Instruction for use: Fluoxetine

Latin name of substance Fluoxetine

Fluoxetinum (genus. Fluoxetini)

Chemical name

(±) -N-Methyl-gamma- [4- (trifluoromethyl) phenoxy] benzenepropanamine (and as hydrochloride); racemic (50/50) mixture of R- and S-enantiomers

Gross formula

C₁₇H₁₈F₃NO

Pharmacological group:

Antidepressant

The nosological classification (ICD-10)

F32 Depressive episode: Adynamic subdepression; Astheno-adynamic subdepressive states; Asthenoadressive disorder; Astheno-depressive disorder; Asthenodepressive state; Astheno-depressive state; Major Depressive Disorder; Vyaloapatichesky depression with retardation; Double Depression; Depressive pseudodement; Depressive illness; Depressive mood disorder; Depressive disorder; Depressive mood disorder; Depressive state; Depressive disorders; Depressive syndrome; Depressive syndrome larviated; Depressive syndrome in psychoses; Depressed masks; Depression; Depression Depletion; Depression with the phenomena of inhibition within the framework of cyclothymia; Depression is smiling; Involutional depression; Involutionary melancholy; Involutional depression; Manic-depressive disorder; Masked Depression; Melancholic Attack; Neurotic depression; Neurotic depression; Shallow Depression; Organic depression; Organic depressive syndrome; Simple depression; Simple melancholic syndrome; Psychogenic depression; Reactive depression; Reactive depression with moderate psychopathological symptoms; Reactive depressive states; Reactive depression; Recurrent depression; Seasonal depressive syndrome; Severostatic depression; Senile Depression; Symptomatic Depression; Somatogenic depression; Cyclotymic depression; Exogenous depression; Endogenous depression; Endogenous Depressive Conditions; Endogenous Depression; Endogenous depressive syndrome

F41.2 Mixed anxiety and depressive disorder: Depression with anxiety-depressive components; Mixed anxiety-depressive conditions; Anxiety Depression; Anxious and depressing mood; Anxiety-depressive state; Anxious-depressive conditions; Anxiety-depressive syndrome; Anxious-Neurotic Conditions

F42 Obsessive-compulsive disorder: Obsessive-compulsive syndrome; Obsessive compulsive states; Obsessive-compulsive syndrome; The Obsession Syndrome; The obsession neurosis; Obsessive-compulsive neurosis; Obsessions

F50.2 Nervous Bulimia: Bulimic Neurosis; Bulimia; Wolf hunger; Kinorexia

CAS code

54910-89-3

Characteristics of substance Fluoxetine

Bicyclic antidepressant, SSRIs.

Fluoxetine hydrochloride is a white or off-white crystalline powder that is hardly soluble in water (14 mg / ml). Molecular weight 345.79.

Pharmacology

Pharmacological action - antidepressant, anorexigenic.

Selectively inhibits the reuptake of serotonin, which leads to an increase in its concentration in the synaptic cleft, enhancing and prolonging its effect on postsynaptic receptors. Increasing serotonergic transmission, by the mechanism of negative feedback inhibits the exchange of the neurotransmitter. With prolonged use lowers the activity of 5-HT1-receptors. It also blocks the reuptake of serotonin in platelets. Poorly affects the re-uptake of norepinephrine and dopamine. Has no direct effect on serotonin, m-cholinergic, H1-histamine and alpha-adrenergic receptors. Unlike most antidepressants, does not cause a decrease in the activity of postsynaptic beta-adrenoreceptors.

Effective with endogenous depression and obsessive-compulsive disorders. Improves mood, reduces tension, anxiety and fear, eliminates dysphoria. Has an anorexigenic effect, can cause weight loss. In patients with diabetes mellitus can cause hypoglycemia, with the abolition of fluoxetine - hyperglycemia. The expressed clinical effect at depression comes in 1-4 weeks of treatment, at obsessive-compulsive disorders - after 5 weeks or more.

Well absorbed from the digestive tract. The effect of "first passage" through the liver is weakly expressed. Capsules and an aqueous solution of fluoxetine are equivalent in effectiveness. After a single dose of 40 mg Cmax fluoxetine is achieved after 4-8 hours and is 15-55 ng / ml, with the same dose for 30 days Cmax fluoxetine is 91-302 ng / ml, norfluoxetine - 72-258 ng / ml. At a concentration of 200-1000 ng / ml, fluoxetine is 94.5% bound to blood proteins, including albumin and alpha1-glycoprotein. Enantiomers are equally effective, but S-fluoxetine is more slowly excreted and predominates over the R-form at equilibrium concentration. Easily penetrates the BBB. In the liver, the enantiomers are demethylated with the participation of cytochrome P450 isoenzyme CYP2D6 to norfluoxetine and other unidentified metabolites, with S-norfluoxetine in activity equal to R- and S-fluoxetine and superior to R-norflouxetine. T1 / 2 fluoxetine is 1-3 days after a single dose and 4-6 days with prolonged administration. T1 / 2 norfluoxetine - 4-16 days in both cases, which causes significant cumulation of substances, slow achievement of their equilibrium level in plasma and prolonged presence in the body after cancellation. In patients with cirrhosis of the liver, T1 / 2 fluoxetine and its metabolites are lengthened. It is excreted for 1 week mainly with kidneys (80%): unchanged, 11.6%, fluoxetine glucuronide 7.4%, norfluoxetine 6.8%, norfluoxetine glucuronide 8.2%, more than 20% - hippuric acid, 46% - other compounds; 15% is excreted by the intestine. If the renal function is impaired, the excretion of fluoxetine and its metabolites slows down. When dialysis is not withdrawn (due to the large volume of distribution and a high degree of binding to plasma proteins).

There are data on the effectiveness of fluoxetine in eating disorders (anorexia nervosa), alcoholism, anxiety disorders, including social phobia; Diabetic neuropathy, affective, incl. bipolar, disorders; dysthymia, autism, panic attacks, premenstrual syndrome, narcolepsy, catalepsy, obstructive sleep apnea syndrome, kleptomania, schizophrenia, schizoaffective disorders, etc.

Use of fluoxetine

Depression (especially accompanied by fear), incl. with inefficacy of other antidepressants, obsessive-compulsive disorders, bulimia nervosa.

Contraindications

Hypersensitivity, the use of MAO inhibitors (in the previous 2 weeks), hepatic and renal insufficiency (creatinine clearance less than 10 ml / min), epilepsy and convulsions (in the anamnesis), suicidal tendencies, diabetes mellitus, atony of the bladder, angle-closure glaucoma, hypertrophy of the prostate glands.

Restrictions on the use

Children's age (safety and efficacy not established), myocardial infarction, incl. in history, cirrhosis.

Application in pregnancy and lactation

When pregnancy should be prescribed only in case of emergency. When fluoxetine was used during pregnancy, there was an increased risk of premature birth, developmental abnormalities, and low adaptation of newborns (including difficulty breathing, cyanosis, excitability).

The action category for fetus by FDA is C.

For the duration of treatment, breastfeeding should be discarded (fluoxetine penetrates the breast milk of lactating women).

Update of information

The use of fluoxetine in the first trimester of pregnancy

A sufficient number of controlled studies to study the safety of fluoxetine in women during the first trimester of pregnancy have not been carried out, and the results of some published epidemiological studies are inconsistent. More than 10 cohort studies and case-control studies did not reveal an increase in the likelihood of congenital malformations. At the same time, a prospective cohort study conducted by the European Network of Teratology Information Services suggests an increased risk of developing congenital cardiovascular malformations in neonates whose mothers (n = 253) used fluoxetine during the first trimester of pregnancy compared to newborns , whose mothers (n = 1359) did not take fluoxetine. At the same time, a specific group of developmental defects of the cardiovascular system was not identified and it was not possible to establish a reliable causal relationship between fluoxetine intake during the first trimester of pregnancy and an increased risk of fetal development abnormalities.

The use of fluoxetine in the III trimester of pregnancy

The use of serotonin and norepinephrine reuptake inhibitors (SSRIs), as well as SSRIs, including fluoxetine, at the end of the third trimester of pregnancy led to the development of complications in newborns (the length of hospitalization, the duration of artificial lung ventilation and probe feeding increased). There are reports of the development of such pathological conditions as neonatal respiratory distress syndrome, apnea, convulsions, lability of body temperature, hypoglycemia, lowering or elevation of arterial pressure, vomiting, difficulty in adequate nutrition, cyanosis, hyperreflexia, tremor, nervous irritability, excitability, constant crying. The listed disorders can be a manifestation of the toxic effects of SSRIs and SSRIs, or be a consequence of the withdrawal syndrome.

Data of studies of teratogenicity of fluoxetine in animals

When fluoxetine is administered, at doses exceeding 12.5 mg / kg per day in pregnant female rats, and at doses exceeding 15 mg / kg per day in pregnant rabbit females (1.5 and 3.6 times, respectively, the maximum dose recommended for human - 80 mg / m2), there was no reliable evidence of the teratogenicity of fluoxetine during the organogenesis process. However, data from other tests in rats indicate an increase in stillbirths, a decrease in the weight of newborns, and an increase in the mortality of newborn rats for 7 days after birth with fluoxetine administered at a dose of 12 mg / kg per day (1.5 times the maximum dose recommended for humans) during pregnancy and at a dose of 7.5 mg / kg per day (90% of the maximum dose recommended for a person) during pregnancy and lactation. At the same time, there were no signs of neurotoxicity in surviving newborn female rats receiving 12 mg / kg fluoxetine per day during pregnancy. The dose of fluoxetine 5 mg / kg per day (60% of the maximum dose recommended for humans) was defined as not increasing the mortality of newborn animals.

Side effects of substance Fluoxetine

From the nervous system and sense organs: headache, dizziness, anxiety, nervousness, lethargy, fatigue, asthenic syndrome, emotional lability, sleep disorders (insomnia, drowsiness), nightmares, motor anxiety, muscle twitching, myoclonus, tremor, hyperkinesia, convulsive states, hypo- or hyperreflexia, extrapyramidal syndrome, carpal tunnel syndrome, ataxia, akathisia, dysarthria, hyper- or hypoesthesia, paresthesia, neuralgia, neuropathy, neuritis, neurosis, muscle disorders difficulty in concentrating, amnesia, euphoria, mania or hypomania, hallucinations, depersonalization, paranoid reactions, psychosis, suicidal tendencies, EEG changes, stupor, coma, visual acuity, amblyopia, strabismus, diplopia, exophthalmus, mydriasis, conjunctivitis, iritis, scleritis, blepharitis, xerophthalmia, photophobia, glaucoma, taste disorders, parosmia, noise and pain in the ears, and hyperacia.

From the cardiovascular system and blood (hematopoiesis, hemostasis): tachy- or bradycardia, extrasystole, atrial fibrillation or ventricles, cardiac arrest, myocardial infarction, congestive heart failure, hyper- or hypotension, vascular dilation, phlebitis, thrombophlebitis, vascular thrombosis , vasculitis with hemorrhagic rash, cerebral ischemia, cerebral vascular embolism, anemia, leukocytosis or leukopenia, lymphocytosis, thrombocythemia, thrombocytopenia, pancytopenia.

On the part of the respiratory system: nasal congestion, epistaxis, sinusitis, laryngeal edema, shortness of breath, stridor, hyper or hypoventilation, hiccough, cough, respiratory distress syndrome, changes in lung inflammatory or fibrotic nature, atelectasis, emphysema, pulmonary edema, hypoxia , apnea, chest pain.

On the part of the digestive system: a decrease in the (rarely increased) appetite, anorexia, dry mouth, increased salivation, an increase in salivary glands, aphthous stomatitis, glossitis, dysphagia, esophagitis, gastritis, dyspepsia, nausea, vomiting, incl. hematemesis, abdominal pain, acute stomach syndrome, gastric and duodenal ulcer, gastrointestinal bleeding, flatulence, diarrhea, constipation, melena, colitis, intestinal obstruction, increased levels of hepatic transaminases, creatine phosphokinase and alkaline phosphatase in the blood, hepatitis, cholelithiasis, cholestatic jaundice, hepatic insufficiency, liver necrosis, pancreatitis.

On the part of metabolism: violation of ADH secretion, hyponatremia, hypo- or hyperkalemia, hypocalcemia, hyperuricemia, gout, hypercholesterolemia, diabetes mellitus, hypoglycemia, diabetic acidosis, hypothyroidism, edema, dehydration.

On the part of the genitourinary system: dysuria, frequent urination, nocturia, poly- or oliguria, albumin and proteinuria, glucosuria, hematuria, urinary tract infections, cystitis, renal failure, hyperprolactinaemia, increased and pain in the mammary glands, decreased libido, ejaculatory disorders, priapism, impotence, anorgasmia, painful menstruation, meno- and metrorrhagia.

From the musculoskeletal system: myasthenia gravis, myopathy, myalgia, myositis, arthralgia, arthritis, rheumatoid arthritis, bursitis, tenosynovitis, chondrodystrophy, osteomyelitis, osteoporosis, bone pain.

From the skin: polymorphic rash, incl. hemorrhagic, ulcerative skin lesions, acne, alopecia, contact dermatitis, photosensitivity, discoloration, furunculosis, shingles, hirsutism, eczema, psoriasis, seborrhea, epidermal necrosis, exfoliative dermatitis.

Allergic reactions: rash, itching, urticaria, Quincke's edema, reactions like serum sickness, anaphylactic and anaphylactoid reactions.

Other: weight loss, sweating, hyperemia of the face and neck with a sensation of heat, malignant neuroleptic syndrome, yawning, chills, fever, flu-like syndrome, hypothermia, lymphadenopathy, incl. augmentation of tonsils, pharyngitis. Lethal outcomes are described.

Interaction

Incompatible with MAO inhibitors, other antidepressants, furazolidone, procarbazine, t. causes serotonergic syndrome (chills, hyperthermia, muscle rigidity, myoclonus, autonomic lability, hypertensive crisis, agitation, tremor, motor anxiety, convulsions, diarrhea, hypomanic condition, delirium, coma, possible fatal outcome. With simultaneous reception with drugs having a high degree binding with plasma proteins (oral anticoagulants, oral hypoglycemic agents, cardiac glycosides, etc.), it is possible to mutually displace from the bond with the protein with a change in the concentration of free ph blood pressure, the risk of side effects increases, the risk of bleeding increases with the use of warfarin, inhibits the biotransformation of drugs metabolized with the participation of the cytochrome P450 isoenzyme CYP2D6 (tricyclic antidepressants, dextromethorphan, etc.) Extends T1 / 2 diazepam, potentiates the effects of alprazolam. With simultaneous administration changes (increases or decreases) the concentration of lithium in blood plasma, increases the content of phenytoin (before the clinical manifestations of its overdose); the level of tricyclic antidepressants (imipramine, desipramine) increases 2-10 times. Tryptophan enhances the serotonergic properties of fluoxetine (agitation, motor anxiety, and abnormal gastrointestinal function are possible). Incompatible with ethanol.

Update of information

Additional information about the drug interaction of fluoxetine

Contraindicated the use of fluoxetine in combination with MAO inhibitors, as well as within 14 days after their withdrawal in order to avoid the risk of interaction. The appointment of MAO inhibitors is possible only 5 weeks after the abolition of fluoxetine.

It is not recommended simultaneous use of fluoxetine and pimozide. Clinical studies of the safety of pimozide in combination with other antidepressants have shown that their simultaneous administration may lead to an extension of the corrected QT interval (QTc). Although no special studies have been conducted to study the safety of simultaneous use of pimozide and fluoxetine, the potential for drug interaction, mainly the prolongation of the QTc interval, is sufficient to limit the combined use of these drugs.

A study was conducted with 19 healthy volunteers - 6 slow and 13 fast metabolizers for the enzyme debrizohin hydroxylase, taking 25 mg thioridazine orally once. Cmax in slow metabolizers was 2.4 times higher, AUC - 4.5 times more compared to fast metabolizers. It is known that the activity of debrisohin hydroxylase depends on the level of activity of the isoenzyme of the cytochrome P450 CYP2D6 system. Thus, this study demonstrated that preparations inhibiting the isoenzyme CYP2D6, such as selective serotonin reuptake inhibitors, in particular fluoxetine, can increase the concentration of thioridazine in the blood plasma. Thioridazine has the ability to dose-dependently prolong QTc, which causes the risk of life-threatening forms of ventricular arrhythmias, such as pirouette torsades de pointes, and sudden death, the likelihood of which increases with simultaneous administration of thioridazine with fluoxetine.

Taking into account the risk of developing life-threatening forms of ventricular arrhythmias and sudden death with simultaneous administration of thioridazine and fluoxetine, it should be noted that such a therapeutic combination is contraindicated, and thioridazine is possible after 5 weeks from the last administration of fluoxetine.

Fluoxetine inhibits the activity of the cytochrome P450 isoenzyme system of CYP2D6 and thus changes the normal metabolic activity of the isoenzyme to a level similar to that of slow metabolizers. Other drugs metabolized by the CYP2D6 isoenzyme, such as tricyclic antidepressants (TCAs), neuroleptics (including phenothiazines and most atypical antipsychotics), antiarrhythmics (propafenone, flecainide, etc.) should be used with caution in combination with fluoxetine. If a patient takes fluoxetine or has taken it for the last 5 weeks, therapy with drugs metabolized primarily by CYP2D6 and having a narrow therapeutic range (eg, flecainide, propafenone, vinblastine and TCAs) should begin with the lowest possible doses (dose selection should occur as in the case of the appointment of slow metabolizers for this isoenzyme of the cytochrome P450 system). When administering fluoxetine to a patient already receiving drugs metabolized by the CYP2D6 isoenzyme, the need to adjust the dosage of these drugs towards reducing it should be considered.

In some patients, lengthening of T1 / 2 diazepam is possible with simultaneous administration of fluoxetine. The combined use of alprazolam and fluoxetine was accompanied by an increase in serum concentrations of alprazolam, leading to inhibition of psychomotor activity.

Some clinical data indicate a possible drug interaction between neuroleptics and selective serotonin reuptake inhibitors. In particular, there was an increase in the concentrations of haloperidol and clozapine in patients receiving fluoxetine as a concomitant therapy.

Both the decrease and increase of serum lithium concentration are reported with the simultaneous use of fluoxetine. In the latter case, the likelihood of developing toxic effects of both normotimic drugs and selective serotonin reuptake inhibitors increases. With the simultaneous administration of lithium and fluoxetine, it is necessary to constantly monitor the concentration of lithium in the blood plasma.

An in vivo study showed that a single administration of terfenadine (substrate CYP3A4) against fluoxetine is not accompanied by an increase in serum concentrations of terfenadine.

In vitro studies have shown that ketoconazole, an effective inhibitor of the cytochrome P450 isoenzyme inhibitor CYP3A4, is at least 100 times more active than fluoxetine and norfluoxetine interferes with the metabolism of CYP3A4 substrates (such as astemizole, cisapride, midazolam). Thus, the inhibitory ability of fluoxetine in relation to the isoenzyme of the cytochrome P450 CYP3A4 system is not clinically significant.

Fluoxetine, when administered at a dose of 60 mg once or for 8 days, leads to a slight (about 16%) decrease in the clearance of olanzapine and an increase in the value of C max.

In patients receiving fixed doses of phenytoin and carbamazepine, their plasma concentrations increased with the development of clinical manifestations of toxic effects, with the addition of fluoxetine as a concomitant therapy.

Overdose

Symptoms: nausea, vomiting, agitation, anxiety, hypomania, seizures, major epileptic seizures. Two deaths from an acute fluoxetine overdose (in combination with maprotiline, codeine, temazepam) are described.

Treatment: gastric lavage, reception of activated charcoal, sorbitol, ECG monitoring, symptomatic and maintenance therapy, with convulsions - diazepam. There is no specific antidote. Forced diuresis, peritoneal dialysis, hemodialysis, blood transfusion are ineffective.

Routes of administration

Inside.

Precautions for the substance Fluoxetine

With caution appoint in the elderly, with cardiovascular disease, insufficiency of the liver and / or kidney function. It requires careful monitoring of patients with suicidal tendencies, especially at the beginning of treatment. The greatest risk of suicide in patients who have previously taken other antidepressants, and patients who have excessive fatigue, hypersomnia, or motor anxiety with fluoxetine. In the treatment of patients with low body weight, the anorexigenic properties of fluoxetine should be taken into account. When conducting electroconvulsive therapy with fluoxetine, prolonged epileptic seizures are possible. The interval between cancellation of MAO inhibitors and the onset of fluoxetine should be more than 2 weeks, and between the abolition of fluoxetine and the intake of MAO inhibitors - at least 5 weeks.

With caution apply to drivers of vehicles and people whose activities require increased concentration and speed of psychomotor reactions. During treatment should avoid drinking alcohol.

Update of information

Use of fluoxetine in older patients

Clinical studies, including 687 patients over 65 years of age and 93 patients older than 75 years, demonstrated the efficacy of fluoxetine in these patients. There was no difference in the safety and efficacy of fluoxetine between this age group of patients and young patients. According to the data obtained during the clinical use of the drug, the response to fluoxetine therapy in older patients and young patients did not differ. Despite this, it should be taken into account the possible increased sensitivity to the drug in some patients of the older age group. The use of serotonin and noradrenaline reuptake inhibitors (SSRIs), as well as SSRIs, including fluoxetine, is associated with cases of clinically significant hyponatremia in elderly patients, the risk of which may initially be higher in this group of patients.

QT interval extension

In the postmarketing period, cases of prolongation of the QT interval and development of ventricular arrhythmia were recorded in patients taking fluoxetine, incl. torsade de pointes.

Caution should be used fluoxetine in patients with conditions that predispose to prolongation of QT and ventricular arrhythmia, including. with congenital forms of QT prolongation syndrome, with QT prolongation in history, incl. family. In addition, the risk of QT prolongation increases concurrently used drugs that cause prolongation of the QT interval, hypokalemia or hypomagnesemia, recent myocardial infarction, uncompensated heart failure, bradyarrhythmia and other significant arrhythmias, as well as conditions that predetermine an increase in fluoxetine exposure (overdosage, liver failure, use of inhibitors of CYP2D6, weak CYP2D6 metabolo, use of other drugs with high binding to proteins).