the metabolism of TCAs and may lead to significant increases in their plasma concentrations. Consider monitoring TCA plasma concentrations when a TCA is co-administered with another medicinal product known to be a potent CYP2D6 inhibitor. Dose adjustments of amitriptyline may be necessary (see section 4.2).
Caution is advised when co-administering amitriptyline with duloxetine, a moderate CYP2D6 inhibitor.

Other cytochrome P450 inhibitors  : Cimetidine, methylphenidate, and calcium channel blockers (e.g., diltiazem and verapamil) may increase plasma concentrations of tricyclic antidepressants and the resulting toxicity.

CYP3A4 and CYP1A2 are known to metabolize amitriptyline to a lesser extent. However, fluvoxamine (a strong CYP1A2 inhibitor) has been shown to increase plasma concentrations of amitriptyline, and this combination should be avoided. Clinically significant interactions can be expected with the concomitant use of amitriptyline and strong CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir.

Tricyclic antidepressants and neuroleptics inhibit each other's metabolism; this can lead to a lower seizure threshold and seizures. It may be necessary to adjust the dosage of these medications.

Cytochrome P450 inducers  : Rifampicin, phenytoin, barbiturates, carbamazepine, and St. John's wort ( Hypericum perforatum ) may accelerate the metabolism of tricyclic antidepressants, resulting in lower plasma concentrations of tricyclic antidepressants and decreased response to antidepressants.

In the presence of ethanol , free plasma concentrations of amitriptyline and nortriptyline concentrations were increased.

Sodium valproate and valpromide may cause an increase in the plasma concentration of amitriptyline. Clinical monitoring is therefore recommended.

Pregnancy

For amitriptyline, limited clinical data are available regarding exposure during pregnancy.

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 benefit/risk ratio.

In case of chronic use and after administration during the last weeks of pregnancy, withdrawal symptoms may appear in the newborn. This may include irritability, hypertonia, tremors, irregular breathing, poor feeding and intense crying, and potentially anticholinergic symptoms (urinary retention, constipation).

Breastfeeding

Amitriptyline and its metabolites are excreted in breast milk (corresponding to a value between 0.6% and 1% of the maternal dose). A risk to the breastfed infant cannot be excluded. A decision to discontinue breastfeeding or to discontinue treatment with this medicinal product or not to use it should be made taking into account the benefit of breastfeeding for the child and the benefit of treatment for the mother.

Fertility

Amitriptyline decreased the pregnancy rate in rats (see section 5.3).
No data are available on the effects of amitriptyline on fertility in humans.

Amitriptyline is a sedative.
Patients prescribed psychotropic drugs can expect some impairment in general attention and concentration and should be cautioned about their ability to drive or operate machinery. These adverse effects may be potentiated by concomitant alcohol intake.

Symptoms

Anticholinergic symptoms  : Mydriasis, tachycardia, urinary retention, dryness of the mucous membranes, decreased intestinal motility, convulsions, fever, sudden onset of CNS depression, decreased level of consciousness, progressing to coma, respiratory depression.

Cardiac symptoms  : Arrhythmias (ventricular tachyarrhythmias, torsades de pointes, ventricular fibrillation). Characteristically, the ECG shows PR interval prolongation, QRS complex widening, QT interval prolongation, T wave flattening or inversion, ST segment depression, and varying degrees of heart block, progressing to cardiac arrest. QRS complex widening generally correlates well with the severity of toxicity following acute overdoses. Heart failure, hypotension, cardiogenic shock, metabolic acidosis, hypokalemia, hyponatremia. In post-marketing surveillance and in the literature, cases of previously unknown Brugada syndrome and ECG patterns suggestive of Brugada syndrome have been reported in amitriptyline overdoses.

Ingestion of 750 mg or more by an adult may result in severe toxicity. The effects of overdose will be potentiated by the simultaneous ingestion of alcohol and other psychotropic drugs . There is considerable variability among individuals in the response to overdose.

Amitriptyline overdose can have serious consequences in children. Children are particularly prone to coma, cardiotoxicity, respiratory depression, seizures, hyponatremia, lethargy, sinus tachycardia, drowsiness, nausea, vomiting, and hyperglycemia.

Upon awakening, confusion, agitation, hallucinations and ataxia are also possible.

Treatment
1. Hospitalization (in intensive care) if necessary. Treatment is symptomatic and supportive.
2. Assess and treat any cardiopulmonary arrest. Establish venous access. Establish strict monitoring even in cases without apparent complications.
3. Establish the clinical picture. Check urea and electrolytes - look for hypokalemia and monitor urine output. Check arterial blood gases - look for acidosis. Perform an electrocardiogram - look for a QRS > 0.16 seconds.
4. Do not administer flumazenil to counteract benzodiazepine toxicity in mixed overdoses.
5. Consider gastric lavage only if the overdose is potentially fatal and has occurred within the preceding hour.
6. Administer 50 g of charcoal if the overdose has occurred within the preceding hour.
7. A patent airway is maintained by intubation, if necessary. Respiratory support is recommended to prevent possible respiratory arrest. Continuous ECG monitoring of cardiac function for 3 to 5 days. Treatment of the following disorders will be determined on a case-by-case basis:
- Widened QRS intervals, heart failure, and ventricular arrhythmias;
- Circulatory collapse;
- Hypotension;
- Hyperthermia;
- Seizures;
- Metabolic acidosis.
8. Agitation and seizures may be treated with diazepam.
9. Patients who show signs of toxicity should remain under observation for at least 12 hours.
10. Monitor for signs of rhabdomiolysis if the patient has been unconscious for a long time.
11. Since overdose is often deliberate, patients may attempt suicide by other means during the recovery phase. Cases of death from deliberate or accidental overdose have been observed with this class of drug.

Pharmacotherapeutic group: Antidepressants - non-selective monoamine reuptake inhibitors (tricyclic antidepressants)
ATC code: N 06 AA 09

Mechanism of action

Amitriptyline is a tricyclic antidepressant and analgesic. It has significant anticholinergic and sedative properties. It prevents the reuptake, and thus results in the inactivation of norepinephrine and serotonin in nerve endings. Preventing the reuptake of these monoaminergic neurotransmitters potentiates their action in the brain. This appears to be associated with antidepressant activity.

The mechanism of action also includes blocking effects on sodium, potassium, and NMDA channels at both the central and spinal cord levels. Effects on norepinephrine, sodium, and NMDA receptors are known mechanisms involved in the maintenance of neuropathic pain, the prophylaxis of chronic tension-type headaches, and the prophylaxis of migraines. The analgesic effect of amitriptyline is not related to its antidepressant properties.

Tricyclic antidepressants have varying degrees of affinity for muscarinic and histamine _{H1 receptors.}

Clinical efficacy and safety

The efficacy and safety of amitriptyline have been demonstrated in the treatment of the following indications in adults:
• Major depressive episode
• Neuropathic pain
• Prophylaxis of tension-type headaches
• Background treatment of migraine

The efficacy and safety of amitriptyline have been demonstrated in the treatment of nocturnal enuresis in children aged 6 years and older (see section 4.1).

Recommended doses are given in section 4.2. For the treatment of depression, doses up to 200 mg daily and sometimes up to 300 mg daily have been used in hospital in patients with severe depression.

Antidepressant and analgesic effects are usually felt after 2 to 4 weeks; the sedative action is immediate.

Absorption

Film-coated tablets
With oral administration of tablets, peak serum concentrations are reached in approximately 4 hours (t _max = 3.89 ± 1.87 hours; range 1.93-7.98 hours). After oral administration of 50 mg, mean C _max = 30.95 ± 9.61 ng/ml; range 10.85-45.70 ng/ml (111.57 ± 34.64 nmol/l; range 39.06-164.52 nmol/l). The mean absolute oral bioavailability is 53% (F _abs = 0.527 ± 0.123; range 0.219-0.756).

Distribution

The estimated apparent volume of distribution (Vd)β after intravenous administration is 1221 L ± 280 L; range 769-1702 L (16 ± 3 L/kg).
Plasma protein binding is approximately 95%.
Amitriptyline and its major metabolite, nortriptyline, cross the placental barrier.

In breastfeeding women, amitriptyline and nortriptyline are excreted in breast milk in small amounts. The milk concentration/plasma concentration ratio in women is approximately 1:1. The estimated daily exposure of the newborn (amitriptyline + nortriptyline) is on average 2% of the maternal amitriptyline doses based on weight (mg/kg) (see section 4.6).

Biotransformation

In vitro, amitriptyline metabolism occurs primarily by demethylation (CYP2C19, CYP3A4) and hydroxylation (CYP2D6) followed by glucuronidation. Other enzymes involved are CYP1A2 and CYP2C9. Metabolism is subject to genetic polymorphisms. The major active metabolite is the secondary amine nortriptyline.
Nortriptyline is a more potent inhibitor of serotonin reuptake than norepinephrine, whereas amitriptyline inhibits both norepinephrine and serotonin reuptake. Other metabolites such as cis- and trans-10-hydroxyamitriptyline and cis- and trans-10-hydroxynortriptyline have the same profile as nortriptyline but are considerably less potent. Only demethylnortriptyline and N-oxide-amitriptyline are present in plasma in trace amounts; the latter is virtually inactive. All metabolites are less anticholinergic than amitriptyline and nortriptyline. In plasma, the total amount of 10-hydroxynortriptyline dominates, but most metabolites are conjugated.

Elimination

The elimination half-life (t½ _β ) of amitriptyline after oral administration is approximately 25 hours (24.65 ± 6.31 hours; range 16.49-40.36 hours). The mean systemic clearance (Cl _s ) is 39.24 ± 10.18 L/h, range 24.53-53.73 L/h.

Excretion is primarily via urine. Renal elimination of unchanged amitriptyline is insignificant (approximately 2%).

Steady-state plasma concentrations of amitriptyline + nortriptyline are achieved within one week for the majority of patients, and steady-state plasma concentrations comprise approximately equal amounts of amitriptyline and nortriptyline over 24 hours after treatment with the conventional dosage of 3 tablets per day.

Elderly patients Longer half-lives and reduced oral clearance (Cl _o
) values due to reduced metabolism observed in elderly patients.

Reduced hepatic function
Impaired hepatic function may reduce hepatic extraction, resulting in higher plasma concentrations and administration to these patients should be done with caution (see section 4.2).

Impairment of renal function
Renal failure has no influence on the kinetics.

Polymorphism

Metabolism is subject to genetic polymorphisms (CYP2D6 and CYP2C19) (see section 4.2).

Pharmacokinetic/pharmacodynamic relationship

Plasma concentrations of amitriptyline and nortriptyline vary widely among individuals, and no simple correlation with therapeutic response has been established.
The therapeutic plasma concentration in major depression is approximately 80–200 ng/ml (≈ 280–700 nmol/l) (for amitriptyline + nortriptyline). Concentrations above 300–400 ng/ml are associated with an increased risk of cardiac conduction disturbances, including prolonged QRS complex or atrioventricular block.

Amitriptyline inhibited ion channels responsible for cardiac repolarization (hERG channels) at the upper micromolar range of therapeutic plasma concentrations. Therefore, amitriptyline may increase the risk of cardiac arrhythmias (see section 4.4).

The genotoxic potential of amitriptyline has been investigated in various in vitro and in vivo studies . Although these studies have revealed partly contradictory results, a potential for induction of chromosomal aberrations cannot be excluded. No long-term carcinogenicity studies have been conducted.

In reproduction studies, no teratogenic effects were observed in mice, rats, or rabbits receiving amitriptyline 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, published data in the literature have suggested a risk of malformations and delayed ossification in mice, hamsters, rats, and rabbits at 9-33 times the maximum recommended dose. A link to an effect on fertility in rats, namely a reduced pregnancy rate, is possible. The reason for this effect on fertility is unknown.

Tablet core:  corn starch, lactose monohydrate, colloidal anhydrous silica, microcrystalline cellulose, copovidone, croscarmellose sodium, magnesium stearate.

Coating:      Macrogol 400.
Colorant:      Opadry OY-S-9470 red-brown (E172; E171).

Not applicable.

5 years.

This medicine does not require any special storage precautions.

10 mg: 50 tablets and 100 tablets in a high-density polyethylene (HDPE) pill bottle.
25 mg: 30 tablets, 50 tablets, 100 tablets and 250 tablets in a high-density polyethylene (HDPE) pill bottle.

Not all presentations may be marketed.

Any unused medicine or waste material should be disposed of in accordance with local regulations.

Date of first authorization: October 1, 1966.
Date of last renewal: May 8, 2017.