Saroten

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SAROTEN (SAROTEN®)

Composition:

Active substance: amitriptyline;

One tablet contains amitriptyline hydrochloride equivalent to 25 mg of amitriptyline;

Excipients: maize starch; lactose monohydrate; colloidal anhydrous silicon dioxide; microcrystalline cellulose; copovidone; sodium croscarmellose; magnesium stearate; macrogol 400; OPADRY OY-S-9470 red-brown.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets, red-brown in colour.

Pharmacotherapeutic group. Antidepressants. Non-selective inhibitors of monoamine reuptake.

ATC code N06A A09.

Pharmacological Properties.

Pharmacodynamics.

Amitriptyline is a tricyclic antidepressant and analgesic.

Its anticholinergic properties prevent the reuptake and, therefore, inactivation of norepinephrine and serotonin at nerve receptors, thereby potentiating the effects 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, blockade of sodium and NMDA channels—these are the 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 after 2–4 weeks of therapy, while the sedative effect does not diminish.

Pharmacokinetics.

Absorption.

Oral administration of the drug in tablet form results in reaching maximum serum concentration approximately 4 hours later (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 concentrations in breast milk to serum in women is 1:1. The estimated daily amount (amitriptyline + nortriptyline) received by the infant is approximately 2% of the maternal dose of amitriptyline, adjusted for infant body weight (in mg/kg).

Biotransformation. In vitro, amitriptyline metabolism occurs mainly 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 the reuptake of both neurotransmitters. Other metabolites (cis- and trans-10-hydroxyamitriptyline, as well as cis- and trans-10-hydroxynortriptyline) have profiles identical to that of nortriptyline but with significantly lower potency. Demethylnortriptyline and amitriptyline-N-oxide are present in plasma only in negligible amounts, with 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 predominantly in urine. Renal excretion of unchanged amitriptyline is minimal (approximately 2%).

Steady-state plasma concentrations of amitriptyline and nortriptyline are achieved in most patients within 1 week. At steady state, plasma levels over a 24-hour period are represented approximately equally by amitriptyline and nortriptyline during treatment with the usual tablet dosage regimen 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 intensive metabolism.

Impaired liver function.

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

Impaired kidney function.

Renal impairment does not affect the drug's kinetics.

Polymorphism.

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

Pharmacokinetic/pharmacodynamic relationship. 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 the active substance 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 (monoamine oxidase inhibitors) is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Simultaneous administration of amitriptyline and MAO inhibitors may lead to the development of serotonin syndrome (a combination of symptoms that may include anxiety, confusion, tremor, myoclonus, and hyperthermia).

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

Treatment with MAO inhibitors may be started 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 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 eye, central nervous system, gastrointestinal tract, and urinary bladder; their concomitant use should be avoided due to increased risk of paralytic ileus, hyperpyrexia, etc.

Medicinal products causing QT interval prolongation on electrocardiogram, including antiarrhythmics such as quinidine, antihistamines – astemizole and terfenadine, certain antipsychotics (e.g. pimozide and sertindole), cisapride, halofantrine, and sotalol, may increase the likelihood of ventricular arrhythmias when used together 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.

Antifungal agents, such as fluconazole (CYP2C9 inhibitor) and terbinafine (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

Serotonergic medicinal products, such as buprenorphine, increase the risk of serotonin syndrome, which is a potentially life-threatening condition (see section "Special precautions for use").

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

Pharmacokinetic interactions

Effect of other medicinal products on the pharmacokinetics of amitriptyline

Tricyclic antidepressants (TCAs), including amitriptyline, are primarily 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 the metabolism of amitriptyline.

CYP2D6 inhibitors: the CYP2D6 isoenzyme can be inhibited by many medicinal products, e.g. neuroleptics, serotonin reuptake inhibitors, β-adrenergic receptor blockers, and antiarrhythmic agents. Examples of strong CYP2D6 inhibitors include bupropion, fluoxetine, paroxetine, and quinidine. These drugs may cause significant reduction in drug metabolism and substantial increase in plasma concentrations of TCAs. Plasma concentrations of TCAs should be monitored when TCAs are co-administered with another drug known to be a strong CYP2D6 inhibitor. 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), 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 such 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 occurrence of seizures. Dose adjustments of these medicinal products may be necessary.

Cytochrome P450 inducers: rifampicin, phenytoin, barbiturates, carbamazepine, and St John's wort (Hypericum perforatum) may enhance metabolism and thereby reduce plasma concentrations of tricyclic antidepressants and diminish the antidepressant effect.

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

Plasma concentrations of amitriptyline may be increased by sodium valproate and valpromide. Therefore, clinical monitoring is recommended.

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 used in patients with pre-existing heart diseases.

QT interval prolongation

Cases of QT interval prolongation and arrhythmias have been reported in the postoperative period. Use with caution in patients with marked bradycardia, decompensated heart failure, or those concurrently receiving drugs that prolong the QT interval. Electrolyte disturbances (hypokalemia, hyperkalemia, hypomagnesemia) are known to increase the proarrhythmic risk.

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 mandatory to inform the anesthesiologist about amitriptyline treatment.

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

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

The drug should be prescribed with caution to patients with seizure disorders, urinary retention, prostatic hypertrophy, hyperthyroidism, paranoid symptoms, severe liver or cardiovascular diseases, pylorus stenosis, and paralytic ileus.

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

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 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 events or significant suicidal ideation prior to treatment initiation are known to be at higher risk of suicide or suicide attempts and should be under close supervision during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants involving adult patients with psychiatric disorders showed an increased risk of suicidal behavior with antidepressants 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 the drug, especially at the beginning of therapy and after dose adjustments. Patients (and 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 as soon as a manic phase begins.

Serotonin syndrome

Concomitant use of tricyclic antidepressants, including amitriptyline, and other serotonergic agents such as MAO inhibitors (see section "Contraindications"), tramadol, or buprenorphine, may lead to the development of serotonin syndrome, a potentially life-threatening condition (see section "Interaction with other medicinal products and other forms of interaction").

If concomitant treatment with other serotonergic agents, except MAO inhibitors (see section "Contraindications"), is clinically justified, careful monitoring of the patient is recommended, particularly at the beginning of treatment and during dose escalation.

Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, consideration should be given to reducing the dose or discontinuing therapy depending on the severity of symptoms.

Severe skin reactions

Severe skin adverse reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with amitriptyline use, which may be life-threatening or result in fatal outcomes. Most of these reactions occurred within 2–6 weeks after initiation of amitriptyline therapy.

Patients should be informed about the signs and symptoms of these reactions, and skin reactions should be carefully monitored during drug administration.

If symptoms of severe skin reactions occur, the drug Saroten must be discontinued immediately. Reinitiation of amitriptyline therapy in such a patient is absolutely contraindicated — alternative treatment options should be considered (if necessary).

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

Cases of hyperpyrexia have been reported with the use of tricyclic antidepressants when co-administered with anticholinergic or neuroleptic drugs, especially in hot weather conditions.

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.

Nocturnal enuresis

An ECG should be performed before starting 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.

Children

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

Excipients: 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.

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 is possible only after careful assessment of the risk-benefit ratio.

With prolonged use and administration during the last weeks of pregnancy, neonatal withdrawal symptoms may occur, which may include irritability, hypertension, tremor, irregular respiration, feeding difficulties, excessive 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 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 woman.

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 ability may be expected, which poses a danger and contraindicates driving vehicles or operating machinery. These adverse effects may be enhanced 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 sensitivity to the drug.

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 remission 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 individually titrated for each patient to achieve adequate analgesia and tolerability of adverse reactions. Generally, the lowest effective dose should 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 higher than 75 mg is not recommended.

Elderly patients (over 65 years) 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 prophylactic treatment of migraine 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

Children aged 11 years and older: 25–50 mg per day.

The dose should be increased gradually.

The medication should be taken 1–1.5 hours before bedtime.

An ECG should be performed before initiating amitriptyline therapy to exclude the risk of QT interval prolongation syndrome.

Duration of Treatment

The maximum treatment course should not exceed 3 months.

If repeated courses of amitriptyline treatment are required, medical evaluation should be performed every 3 months.

When discontinuing treatment, the dose of amitriptyline should be tapered gradually.

Renal Impairment

The drug may be prescribed at usual doses to patients with impaired renal function.

Hepatic Impairment

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

Cytochrome P450 CYP2D6 Inhibitors

Depending on individual patient response, dose reduction 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 of the recommended initial dose may be considered.

Method of Administration

Saroten is taken orally.

Tablets should be swallowed 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 may be considered 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 medication should be prescribed only by a physician experienced in managing refractory enuresis.

Overdose.

Symptoms

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

Cardiac symptoms: arrhythmias (ventricular tachyarrhythmias, flutter-fibrillation, ventricular fibrillation). ECG typically shows prolonged PR interval, widened QRS complex, QT prolongation, T-wave flattening or inversion, ST-segment depression, and varying degrees of heart block up to cardiac arrest. QRS widening usually 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 reports and literature describe cases of unmasking Brugada syndrome and Brugada-type ECG patterns following amitriptyline overdose.

Ingestion of 750 mg or more by adults may lead to severe toxicity. Toxic effects are potentiated when taken concomitantly with alcohol or other psychotropic substances. There is considerable individual variability in response to overdose. Amitriptyline overdose in children may have serious consequences. Children are particularly susceptible to 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

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

A comprehensive approach to assess and rapidly restore respiratory and cardiovascular functions should be implemented and managed as needed. Airway patency should be ensured, if necessary, by intubation. 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 the past 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 overdoses are often intentional, patients during remission periods may attempt suicide by other means. Cases of death due to intentional or accidental overdose have been reported 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 (e.g. headache, tremor, attention disturbances, constipation, and decreased libido) may also be symptoms of depression and usually diminish as the depressive state improves.

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

The list of adverse reactions below is classified by system organ classes according to the MedDRA classification: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000); not known (cannot be estimated from the available data).

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

** Such cases have been reported with the use of serotonergic medicinal products, such as tricyclic antidepressants (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Epidemiological studies, mainly conducted in patients aged 50 years and older, have shown an increased risk of bone fractures in patients treated with SSRIs and TCAs. The mechanism underlying this risk 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. 5 years.

Storage conditions. Store in the original packaging, out of the reach of children. No special storage conditions are required for this medicinal product.

Packaging. 100 tablets in a plastic container in a cardboard box.

Prescription status. Prescription only.

Manufacturer. H. Lundbeck A/S.

Address of the manufacturer's location and place of business. Ottiliavej 9, 2500 Valby, Denmark.