Amitriptyline hydrochloride-oz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMITRIPTYLINE HYDROCHLORIDE–OZ

Composition:

Active substance: amitriptyline;

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

Excipients: glucose monohydrate; water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: colorless, clear liquid.

Pharmacotherapeutic 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 to any of the excipients of the medicinal product. Glaucoma, benign prostatic hyperplasia, urinary bladder atony.

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

Concomitant use of amitriptyline and monoamine oxidase inhibitors (MAOIs) may lead to the development of serotonin syndrome (a combination of symptoms that may include agitation, confusion, tremor, myoclonus, and hyperthermia).

Treatment with amitriptyline may be initiated 14 days after discontinuation of irreversible non-selective MAOIs, and at least 1 day after discontinuation of reversible inhibitors such as moclobemide and selegiline.

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

Interaction with other medicinal products and other forms of interactions.

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 such medicinal products on the eyes, central nervous system (CNS), gastrointestinal tract, and urinary bladder; concomitant use should be avoided due to increased risk of paralytic ileus and hyperpyrexia.

MEDICINAL PRODUCTS CAUSING PROLONGATION OF THE QT INTERVAL ON ELECTROCARDIOGRAM, including antiarrhythmic agents (quinidine), antihistamines (astemizole and terfenadine), certain antipsychotics (particularly pimozide and sertindole), cisapride, halofantrine, and sotalol, may increase the risk of ventricular arrhythmias when used concomitantly with tricyclic antidepressants.

Antifungal agents, such as fluconazole and terbinafine, may increase serum concentrations of tricyclic antidepressants and the severity of 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

Effect of other medicinal products on the pharmacokinetics of tricyclic antidepressants

Tricyclic antidepressants, including amitriptyline, are metabolized by the CYP2D6 isoenzyme of hepatic cytochrome P450. CYP2D6 exhibits polymorphism in the population and its activity 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), β-adrenergic receptor blockers, and antiarrhythmic agents.

Examples of strong CYP2D6 inhibitors include bupropion, fluoxetine, paroxetine, and quinidine. These agents may cause a significant reduction in metabolism and marked increase in plasma concentrations of tricyclic antidepressants. Plasma levels 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 required. Caution is recommended when using amitriptyline concomitantly with duloxetine, a moderate CYP2D6 inhibitor.

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 and diminish their antidepressant effect.

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

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

Antifungal agents such as fluconazole and terbinafine have been shown to increase 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 MAO inhibitors (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Concurrent administration of amitriptyline and MAO inhibitors may lead to the development of serotonin syndrome (a combination of symptoms that may include agitation, confusion, tremor, myoclonus, and hyperthermia).

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

Amitriptyline should be used with caution in patients with seizure disorders, urinary retention, hyperthyroidism, presence of paranoid symptoms, as well as in patients with liver or cardiovascular diseases.

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.

Depression is associated with an increased risk of suicide. This risk may persist until a stable 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 under close supervision 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 with significant suicidal ideation prior to initiation of therapy are known to be at higher risk for suicide or suicide attempts 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 antidepressants compared to placebo in patients under 25 years of age. Patients, especially those at high risk of suicidal behavior, require careful monitoring, particularly 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.

Patients with suicidal tendencies should have limited access to medicinal products.

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

Elderly patients are particularly susceptible to postural hypotension during treatment with amitriptyline.

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 for 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 provoked due to pupillary dilation (see section "Contraindications").

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

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 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 during 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 skin reactions should be closely monitored during treatment.

If signs or symptoms suggestive of these reactions occur, the drug should be discontinued immediately. Re-administration of amitriptyline to such a patient is absolutely 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 this drug may experience impaired attention and concentration, which contraindicates driving a vehicle or operating 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 3–4 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 for continued therapy.

Elderly patients should be prescribed lower doses of the drug.

Mild renal impairment: use with caution.

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

Children. Amitriptyline hydrochloride is contraindicated for the treatment of depression in children due to insufficient data on safety and efficacy. Amitriptyline therapy has been associated with risk of cardiovascular adverse reactions in all age groups.

Overdose. Symptoms: clinical manifestations may develop insidiously and be masked, 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, 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). On ECG, typical findings include prolonged PR interval, widened QRS complex, prolonged QT interval, widening or inversion of the T wave, 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 progressively. Post-marketing reports and literature describe cases of unmasked Brugada syndrome and Brugada-type ECG patterns following amitriptyline overdose.

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.

After awakening, confusion, anxious agitation, hallucinations, and ataxia may recur.

Treatment: hospitalization (in an intensive care unit) is required. Management is symptomatic and supportive. Gastric lavage and administration of activated charcoal are indicated, even when performed late after oral ingestion. Careful monitoring is mandatory, even in apparently mild cases. Assessment of consciousness level, pulse characteristics, arterial blood pressure, and respiratory function should be performed. Electrolyte levels and blood gas parameters should be determined at regular intervals. Airway patency must be ensured, with intubation if necessary. In general, 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, and ventricular arrhythmias, alkalinization of blood pH (administration of bicarbonate solution or induction of hyperventilation) combined 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 infusion at 1–3 mg/min) may be used.

Cardioversion and defibrillation should be performed if necessary. Circulatory failure should be managed with plasma expanders; in severe cases, dopamine infusion (initially 2–3 mcg/kg/min) should be administered, with dose titration according to response. Agitation and seizures can be controlled with diazepam.

Sensitivity to overdose is largely individual.

In adults, doses exceeding 500 mg may cause moderate to severe intoxication, while doses slightly below 1000 mg have been reported to be fatal.

Adverse reactions.

Blood and lymphatic system disorders: bone marrow depression, agranulocytosis, leukopenia, eosinophilia, thrombocytopenia.

Metabolic and nutritional disorders: decreased appetite.

Psychiatric disorders: confusion, decreased libido, hypomania, mania, anxiety, insomnia, nightmares, delirium (in elderly patients), hallucinations (in patients with schizophrenia), suicidal thoughts or behavior*.

Nervous system disorders: somnolence, tremor, dizziness, headache, attention disturbances, dysgeusia, paresthesia, ataxia, seizures.

Eye disorders: accommodation disorder, mydriasis, increased intraocular pressure, xerophthalmia.

Ear and labyrinth disorders: tinnitus.

Cardiac disorders: palpitations, tachycardia, orthostatic hypotension, atrioventricular blocks, bundle branch blocks, electrocardiographic abnormalities (prolongation of QT and QRS intervals), arterial hypertension, arrhythmia.

Gastrointestinal disorders: dry mouth, constipation, nausea, diarrhea, vomiting, tongue swelling, salivary gland enlargement, paralytic ileus.

Hepatobiliary disorders: jaundice, impaired liver function tests, increased blood alkaline phosphatase and transaminase activity.

Skin and subcutaneous tissue disorders: hyperhidrosis, rash, urticaria, facial swelling, alopecia, photosensitivity reactions; severe skin adverse reactions, including drug-induced eosinophilia with systemic symptoms (DRESS syndrome) (see section "Special precautions").

Renal and urinary disorders: urinary retention.

Reproductive system and breast disorders: erectile dysfunction, gynecomastia.

General disorders and administration site conditions: fatigue, pyrexia.

Other: weight gain or weight loss, injection site reactions.

*— 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 SSRIs and TCAs. The mechanism underlying this risk is unknown.

Shelf life. 5 years.

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

Keep out of reach of children.

Incompatibility. Do not mix with other medicinal products.

Packaging. 2 ml in ampoules, 10 in a pack; 10, 5×2 in blisters in a pack.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Research Plant "GNCLS".

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Manufacturer's address and place of business.

Ukraine, 61057, Kharkiv region, city of Kharkiv, Vorobiova Street, 8.

(Limited Liability Company "Research Plant "GNCLS")

Ukraine, 61002, Kharkiv region, city of Kharkiv, Kulikivska Street, 41.

(Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu")

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

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA")