Amitriptyline-«Grindeks»

Therapeutic Indications
Drug is used in the treatment of depressions, especially in the treatment of endogenous depressions.

Posology and Methods of Administration
AMITRIPTYLINE–GRINDEKSfilm-coated tablets are taken orally. Dosage depends upon the symptomsof illness and age of the patients, gradually reaching the daily dose.

Foroutpatients daily dose usually is 75 mg, taken in divided doses (may betaken once in the evening). If necessary, dose may be increased tomaximal, i.e. 150 mg a day. It is advised to take most of the dose inthe late afternoon or evening. Sedative effect is achieved faster thanantidepressive. Optimal therapeutic effect is achieved within 30 days.

Alternativetreatment method. Single dose of 50 to 100 mg before bedtime. This dosemay be gradually increased by 25 or 50 mg, till maximal daily dose of150 mg.

In-patients – administration may be started withdose 100 mg a day; with gradually increase to 200 mg. In rare casesnecessity may arise to increase the dose to 300 mg a day.

Children.The efficacy of amitriptyline has not been established, therefore, drugmay be used only in the treatment of depressions for patients above 12years of age.

Adolescent and elderly patients – amitriptyline daily dose is usually 10 mg
 3 times daily an 20 mg before bedtime.

Maintenance treatment – the usual maintenance treatment dose is 50 to
100mg per day. In some cases daily dose may be lower - 40 mg. The dailydose is taken usually at bedtime. When optimal therapeutic effect hasbeen reached, dosage is decreased to lowest dose that will sustain therelief of symptoms. Duration of maintenance treatment is 3 months orlonger.

Contraindications  
Drug iscontraindicated in case of increased sensitivity towards amitriptylineor any of the excipients; in case of acute recovery period followingmyocardial infarction, arrhythmia (especially heart blockade); inchildren younger than 12 years of age, and concomitantly with monoamineoxidase (MAO) inhibitors.
In cases of substitution of MAO inhibitors for amitriptyline, at least
 2weeks before starting the treatment with amitriptyline the use of MAOinhibitors should be discontinued, the same is true for substitution ofamitriptyline for MAO inhibitors. Optimal dose of the drug is reachedgradually.
Drug should not be used in patients with severe liver disease or acute maniacal depression in stage of delusion.

Special Warnings and Special Precautions for Use
Duringfirst 2-4 weeks of treatment close observation of patients should beexerted, especially patients with tendency to suicide.
High doses used in debilitated patients may cause drug overdose.
Amitriptylineshould be used with caution, if there is a history of convulsions, aswell as in cases of urinary retention, because for preparation displaysatropine like preparation characteristics. In patients suffering fromnarrow-angle glaucoma or increased intraocular pressure may causeglaucoma attack. Amitripyline close observation of patients havingheart and vascular disease should be exerted, for drug in high dosesmay cause arrhythmia, sinus tachycardia and retard conduction ofimpulse in heart. Drugs of this group may cause angina attack ormiocardial infarction. Patients with pheochromocytoma or hyperthyreosisas well as patients, who are taking thyroid hormones concomitantly,should be observed closely. In patients with habit of frequent alcoholintake, preparation may cause suicidal attempts or tendency to take anoverdose of the drug.
In schizophrenic patients increased symptoms of psychosis may develop, paranoid symptomatology may be increased as well.
Depressive patients, especially patients with history of manic-depressive illness, may experience shift to mania or hypomania.
Takingamitriptyline concomitantly with cholinoblockers or sympatomimetics,also epinephrine in combination with local anaesthetics, patientsshould be closely observed by physician, and doses of the drug must beadjusted with caution. 
If possible, drug should be discontinued before surgery.
The drug may increase or decrease blood sugar level.
Especiallycaution should be exerted prescribing amitriptyline to elderly andpatients with liver function impairment, in the case of porphyry andnocturnal enuresis.
Amitriptyline–«Grindeks» tablets contain lactose.This medicine should not be used in patients with rare hereditarygalactose intolerance, Lapp lactase deficiency or glucose-galactosemalabsorption.

Interaction with Other Medicinal Products and Other Forms of Interaction 
Concomitantuse of amitriptyline and MAO inhibitors may cause severe adverseeffects (hyperpyretic crisis, cramps), even death. 
There arereports showing hyperpyretic episodes while combining amitriptylinewith cholinoblockers or neuroleptic drugs. Tricyclic antidepressants incombination with cholinoblockers may cause also paralytic ileus
Takingthe drug concomitantly with sympathomimetics (for example, epinephrine,ephedrine, izoprenaline, norepinephrine, phenylephrine, andphenylpropanolamine, etc.) and in combination with local anaesthetics,causes heart arrhythmia and hypotension.
Methylphenidate may retard the metabolism of tricyclic antidepressants.
Concomitantuse of amitriptyline and amiodaron, pimozide or terphenadine increasesthe risk of ventricular arrhythmia (concomitant use should be avoided).
Amitriptylinemay inhibit the action of guanethidine. Amitriptyline decreases thehypotensive effect of clonidine, moreover, the risk of hypertension isincreased after the withdrawal of clonidine.
Preparation potentates the effect of alcohol, barbiturates and other Central Nervous System (CNS) depressants.
Concomitant use of antiepileptic drugs lowers cramp barrier.
Tramadol in combination with tricyclic antidepressants increases the risk of CNS intoxication.
Concomitant use of amitriptyline and disulfiram bears the risk of delirium.
Cimetidine retards the metabolism of tricyclic antidepressants in liver and increases their adverse effects.
The use of rifampicine, likely, decreases amitriptyline plasma concentration and lowers efficacy of antidepressants.
Ritonavir, likely, increases plasma concentration of antidepressant.
Concomitant use of amitriptyline and ethchlorvinol in high doses may cause delirium.
Administration of the drug at the same time with electroshock is dangerous.

Pregnancy and Lactation  
Amitriptylinecrosses the placental barrier. There have been isolated reports aboutdrug undesirable effect on CNS, limbic system, or about malformationsin neonates whose mothers took amitriptyline during pregnancy.Physician only in a case of real necessity should undertakeadministration of the drug during pregnancy.

Duringbreast-feeding, administration of the drug should be discontinued.Amitriptyline is excreted into breast milk. There are reports showingthat in mothers taking amitriptyline at the dose 100 mg daily andbreast feeding the neonates the level of amitriptyline in blood serumwas 83-141 ng/ml, but in milk – 135-151 ng/ml. No drug was found inblood serum of the neonates.

Effects on ability to drive and use machines  
Amitriptylinemay influence upon the ability to drive vehicles and operate mechanisms(reversibly affect the concentration abilities, motoric coordinationand speed of reaction).
While on medication one should avoid activities connected with risk and for which quick reaction and skills is needed.

Undesirable Effects
Undesirable effects are shown with emphasis on most severe signs.

Cardiovasculareffects: miocardial infarction, stroke, uncharacteristic changes in ECGand AV conduction, cardiac block, arrhythmia, hypotension, especiallyorthostatic hypotension, syncope, tachycardia, palpitation.

CNSand neuromuscular effects: coma, seizures, hallucinations, manias,confusion, disorientation, impairment of movements, ataxia, tremor,peripheral neuropathy, rigor, paresthesia of limbs, extrapyramidalsymptoms, among them involuntary movements, dyskinesia, dysarthria,impairment of concentration abilities, excitement, anxiety,sleeplessness, troubled sleep, nightmares, somnolence, vertigo,tiredness, muscle weakness, headache, syndrome of inappropriateproduction of ADH, tinnitus, alterations of EEG patterns.

Anticholinergic effects:paralytic ileus, hyperpyrexia, urinary retention, dilatation of urinaryducts, obstipation, disturbances of vision, impairment ofaccommodation, increase of intraocular pressure, mydriasis, dry mouth.

Allergic reactions: skin rash, urticaria, photosensitization, and oedema of face and tongue.

Hematologic: bone marrow depression, including agranulocytosis, leukopenia, thrombocytopenia, purpura, eosinophilia.

Gastrointestinal:rarely hepatitis (including altered liver function and jaundice),heartburn, nausea, epigastric distress, vomiting, anorexia, stomatitis,peculiar taste, diarrhea, constipation, swelling of parotid gland,black tongue.

Endocrine: testicular swelling andgynecomastia in the male, breast enlargement and galactorrhea in thefemale, increased or decreased libido, impotence, elevation or loweringof blood sugar levels.

Other: alopecia, edema, weight gain or loss, increased urinary frequency, increased perspiration.

Withdrawal symptoms:Patients, who had prolonged treatment and high doses of amitriptylineshould avoid abrupt cessation of treatment, because there may bemalaise, headache, discomfort feeling. Doses of the drug should bereduced gradually within 2 weeks and even then there exists thepossibility of temporary excitement, nightmares and dream disturbances.In rare instances 2 to 7 days after the cessation of treatment, maniaor hypomania has been reported.

Causal relationship unknown: lupus-like syndrome (migratory arthritis, positive ANA and rheumatoid factor); hepatic failure, ageusia.

Pharmacodynamic properties
Pharmacotherapeutic group: Antidepressant
ATC-CODE: N06A A09
Amitriptylineis psychotropic drug from the group of tricyclic antidepressants withsedative action. Medicine does not influence the activity of enzymemonoamine oxidase (MAO) and does not directly stimulate the centralnervous systems (CNS). It inhibits the uptake of noradrenalin andserotonin in adrenergic and serotoninergic synapses of the CNS.
Drug has pronounced cholinolytic properties.
Amitriptylineis used mainly for the treatment of endogenous depression. Thepronounced efficiacy of the amitriptyline has been shown in the casesof agitated depression. It improves mood and abandons anxiety indepressive patients, diminishes the signs of depression, does notincrease occurrence of nightmares, hallucinations and other symptoms,characteristic for antidepressants having stimulating action.
Mechanism of action in a case of depression is not understood.

Pharmacokinetic properties  
Amitriptylineis easily absorbed in gastrointestinal tract, after oral administrationit reaches maximum concentration in blood within several hours.Amitriptyline, decreasing the motility of gastrointestinal tract, slowsdown the absorption of the drug itself, especially in a case ofoverdose.
Characteristic for amitriptyline is presystemicmetabolism, in liver it metabolizes to primary active metabolite –nortriptyline. Other biotransformation ways of amitriptyline arehydroxylation and N-oxidation. Nortriptyline undergoes similartransformations. Amitriptyline and nortriptyline are readilydistributed in the body and in higher degree bound to the plasma andtissue proteins. Amitriptyline is excreted in the urine mainly in theform of its metabolites either free or in conjugated form. Eliminationhalf-life is ranging from 9 to 25 hours, which may be considerablyextended in overdosage.
Concentration of amitriptyline andnortriptyline in plasma in different individuals is variable;correlation between the dose and therapeutic action does not exist.

Preclinical safety data  
Dataobtained at the result of preclinical tests concerning toxicity,genotoxicity and possible carcinogenicity of dose and toxic influenceupon reproductive function (reproductive ability) do not suggestespecial risk for humans.
Toxic effects have been observed inanimals in cases when doses and duration of action exceeded maximumallowable value for humans.

List of excipients  
10 mg film-coated tablets. Lactose monohydrate, maize starch, povidone, silicon dioxide, magnesium stearate.
Film coat: colorant – Opadry II Blue 85 F 20753, Carnauba wax.

25 mg film-coated tablets. Lactose monohydrate, maize starch, povidone, silicon dioxide,  magnesium stearate.
Film coat: colorant – Opadry II Yellow 85 F 22450, Carnauba wax.
 
Incompatibilities
Not known.

Shelf-life
3 years.

Special precautions for storage
Do not store above 25o C. Protect from light and moisture.
Store in the original package.
Do not use after the expiry date stated on the label.

Nature and contents of container
10 film-coated tablets per blister, consisting of PVC/Al folia;
5 blisters (50 film-coated tablets) in a cardboard box.