Active ingredients: Fluoxetine
AZUR 20 mg hard capsules Fluoxetine
Why is Azur used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antidepressants. Selective serotonin reuptake inhibitors.
THERAPEUTIC INDICATIONS
AZUR is indicated in the treatment of depression, obsessive compulsive disorder and bulimia nervosa.
Contraindications When Azur should not be used
On rare occasions, the development of a serotonin syndrome or neuroleptic malignant syndrome-like events have been reported in association with fluoxetine treatment, particularly when fluoxetine is administered in combination with other serotonergic drugs (among others L-tryptophan) and / or neuroleptics. Since these syndromes can give rise to potentially life-threatening conditions for the patient, if such events occur (characterized by groupings of symptoms such as hyperthermia, rigidity, myoclonus, autonomic nervous system instability with possible rapid fluctuations of vital signs, changes in the state including confusion, irritability and extreme agitation up to delirium and coma) treatment with fluoxetine should be discontinued and symptomatic supportive treatment initiated.
Precautions for use What you need to know before taking Azur
For use by children and adolescents under the age of 18
Suicide-related behaviors (suicide attempt and suicidal thoughts) and hostile attitude (especially aggressive, oppositional and anger behavior) were observed more frequently in clinical trials in children and adolescents treated with antidepressants than in those treated with placebo. Azur is for use in children and adolescents 8 to 18 years of age only for the treatment of moderate to severe major depressive episodes and should not be used in other indications. If, based on medical need, a decision to treat is made, the patient should be carefully monitored for the appearance of suicidal symptoms. Furthermore, only limited data are available in children and adolescents regarding long-term effects on safety, including effects on growth, sexual maturation, and cognitive, emotional and behavioral development.
In a clinical study of 19 weeks duration, a reduction in height and weight gain was observed in children and adolescents treated with fluoxetine (see section Undesirable effects). It has not been established whether there is an effect on the achievement of "normal height of the adult". The possibility of a delay in puberty cannot be excluded (see section Undesirable effects). Pubertal growth and development (height, weight and TANNER staging) should therefore be monitored during and after treatment with fluoxetine. If both are slowed, a pediatric evaluation should be requested.
In pediatric clinical trials, mania and hypomania were reported frequently (see Undesirable effects section). Therefore, regular monitoring for the onset of mania / hypomania is recommended. Fluoxetine should be discontinued in any patient entering a manic phase.
It is important that the doctor carefully discusses the risks and benefits of treatment with the child or young person and / or their parents.
Rash and allergic reactions: Rash, anaphylactoid events and progressive systemic events, sometimes serious (involving skin, kidney, liver or lung), have been reported. Upon the appearance of skin rash or other allergic phenomena for which a different etiology cannot be identified, the administration of fluoxetine must be discontinued.
Precautions
Seizures: Seizures pose a potential risk with antidepressant medications. Therefore, as with other antidepressants, fluoxetine should be administered with caution to patients with a history of seizures. Treatment should be discontinued in any patient who experiences seizures or in whom an increase in seizure frequency is observed. Administration of fluoxetine should be avoided in patients with unstable seizure disorders / epilepsy and patients with controlled epilepsy should be carefully monitored.
Mania: Antidepressants should be used with caution in patients with a history of mania / hypomania. Like all antidepressant drugs, fluoxetine should be discontinued in any patient entering a manic phase.
Hepatic / Renal Function: Fluoxetine is extensively metabolised by the liver and eliminated by the kidneys. In patients with significant hepatic dysfunction a lower dose of 20 mg per day is recommended, e.g. an alternate day dosage. When fluoxetine 20 mg daily was administered for 2 months, patients with severe renal impairment (GFR <10 mL / min) requiring dialysis showed no difference in plasma levels of fluoxetine or norfluoxetine compared to controls with normal renal function. .
Cardiac Disease: None of the conduction alterations leading to cardiac arrest were observed on ECG in 312 patients who received fluoxetine in double-blind clinical trials. However, clinical experience in acute cardiac disease is limited, so caution is advised.
Weight loss: Weight loss may occur in patients taking fluoxetine, but this is usually proportional to the starting body weight.
Diabetes: In diabetic patients, treatment with an SSRI can alter glycemic control. Hypoglycaemia occurred during fluoxetine therapy, while hyperglycaemia developed after drug discontinuation. Dosage adjustment of the insulin and / or oral hypoglycemic agent may be required.
Suicide / suicidal thoughts or clinical worsening: Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission of the disease occurs. As improvement may not occur during the first or subsequent weeks of treatment, patients should be closely monitored until improvement occurs. It is general clinical experience that the risk of suicide can increase early in the healing process.
Other psychiatric conditions in which Azur is prescribed may also be associated with an increased risk of suicide-related events. Furthermore, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be implemented when treating patients with other psychiatric disorders.
Among patients with a history of suicide-related events, those with a significant degree of suicidal ideation prior to initiation of treatment have an increased risk of suicidal thoughts and suicide attempts, and should receive close monitoring during treatment.A meta-analysis of clinical trials conducted with antidepressant medicinal products compared with placebo in the treatment of psychiatric disorders showed an increased risk of suicidal behavior in patients under 25 years of age treated with antidepressants compared to placebo.
Close surveillance of patients, and particularly those at high risk, should accompany drug therapy especially in the initial stages of treatment and after dose changes. Patients (or their carers) should be advised of the need to monitor and report immediately to the treating physician any worsening of the clinical picture, the onset of suicidal behavior or thoughts or unusual changes in behavior if these symptoms occur. .
Akathisia / psychomotor restlessness: The use of fluoxetine has been associated with the development of akathisia, characterized by a "subjectively unpleasant or distressing restlessness and need to move often accompanied by an" inability to sit or stand still. This is more likely to occur. occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be harmful.
Discontinuation symptoms observed on discontinuation of SSRI treatment: Discontinuation symptoms are common when treatment is stopped, especially if discontinuation occurs abruptly (see section "Undesirable effects"). In clinical trials, adverse events observed with abrupt discontinuation of treatment occurred in approximately 60% of patients in both the fluoxetine and placebo groups. Of these adverse events, 17% in the fluoxetine group and 12% in the fluoxetine group. with placebo were severe in nature.
The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. The most commonly reported reactions are dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and / or vomiting, tremor and headache. Generally these symptoms are mild to moderate in intensity, however in some patients they may be severe in intensity. These symptoms usually occur within the first few days of stopping treatment. Generally these symptoms are self-limiting and usually resolve within 2 weeks, although in some individuals they may be prolonged (2-3 months or more). We therefore recommend Azur is gradually tapered over a period of at least 1-2 weeks prior to stopping treatment, as needed by the patient (see "Withdrawal symptoms seen on discontinuation of Azur" section Dose, method and time of administration ") .
Haemorrhage: Skin bleeding manifestations such as ecchymosis and purpura have been reported with SSRIs. Ecchymosis has been reported as an infrequent event during treatment with fluoxetine. Other haemorrhagic manifestations (e.g. gynecological haemorrhages, gastrointestinal bleeding and other cutaneous or mucosal bleeding) have been reported rarely.
Caution is advised in patients taking SSRIs, especially during concomitant use with oral anticoagulants, drugs known to affect platelet function (eg atypical antipsychotics such as clozapine, phenothiazines, most tricyclic antidepressants, aspirin , NSAIDs) or other drugs that may increase the risk of bleeding, as well as in patients with a history of bleeding disorders.
Electroconvulsive therapy (ECT): In fluoxetine-treated patients receiving ECT treatment, there have been rare reports of prolonged seizures, so caution is advised.
St John's wort: When selective setononin reuptake inhibitors and herbal preparations containing St John's wort (Hypericum perforatum) are used together, increased serotonergic-type effects, such as serotonin syndrome, may occur.
Interactions Which drugs or foods may change the effect of Azur
Tell your doctor or pharmacist if you have recently taken any medicines, even those without a prescription
Interaction studies have only been performed in adults.
Half-life: The long elimination half-lives of both fluoxetine and norfluoxetine should be borne in mind when considering pharmacodynamic or pharmacokinetic drug interactions (e.g. when switching from fluoxetine to other antidepressants).
Monoamine Oxidase Inhibitors: (see "Contraindications" section).
Combinations not recommended: MAOI-Type A (see section "Contraindications").
Associations requiring precautions for their use:
MAOI-Type B (selegiline): risk of serotonin syndrome. Clinical monitoring is recommended.
Phenytoin: Alterations in blood levels have been observed when combined with fluoxetine. In some cases, manifestations of toxicity have occurred. It is therefore advisable to administer phenytoin according to conservative therapeutic schemes and to carefully follow the patient's clinical conditions.
Central Nervous System Drugs: Administration of fluoxetine may cause increased blood levels of carbamazepine, haloperidol, clozapine, alprazolam, imipramine, and desipramine; in some cases clinical manifestations of toxicity were observed. It is therefore advisable to administer the concomitant drug according to prudent therapeutic schemes and to follow the patient's clinical conditions.
Diazepam: There may be a prolongation of the effects of this drug.
Serotonergic drugs: Co-administration with serotonergic drugs (eg tramadol, triptans) may increase the risk of developing a serotonin syndrome. The association with triptans adds an additional risk of coronary vasoconstriction and arterial hypertension.
Lithium and tryptophan: When SSRIs have been administered in combination with lithium or tryptophan there have been reports of serotonin syndrome and, therefore, the concomitant use of fluoxetine with these drugs should be done with caution. When fluoxetine is given in combination with lithium, more targeted and frequent clinical monitoring is required.
CYP2D6 isoenzyme: Since the metabolism of fluoxetine (as for tricyclic antidepressants and other selective antidepressants for serotonin) affects the isoenzymatic system of cytochrome CYP2D6 in the liver, concomitant therapy with drugs equally metabolised by this enzyme system may lead to drug interactions. Concomitant therapy with drugs predominantly metabolised by this isoenzyme, and which have a limited therapeutic index (such as flecainide, encainide, carbamazepine and tricyclic antidepressants), should be initiated or adapted from the lowest effective dose. This will need to be done even if fluoxetine was taken within the previous 5 weeks.
Oral anticoagulants: Altered anticoagulant effects (laboratory data and / or clinical symptoms and signs), which do not fit into a homogeneous category, but include increased bleeding, have been observed infrequently following concomitant administration of fluoxetine and oral anticoagulants. When fluoxetine therapy is initiated or discontinued in patients receiving warfarin, close coagulation monitoring should be performed (see section "Precautions for use", Haemorrhage).
Electroconvulsive therapy (ECT): In fluoxetine-treated patients receiving ECT treatment, there have been rare reports of prolonged seizures, so caution is advised.
Alcohol: In routine testing, fluoxetine does not cause an increase in blood alcohol levels or potentiate the effects of alcohol. However, the combination of SSRI and alcohol treatment is not recommended.
St John's wort: Pharmacodynamic interactions between fluoxetine and the herbal preparation containing St John's wort (Hypericum perforatum) may occur, which may lead to increased serotonergic effects and increased side effects.
Warnings It is important to know that:
Pregnancy, breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine. Tell your doctor as soon as possible if you are pregnant, think you are pregnant, or plan to become pregnant.
In pregnant and lactating women, treatment with Azur should be carefully evaluated by the doctor and the medicine used only if the expected benefits justify the potential risk to the fetus.
Regarding newborn babies whose mothers took Azur during the first months of pregnancy, there are data available indicating an increased risk of birth defects, particularly concerning the heart. In the general population, about 1 in 1000 babies are born with heart defects. This ratio increases to about 2 in 1000 babies in mothers who have taken Azur. Together with your doctor, you may decide whether it is more appropriate to gradually decrease your intake of Azur during pregnancy. However, depending on the circumstances, your doctor may suggest that you continue taking Azur or not.
Make sure your midwife and / or doctor know you are being treated with Azur. When taken during pregnancy, particularly in the last 3 months of pregnancy, drugs such as Azur, may increase the risk of a serious pediatric condition called persistent pulmonary hypertension in the newborn (IPPN), which involves rapid breathing in the newborn and the appearance of color. bluish. Usually, these symptoms appear during the first 24 hours after the baby is born. Tell your midwife and / or doctor immediately if your baby develops these symptoms.
Caution should be exercised when fluoxetine is used during pregnancy especially during late pregnancy or just before the onset of labor as the following effects have been reported in newborns: irritability, tremor, hypotonia, persistent crying, difficulty in sucking or to sleep.These symptoms may indicate both serotonergic effects and a withdrawal syndrome.
Lactation: Fluoxetine and its active metabolite norfluoxetine are known to be excreted in human breast milk. Adverse events have been reported in breastfed infants. If treatment with fluoxetine is deemed necessary, discontinuation of breastfeeding should be considered; however, if breastfeeding is continued, the lowest effective dose of fluoxetine should be prescribed.
Male Fertility: Fluoxetine, in animal studies, has been shown to reduce sperm quality. In theory, this could affect fertility but, the impact on human fertility has not yet been observed.
Driving and using machines
Although fluoxetine has been shown not to interfere with psychomotor performance in healthy volunteers, any psychoactive drug can impair judgment or professional skills. Patients should be advised to avoid driving a vehicle or operating hazardous machinery.
Dosage and method of use How to use Azur: Dosage
For oral administration.
Major depressive episodes
Adults and the elderly:
The recommended dose is 20 mg per day. If necessary, the dosage should be reviewed and corrected within 3-4 weeks of initiation of therapy and then evaluated if clinically appropriate. Although at higher doses there may be a potential for increased side effects, in some patients with insufficient therapeutic response to 20 mg, the dose may be gradually increased up to a maximum of 60 mg Dosage adjustments should be made carefully on each individual to keep the patient at the lowest effective dose.
Patients with depression should be treated for a sufficient period of at least 6 months to be sure they are symptom-free.
Obsessive Compulsive Disorder
Adults and the elderly: The recommended dose is 20 mg per day. Although at doses higher than 20 mg per day there may be a potential increase in side effects in some patients, the dose may be gradually increased up to a maximum of 60 mg if after two weeks there is insufficient therapeutic response to 20 mg .
If no improvement is observed within 10 weeks, fluoxetine treatment should be reconsidered. If a good therapeutic response has been achieved, treatment can be continued at an individually adjusted dosage. Although there are no systematic studies to establish how long to continue fluoxetine treatment, OCD is a chronic condition and it is reasonable to consider prolonging therapy beyond 10 weeks in responding patients. Variations in dosage should be made carefully on each individual to keep the patient at the lowest effective dose. The need for treatment should be reassessed periodically. In patients who have responded well to pharmacotherapy, some clinicians find simultaneous behavioral psychotherapy useful.
Long-term efficacy (beyond 24 weeks) has not been demonstrated in OCD.
Bulimia nervosa
Adults and the elderly: A dose of 60 mg per day is recommended. Long-term efficacy (beyond 3 months) has not been demonstrated in bulimia nervosa.
Adults
In all indications: The recommended dose can be increased or decreased. Doses above 80 mg per day have not been systematically evaluated.
Fluoxetine can be administered in single or divided doses, with or without meals.
When dosing is stopped, the pharmacologically active substances will persist in the body for weeks. This should be borne in mind when starting or stopping treatment.
Children and adolescents aged 8 years and over (Moderate to severe major depressive episode)
Azur is for use in children and adolescents 8 to 18 years of age only for the treatment of moderate to severe major depressive episodes and should not be used in other indications.
Treatment should be initiated and monitored under the supervision of the specialist. The starting dose is 10 mg per day. Dose adjustments should be made carefully, on an individual basis, to maintain the patient at the lowest effective dose.
After one to two weeks, the dose can be increased to 20 mg per day. Clinical experience with daily doses above 20 mg is minimal. There is only limited data on treatment beyond 9 weeks.
Children of low body weight
Due to the higher plasma levels that are achieved in children of low body weight, the therapeutic effect can be achieved with lower dosages.
In pediatric patients who respond to treatment, the need to continue treatment after 6 months should be re-evaluated. If no clinical benefit has been achieved within 9 weeks, treatment should be reconsidered.
Elderly: Caution is recommended when increasing the dose and the daily dose should generally not exceed 40 mg. The maximum recommended dose is 60 mg per day.
A lower or less frequent dose (eg 20 mg every other day) should be considered in patients with hepatic insufficiency, or in patients where there is the possibility of an "interaction between Azur and medicinal products taken in combination (see Interactions paragraph).
Withdrawal symptoms seen on discontinuation of Azur treatment:
Abrupt discontinuation should be avoided. When discontinuing treatment with Azur the dose should be gradually reduced over a period of at least 1-2 weeks in order to reduce the risk of withdrawal reactions (see section "Precautions for" use "and section" Undesirable effects "). If intolerable symptoms occur following a dose reduction or discontinuation of treatment, resuming the previously prescribed dose may be considered. Thereafter, the doctor may continue to reduce the dose, but more gradually.
Overdose What to do if you have taken too much Azur
In case of accidental ingestion / intake of an excessive dose of Azur, notify your doctor immediately or go to the nearest hospital
Cases of overdose due to fluoxetine alone generally have a mild course. Symptoms of overdose include nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic arrhythmia to cardiac arrest, pulmonary dysfunction and signs of an altered CNS condition ranging from excitation to coma. Fatal outcome attributed to overdose of fluoxetine alone has been Extremely rare It is advisable to monitor cardiac function and vital signs, as well as general symptomatic and supportive measures No specific antidotes are known.
Forced diuresis, dialysis, haemoperfusion and replacement transfusion are unlikely to offer benefits. Activated charcoal, which can be used in combination with sorbitol, may be an even more effective treatment than emesis or gastric lavage. When treating an overdose, consider the possibility of multiple drug involvement.In patients who have taken excessive amounts of a tricyclic antidepressant, a longer period of time for close medical observation may be required if they are also taking, or have recently taken, fluoxetine.
If in doubt about the use of Azur, ask your doctor or pharmacist.
OMITTED ADMINISTRATION (WITHDRAWAL SYNDROME).
In case of accidental failure to take one or more doses, the risk of the onset of a withdrawal syndrome is minimal.
Side Effects What are the side effects of Azur
Like all medicines, Azur can cause side effects, although not everybody gets them. Undesirable effects may decrease in intensity and frequency with continued treatment and generally do not lead to discontinuation of therapy.
As with other SSRIs, the following side effects have been observed:
Body as a whole: Manifestations of hypersensitivity (eg, itching, rash, urticaria, anaphylactoid reaction, vasculitis, serum sickness-like reaction, angioedema) (see section "Contraindications" and section "Precautions for use"), tremors , serotonin syndrome, photosensitivity and very rarely erythema multiforme which may progress to the onset of Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell's syndrome).
Cardiovascular system: Angina pectoris, arrhythmias, 1st degree atrioventricular block, hypotension, hypertension.
Digestive system: Gastrointestinal disturbances (e.g. diarrhea, nausea, vomiting, dyspepsia, dysphagia, altered taste), dry mouth. Abnormal liver function tests have been reported rarely. Very rare cases of idiosyncratic hepatitis.
Nervous system: Headache, sleep disturbances (e.g. abnormal dreams, insomnia, somnolence), dizziness, anorexia, fatigue, somnolence (e.g. drowsiness), euphoria, transient abnormal movements (e.g. nervous tics, ataxia, tremor , myoclonus), seizures and rarely psychomotor restlessness / akathisia (see section "Precautions for use") Very rarely serotonin syndrome.
Psychiatric disorders: Hallucinations, manic reaction, confusion, agitation, anxiety and associated symptoms (e.g. nervousness), impaired concentration and cognitive process (e.g. depersonalization), panic attacks, suicidal behavior and thoughts (these symptoms may be due to an underlying disease).
Cases of suicidal ideation and suicidal behaviors have been reported during fluoxetine therapy or early after treatment discontinuation (see "Precautions for use" section).
Urogenital system: Urinary retention and altered urinary frequency.
Reproductive system disorders: sexual dysfunction (delayed or absent ejaculation, anorgasmia), priapism, galactorrhea, hyperprolactinemia.
Miscellaneous: Alopecia, yawning, vision abnormalities (e.g. blurred vision, mydriasis), sweating, vasodilation, arthralgia, myalgia, postural hypotension, ecchymosis, hypoglycemia, hypokalaemia. Other haemorrhagic manifestations (eg gynecological haemorrhages, gastrointestinal bleeding and other cutaneous or mucosal bleeding) have been reported rarely (see section "Precautions for use", Haemorrhage).
Hyponatremia: Hyponatremia (including sodium levels below 110 mmol / l) has been reported rarely and was reversible on discontinuation of fluoxetine. Some cases were probably due to the syndrome of inappropriate antidiuretic hormone secretion. Most reports were found in older patients, and in patients treated with diuretics or with reduced blood volume for any other reason.
Respiratory system: Pharyngitis, dyspnoea. Pulmonary events (including inflammatory processes of variable histopathology and / or fibrosis) have been reported rarely. Dyspnea may be the only warning symptom.
Bone fractures: An increased risk of bone fractures has been observed in patients taking this type of medicine.
Withdrawal Symptoms Seen on Discontinuation of Fluoxetine Treatment: Discontinuation of fluoxetine treatment commonly leads to withdrawal symptoms. The most commonly reported reactions are dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and / or vomiting, tremor and headache. Generally these symptoms are mild to moderate in intensity and are self-limiting, however in some patients they may be severe and / or prolonged (see section "Precautions for use"). A "discontinuation" is therefore recommended. gradually by gradually reducing the dose when treatment with Azur is no longer required (see section "Dose, method and time of administration" and section "Precautions for use").
Children and adolescents (see section "Precautions for" use "):
In pediatric clinical trials, suicide-related behaviors (suicide attempt and suicidal thoughts) and hostile attitude were more frequently observed in children and adolescents treated with antidepressants than in those treated with placebo.
The safety of fluoxetine has not been systematically evaluated for chronic treatments lasting longer than 19 weeks.
In pediatric clinical trials, manic reactions, including mania and hypomania (2.6% in fluoxetine-treated patients vs. 0% in placebo-controlled patients) were reported, leading to treatment discontinuation in most cases. These patients had no previous episodes of hypomania / mania.
After 19 weeks of treatment, pediatric patients treated with fluoxetine in a clinical study report an average of 1.1 cm less in height (p = 0.004) and 1.1 kg less in weight (p = 0.008) compared to subjects treated with placebo.
Isolated cases of growth retardation have also been reported in clinical use. Isolated cases of adverse events potentially indicating delayed sexual maturation or sexual dysfunction have been reported in pediatric clinical use.
In pediatric clinical trials, fluoxetine treatment was associated with a reduction in blood levels of alkaline phosphatase.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please inform your doctor or pharmacist.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects. It is important to inform the doctor or pharmacist of any undesirable effect, even if not described in the package leaflet.
Expiry and Retention
See the expiry date printed on the package.
The expiry date refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date shown on the package. Store below 30 ° C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN
Composition and pharmaceutical form
COMPOSITION
Each capsule contains:
active ingredient: Fluoxetine hydrochloride 22.36 mg
equivalent to fluoxetine 20 mg
excipients: Corn starch, Dimethicone, Gelatin, Titanium dioxide.
PHARMACEUTICAL FORM AND CONTENT
20 mg hard capsules. Box of 28 capsules
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
AZUR 20 MG HARD CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains:
Active principle:
Fluoxetine hydrochloride 22.36 mg
equal to fluoxetine 20 mg
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Hard capsules
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
AZUR is indicated in the treatment of depression, obsessive compulsive disorder and bulimia nervosa.
04.2 Posology and method of administration
For oral administration.
Major depressive episodes
Adults and the elderly:
The recommended dose is 20 mg per day. If necessary, the dosage should be reviewed and corrected within 3-4 weeks of initiation of therapy and then evaluated if clinically appropriate. Although at higher doses there may be a potential for increased side effects, in some patients with insufficient therapeutic response to 20 mg, the dose may be gradually increased up to a maximum of 60 mg (see section 5.1 "Pharmacodynamic properties"). Dose adjustments should be made carefully on an individual basis to maintain the patient at the lowest effective dose.
Patients with depression should be treated for a sufficient period of at least 6 months to be sure they are symptom-free.
Obsessive Compulsive Disorder
Adults and the elderly: The recommended dose is 20 mg per day. Although at doses higher than 20 mg per day there may be a potential increase in side effects in some patients, the dose may be gradually increased up to a maximum of 60 mg if after two weeks there is insufficient therapeutic response to 20 mg .
If no improvement is observed within 10 weeks, fluoxetine treatment should be reconsidered. If a good therapeutic response has been achieved, treatment can be continued at an individually adjusted dosage. Although there are no systematic studies to establish how long to continue fluoxetine treatment, OCD is a chronic condition and it is reasonable to consider prolonging therapy beyond 10 weeks in responding patients. Variations in dosage should be made carefully on each individual to keep the patient at the lowest effective dose. The need for treatment should be reassessed periodically. In patients who have responded well to pharmacotherapy, some clinicians find simultaneous behavioral psychotherapy useful.
Long-term efficacy (beyond 24 weeks) has not been demonstrated in OCD.
Bulimia nervosa
Adults and the elderly: A dose of 60 mg per day is recommended. Long-term efficacy (beyond 3 months) has not been demonstrated in bulimia nervosa.
Adults
In all indications: The recommended dose can be increased or decreased. Doses above 80 mg per day have not been systematically evaluated.
Fluoxetine can be administered in single or divided doses, with or without meals.
When dosing is stopped, the pharmacologically active substances will persist in the body for weeks. This should be borne in mind when starting or stopping treatment.
Children and adolescents aged 8 years and over (Moderate to severe major depressive episode)
Treatment should be initiated and monitored under the supervision of the specialist. The starting dose is 10 mg per day. Dose adjustments should be made carefully, on an individual basis, to maintain the patient at the lowest effective dose.
After one to two weeks, the dose can be increased to 20 mg per day. Clinical experience with daily doses above 20 mg is minimal. There is only limited data on treatment beyond 9 weeks.
Children of low body weight
Due to the higher plasma levels that are achieved in children of low body weight, the therapeutic effect can be achieved with lower doses (see section 5.2).
In pediatric patients who respond to treatment, the need to continue treatment after 6 months should be re-evaluated. If no clinical benefit has been achieved within 9 weeks, treatment should be reconsidered.
Elderly: Caution is recommended when increasing the dose and the daily dose should generally not exceed 40 mg. The maximum recommended dose is 60 mg per day.
A lower or less frequent dose (eg 20 mg every other day) should be considered in patients with hepatic impairment (see section 5.2 Pharmacokinetic properties), or in patients where there is a potential for an "interaction between Azur. and medicinal products taken in combination (see section 4.5 Interactions with other medicinal products and other forms of interaction).
Withdrawal symptoms observed on discontinuation of Azur treatment:
Abrupt discontinuation should be avoided. When discontinuing treatment with Azur the dose should be gradually reduced over a period of at least 1-2 weeks in order to reduce the risk of withdrawal reactions (see section 4.4 "Special warnings and precautions for use "and section 4.8" Undesirable effects "). If intolerable symptoms occur following a dose reduction or discontinuation of treatment, resuming the previously prescribed dose may be considered. Thereafter, the doctor may continue reducing the dose, but more gradually.
04.3 Contraindications
Hypersensitivity to the components of the product or other closely related substances from a chemical point of view.
Fluoxetine must not be taken at the same time as MAO inhibitors (see section 4.4 "Special warnings and special precautions for use" and section 4.5 "Interactions with other medicinal products and other forms of interaction").
Generally contraindicated in pregnancy (see section 4.6 "Pregnancy and lactation").
Hypersensitivity to fluoxetine or to any of the excipients.
Monoamine Oxidase Inhibitors: Cases of severe and sometimes fatal reactions have been reported in patients taking SSRIs in combination with a monoamine oxidase inhibitor (MAOI), and in patients who had recently stopped treatment with an SSRI and started that with a MAOI. Fluoxetine treatment should only be started 2 weeks after stopping treatment with an irreversible MAOI and one day after stopping a reversible MAO-A.
Some cases have presented with features similar to serotonin syndrome (which may resemble and be diagnosed as neuroleptic malignant syndrome). Cyproheptadine or dantrolene may be of benefit to patients with such reactions. Symptoms of a drug interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic nervous system instability with possible rapid fluctuations in vital signs, mental status changes including confusion, irritability and extreme agitation leading to delirium and coma.
Therefore, fluoxetine is contraindicated in combination with a non-selective MAOI. Likewise, at least 5 weeks should elapse after discontinuing fluoxetine treatment before initiating therapy with a MAOI. If fluoxetine is prescribed for a long time and / or at high doses, a time interval should be considered. longer.
The combination of fluoxetine with a reversible MAOI (eg moclobemide) is not recommended. Fluoxetine treatment can be started the day after stopping treatment with a reversible MAOI.
04.4 Special warnings and appropriate precautions for use
Special Warnings and Precautions for Use
Warnings
For use by children and adolescents under the age of 18
Suicide-related behaviors (suicide attempt and suicidal thoughts) and hostile attitude (especially aggressive, oppositional and anger behavior) were observed more frequently in clinical trials in children and adolescents treated with antidepressants than in those treated with placebo. Azur is for use in children and adolescents 8 to 18 years of age only for the treatment of moderate to severe major depressive episodes and should not be used in other indications.If, based on medical need, a decision to treat is made, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, only limited data are available in children and adolescents regarding long-term effects on safety, including effects on growth, sexual maturation and cognitive, emotional and behavioral development (see section 5.3).
In a 19-week clinical study, decreased height and weight gain were observed in children and adolescents treated with fluoxetine (see section 4.8). It has not been established whether there is an effect on the achievement of height. normal adult height. The possibility of a delay in puberty cannot be excluded (see sections 5.3 and 4.8). Pubertal growth and development (height, weight and stages of action according to TANNER) should therefore be monitored during and after treatment with fluoxetine. If both are slowed, a pediatric evaluation should be requested.
In pediatric clinical trials, mania and hypomania were reported frequently (see section 4.8). Therefore, regular monitoring for the onset of mania / hypomania is recommended. Fluoxetine should be discontinued in any patient entering a manic phase.
It is important that the doctor carefully discusses the risks and benefits of treatment with the child or young person and / or their parents.
Skin rash and allergic reactions: Rash, anaphylactoid events and progressive systemic events, sometimes serious (involving skin, kidney, liver or lung), have been reported. Upon the appearance of skin rash or other allergic phenomena for which a different etiology cannot be identified, the administration of fluoxetine must be discontinued.
Precautions
Convulsions: seizures pose a potential risk with antidepressant medications. Therefore, as with other antidepressants, fluoxetine should be administered with caution to patients with a history of seizures. Treatment should be discontinued in any patient who experiences seizures or in whom an increase in seizure frequency is observed. Administration of fluoxetine should be avoided in patients with unstable seizure disorders / epilepsy and patients with controlled epilepsy should be carefully monitored.
Mania: Antidepressants should be used with caution in patients with a history of mania / hypomania. Like all antidepressant drugs, fluoxetine should be discontinued in any patient entering a manic phase.
Hepatic / Renal Function: Fluoxetine is extensively metabolised by the liver and eliminated by the kidneys. In patients with significant hepatic dysfunction a lower dose of 20 mg per day is recommended, e.g. an alternate day dosage. When fluoxetine 20 mg daily was administered for 2 months, patients with severe renal impairment (GFR dialysis showed no difference in plasma levels of fluoxetine or norfluoxetine compared to control subjects with normal renal function.
Heart disease: None of the conduction alterations leading to cardiac arrest were observed on ECG in 312 patients who received fluoxetine during double-blind clinical trials.
However, clinical experience in acute heart disease is limited and caution is advised.
Weight lossWeight loss may occur in patients taking fluoxetine, but this is usually proportional to the starting body weight.
Diabetes: In diabetic patients, treatment with an SSRI can impair glycemic control. Hypoglycaemia occurred during fluoxetine therapy, while hyperglycaemia developed after drug discontinuation. Dosage adjustment of the insulin and / or oral hypoglycemic agent may be required.
Suicide / suicidal thoughts or clinical worsening: Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission of the disease occurs. As improvement may not occur during the first or subsequent weeks of treatment, patients should be closely monitored until improvement occurs. It is general clinical experience that the risk of suicide can increase early in the healing process.
Other psychiatric conditions in which Azur is prescribed may also be associated with an increased risk of suicide-related events. Furthermore, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be implemented when treating patients with other psychiatric disorders.
Among patients with a history of suicide-related events, those with a significant degree of suicidal ideation prior to initiation of treatment have an increased risk of suicidal thoughts and suicide attempts, and should receive close monitoring during treatment. A meta-analysis of clinical trials conducted with antidepressant medicinal products compared with placebo in the treatment of psychiatric disorders showed an increased risk of suicidal behavior in patients under 25 years of age treated with antidepressants compared to placebo.
Close surveillance of patients, and particularly those at high risk, should accompany drug therapy especially in the initial stages of treatment and after dose changes. Patients (or their carers) should be advised of the need to monitor and report immediately to the treating physician any worsening of the clinical picture, the onset of suicidal behavior or thoughts or unusual changes in behavior if these symptoms occur. .
Akathisia / psychomotor restlessness: The use of fluoxetine has been associated with the development of akathisia, characterized by a "subjectively unpleasant or distressing restlessness and need to move often accompanied by an" inability to sit or stand still. This is more likely to occur within first weeks of treatment. In patients who develop these symptoms, increasing the dose may be harmful.
Withdrawal symptoms observed on discontinuation of SSRI treatment: Discontinuation symptoms are common when treatment is stopped, especially if discontinuation occurs abruptly (see section 4.8 "Undesirable effects"). In clinical trials, adverse events observed with abrupt discontinuation of treatment occurred in approximately 60% of patients in both fluoxetine and placebo groups. Of these adverse events, 17% in the fluoxetine group and 12% in the placebo group were severe in nature.
The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. The most commonly reported reactions are dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and / or vomiting, tremor and headache. Generally these symptoms are mild to moderate in intensity, however in some patients they may be severe in intensity. These symptoms usually occur within the first few days of stopping treatment. Generally these symptoms are self-limiting and usually resolve within 2 weeks, although in some individuals they may be prolonged (2-3 months or more). We therefore recommend Azur is gradually tapered over a period of at least 1-2 weeks prior to stopping treatment, as needed by the patient (see "Withdrawal symptoms observed on discontinuation of Azur" section 4.2 Posology and method of administration).
HemorrhageSkin bleeding manifestations such as ecchymosis and purpura have been reported with the use of SSRIs. Ecchymosis has been reported as an infrequent event during treatment with fluoxetine. Other haemorrhagic manifestations (e.g. gynecological haemorrhages, gastrointestinal bleeding and other cutaneous or mucosal bleeding) have been reported rarely.
Caution is advised in patients taking SSRIs, especially during concomitant use with oral anticoagulants, drugs known to affect platelet function (eg atypical antipsychotics such as clozapine, phenothiazines, most tricyclic antidepressants, aspirin , NSAIDs) or other drugs that may increase the risk of bleeding, as well as in patients with a history of bleeding disorders.
Electroconvulsive therapy (ECT): In fluoxetine-treated patients receiving ECT treatment, there have been rare reports of prolonged seizures, so caution is advised.
St. John's wort: When selective serotonin reuptake inhibitors and herbal preparations containing St. John's wort (Hypericum perforatum) are used together, increased serotonergic-type effects, such as serotonin syndrome, may occur.
On rare occasions, the development of a serotonin syndrome or neuroleptic malignant syndrome-like events have been reported in association with fluoxetine treatment, particularly when fluoxetine is administered in combination with other serotonergic drugs (among others L-tryptophan) and / or neuroleptics. Since these syndromes can give rise to potentially life-threatening conditions for the patient, if such events occur (characterized by groupings of symptoms such as hyperthermia, rigidity, myoclonus, autonomic nervous system instability with possible rapid fluctuations of vital signs, changes in the state including confusion, irritability and extreme agitation up to delirium and coma) treatment with fluoxetine should be discontinued and symptomatic supportive treatment initiated.
04.5 Interactions with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
Half-life: The long elimination half-lives of both fluoxetine and norfluoxetine should be taken into account (see section 5.2 "Pharmacokinetic properties") when considering pharmacodynamic or pharmacokinetic drug interactions (e.g. when switching from fluoxetine to others). antidepressants).
Monoamine Oxidase Inhibitors: (see section 4.3 "Contraindications").
Combinations not recommended: MAOI-Type A (see section 4.3).
Associations requiring precautions for their use:
MAOI-Type B (selegiline): risk of serotonin syndrome. Clinical monitoring is recommended.
PhenytoinChanges in blood levels have been observed when combined with fluoxetine. In some cases, manifestations of toxicity have occurred. It is therefore advisable to administer phenytoin according to conservative therapeutic schemes and to carefully follow the patient's clinical conditions.
Central nervous system drugs: Administration of fluoxetine may result in increased blood levels of carbamazepine, haloperidol, clozapine, alprazolam, imipramine, and desipramine; in some cases clinical manifestations of toxicity were observed. It is therefore advisable to administer the concomitant drug according to prudent therapeutic schemes and to follow the patient's clinical conditions.
Diazepam: There may be a lengthening of the effects of this drug.
Serotonergic drugs: Co-administration with serotonergic drugs (eg tramadol, triptans) may increase the risk of developing a serotonin syndrome. The association with triptans adds an additional risk of coronary vasoconstriction and arterial hypertension.
Lithium and tryptophan: There have been reports of serotonin syndrome when SSRIs have been administered in combination with lithium or tryptophan and, therefore, the concomitant use of fluoxetine with these drugs should be done with caution. When fluoxetine is given in combination with lithium, more targeted and frequent clinical monitoring is required.
CYP2D6 isoenzyme: Since the metabolism of fluoxetine (as for tricyclic antidepressants and other selective antidepressants for serotonin) affects the CYP2D6 isoenzymatic system in the liver, concomitant therapy with drugs equally metabolised by this enzyme system may lead to drug interactions. Concomitant therapy with drugs predominantly metabolised by this isoenzyme, and which have a limited therapeutic index (such as flecainide, encainide, carbamazepine and tricyclic antidepressants), should be initiated or adapted from the lowest effective dose. This will need to be done even if fluoxetine was taken within the previous 5 weeks.
Oral anticoagulantsAltered anticoagulant effects (laboratory data and / or clinical symptoms and signs), which do not fit into a homogeneous category, but include increased bleeding, have been observed infrequently following co-administration of fluoxetine and oral anticoagulants. When fluoxetine therapy is initiated or discontinued in patients receiving warfarin, careful coagulation monitoring should be performed (see section 4.4 "Special warnings and precautions for use", Hemorrhage).
Electroconvulsive therapy (ECT): In fluoxetine-treated patients receiving ECT treatment, there have been rare reports of prolonged seizures, so caution is advised.
Alcohol: In routine testing, fluoxetine does not cause an increase in blood alcohol levels or potentiate the effects of alcohol. However, the combination of SSRI and alcohol treatment is not recommended.
St. John's wort: Pharmacodynamic interactions may occur between fluoxetine and the herbal preparation containing St. John's wort (Hypericum perforatum), which can lead to an increase in serotonergic effects and an increase in undesirable effects.
04.6 Pregnancy and lactation
Pregnancy:
In pregnant and lactating women, treatment with Azur should be carefully evaluated by the doctor and the medicine used only if the expected benefits justify the potential risk to the fetus.
Epidemiological data report an increased risk of cardiovascular defects associated with the use of fluoxetine during the first trimester of pregnancy. The mechanism is unknown. Overall, the data suggest that the risk of having a child with a cardiovascular defect following maternal exposure to fluoxetine is on the order of 2% compared to an expected rate of the same defects of about 1% in the general population.
Epidemiological data show that the use of SSRIs in pregnancy, especially in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 in 1000 pregnancies. In the general population , there are 1-2 cases of persistent pulmonary hypertension in the newborn in every 1000 pregnant women.
In addition, although fluoxetine may be used during pregnancy, caution should be exercised, especially during late pregnancy or just before the onset of labor as the following effects have been reported in newborns: irritability, tremor, hypotonia, persistent crying, difficulty in sucking or sleeping. These symptoms may indicate both serotonergic effects and a withdrawal syndrome. The time of onset and duration of these symptoms may be related to the long half-life of fluoxetine (4-6 days) and its active metabolite, norfluoxetine (4-16 days).
Feeding time: Fluoxetine and its active metabolite norfluoxetine are known to be excreted in human breast milk. Adverse events have been reported in breastfed infants. If treatment with fluoxetine is deemed necessary, discontinuation of breastfeeding should be considered; however, if breastfeeding is continued, the lowest effective dose of fluoxetine should be prescribed.
04.7 Effects on ability to drive and use machines
Although fluoxetine has been shown not to interfere with psychomotor performance in healthy volunteers, any psychoactive drug can impair judgment or professional skills. Patients should be advised to avoid driving a vehicle or operating hazardous machinery.
04.8 Undesirable effects
Undesirable effects may decrease in intensity and frequency with continued treatment and generally do not lead to discontinuation of therapy.
As with other SSRIs, the following side effects have been observed:
Body as a whole: Manifestations of hypersensitivity (e.g. pruritus, rash, urticaria, anaphylactoid reaction, vasculitis, serum sickness-like reaction, angioedema) (see section 4.3 "Contraindications" and section 4.4 "Special warnings and precautions for use"), tremors, serotonin syndrome, photosensitivity and very rarely erythema multiforme which may progress to the onset of Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell's syndrome).
Digestive system: Gastrointestinal disorders (eg.diarrhea, nausea, vomiting, dyspepsia, dysphagia, taste disturbance), dry mouth. Abnormal liver function tests have been reported rarely. Very rare cases of idiosyncratic hepatitis.
Nervous system: Headache, sleep disturbances (e.g. abnormal dreams, insomnia, somnolence), dizziness, anorexia, fatigue, somnolence (e.g. drowsiness), euphoria, transient abnormal movements (e.g. nervous tics, ataxia, tremor, myoclonus) , seizures and rarely psychomotor restlessness / akathisia (see section 4.4 "Special warnings and precautions for use"). Very rarely serotonin syndrome.
Cardiovascular system: Angina pectoris, arrhythmias, 1st degree atrioventricular block, hypotension, hypertension.
Psychiatric disorders: Hallucinations, manic reaction, confusion, agitation, anxiety and associated symptoms (e.g. nervousness), impaired concentration and cognitive process (e.g. depersonalization), panic attacks, suicidal behavior and thoughts (these symptoms may be due to an underlying disease).
Cases of suicidal ideation and suicidal behaviors have been reported during fluoxetine therapy or early after treatment discontinuation (see section 4.4).
Urogenital system: Urinary retention and altered urinary frequency.
Disorders of the reproductive system: sexual dysfunction (delayed or absent ejaculation, anorgasmia), priapism, galactorrhea, hyperprolactinaemia.
Miscellaneous: Alopecia, yawning, vision abnormalities (e.g. blurred vision, mydriasis), sweating, vasodilation, arthralgia, myalgia, postural hypotension, ecchymosis, hypoglycemia, hypokalaemia. Other haemorrhagic manifestations (e.g. gynecological haemorrhages, gastrointestinal bleeding and other cutaneous or mucosal bleeding) have been reported rarely (see section 4.4 "Special warnings and precautions for use", Hemorrhage).
Hyponatremia: Hyponatremia (including sodium values below 110 mmol / l) has been reported rarely, found to be reversible with discontinuation of fluoxetine. Some cases were probably due to the syndrome of inappropriate antidiuretic hormone secretion. Most reports were found in older patients, and in patients being treated with diuretics or with reduced blood volume for any other reason.
Respiratory System: Pharyngitis, dyspnoea. Pulmonary events (including inflammatory processes of variable histopathology and / or fibrosis) have been reported rarely. Dyspnea may be the only warning symptom.
Bone fractures: Epidemiological studies, conducted mainly in patients 50 years of age and older, show an increased risk of bone fractures in patients treated with SSRIs and tricyclic antidepressants (TCAs). The mechanism causing this risk is not known.
Withdrawal symptoms observed on discontinuation of fluoxetine treatment: Discontinuation of fluoxetine treatment commonly leads to withdrawal symptoms. The most commonly reported reactions are dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety , nausea and / or vomiting, tremor and headache. Generally these symptoms are mild to moderate in intensity and are self-limiting, however in some patients they may be severe and / or prolonged (see section 4.4 "Special warnings and precautions for use "). It is therefore recommended that a" gradual discontinuation by progressive dose reduction be performed when treatment with Azur is no longer required (see section 4.2 "Posology and method of administration" and section 4.4 "Special warnings and precautions for use. ").
Children and adolescents (see section 4.4):
In pediatric clinical trials, suicide-related behaviors (suicide attempt and suicidal thoughts) and hostile attitude were more frequently observed in children and adolescents treated with antidepressants than in those treated with placebo.
The safety of fluoxetine has not been systematically evaluated for chronic treatments lasting longer than 19 weeks.
In pediatric clinical trials, manic reactions, including mania and hypomania (2.6% in fluoxetine-treated patients vs. 0% in placebo-controlled patients) were reported, leading to treatment discontinuation in most cases. These patients had no previous episodes of hypomania / mania.
After 19 weeks of treatment, pediatric patients treated with fluoxetine in a clinical study reported an average of 1.1 cm less in height (p = 0.004) and 1.1 kg less in weight (p = 0.008) compared to subjects treated with placebo. Isolated cases of growth retardation have also been reported in clinical use.
Isolated cases of adverse events potentially indicating delayed sexual maturation or sexual dysfunction have been reported in pediatric clinical use (see also section 5.3).
In pediatric clinical trials, fluoxetine treatment was associated with a reduction in blood levels of alkaline phosphatase.
04.9 Overdose
Cases of overdose due to fluoxetine alone generally have a mild course. Symptoms of overdose include nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic arrhythmia to cardiac arrest, pulmonary dysfunction and signs of an altered CNS condition ranging from excitation to coma. Fatal outcome attributed to overdose of fluoxetine alone has been Extremely rare It is advisable to monitor cardiac function and vital signs, as well as general symptomatic and supportive measures No specific antidotes are known.
Forced diuresis, dialysis, haemoperfusion and replacement transfusion are unlikely to offer benefits. Activated charcoal, which can be used in combination with sorbitol, may be an even more effective treatment than emesis or gastric lavage. When treating an overdose, consider the possibility of multiple drug involvement. In patients who have taken excessive amounts of a tricyclic antidepressant, a longer period of time for close medical observation may be required if they are also taking, or have recently taken, fluoxetine.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
ATC code: N06AB03
Fluoxetine (INN) is a selective serotonin reuptake inhibitor.
Fluoxetine is a (±) -N-methyl-3-phenyl-3 - [(a, a, a, -trifluoro-p-tolyl) -oxy] -propylamine hydrochloride with a non-tricyclic structure whose antidepressant action is presumably linked inhibition of serotonin uptake in central neurons. In human platelet studies, fluoxetine has been shown to block serotonin uptake into platelets.
Animal studies also suggest that fluoxetine exerts a much more potent inhibitory action on serotonin uptake than that exerted on the uptake of other monoamines.
It has been hypothesized that an "antagonistic action on muscarinic, histamine and alpha1-adrenergic receptors is responsible for the various anticholinergic and cardiovascular effects of classical tricyclic antidepressants. Fluoxetine binds much less than tricyclic drugs to these and other membrane receptors.
05.2 Pharmacokinetic properties
Absorption after oral administration is rapid and complete. In humans, after a single dose of 40 mg, plasma peaks of fluoxetine ranging from 15 to 55 ng / ml are observed after 6-8 hours.
The preparations of fluoxetine in capsules, soluble tablets and in solution for oral use are bioequivalent.
Fluoxetine can be administered with or without meals as food does not alter systemic bioavailability, although it may slightly slow absorption.
Fluoxetine is metabolised in the liver predominantly to norfluoxetine and other inactive metabolites which are subsequently excreted by the kidney.
Fluoxetine is widely distributed in the body and is extensively bound to plasma proteins.
The elimination half-life of fluoxetine is 4-6 days, while that of its active metabolite is 4-16 days (these values may be further prolonged in patients with deficiency of the P450IID6 enzyme system). This results in a significant accumulation of these. active products in chronic use. Equilibrium plasma concentrations are reached only after weeks of treatment.
The following table summarizes the most salient pharmacokinetic characteristics.
* These values may be further prolonged in patients with deficiency of the P450IID6 enzyme system.
The presence of hepatic insufficiency can hinder the elimination of fluoxetine.
Further accumulation of fluoxetine or its metabolites may occur in patients with severe renal insufficiency.
05.3 Preclinical safety data
Both fluoxetine and its active metabolite norfluoxetine demonstrated a high degree of tolerability in single and repeated dose, sub-acute and chronic toxicity tests in various animal species including primates.
The LD50 (mg / kg) for acute administration were:
The acute doses that cause toxic phenomena are several times higher than the therapeutic doses in humans (0.3-1.0 mg / kg / day). Any toxic effects found in chronic toxicity tests (anorexia, weight loss , phospholipidosis in some animal species) have been shown to be reversible upon discontinuation of treatment.
Reproductive Studies: Fluoxetine, at tested doses, does not affect fertility and reproductive capacity.
Teratogenic studies: Fluoxetine does not adversely affect prenatal development or fetal weight, and no significant teratogenic effects have been noted.
Mutagenicity Studies: Fluoxetine and norfluoxetine are free of mutagenic effects both in vitro and in vivo.
Carcinogenicity Studies: With average doses approximately ten times the proposed daily dose in humans over a period of 2 years, no carcinogenic effects were observed in rats and mice.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Corn starch, Dimethicone, Gelatin, Titanium dioxide.
06.2 Incompatibility
Don't report.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
Store below 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Lithographed cardboard box of 28 capsules containing 1 package leaflet.
06.6 Instructions for use and handling
No special instructions
07.0 MARKETING AUTHORIZATION HOLDER
BIORES ITALIA S.r.l. . "Via Vittorio Grassi n. 13." 00155 Rome
08.0 MARKETING AUTHORIZATION NUMBER
AZUR 20 mg capsules. "28 capsules A.I.C. n .: 034375030
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
22.11.2000
10.0 DATE OF REVISION OF THE TEXT
May 2011
