Iglodep

Iglodep está indicado no tratamento do seguinte:

• Transtorno depressivo maior (MDD)
• Transtorno obsessivo-compulsivo (TOC)
• Distúrbio do pânico (DP)
• Transtorno de estresse pós-traumático (TEPT)
• Transtorno de ansiedade social (DAU)
• Distúrbio disfórico pré-menstrual (PMDD)

Dosagem em pacientes com MDD, TOC, DP, TEPT e SAD

A dosagem inicial recomendada e a dose máxima de Iglodep em pacientes com MDD, TOC, DP, TEPT e SAD são exibidas na Tabela 1 abaixo. Uma dose de 25 mg ou 50 mg por dia é a dose terapêutica inicial.

Para adultos e pacientes pediátricos, as dosagens subsequentes podem ser aumentadas em caso de resposta inadequada em incrementos de 25 a 50 mg por dia uma vez por semana, dependendo da tolerabilidade, até um máximo de 200 mg por dia. Dada a meia-vida de eliminação de 24 horas do Iglodep, o intervalo recomendado entre as alterações de dose é de uma semana.

Tabela 1: Dosagem diária recomendada de Iglodep em pacientes com MDD, TOC, DP, TEPT e SAD

Dosagem em pacientes com PMDD

A dose inicial recomendada de Iglodep em mulheres adultas com PMDD é de 50 mg por dia. O Iglodep pode ser administrado continuamente (todos os dias durante o ciclo menstrual) ou intermitentemente (apenas durante a fase lútea do ciclo menstrual, ou seja,., iniciando a dose diária 14 dias antes do início previsto da menstruação e continuando pelo início da menstruação). A dosagem intermitente seria repetida a cada novo ciclo.

• Ao administrar continuamente, os pacientes que não respondem a uma dose de 50 mg podem se beneficiar de aumentos de dose a incrementos de 50 mg por ciclo menstrual de até 150 mg por dia.
• Ao administrar intermitentemente, pacientes que não respondem a uma dose de 50 mg podem se beneficiar do aumento da dose até um máximo de 100 mg por dia durante o próximo ciclo menstrual (e ciclos subsequentes) do seguinte modo: 50 mg por dia durante os primeiros 3 dias de administração, seguidos de 100 mg por dia durante os dias restantes no ciclo de dosagem.

Tela para transtorno bipolar antes de iniciar o Iglodep

Antes de iniciar o tratamento com Iglodep ou outro antidepressivo, examine os pacientes quanto a um histórico pessoal ou familiar de transtorno bipolar, mania ou hipomania.

Modificações de dosagem em pacientes com comprometimento hepático

Tanto a dose inicial recomendada quanto a faixa terapêutica em pacientes com insuficiência hepática leve (escores de Child Pugh 5 ou 6) são metade da dose diária recomendada. O uso de Iglodep em pacientes com insuficiência hepática moderada (escores de Child Pugh 7 a 9) ou grave (escores de Child Pugh 10 a 15) não é recomendado.

Mudando pacientes para ou de um antidepressivo inibidor da monoamina oxidase

Pelo menos 14 dias devem decorrer entre a descontinuação de um antidepressivo inibidor da monoamina oxidase (MAOI) e o início do Iglodep. Além disso, pelo menos 14 dias devem decorrer após a interrupção do Iglodep antes de iniciar um antidepressivo MAOI.

Descontinuação do tratamento com Iglodep

Reações adversas podem ocorrer após a descontinuação de Iglodep. Reduza gradualmente a dose em vez de parar o Iglodep abruptamente sempre que possível.

Preparação da solução oral de Iglodep

A solução oral de Iglodep deve ser diluída antes do uso.

• Use o conta-gotas calibrado fornecido para medir a quantidade de solução oral Iglodep necessária
• Nota: O conta-gotas calibrado fornecido possui apenas 25 mg e 50 mg de marcas de graduação
• Misture com 4 onças (½ xícara) de água, ginger ale, limão / limão, limonada ou suco de laranja. Após a mistura, uma leve névoa pode aparecer, o que é normal.

Instrua pacientes ou cuidadores a tomar imediatamente a dose após a mistura.

Iglodep is contraindicated in patients:

• Taking, or within 14 days of stopping, MAOIs, (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome.
• Taking pimozide.
• With known hypersensitivity to sertraline (e.g., anaphylaxis, angioedema).

In addition to the contraindications for all Iglodep formulations listed above, Iglodep oral solution is contraindicated in patients:

• Taking disulfiram. Iglodep oral solution contains contain alcohol, and concomitant use of Iglodep and disulfiram may result in a disulfiram-alcohol reaction.

Store Iglodep tablets and oral solution at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Distributed by: Roerig, Division of Pfizer Inc., NY,NY 10017. Revised: Dec 2017

SIDE EFFECTS

The following adverse reactions are described in more detail in other sections of the prescribing information:

• Hypersensitivity reactions to sertraline
• Disulfiram-alcohol reaction when Iglodep oral solution is taken with disulfiram
• QTc prolongation and ventricular arrhythmias when taken with pimozide
• Suicidal thoughts and behaviors
• Serotonin syndrome
• Increased risk of bleeding
• Activation of mania/hypomania
• Discontinuation syndrome
• Seizures
• Angle-closure glaucoma
• Hyponatremia

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below are from randomized, double-blind, placebo-controlled trials of Iglodep (mostly 50 mg to 200 mg per day) in 3066 adults diagnosed with MDD, OCD, PD, PTSD, SAD, and PMDD. These 3066 patients exposed to Iglodep for 8 to12 weeks represent 568 patient-years of exposure. The mean age was 40 years; 57% were females and 43% were males.

The most common adverse reactions (>5% and twice placebo) in all pooled placebo-controlled clinical trials of all Iglodep-treated patients with MDD, OCD, PD, PTSD, SAD and PMDD were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido (see Table 3). The following are the most common adverse reactions in trials of Iglodep (>5% and twice placebo) by indication that were not mentioned previously.

• MDD: somnolence;
• OCD: insomnia, agitation;
• PD: constipation, agitation;
• PTSD: fatigue;
• PMDD: somnolence, dry mouth, dizziness, fatigue, and abdominal pain;
• SAD: insomnia, dizziness, fatigue, dry mouth, malaise.

Table 3: Common Adverse Reactions in Pooled Placebo-Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD*

Adverse Reactions Leading To Discontinuation In Placebo-Controlled Clinical Trials

In all placebo-controlled studies in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 368 (12%) of the 3066 patients who received Iglodep discontinued treatment due to an adverse reaction, compared with 93 (4%) of the 2293 placebo-treated patients. In placebo-controlled studies, the following were the common adverse reactions leading to discontinuation in Iglodep-treated patients:

• MDD, OCD, PD, PTSD, SAD and PMDD: nausea (3%), diarrhea (2%), agitation (2%), and insomnia (2%).
• MDD (>2% and twice placebo): decreased appetite, dizziness, fatigue, headache, somnolence, tremor, and vomiting.
• OCD: somnolence.
• PD: nervousness and somnolence.

Male And Female Sexual Dysfunction

Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence.

Table 4 below displays the incidence of sexual adverse reactions reported by at least 2% of Iglodep-treated patients and twice placebo from pooled placebo-controlled trials. For men and all indications, the most common adverse reactions (>2% and twice placebo) included: ejaculation failure, decreased libido, erectile dysfunction, ejaculation disorder, and male sexual dysfunction. For women, the most common adverse reaction (≥2% and twice placebo) was decreased libido.

Table 4: Most Common Sexual Adverse Reactions (≥2% and twice placebo) in Men or Women from Iglodep Pooled Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD

Adverse Reactions In Pediatric Patients

In 281 pediatric patients treated with Iglodep in placebo-controlled studies, the overall profile of adverse reactions was generally similar to that seen in adult studies. Adverse reactions that do not appear in Table 3 (most common adverse reactions in adults) yet were reported in at least 2% of pediatric patients and at a rate of at least twice the placebo rate include fever, hyperkinesia, urinary incontinence, aggression, epistaxis, purpura, arthralgia, decreased weight, muscle twitching, and anxiety.

Other Adverse Reactions Observed During The Premarketing Evaluation Of Iglodep

Other infrequent adverse reactions, not described elsewhere in the prescribing information, occurring at an incidence of < 2% in patients treated with Iglodep were:

Cardiac disorders – tachycardia

Ear and labyrinth disorders – tinnitus

Endocrine disorders - hypothyroidism

Eye disorders - mydriasis, blurred vision

Gastrointestinal disorders - hematochezia, melena, rectal hemorrhage

General disorders and administration site conditions - edema, gait disturbance, irritability, pyrexia

Hepatobiliary disorders - elevated liver enzymes

Immune system disorders - anaphylaxis

Metabolism and nutrition disorders - diabetes mellitus, hypercholesterolemia, hypoglycemia, increased appetite

Musculoskeletal and connective tissue disorders - arthralgia, muscle spasms, tightness, or twitching

Nervous system disorders - ataxia, coma, convulsion, decreased alertness, hypoesthesia, lethargy, psychomotor hyperactivity, syncope

Psychiatric disorders - aggression, bruxism, confusional state, euphoric mood, hallucination

Renal and urinary disorders - hematuria

Reproductive system and breast disorders - galactorrhea, priapism, vaginal hemorrhage

Respiratory, thoracic and mediastinal disorders - bronchospasm, epistaxis, yawning

Skin and subcutaneous tissue disorders - alopecia; cold sweat; dermatitis; dermatitis bullous; pruritus; purpura;erythematous, follicular, or maculopapular rash; urticaria

Vascular disorders – hemorrhage, hypertension, vasodilation

Post-marketing Experience

The following adverse reactions have been identified during postapproval use of Iglodep. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Bleeding or clotting disorders - increased coagulation times (altered platelet function)

Cardiac disorders - AV block, bradycardia, atrial arrhythmias, QTc-interval prolongation, ventricular tachycardia (including Torsade de Pointes)

Endocrine disorders - gynecomastia, hyperprolactinemia, menstrual irregularities, SIADH

Eye disorders - blindness, optic neuritis, cataract

Hepatobiliary disorders - severe liver events (including hepatitis, jaundice, liver failure with some fatal outcomes), pancreatitis

Hemic and lymphatic disorders - agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness

Immune system disorders - angioedema

Metabolism and nutrition disorders - hyponatremia, hyperglycemia

Musculoskeletal and connective tissue disorders - rhabdomyolysis, trismus

Nervous system disorders - serotonin syndrome, extrapyramidal symptoms (including akathisia and dystonia), oculogyric crisis

Psychiatric disorders - psychosis, enuresis, paroniria

Renal and urinary disorders - acute renal failure

Respiratory, thoracic and mediastinal disorders - pulmonary hypertension

Skin and subcutaneous tissue disorders - photosensitivity skin reaction and other severe cutaneous reactions, which potentially can be fatal, such as Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN)

Vascular disorders - cerebrovascular spasm (including reversible cerebral vasoconstriction syndrome and Call-Fleming syndrome), vasculitis

DRUG INTERACTIONS

Clinically Significant Drug Interactions

Table 5 includes clinically significant drug interactions with Iglodep.

Table 5: Clinically-Significant Drug Interactions with Iglodep

Drugs Having No Clinically Important Interactions With Iglodep

Based on pharmacokinetic studies, no dosage adjustment of Iglodep is necessary when used in combination with cimetidine. Additionally, no dosage adjustment is required for diazepam, lithium, atenolol, tolbutamide, digoxin, and drugs metabolized by CYP3A4, when Iglodep is administered concomitantly.

False-Positive Screening Tests For Benzodiazepines

False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking Iglodep. 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 Iglodep. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines.

Drug Abuse And Dependence

Controlled Substance

Iglodep contains sertraline, which is not a controlled substance.

Abuse

In a placebo-controlled, double-blind, randomized study of the comparative abuse liability of Iglodep, alprazolam, and d-amphetamine in humans, Iglodep did not produce the positive subjective effects indicative of abuse potential, such as euphoria or drug liking, that were observed with the other two drugs.

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 Iglodep, 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 Iglodep, 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 Iglodep with MAOIs is contraindicated. In addition, do not initiate Iglodep 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 Iglodep, discontinue Iglodep before initiating treatment with the MAOI.

Monitor all patients taking Iglodep for the emergence of serotonin syndrome. Discontinue treatment with Iglodep and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Iglodep 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 Iglodep, 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 Iglodep and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.

Activation Of 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

Iglodep has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. Iglodep 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 Iglodep 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 Iglodep, in patients with untreated anatomically narrow angles.

Hyponatremia

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including Iglodep. 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 Iglodep 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 Iglodep. 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 Iglodep. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish Iglodep 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 Iglodep oral solution, inform them that:

• Iglodep oral solution must be diluted before use. Do not mix in advance.
• Use the dropper provided to remove the required amount of Iglodep 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 Iglodep 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 Iglodep Oral Solution

Inform patients not to take disulfiram when taking Iglodep 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 Iglodep 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 Iglodep 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 Iglodep and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when Iglodep 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 Iglodep may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment O

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 Iglodep, 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 Iglodep, 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 Iglodep with MAOIs is contraindicated. In addition, do not initiate Iglodep 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 Iglodep, discontinue Iglodep before initiating treatment with the MAOI.

Monitor all patients taking Iglodep for the emergence of serotonin syndrome. Discontinue treatment with Iglodep and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Iglodep 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 Iglodep, 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 Iglodep 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 Iglodep 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 Iglodep. Prior to initiating treatment with Iglodep, 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

Iglodep has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. Iglodep 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 Iglodep 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 Iglodep, in patients with untreated anatomically narrow angles.

Hyponatremia

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including Iglodep. 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 Iglodep 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 Iglodep. 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 Iglodep. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish Iglodep 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 Iglodep oral solution, inform them that:

• Iglodep oral solution must be diluted before use. Do not mix in advance.
• Use the dropper provided to remove the required amount of Iglodep 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 Iglodep 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 Iglodep Oral Solution

Inform patients not to take disulfiram when taking Iglodep 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 Iglodep 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 Iglodep 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 Iglodep and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when Iglodep 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 Iglodep 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 Iglodep, 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 Iglodep.

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

Data

Human Data

Third Trimester Exposure

Neonates exposed to Iglodep 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 Iglodep 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 Iglodep

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 Iglodep.

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 Iglodep 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 Iglodep group compared to a slight gain for the placebo group. For children, about 7% of the Iglodep-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 Iglodep-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 (Iglodep n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. Those subjects who completed 34 weeks of Iglodep 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 Iglodep on the growth, development, and maturation in pediatric patients.

Alcohol Content In Iglodep Oral Solution

Iglodep 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 Iglodep 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 Iglodep 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 Iglodep, 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 Iglodep in patients with moderate (Child-Pugh score 7 to 10) or severe hepatic impairment (Child-Pugh score 10-15) is not recommended, because Iglodep is extensively metabolized, and the effects of Iglodep 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.

As seguintes reações adversas são descritas em mais detalhes em outras seções das informações de prescrição :

• Reações de hipersensibilidade à sertralina
• Reação dissulfiram-álcool quando a solução oral de Iglodep é tomada com dissulfiram
• Prolongamento do intervalo QTc e arritmias ventriculares quando tomado com pimozida
• Pensamentos e comportamentos suicidas
• Síndrome da serotonina
• Aumento do risco de sangramento
• Ativação da mania / hipomania
• Síndrome de descontinuação
• Convulsões
• Glaucoma de fechamento de ângulo
• Hiponatremia

Experiência em ensaios clínicos

Como os ensaios clínicos são conduzidos em condições muito variadas, as taxas de reação adversa observadas nos ensaios clínicos de um medicamento não podem ser diretamente comparadas às taxas nos ensaios clínicos de outro medicamento e podem não refletir as taxas observadas na prática.

Os dados descritos abaixo são de ensaios randomizados, duplo-cegos e controlados por placebo de Iglodep (principalmente 50 mg a 200 mg por dia) em 3066 adultos diagnosticados com MDD, TOC, PD, PTSD, SAD e PMDD. Esses 3066 pacientes expostos ao Iglodep por 8 a 12 semanas representam 568 pacientes-ano de exposição. A idade média foi de 40 anos; 57% eram do sexo feminino e 43% eram do sexo masculino.

As reações adversas mais comuns (> 5% e duas vezes placebo) em todos os ensaios clínicos combinados controlados por placebo de todos os pacientes tratados com Iglodep com MDD, TOC, DP, TEPT, SAD e PMDD foram náusea, diarréia / fezes soltas, tremor, dispepsia , diminuição do apetite, hiperidrose, falha na ejaculação e diminuição da libido (consulte a Tabela 3). A seguir, são apresentadas as reações adversas mais comuns em ensaios de Iglodep (> 5% e duas vezes placebo) por indicação que não foram mencionadas anteriormente.

• MDD: sonolência;
• TOC: insônia, agitação;
• PD: constipação, agitação;
• TEPT: fadiga;
• PMDD: sonolência, boca seca, tontura, fadiga e dor abdominal;
• TRISTE: insônia, tontura, fadiga, boca seca, mal-estar.

Tabela 3: Reações adversas comuns em ensaios combinados controlados por placebo em adultos com MDD, OCD, PD, TEPT, SAD e PMDD *

Reações adversas que levam à descontinuação em ensaios clínicos controlados por placebo

Em todos os estudos controlados por placebo em pacientes com MDD, TOC, DP, TEPT, SAD e PMDD, 368 (12%) dos 3066 pacientes que receberam Iglodep interromperam o tratamento devido a uma reação adversa, em comparação com 93 (4%) dos 2293 pacientes tratados com placebo. Em estudos controlados por placebo, foram apresentadas as reações adversas comuns que levaram à descontinuação em pacientes tratados com Iglodep:

• MDD, TOC, DP, TEPT, SAD e PMDD: náusea (3%), diarréia (2%), agitação (2%) e insônia (2%).
• MDD (> 2% e duas vezes placebo): diminuição do apetite, tontura, fadiga, dor de cabeça, sonolência, tremor e vômito.
• TOC: sonolência.
• DP: nervosismo e sonolência.

Disfunção sexual masculina e feminina

Embora as mudanças no desejo sexual, desempenho sexual e satisfação sexual ocorram frequentemente como manifestações de um distúrbio psiquiátrico, elas também podem ser uma conseqüência do tratamento com ISRS. No entanto, é difícil obter estimativas confiáveis da incidência e gravidade de experiências desagradáveis envolvendo desejo sexual, desempenho e satisfação, em parte porque pacientes e profissionais de saúde podem relutar em discuti-las. Consequentemente, estimativas da incidência de experiência e desempenho sexual indesejáveis citados na rotulagem podem subestimar sua incidência real.

A Tabela 4 abaixo mostra a incidência de reações adversas sexuais relatadas por pelo menos 2% dos pacientes tratados com Iglodep e duas vezes o placebo em estudos combinados controlados por placebo. Para os homens e todas as indicações, as reações adversas mais comuns (> 2% e duas vezes o placebo) incluíram: falha na ejaculação, diminuição da libido, disfunção erétil, distúrbio da ejaculação e disfunção sexual masculina. Para as mulheres, a reação adversa mais comum (≥2% e duas vezes placebo) foi diminuição da libido.

Tabela 4: Reações adversas sexuais mais comuns (≥2% e duas vezes placebo) em homens ou mulheres de ensaios controlados em conjunto com Iglodep em adultos com MDD, TOC, PD, TEPT, SAD e PMDD

Reações adversas em pacientes pediátricos

Em 281 pacientes pediátricos tratados com Iglodep em estudos controlados por placebo, o perfil geral de reações adversas foi geralmente semelhante ao observado em estudos adultos. Reações adversas que não aparecem na Tabela 3 (reações adversas mais comuns em adultos) ainda foram relatados em pelo menos 2% dos pacientes pediátricos e a uma taxa de pelo menos duas vezes a taxa de placebo inclui febre, hipercinesia, incontinência urinária, agressão, epistaxe, púrpura, artralgia, diminuição de peso, contração muscular, e ansiedade.

Outras reações adversas observadas durante a avaliação de pré-comercialização de Iglodep

Outras reações adversas pouco frequentes, não descritas em outras partes das informações prescritas, ocorrendo com uma incidência <2% em pacientes tratados com Iglodep foram:

Cardiopatias - taquicardia

Distúrbios do ouvido e do labirinto - zumbido

Distúrbios endócrinos - hipotireoidismo

Distúrbios oculares - midríase, visão turva

Distúrbios gastrointestinais - hematochezia, melena, hemorragia retal

Perturbações gerais e alterações no local de administração - edema, distúrbio da marcha, irritabilidade, pirexia

Distúrbios hepatobiliares - enzimas hepáticas elevadas

Distúrbios do sistema imunológico - anafilaxia

Distúrbios do metabolismo e nutrição - diabetes mellitus, hipercolesterolemia, hipoglicemia, aumento do apetite

Afecções musculosqueléticas e dos tecidos conjuntivos - artralgia, espasmos musculares, aperto ou contração

Distúrbios do sistema nervoso - ataxia, coma, convulsão, diminuição do estado de alerta, hipoestesia, letargia, hiperatividade psicomotor, síncope

Distúrbios psiquiátricos - agressão, bruxismo, estado de confusão, humor eufórico, alucinação

Distúrbios renais e urinários - hematúria

Sistema reprodutivo e distúrbios da mama - galactorréia, priapismo, hemorragia vaginal

Distúrbios respiratórios, torácicos e mediastinais - broncoespasmo, epistaxe, bocejo

Afecções dos tecidos cutâneos e subcutâneos - alopecia; suor frio; dermatite; dermatite bolhosa; prurido; púrpura; erupção cutânea eritematosa, folicular ou maculopapular; urticária

Distúrbios vasculares - hemorragia, hipertensão, vasodilatação

Experiência pós-comercialização

As seguintes reações adversas foram identificadas durante o uso pós-aprovação de Iglodep. Como essas reações são relatadas voluntariamente a partir de uma população de tamanho incerto, nem sempre é possível estimar com segurança sua frequência ou estabelecer uma relação causal com a exposição a medicamentos.

Distúrbios hemorrágicos ou de coagulação - aumento dos tempos de coagulação (função plaquetária alterada)

Cardiopatias - Bloco AV, bradicardia, arritmias atriais, prolongamento do intervalo QTc, taquicardia ventricular (incluindo Torsade de Pointes)

Distúrbios endócrinos - ginecomastia, hiperprolactinemia, irregularidades menstruais, SIADH

Distúrbios oculares - cegueira, neurite óptica, catarata

Distúrbios hepatobiliares - eventos hepáticos graves (incluindo hepatite, icterícia, insuficiência hepática com alguns resultados fatais), pancreatite

Distúrbios hêmicos e linfáticos - agranulocitose, anemia aplástica e pancitopenia, leucopenia, trombocitopenia, síndrome do tipo lúpus, doença sérica

Distúrbios do sistema imunológico - angioedema

Distúrbios do metabolismo e nutrição - hiponatremia, hiperglicemia

Afecções musculosqueléticas e dos tecidos conjuntivos - rabdomiólise, trismo

Distúrbios do sistema nervoso - síndrome da serotonina, sintomas extrapiramidais (incluindo acatisia e distonia), crise oculogírica

Distúrbios psiquiátricos - psicose, enurese, paroniria

Distúrbios renais e urinários - insuficiência renal aguda

Distúrbios respiratórios, torácicos e mediastinais - hipertensão pulmonar

Afecções dos tecidos cutâneos e subcutâneos - reação cutânea por fotosensibilidade e outras reações cutâneas graves, que podem ser potencialmente fatais, como Síndrome de Stevens-Johnson (SJS) e necrólise epidérmica tóxica (RTE)

Distúrbios vasculares - espasmo cerebrovascular (incluindo síndrome de vasoconstrição cerebral reversível e síndrome de Call-Fleming), vasculite

Experiência humana

Os sinais e sintomas mais comuns associados à superdosagem não fatal de Iglodep foram sonolência, vômito, taquicardia, náusea, tontura, agitação e tremor. Não foram relatados casos de superdosagem fatal com apenas sertralina.

Outros eventos adversos importantes relatados com overdose de Iglodep (medicamentos únicos ou múltiplos) incluem bradicardia, bloqueio de ramo, coma, convulsões, delírio, alucinações, hipertensão, hipotensão, reação maníaca, pancreatite, prolongamento do intervalo QTc, Torsade de Pointes, síndrome da serotonina, estupor e síncope.

Gerenciamento de overdose

Não são conhecidos antídotos específicos para o Iglodep. Entre em contato com o Controle de veneno (1-800-222-1222) para obter as recomendações mais recentes.

Estudos em doses clinicamente relevantes demonstraram que a sertralina bloqueia a captação de serotonina em plaquetas humanas. In vitro estudos em animais também sugerem que a sertralina é um inibidor potente e seletivo da recaptação neuronal de serotonina e tem efeitos muito fracos na recaptação neuronal de noradrenalina e dopamina. In vitro estudos demonstraram que a sertralina não possui afinidade significativa para receptores adrenérgicos (alfa1, alfa2, beta), colinérgicos, GABA, dopaminérgicos, histaminérgicos, serotoninérgicos (5HT1A, 5HT1B, 5HT2) ou benzodiazepínicos. A administração crônica de sertralina foi encontrada em animais para regular os receptores da noradrenalina cerebral. A sertralina não inibe a monoamina oxidase.

Álcool

Em indivíduos saudáveis, os efeitos cognitivos e psicomotor agudos do álcool não foram potencializados pelo Iglodep.

Eletrofisiologia Cardíaca

O efeito da sertralina no intervalo QTc foi avaliado em um estudo QTc completo de três períodos, randomizado, duplo-cego, controlado por placebo e positivo, em 54 indivíduos adultos saudáveis. Com 2 vezes a dose diária máxima recomendada (~ 3 vezes a exposição em estado estacionário para sertralina e N-desmetilsertralina), a maior média ΔΔQTc foi de 10 ms com limite superior de 90% do intervalo de confiança de 12 ms. O comprimento do intervalo QTc também foi positivamente correlacionado com as concentrações séricas de sertralina e N-desmetilsertralina. Essas análises baseadas em concentração, no entanto, indicaram um efeito menor no QTc na concentração máxima observada do que na análise primária.

Absorção

Após a administração oral de Iglodep uma vez ao dia na faixa de 50 a 200 mg por 14 dias, as concentrações plasmáticas máximas médias (Cmax) de sertralina ocorreram entre 4,5 e 8,4 horas após a administração. A meia-vida média de eliminação terminal da sertralina plasmática é de cerca de 26 horas. Consistente com a meia-vida de eliminação terminal, há um acúmulo aproximadamente duplo até concentrações no estado estacionário, que são alcançadas após uma semana de administração uma vez ao dia. A farmacocinética proporcional à dose linear foi demonstrada em um estudo de dose única em que a Cmax e a área sob a curva de tempo de concentração plasmática (AUC) da sertralina foram proporcionais à dose na faixa de 50 a 200 mg. A biodisponibilidade da dose única dos comprimidos de Iglodep é aproximadamente igual a uma dose equivalente de solução oral de Iglodep. A administração com alimentos causa um pequeno aumento na Cmax e na AUC

Metabolismo

A sertralina sofre extenso metabolismo de primeira passagem. A principal via inicial do metabolismo da sertralina é a N-desmetilação. A N-desmetilsertralina tem uma meia-vida de eliminação terminal plasmática de 62 a 104 horas. Ambos in vitro bioquímico e in vivo testes farmacológicos demonstraram que a N-desmetilsertralina é substancialmente menos ativa que a sertralina. Tanto a sertralina quanto a N-desmetilsertralina sofrem deaminação oxidativa e subsequente redução, hidroxilação e conjugação de glucuronido. Em um estudo de sertralina radiomarcada envolvendo dois indivíduos saudáveis do sexo masculino, a sertralina representou menos de 5% da radioatividade plasmática. Cerca de 40-45% da radioatividade administrada foi recuperada na urina em 9 dias. A sertralina inalterada não era detectável na urina. No mesmo período, cerca de 40-45% da radioatividade administrada foi contabilizada nas fezes, incluindo 12-14% de sertralina inalterada.

A desmetilsertralina exibe aumentos dependentes da dose e relacionados ao tempo na AUC (0-24 horas), Cmax e Cmin, com um aumento de cerca de 5 a 9 vezes nesses parâmetros farmacocinéticos entre o dia 1 e o dia 14.

Ligação às proteínas

In vitro estudos de ligação às proteínas realizados com 3H-sertralina radiomarcada mostraram que a sertralina está altamente ligada às proteínas séricas (98%) na faixa de 20 a 500 ng / mL. Contudo, em concentrações de até 300 e 200 ng / mL, respectivamente, a sertralina e a N-desmetilsertralina não alteraram a ligação às proteínas plasmáticas de dois outros medicamentos altamente ligados às proteínas, varfarina e propranolol.