Mutabon Antidepressant - Package Leaflet

Active principles: Perfenazine, Amitriptyline hydrochloride

Mutabon Antidepressant 2 mg + 25 mg film-coated tablets

Why is Mutabon Antidepressant used? What is it for?

Mutabon Antidepressant contains two active ingredients: perphenazine and amitriptyline hydrochloride.

Perphenazine belongs to a group of medicines called phenothiazines which act on the central nervous system by relieving anxiety states (anxiolytic properties) and carrying out therapeutic activity against psychotic symptoms (delusions and hallucinations).

Amitriptyline hydrochloride belongs to a group of medicines called 'tricyclic antidepressants' used to treat depression.

Mutabon Antidepressant is therefore an antidepressant in combination with a psycholeptic, used for the treatment of some mental disorders, which may have genetic (endogenous) causes, or which may be triggered by an unpleasant life event (reactive type disorders), characterized by coexistence of anxiety, tension and agitation, together with a state of depression.

Mutabon Antidepressant is useful for treating the following ailments:

• emotional disorders characterized by depression and anxiety that are caused or associated with other diseases
• psychosomatic disorders, characterized by physical symptoms induced by mental disorders;
• depressive symptoms in which a state of tension coexists, even if this is not evident or can be masked;
• severe insomnia associated with anxiety and depression.

Contraindications When Mutabon Antidepressant should not be used

Do not take Mutabon Antidepressant if:

• you are allergic to the active substances (perphenazine and amitriptyline hydrochloride) or to other similar medicines, or to any of the other ingredients of this medicine (listed in section 6);
• you are taking or taking in the last two weeks medicines for the treatment of depression known as monoamine oxidase inhibitors (iMAOs) (see section "Other medicines and Mutabon Antidepressant");
• has an increase in pressure inside the eye;
• suffer from eye disease due to increased pressure in the eye (glaucoma);
• you have diseases of the urogenital system such as enlargement of the prostate (prostatic hypertrophy) or difficulty in emptying the bladder (urinary retention), suspected or known;
• have muscle disease characterized by loss of tone and strength (myasthenia gravis);
• have a blood disorder characterized by changes in the composition of the blood (blood dyscrasia);
• you have changes in the function of the bone marrow which cannot produce enough cells that are found in the blood (bone marrow depression);
• you suffer from an alteration in the production of blood cells (hematopoiesis disorders); The administration of medicines which can cause the reduction of white blood cells (leukopenizing drugs) should therefore be avoided;
• have liver disease;
• you are taking other medicines that reduce the activity of the central nervous system (such as barbiturates, ethyl alcohol, narcotics, analgesics, antihistamines; see section "Other medicines and Mutabon Antidepressant");
• is in a state of decreased degree of consciousness (severe dulling) or in case of coma;
• suffer from severe depression;
• you have suffered suspected or confirmed brain damage (subcortical brain damage) as you may experience an increase in your body temperature up to a temperature of over 40 ° C, sometimes 14 or 16 hours after taking the medicine;
• you are pregnant or breast-feeding (see section "Pregnancy and breast-feeding");
• have recently had a heart attack (myocardial infarction).

Precautions for use What you need to know before taking Mutabon Antidepressant

Talk to your doctor or pharmacist before taking Mutabon Antidepressant.

Tell your doctor if:

• have or have had episodes of epilepsy or seizures (involuntary muscle contractions) or are being treated with medicines used to relieve seizures. Your doctor will assess the need to increase the dose of these medicines when taken at the same time as Mutabon Antidepressant;
• you are taking other medicines with similar action (neuroleptics);
• have a tumor of the adrenal glands (pheochromocytoma) or an alteration of the mitral valve of the heart (mitral insufficiency). In this case you will be subjected to greater control in the administration of perphenazine due to the risks related to the lowering of blood pressure (hypotension). If you have pheochromocytoma you may experience hypertension after stopping treatment with Mutabon Antidepressant (rebound hypertension);
• have breast cancer. In this case, perphenazine will be given to you with particular care, as it causes an increase in the concentration of a hormone (prolactin) which can worsen your disease;
• must undergo surgery. Your doctor will advise you on whether or not you need to stop taking Mutabon Antidepressant a few days before the surgery;
• is in the post-operative phase, as it could occur aspiration of vomit;
• you have had surgery and are taking high doses of this medicine. In this case, your doctor will monitor you closely as there is a risk of a drop in blood pressure (hypotension). It may also be necessary to reduce the amount of anesthetics or sedatives you are taking;
• is generally exposed to temperatures that are too high or too low, as the perphenazine contained in Mutabon Antidepressant can compromise the body's temperature regulation mechanisms;
• have severe kidney disease or reduced kidney function;
• is predisposed to or already suffering from Parkinson's disease or Parkinson-like forms, or other motor disorders, since perphenazine can increase the state of muscle rigidity;
• have ever had problems with emptying your bladder (urinary retention);
• have or have had difficulty emptying the stomach (pyloric stenosis) or have a blockage of intestinal transit (intestinal obstruction);
• suffer from thyroid disease (hyperthyroidism) or if you are taking thyroid hormone medicines. Your doctor will keep you under close control;
• have respiratory diseases caused by lung infections or chronic breathing disorders such as severe asthma or emphysema;
• take alcohol, as it may enhance the effects of the medicine, significantly lower your blood pressure (hypotension). If you abuse alcohol this may increase the risk of suicide or the danger of an overdose (see section "Mutabon Antidepressant with alcohol);
• you are abstinent from alcohol;
• experience sudden onset of sore throat or other signs of infection, as Mutabon Antidepressant can cause changes in the production of blood cells. Your doctor will carry out blood tests especially between the fourth and tenth week of therapy. If the tests show a significant decrease in white blood cells, your doctor will tell you to stop the treatment; while a slight drop in white blood cells is not in itself indicative of stopping treatment;
• have cognitive impairment (dementia) as treatment with Mutabon Antidepressant could increase the risk of problems with the blood vessels of the brain (cerebrovascular events);
• suffer from diseases of the heart and blood vessels (cardiovascular disease), especially if you are elderly, or have a family history of abnormal heart beat conduction (QT prolongation), or have risk factors for stroke (pathological vascular event at the level of of the brain), because antidepressant medicines, when given in high doses, can cause altered heart rhythms (arrhythmias, sinus tachycardia and prolonged conduction times) or more serious events such as myocardial infarction and stroke;
• have had diseases associated with blood clot formation or have a family history of such diseases;
• has a hardening, thickening and loss of elasticity of the arterial wall in the brain (cerebral arteriosclerosis);
• suffer from mental disorders such as manic-depressive psychosis (a disorder characterized by cyclic changes in mood, passing from excessive arousal to depression), or a personality disorder characterized by a persistent tendency to interpret the behaviors of others with distrust and suspicion (disorder paranoid), as tricyclic antidepressants such as amitriptyline can accentuate the symptoms of these diseases. However, the tranquilizing action of Mutabon Antidepressant reduces the risk of such effects;
• must undergo electroshock therapy, as the risks associated with this practice may increase in conjunction with the intake of amitriptyline; in this case the doctor will limit the intake of Mutabon Antidepressant only to cases where therapy is absolutely essential.

Interactions Which drugs or foods can modify the effect of Mutabon Antidepressant

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Do not take Mutabon Antidepressant together with the following medicines:

• monoamine oxidase inhibitors (iMAO). Do not take Mutabon Antidepressant at the same time or in the two weeks following the end of treatment with monoamine oxidase inhibitors as this may result in severe reactions, elevated temperature (hyperpyretic crisis) up to convulsions, coma and death (see section "Do not take Mutabon Antidepressant if "). Once this period of time has elapsed, your doctor will cautiously begin treatment with Mutabon Antidepressant, gradually increasing the dose until a satisfactory response is achieved.
• opiates, barbiturates or other sedatives, antihistamines, anesthetics, tranquilizers and meperidine (and other opiate analgesics). Co-administration with Mutabon Antidepressant may potentiate the central nervous system depressant effects of these medicinal products, including respiratory depression. Conversely, these medicines may potentiate the effects of Mutabon Antidepressant. Therefore, you should not take Mutabon Antidepressant together with these medicines (see section "Do not take Mutabon Antidepressant if").

Talk to your doctor or pharmacist if you are taking:

• medicines which can cause reduction of white blood cells (leukopenizing drugs), as Mutabon Antidepressant can cause changes in the production of blood cells (see sections "Do not take Mutabon Antidepressant if:" and "Warnings and precautions");
• other psychotropic drugs, medicines with anticholinergic action (inhibitory action of acetylcholine, a substance that acts on the nervous system) or medicines that act on the autonomic nervous system (sympathomimetics), due to the possible occurrence of undesirable effects due to their interaction with Mutabon Antidepressant ;
• medicines with anticholinergic action, such as atropine or similar medicines, or antihistamines, as it is possible that an increase in the effects on the cholinergic system may occur with consequent risk of intestinal obstruction (paralytic ileus), blurred vision and possible alteration of ocular pressure in the presence of of glaucoma;
• medicines that affect the autonomic nervous system (sympathomimetic amines) such as epinephrine combined with local anesthetics, as it is possible that an increase in the activity of these medicines or Mutabon Antidepessive may occur. Your doctor will monitor you closely and adjust your dose to avoid the onset of effects on blood pressure and heart function, sometimes fatal;
• reserpine, methyldopa, other medicines to treat high blood pressure (hypertension) such as guanethidine (concomitant use requires a dose adjustment by the doctor), beta-blockers that block adrenergic receptors such as propranolol or similar medicines, in how low blood pressure (hypotension) can occur; The concomitant use of Mutabon Antidepressant and such medicinal products is therefore not recommended. Your doctor may ask you to have your blood pressure checked before starting treatment with Mutabon Antidepressant and weekly checks in the first month of treatment;
• medicines to treat seizures (see section "Warnings and precautions");
• phenytoin, a medicine used to treat epilepsy as Mutabon Antidepressant can alter its effectiveness;
• antipsychotic medicines; - sedative medicines such as diazepam;
• high doses of etcorvinol (sedative and hypnotic medicine), as transient delirium has been reported with this combination of medicines. The combination with Mutabon Antidepressant should be used with caution;
• medicines for the treatment of stomach hyperacidity based on aluminum salts as they can reduce the absorption of Mutabon Antidepressant;
• medicines that prolong the QT interval, as this increases the risk of developing changes in the heart beat (heart arrhythmias);
• medicines that cause changes in blood electrolytes;
• medicines based on cimetidine, as it can increase the concentrations of amitriptyline in the blood and its effects, which could lead to serious side effects;
• medicines that can inhibit cytochrome P450 2D6 (an enzyme in the body that is involved in the metabolism of medicines), such as quinidine, cimetidine, many other antidepressants, phenothiazines, propafenone and flecainide, and all medicines called selective re-inhibitors serotonin uptake (SSRI), such as fluoxetine, sertraline and paroxetine. In this case, your doctor may prescribe lower than recommended doses, both for these medicines and for Mutabon Antidepressant. Your doctor will also closely monitor you if you switch from one medicine to another, especially if you switch from fluorexetine to Mutabon Antidepressant;
• levodopa and phenylbutazone, as Mutabon Antidepressant can interfere with the absorption of these medicines.

Mutabon Antidepressant can interfere with the absorption of various other medications.

Tell your doctor if you are exposed to organic phosphorus insecticides.

Mutabon Antidepressant and laboratory tests

Taking Mutabon Antidepressant can darken the urine and cause changes in the results of some laboratory tests:

• false-positive (non-real positive results) in the values ​​of the following tests: urobilinogen, amylase, uroporphyrins, porphobilinogens and 5-hydroxy-indolacetic acid;
• changes in the electrocardiogram such as prolongation of the QT interval;
• abnormalities in the electroencephalogram;
• alteration (increase) in the levels of iodine bound to blood proteins;
• changes in the results of hypothalamic-pituitary function tests, as the medicine may cause a decrease in some hormones;
• false-positive and false-negative in the urine pregnancy test;
• possible rises and falls in blood sugar levels.

Mutabon Antidepressant with alcohol

Mutabon Antidepressant must not be administered simultaneously with alcohol (ethanol) due to a possible increase in the effects of the medicine, including a decrease in blood pressure (hypotension). Furthermore, this combination may increase the risk of suicide and the danger of overdose.

Warnings It is important to know that:

Suicide / Suicide idea

Depression is associated with an increased risk of thoughts associated with suicide, willingness to harm oneself physically (self-harm) and suicide. The risk of you experiencing these thoughts may increase in the early stages of improvement and persist until you experience a significant improvement in your symptoms. As improvement may not occur during the first weeks of treatment or in the weeks immediately following, you will be closely monitored by your doctor until improvement has occurred.

Other psychiatric mental disorders for which Mutabon Antidepressant is prescribed may increase the risk of suicidal behavior and a depressive disorder characterized by alternating periods of well-being and phases of depression (major depressive disorder). If you have major depressive disorder, your doctor will observe the same precautions followed when treating patients with other psychiatric conditions.

You are more likely to have suicidal thoughts if:

• he has already thought in the past about taking his own life;
• is a young man under the age of 25, being treated with antidepressants.

Your doctor will monitor you closely, especially in the initial stages of treatment and after any dose adjustments, and if you are a patient at high risk for having thoughts of suicide. Contact your doctor immediately if you experience any worsening of your symptoms, the onset of behavior or thoughts associated with suicide, or changes in behavior.

It is possible that during treatment with Mutabon Antidepressant you may experience:

• appearance of involuntary movements of the muscles (tardive dyskinesia), especially if you are an elderly patient. Both the risk of developing dyskinesia and the possibility of it becoming irreversible increase with the duration of treatment and with the total dose of the medicine taken, although, less frequently, it can also arise after short periods of treatment and at low doses. Discontinuation of treatment can lead to resolution of this disease. If you notice these symptoms, please inform your doctor who will consider adjusting the dose or stopping the treatment;
• raising or lowering blood sugar levels;
• appearance of skin sensitivity reactions to light (photosensitivity). For this reason, avoid excessive exposure to sunlight while taking Mutabon Antidepressant;

A heart problem, called "QT prolongation" (seen in the electrocardiogram, ECG) and heart rhythm disturbances (fast or irregular heartbeat) have been reported in connection with taking Mutabon Antidepressant. Talk to your doctor if:

• have a slow heart rate,
• have or have had a problem where your heart has not been able to pump blood through your body as it should (a condition called heart failure),
• are taking other medicines that can cause heart problems or
• have a problem that causes too low a level of potassium or magnesium or too high a level of potassium in your blood.

Stop taking Mutabon Antidepressant and tell your doctor if you experience:

• a significant increase in temperature not attributable to a specific cause. This increase in temperature could suggest hypersensitivity to perphenazine and in this case your doctor will advise you to stop the therapy.
• a potentially fatal symptom complex called neuroleptic malignant syndrome, characterized by: increased body temperature, muscle stiffness, decreased or loss of the ability to spontaneously move (akinesia), vegetative disturbances (irregular pulse and blood pressure, sweating, increased heart rate (tachycardia), changes in heart rhythm (arrhythmias), changes in consciousness which can progress to partial loss of consciousness (stupor) and coma. Your doctor will tell you to stop the therapy and will to initiate therapy for the treatment of these symptoms.
• abnormal blood urea values

During treatment with Mutabon Antidepressant, you will need to periodically check the values ​​of the red blood cells and the function of the liver and kidneys. Should any abnormal results occur, the doctor will discontinue the therapy.

Taking Mutabon Antidepressant may mask signs of overdose of other medicines, or make it more difficult to diagnose diseases such as intestinal obstruction, Reye's syndrome (acute disease usually found in patients under the age of 18, potentially fatal characterized by symptoms mainly affecting the brain and liver), brain tumors or other diseases that alter the structure and / or functions of the brain (encephalopathies).

Children and adolescents

Mutabon Antidepressant is not recommended for use in children below 12 years of age due to a lack of data on safety and efficacy.

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

Mutabon Antidepressant should not be used during pregnancy, whether known or suspected due to the risk of side effects in the newborn (see section "Do not take Mutabon Antidepressant if" and section 4 "Undesirable effects in children").

Feeding time

You should not use Mutabon Antidepressant if you are breast-feeding (see section "Do not take Mutabon Antidepressant if") as Mutabon Antidepressant passes into breast milk and may cause side effects in the baby.

Driving and using machines

Mutabon Antidepressant influences the ability to drive and use machines, since it can induce changes in the reaction time (time interval between the moment you perceive a danger and the moment you start to react to avoid it). Therefore, take due care when driving vehicles and using machines.

Mutabon Antidepressant contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dosage and method of use How to use Mutabon Antidepressant: Posology

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

The optimal dose of Mutabon Antidepressant must be established by the doctor, according to the specific disorder to be treated, the duration and severity of the disease, and its response to therapy.

The recommended dose is 1 tablet, 3-4 times a day. It usually takes several days to achieve an appreciable effect of Mutabon Antidepressant.

Keep in mind that the tranquilizing action occurs more rapidly (after 2 or 3 days) than the antidepressant action (1 week or more), therefore the symptoms of tension and anxiety disappear long before the depressive symptoms.

If you suffer from persistent insomnia, it is advisable, especially in the first days of therapy, to take 1 or 2 tablets in the evening, half an hour before going to sleep; the remaining tablets prescribed by the doctor can be taken throughout the day.

To get a full effect you will have to continue the treatment for several weeks, according to the doctor's opinion. Once your symptoms are controlled, your doctor will gradually reduce your dose until a maintenance dose is found that is most suitable for you.

Your doctor will periodically evaluate the need to continue treatment with Mutabon Antidepressant.

Use in children and adolescents

Mutabon Antidepressant is not recommended for children and adolescents under 12 years of age (see section "Children and adolescents").

Use in the elderly

The dose and frequency of administration of Mutabon Antidepressant in elderly patients should be carefully determined by the physician, who will evaluate a possible reduction in the dose indicated above on the basis of individual needs.

If you forget to take Mutabon Antidepressant

Do not take double the prescribed dose to make up for a forgotten tablet; continue therapy according to the usual schedule.

If you stop taking Mutabon Antidepressant

Do not stop taking Mutabon Antidepressant before consulting your doctor.

Generally phenothiazines (perphenazine) do not cause psychic dependence. However, following sudden discontinuation of high-dose treatment, gastritis, nausea, vomiting, dizziness, tremors and motor hyperactivity may occur. If you experience these symptoms, consult your doctor who will prescribe an appropriate therapy.

Suddenly discontinuing high-dose tricyclic antidepressant therapy (amitriptyline hydrochloride) can cause symptoms such as: malaise, chills, cold, muscle pain, headache, nausea, vomiting, anxiety, unsteadiness, dizziness and a constant need to move ( akathisia). These symptoms are not indicative of addiction.

If you suddenly stop taking high-dose Mutabon Antidepressant therapy, please inform your doctor and pay attention to any symptoms you may experience. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken an overdose of Mutabon Antidepressant

If you have taken too much Mutabon Antidepressant, contact your doctor or pharmacist immediately or go to the nearest hospital.

The signs and symptoms of an overdose come on quickly, therefore hospital check-up is required as soon as possible.

Overdose with Mutabon Antidepressant, as with other medicines of the same category, can result in death.

Symptoms of overdose with Mutabon Antidepressant may correspond to any of the undesirable effects listed for the two active substances, perphenazine or amitriptyline hydrochloride (see section "Possible side effects").

Symptoms of perphenazine overdose are manifested by motor system abnormalities (extrapyramidal symptoms), such as involuntary muscle movements (dyskinesia) and abnormal muscle contractions (dystonia); however, they may be masked by the anticholinergic effects of amitriptyline. Other symptoms may include partial loss of consciousness (stupor) or coma; children can experience seizures.

Symptoms of an amitriptyline overdose are manifested by irregular heartbeat (cardiac arrhythmias), severe drop in blood pressure (severe hypotension), involuntary muscle twitching (seizures) and decreased nervous system activity (depression of the central nervous system, including coma.

There have also been reports of abnormal heart beat conduction detectable on electrocardiogram.

Other symptoms of overdose include: confusion, disturbances in concentration, temporary visual hallucinations, dilated pupils, agitation, overactive reflexes, drowsiness, muscle stiffness, vomiting, low body temperature (hypothermia), fever or any of the symptoms listed among the effects unwanted.

Method of treatment in case of overdose of Mutabon Antidepressant

There is no specific substance that can counteract the effect of overdosing with Mutabon Antidepressant. If you accidentally or intentionally take an overdose of Mutabon Antidepressant, contact your doctor or pharmacist immediately or go to the nearest hospital.

Your doctor will undergo appropriate emergency treatments, such as gastic lavage and electrocardiographic examination (ECG), and will closely observe you for any signs affecting the central nervous system, breathing difficulties, lowering of blood pressure, abnormalities of the heart rhythm and / or conduction block of the heart and seizures.

The doctor may decide to contact the local poison control center.

Side Effects What are the side effects of Mutabon Antidepressant

Like all medicines, Mutabon Antidepressant can cause side effects, although not everybody gets them.

The side effects of Mutabon Antidepressant are the same referable to the two active ingredients (perphenazine and amitriptyline), when taken individually. No undesirable effects have been reported due solely to their combination in Mutabon Antidepressant.

In very rare cases, patients with hypersensitivity to phenothiazines (perphenazine) have experienced excessive accumulation of fluid in the brain (cerebral edema), circulatory collapse and death.

Occasionally, treatment with phenothiazines can cause blockage of the gut musculature with consequent arrest of the progression of the contents of the gut (adynamic ileus) which, if severe, can cause complications and death.

Stop taking Mutabon Antidepressant and contact your doctor immediately if you experience:

• Neuroleptic Malignant Syndrome (NMS), a potentially fatal syndrome characterized by the manifestation of symptoms such as increased body temperature, muscle stiffness, decreased movement (akinesia), vegetative disorders (irregular pulse and blood pressure, sweating, increased heart rate (tachycardia), changes in heart rhythm (arrhythmias)), changes in consciousness which may progress to stupor and coma (see "Stop taking Mutabon Antidepressant and tell your doctor if it occurs" in section 2);
• persistent abnormalities in muscle contraction and movement, including abnormal, involuntary movements of the tongue, jaw, trunk, or limbs (persistent late dyskinesia) (see "Stop taking Mutabon Antidepressant and tell your doctor if it occurs" in section 2);
• swelling of the hands, feet, ankles, or also of the face, lips, tongue and / or throat resulting in difficulty in swallowing or breathing (angioedema);
• increased body temperature (hyperpyrexia);
• allergic reaction with skin rashes (hives), irritation and red spots on the skin (erythema), itchy inflammatory reactions on the skin (eczema), inflammation of the skin with formation of lesions and loss of the surface layer (exfoliative dermatitis), itching, sensitivity of the skin to light (photosensitivity), asthma, fever, allergic (anaphylactoid) reactions, swelling due to fluid accumulation in the upper airways (edema of the larynx), contact dermatitis;
• formation of blood clots in the veins especially in the legs (symptoms include swelling, pain and redness in the legs), which can migrate through blood vessels to the lungs causing chest pain and difficulty in breathing (frequency of this side effect may not be defined on the basis of available data);
• worsening of depressive state, including, rarely, thoughts or behavior related to suicide (see section "Warnings and precautions").

Undesirable effects related to perphenazine

The most common symptoms reported during treatment with perphenazine, as with all medicines belonging to the same pharmacological category as perphenazine, are alterations and abnormalities of the motor system (extrapyramidal reactions), such as:

• abnormal posture characterized by hyperextension of the neck, stiffness and severe arching of the back (opisthotonus), abnormal contraction of the jaw muscles with difficulty opening the mouth (trismus), limited mobility or blockage of the neck accompanied by cervical pain and contracture of the lateral muscles of the neck (torticollis), torticollis associated with a deviated posture of the head and in which sudden muscle spasms may occur, which cause sudden rotations of the head ("spastic" torticollis), pain and tingling in the limbs, state of agitation with an excess of motor activity (motor restlessness), alteration and deviations of the eyes in one direction (oculogyric crisis), hyper-reactivity of reflexes characterized by abnormal muscle contractions (hyper-reflexia), movement disorder characterized by involuntary muscle contractions ( dystonia) including changes in the tongue (color, pain, protrusion or rolling),sudden, involuntary contractions of the chewing muscles, constriction in the throat, difficulty in pronouncing words and swallowing (dysphagia), inability to sit up, a range of symptoms including tremor, muscle stiffness, slowing of movement speed and abnormalities posture (parkinsonism) and loss of muscle coordination (ataxia).
• The frequency and severity of these symptoms generally increases with increasing dosage of Mutabon Antidepressant.

It can also occur:

• abnormalities in the protein composition of the cerebrospinal fluid, headache (headache), drowsiness;
• worsening of psychotic symptoms such as thought disturbances, delusions and hallucinations, motor, emotional and behavioral abnormalities (catatonic-like states), thought forms that deviate from reality (paranoid reactions), deep sleep (lethargy), excitement, restlessness and hyperactivity, nocturnal confusion, bizarre dreams, sleep disturbances (insomnia);
• abnormal breast milk secretion (galactorrhea), enlarged breasts in women and men (gynaecomastia), menstrual cycle disturbances, prolonged absence of menstruation (amenorrhea), changes in sexual desire, inhibition of ejaculation, false positives in pregnancy test, increased and decreased blood sugar concentration (hyperglycemia and hypoglycemia), presence of sugar in the urine (glycosuria), excessive release of an antidiuretic hormone (syndrome of inappropriate antidiuretic hormone secretion, SIADH);
• low blood pressure when rising from a sitting or lying position (postural hypotension), increased and decreased heart rate (tachycardia and bradycardia), cardiac arrest, fainting and dizziness;
• decrease in white blood cells (agranulocytosis, leukopenia), increase in a particular type of white blood cells (eosinophilia), decrease in the number of red blood cells (haemolytic anemia), abnormal destruction of platelets (thrombocytopenic purpura), decrease in the number of all blood cells blood (pancytopenia);
• inflammation and obstruction of particular channels that carry bile (biliary stasis),
• yellowing of the skin and whites of the eyes (jaundice)

Less frequent side effects:

• sedation, blood disorders (blood dyscrasia), involuntary muscle contractions (convulsions).

Occasionally it can occur:

• dry mouth and hypersalivation, nausea, vomiting and diarrhea, gastric retention, anorexia, constipation (constipation), stubborn constipation and hard lump of dehydrated stools in the bowel (fecal impaction), difficulty emptying the bladder (urinary retention), frequent urge to pass urine and involuntary passing of urine (incontinence), loss of bladder function (bladder paralysis), increased amount of urine passed (polyuria);
• stuffy nose (nasal congestion);
• paleness, increase (mydriasis) and decrease (miosis) in pupil size, blurred vision, eye disease characterized by increased pressure in the eye (glaucoma), excessive sweating, increased blood pressure (hypertension), low blood pressure (hypotension), altered pulse rate;

Rarely have been observed:

• heart beat conduction abnormalities (QT prolongation), ventricular arrhythmias such as torsades de pointes, ventricular tachycardia, ventricular fibrillation and cardiac arrest;
• swelling of the salivary glands (parotid swelling).

Side effects related to long-term therapy:

• liver damage
• appearance of spots on the skin (skin pigmentation), changes in vision which consist in the deposit of fine particulate matter in the cornea and in the lens and which, in the most serious cases, lead to opacity of the star-shaped lens, inflammation of the cornea (epithelial keratopathies) changes in the retina, destruction of the retina up to loss of vision (pigment retinopathy);
• persistent abnormalities in the contraction of muscles and movements, such as abnormal, involuntary movements of the tongue, jaw, trunk, or limbs (persistent delayed dyskinesia) which may occur even after treatment is stopped.

Other side effects:

• fluid accumulation in the lower limbs (peripheral edema), state of sedation (reverse epinephrine effect), change in the amount of iodine-binding proteins (increase in PBI not attributable to an increase in thyroxine), syndrome similar to systemic lupus erythematosus (a inflammatory disease of the immune system affecting various organs and tissues of the body), increased appetite and weight, abnormal increase in food consumption (polyphagia), excessive sensitivity to light (photophobia), muscle weakness.

Sudden death has occasionally been reported in patients undergoing treatment with phenothiazines

In some patients it was not possible to determine the cause of death or to establish whether the death was attributable to phenothiazine.

In elderly patients with dementia, a small increase in the number of deaths has been reported in patients taking antipsychotics compared with patients not taking them.

Undesirable effects related to amitriptyline hydrochloride

Treatment with antidepressant drugs, including amitriptyline hydrochloride, can induce the onset of latent schizophrenia, which can be avoided, in some cases, thanks to the antipsychotic effect of the perphenazine contained in Mutabon Antidepressant.

Cases of seizures (epileptic seizures) have been reported in chronic schizophrenia during treatment with amitriptyline hydrochloride.

Furthermore, the intake of amitriptyline hydrochloride may cause, in addition to some of the undesirable effects reported for perfanazine, the following undesirable effects:

• increased risk of bone fractures;
• skin rash (rash);
• changes in the pupil (accommodation disorders), difficulty emptying the bladder (urinary retention and dilation of the urinary tract);
• perception of heartbeat (palpitations), heart attack and stroke, altered heartbeat (arrhythmias), impaired conduction of electrical impulses in the heart which can lead to complete or partial arrest of the heart (heart block);
• confusional states, disturbances in concentration, disorientation, delusions and hallucinations, excitement, nervousness, anxiety and agitation, insomnia and nightmares, hearing loss, tingling and altered perception of stimuli in the limbs (paraesthesia), disturbance of function at the level of the peripheral nervous system (peripheral neuropathy), tremors and convulsions, changes in the electroencephalogram, hearing disorders (tinnitus);
• increase in the size of the testicles;
• disorders of the gastrointestinal system (epigastric disorders and heartburn), inflammation of the oral cavity (stomatitis), taste disturbance, dark coloring of the tongue;
• inflammation of the liver (hepatitis) has rarely occurred;
• depression of the bone marrow (when the bone marrow cannot produce enough cells found in the blood), decrease in white blood cells (agranulocytosis, leukopenia), breakage of the capillaries below the surface of the skin (purpura), increase of a particular type of white blood cells (eosinophilia), reduction in the number of platelets (thrombocytopenia); - a heart problem called "QT prolongation" (seen on the electrocardiogram, ECG) (common rate);
• dizziness, weakness and fatigue, weight gain or loss, hair loss (alopecia).

Abrupt discontinuation of treatment in long-term therapies can result in:

• nausea, headache (headache), malaise.

Side effects in children

The following symptoms have been observed in newborn babies of mothers who have taken antipsychotics, including Mutabon Antidepressant, during the last three months of pregnancy: muscle agitation, stiffness and / or weakness, overactive reflexes, tremor, alterations and abnormalities of the motor system (extrapyramidal symptoms ), sleepiness, breathing problems, difficulty in food intake and neonatal withdrawal syndrome.

If your baby shows any of these symptoms, contact your doctor immediately.

Reporting of side effects

 By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package after "EXP". The expiry date refers to the last day of that month.

The expiry date indicated refers to the product in intact packaging, correctly stored.

This medicinal product does not require any special storage temperatures.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Further information

What Mutabon Antidepressant contains

• The active ingredients are perphenazine and amitriptyline hydrochloride. Each film-coated tablet contains 2 mg of perphenazine and 25 mg of amitriptyline hydrochloride.
• The other ingredients are rice starch, lactose, magnesium stearate, povidone, Opadry® pink (hypromellose E-464, macrogol, titanium dioxide E-171, hydroxypropylcellulose E-464, erythrosine E-127, aluminum lake).

What Mutabon Antidepressant looks like and contents of the pack

Mutabon Antidepressant is available in packs of 30 film-coated tablets, contained in a blister.

Learn more about Mutabon Antidepressant are available in the "Summary of Characteristics" tab.

01.0 NAME OF THE MEDICINAL PRODUCT -

MUTABON ANTIDEPRESSIVE 2 MG + 25 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Each film-coated tablet contains:

Active ingredients: perphenazine 2 mg + amitriptyline hydrochloride 25 mg.

Excipient with known effects:

lactose.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Film-coated tablets.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Mutabon Antidepressant is indicated in the treatment of various mental disorders, both reactive and endogenous, characterized by the coexistence of depression with anxiety, tension and agitation.

Mutabon Antidepressant finds application in many emotional disorders characterized by depression and anxiety due or associated with organic or functional diseases, psychosomatic forms, etc. Mutabon Antidepressant is equally effective in the treatment of patients with depressive symptoms as in most of them a state of tension coexists, even if this is not evident or may be masked.

Mutabon Antidepressant is shown to be effective in patients with severe insomnia associated with anxiety and depression.

04.2 Posology and method of administration -

dosage

The dosage of Mutabon Antidepressant should be individualized according to the particular disorder being treated, the duration and severity of the disease and the patient's response.

One Mutabon Antidepressant tablet 3-4 times a day is usually sufficient; it generally takes several days of treatment to fully appreciate the therapeutic activity of the preparation.

It should be borne in mind that the tranquilizing action occurs more rapidly (2 or 3 days) than the antidepressant action (1 week or more); therefore the symptoms of tension and anxiety disappear long before the depressive symptoms.

To achieve a full effect it will be necessary to continue the treatment for several weeks; once symptom control is achieved, the doctor may gradually reduce the dosage until the individual maintenance dose is established. The need for continued treatment should be reassessed periodically.

In cases of persistent insomnia it may be advisable, especially in the first days of therapy, to administer one or two tablets of Mutabon Antidepressant in the evening half an hour before bedtime and the remaining tablets during the day.

Pediatric population

The safety and efficacy of Mutabon Antidepressant in children below 12 years of age have not been established and its use in children is not recommended.

Senior citizens

In the treatment of elderly patients, the posology must be carefully established by the physician, who will have to evaluate a possible reduction in the dosage.

Method of administration

Oral use.

04.3 Contraindications -

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Cases of cross-allergenicity with other drugs with similar chemical structure have been reported.

Glaucoma, increased intraocular pressure, prostatic hypertrophy, known or suspected urinary retention, myasthenia gravis, blood dyscrasia, bone marrow depression or liver damage.

The administration of Mutabon Antidepressant is contraindicated in combination with CNS depressant drugs (barbiturates, ethyl alcohol, narcotics, analgesics, antihistamines).

In comatose states or in severe dullness and in severe states of depression.

Disorders of hematopoiesis (therefore avoid the simultaneous administration of potentially leukopenizing drugs).

In patients with suspected or known subcortical brain damage, with or without hypothalamic damage, as a hyperthermic reaction with temperatures above 40 ° C may arise in such patients, sometimes not until 14 or 16 hours after drug administration. Useful for the treatment of this reaction are the ice pack on the whole body and the administration of antipyretics.

Known or suspected pregnancy.

Feeding time.

In order to avoid even serious manifestations, hyperpyretic crises up to convulsions, coma and exit, the product must not be administered in combination with MAOIs, nor before at least 2 weeks have elapsed from the interruption of a previous treatment with these drugs, to allow the disappearance of the effects of MAOIs and any possible enhancement.

Amitriptyline hydrochloride is not recommended during the acute recovery phase after myocardial infarction.

04.4 Special warnings and appropriate precautions for use -

Since phenothiazines and tricyclic antidepressants affect many organic functions, their safe and effective use requires pre-treatment and periodic laboratory tests, especially during high-dose or prolonged treatments. Red blood cell counts and liver and kidney function should be checked periodically. If there is a suspicion that the drug induces cardiovascular effects, an electrocardiogram should be done. If abnormal liver or kidney function tests appear, treatment with Mutabon Antidepressant should be discontinued.

The possibility of suicide in depressed patients continues during treatment until significant remission of symptoms occurs. Suicidal patients should not have access to large quantities of Mutabon Antidepressant.

Tardive dyskinesia may develop in patients treated with neuroleptics. Older patients are at greater risk of the disease. Both the risk of developing the syndrome and the likelihood of it becoming irreversible increase with the duration of treatment and with the cumulative total dose of neuroleptics administered to the patient. However, although less frequently, the syndrome can develop even after relatively short periods of low dose therapy.

If neuroleptic treatment is eliminated, tardive dyskinesia can have a partial or complete remission. Neuroleptic treatment itself can, however, suppress (or partially eliminate) the signs and symptoms of the syndrome, and therefore mask the progression of the disease. In patients requiring chronic treatment, the lowest dose and shortest duration of treatment should be expected to produce a satisfactory clinical response. The need to continue with treatment should be periodically evaluated.

If signs and symptoms of tardive dyskinesia appear in a patient, consideration should be given to discontinuing the drug. However, some patients may need treatment even in the presence of the syndrome.

A potentially fatal symptom complex called neuroleptic malignant syndrome has been reported during treatment with antipsychotic drugs. Clinical manifestations of this syndrome are: hyperpyrexia, muscle stiffness, akinesia, vegetative disorders, pulse and blood pressure irregularities, sweating, tachycardia, arrhythmias: changes in consciousness that can progress to stupor and coma. The treatment of neuroleptic malignant syndrome consists in immediately stopping the administration of antipsychotic drugs and other non-essential drugs and in instituting intensive symptomatic therapy (particular care must be taken to reduce hyperthermia and correct dehydration). If the resumption of antipsychotic treatment is deemed essential, the patient should be carefully monitored.

In general, the same precautions that are followed during single administration of the two components should be observed.

Perphenazine can lower the seizure threshold in predisposed individuals. It must be used with caution in situations of alcohol withdrawal and in subjects with convulsive pathology. If the patient is being treated with anticonvulsant drugs, an increase in the dose of these drugs may be necessary when used in conjunction with Mutabon Antidepressant.

Pediatric population

The safety and efficacy of Mutabon Antidepressant in children below 12 years of age have not been established and its use in children is not recommended.

Perphenazine

As with all phenothiazine derivatives, perphenazine should not be used indiscriminately. Some of the side effects of perphenazine tend to occur more frequently when high doses are given. However, as with other phenothiazines, patients treated with perphenazine should be closely monitored. Avoid concomitant therapy with other neuroleptics.

Particular attention should be paid to administering perphenazine to patients with pheochromocytoma or mitral insufficiency, due to any hypotensive effects that may occur, which can also be controlled with noradrenaline. The antiemetic effect of perphenazine can mask the signs of overdosing of other drugs or can make it more difficult to diagnose conditions such as intestinal obstruction, Reye's syndrome, brain tumors or other encephalopathies. Since perphenazine causes an increase in the plasma level of prolactin, products containing phenothiazines should be used with appropriate caution in women with breast cancer.

Aspiration of vomiting occurred in a few patients receiving phenothiazines during the postoperative phase. Even if a causal relationship has not been established, this possible occurrence must be taken into consideration during post-operative management.

Patients undergoing surgery who receive high doses of perphenazine should be carefully monitored for the possible occurrence of hypotension phenomena. In addition, it may be necessary to reduce the amount of central nervous system (CNS) anesthetics or sedatives.

Use with caution in subjects exposed to too high or too low temperatures as phenothiazines can compromise the ordinary thermoregulation mechanisms.

A significant increase in body temperature, which cannot be explained otherwise, may suggest an intolerance to perphenazine; if so, discontinue therapy.

Since hypersensitivity reactions to phenothiazines have been reported, patients receiving these drugs should avoid excessive exposure to sunlight.

Red blood cell counts and liver and kidney function should be checked periodically. If blood dyscrasias or liver function abnormalities occur, treatment should be discontinued. If blood urea (BUN) values ​​become abnormal, treatment should be stopped. The use of phenothiazine derivatives in patients with impaired renal function should be undertaken with caution.

Perphenazine can increase the state of muscle stiffness in individuals predisposed to or already suffering from Parkinson's disease or Parkinson-like forms, or other motor disorders.

The conduct of therapy must be characterized by particular caution in all the following cases, namely: in subjects with a history of epilepsy or convulsive events, in patients in alcohol withdrawal, in cardiac patients, especially if elderly, in cerebral arteriosclerosis, in patients with a history of urinary retention or intestinal obstruction or pyloric stenosis, in severe renal or hepatopatients, in hyperthyroid glands and in those undergoing treatment with thyroid hormones, in subjects exposed to high temperatures, in patients with respiratory damage, due to acute lung infections or chronic breathing disorders, such as severe asthma or emphysema.

The use of alcohol should be avoided, as it may potentiate the effects of the drug, including hypotension. The risk of suicide and the danger of overdose may be increased in patients who abuse alcohol.

In patients on long-term therapy, the possible occurrence of liver damage, corneal or lenticular deposits, alterations to the retina and irreversible dyskinesia should be considered (see for the latter the specific section "4.8 Undesirable effects").

Patients should be carefully monitored for haematological effects, especially between the fourth and tenth week of therapy, for sudden onset of sore throat or other signs of infection. If the white blood cell count falls and the differential count shows a significant decrease in granulocytes, the drug should be discontinued and appropriate therapy initiated. However, a slight decrease in white blood cells is not in itself indicative of stopping treatment.

As cases of photosensitivity have been reported, sun exposure should be avoided during treatment with phenothiazines.

An approximately three-fold increased risk of cerebrovascular events was observed in randomized clinical trials versus placebo in a population of patients with dementia treated with some atypical antipsychotics. The mechanism of this increased risk is unknown. An increased risk for other antipsychotics or other patient populations cannot be excluded. Mutabon Antidepressant should be used with caution in patients with risk factors for stroke. Use with caution in patients with cardiovascular disease or a family history of QT prolongation.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. As patients receiving antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE must be identified before and during treatment with "Mutabon Antidepressant" and appropriate preventive measures undertaken.

Increased mortality in elderly patients with dementia

Data from two large observational studies showed that elderly patients with dementia treated with antipsychotics have a slightly increased risk of death compared to untreated patients. However, the available data are insufficient to be able to provide a precise estimate of the size of the risk. The cause of the increased risk is unknown.

"Mutabon Antidepressant" is not licensed for the treatment of dementia-related behavioral disorders.

Amitriptyline hydrochloride

In patients undergoing treatment with a monoamine oxidase inhibitor, an interval of two weeks or more is recommended between stopping the MAO inhibitor administration and starting treatment with Mutabon Antidepressant tablets in order to allow healing of the effects of the inhibitor of MAO and avoid a possible enhancement. Treatment with Mutabon Antidepressant Tablets should be initiated with caution in such patients with gradual dose escalation until a satisfactory response is achieved.

Carefully monitor patients with cardiovascular disorders while on Mutabon Antidepressant therapy. Tricyclic antidepressant drugs act markedly on the cardiovascular system, even at therapeutic doses. These drugs, including amitriptyline hydrochloride, have caused arrhythmias, sinus tachycardia and prolonged conduction times, particularly when administered at high doses. Myocardial infarction and stroke have been reported with drugs in this category.

Due to the anticholinergic activity of amitriptyline hydrochloride, Mutabon Antidepressant tablets should be used with caution in patients with glaucoma and increased intraocular pressure as well as in patients with present or anticipated urinary retention. Even usual doses can cause severe increases in intraocular pressure in patients with narrow-angle glaucoma.

Strict monitoring is necessary when administering amitriptyline hydrochloride to hyperthyroid patients or to subjects undergoing treatment with thyroid drugs.

In manic-depressive psychosis, depressed patients may progress to the manic phase when treated with a tricyclic antidepressant agent. Patients with paranoid symptoms may experience an excess of these symptoms. The tranquilizing action of Mutabon Antidepressant Tablets may reduce the possibility of this effect occurring.

Both rises and falls in blood sugar levels have been reported.

The risk of electroshock therapy may be increased by the concomitant administration of amitriptyline hydrochloride. Such concomitant treatment should be limited to patients for whom it is considered absolutely essential.

If possible, stop taking Mutabon Antidepressant Tablets a few days before elective surgery.

Mutabon Antidepressant should not be administered concomitantly with guanethidine or similarly acting compounds, as amitriptyline, like other tricyclic antidepressants, can block the antihypertensive effect of these drugs. If hypotension occurs, epinephrine (adrenaline) should not be administered as its action is blocked and partially reversed by perphenazine. If a vasopressor is needed, norepinephrine can be used. Severe acute hypotension has occurred with the use of phenothiazines and particularly more easily in patients with mitral insufficiency or pheochromocytoma. Rebound hypertension may arise in patients with pheochromocytoma.

ABUSE AND DRUG DEPENDENCY: Generally, phenothiazines, including perphenazine, do not cause psychic dependence. However, gastritis, nausea, vomiting, dizziness, tremor and motor hyperactivity have been reported following the sudden discontinuation of high-dose therapy. Studies suggest that these symptoms may be reduced with continued administration of antiparkinsonian agents for a few weeks after discontinuation of phenothiazine treatment.

The usefulness of amitriptyline in the treatment of depression has been widely demonstrated; however, it should be understood that amitriptyline abuse among addicts is not uncommon.

Suddenly discontinuing high-dose tricyclic antidepressant therapy can cause cascading symptoms, including malaise, chills, shortness of breath, muscle pain, headache, nausea, vomiting, anxiety, unsteadiness, dizziness and akathisia. These symptoms are not indicative of addiction.

SUICIDARY IDEATION / BEHAVIOR

Suicide / Suicidal ideation

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide / related events). This risk persists until significant remission occurs. As improvement may not occur during the first or immediate weeks of treatment, patients should be monitored closely until improvement occurs. It is clinical experience in general that the risk of suicide may increase in the early stages of improvement.

Other psychiatric conditions for which Mutabon Antidepressant is prescribed may also be associated with an increased risk of suicidal behavior. Additionally, these conditions can be associated with major depressive disorder. Therefore, the same precautions followed when treating patients with other psychiatric disorders should be observed when treating patients with major depressive disorders.

Patients with a history of suicidal behavior or thoughts, or who exhibit a significant degree of suicidal ideation prior to initiation of treatment, are at increased risk of suicidal thoughts or suicidal thoughts, and should be closely monitored during treatment. A meta-analysis of clinical trials conducted with antidepressant drugs compared to placebo in the therapy of psychiatric disorders showed an increased risk of suicidal behavior in the age group below 25 years of patients treated with antidepressants compared to placebo.

Drug therapy with antidepressants should always be associated with close surveillance of patients, particularly those at high risk, especially in the initial stages of treatment and after dose changes. Patients (or caregivers) should be advised of the need to monitor and report immediately to their physician any clinical worsening, the onset of suicidal behavior or thoughts, or changes in behavior.

QT prolongation

Cases of QT interval prolongation and arrhythmias have been reported in the post-marketing period. Caution is advised in patients with significant bradycardia, uncompensated heart failure or in patients taking concomitant medications that prolong the QT interval. Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) are known as conditions that increase the proarrhythmic risk.

Important information about some of the ingredients

The medicine contains lactosetherefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose / galactose malabsorption should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction -

Perphenazine

Concomitant administration of phenothiazines may potentiate the central nervous system (CNS) depressant effects of opiates, barbiturates or other sedatives, antihistamines, anesthetics, tranquilizers, alcohol (ethanol) and meperidine (and other opioid analgesics), for which it may be necessary a reduction in the doses of these agents and overdose should be avoided. Similarly, concomitant use of these products may potentiate phenothiazines.

The association with other psychotropic drugs, with anticholinergics or sympathomimetics requires particular caution and vigilance on the part of the physician, in order to avoid undesirable effects from interaction.

Use with caution in patients treated with atropine or similar drugs due to additive anticholinergic effects and also in patients who will be exposed to high temperatures or organic phosphorus insecticides.

The use of alcohol should be avoided as it can have additive effects and hypotension. Patients should be advised that they may be more sensitive to alcohol when treated with Mutabon Antidepressant. The risk of suicide and the danger of overdose may be increased in patients who consume excessive alcohol due to the potentiation of the drug's effects.

Mutabon Antidepressant should be administered with caution in conjunction with antihypertensive therapy with reserpine, guanethidine, methyldopa, beta-blockers or similar compounds. The possible occurrence of hypotension can be controlled with norepinephrine (not adrenaline, as its activity is antagonized by perphenazine).

Co-administration of cimetidine may increase plasma concentrations of amitriptyline and related anticholinergic effects.

If the patient is being treated with anticonvulsants, a higher dose of these drugs may be required in conjunction with the administration of perphenazine.

Caution should be exercised in case of concomitant administration of perphenazine and phenytoin.

Antipsychotics can cause an increase or decrease in serum phenytoin levels.

Barbiturates can reduce plasma levels of phenothiazines and phenothiazines can reduce levels of barbiturates.

Plasma levels of propranolol (beta-adrenergic receptor blocking drug) and phenothiazines are both increased when the two drugs are administered simultaneously.

Aluminum salt antacids can inhibit the absorption of phenothiazines.

When neuroleptics are given concomitantly with QT-prolonging drugs, the risk of developing cardiac arrhythmias increases.

Do not administer concomitantly with drugs that cause changes in electrolytes.

Amitriptyline hydrochloride

Concomitant administration of tricyclic antidepressant drugs and monoamine oxidase inhibitors (MAOIs) has been reported to cause reactions similar to atropine poisoning resulting in hyperpyretic seizures, convulsions and death. These effects have usually occurred following overdose or parenteral administration of both drugs. Non-fatal hyperpyrexia, hypertension, tachycardia, confusion and convulsions have been reported following oral administration of the two therapeutic doses.

Concomitant administration of cimetidine and tricyclic antidepressants may increase the plasma concentrations of the latter. Severe anticholinergic symptoms have been associated with elevated serum tricyclic antidepressant levels. When treatment with this component was introduced in patients already taking cimetidine, higher than expected steady-state serum concentrations were observed. Conversely, lower steady-state serum concentrations of tricyclic antidepressants have been reported upon discontinuation of cimetidine treatment. A dose adjustment may be necessary.

Concomitant use of amitriptyline and anticholinergics or sympathomimetic amines, including epinephrine combined with local anesthetics, may increase the activity of amitriptyline or sympathomimetic amine. Close patient monitoring and careful dosage adjustment are required. The pronounced pressure and cardiac effects of sympathomimetics can be fatal.

The combination with high doses of etcorvinol should be used with caution as transient delirium has been reported in patients treated with this combination of drugs.

Concomitant treatment with amitriptyline and electroshock therapy can increase the dangers of this treatment which must be limited to patients for whom it is absolutely essential.

The combination of amitriptyline and guanethidine may antagonize the antihypertensive effect of guanethidine. Tricyclic drugs block the uptake of adrenergic neurons of guanethidine and compounds with similar effect. Dosage adjustment of guanethidine or tricyclic drug will be required. Concomitant administration of Mutabon tablets and guanethidine or compounds with similar effect is not recommended. Where possible, a check of hypertension is required before starting treatment with antidepressant drugs and blood pressure should be checked weekly during the first month of such treatment.

Concomitant use of amitriptyline, anticholinergics or antihistamines may potentiate their anticholinergic effects. The increased anticholinergic activity can cause paralytic ileus or blurred vision and can affect intraocular pressure in patients with glaucoma.

Concomitant use of amitriptyline and central nervous system (CNS) depressant agents, such as alcohol, barbiturates, sedatives or opioid analgesics, may potentiate CNS depressant effects, including respiratory depression.

Concomitant intake of amitriptyline and diazepam results in an increase in the half-life and constant plasma levels of amitriptyline. This interaction varies in a very important way between the various subjects.

Concomitant use of amitriptyline and reserpine may antagonize the effects of reserpine.

Concomitant use of amitriptyline and anticonvulsants may reduce effective control of seizures in epileptic patients.

It appears that tricyclic agents may act as weak inducers of drug metabolism.

The anticholinergic effects of tricyclic antidepressants can slow gastrointestinal motility in such a way that it interferes with the absorption of various other drugs. Furthermore, delayed transit from the stomach can result in the inactivation of drugs such as levodopa and phenylbutazone.

Drugs metabolised by Cytochrome P450 2D6

The biochemical activity of the cytochrome P450 2D6 isoenzyme (debrisoquine hydroxylase) which metabolizes the drug is reduced in a subgroup of the Caucasian population (about 7-10% of the Caucasian population is composed of subjects called "poor metabolisers"); however, no reliable estimates are available on the prevalence of the reduced activity of the isoenzyme P450 2D6 in Asian, African and other populations. "Poor metabolisers" have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) after administration of usual dosages. Depending on the fraction of the drug metabolised by P450 2D6, the increase in plasma concentration may be small or quite large (8-fold the increase in plasma AUC of the tricyclic antidepressant). In a study of 45 elderly patients with dementia and treated with perphenazine, the 5 patients prospectively identified as "poor metabolisers" of P450 2D6 had significantly greater side effects during the first 10 days of treatment than the 40 "strong metabolisers. "; after this period, the groups tended to converge. The prospective phenotyping of elderly patients before neuroleptic treatment allows to identify subjects at risk of adverse events.

In addition, some drugs inhibit the activity of this isoenzyme and make normal metabolisers similar to poor metabolisers. An individual stable at a given dosage of TCA can develop very strong toxicity if he is subjected to concomitant therapy with one of these inhibitory drugs. Cytochrome P450 2D6 inhibitor drugs include some that are not metabolised by the enzyme (quinidine, cimetidine) and many that are substrates of P450 2D6 (many other antidepressants, phenothiazines and type 1C antiarrhythmics propafenone and flecainide). All selective serotonin re-uptake inhibitors (SSRIs), such as fluoxetine, sertraline and paroxetine, inhibit P450 2D6, but the extent of this inhibition may vary. The extent to which interactions of TCAs with SSRIs can pose clinical problems depends on the degree of inhibition and pharmacokinetics of the SSRIs involved. Nonetheless, caution should be exercised in the combined administration of TCAs and any SSRIs and also in switching from one drug category to another. It is particularly important that sufficient time must elapse before starting TCA treatment in a patient who has stopped taking fluoxetine: this is due to the long half-life of the parent and active metabolite (this may take at least 5 weeks).

Concomitant use of tricyclic antidepressants and drugs that can inhibit cytochrome P450 2D6 may require lower than commonly prescribed doses for both tricyclic antidepressants and other drugs. Also, where one of these other drugs is removed from the therapeutic combination, a higher dose of tricyclic antidepressant may be required. It is desirable to monitor plasma TCA levels when these are co-administered with another drug known to be a P450 2D6 inhibitor (see also Clinical Pharmacology).

INTERACTIONS BETWEEN DRUG AND LABORATORY TESTS: The urinary metabolites of phenothiazines can darken the urine, giving false-positive results for urobilinogen, amylase, uroporphyrins, porphobilinogens and 5-hydroxy-indolacetic acid.

Patients receiving therapeutic doses of phenothiazines may present with electrocardiographic changes, such as a lengthening of the QT interval accompanied by a widening, blunting and incision of the T wave. T wave

The main electrocardiographic alteration observed with amitriptyline is flattening or inversion of T waves. QRS complex enlargement, QT prolongation, as well as abnormal ST segments and T waves are observed following overdose.

Tricyclic antidepressants can lower the seizure threshold and produce abnormal electroencephalographic pictures.

Perphenazine can increase plasma protein-bound iodine levels without causing clinical thyrotoxicosis.

Since phenothiazines can cause decreased adrenocorticoid secretion as a consequence of decreased corticotropin release, perphenazine may interfere with the metyrapone test of hypothalamic-pituitary function.

In patients being treated with phenothiazines, the urine pregnancy test can give both false positive and false negative results.

04.6 Pregnancy and breastfeeding -

Mutabon Antidepressant Tablets should be used during established or suspected pregnancy and lactation only if the potential benefits to the mother justify the potential risk to the fetus or baby.

Pregnancy

Infants exposed to conventional or atypical antipsychotics including Mutabon Antidepressant during the third trimester of pregnancy are at risk for side effects including extrapyramidal or withdrawal symptoms which may vary in severity and duration after birth. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, food intake disturbances. Therefore infants should be carefully monitored.

Feeding time

Perphenazine is rapidly excreted in breast milk and may cause side effects in the breastfed infant. Amitriptyline was measured in human milk. The safety of use of Mutabon Antidepressant during breastfeeding has not been established; therefore, when administering the drug to nursing mothers, it is necessary to evaluate the possible benefits with respect to the possible risks for the mother and the child.

04.7 Effects on ability to drive and use machines -

During therapy with Mutabon Antidepressant, people who work with machines or who drive vehicles should use caution, as the product can induce changes in the reaction time.

04.8 Undesirable effects -

The side effects of Mutabon Antidepressant are the same as its components, perphenazine and amitriptyline hydrochloride. No effects have been reported due solely to their association in Mutabon Antidepressant.

Perphenazine

Not all adverse events listed below have been reported with the use of perphenazine; however, due to the pharmacological similarities between the various phenothiazine derivatives it is necessary to consider them individually. With the piperazine group (to which perphenazine belongs) the most common symptoms are extrapyramidal symptoms while others are less frequent (for example, sedation, jaundice, blood dyscrasia, convulsions and effects on the autonomic nervous system).

Nervous system disorders

Extrapyramidal reactions: opisthotonus, trismus, torticollis, spastic torticollis, pain and numbness in limbs, motor restlessness, oculogyric crisis, hyperreflexia, dystonia, including protrusion, discolouration, pain and rolling of the tongue, tonic spasm of the chewing muscles, constriction throat, confused diction, dysphagia, inability to sit, dyskinesia, parkinsonism and ataxia. Their incidence and severity usually increases with increasing dosage, but there is considerable individual variation in the tendency to develop such symptoms. Extrapyramidal symptoms can usually be controlled with concomitant use of anti-parkinsonian agents, such as benzatropine mesylate, and / or dose reduction. However, in some cases extrapyramidal reactions may persist after discontinuation of treatment with perphenazine.

Late persistent dyskinesia

As with all antipsychotic agents, tardive dyskinesia may occur in some patients on long-term therapy or may arise after discontinuation of treatment. Although the risk appears greater in the elderly, especially in women, treated with high doses of the drug, this phenomenon can also occur in patients of both sexes and in children. Symptoms are persistent and appear irreversible in some patients. There are no known effective therapies for tardive dyskinesia: anti-parkinson drugs do not normally relieve symptoms of this syndrome. Although much less commonly than with prolonged use, this syndrome can develop after relatively short, low-dose treatment periods. Should these symptoms occur, it is suggested that treatment with all antipsychotic agents be discontinued. The syndrome may be hidden if it is necessary to re-institute treatment, increase the dosage or switch to another antipsychotic agent. Mild vermicular movements of the tongue can be an early sign of the syndrome. If you stop treatment at this time, the complete syndrome may not develop.

Other effects on the nervous system

Cerebral edema; abnormalities of cerebrospinal fluid proteins; seizures, particularly in patients with EEG abnormalities or with a history of such disorders, and headache.

Neuroleptic malignant syndrome (NMS) has been reported in patients treated with neuroleptic drugs. It is a relatively uncommon, life-threatening syndrome characterized by severe extrapyramidal dysfunction, accompanied by rigidity and possibly stupor or coma, hyperthermia and autonomic disturbances, including cardiovascular effects (irregular pulse, tachycardia). There is no specific treatment; administration of the neuroleptic drug should be discontinued immediately and appropriate intensive supportive treatment initiated. If treatment with antipsychotic drugs is required for the patient after recovery from NMS, cautionary monitoring is advised, as NMS may recur.

Somnolence may occur, especially during the first or second week of treatment; after which this disorder usually disappears. Hypnotic effects appear to be minimal, especially in patients who are allowed to remain active.

Behavioral Adverse Events

Paradoxical aggravation of psychotic symptoms, catatonic-like states, paranoid reactions, lethargy, paradoxical excitement, restlessness, hyperactivity, nocturnal confusion, bizarre dreams and insomnia. Hyperreflexia has been reported in the newborn when a phenothiazine was administered during pregnancy.

Effects of the autonomous system

Occasionally dry mouth or salivation, nausea, vomiting, gastric retention, diarrhea, anorexia, constipation, obstinate constipation, fecaloma, urinary retention, frequent urination or incontinence, bladder paralysis, polyuria, nasal congestion, pallor, myosis, mydriasis, blurred vision, glaucoma, sweating, hypertension, hypotension and an altered pulse rate. Significant autonomic effects were infrequent in patients treated with less than 24 mg of perphenazine per day.

Adynamic ileus may occasionally occur following phenothiazine therapy and, if severe, can cause complications and death. This is of particular concern in psychiatric patients who may not spontaneously request treatment for this condition.

General disorders and administration site conditions

Urticaria, erythema, eczema, exfoliative dermatitis, pruritus, photosensitivity, asthma, fever, anaphylactoid reactions and laryngeal edema may occur. Angioneurotic edema and contact dermatitis have been reported in nurses who have administered phenothiazines. In extremely rare cases, individual idiosyncrasy or hypersensitivity to phenothiazines have caused cerebral edema, circulatory collapse and death.

Endocrine pathologies

Lactation, galactorrhea, moderate breast enlargement in women and gynecomastia in men after high doses, menstrual disturbances, amenorrhea, libido changes, ejaculation inhibition, false positive pregnancy tests, hyperglycemia, hypoglycemia, glucosuria, inappropriate secretion syndrome antidiuretic hormone (ADH).

Cardiovascular pathologies

Postural hypotension, tachycardia (especially with sudden marked increase in dosage), bradycardia, cardiac arrest, fainting and dizziness. Sometimes the hypotensive effect can cause a shock-like condition. Non-specific changes (quinidine-like effect), usually reversible, of the ECG have been observed in some patients undergoing treatment with phenothiazine tranquilizers.

The following side effects have been observed with other drugs of the same class: rare cases of QT prolongation, ventricular arrhythmias such as torsades de pointes, ventricular tachycardia, ventricular fibrillation and cardiac arrest.

Sudden death has occasionally been reported in patients undergoing treatment with phenothiazines. In some cases, death was apparently due to cardiac arrest; in others, the cause appeared to be asphyxiation due to insufficient cough reflex. In some patients it was not possible to determine the cause of death or to establish whether the death was attributable to phenothiazine.

Cases of venous thromboembolism, including cases of pulmonary embolism and deep vein thrombosis, have been reported with antipsychotic drugs (frequency not known).

Disorders of the blood and lymphatic system

Agranulocytosis, eosinophilia, leukopenia, haemolytic anemia, thrombocytopenic purpura and pancytopenia. Most cases of agranulocytosis occurred between the fourth and tenth week of therapy.

Hepatobiliary disorders

Liver damage (biliary stasis) can occur. Jaundice - which usually appears between the second and fourth weeks of treatment - is considered to be a hypersensitivity reaction. The incidence is low. The clinical picture resembles that of infectious hepatitis but with the laboratory features of obstructive jaundice. It is usually reversible; however chronic jaundice has been reported.

Pregnancy, puerperium and perinatal conditions: neonatal withdrawal syndrome, extrapyramidal symptoms (frequency not known. See section 4.6).

Other effects

Particular factors related to long-term therapy include: skin pigmentation, especially in exposed areas; ocular alterations which consist in the deposit of fine particle substance in the cornea and in the lens and which, in the most serious cases, lead to opacity of the star-shaped lens; epithelial keratopathies; retinal changes; pigmentary retinopathy.

Furthermore: peripheral edema; reverse epinephrine effect; increase in PBI not attributable to an increase in thyroxine; parotid swelling (rare); hyperpyrexia; systemic lupus erythematosus-like syndrome; increased appetite and weight; polyphagia; photophobia; muscle weakness.

Amitriptyline hydrochloride

Although activation of latent schizophrenia has been reported with antidepressant drugs, including amitriptyline hydrochloride, it can be avoided in some cases with Mutabon Antidepressant, due to the antipsychotic effect of perphenazine. Some examples of epileptic seizures have been reported in chronic schizophrenic patients during treatment with amitriptyline hydrochloride.

When using a tricyclic antidepressant, the following adverse reactions should be considered:

General Disorders and Administration Site Conditions: Rash, pruritus, urticaria, photosensitization, face and tongue edema.

Anticholinergic effects

Dry mouth, blurred vision, accommodation disorders, constipation, paralytic ileus, urinary retention, dilation of the urinary tract.

Cardiovascular pathologies

Hypotension, hypertension, tachycardia, palpitations, myocardial infarction, arrhythmias, heart block, stroke.

Nervous system disorders

Confusional states, disturbances in concentration, disorientation, fixations, hallucinations, excitement, nervousness, anxiety, agitation, insomnia, nightmares, deafness, tingling and paraesthesia in the extremities, peripheral neuropathy, lack of coordination, ataxia, tremors, convulsions, alterations in the EEG, extrapyramidal symptoms, tinnitus.

Rare: suicidal ideation / behavior (see section 4.4 Special warnings and precautions for use).

Endocrine pathologies

Swelling of the testicles and gynecomastia in the male, breast enlargement and galactorrhea in the female, increased or decreased libido, raised and lowered blood sugar levels, syndrome of inappropriate ADH secretion.

Gastrointestinal disorders

Nausea, epigastric disorders, heartburn, vomiting, anorexia, stomatitis, taste disturbance, diarrhea, jaundice, swelling of the parotids, dark tongue. Hepatitis (including impaired liver function and jaundice) has occurred rarely.

Disorders of the blood and lymphatic system

Bone marrow depression, including agranulocytosis, leukopenia, eosinophilia, purpura, thrombocytopenia.

Effects related to the therapeutic class

Epidemiological studies, mainly conducted in patients aged 50 or over, show an increased risk of bone fractures in patients being treated with SSRIs and TCAs. The mechanism leading to this increased risk is unknown.

Diagnostic tests

Prolongation of the QT interval on ECG (common rate).

Others

Dizziness, weakness, fatigue, headache, weight gain or loss, increased sweating, urination frequency, mydriasis, somnolence, alopecia.

Withdrawal Symptoms: Abrupt discontinuation of treatment after prolonged administration can produce nausea, headache and malaise. These are not indicative of addiction.

Reporting of suspected adverse reactions

04.9 Overdose -

With this category of drugs, overdose can result in patient death. Ingestion of multiple drugs (including alcohol) is common in deliberate overdose. As the treatment of overdose is complex and changing, it is recommended that the doctor contact a poison control center for up-to-date information on this. The signs and symptoms of toxicity develop rapidly after an overdose; a check-up in the hospital is therefore required as soon as possible.

Symptoms :

Overdose of Mutabon Antidepressant can result in any of the adverse events listed for perphenazine or amitriptyline hydrochloride.

Overdose of perphenazine usually produces extrapyramidal symptoms, such as dyskinesia and dystonia, as described in adverse events; however, they may be masked by the anticholinergic effects of amitriptyline. Other symptoms can include stupor or coma; children can have seizures.

Clinical manifestations of tricyclic antidepressant overdose include: cardiac dysrhythmias, severe hypotension, seizures and CNS depression, including coma. Electrocardiographic changes, particularly in the axis or depth of the QRS, are clinically significant indicators of the toxicity of tricyclic antidepressants. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, overactive reflexes, stupor, sleepiness, muscle stiffness, vomiting, hypothermia, hyperpyrexia or any of the symptoms listed as adverse events.

Treatment :

Generic: Take an ECG and begin cardiac monitoring immediately. Maintain a patent airway for the patient, establish an intravenous line and initiate gastric disinfection. At least 6 hours of cardiac monitoring and observation for signs of the CNS or respiratory depression, hypotension, cardiac dysrhythmias and / or conduction block and seizures are required. Should signs of toxicity occur within this time period, prolongation of monitoring is required. There have been reports of patients dying from fatal dysrhythmias occurring long after overdose; these patients had clinical evidence of significant poisoning prior to death and most of them had undergone inadequate gastrointestinal disinfection. Monitoring of plasma drug levels should not guide patient management. There are no specific antidotes.

Gastrointestinal Disinfection: All patients suspected of overdose with tricyclic antidepressants should undergo gastrointestinal disinfection. It should include large volume gastric lavage followed by administration of activated charcoal. In case of an altered state of consciousness, ensure that the airways are clear before the lavender. Emesis is contraindicated due to the possibility of seizures, central nervous system depression, or a dystonic reaction of the head or neck with subsequent aspiration.

Cardiovascular system: A maximum duration of the QRS trace of the extremities ≥ 0,10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be administered to maintain serum pH in the range 7,45 to 7,55. If the pH response is inadequate, hyperventilation can be used. The simultaneous use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. Values ​​of pH> 7,60 or pCO2 lidocaine, brethyl or phenytoin are not desirable. Type 1A and 1C antiarrhythmic agents are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).

In rare cases, haemoperfusion may be beneficial in refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, transfusions and forced diuresis have generally been reported as ineffective in tricyclic antidepressant poisoning.

Central nervous system (CNS): In patients with CNS depression, early intubation is recommended due to the potential for rapid deterioration of the condition. Seizures can be controlled with benzodiazepines or, if these are ineffective, with other anticonvulsants (eg phenobarbital, phenytoin). Physostigmine is not recommended except for the treatment of life-threatening symptoms that have not reacted to other therapies, and only after consultation with a poison control center.

Psychiatric Follow-up: Since overdose is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric support will be appropriate.

Pediatric population: The principles of managing overdose in children and adults are similar. It is strongly recommended that the physician contact the local poison control center for specific treatment in pediatric age. Although Mutabon Antidepressant is not indicated for children, accidental ingestion can occur.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 Pharmacodynamic properties -

Pharmacotherapeutic group: antidepressants in combination with psycholeptics.

ATC code: N06CA01.

Mutabon Antidepressant combines the anxiolytic, antipsychotic and antiemetic properties of perphenazine with the antidepressant activity of amitriptyline.

Perphenazine carries out actions at all levels of the central nervous system, particularly at the level of the hypothalamus and demonstrates anxiolytic, antipsychotic and antiemetic properties.

Amitriptyline hydrochloride exhibits 3 major pharmacological actions: sedation, anticholinergic activity, and blocking the re-uptake of sympathomimetic amines released into the synaptic space.

The latter action is considered to be more relevant in the relief of depression, although the precise mechanism of clinical antidepressant activity is not known.

05.2 Pharmacokinetic properties -

Perphenazine:

Absorption

Phenothiazines are readily absorbed from the gastrointestinal tract and parenteral sites.

60% to 70% of an orally administered dose is rapidly removed from the portal circulation and the enterohepatic circulation is very active.

This results in less unchanged drug in the circulation, compared to what happens after parenteral administration.

Distribution

After absorption, phenothiazines are rapidly distributed in the tissues. Drugs are highly lipophilic and highly bound to membranes and proteins.

High concentrations of unchanged drug are found in the brain, while metabolites predominate in the lungs, liver, kidney and spleen.

Biotrasformazione

Phenothiazines are metabolised mainly in the liver, through mechanisms of oxidation, hydroxylation, demethylation, sulfoxide formation and conjugation with glucuronic acid. The pharmacokinetics of perphenazine varies with debrisoquine hydroxylation which is mediated by cytochrome P450 2D6 (CYP 2D6) and is therefore prone to polymorphism - i.e., 7-10% of the Caucasian population and a low percentage of Asians have little or no activity. and are referred to as "poor metabolisers". CYP 2D6 "poor metabolisers" metabolize perphenazine more slowly and will have higher concentrations of this substance than normal or "strong" metabolisers.

Elimination from plasma may be faster than from high-fat, highly bound sites, particularly in the central nervous system.

Amitriptyline hydrochloride:

Absorption

Following oral administration, tricyclic antidepressants are absorbed relatively rapidly with peak plasma levels observed within 2-4 hours.

The amount of unchanged drug available is affected by hepatic "first-pass" metabolism.

Steady-state plasma levels are generally reached within 7-21 days and remain relatively constant thereafter.

The elimination half-life of amitriptyline after a single oral dose ranges from 10 to 43 hours. At usual therapeutic concentrations, plasma concentrations of tricyclic antidepressants are low.

Biotrasformazione

Amitriptyline, a tertiary amine is metabolized to nortriptyline, a secondary amine, its derivative. The N-demethylation process is mediated by cytochrome P450 3A4, -2C9, -2D6 and an unidentified enzyme. Both amitriptyline and nortriptyline undergo CYP 2D6-mediated hydroxylation. Subjects with reduced cytochrome P450 2D6 activity ("poor metabolisers") may have higher than expected plasma concentrations of amitriptyline.

Subsequent oxidation, followed by glucuronidation, leads to the formation of metabolites that are less pharmacologically active.

elimination

The active ingredients and their metabolites are excreted in the urine and via the bile, in the faeces.

05.3 Preclinical safety data -

Experimental animals tolerate, without showing toxic symptoms, doses of Mutabon Antidepressant much higher than those recommended in humans, even for 2-3 months of administration.

La perfenazine, like most neuroleptics, at low doses it reduces the exploratory behavior of the animals, without eliminating their discriminatory capacities and inhibits nutrition.

At high doses it causes the characteristic catatonic immobility of the animals, which maintain the position in which they are placed, even if uncomfortable, with an increase in muscle tone and indifference to most of the stimuli.

Even at very high doses, perphenazine does not cause coma and the lethal dose is extremely high.

There is published evidence indicating that chlorinated phenothiazine drugs, such as perphenazine, potentially induce photogotoxicity in vitro upon light activation. Post marketing experience has not identified any increased risk of photomutagenesis and / or carcinogenesis due to exposure to light in more than 40 years of marketing.

L'amitriptilina hydrochloride causes cerebral intoxication with antimuscarinic, but also cardiotoxic effects.

The LD50 is 800-900 mg / kg in rats and 322 mg / kg in rabbits. Rat and rabbit tolerated, respectively, 6-18 mg / kg and 10 mg / kg for 5 days a week, for 6 and 4 weeks both in behavioral and laboratory terms.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Rice starch, lactose, magnesium stearate, povidone, opadry pink (hypromellose E-464, macrogol, titanium dioxide E-171, hydroxypropylcellulose E-464, erythrosine E-127, aluminum lake).

06.2 Incompatibility -

Not relevant.

06.3 Period of validity -

3 years.

06.4 Special precautions for storage -

No particular precautions for storage.

06.5 Nature of the immediate packaging and contents of the package -

Carton containing blisters of 30 film-coated tablets of 2 mg + 25 mg.

06.6 Instructions for use and handling -

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER -

Neopharmed Gentili S.r.l.

Via San Giuseppe Cottolengo, 15

20143 Milan

08.0 MARKETING AUTHORIZATION NUMBER -

Mutabon Antidepressant 2 mg + 25 mg film-coated tablets 30 tablets

AIC: 021460023

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

Date of first authorization: December 1984

Date of most recent renewal: 01 June 2010

10.0 DATE OF REVISION OF THE TEXT -

July 2016

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -