Amitriptyline hydrochloride-zn

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMITRIPTYLINE HYDROCHLORIDE-ZN (AMITRIPTYLINE HYDROCHLORIDE-ZN)

Composition:

Active substance: amitriptiline;

1 ml of solution contains amitriptyline hydrochloride equivalent to 10 mg of amitriptiline;

Excipients: glucose, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: colorless clear liquid.

Pharmatherapeutic group. Antidepressants. Non-selective inhibitors of neuronal reuptake of monoamines. ATC code N06A A09.

Pharmacological properties.

Pharmacodynamics. Amitriptyline is a tricyclic antidepressant and a non-selective inhibitor of neuronal reuptake of monoamines. It exerts a pronounced thymoleptic effect and belongs to the group of tertiary amine antidepressants. The thymoleptic effect is combined with a pronounced sedative effect. It also exhibits anti-serotonin, antihistaminic, and anticholinergic activities.

Pharmacokinetics. More than 90% is bound to plasma proteins. It is metabolized in the liver, forming pharmacologically active metabolites—nortriptyline and 10-hydroxyamitriptyline (dinortriptyline). The elimination half-life is approximately 17–30 hours, sometimes longer. It is excreted predominantly in the form of metabolites in the urine.

Clinical characteristics.

Indications. Endogenous depressions, including depressive episode, recurrent depressive disorder; bipolar affective disorder, current depressive episode.

Contraindications. Hypersensitivity to amitriptyline or any of the excipients of the drug. Glaucoma, prostatic hypertrophy, urinary bladder atony.

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

Concomitant administration of amitriptyline and MAOIs is contraindicated due to the risk of serotonin syndrome (a combination of symptoms that may include anxious 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 stopping reversible inhibitors such as moclobemide and selegiline.

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").

Unwanted combinations

Sympathomimetic agents: amitriptyline may potentiate cardiovascular effects of adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, and phenylpropanolamine.

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 drugs on the eyes, CNS, gastrointestinal tract, and urinary bladder; simultaneous use should be avoided due to increased risk of paralytic ileus and hyperpyrexia.

Medicinal products causing QT interval prolongation on electrocardiogram, including antiarrhythmics (quinidine), antihistamines (astemizole and terfenadine), some antipsychotics (particularly pimozide and sertindole), cisapride, halofantrine, and sotalol, may increase the likelihood of ventricular arrhythmias when taken concomitantly with tricyclic antidepressants.

Antifungal agents, such as fluconazole and terbinafine, lead to increased serum concentrations of tricyclic antidepressants and enhanced associated toxicity. Cases of loss of consciousness and development of chaotic polymorphic ventricular tachycardia have been reported.

CNS depressants: amitriptyline may enhance the effects of alcohol, barbiturates, and other CNS depressants.

Pharmacokinetic interactions

Effects of other medicinal products on the pharmacokinetics of tricyclic antidepressants

Tricyclic antidepressants, including amitriptyline, are metabolized by the CYP2D6 isoenzyme of the hepatic cytochrome P450 system. CYP2D6 exhibits polymorphism in the population, and its activity may be inhibited by many psychotropic and other medicinal products, such as neuroleptics, serotonin reuptake inhibitors (except citalopram, which is a very weak inhibitor of the isoenzyme), β-adrenergic blockers, and antiarrhythmic agents.

Examples of strong CYP2D6 inhibitors include bupropion, fluoxetine, paroxetine, and quinidine. These drugs may cause significant reduction in metabolism and marked increase in plasma concentrations of tricyclic antidepressants. Plasma concentrations of tricyclic antidepressants should be monitored when co-administered with another medicinal product 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 inhibitor of CYP2D6.

The isoenzymes CYP2C19 and CYP3A are also involved in the metabolism of amitriptyline.

Barbiturates, as well as other enzyme inducers such as rifampicin and carbamazepine, may enhance metabolism and thereby reduce plasma levels of tricyclic antidepressants, leading to diminished antidepressant effect.

Cimetidine and methylphenidate, as well as calcium channel blockers, increase plasma levels of tricyclic compounds and associated toxicity.

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

Antifungal agents such as fluconazole and terbinafine have increased serum levels of amitriptyline and nortriptyline. In the presence of ethanol, free plasma concentrations of amitriptyline and concentrations of nortriptyline were increased.

Special precautions for use.

Amitriptyline is contraindicated for concomitant use with monoamine oxidase inhibitors (MAOIs) (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. These conditions may also occur with standard doses in patients who already have pre-existing heart disease.

Amitriptyline should be administered with caution in patients with seizure disorders, urinary retention, hyperthyroidism, paranoid symptoms, as well as in those with hepatic or cardiovascular disorders.

The risk of depression associated with an increased risk of suicide may persist until a stable remission is achieved and may occur spontaneously during the course of therapy. Patients receiving antidepressant therapy should be closely monitored, especially at the beginning of treatment, for clinical worsening and/or emergence of suicidal thoughts and behavior.

Patients with suicidal tendencies should not have access to large quantities of medication.

Depression is associated with an increased risk of suicide. This risk may persist until a stable remission is achieved and may arise spontaneously during treatment. 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 significant suicidal ideation prior to treatment initiation are known to be at higher risk of suicide or suicide attempts and should be closely 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 antidepressants compared to placebo in patients under 25 years of age. Close supervision of patients, particularly those at high risk, should accompany pharmacotherapy, especially at the beginning of treatment 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.

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

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

In patients with manic-depressive disorders, the condition may shift into a manic phase; amitriptyline therapy should be discontinued as soon as a manic phase begins.

When amitriptyline is used to treat the depressive component of schizophrenia, psychotic symptoms may be exacerbated. Amitriptyline should be prescribed in combination with neuroleptics.

In patients with the rare condition of shallow anterior chamber and narrow chamber angle of the eye, acute attacks of glaucoma may be precipitated due to pupillary dilation (see section "Contraindications").

The use of anesthetics during therapy with tricyclic/tetracyclic antidepressants may increase the risk of arrhythmias and arterial hypotension. If possible, amitriptyline should be discontinued several days before surgical intervention. In cases of unavoidable emergency surgery, the anesthesiologist must be informed about amitriptyline treatment.

Like other psychotropic agents, amitriptyline may alter sensitivity to insulin and glucose, necessitating adjustment of antidiabetic therapy in patients with diabetes mellitus; additionally, depressive illness itself may manifest with disturbances in glucose balance.

Cases of hyperpyrexia have been reported during treatment with tricyclic antidepressants when used 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.

Alcohol consumption should be avoided during treatment.

Severe skin reactions

Severe skin adverse reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with amitriptyline use, which may be life-threatening or result in fatal outcomes. These reactions typically occur within 2–6 weeks of starting treatment.

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

If signs or symptoms suggestive of these reactions occur, the drug should be discontinued immediately. Reinitiation of amitriptyline therapy in such patients is strictly contraindicated. Alternative treatment options (if needed) should be considered.

Use during pregnancy or breastfeeding. The drug is contraindicated during pregnancy.

Breastfeeding should be discontinued during treatment.

Ability to affect reaction speed when driving or operating machinery.

The drug is intended for use in a hospital setting.

Patients receiving Amitriptyline hydrochloride-ZN may experience impaired general attention and concentration, which contraindicates driving a vehicle or operating other machinery.

Dosage and Administration

In severe depression, treatment may begin with parenteral administration of the drug – intramuscularly or by slow intravenous injection – at a dose of 25–40 mg three to four times daily in adults. The treatment course consists of 3–12 administrations. After this, it is advisable to switch to oral amitriptyline hydrochloride in tablet form.

Elderly patients should be prescribed lower doses of the drug.

Moderate renal impairment: use with caution.

Moderate hepatic impairment: cautious dose titration is recommended, and, if possible, monitoring of drug plasma levels should be performed.

Children. Amitriptyline hydrochloride is contraindicated for the treatment of depression in children (under 18 years of age) due to insufficient data on safety and efficacy. Amitriptyline treatment is associated with a risk of cardiovascular adverse reactions in all age groups.

Overdose.

Symptoms: clinical manifestations may develop slowly and insidiously, but sometimes occur abruptly and suddenly. Early symptoms include drowsiness or agitation and hallucinations. Anticholinergic symptoms include mydriasis, tachycardia, urinary retention, dryness of mucous membranes, and decreased gastrointestinal motility. Seizures, fever, and sudden onset of central nervous system (CNS) depression may occur. Decreased level of 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 various degrees of heart block, up to cardiac arrest. Widening of the QRS complex usually correlates clearly with the severity of toxicity following acute overdose. Cardiac failure, arterial hypotension, and cardiogenic shock may develop. Metabolic acidosis and hypokalemia worsen. Post-marketing studies and literature report cases of unmasking Brugada syndrome and Brugada-type ECG patterns following amitriptyline overdose.

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

After regaining consciousness, confusion, anxious agitation, hallucinations, and ataxia may recur.

Treatment: hospitalization (in an intensive care unit). Treatment is symptomatic and supportive. Gastric lavage via tube, even at a late stage after oral ingestion, and administration of activated charcoal are indicated. Careful monitoring is mandatory, even in apparently mild cases. Assessment of consciousness, pulse characteristics, arterial blood pressure, and respiratory function should be performed. Electrolyte and blood gas levels should be measured at regular intervals. Airway patency must be ensured, including by intubation if necessary. In general, treatment involving mechanical ventilation is recommended to prevent potential respiratory arrest. Continuous ECG monitoring should be maintained for 3–5 days. In cases of QRS widening, cardiac failure, or ventricular arrhythmias, alkalinization of blood pH (administration of sodium bicarbonate solution or induction of hyperventilation) with rapid infusion of hypertonic sodium chloride solution (100–200 mmol Na+) may be effective.

For ventricular arrhythmias, conventional antiarrhythmic agents such as lidocaine (50–100 mg or 1–1.5 mg/kg intravenously), followed by continuous infusion at 1–3 mg/min, may be used.

Cardioversion and defibrillation should be applied if necessary. Circulatory failure should be managed with plasma expanders; in severe cases, by infusion of dobutamine (initially at 2–3 mcg/kg/min), with dose escalation based on response. Agitation and seizures can be controlled with diazepam.

Sensitivity to overdose is highly individual.

In adults, doses exceeding 500 mg may cause moderate to severe intoxication; doses slightly below 1000 mg have been reported as lethal.

Adverse reactions.

The adverse reactions listed below are classified using MedDRA (Medical Dictionary for Regulatory Activities) system organ class terms.

The frequency of adverse reactions is defined according to the following categories: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (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 "Special 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 TCAs. The mechanism of this risk is unknown.

Shelf life. 5 years.

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

Keep out of reach of children.

Incompatibility. Do not mix with other medicinal products.

Packaging. 2 ml in a vial. 5 vials in a blister pack. 2 blisters per carton.

2 ml in a vial. 10 vials in a blister pack. 1 blister per carton.

2 ml in a vial. 10 vials in a carton.

Prescription status. Prescription only.

Manufacturer. Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu".

CORPORATION "ZDOROVYA" LTD.

Address of manufacturer and location of its business operations.

Ukraine, 61002, Kharkiv region, city of Kharkiv, Kulikovska Street, building 41.

(Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu")

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, building 22.

(CORPORATION "ZDOROVYA" LTD.)