Amitriptyline hydrochloride
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMITRIPTYLINE HYDROCHLORIDE (AMITRIPTYLINE HYDROCHLORIDE)
Composition:
Active substance: amitriptyline;
One tablet contains 25 mg of amitriptyline hydrochloride;
Excipients: maize starch; lactose monohydrate; microcrystalline cellulose; colloidal anhydrous silicon dioxide; magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties: white tablets with a flat surface and bevel.
Pharmacotherapeutic group. Antidepressants. ATC code N06A A09.
Pharmacological Properties.
Pharmacodynamics
Amitriptyline is a tricyclic antidepressant and analgesic.
Its anticholinergic properties prevent the reuptake and, thus, inactivation of norepinephrine and serotonin at nerve receptors, thereby enhancing the activity of norepinephrine and serotonin in the brain. This is the mechanism of action of amitriptyline.
The mechanism of action also includes blockade of sodium, potassium, and N-methyl-D-aspartate (NMDA) ion channels at the level of the central and spinal cord. The action of norepinephrine, along with blockade of sodium and NMDA channels, are mechanisms involved in suppression of neuropathic pain, prophylaxis of chronic tension-type headache, and prophylaxis of migraine. 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.
Antidepressant and analgesic effects usually become evident within 2–4 weeks of therapy, while the sedative effect remains unchanged.
Pharmacokinetics
Absorption.
Oral administration of the drug in tablet form results in peak serum concentrations being reached approximately 4 hours post-dose (tmax = 3.89 ± 1.87 hours; range 1.93–7.98 hours). After oral administration of 50 mg, the mean Cmax value is 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 value of 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 main metabolite nortriptyline cross the placental barrier.
In breastfeeding women, amitriptyline and nortriptyline pass into breast milk in small amounts. The ratio of concentration in breast milk to serum 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 (in 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 serotonin reuptake, whereas amitriptyline equally inhibits the reuptake of both neurotransmitters. Other metabolites (cis- and trans-10-hydroxyamitriptyline, as well as cis- and trans-10-hydroxynortriptyline) have a profile identical to that of 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. In plasma, the total concentration of 10-hydroxynortriptyline predominates quantitatively, 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 hours, range 16.49–40.36 hours). The mean value of 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 negligible (approximately 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 (Clo) have been observed due to less intense metabolism.
Impaired liver function.
Liver dysfunction may reduce hepatic extraction, leading to higher drug plasma concentrations. The drug should be administered with caution in patients with hepatic insufficiency.
Impaired renal function.
Renal impairment does not affect the drug's kinetics.
Polymorphism.
Drug metabolism depends on genetic polymorphism (CYP2D6 and CYP2C19 isoenzymes).
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). Levels above 300–400 ng/mL are associated with an increased risk of cardiac conduction disturbances, such as QRS complex widening or 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 to any excipient of the medicinal product.
Recent myocardial infarction. Any type of heart block or cardiac arrhythmia, as well as coronary artery insufficiency.
Concomitant use of monoamine oxidase 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 such as 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 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
MAOIs (non-selective, as well as selective type A [moclobemide] and type B [selegiline]): risk of serotonin syndrome (see section "Contraindications").
Unrecommended combinations
Sympathomimetic agents: amitriptyline may potentiate cardiovascular effects of adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, and phenylpropanolamine (which are, for example, components of local and general anesthetics and nasal decongestants).
Adrenergic neuron blockers: tricyclic antidepressants may interfere with the antihypertensive effects of centrally acting antihypertensive agents such as 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 drugs on the eyes, central nervous system, gastrointestinal tract, and urinary bladder; simultaneous 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 likelihood of ventricular arrhythmias when taken 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 that may cause 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 such as amitriptyline increases the risk of seizures and serotonin syndrome. Additionally, this combination may inhibit the metabolism of tramadol to its active metabolite, thereby increasing tramadol concentration and potentially causing opioid toxicity.
Antifungal agents, such as fluconazole and terbinafine, may increase serum concentrations of tricyclic antidepressants and the severity of associated toxicity. Cases of unconsciousness and torsade de pointes arrhythmia have been reported.
Combinations requiring special caution
CNS depressants: amitriptyline may enhance the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants.
Pharmacokinetic interactions
Effect of other medicinal products on the pharmacokinetics of tricyclic antidepressants
Tricyclic antidepressants, 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 activity of the CYP2D6 isoenzyme may be inhibited by numerous psychotropic and other medicinal products, e.g., neuroleptics, serotonin reuptake inhibitors (except citalopram, which is a very weak inhibitor of the isoenzyme), beta-blockers, and antiarrhythmic agents. Examples of strong CYP2D6 inhibitors include bupropion, fluoxetine, paroxetine, and quinidine. These drugs may cause a significant reduction in metabolism and a substantial increase in plasma concentrations of tricyclic antidepressants. Plasma concentrations of tricyclic antidepressants should be monitored when used concomitantly with other drugs that are strong CYP2D6 inhibitors. Dose adjustment of amitriptyline may be necessary. Caution is recommended when amitriptyline is used concomitantly with duloxetine, a moderate CYP2D6 inhibitor.
Other cytochrome P450 inhibitors: cimetidine and methylphenidate, as well as calcium channel blockers (e.g., diltiazem and verapamil), increase plasma levels of tricyclic antidepressants and their associated toxicity. Antifungal agents such as fluconazole (a CYP2C9 inhibitor) and terbinafine (a CYP2D6 inhibitor) have increased serum levels of amitriptyline and nortriptyline.
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 with concomitant use of amitriptyline and strong CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir.
Tricyclic antidepressants and neuroleptics mutually inhibit each other's metabolism; this may lead to a reduced seizure threshold and occurrence of seizures. Dose adjustments of these medicinal products may be necessary.
Cytochrome P450 inducers: barbiturates, as well as other enzyme inducers such as rifampicin, carbamazepine, phenytoin, oral contraceptives, and St. John's wort (Hypericum perforatum) preparations, may enhance metabolism and thereby reduce plasma concentrations of tricyclic antidepressants and diminish their antidepressant effect.
In the presence of ethanol, free plasma concentrations of amitriptyline and nortriptyline concentrations were increased.
Plasma concentrations of amitriptyline may be increased by sodium valproate and valpromide. Therefore, clinical monitoring is recommended.
Special precautions for use.
Amitriptyline should not be administered concurrently with MAO inhibitors (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
When high doses of the drug are used, the risk of cardiac arrhythmias and severe arterial hypotension increases. Such conditions may also occur with standard doses in patients who already have pre-existing heart disease.
QT interval prolongation.
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 patients who are concurrently taking medicinal products that prolong the QT interval. Electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia) are known risk factors that increase the proarrhythmic potential.
The use of anesthetics during therapy with tricyclic or tetracyclic antidepressants increases the risk of arrhythmias and arterial hypotension.
If possible, amitriptyline should be discontinued several days before surgical intervention. In the case of an unavoidable emergency surgery, it is mandatory to inform the anesthesiologist about amitriptyline treatment.
Particular caution is required when prescribing amitriptyline to patients with hyperthyroidism or those taking thyroid hormone preparations, as cardiac arrhythmias may develop.
Elderly patients are especially prone to postural hypotension during treatment with amitriptyline.
Amitriptyline should be administered with caution in patients with seizure disorders, urinary retention, benign prostatic hyperplasia, hyperthyroidism, paranoid symptoms, as well as in patients with severe liver or cardiovascular diseases, pyloric stenosis, and paralytic ileus.
In patients with the rare condition of shallow anterior chamber and narrow anterior chamber angle of the eye, amitriptyline may provoke acute attacks of glaucoma due to pupillary dilation.
Depression is associated with an increased risk of suicidal thoughts, self-harm, suicide (and related events). This risk may persist until a sustained remission is achieved and may occur spontaneously during the course of therapy. Since improvement may not occur within 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 suicidal ideation prior to treatment initiation are known to have a higher risk of suicide and require careful monitoring 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 pharmacological therapy, especially at the beginning of treatment and after dose adjustments. Patients (and their caregivers) should be warned to monitor for any clinical worsening, suicidal behavior or thoughts, and unusual changes in behavior, and to seek medical help if these symptoms occur.
In patients with bipolar disorder, there is a possibility of switching into a manic phase; amitriptyline therapy should be discontinued once a manic phase begins.
Like other psychotropic agents, amitriptyline may alter sensitivity to insulin and glucose, necessitating adjustments in antidiabetic therapy in diabetic patients; additionally, depressive illness itself may manifest with changes in glucose balance in the patient.
Cases of hyperpyrexia have been reported during treatment with tricyclic antidepressants when used concomitantly with anticholinergic or neuroleptic medicinal products, 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 signs of drug dependence.
Amitriptyline should be used with caution in patients taking SSRIs.
Night enuresis.
An ECG should be performed before 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 patients with enuresis.
Severe skin reactions.
Severe cutaneous adverse reactions have been reported with amitriptyline, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal. These reactions typically occur within 2–6 weeks of treatment initiation.
Patients should be informed about the signs and symptoms of these reactions and carefully monitored for skin reactions.
If signs or symptoms suggestive of these reactions occur, the drug should be discontinued immediately. Reinitiating amitriptyline treatment in such patients is strictly contraindicated. Alternative treatment options (if needed) should be considered.
Children.
Long-term safety data regarding growth, sexual maturation, cognitive, and behavioral development in children and adolescents are lacking.
Excipients: the medicinal product contains lactose monohydrate. If the patient has been diagnosed with an intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.
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.
Prolonged use and administration during the last weeks of pregnancy may lead to neonatal withdrawal symptoms, which may include irritability, hypertension, tremor, irregular respiration, feeding difficulties, high-pitched crying, and possibly anticholinergic symptoms (urinary retention, constipation).
Breastfeeding
Amitriptyline and its metabolites are excreted in breast milk (0.6–1% of the maternal dose).
Risk to infants cannot be excluded. A decision on whether to discontinue breastfeeding or to discontinue/abstain from treatment with this medicinal product should be made, taking into account 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 drugs, impaired attention and concentration may be expected, which poses a danger and contraindicates driving a vehicle or operating machinery. These adverse effects may be potentiated by concomitant alcohol consumption.
Method of Administration and Dosage
Major Depressive Disorder
Treatment should begin with low doses, gradually increasing them under careful monitoring of clinical response and signs of drug sensitivity.
Adults
Initially 25 mg twice daily (50 mg per day). If necessary, the dose may be increased by 25 mg every other day up to 150 mg per day, divided into two doses.
The maintenance dose corresponds to the lowest effective dose.
Patients aged 65 years and older and patients with cardiovascular disease
Initially 25 mg per day.
The daily dose may be increased to 100–150 mg per day, 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 effect usually develops within 2–4 weeks. Antidepressant treatment is symptomatic in nature and therefore should be continued for an appropriate period, typically up to 6 months after recovery to prevent relapse. In 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 titrated individually for each patient to ensure adequate analgesia and tolerability of adverse reactions. The lowest effective dose should generally be used for the shortest duration necessary to control symptoms.
Adults
Recommended doses are 25–75 mg per day, taken 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. A single dose above 75 mg is not recommended.
Patients aged 65 years and older and patients with cardiovascular diseases
The recommended initial dose is 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 migraine prophylaxis 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 Treatment
Neuropathic Pain.
Treatment is symptomatic and should therefore 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 certain period. Regular assessment of the need for continued treatment is recommended.
Nocturnal Enuresis
Children
Recommended doses for children aged 11 years and older: 25–50 mg per day.
The dose should be increased gradually.
The medicinal product should be taken 1–1.5 hours before bedtime.
Prior to initiating amitriptyline therapy, an ECG should be performed to exclude the QT interval prolongation syndrome.
Duration of Treatment
The maximum treatment course duration should not exceed 3 months.
If repeated treatment with amitriptyline is required, a medical examination should be conducted every 3 months.
When discontinuing treatment, the dose of amitriptyline should be gradually reduced.
Renal Impairment
The medicinal product may be prescribed at usual doses to patients with impaired renal function.
Hepatic Impairment
Careful dose titration is recommended, and, if possible, measurement of drug concentration in blood serum should be considered.
Cytochrome P450 CYP2D6 Inhibitors
Depending on individual patient response, a reduction in the dose of amitriptyline may be considered 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 increased plasma concentrations of amitriptyline and its active metabolite nortriptyline. A 50% reduction in the recommended initial dose may be considered.
Method of Administration
The medicinal product is taken orally.
Tablets should be swallowed with water.
Discontinuation of Treatment
When discontinuing treatment, the dose of the drug 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, including antispasmodic agents and vasopressin preparations.
This medicinal product should be prescribed only by a physician experienced in the management of persistent enuresis.
Overdose.
Symptoms
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. Impaired consciousness may progress to coma with respiratory depression.
Cardiac symptoms: arrhythmias (ventricular tachyarrhythmias, flutter-fibrillation, ventricular fibrillation). ECG findings include prolonged PR interval, widened QRS complex, prolonged QT interval, widened or inverted T wave, ST segment depression, and various degrees of heart block up to cardiac arrest. QRS widening generally correlates clearly with the severity of toxicity following acute overdose. Cardiac failure, arterial hypotension, and cardiogenic shock may develop. Metabolic acidosis, hypokalemia, and hyponatremia may worsen. Post-marketing studies and literature report cases of unmasking Brugada syndrome and Brugada-type ECG patterns following amitriptyline overdose.
Ingestion of 750 mg or more by an adult may lead to severe toxicity. Effects of overdose are potentiated when taken concomitantly with alcohol and other psychotropic substances. There is considerable individual variability in response to overdose.
Overdose in children may have serious consequences. Children are particularly sensitive to the development of coma, cardiotoxicity, respiratory depression, seizures, hyponatremia, lethargy, sinus tachycardia, somnolence, nausea, vomiting, and hyperglycemia.
After awakening, confusion, anxious agitation, hallucinations, and ataxia may recur.
Treatment
Hospitalization (in an intensive care unit) and careful monitoring of the patient's condition are required, even in apparently mild cases.
Treatment is symptomatic and supportive.
A comprehensive approach to rapidly assess and restore respiratory and cardiovascular functions should be implemented and managed as needed. Airway patency should be ensured, including endotracheal intubation if necessary. Mechanical ventilation is recommended to prevent potential respiratory arrest.
Urea, electrolytes, arterial blood CO2 and O2 levels, and ECG should be checked. Continuous ECG monitoring should be performed for 3–5 days. Gastric lavage should be performed if a potentially lethal dose was ingested within one hour. Administer 50 g of activated charcoal within one hour after overdose. Management of the following conditions should be addressed on a case-by-case basis:
- QRS widening, cardiac failure, and ventricular arrhythmias;
- circulatory failure;
- hypotension;
- hyperthermia;
- seizures;
- metabolic acidosis.
Agitation and seizures may be treated with diazepam.
Since overdose is often intentional, patients during remission may attempt suicide by other means. Fatal cases due to intentional or accidental overdose of drugs in this class have been reported.
Adverse reactions.
Amitriptyline may cause adverse effects similar to those occurring with other tricyclic antidepressants. Some of the adverse effects (headache, tremor, difficulty concentrating, constipation, decreased libido) may also be symptoms of depression and, therefore, usually diminish as the patient's condition improves.
The adverse reactions listed below are classified by frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency not known (cannot be estimated from the available data).
| Systems and organs by MedDRA |
Frequency |
Manifestations |
| Disorders of the blood and lymphatic system |
Uncommon |
Bone marrow depression, agranulocytosis, leukopenia, eosinophilia, thrombocytopenia |
| Nutritional and metabolic disorders |
Common |
Hypnatremia |
| Uncommon |
Decreased appetite |
|
| Frequency unknown |
Anorexia, increased or decreased blood glucose levels |
|
| Psychiatric disorders |
Very common |
Aggression |
| Common |
Confusional state, decreased libido, agitation |
|
| Uncommon |
Hypomania, mania, anxiety, insomnia, night terrors |
|
| Uncommon |
Delirium (in elderly patients), hallucinations, suicidal thoughts or behavior* |
|
| Frequency unknown |
Paranoia |
|
| Nervous system disorders |
Very common |
Somnolence, tremor, dizziness, headache, lethargy, speech disorders (dysarthria) |
| Common |
Attention disorders, dysgeusia, paresthesia, ataxia |
|
| Uncommon |
Seizures |
|
| Very rare |
Akathisia, polyneuropathy |
|
| Frequency unknown |
Extrapyramidal disorder |
|
| Eye disorders |
Very common |
Accommodation disorders |
| Common |
Mydriasis |
|
| Uncommon |
Increased intraocular pressure |
|
| Very rare |
Acute glaucoma attack |
|
| Frequency unknown |
Xerophthalmia |
|
| Ear and labyrinth disorders |
Uncommon |
Tinnitus |
| Cardiac disorders |
Very common |
Pounding heartbeat, tachycardia |
| Common |
Atrioventricular blocks, bundle branch blocks, abnormal electrocardiogram, electrocardiographic abnormalities (prolongation of QT interval and QRS complex) |
|
| Uncommon |
State of collapse, worsening of heart failure |
|
| Uncommon |
Arrhythmia |
|
| Very rare |
Cardiomyopathy, torsades de pointes |
|
| Frequency unknown |
Drug hypersensitivity-induced myocarditis |
|
| Vascular disorders |
Very common |
Orthostatic hypotension |
| Uncommon |
Arterial hypertension |
|
| Frequency unknown |
Hyperthermia |
|
| Respiratory, thoracic and mediastinal disorders |
Very common |
Nasal congestion |
| Very rare |
Allergic alveolitis and pulmonary tissue inflammation (alveolitis, Löffler's syndrome) |
|
| Gastrointestinal disorders |
Very common |
Dry mouth, constipation, nausea |
| Uncommon |
Diarrhea, vomiting, tongue edema |
|
| Uncommon |
Salivary gland enlargement, paralytic ileus |
|
| Hepatobiliary disorders |
Uncommon |
Liver failure (e.g., cholestatic liver disease) |
| Uncommon |
Jaundice, abnormal liver function tests, increased blood phosphatase and transaminase activity |
|
| Frequency unknown |
Hepatitis |
|
| Skin and subcutaneous tissue disorders |
Very common |
Hyperhidrosis |
| Uncommon |
Rash, urticaria, facial swelling |
|
| Uncommon |
Alopecia, photosensitivity reactions |
|
| Frequency unknown |
Severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions for use"). |
|
| Renal and urinary disorders |
Common |
Urination disorders |
| Uncommon |
Urinary retention |
|
| Reproductive system and breast disorders |
Common |
Erectile dysfunction |
| Uncommon |
Galactorrhea |
|
| Uncommon |
Gynecomastia |
|
| General disorders |
Common |
Fatigue, thirst |
| Uncommon |
Pyrexia |
|
| Other manifestations |
Very common |
Weight gain |
| Uncommon |
Weight loss |
* Cases of suicidal thoughts or behavior have been reported during treatment or immediately after discontinuation of amitriptyline (see section "Special precautions").
Epidemiological studies, mainly conducted in patients aged 50 years and older, have shown an increased risk of bone fractures in patients receiving selective serotonin reuptake inhibitors and tricyclic antidepressants. The mechanism of this phenomenon is unknown.
Reporting of suspected adverse reactions
It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This allows ongoing 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 the reach and sight of children.
Packaging.
25 tablets in a blister; 1 blister per carton.
10 tablets in a blister; 5 blisters per carton.
Prescription status. Prescription only.
Manufacturer.
Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".
Manufacturer's address and site of business activity.
41, Kulikivska Street, Kharkiv, Kharkiv region, 61002, Ukraine.