Amitriptyline

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMITRIPTYLINE (AMITRIPTYLINE)

Composition:

Active ingredient: amitriptyline;

One tablet contains 25 mg of amitriptyline hydrochloride calculated as amitriptyline;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, hypromellose, magnesium stearate, colloidal anhydrous silicon dioxide, polyethylene glycol 6000, titanium dioxide (E 171), talc, polysorbate 80, carmoisine (E 122).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: round film-coated tablets of light pink to pink color, with convex upper and lower surfaces. When broken and examined under a magnifying glass, a core surrounded by a single continuous layer is visible.

Pharmacotherapeutic group. Antidepressants. Non-selective inhibitors of monoamine reuptake. ATC code N06AA09.

Pharmacological Properties.

Pharmacodynamics.

Amitriptyline is a tricyclic antidepressant and analgesic. As a tertiary amine, amitriptyline occupies a central position among tricyclic antidepressants because it is approximately equally active in vivo as an inhibitor of serotonin and norepinephrine reuptake by presynaptic nerve terminals. The primary active metabolite, nortriptyline, is a relatively more potent inhibitor of norepinephrine reuptake, but also blocks serotonin reuptake. Amitriptyline has significant anticholinergic, antihistaminergic, and sedative properties and potentiates the effects of catecholamines.

The mechanism of action also includes blockade of sodium, potassium, and N-methyl-D-aspartate (NMDA) ion channels at the level of the central nervous system and spinal cord. The effects of norepinephrine, along with blockade of sodium and NMDA channels, are mechanisms involved in the suppression of neuropathic pain, prevention of chronic tension-type headache, and prevention of migraine.

Tricyclic antidepressants exhibit varying degrees of affinity for muscarinic and histamine H1 receptors.

Suppression of rapid eye movement (REM) sleep phase is considered a hallmark of antidepressant activity. Tricyclic antidepressants, like selective serotonin reuptake inhibitors and monoamine oxidase inhibitors (MAOIs), suppress REM sleep and enhance deep slow-wave sleep.

Amitriptyline elevates pathologically low mood levels.

Due to its sedative properties, amitriptyline is particularly valuable in the treatment of depression accompanied by anxiety, agitation, restlessness, and sleep disturbances. The antidepressant and analgesic effects typically develop after 2–4 weeks of therapy, while the sedative effect remains unchanged.

The analgesic effect of the drug is not related to its antidepressant action, as analgesia occurs significantly earlier than any mood changes and often results from administration of much lower doses than those required to achieve mood improvement.

Pharmacokinetics.

Absorption. Oral administration of the drug in tablet form results in peak plasma concentration being reached approximately 4 hours later (tmax = 3.89 ± 1.87 h; range 1.03–7.98 h).

After oral administration of 50 mg, mean Cmax = 30.95 ± 9.61 ng/mL, range 10.85–45.7 ng/mL (111.57 ± 34.64 nmol/L; range 39.06–164.52 nmol/L). Mean absolute oral bioavailability is 53% (Fabs = 0.527 ± 0.123; range 0.219–0.756).

Distribution. The apparent volume of distribution (Vd)β, estimated 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 primary metabolite, nortriptyline, cross the placental barrier.

In breastfeeding women, amitriptyline and nortriptyline pass into breast milk in small amounts. The ratio of concentrations in breast milk to plasma in women is 1:1. The estimated daily dose (amitriptyline + nortriptyline) received by the infant is approximately 2% of the maternal amitriptyline dose, normalized to infant body weight (mg/kg).

Biotransformation. In vitro, amitriptyline metabolism occurs primarily via demethylation (CYP2C19, CYP3A) and hydroxylation (CYP2D6), followed by conjugation with glucuronic acid. This metabolism is characterized by genetically determined polymorphism. The main active metabolite is the secondary amine nortriptyline. Nortriptyline is a more potent inhibitor of norepinephrine reuptake than of serotonin reuptake, whereas amitriptyline equally inhibits reuptake of both neurotransmitters. Other metabolites (cis- and trans-10-hydroxyamitriptyline, and cis- and trans-10-hydroxynortriptyline) have profiles identical to nortriptyline but with significantly lower potency. Demethylnortriptyline and amitriptyline-N-oxide are present in plasma only in negligible amounts, the latter being completely devoid of activity. All metabolites have lower anticholinergic activity compared to amitriptyline and nortriptyline. Quantitatively, the total plasma concentration of 10-hydroxynortriptyline predominates, although most metabolites are present in conjugated form.

Elimination. The elimination half-life (t½β) of amitriptyline after oral administration is approximately 25 hours (24.65 ± 6.31 h; range 16.49–40.36 h). Mean systemic clearance (Cls) is 39.24 ± 10.18 L/h; range 24.53–53.73 L/h.

Excretion occurs primarily via urine. Renal excretion of unchanged amitriptyline is minimal (about 2%).

Steady-state plasma concentrations of amitriptyline and nortriptyline are achieved in most patients within 1 week. At steady state, plasma levels over 24 hours consist of approximately equal proportions of amitriptyline and nortriptyline during treatment with the standard tablet formulation administered three times daily.

Elderly patients.

In elderly patients, a prolonged elimination half-life and reduced oral clearance have been observed due to less intensive metabolism.

Impaired liver function.

Liver dysfunction may reduce hepatic extraction, leading to higher plasma drug concentrations. The drug should be administered with caution in patients with hepatic insufficiency.

Impaired kidney function.

Renal insufficiency does not affect the drug's pharmacokinetics.

Polymorphism. Drug metabolism depends on genetic polymorphism (isoenzymes CYP2D6 and CYP2C19).

Pharmacokinetic/pharmacodynamic relationship. The therapeutic plasma concentration in major depressive disorders is 80–200 ng/mL (≈280–700 nmol/L) (combined for amitriptyline and nortriptyline). Concentrations above 300–400 ng/mL are associated with an increased risk of cardiac conduction disturbances, such as QRS complex widening or atrioventricular block (AV block).

Clinical characteristics.

Indications.

Major depressive disorder.

Neuropathic pain.

Prevention of chronic tension-type headache.

Prevention of migraine.

Nocturnal enuresis in children aged 11 years and older in the absence of organic pathology (see section "Dosage and administration").

Contraindications.

Hypersensitivity to amitriptyline or any of the excipients of the medicinal product.

Recent myocardial infarction. Any type of heart block or cardiac arrhythmia, as well as coronary artery insufficiency.

Concomitant use of MAO inhibitors (MAOIs) is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant administration of amitriptyline and MAOIs may lead to the development of serotonin syndrome (a combination of symptoms including agitation, confusion, tremor, myoclonus, and hyperthermia).

Treatment with amitriptyline may be initiated 14 days after discontinuation of irreversible non-selective MAOIs and no less than 1 day after discontinuation of reversible inhibitors such as moclobemide and selegiline.

Treatment with MAOIs may be initiated 14 days after discontinuation of amitriptyline.

Severe liver disease.

Children under 11 years of age.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

Contraindicated combinations

MAO inhibitors (non-selective, as well as selective A [moclobemide] and B [selegiline]) – risk of serotonin syndrome (see section "Contraindications").

Undesirable combinations

Sympathomimetic agents: amitriptyline may potentiate cardiovascular effects of adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, and phenylpropanolamine (which, for example, are components of local and general anesthetics and nasal decongestants).

Adrenergic neuron blockers: tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine, betanidine, reserpine, clonidine, and methyldopa. It is recommended to review the entire antihypertensive therapy regimen during treatment with tricyclic antidepressants.

Anticholinergic agents: tricyclic antidepressants may potentiate the effects of these medicinal products on the eyes, central nervous system, gastrointestinal tract, and urinary bladder; concomitant use should be avoided due to increased risk of paralytic ileus, hyperpyrexia, etc.

Medicinal products causing QT interval prolongation on electrocardiogram, including antiarrhythmic agents (quinidine), antihistamines (astemizole and terfenadine), certain antipsychotics (particularly pimozide and sertindole), cisapride, halofantrine, and sotalol increase the risk of ventricular arrhythmias when used concomitantly with tricyclic antidepressants. Caution is required when using amitriptyline concomitantly with methadone due to possible additive effects on the QT interval and increased risk of serious cardiovascular events.

Caution is also recommended when amitriptyline is used concomitantly with diuretics causing hypokalemia (e.g., furosemide).

Thioridazine: concomitant use of amitriptyline and thioridazine (a CYP2D6 substrate) should be avoided due to inhibition of thioridazine metabolism and, consequently, increased risk of cardiac adverse 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 and thus increase tramadol concentration, potentially leading to opioid toxicity.

Antifungal agents, such as fluconazole (a CYP2C9 inhibitor) and terbinafine (a CYP2D6 inhibitor), may increase serum levels of amitriptyline and nortriptyline and the severity of associated toxicity. Cases of unconsciousness and torsade de pointes arrhythmia have been reported.

Combinations requiring special caution

Central nervous system (CNS) depressants: amitriptyline may enhance the sedative effects of alcohol, barbiturates, and other CNS depressants.

Pharmacokinetic interactions

Effect of other medicinal products on the pharmacokinetics of amitriptyline

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

Inhibitors of CYP2D6: the CYP2D6 isoenzyme may be inhibited by many medicinal products, such as neuroleptics, serotonin reuptake inhibitors, β-blockers, and antiarrhythmic agents. Examples of strong CYP2D6 inhibitors include bupropion, fluoxetine, paroxetine, and quinidine. These agents may cause significant reduction in metabolism and marked increase in plasma concentrations of TCAs. Plasma concentrations of TCAs should be monitored when TCAs are co-administered with another agent known to be a strong CYP2D6 inhibitor. Dose adjustment of amitriptyline may be necessary. Caution is recommended when amitriptyline is used concomitantly with duloxetine, a moderate CYP2D6 inhibitor.

Other inhibitors of cytochrome P450: cimetidine and methylphenidate, as well as calcium channel blockers (e.g., diltiazem and verapamil), may increase plasma levels of tricyclic antidepressants and the corresponding toxicity.

Isoenzymes CYP3A4 and CYP1A2 metabolize amitriptyline to a lesser extent. However, fluvoxamine (a strong CYP1A2 inhibitor) increases plasma concentrations of amitriptyline, and this combination should be avoided. Clinically significant interactions may be expected when amitriptyline is used concomitantly with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir.

Tricyclic antidepressants and neuroleptics mutually inhibit each other's metabolism; this may lead to a lowered seizure threshold and seizures. Dose adjustments of these medicinal products may be necessary.

Inducers of cytochrome P450: oral contraceptives, rifampicin, phenytoin, barbiturates, carbamazepine, and St John's wort (Hypericum perforatum) may enhance metabolism and thus reduce plasma concentrations of tricyclic antidepressants, leading to diminished antidepressant effect.

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

Plasma concentrations of amitriptyline may be increased by sodium valproate and valpromide.

Special precautions for use.

When high doses of the drug are used, the risk of developing cardiac arrhythmias and severe arterial hypotension increases. Such conditions may also occur when standard doses are administered to patients with pre-existing heart disease.

Cases of QT interval prolongation and arrhythmias have been reported in the postoperative period. Amitriptyline should be used with caution in patients with marked bradycardia, in patients with decompensated heart failure, or in those receiving concomitant medications that prolong the QT interval. Electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia) are known risk factors that increase the proarrhythmic potential.

The use of anesthetics in patients receiving tricyclic or tetracyclic antidepressants may increase the risk of arrhythmias and arterial hypotension. If possible, amitriptyline should be discontinued several days before surgery. In the case of emergency surgery, it is essential to inform the anesthesiologist about amitriptyline therapy.

Particular caution is required when prescribing amitriptyline to patients with hyperthyroidism or those receiving thyroid hormone medications, as cardiac arrhythmias may develop.

Elderly patients are especially prone to postural hypotension during amitriptyline therapy.

The drug should be prescribed with caution in patients with seizure disorders, urinary retention, benign prostatic hyperplasia, hyperthyroidism, paranoid symptoms, or severe hepatic or cardiovascular disease, pylorus stenosis, and paralytic ileus.

In patients with the rare condition of shallow anterior chamber and narrow anterior chamber angle of the eye, pupillary dilation may provoke acute glaucoma attacks.

Depression is associated with an increased risk of suicidal thoughts, self-harm, suicide (and related events). This risk may persist until sustained remission is achieved. Since improvement may not occur during the first few weeks of treatment or longer, patients should be closely monitored until such improvement occurs. Clinical experience indicates that the risk of suicide may increase during the early stages of recovery. Patients with a history of suicidal behavior or significant suicidal ideation prior to treatment initiation are known to be at higher risk of suicide or suicide attempts and should be carefully monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behavior with antidepressant use compared to placebo in patients under 25 years of age. Close monitoring of patients, particularly those at high risk of suicidal behavior, should accompany treatment with this drug, especially at the beginning of therapy and after dose adjustments. Patients (and their caregivers) should be warned to monitor for any clinical worsening, suicidal thoughts or behavior, and unusual changes in behavior, and to seek medical help if such symptoms occur.

In patients with bipolar disorder, there is a possibility of switching into a manic phase; amitriptyline therapy should be discontinued as soon as a manic phase begins.

Like other psychotropic agents, amitriptyline may alter insulin and glucose sensitivity, necessitating adjustment of antidiabetic therapy in diabetic patients; additionally, depressive illness itself may manifest with changes in glucose metabolism.

Cases of hyperpyrexia have been reported with the use of tricyclic antidepressants when administered concomitantly with anticholinergic or neuroleptic drugs, particularly in hot weather.

Sudden discontinuation of therapy after prolonged treatment may lead to withdrawal symptoms such as headache, malaise, insomnia, and irritability. These symptoms are not indicative of drug dependence.

Amitriptyline should be used with caution in patients taking SSRIs.

Night enuresis

An ECG should be performed prior to initiating amitriptyline therapy to exclude QT interval prolongation syndrome.

Amitriptyline used for enuresis should not be combined with anticholinergic drugs.

Suicidal thoughts and behavior may also emerge during early treatment with antidepressants for disorders other than depression. Therefore, the same precautionary measures should be followed when treating both depressed patients and those with enuresis.

Excipients: The tablets contain lactose monohydrate. Patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

The product contains carmoisine (E 122), which may cause allergic reactions.

Children

Long-term safety data regarding growth, sexual maturation, and cognitive and behavioral development in children and adolescents are lacking.

Severe skin reactions

Severe cutaneous adverse reactions (SCARs), including drug-induced eosinophilia with systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported with amitriptyline use. Most of these reactions occurred within 2–6 weeks of treatment initiation.

Patients should be informed about the signs and symptoms of such reactions, and skin reactions should be carefully monitored during treatment.

If signs or symptoms suggestive of these reactions appear, amitriptyline should be discontinued immediately; re-administration of amitriptyline to such patients is absolutely contraindicated, and alternative treatment options should be considered (if necessary).

Use during pregnancy or breastfeeding.

Pregnancy

Clinical data on the use of amitriptyline during pregnancy are limited.

Animal studies have shown reproductive toxicity.

Amitriptyline is not recommended during pregnancy unless clearly necessary. Use should only be considered after careful assessment of the benefit-risk ratio.

With prolonged use and administration during the last weeks of pregnancy, neonatal withdrawal symptoms may occur, including irritability, hypertension, tremor, irregular respiration, feeding difficulties, loud crying, and possibly anticholinergic symptoms (urinary retention, constipation).

Breastfeeding

Amitriptyline and its metabolites are excreted in breast milk (0.6–1% of maternal dose).

Risk to the infant cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abstain from treatment with this medicinal product should be made considering the benefits of breastfeeding for the child and the benefits of treatment for the mother.

Fertility

Amitriptyline reduced the frequency of pregnancy in rats.

There are no data on the effect of amitriptyline on human fertility.

Ability to affect reaction speed when driving or operating machinery.

Amitriptyline is a sedative medicinal product. In patients receiving psychotropic medication, impaired attention and concentration may be expected, posing a danger and contraindicating driving or operating machinery. These adverse effects may be enhanced by concomitant alcohol consumption.

Dosage and Administration

Major Depressive Disorder

Treatment should be initiated with low doses, gradually increasing while carefully monitoring clinical response and signs of drug sensitivity. Doses exceeding 150 mg per day (up to 225 mg per day, and occasionally up to 300 mg per day) should be administered only in a hospital setting.

Adults

Initially, 25 mg twice daily (50 mg per day), gradually increasing as needed by 25 mg every other day up to 150 mg per day (rarely up to 225–300 mg per day in a hospital setting).

The maintenance dose corresponds to the lowest effective dose.

Patients aged 65 years and older, and patients with cardiovascular disease

Initially, 25 mg once daily. The daily dose may be increased to 100–150 mg, divided into two doses, depending on individual patient response and tolerability. Doses above 100 mg should be used with caution. The maintenance dose corresponds to the lowest effective dose.

Children

Amitriptyline should not be used for the treatment of major depressive disorder in children and adolescents (under 18 years of age), as the safety and efficacy of the drug in this age group have not been established.

Duration of Therapy

Antidepressant effects typically develop within 2–4 weeks. Antidepressant treatment is symptomatic in nature; therefore, it should be continued for an appropriate duration, usually up to 6 months after recovery, to prevent relapse. For patients with recurrent (unipolar) depression, maintenance therapy may be required for several years to prevent new episodes.

Neuropathic Pain, Prophylactic Treatment of Chronic Tension-Type Headache, and Prophylactic Treatment of Migraine in Adults

The dose should be individually titrated for each patient to achieve adequate analgesia and tolerability of adverse drug reactions. Generally, the lowest effective dose should be used for the shortest duration necessary to treat symptoms.

Adults

Recommended doses: 25–75 mg once daily in the evening. Doses above 100 mg should be used with caution. The initial dose is 25 mg taken in the evening. The dose may be increased by 25 mg every 3–7 days, provided tolerability is acceptable.

The dose may be taken once daily or divided into two doses. Single doses exceeding 75 mg are not recommended.

Elderly patients (over 65 years of age) and patients with cardiovascular diseases

Recommended initial dose: 25 mg in the evening. Doses above 75 mg should be used with caution. The dose may be increased depending on individual patient response and tolerability.

Children

Amitriptyline should not be used for the treatment of neuropathic pain, prophylactic treatment of chronic tension-type headache, or prophylactic treatment of migraine in children and adolescents (under 18 years of age), as the safety and efficacy of the drug in this patient population have not been established.

Duration of Treatment

Neuropathic Pain

Treatment is symptomatic and should be continued for an appropriate period. In many patients, therapy may last several years. Regular assessment of the need for continued treatment is recommended.

Prophylactic Treatment of Chronic Tension-Type Headache and Prophylactic Treatment of Migraine in Adults

Treatment should be continued for a defined period. Regular assessment of the need for continued treatment is recommended.

Nocturnal Enuresis

Children aged 11 years and older

Recommended dose: 25–50 mg once daily, 1–1.5 hours before bedtime. The dose should be increased gradually. Prior to initiating amitriptyline therapy, an ECG should be performed to rule out QT interval prolongation syndrome.

Duration of Treatment

The maximum treatment course should not exceed 3 months. If a repeat course of amitriptyline treatment is required, a medical evaluation should be conducted every 3 months. When discontinuing treatment, the amitriptyline dose should be tapered gradually.

Renal Impairment

Amitriptyline may be administered at usual doses in patients with renal impairment.

Hepatic Impairment

Careful dose titration is recommended, and, if possible, monitoring of plasma drug concentrations.

Cytochrome P450 CYP2D6 Inhibitors

Depending on individual patient response, consideration should be given to reducing the amitriptyline dose when co-administered with a strong CYP2D6 inhibitor (e.g., bupropion, quinidine, fluoxetine, paroxetine).

Known Poor Metabolizers of CYP2D6 or CYP2C19

Patients known to be poor metabolizers of CYP2D6 or CYP2C19 may have elevated plasma concentrations of amitriptyline and its active metabolite nortriptyline. A 50% reduction of the recommended initial dose may be considered.

Route of Administration

The drug is administered orally. Tablets should be swallowed whole, without chewing, with water.

Discontinuation of Treatment

When discontinuing treatment, the dose should be gradually reduced over several weeks.

Children

Treatment of nocturnal enuresis in children aged 11 years and older is possible only in the absence of organic pathology, including spina bifida, and concomitant disorders, and only if there is no response to non-pharmacological and pharmacological treatments, such as antispasmodic agents and vasopressin preparations.

This medicinal product should be prescribed only by a physician experienced in the management of refractory enuresis.

Overdose

Symptoms

Symptoms may develop gradually and insidiously, but sometimes abruptly and suddenly. Early signs include drowsiness or agitation and hallucinations.

Anticholinergic symptoms include mydriasis, tachycardia, urinary retention, dry mucous membranes, and decreased gastrointestinal motility. Seizures, hyperthermia, and sudden onset of central nervous system (CNS) depression may occur. Decreased consciousness may progress to coma with respiratory depression.

Toxicity in Children

Overdose in children may have serious consequences. Children are particularly susceptible to coma, cardiotoxicity, respiratory depression, seizures, hyponatremia, lethargy, sinus tachycardia, drowsiness, nausea, vomiting, and hyperglycemia.

Brugada Syndrome

Cardiovascular effects: arrhythmias (ventricular tachyarrhythmias, flutter-fibrillation, ventricular fibrillation). ECG typically shows prolonged PR interval, widened QRS complex, QT prolongation, T-wave widening or inversion, ST-segment depression, and varying degrees of heart block, up to cardiac arrest. QRS complex widening usually correlates clearly with the severity of toxicity following acute overdose. Cardiac failure, arterial hypotension, and cardiogenic shock may develop. Metabolic acidosis and hypokalemia may worsen. After awakening, confusion, anxious agitation, hallucinations, and ataxia may recur. Post-marketing studies and publications report cases of unmasking Brugada syndrome and Brugada-type ECG patterns following amitriptyline overdose.

In adults, doses exceeding 500 mg may cause moderate to severe intoxication; doses around 1000 mg have been fatal.

Effects of overdose are potentiated when taken concomitantly with alcohol and other psychotropic substances. There is considerable individual variability in response to overdose. Children are particularly sensitive to cardiotoxicity, seizures, and hyponatremia.

Treatment

Patients should be hospitalized (in an intensive care unit) and closely monitored, even in apparently mild cases. Treatment is symptomatic and supportive.

Gastric lavage and administration of activated charcoal are indicated, even if performed late after oral ingestion. Close monitoring is mandatory, even in apparently mild cases. Assess level of consciousness, pulse characteristics, blood pressure, and respiratory function; frequently monitor blood electrolytes and blood gas levels. Airway patency should be ensured, with intubation if necessary. In general, mechanical ventilation is recommended to prevent potential respiratory arrest. Continuous ECG monitoring should be performed for 3–5 days. In cases of QRS widening, cardiac failure, or ventricular arrhythmias, alkalinization of blood pH (administration of sodium bicarbonate or hyperventilation) and rapid infusion of hypertonic sodium chloride solution (100–200 mmol Na+) may be effective. For ventricular arrhythmias, traditional antiarrhythmic agents such as lidocaine (50–100 mg or 1–1.5 mg/kg intravenously, followed by infusion at 1–3 mg/min) may be used.

Cardiac pacing and defibrillation should be applied if necessary. Circulatory failure should be managed with plasma expanders, and in severe cases, by infusion of dobutamine (initially at 2–3 mcg/kg/min), increasing the dose according to effect. Agitation and seizures may be controlled with diazepam.

Since overdose is often intentional, patients in remission may attempt suicide by other means. Fatalities have been reported following intentional or accidental overdose with drugs of this class.

Adverse reactions.

Amitriptyline may cause adverse effects similar to those observed with other tricyclic antidepressants. Some of the adverse effects listed below (headache, tremor, difficulty concentrating, constipation, and decreased libido) may also be symptoms of depression and usually diminish as the depressive condition improves.

Severe cutaneous adverse reactions (SCARs), including drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with amitriptyline use (see section "Special precautions").

The list of adverse reactions below is presented according to MedDRA organ system classes and frequency of occurrence, namely: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000); unknown (cannot be estimated from the available data).

* Cases of suicidal thoughts or behavior have been reported during therapy or immediately after discontinuation of amitriptyline (see section "Precautions").

Epidemiological studies, mainly conducted in patients aged 50 years and older, have shown an increased risk of bone fractures in patients receiving SSRIs and tricyclic antidepressants (TCAs). The mechanism underlying this risk is unknown.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after the drug has been authorized. This allows continued monitoring of the benefit-risk balance of the medicinal product.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister. 5 blisters in a cardboard box.

10 tablets in a blister. 100 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

JSC "Tekhnolohiya".

Manufacturer's address and place of business.

8 Stara Prorizna Street, Uman, Cherkasy region, 20300, Ukraine.