用量と投与方法
2 DOSAGE AND ADMINISTRATION Indication Starting Dosage Maximum Dosage MDD (2.1) 50 mg per day 200 mg per day OCD (2.1) 25 mg per day (ages 6 to 12) 200 mg per day 50 mg per day (ages ≥ 13) PD, PTSD, SAD (2.1) 25 mg per day 200 mg per day PMDD (2.2) continuous dosing 50 mg per day 150 mg per day PMDD (2.2) intermittent dosing 50 mg per day during luteal phase only 100 mg per day during luteal phase only If inadequate response to starting dosage, titrate in 25 to 50 mg per day increments once weekly in MDD, OCD, PD, PTSD, and SAD ( 2.1 ) See Full Prescribing Information for titration in PMDD ( 2.2 ) Hepatic impairment: Mild: Recommended starting and maximum dosage is half recommended dosage ( 2.4 ) Moderate or severe: Not recommended ( 2.4 ) When discontinuing sertraline hydrochloride tablets, reduce dose gradually ( 2.6 , 5.4 ) 2.1 Dosage in Patients with MDD, OCD, PD, PTSD, and SAD The recommended initial dosage and maximum sertraline hydrochloride dosage in patients with MDD, OCD, PD, PTSD, and SAD are displayed in Table 1 below. A dosage of 25 mg or 50 mg per day is the initial therapeutic dosage. For adults and pediatric patients, subsequent dosages may be increased in case of an inadequate response in 25 to 50 mg per day increments once a week, depending on tolerability, up to a maximum of 200 mg per day. Given the 24-hour elimination half-life of sertraline hydrochloride, the recommended interval between dose changes is one week. Table 1 : Recommended Daily Dosage of Sertraline Hydrochloride in Patients with MDD , OCD , PD , PTSD , and SAD Indication Starting Dose Therapeutic Range Adults MDD 50 mg OCD 50 mg 50 to 200 mg PD, PTSD, SAD 25 mg Pediatric Patients OCD (ages 6 to 12 years old) 25 mg 50 to 200 mg OCD (ages 13 to 17 years old) 50 mg 2.2 Dosage in Patients with PMDD The recommended starting sertraline hydrochloride dosage in adult women with PMDD is 50 mg per day. Sertraline hydrochloride tablets may be administered either continuously (every day throughout the menstrual cycle) or intermittently (only during the luteal phase of the menstrual cycle, i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the onset of menses). Intermittent dosing would be repeated with each new cycle. When dosing continuously , patients not responding to a 50 mg dosage may benefit from dosage increases at 50 mg increments per menstrual cycle up to 150 mg per day. When dosing intermittently , patients not responding to a 50 mg dosage may benefit from increasing the dosage up to a maximum of 100 mg per day during the next menstrual cycle (and subsequent cycles) as follows: 50 mg per day during the first 3 days of dosing followed by 100 mg per day during the remaining days in the dosing cycle. 2.3 Screen for Bipolar Disorder Prior to Starting Sertraline Hydrochloride Tablets Prior to initiating treatment with sertraline hydrochloride tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [See Warnings and Precautions ( 5.4) ] . 2.4 Dosage Modifications in Patients with Hepatic Impairment Both the recommended starting dosage and therapeutic range in patients with mild hepatic impairment (Child Pugh scores 5 or 6) are half the recommended daily dosage [See Dosage and Administration ( 2.1 , 2.2 )] . The use of sertraline hydrochloride tablets in patients with moderate (Child Pugh scores 7 to 9) or severe hepatic impairment (Child Pugh scores 10 to 15) is not recommended [See Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . 2.5 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of sertraline hydrochloride tablets. In addition, at least 14 days must elapse after stopping sertraline hydrochloride tablets before starting an MAOI antidepressant [See Contraindications ( 4 ), Warnings and Precautions ( 5.2 )] . 2.6 Discontinuation of Treatment with Sertraline Hydrochloride Tablets Adverse reactions may occur upon discontinuation of sertraline hydrochloride tablets [See Warnings and Precautions ( 5.5 )] . Gradually reduce the dosage rather than stopping sertraline hydrochloride tablets abruptly whenever possible.
Side Effects Overview
6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the prescribing information: Hypersensitivity reactions to sertraline [See Contraindications ( 4 )] QTc prolongation and ventricular arrhythmias when taken with pimozide [See Contraindications ( 4 ) , Clinical Pharmacology ( 12.2 )] ] Suicidal thoughts and behaviors [See Warnings and Precautions ( 5.1 )] Serotonin syndrome [See Contraindications ( 4 ), Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 )] Increased risk of bleeding [See Warnings and Precautions ( 5.3 )] Activation of mania/hypomania [See Warnings and Precautions ( 5.4) ] Discontinuation syndrome [See Warnings and Precautions ( 5.5 )] Seizures [See Warnings and Precautions ( 5.6 )] Angle-closure glaucoma [See Warnings and Precautions ( 5.7 )] Hyponatremia [See Warnings and Precautions ( 5.8 )] Sexual Dysfunction [See Warnings and Precautions ( 5.11 )] Most common adverse reactions (≥5% and twice placebo) in pooled placebo-controlled MDD, OCD, PD, PTSD, SAD and PMDD clinical trials were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 sertraline hydrochloride (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 sertraline hydrochloride 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 sertraline hydrochloride-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 sertraline hydrochloride (≥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 that occurred greater than 2% in sertraline hydrochloride-treated patients and at least 2% greater in sertraline hydrochloride-treated patients than placebo-treated patients. Sertraline Hydrochloride ( N = 3066 ) Placebo ( N = 2293 ) Cardiac disorders Palpitations 4% 2% Eye disorders Visual impairment 4% 2% Gastrointestinal Disorders Nausea 26% 12% Diarrhea/Loose Stools 20% 10% Dry mouth 14% 9% Dyspepsia 8% 4% Constipation 6% 4% Vomiting 4% 1% General disorders and administration site conditions Fatigue 12% 8% Metabolism and nutrition disorders Decreased appetite 7% 2% Nervous system disorders Dizziness 12% 8% Somnolence 11% 6% Tremor 9% 2% Psychiatric Disorders Insomnia 20% 13% Agitation 8% 5% Libido Decreased 6% 2% Reproductive system and breast disorders Ejaculation failure ( 1 ) 8% 1% Erectile dysfunction ( 1 ) 4% 1% Ejaculation disorder ( 1 ) 3% 0% Male sexual dysfunction ( 1 ) 2% 0% Skin and subcutaneous tissue disorders Hyperhidrosis 7% 3% 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 sertraline hydrochloride 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 sertraline hydrochloride-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 sertraline hydrochloride-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 Sertraline Hydrochloride Pooled Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD Sertraline Hydrochloride Placebo Men only ( N = 1316 ) ( N = 973 ) Ejaculation failure 8% 1% Libido decreased 7% 2% Erectile dysfunction 4% 1% Ejaculation disorder 3% 0% Male sexual dysfunction 2% 0% Women only ( N = 1750 ) ( N = 1320 ) Libido decreased 4% 2% Adverse Reactions in Pediatric Patients In 281 pediatric patients treated with sertraline hydrochloride 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 Sertraline Hydrochloride Other infrequent adverse reactions, not described elsewhere in the prescribing information, occurring at an incidence of < 2% in patients treated with sertraline hydrochloride 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 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of sertraline hydrochloride tablets. 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) [See Clinical Pharmacology ( 12.2 )] 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, eosinophilic pneumonia, anosmia, hyposmia 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
警告と注意事項
5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue sertraline hydrochloride tablets and serotonergic agents and initiate supportive treatment. ( 5.2 ) Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti- inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk. ( 5.3 ) Activation of Mania/Hypomania: Screen patients for bipolar disorder. ( 5.4 ) Seizures: Use with caution in patients with seizure disorders. ( 5.6 ) Angle Closure Glaucoma: Avoid use of antidepressants, including sertraline hydrochloride tablets, in patients with untreated anatomically narrow angles. ( 5.7 ) QTc Prolongation: sertraline hydrochloride tablets should be used with caution in patients with risk factors for QTc prolongation. ( 5.10 ) Sexual Dysfunction: sertraline hydrochloride tablets may cause symptoms of sexual dysfunction. ( 5.11 ) 5.1 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 Age Range ( years ) Drug - Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18 to 24 5 additional patients Decreases Compared to Placebo 25 to 64 1 fewer patient ≥65 6 fewer 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 sertraline hydrochloride tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), including sertraline hydrochloride, 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, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [See Contraindications ( 4 ), Drug Interactions ( 7.1 )] . 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 sertraline hydrochloride with MAOIs is contraindicated. In addition, do not initiate sertraline hydrochloride tablets 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 sertraline hydrochloride tablets, discontinue sertraline hydrochloride tablets before initiating treatment with the MAOI [See Contraindications ( 4 ), Drug Interactions ( 7.1 )] . Monitor all patients taking sertraline hydrochloride tablets for the emergence of serotonin syndrome. Discontinue treatment with sertraline hydrochloride tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of sertraline hydrochloride with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including sertraline hydrochloride, 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. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations ( 8.1 )] .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 sertraline hydrochloride tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio. 5.4 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with sertraline hydrochloride tablets 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 sertraline hydrochloride tablets. Prior to initiating treatment with sertraline hydrochloride tablets, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.5 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 [See Dosage and Administration ( 2.6 )] . 5.6 Seizures Sertraline hydrochloride has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. Sertraline hydrochloride tablets should be prescribed with caution in patients with a seizure disorder. 5.7 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including sertraline hydrochloride 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 sertraline hydrochloride tablets, in patients with untreated anatomically narrow angles. 5.8 Hyponatremia Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including sertraline hydrochloride. 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 sertraline hydrochloride tablets 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 [See Use in Specific Populations ( 8.5 )] . 5.9 False-Positive Effects on Screening Tests for Benzodiazepines False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking sertraline hydrochloride tablets. 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 sertraline hydrochloride tablets. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish sertraline hydrochloride from benzodiazepines [See Drug Interactions ( 7.3 )]. 5.10 QTc Prolongation During post-marketing use of sertraline, cases of QTc prolongation and Torsade de Pointes (TdP) have been reported. Most reports were confounded by other risk factors. In a randomized, doubleblind, placebo- and positive-controlled three-period crossover thorough QTc study in 54 healthy adult subjects, there was a positive relationship between the length of the rate-adjusted QTc interval and serum sertraline concentration. Therefore, sertraline hydrochloride tablets should be used with caution in patients with risk factors for QTc prolongation [See Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.2 )] . 5.11 Sexual Dsyfunction Use of SSRIs, including sertraline hydrochloride tablets, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1 )]. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of sertraline hydrochloride tablets and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment
薬物動態
12.3 Pharmacokinetics Absorption Following oral once-daily sertraline hydrochloride dosing over the range of 50 to 200 mg for 14 days, mean peak plasma concentrations (C max ) 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 C max 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 sertraline hydrochloride tablets is approximately equal to an equivalent dose of sertraline hydrochloride oral solution. Administration with food causes a small increase in C max 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 to 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 to 45% of the administered radioactivity was accounted for in feces, including 12 to 14% unchanged sertraline. Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0 to 24-hour), C max and C min , 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. Studies in Specific Populations Pediatric Patients: Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6 to 12 years, 32 aged 13 to 17 years) including both males (N=28) and females (N=33). Relative to the adults, pediatric patients aged 6 to 12 years and 13 to 17 years showed about 22% lower AUC (0 to 24 hr) and C max values when plasma concentration was adjusted for weight. The half-life was similar to that in adults, and no gender-associated differences were observed [See Dosage and Administration ( 2.1 ), Use in Specific Populations ( 8.4 )]. Geriatric Patients: Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated with 100 mg/day of sertraline hydrochloride for 14 days was approximately 40% lower than in a similarly studied group of younger (25 to 32 year old) individuals. Steady-state, therefore, was achieved after 2 to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but not in older females [See Use in Specific Populations ( 8.5 )]. Hepatic Impairment: In patients with chronic mild liver impairment (N=10: 8 patients with Child-Pugh scores of 5 to 6; and 2 patients with Child-Pugh scores of 7 to 8) who received 50 mg of sertraline hydrochloride per day for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared to age-matched volunteers with normal hepatic function (N=10). The exposure to desmethylsertraline was approximately 2-fold greater in patients with mild hepatic impairment compared to age-matched volunteers with normal hepatic function. There were no significant differences in plasma protein binding observed between the two groups. The effects of sertraline hydrochloride in patients with moderate and severe hepatic impairment have not been studied [See Dosage and Administration ( 2.4 ), Use in Specific Populations ( 8.6 )]. Renal Impairment: Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination. In volunteers with mild to moderate (CLcr=30 to 60 mL/min), moderate to severe (CLcr=10 to 29 mL/min) or severe (receiving hemodialysis) renal impairment (N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment [See Use in Specific Populations ( 8.7 )]. Drug Interaction Studies Pimozide: In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline hydrochloride (once daily) co-administration to steady state was associated with a mean increase in pimozide AUC and C max of about 40%, but was not associated with any changes in ECG. The highest recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline hydrochloride. The effect on QTc interval and PK parameters at doses higher than 2 mg of pimozide are not known [See Drug Interactions ( 7.1 )]. Drugs Metabolized by CYP2D6 Many antidepressant drugs (e.g., SSRIs, including sertraline hydrochloride, and most tricyclic antidepressant drugs) inhibit the biochemical activity of the drug metabolizing isozyme CYP2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of co-administered drugs that are metabolized by CYP2D6. The drugs for which this potential interaction is of greatest concern are those metabolized primarily by CYP2D6 and that have a narrow therapeutic index (e.g., tricyclic antidepressant drugs and the Type 1C antiarrhythmics propafenone and flecainide). The extent to which this interaction is an important clinical problem depends on the extent of the inhibition of CYP2D6 by the antidepressant and the therapeutic index of the co-administered drug. There is variability among the drugs effective in the treatment of MDD in the extent of clinically important 2D6 inhibition, and in fact sertraline hydrochloride at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class. Nevertheless, even sertraline hydrochloride has the potential for clinically important 2D6 inhibition [See Drug Interactions ( 7.1 )]. Phenytoin Clinical trial data suggested that sertraline hydrochloride may increase phenytoin concentrations [See Drug Interactions ( 7.1 )]. Cimetidine In a study assessing disposition of sertraline hydrochloride (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were increases in sertraline hydrochloride mean AUC (50%), C max (24%) and half-life (26%) compared to the placebo group [See Drug Interactions ( 7.2 )]. Diazepam In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either sertraline hydrochloride (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the sertraline hydrochloride group compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was a 23% increase in T max for desmethyldiazepam in the sertraline hydrochloride group compared to a 20% decrease in the placebo group (p<0.03) [See Drug Interactions ( 7.2 )]. Lithium In a placebo-controlled trial in normal volunteers, the administration of two doses of sertraline hydrochloride did not significantly alter steady-state lithium levels or the renal clearance of lithium [See Drug Interactions ( 7.2 )]. Tolbutamide In a placebo-controlled trial in normal volunteers, administration of sertraline hydrochloride for 22 days (including 200 mg/day for the final 13 days) caused a statistically significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous 1000 mg dose. Sertraline hydrochloride administration did not noticeably change either the plasma protein binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased clearance was due to a change in the metabolism of the drug [See Drug Interactions ( 7.2 )]. Atenolol Sertraline hydrochloride (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol [See Drug Interactions ( 7.2 )]. Digoxin In a placebo-controlled trial in normal volunteers, administration of sertraline hydrochloride for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance [See Drug Interactions ( 7.2 )]. Drugs Metabolized by CYP3A4 In three separate in vivo interaction studies, sertraline hydrochloride was co-administered with CYP3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions. The results of these studies indicated that sertraline hydrochloride did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that sertraline hydrochloride's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Results of the interaction study with cisapride indicate that sertraline hydrochloride 200 mg (once daily) induces the metabolism of cisapride (cisapride AUC and C max were reduced by about 35%) [See Drug Interactions ( 7.2 )]. Microsomal Enzyme Induction Preclinical studies have shown sertraline hydrochloride to induce hepatic microsomal enzymes. In clinical studies, sertraline hydrochloride was shown to induce hepatic enzymes minimally as determined by a small (5%) but statistically significant decrease in antipyrine half-life following administration of 200 mg of sertraline hydrochloride per day for 21 days. This small change in antipyrine half-life reflects a clinically insignificant change in hepatic metabolism.