Tatig

Tatig est indiqué pour le traitement des éléments suivants:

• Trouble dépressif majeur (TDM)
• Trouble obsessionnel-compulsif (TOC)
• Trouble panique (PD)
• Trouble de stress post-traumatique (SSPT)
• Trouble d'anxiété sociale (TAS)
• Trouble dysphorique prémenstruel (PMDD)

Posologie chez les patients atteints de MDD, de TOC, de PD, de SSPT et de TAS

La posologie initiale recommandée et la posologie maximale de Tatig chez les patients atteints de MDD, de trouble obsessionnel-compulsif, de PD, de SSPT et de TAS sont présentées dans le tableau 1 ci-dessous. Une posologie de 25 mg ou 50 mg par jour est la posologie thérapeutique initiale.

Pour les adultes et les patients pédiatriques, les doses suivantes peuvent être augmentées en cas de réponse inadéquate par incréments de 25 à 50 mg par jour une fois par semaine, selon la tolérabilité, jusqu'à un maximum de 200 mg par jour. Compte tenu de la demi-vie d'élimination de 24 heures de Tatig, l'intervalle recommandé entre les changements de dose est d'une semaine.

Tableau 1: Posologie quotidienne recommandée de Tatig chez les patients atteints de MDD, de TOC, de PD, de SSPT et de TAS

Posologie chez les patients atteints de PMDD

La posologie initiale recommandée de Tatig chez les femmes adultes atteintes de PMDD est de 50 mg par jour. Tatig peut être administré en continu (tous les jours tout au long du cycle menstruel) ou par intermittence (uniquement pendant la phase lutéale du cycle menstruel, c'est-à-dire., en commençant la posologie quotidienne 14 jours avant le début prévu des menstruations et en continuant jusqu'au début des règles). Le dosage intermittent serait répété à chaque nouveau cycle.

• Lors de l'administration continue, les patients ne répondant pas à une posologie de 50 mg peuvent bénéficier d'augmentations posologiques à 50 mg par cycle menstruel jusqu'à 150 mg par jour.
• Lors du dosage par intermittence, les patients ne répondant pas à une posologie de 50 mg peuvent bénéficier d'une augmentation de la posologie jusqu'à un maximum de 100 mg par jour au cours du prochain cycle menstruel (et les cycles suivants) comme suit: 50 mg par jour pendant les 3 premiers jours de dosage suivis de 100 mg par jour pendant les jours restants du cycle de dosage.

Écran pour le trouble bipolaire avant de commencer Tatig

Avant d'initier un traitement par Tatig ou un autre antidépresseur, dépister les patients pour des antécédents personnels ou familiaux de trouble bipolaire, de manie ou d'hypomanie.

Modifications posologiques chez les patients présentant une insuffisance hépatique

La posologie initiale recommandée et la plage thérapeutique chez les patients présentant une insuffisance hépatique légère (scores de Child Pugh 5 ou 6) représentent la moitié de la posologie quotidienne recommandée. L'utilisation de Tatig chez les patients présentant une insuffisance hépatique modérée (Child Pugh marque 7 à 9) ou sévère (Child Pugh marque 10 à 15) n'est pas recommandée.

Passer des patients à ou à partir d'un antidépresseur inhibiteur de la monoamine oxydase

Au moins 14 jours doivent s'écouler entre l'arrêt d'un antidépresseur inhibiteur de la monoamine oxydase (IMAO) et l'initiation de Tatig. De plus, au moins 14 jours doivent s'écouler après l'arrêt de Tatig avant de démarrer un antidépresseur MAOI.

Arrêt du traitement par Tatig

Des effets indésirables peuvent survenir à l'arrêt de Tatig. Réduisez progressivement le dosage plutôt que d'arrêter Tatig brusquement chaque fois que possible.

Préparation de la solution buvable de Tatig

La solution buvable de Tatig doit être diluée avant utilisation.

• Utilisez le compte-gouttes calibré fourni pour mesurer la quantité de solution buvable Tatig nécessaire
• Remarque: Le compte-gouttes calibré fourni a des graduations de 25 mg et 50 mg uniquement
• Mélanger avec 4 onces (½ tasse) d'eau, de bière au gingembre, de soude citron / citron vert, de limonade ou de jus d'orange UNIQUEMENT. Après mélange, une légère brume peut apparaître, ce qui est normal.

Demandez aux patients ou aux soignants de prendre immédiatement la dose après le mélange.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Suicidal Thoughts And Behaviors In Pediatric And Young Adult Patients

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.

Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Tatig, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Serotonin Syndrome

Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including Tatig, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs. Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of Tatig with MAOIs is contraindicated. In addition, do not initiate Tatig in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Tatig, discontinue Tatig before initiating treatment with the MAOI.

Monitor all patients taking Tatig for the emergence of serotonin syndrome. Discontinue treatment with Tatig and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Tatig with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

Increased Risk Of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including Tatig, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients of the increased risk of bleeding associated with the concomitant use of Tatig and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.

Activation Of Mania Or Hypomania

In patients with bipolar disorder, treating a depressive episode with Tatig or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.4% of patients treated with Tatig. Prior to initiating treatment with Tatig, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible.

Seizures

Tatig has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. Tatig should be prescribed with caution in patients with a seizure disorder.

Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including Tatig may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including Tatig, in patients with untreated anatomically narrow angles.

Hyponatremia

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including Tatig. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue Tatig and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs and SNRIs.

False-Positive Effects On Screening Tests For Benzodiazepines

False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking Tatig. This finding is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of Tatig. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish Tatig from benzodiazepines.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts And Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider.

Important Administration Instructions for Oral Solution

For patients prescribed Tatig oral solution, inform them that:

• Tatig oral solution must be diluted before use. Do not mix in advance.
• Use the dropper provided to remove the required amount of Tatig oral solution and mix with 4 ounces (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY. Do not mix Tatig oral solution with anything other than the liquids listed.
• Take the dose immediately after mixing. At times, a slight haze may appear after mixing; this is normal.
• The dropper dispenser contains dry natural rubber, a consideration for patients with latex sensitivity.

Disulfiram Contraindication For Tatig Oral Solution

Inform patients not to take disulfiram when taking Tatig oral solution. Concomitant use is contraindicated due the alcohol content of the oral solution.

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of Tatig with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Patients should contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

Increased Risk Of Bleeding

Inform patients about the concomitant use of Tatig with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-thecounter medications that increase the risk of bleeding.

Activation Of Mania/Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider.

Discontinuation Syndrome

Advise patients not to abruptly discontinue Tatig and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when Tatig is discontinued.

Allergic Reactions

Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.

Pregnancy

Inform pregnant women that Tatig may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m² basis. There was a dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg (0.25-1.0 times the MRHD on a mg/m² basis). No increase was seen in female mice or in rats of either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m² basis); this was not accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m² basis) compared to placebo controls, this effect was not clearly drug related.

Mutagenesis

Sertraline had no genotoxic effects, with or without metabolic activation, based on the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.

Impairment Of Fertility

A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (3.1 times the maximum recommended human dose on a mg/m² basis in adolescents).

Use In Specific Populations

Pregnancy

Risk Summary

Overall, available published epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in comparator populations. Some studies have reported increases for specific major birth defects; however, these study results are inconclusive [See Data]. There are clinical considerations regarding neonates exposed to SSRIs and SNRIs, including Tatig, during the third trimester of pregnancy [See Clinical Considerations].

Although no teratogenicity was observed in animal reproduction studies, delayed fetal ossification was observed when sertraline was administered during the period of organogenesis at doses less than the maximum recommended human dose (MRHD) in rats and doses 3.1 times the MRHD in rabbits on a mg/m² basis in adolescents. When sertraline was administered to female rats during the last third of gestation, there was an increase in the number of stillborn pups and pup deaths during the first four days after birth at the MRHD [See Data].

The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise a pregnant woman of possible risks to the fetus when prescribing Tatig.

Tatig oral solution contains 12% alcohol and is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

A prospective longitudinal study followed 201 pregnant women with a history of major depression who were euthymic taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

Fetal/Neonatal adverse reactions

Exposure to SSRIs and SNRIs, including Tatig in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN).

When treating a pregnant woman with Tatig during the third trimester, carefully consider both the potential risks and benefits of treatment. Monitor neonates who were exposed to Tatig in the third trimester of pregnancy for PPHN and drug discontinuation syndrome [See Data].

Data

Human Data

Third Trimester Exposure

Neonates exposed to Tatig and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on post-marketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In some cases, the clinical picture was consistent with serotonin syndrome.

Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20^th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997-2005 found a PPHN risk ratio of 2.4 (95% CI 1.2-4.3) associated with patient-reported maternal use of SSRIs “in early pregnancy” and a PPHN risk ratio of 3.6 (95% CI 1.2-8.3) associated with a combination of patient-reported maternal use of SSRIs “in early pregnancy” and an antenatal SSRI prescription “in later pregnancy”.

First Trimester Exposure

The weight of evidence from epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in pregnant women who were not exposed to sertraline. A meta-analysis of studies suggest no increase in the risk of total malformations (summary odds ratio=1.01, 95% CI=0.88-1.17) or cardiac malformations (summary odds ratio=0.93, 95% CI=0.70-1.23) among offspring of women with first trimester exposure to sertraline. An increased risk of congenital cardiac defects, specifically septal defects, the most common type of congenital heart defect, was observed in some published epidemiologic studies with first trimester sertraline exposure; however, most of these studies were limited by the use of comparison populations that did not allow for the control of confounders such as the underlying depression and associated conditions and behaviors, which may be factors associated with increased risk of these malformations.

Animal Data

Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 3.1 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m² basis in adolescents. There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.4 times the MRHD on a mg/m² basis) in rats and 40 mg/kg (3.1 times the MRHD on a mg/m² basis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in stillborn pups and pup deaths during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg 0.8 times the MRHD on a mg/m² basis). The no effect dose for rat pup mortality was 10 mg/kg (0.4 times the MRHD on a mg/m² basis). The decrease in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown.

Lactation

Risk Summary

Available data from published literature demonstrate low levels of sertraline and its metabolites in human milk [See Data]. There are no data on the effects of sertraline on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Tatig and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Data

In a published pooled analysis of 53 mother-infant pairs, exclusively human milk-fed infants had an average of 2% (range 0% to 15%) of the sertraline serum levels measured in their mothers. No adverse reactions were observed in these infants.

Pediatric Use

Monitoring Pediatric Patients Treated With Tatig

Monitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and unusual changes in behavior, especially during the initial few months of treatment, or at times of dose increases or decreases. Decreased appetite and weight loss have been observed with the use of SSRIs. Monitor weight and growth in pediatric patients treated with an SSRI such as Tatig.

Weight Loss In Studies In Pediatric Patients With MDD

In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for MDD (n=373), there was a difference in weight change between Tatig and placebo of roughly 1 kg, for both children (ages 6-11) and adolescents (ages 12-17), in both age groups representing a slight weight loss for the Tatig group compared to a slight gain for the placebo group. For children, about 7% of the Tatig-treated patients had a weight loss greater than 7% of body weight compared to 0% of the placebo-treated patients; for adolescents, about 2% of Tatig-treated patients had a weight loss > 7% of body weight compared to about 1% of placebo-treated patients.

A subset of patients who completed the randomized controlled trials in patients with MDD (Tatig n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. Those subjects who completed 34 weeks of Tatig treatment (10 weeks in a placebo-controlled trial + 24 weeks open-label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers. However, there are no studies that directly evaluate the long-term effects of Tatig on the growth, development, and maturation in pediatric patients.

Alcohol Content In Tatig Oral Solution

Tatig oral solution contains 12% alcohol.

Juvenile Animal Data

A study conducted in juvenile rats at clinically relevant doses showed delay in sexual maturation, but there was no effect on fertility in either males or females.

In this study in which juvenile rats were treated with oral doses of sertraline at 0, 10, 40 or 80 mg/kg/day from postnatal day 21 to 56, a delay in sexual maturation was observed in males treated with 80 mg/kg/day and females treated with doses ≥10 mg/kg/day. There was no effect on male and female reproductive endpoints or neurobehavioral development up to the highest dose tested (80 mg/kg/day), except a decrease in auditory startle response in females at 40 and 80 mg/kg/day at the end of treatment but not at the end of the drug –free period. The highest dose of 80 mg/kg/day produced plasma levels (AUC) of sertraline 5 times those seen in pediatric patients (6 -17 years of age) receiving the maximum recommended dose of sertraline (200 mg/day).

Geriatric Use

Of the total number of patients in clinical studies of Tatig in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 797 (17%) were ≥ 65 years old, while 197 (4%) were ≥ 75 years old.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In 354 geriatric subjects treated with Tatig in MDD placebo-controlled trials, the overall profile of adverse reactions was generally similar to that shown in Table 3, except for tinnitus, arthralgia with an incidence of at least 2% and at a rate greater than placebo in geriatric patients.

SNRIs and SSRIs, including Tatig, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction.

Hepatic Impairment

The recommended dosage in patients with mild hepatic impairment (Child-Pugh score 5 or 6) is half the recommended dosage due to increased exposure in this patient population. The use of Tatig in patients with moderate (Child-Pugh score 7 to 10) or severe hepatic impairment (Child-Pugh score 10-15) is not recommended, because Tatig is extensively metabolized, and the effects of Tatig in patients with moderate and severe hepatic impairment have not been studied.

Renal Impairment

No dose adjustment is needed in patients with mild to severe renal impairment. Sertraline exposure does not appear to be affected by renal impairment.

Les effets indésirables suivants sont décrits plus en détail dans d'autres sections des informations de prescription:

• Réactions d'hypersensibilité à la sertraline
• Réaction disulfirame-alcool lorsque la solution buvable de Tatig est prise avec du disulfirame
• Allongement de l'intervalle QTc et arythmies ventriculaires pris avec du pimozide
• Pensées et comportements suicidaires
• Syndrome sérotoninergique
• Risque accru de saignement
• Activation de la manie / hypomanie
• Syndrome d'arrêt
• Convulsions
• Glaucome à angle fermé
• Hyponatrémie

Expérience des essais cliniques

Étant donné que les essais cliniques sont menés dans des conditions très variables, les taux d'effets indésirables observés dans les essais cliniques d'un médicament ne peuvent pas être directement comparés aux taux dans les essais cliniques d'un autre médicament et peuvent ne pas refléter les taux observés dans la pratique.

Les données décrites ci-dessous proviennent d'essais randomisés, en double aveugle et contrôlés contre placebo de Tatig (principalement 50 mg à 200 mg par jour) chez 3066 adultes diagnostiqués avec un TDM, un TOC, une PD, un ESPT, une TAS et un TMDD. Ces 3066 patients exposés à Tatig pendant 8 à 12 semaines représentent 568 patients. L'âge moyen était de 40 ans; 57% étaient des femmes et 43% étaient des hommes.

Les effets indésirables les plus courants (> 5% et deux fois le placebo) dans tous les essais cliniques regroupés contrôlés contre placebo de tous les patients traités par Tatig atteints de MDD, de TOC, de PD, de STSD, de TAS et de TMDD étaient des nausées, de la diarrhée / selles molles, des tremblements, dyspepsie, diminution de l'appétit, hyperhidrose et diminution de la libido (libido). Les effets indésirables les plus courants dans les essais de Tatig (> 5% et deux fois le placebo) sont les suivants, ce qui n'a pas été mentionné précédemment.

• MDD: somnolence;
• TOC: insomnie, agitation ;
• PD: constipation, agitation;
• SSPT: fatigue;
• PMDD: somnolence, bouche sèche, étourdissements, fatigue et douleurs abdominales ;
• TRISTE: insomnie, vertiges, fatigue, bouche sèche, malaise.

Tableau 3: Effets indésirables courants dans les essais contrôlés par placebo regroupés chez des adultes atteints de MDD, de TOC, de PD, de SSPT, de TASD et de PMDD *

Effets indésirables conduisant à l'arrêt dans les essais cliniques contrôlés par placebo

Dans toutes les études contrôlées contre placebo chez des patients atteints de MDD, de TOC, de PD, de SSPT, de TASD et de PMDD, 368 (12%) des 3066 patients ayant reçu Tatig ont arrêté le traitement en raison d'un effet indésirable, contre 93 (4%) des 2293 patients sous placebo. Dans les études contrôlées contre placebo, les effets indésirables courants ayant conduit à l'arrêt chez les patients traités par Tatig étaient les suivants:

• MDD, TOC, PD, STSD, SAD et PMDD: nausées (3%), diarrhée (2%), agitation (2%) et insomnie (2%).
• MDD (> 2% et deux fois placebo): diminution de l'appétit, étourdissements, fatigue, maux de tête, somnolence, tremblements et vomissements.
• TOC: somnolence.
• PD: nervosité et somnolence.

Dysfonction sexuelle masculine et féminine

Bien que les changements dans le désir sexuel, les performances sexuelles et la satisfaction sexuelle se produisent souvent comme des manifestations d'un trouble psychiatrique, ils peuvent également être une conséquence du traitement ISRS. Cependant, des estimations fiables de l'incidence et de la gravité des expériences fâcheuses impliquant le désir sexuel, les performances et la satisfaction sont difficiles à obtenir, en partie parce que les patients et les prestataires de soins de santé peuvent être réticents à en discuter. Par conséquent, les estimations de l'incidence des expériences et performances sexuelles non fâcheuses citées dans l'étiquetage peuvent sous-estimer leur incidence réelle.

Le tableau 4 ci-dessous présente l'incidence des effets indésirables sexuels rapportés par au moins 2% des patients traités par Tatig et deux fois le placebo des essais contrôlés contre placebo groupés. Pour les hommes et toutes les indications, les effets indésirables les plus courants (> 2% et deux fois le placebo) comprenaient: une insuffisance d'éjaculation, une diminution de la libido, une dysfonction érectile, un trouble de l'éjaculation et une dysfonction sexuelle masculine. Pour les femmes, l'effet indésirable le plus courant (≥2% et deux fois le placebo) a diminué la libido.

Tableau 4: Effets indésirables sexuels les plus courants (≥2% et deux fois le placebo) chez les hommes ou les femmes des essais contrôlés groupés Tatig chez les adultes atteints de MDD, de TOC, de PD, de STSD, de SAD et de PMDD

Effets indésirables chez les patients pédiatriques

Chez 281 patients pédiatriques traités par Tatig dans des études contrôlées contre placebo, le profil global des effets indésirables était généralement similaire à celui observé dans les études chez l'adulte. Effets indésirables qui n'apparaissent pas dans le tableau 3 (effets indésirables les plus courants chez l'adulte) pourtant ont été signalés chez au moins 2% des patients pédiatriques et à un taux d'au moins le double du taux placebo, la fièvre, hyperkinésie, incontinence urinaire, agression, épistaxis, purpura, arthralgie, poids diminué, contraction musculaire, et l'anxiété.

Autres effets indésirables observés lors de l'évaluation pré-commercialisation de Tatig

Les autres effets indésirables peu fréquents, non décrits ailleurs dans les informations de prescription, survenant à une incidence <2% chez les patients traités par Tatig étaient:

Troubles cardiaques - tachycardie

Affections de l'oreille et du labyrinthe - acouphènes

Troubles endocriniens - hypothyroïdie

Troubles oculaires - mydriase, vision floue

Affections gastro-intestinales - hématochezia, melena, hémorragie rectale

Troubles généraux et anomalies au site d'administration - œdème, troubles de la marche, irritabilité, pyrexie

Troubles hépatobiliaires - enzymes hépatiques élevées

Troubles du système immunitaire - anaphylaxie

Troubles du métabolisme et de la nutrition - diabète sucré, hypercholestérolémie, hypoglycémie, augmentation de l'appétit

Affections musculo-squelettiques et du tissu conjonctif - arthralgie, spasmes musculaires, oppression ou contraction

Troubles du système nerveux - ataxie, coma, convulsion, diminution de la vigilance, hypoesthésie, léthargie, hyperactivité psychomoteur, syncope

Troubles psychiatriques - agression, bruxisme, état confusionnel, humeur euphorique, hallucinations

Troubles rénaux et urinaires - hématurie

Système reproducteur et troubles mammaires - galactorrhée, priapisme, hémorragie vaginale

Affections respiratoires, thoraciques et médiastinales - bronchospasme, épistaxis, bâillement

Affections de la peau et du tissu sous-cutané - alopécie; sueur froide; dermatite; dermatite bulleuse; prurit; purpura; éruption érythémateuse, folliculaire ou maculopapuleuse; urticaire

Troubles vasculaires - hémorragie, hypertension, vasodilatation

Expérience post-commercialisation

Les effets indésirables suivants ont été identifiés lors de l'utilisation post-approbation de Tatig. Étant donné que ces réactions sont rapportées volontairement à partir d'une population de taille incertaine, il n'est pas toujours possible d'estimer de manière fiable leur fréquence ou d'établir une relation causale avec l'exposition au médicament.

Troubles du saignement ou de la coagulation - temps de coagulation accrus (fonction plaquettaire altérée)

Troubles cardiaques - Bloc AV, bradycardie, arythmies auriculaires, allongement de l'intervalle QTc, tachycardie ventriculaire (y compris Torsade de Pointes)

Troubles endocriniens - gynécomastie, hyperprolactinémie, irrégularités menstruelles, SIADH

Troubles oculaires - cécité, névrite optique, cataracte

Troubles hépatobiliaires - événements hépatiques sévères (y compris hépatite, jaunisse, insuffisance hépatique avec certains résultats mortels), pancréatite

Troubles hémicmiques et lymphatiques - agranulocytose, anémie aplasique et pancytopénie, leucopénie, thrombocytopénie, syndrome du lupus, maladie sérique

Troubles du système immunitaire - œdème de Quincke

Troubles du métabolisme et de la nutrition - hyponatrémie, hyperglycémie

Affections musculo-squelettiques et du tissu conjonctif - rhabdomyolyse, trismus

Troubles du système nerveux - syndrome sérotoninergique, symptômes extrapyramidaux (y compris akathisie et dystonie), crise oculogyrique

Troubles psychiatriques - psychose, énurésie, paronirie

Troubles rénaux et urinaires - insuffisance rénale aiguë

Affections respiratoires, thoraciques et médiastinales - hypertension pulmonaire

Affections de la peau et du tissu sous-cutané - réaction cutanée de photosensibilité et autres réactions cutanées sévères, qui peuvent potentiellement être fatales, telles que le syndrome de Stevens-Johnson (SJS) et la nécrolyse épidermique toxique (RTE)

Troubles vasculaires - spasme cérébrovasculaire (y compris syndrome de vasoconstriction cérébrale réversible et syndrome de flocons d'appel), vascularite

Human Experience

The most common signs and symptoms associated with non-fatal Tatig overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor. No cases of fatal overdosage with only sertraline have been reported.

Other important adverse events reported with Tatig overdose (single or multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QTc-interval prolongation, Torsade de Pointes, serotonin syndrome, stupor, and syncope.

Overdose Management

No specific antidotes for Tatig are known. Contact Poison Control (1-800-222-1222) for latest recommendations.

Studies at clinically relevant doses have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors. The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors. Sertraline does not inhibit monoamine oxidase.

Alcohol

In healthy subjects, the acute cognitive and psychomotor effects of alcohol were not potentiated by Tatig.

Cardiac Electrophysiology

The effect of sertraline on the QTc interval was evaluated in a randomized, double-blind, placebo- and positive-controlled three-period crossover thorough QTc study in 54 healthy adult subjects. At 2-fold the maximum recommended daily dose (~3-fold the steady-state exposure for sertraline and N-desmethylsertraline), the largest mean ΔΔQTc was 10 ms with upper bound of two-sided 90% confidence interval of 12 ms. The length of the QTc interval was also positively correlated with serum concentrations of sertraline and N- desmethylsertraline concentrations. These concentration-based analyses, however, indicated a lesser effect on QTc at maximally observed concentration than in the primary analysis.

Absorption

Following oral once-daily Tatig dosing over the range of 50 to 200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation up to steady-state concentrations, which are achieved after one week of once-daily dosing. Linear dose-proportional pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg. The single dose bioavailability of Tatig tablets is approximately equal to an equivalent dose of Tatig oral solution. Administration with food causes a small increase in Cmax and AUC.

Metabolism

Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40-45% of the administered radioactivity was accounted for in feces, including 12-14% unchanged sertraline.

Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24-hour), Cmax and Cmin, with about a 5- to 9-fold increase in these pharmacokinetic parameters between day 1 and day 14.

Protein Binding

In vitro protein binding studies performed with radiolabeled 3H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL. However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, warfarin and propranolol.