Approval date: March 18, 2008
Modification date: April 28, 2008
Modification date: June 11, 2008
Revision date: August 12, 2008
Modification date: 09/27/2008
Modification date: 07 December 2015
Date of revision: ×××× xxxxxxxxx
Sertraline hydrochloride tablets instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
Suicidal tendencies and antidepressants
Results of short-term clinical trials of depression (MDD) and other psychiatric disorders have shown that antidepressant medications increase the risk of suicidal thoughts and committing suicidal acts (suicidal ideation) in children, adolescents, and young adults (<24 years of age) compared to placebo. Anyone considering the use of sertraline or other antidepressants in children, adolescents, or young adults (<24 years of age) must weigh their risks against their clinical needs. Short-term clinical trials have not shown an increased risk of suicidal ideation with antidepressant use compared with placebo in adults older than 24 years of age; and in adults aged 65 years and older, the risk of suicidal ideation was reduced with antidepressant use. Depression and certain psychiatric disorders are themselves associated with an increased risk of suicide, and patients of all ages must be closely monitored for worsening clinical symptoms, suicidal ideation, and abnormal changes in behavior after initiation of treatment with antidepressants. Families and caregivers should be advised that they must closely observe and communicate with their physicians. Sertraline has not been approved for pediatric patients for indications other than obsessive-compulsive disorder (see [Precautions]-Warnings, Worsening of Clinical Symptoms and Risk of Suicide, and [Pediatric Dosage]).
Drug Name]
Generic Name: Sertraline Hydrochloride Tablets
Trade name: Leyuan
English name: Sertraline Hydrochloride Tablets
Hanyu Pinyin：Yansuan Shequlin Pian
Ingredients
The main component of this product is: Sertraline Hydrochloride
Chemical name: (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine hydrochloride
Chemical structure formula.
Molecular formula: C17H17Cl2NHCl
Molecular weight: 342.70
Properties
This product is a blue oval film-coated tablet, one side inscribed, one side blank, after removing the coating appears white or off-white.
Indications】
Sertraline is used for the treatment of symptoms associated with depression, including depression with anxiety, with or without a history of mania. After satisfactory treatment, continued administration of sertraline can effectively prevent recurrence and relapse of depression.
Sertraline is also used to treat obsessive-compulsive disorder. After satisfactory efficacy, continued administration of sertraline is effective in preventing recurrence of the initial symptoms of OCD.
Specification
50mg (based on C17H17Cl2N).
Dosage]
Sertraline tablets can be given orally once a day, either in the morning or in the evening. It can be taken with food or alone. Adult dose.
Initial treatment: 1 tablet (50mg) of sertraline daily.
Dose adjustment: The dose may be increased for patients who do not respond well to 1 tablet (50 mg) daily and who tolerate the drug well, as the elimination half-life of sertraline is 24 hours and the interval between dose adjustments should not be shorter than 1 week. The maximum dose is 4 tablets (200 mg)/day.
Efficacy is seen within seven days of dosing. Full effect may take longer, especially for OCD.
Maintenance therapy: Long-term use of the drug should be adjusted according to efficacy and the minimum effective therapeutic dose should be maintained.
Dosage in pediatric populations (children and adolescents).
OCD – In children (6-12 years of age), the starting dose of this product should be 25 mg once daily; in adolescents (13-17 years of age), the starting dose of this product should be 50 mg once daily.
Although a dose-effect relationship has not been established for the treatment of OCD, clinical trials have demonstrated that patients can be effectively treated in the 25-200 mg/day range for pediatric OCD patients (6-17 years of age). If the product is less effective at 25 or 50 mg/day, patients may benefit from an increased dose (up to 200 mg/day). The body weight of pediatric patients with OCD is usually lower than that of adults and this should be considered before administration to avoid overdosing. The clearance half-life of sertraline is 24 hours and the dose adjustment interval should not be shorter than 1 week.
[Adverse Reactions].
Although it is not certain that all events were caused by sertraline, we still report all adverse events collected from reports during clinical trials and after the product was launched.
The adverse reactions observed in the double-blind, placebo-controlled trial in patients with OCD were similar to those observed in the clinical trial in patients with depression.
Table 1. list of adverse reactions stratified by SOC and CIOMS frequency categories and listed in descending order of medical severity or clinical significance in each frequency category and SOC Organ system classification Very common (≥1/10) Common
(≥1/100 to <1/10) Occasional
(≥1/1000 to <1/100) Rare
(≥1/10,000 to <1/1000) Frequency unknown
(cannot be determined from available data) Blood and lymphatic system abnormalities Thrombocytopenia*§
Leukopenia*§
Abnormal platelet function tests*§ Immune system abnormalities Hypersensitivity* allergy-like reactions* Endocrine abnormalities Inappropriate secretion of antidiuretic hormone*§ Hyperprolactinemia*§
Hypothyroidism* Metabolic and nutritional abnormalities Decreased appetite.
Increased appetite* Diabetes mellitus
Hyponatremia*§ Hyponatremia
Hypoglycemia*
Hyperglycemia*§ Mental abnormalities insomnia depressive symptoms
Anxiety*
Agitation*
Teeth grinding disorder§
Nightmares*§
Hypersexuality*
Hallucinations*
Aggression*
Blurred state of consciousness*
Euphoria*
Psychotic disorders* § Neurological abnormalities Dizziness
Headache* Increased muscle tone*
Tremor
Drowsiness
Sensory inversions* Syncope
Extrapyramidal symptoms*
involuntary muscle contractions*
Hypesthesia*
Hyperkinesia*
Migraine*
5-hydroxytryptamine syndrome*§
coma*.
convulsions*,
dystonia*§
inability to sit still*
Eye abnormalities Visual impairment* Pupil enlargement*
Periorbital edema* Ear and vagus abnormalities Tinnitus* Cardiac abnormalities Palpitations* Tachycardia* Tip-twisting ventricular tachycardia*§ (see [Precautions], and [Drug Interactions])
Prolonged electrocardiogram QT interval* (see [Precautions], and [Drug Interactions])
Elevated blood cholesterol*§ Vascular abnormalities Hot flashes* Bleeding*,
Hypertension* Cerebral vasospasm*§ (including reversible cerebral vasoconstriction syndrome and call-fleming syndrome) Respiratory, thoracic and mediastinal abnormalities Yawning* Bronchospasm*,
Epistaxis* Gastrointestinal abnormalities Diarrhea
Nausea and vomiting*
Constipation*
abdominal pain*
dry mouth.
Indigestion Gastrointestinal bleeding* Pancreatitis*§ Hepatobiliary system abnormalities Elevated alanine aminotransferase*
Elevated aspartate aminotransferase* Liver damage* § Skin and subcutaneous tissue abnormalities Rash*
Excessive sweating urticaria*
Purpura*
pruritus*
Alopecia areata* Toxic epidermal necrolysis relaxation*§
Stevens-Johnson syndrome*§
angioedema*§
Exfoliative rash§
Photosensitivity
Skin reactions*§ Musculoskeletal and connective tissue and bone abnormalities Arthralgia* Muscle spasms* Rhabdomyolysis*§
Tooth clenching disorder*§ Renal and urinary system abnormalities Urinary retention*,
Hematuria*
Urinary incontinence*, enuresis*§ Reproductive and breast abnormalities Ejaculatory disorders
Sexual dysfunction
Irregular menstruation* Abnormal penile erection
Overflowing breast*
Male breast development* § Systemic and drug administration site abnormalities Chest pain*.
discomfort*
fever*.
malaise*.
Fatigue*, abnormal gait*
Peripheral edema*.
Facial edema*.
Drug withdrawal syndrome* § Examination Weight gain* Weight loss*
Abnormal laboratory findings* Trauma, toxicity and operative complications Fractures* *-ADRs identified after marketing
§ ADR frequency is expressed as the estimated upper limit of the 95% confidence interval calculated using the Rule of 3. ADR = adverse drug reaction; SOC = Systematic Organ Classification; CIOMS = Council for International Organizations of Medical Sciences [Contraindication].
This product is contraindicated in persons with hypersensitivity to sertraline.
Sertraline is contraindicated in combination with monoamine oxidase inhibitors (MAOIs) (see [Drug Interactions]).
Sertraline is contraindicated in combination with pimozide (see [Drug Interactions]).
[Caution].
Warning.
Worsening of clinical symptoms and risk of suicide
All patients treated with sertraline, especially those at high risk, should be monitored appropriately and closely for worsening clinical symptoms and suicidal ideation. Patients, family members, and caregivers should be encouraged to be alert to the need to monitor patients for any worsening of clinical symptoms, suicidal behavior or ideation, and abnormal changes in behavior, especially at the time of initial treatment, or during any dose or dosing regimen changes. The risk of suicide attempts in patients must be considered, especially in depressed patients, and should be provided with minimal dosing, in conjunction with good patient management, to reduce the risk of overdose.
Adult and pediatric patients with depression, with or without antidepressants, are at risk for worsening depression and for suicidal ideation and suicidal behavior and abnormal changes in behavior that will persist until such time as significant remission occurs. Depression and certain psychiatric disorders are known to be associated with suicide risk, and these psychiatric disorders themselves are the strongest predictors of suicide. However, there are long-standing concerns that antidepressants may play a role in inducing worsening depressive symptoms and suicidal ideation and behavior in some patients early in treatment. A pooled analysis of short-term placebo-controlled studies of antidepressants (including SSRIs and others) showed that in children, adolescents, and young adults (aged 18-24 years) with depression (MMD) and other psychiatric disorders, antidepressants increased the risk of suicidal thoughts and behaviors (suicidal ideation, behaviors) compared with placebo; in short-term clinical trials did not show an increased risk of suicidal thoughts and behaviors (suicidal ideation, behaviors) compared with placebo in adults aged >24 years. 24 years of age, the use of antidepressants increased the risk of suicidal ideation, behavior compared to placebo; in adults aged 65 years and older, the risk of suicidal ideation, behavior was reduced with the use of antidepressants.
Placebo-controlled trials in children and adolescents with depression, obsessive-compulsive disorder (OCD), or other psychiatric disorders (total of 24 short-term clinical trials, 9 antidepressants, including 4400 patients) and placebo-controlled trials in adult patients with depression or other psychiatric disorders [total of 295 short-term clinical trials (median duration 2 months), 11 antidepressants, 77,000 patients], the risk of drug-induced suicidal ideation and behavior varied considerably among drugs, but most of the drug studies showed a trend toward increased risk of suicide in younger patients. The absolute risk of suicidal ideation and behavior varied across indications, with the highest absolute risk in depression. Although the absolute risk varied across indications (drug versus placebo), the risk was relatively stable across age groups for different indications. The table below provides the risk differences (number of cases per 1000 patients with differences in risk of suicidal ideation, behavior from drug and placebo treatment).
Age range Number of cases of difference in risk of suicidal ideation, behavior from drug and placebo treatment per 1000 patients Number of cases of increase in drug compared to placebo<18 14 cases of increase 18-24 5 cases of decrease in drug compared to placebo 25-64 1 case of decrease ≥65 6 cases of decrease
No suicidal events in pediatric clinical trials There were suicidal events in adult clinical trials, but the number of occurrences was not sufficient to draw conclusions about the effect of the drug in suicide.
It is unknown whether the risk of suicidal ideation and behavior is perpetuated over the course of long-term medication use (e.g., after several months). However, evidence from placebo-controlled maintenance treatment clinical trials conducted in adults with depression strongly suggests that the use of antidepressants delays the recurrence of depression.
Regardless of the indication treated, all patients treated with antidepressants should be appropriately monitored and closely observed for worsening clinical symptoms, suicidal ideation, and abnormal behavioral changes, especially during the initial months of treatment with the medication, and when doses are increased or decreased.
The following symptoms can occur in adult and pediatric patients with depression, other psychotic or non-psychotic disorders treated with antidepressants: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, impulsivity, inability to sit still (psychomotor agitation), and mild mania and hypomania. Although a causal relationship between the presence of these symptoms and the worsening of depression and/or the development of suicidal impulses has not been established, it is noted that the presence of these symptoms may be a precursor to the development of suicidal ideation.
When a patient’s depressive symptoms continue to worsen, suicidal ideation develops, or symptoms that may be a precursor to worsening depressive symptoms or suicidal ideation occur, adjustments to the treatment regimen including possible discontinuation of medication should be carefully considered. This is especially true if these symptoms are severe, sudden, or inconsistent with the patient’s current symptoms.
If a decision is made to discontinue treatment, the dose should be tapered as soon as possible, but be aware that abrupt discontinuation may cause some symptoms (see the description of risks in stopping sertraline treatment).
When treating pediatric patients with depression or other psychotic or non-psychotic disorders with antidepressants, families and caregivers should be reminded of the need to monitor the patient for agitation, irritability, abnormal changes in behavior, other symptoms mentioned above, and suicidal ideation, and to report these symptoms to a health care professional as soon as they occur. Family members and caregivers should monitor the patient daily for these symptoms. When using sertraline, prescriptions should start with the smallest dose and be accompanied by good patient management to reduce the risk of overdose.
Screening of patients with bipolar disorder.
Depressive episodes may be the initial manifestation of bipolar disorder. It is generally believed (although not clarified by controlled trials) that treatment of such episodes with antidepressants alone may increase the likelihood of mixed/manic episodes in patients at risk for bipolar disorder. It is not clear whether the symptoms mentioned above imply that such a transition may occur. However, before initiating treatment with antidepressants, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; this screening should include a detailed psychiatric history including a family history of suicide, bipolar disorder, and a family history of depression. It should be noted that sertraline is not approved for the treatment of depressive episodes in bipolar disorder. Potential interactions with monoamine oxidase inhibitors (MAOIs):
Serious and sometimes fatal adverse reactions have been reported with sertraline hydrochloride (a selective 5-hydroxytryptamine reuptake inhibitor) in combination with monoamine oxidase inhibitors (MAOIs), which include the selective monoamine oxidase inhibitor, stiglitazone; the reversible monoamine oxidase inhibitor, morclobemide; monoamine oxidase inhibitor drugs such as linezolid (an antibiotic that is reversible non-selective MAOI) and methylene blue. These adverse effects include hyperthermia, tonicity, myoclonus and instability of vital signs, and alterations in mental status (including extreme agitation that progresses to delirium and coma). These reactions have also been reported in patients who have recently discontinued SSRI therapy and started MAOI treatment. In some patients, the presentation resembles a psychosuppressive drug malignant syndrome. In addition, limited animal data on the combination of SSRIs and MAOIs suggest that these drugs may have synergistic effects in elevating blood pressure and inducing excitatory behavior. Therefore, sertraline should not be applied in patients treated with MAOIs or within 14 days of discontinuing MAOI therapy. Similarly, sertraline should be discontinued for at least 14 days prior to initiation of MAOI treatment. 5-hydroxytryptamine syndrome-like reactions.
SNRIs and SSRIs, including sertraline, have been reported when applied alone, especially in combination with 5-hydroxytryptaminergic drugs (including traptans and fentanyl and its analogs, tramadol, methadone, tapentadol, pethidine, methadone, pentazocine, amphetamines), with drugs that impair 5-hydroxytryptamine metabolism (including MAOIs), with antipsychotics The 5-hydroxytryptamine syndrome may include altered mental status (e.g., agitation, hallucinations, coma), autonomic disturbances (e.g., tachycardia, blood pressure changes, hyperthermia), neuromuscular disorders (e.g., hyperreflexia, movement disorders), and/or gastrointestinal disorders. and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The most severe form of 5-hydroxytryptamine syndrome is similar to the presentation of psychosuppressive drug malignant syndrome and includes hyperthermia, muscle tonicity, autonomic instability possibly accompanied by rapid fluctuations in vital signs, and altered mental status. The 5-hydroxytryptamine syndrome or psychosuppressive drug malignant syndrome-like signs and symptoms should be monitored.
Caution should be exercised and avoid as much as possible the combination of sertraline with other drugs capable of enhancing 5-hydroxytryptamine neurotransmission because of possible pharmacodynamic interactions between sertraline and these drugs, e.g. tryptophan, fenfluramine, fentanyl, 5-HT agonists, amphetamines or St. John’s wort (onychomycetin).
The combination of sertraline with MAOIs for the treatment of depression is prohibited (see [Contraindications] and [Precautions] – Warning, Potential Interactions with Monoamine Oxidase Inhibitors (MAOIs)).
If there is a reasonable clinical need to combine sertraline and a 5-hydroxytryptamine receptor agonist (treprostin), close patient monitoring is recommended, especially at the beginning of treatment and at increasing doses (see [Drug Interactions]).
The combined use of sertraline and 5-hydroxytryptamine precursor substances (e.g., tryptophan) is not recommended. Sertraline must be discontinued immediately and symptomatic supportive therapy initiated if any of the above events occur in combination with any 5-hydroxytryptaminergic or anti-dopaminergic drug, including tranquilizers. Closed-angle glaucoma
In patients with anatomically narrowed atrial angles who have not undergone definitive iridectomy, pupillary dilation following the use of multiple antidepressants, including sertraline, may cause glaucomatous episodes due to atrial angle closure. prolonged QTc/tip torsion ventricular tachycardia (TdP)
Cases of QTc prolongation/tip torsion ventricular tachycardia (TdP) have been reported during post-marketing use of sertraline. Most of these reports occurred in patients with other risk factors for QTc prolongation/TdP. Therefore, sertraline should be used with caution in patients with risk factors for QTc prolongation (see [Drug Interactions]). Diabetes mellitus/poor glycemic control
Cases of new-onset diabetes have been reported in patients treated with SSRIs, including sertraline. Poor glycemic control, including hyperglycemia and hypoglycemia, has also been reported in patients with/without a history of diabetes mellitus. Patients should therefore be monitored for signs and symptoms of fluctuating blood glucose. Patients with diabetes should be monitored closely for possible dose adjustments of insulin and/or oral hypoglycemic agents. Laboratory Tests
False-positive results for benzodiazepines have been reported in urine immunoassay screening tests in patients taking sertraline. This is due to the lack of specificity of this screening test. False-positive results may occur within a few days after stopping sertraline. Validation tests such as gas chromatography/mass spectrometry can distinguish between benzodiazepines and sertraline. Switching from selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), antidepressants, or medications for obsessive-compulsive disorder to sertraline treatment
There is limited experience with controlled studies on the optimal timing of switching from other SSRIs, antidepressants, or treatment-compulsive medications to sertraline treatment. Care and careful medical evaluation should be taken when switching treatment, especially when switching from a long-acting drug such as fluoxetine to sertraline treatment. The washout period for switching from a selective 5-hydroxytryptamine reuptake inhibitor to another comparable drug has not been determined. General Precautions 1. Causes mania/hypomania – In pre-marketing trials, approximately 0.4% of patients treated with sertraline developed mild mania or hypomania. Mania or hypomania has also been reported in a small number of patients treated with other marketed antidepressants or treatment-compulsive drugs for affective disorders.
2. Weight loss – Some patients may experience significant weight loss when sertraline is administered. However, on average, only a slight weight loss of 1 or 2 pounds occurred after sertraline application compared to placebo in controlled clinical trials. Rarely have patients discontinued medication due to weight loss.3. Seizures – Antidepressants and medications used to treat obsessive-compulsive disorder have a potential risk of inducing seizures. Sertraline has not been evaluated in patients with epilepsy. Therefore, the use of sertraline in patients with unstable epilepsy should be avoided; patients with controlled epilepsy should be monitored closely. Sertraline was excluded from premarketing clinical trials in these patients. No epileptic seizures were identified in approximately 3000 depressed patients treated with sertraline. However, of approximately 1800 (with 220 patients <18 years) patients with OCD treated with sertraline, 4 (approximately 0.2%) developed seizures, 3 of whom were adolescents, 2 had epilepsy, and 1 had a family history of epilepsy, all 4 of whom were not treated with anticonvulsant medication. The association of sertraline with seizures in the above patients has not been established. Therefore, sertraline should be used with caution in patients with epilepsy.4. Discontinuation of sertraline treatment
After sertraline and other SSRIs and SNRIs (5-hydroxytryptamine and norepinephrine reuptake inhibitors) have been marketed, there have been spontaneous reports of adverse events occurring on discontinuation, especially when the drug is abruptly stopped, including the following symptoms: mood irritability, irritability, agitation, dizziness, sensory disturbances [e.g., abnormal sensations (e.g., electric shock-like sensations)], anxiety, confusion, headache, drowsiness, mood instability insomnia, and light mania. Although these events are generally self-limiting, severe withdrawal symptoms have been reported.
When sertraline is discontinued, these symptoms should be monitored. If possible, gradual dose reduction is recommended rather than abrupt discontinuation. If intolerable symptoms develop after dose reduction or discontinuation, consideration may be given to resuming the previous dose. Subsequently, the physician may continue to reduce the dose, but should do so at a slower rate (see [DOSAGE AND ADMINISTRATION]).5. Abnormal bleeding
SSRIs (including sertraline) and SNRIs may increase the risk of bleeding events. This risk may be increased by the combination of, for example, atypical antipsychotics and phenothiazines, most tricyclic antidepressants, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants. Case reports and epidemiologic trials (case-control and cohort designs) have shown that gastrointestinal bleeding events can occur after taking medications that affect 5-hydroxytryptamine reuptake. Bleeding events associated with the use of SSRIs and SNRIs include petechiae, hematomas, epistaxis, petechiae, and bleeding that can be life-threatening.
Patients should be warned of the risk of bleeding when sertraline is combined with NSAIDs, aspirin, or other medications that can affect coagulation.6. Weak pro-uric acid excretion – A decrease in serum uric acid (a mean decrease of approximately 7%) can occur with sertraline application. The clinical significance of this weak pro-uric acid excretory effect is unknown.7. Use in patients with concomitant disease – Clinical experience with sertraline in patients with a concomitant systemic disease is limited. Sertraline should be used with caution in patients with diseases or conditions affecting metabolism or hemodynamics.
Pre-marketing clinical trials of sertraline excluded patients with recent myocardial infarction or unstable heart disease. However, electrocardiographic (ECG) evaluation in 774 patients taking sertraline in a double-blind clinical trial showed that sertraline application was not associated with significant ECG abnormalities.
A post-marketing placebo-controlled flexible-dose (sertraline dose range 50-200 mg/day, mean dose 89 mg/day) trial randomized 372 patients who met diagnostic criteria for DSM-IV depression and who had been recently hospitalized for myocardial infarction (MI) or unstable angina. In addition to other exclusion criteria, the trial excluded the following patients: uncontrolled hypertension, need for cardiac surgery, coronary artery bypass grafting (CABG) within the past 3 months, severe or symptomatic bradycardia, non-atherosclerotic angina, clinically significant renal impairment (creatinine >2.5 mg/dl), and clinically significant hepatic dysfunction. Patients were started on sertraline during the acute recovery period (within 30 days after MI, or after hospitalization for unstable angina). Differences compared to placebo at week 16 were not significant for the following endpoints: left ventricular ejection fraction, all cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, congestive heart failure (CHF), MI, tachycardia, bradycardia and blood pressure changes) and serious cardiovascular events involving death or requiring hospitalization (MI, CHF, stroke or angina).
Patients with hepatic impairment: Sertraline is adequately metabolized in the liver. In patients with chronic mild hepatic impairment, the clearance of sertraline is reduced, resulting in increased AUC and Cmax and prolonged clearance half-life. The effect of sertraline in patients with moderate to severe hepatic impairment has not been evaluated. Sertraline should be used with caution in patients with concomitant hepatic disease. If sertraline is administered to patients with hepatic impairment, the dose or frequency of administration should be reduced (see [PRECAUTIONS] and [DOSAGE AND ADMINISTRATION]).
Patients with renal impairment: Sertraline is adequately metabolized and only a small amount of sertraline is excreted in the urine as a prototype.1 A clinical trial comparing healthy volunteers with patients with mild-moderate (creatinine clearance 30-60 mL/min) to severe (requiring hemodialysis treatment) renal impairment (creatinine clearance 10-29 mL/min) showed that renal disease did not affect the pharmacokinetics of sertraline ( AUC0-24 or Cmax) and protein binding. Based on this pharmacokinetic result, no dose adjustment is required in patients with renal impairment (see Clinical Pharmacology).8. Effects on cognitive and motor function – In controlled trials, sertraline had no sedative effect and did not affect psychomotor function. Although laboratory data indicate that sertraline does not impair complex psychomotor activity in normal subjects. However, drugs that act on the central nervous system may have adverse effects on some individuals. Therefore, patients should be advised to exercise caution in activities that require vigilance, such as driving or operating machinery, until they know how to use sertraline.
9. Hyponatremia – Hyponatremia may occur with treatment with SSRIs (including sertraline) or SNRIs (5-hydroxytryptamine and norepinephrine reuptake inhibitors). In many cases, hyponatremia is the result of the syndrome of antidiuretic hormone hypersecretion (SIADH). Cases with serum sodium levels below 110 mmol/L have been reported. Elderly patients, patients taking diuretics, or patients with other causes of hypovolemia may be at greater risk of hyponatremia with SSRIs and SNRIs (see [Geriatric Dosing]). Discontinuation of sertraline and appropriate therapeutic measures should be considered after the development of symptomatic hyponatremia.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and balance disturbances (which may lead to falls). Signs and symptoms of more severe and/or acute hyponatremia include hallucinations, syncope, seizures, coma, respiratory arrest, and death.10. Platelet Function – Altered platelet function and/or abnormal laboratory findings have rarely been reported in patients taking sertraline. Although a few cases of abnormal bleeding or purpura have been reported after sertraline administration, it is not clear whether they were caused by sertraline. 11. Drug abuse and dependence
Somatic and psychological dependence: A randomized, double-blind, placebo-controlled trial compared the propensity to abuse caused by sertraline, alprazolam, and d-amphetamine. Sertraline did not produce positive subjective effects suggestive of abuse potential, such as euphoria and preference for taking the drug, which were seen with the other two drugs. In pre-marketing clinical experience with sertraline, no propensity for discontinuation syndrome was observed, and no drug foraging behavior was observed. No potential stimulant or barbiturate-like (sedative) abuse was found in sertraline animal studies. However, as with all other CNS-active drugs, physicians should carefully assess patients for a history of drug abuse and follow such patients closely for signs of sertraline misuse or abuse (e.g., tolerance formation, dose escalation, foraging behavior).12. Fractures
Epidemiological studies have shown an increased risk of fracture in patients treated with pentoxifylline reuptake inhibitors (SRIs), including sertraline. However, the mechanism of action leading to fracture risk is unclear.13. Pediatric and Adolescent Dosing
There is only limited clinical evidence of long-term safety data in children and adolescents, including effects on growth, sexual maturation, cognitive and behavioral development. For pediatric patients on long-term treatment, physicians must observe for abnormal growth and development.14. Patients should be informed that sertraline may cause mild pupillary dilation and, in sensitive individuals, may cause closed-angle glaucoma episodes. The majority of existing glaucoma is open-angle glaucoma, as closed-angle glaucoma can be treated with iridotomy after diagnosis. Open-angle glaucoma is not a risk factor for closed-angle glaucoma. Patients may want to be tested to determine if they are at high risk for closed-angle glaucoma, and if so, to use preventive measures (such as iridotomy).
Pregnant and lactating women]
Sertraline should be administered to women during pregnancy only if the benefits of taking the drug clearly outweigh the potential risks of the drug to the fetus. Pregnancy – Non-teratogenic effects
Complications can occur in newborns following late gestational exposure to sertraline and other SSRIs or SNRIs, with consequent prolonged hospitalization, respiratory support, and tube feeding. These findings are based on post-marketing reports. These complications can occur immediately after delivery. Reported clinical manifestations include dyspnea, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypotonia, increased muscle tone, hyperactive tendon reflexes, tremors, hypersensitivity, irritability, and persistent crying. These features may be consistent with the direct toxicity of SSRIs and SNRIs or may be consistent with discontinuation syndrome. It should be noted that in some cases, the clinical presentation is consistent with a 5-hydroxytryptamine syndrome (see WARNINGS).
Infant exposure to SSRIs in late gestation may increase the risk of persistent pulmonary hypertension of the newborn (PPHN). In the overall population, PPHN occurs in 1-2 cases per 1,000 live births and can be associated with significant neonatal morbidity and mortality. A retrospective case-control study enrolled 377 women whose infants were born with PPHN and 836 women whose infants were healthy at birth. Infants exposed to SSRIs after the 20th week of gestation had an approximately 6-fold increased risk of developing PPHN compared with infants not exposed to antidepressants during gestation. There is no conclusive evidence of the risk of PPHN after gestational exposure to SSRIs; this is the first trial to have examined this potential risk. The trial did not have enough cases of a single SSRI to determine whether all SSRIs could cause a similar degree of risk of PPHN. A study of 831,324 infants born in Sweden from 1997-2005 found that: the risk ratio for infants developing PPHN was 2.4 (95% CI 1.2-4.3) (CI: confidence interval) based on reports of mothers taking SSRIs ‘early in gestation’ and ‘late in gestation’ prescription of SSRIs, the risk ratio for the development of PPHN in infants was 3.6 (95% CI 1.2-8.3).
The use of sertraline in women of childbearing age should be accompanied by appropriate contraceptive measures.
When sertraline is administered to pregnant women in late pregnancy, physicians should carefully consider the potential risks and benefits of treatment. Physicians should note that in a prospective longitudinal trial enrolling 201 female patients with a history of depression, they were taking antidepressants and were in a happy mood at the start of pregnancy. Women who discontinued antidepressants during pregnancy were more likely to have a relapse than women who continued to take antidepressants. Labor and Delivery
The effects of sertraline on labor and delivery in humans are unknown. Lactating women
Sporadic studies of small samples of nursing mothers and infants suggest that sertraline levels in infants are negative or not measurable; however, sertraline levels in breast milk are higher than those in maternal serum. Sertraline is not recommended for nursing mothers unless the benefits of sertraline use outweigh the harms as determined by the clinician.
Pediatric Use]
This product can be used in children and adolescents aged 6 to 17 years with OCD. Although sertraline is metabolized slightly more rapidly in pediatric patients, lower doses are recommended for pediatric patients with OCD to avoid excessive blood levels, especially in children 6 to 12 years of age who are lighter in weight. See [Dosage] for more information.
[Geriatric Use].
Clinical trials enrolled 663 elderly depressed US patients ≥65 years of age, 180 of whom were ≥75 years of age. There was no difference in the overall pattern of adverse reactions observed in clinical trials in older patients compared to those reported in younger subjects. Furthermore, based on other reported experiences, no differences in safety patterns between older and younger subjects have been identified. As with other drugs, it cannot be excluded that some elderly patients have a higher sensitivity. A sertraline versus placebo-controlled clinical trial enrolled 947 elderly patients with depression. There was no difference in the overall pattern of efficacy observed in the clinical trial in older patients compared to the efficacy reported in younger subjects.
Other adverse events in elderly patients: In the 354 elderly patients enrolled in sertraline and placebo-controlled trials, the overall adverse events were generally similar to those listed in this prospectus. Urinary tract infection, the only adverse event not listed, was reported in ≥2% of the placebo-controlled trials and was higher than in the placebo group.
Clinically significant hyponatremia can occur in elderly patients following the application of SSRIs (including sertraline) and SNRIs. The risk of this adverse event may be greater in elderly patients (see [Precautions] – Hyponatremia).
[Drug Interactions].
Monoamine oxidase inhibitors: Sertraline in combination with monoamine oxidase inhibitors, including the selective monoamine oxidase inhibitor sellegrin, the reversible monoamine oxidase inhibitor morclobemide, and other monoamine oxidase inhibitor drugs (e.g., linezolid), treatment has been associated with serious, sometimes fatal, side effects. Some cases are similar to 5-hydroxytryptamine syndrome, including: hyperthermia, myotonia, muscle spasms, autonomic dysfunction with rapid fluctuations in vital signs; changes in mental status including psychosis, irritability and extreme agitation until delirium and coma develop. Therefore, sertraline should not be taken while taking monoamine oxidase inhibitors or within 14 days of discontinuation of monoamine oxidase inhibitors; similarly, sertraline discontinuation requires more than 14 days before starting monoamine oxidase inhibitor therapy.
Pimozide: In a study of a single low dose of pimozide (2 mg) in combination with sertraline, it was confirmed that coadministration of the two drugs resulted in elevated plasma concentrations of pimozide. The elevated levels did not cause a change in EKG. The mechanism of this drug interaction is unclear and coadministration of sertraline with pimozide is prohibited due to the narrow therapeutic window of pimozide.
Drugs that prolong the QT interval: Combination with other drugs that prolong the QTc interval (e.g., certain antipsychotics and antibiotics) results in an increased risk of QTc prolongation/ or ventricular arrhythmias (e.g., TdP) (see [Precautions]).
CNS depressants and alcohol: Concomitant administration of sertraline 200 mg daily does not increase the effects of ethanol, carbamazepine, haloperidol, or phenytoin on cognitive function and psychomotor activity in healthy subjects, but the combination of sertraline with alcohol is not advocated.
Lithium: In a placebo-controlled trial in normal volunteers, the combination of sertraline with lithium did not significantly alter the pharmacokinetic parameters of lithium, but increased tremor compared to placebo, suggesting the possibility of pharmacodynamic interaction between the two drugs. Patients should be monitored when sertraline is combined with other drugs that act via 5-hydroxytryptaminergic mechanisms, such as lithium.
Phenytoin: In a placebo-controlled study in healthy volunteers, long-term administration of 200 mg sertraline daily did not significantly inhibit the metabolism of phenytoin. However, if co-administration with sertraline is indicated, phenytoin blood levels should be monitored at the time of initiation of sertraline and the dose of phenytoin should be adjusted appropriately. In addition, co-administration with phenytoin may cause a decrease in sertraline blood concentrations.
Sumatriptan: After the introduction of sertraline, there have been isolated reports of weakness, tendon reflex hyperactivity, ataxia, confusion, anxiety and agitation in patients after the combination of sertraline and sumatriptan. If sertraline is indeed clinically indicated in combination with this drug, the patient should be closely monitored.
Protein-binding drugs: Because sertraline binds to plasma proteins, attention should be paid to the possibility of interaction between sertraline and other plasma protein-binding drugs. However, no significant effects of sertraline on protein binding of these drugs were seen in three formal studies of sertraline interactions with diazepam, toluenosulfonylurea, and warfarin, respectively.
Warfarin: Sertraline 200 mg/day in combination with warfarin caused a smaller but statistically significant prolongation of prothrombin time, the clinical significance of which is unclear. Therefore, the prothrombin time should be closely monitored when sertraline is combined with warfarin or discontinued.
Interaction with other drugs: Interaction studies between sertraline and other drugs have been conducted. The combination of sertraline 200 mg daily with diazepam or toluenosulfonylurea may result in small but statistically significant changes in some pharmacokinetic parameters. Combination with cimetidine significantly reduced sertraline clearance. The clinical significance of these alterations is not known. Sertraline had no effect on the b-adrenergic blocking effect of atenolol. There were no interactions between sertraline 200 mg daily and glibenclamide or digoxin.
Electroconvulsive therapy (ECT): There have been no clinical trials examining the benefits or risks of combining sertraline with ECT.
Drugs metabolized by cytochrome P450 (CYP)2D6: The degree of inhibition of the drug metabolizing isoenzyme CYP2D6 by antidepressants is variable. The clinical significance depends on the degree of inhibition and the therapeutic index of the drugs used in combination. CYP2D6 substrates with narrow therapeutic indices include tricyclic antidepressants such as propafenone and flecainide and class 1C antiarrhythmic drugs. Drug interaction studies have been performed showing that long-term administration of 50 mg of sertraline daily resulted in a mild increase (mean 30-40%) in steady-state blood levels of desipramine, a marker of CYP2D6 isoenzyme activity.
Drugs metabolized by other cytochrome (CYP) enzymes (CYP3A3/4, CYP2C9, CYP2C19, CYP1A2).
CYP3A3/4: In vivo drug interaction tests have shown that long-term administration of sertraline 200 mg/day does not inhibit CYP3A3/4-mediated hydroxylation of endogenous cortisol or the metabolism of carbamazepine and terfenadine. In addition, long-term administration of 50 mg of sertraline daily did not inhibit CYP3A3/4-mediated alprazolam drug metabolism. The data suggest that sertraline is not an inhibitor of CYP3A3/4.
CYP2C9: Long-term administration of sertraline 200 mg/day had no significant effect on the blood concentrations of toluenosulfonylurea, phenytoin and warfarin. This suggests that sertraline is not a clinically relevant inhibitor of CYP2C9.
CYP2C19: Long-term administration of sertraline 200 mg/day had no significant effect on diazepam blood concentrations, indicating that sertraline is also not an inhibitor of CYP2C19.
CYP1A2: In vitro experimental studies have shown that sertraline has no significant inhibitory effect on CYP1A2.
Other 5-hydroxytryptaminergic drugs: Sertraline should be considered carefully when combined with drugs that enhance 5-hydroxytryptamine neurotransmission, such as tryptophan or fenfluramine, 5-hydroxytryptamine agonists, amphetamines, or the Chinese herbal medicine Guan Ye Lian Lian (Hypericum perforatum), to avoid possible pharmacodynamic interactions.
Drug overdose]
There is evidence that sertraline has a wide range of safety in overdose. There have been reports of overdoses of up to 13.5 g of sertraline alone. Deaths have been reported from overdoses of sertraline, but most have occurred in combination with other drugs and/or alcohol. Therefore, any overdose should be treated aggressively.
Symptoms of overdose include 5-hydroxytryptamine-induced adverse effects such as prolonged electrocardiogram QT, tip-twisting ventricular tachycardia, drowsiness, gastrointestinal distress (e.g., nausea and vomiting), tachycardia, tremor, agitation, and dizziness. Coma has rarely been reported. There is no specific antidote for sertraline. Opening and maintaining a patent airway to ensure adequate oxygenation and ventilation may be combined with a laxative with activated carbon, which may be as or more effective than emetic or gastric lavage. Cardiac and vital signs monitoring is recommended along with symptomatic and supportive therapy. Due to the large volume of distribution of sertraline, forced diuresis, dialysis, hemoperfusion and blood exchange therapy are not significant.
Pharmacology and Toxicology
Pharmacological effects
Sertraline hydrochloride is a selective 5-hydroxytryptamine reuptake inhibitor. Its mechanism of action is related to its inhibition of 5-hydroxytryptamine reuptake in central neurons. At clinical doses, sertraline blocks the uptake of 5-hydroxytryptamine by human platelets. Studies suggest that sertraline is a potent and selective inhibitor of neuronal 5-hydroxytryptamine reuptake, with only weak effects on norepinephrine and dopamine reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic receptors (α1, α2, β), cholinergic receptors, GABA receptors, dopamine receptors, histamine receptors, 5-hydroxytryptamine receptors (5HT1A, 5HT1B, 5HT2) or benzodiazepine receptors. Long-term administration of sertraline to animals resulted in downregulation of norepinephrine receptors in the brain, consistent with the effects of other antidepressants in clinical practice. Sertraline has no inhibitory effect on monoamine oxidase.
Toxicological studies
Genotoxicity: Sertraline did not show genotoxicity in bacterial revertant mutation assays, mouse lymphoma assays, in vivo mouse bone marrow and in vitro human lymphocyte genetics assays.
Reproductive toxicity: At a dose of 80 mg/kg [3.1 times the maximum recommended human dose (MRHD) of 200 mg/day in mg/m2], reduced fertility was observed in one of the two rat tests. No teratogenic effects were observed in pregnant rats and rabbits given sertraline at doses up to 80 mg/kg/day and 40 mg/kg/day (approximately 3.1 times the MRHD in mg/m2) during organogenesis, but at doses of 10 mg/kg and 40 mg/kg (approximately 0.4 times and 3.1 times the MRHD in mg/m2), respectively, a Delayed ossification of fetal litter. In female rats given sertraline at a dose of 20 mg/kg (approximately 0.8 times MRHD in mg/m2) during late gestation and lactation, the number of stillborn pups and the number of pups dying in the first 4 days of life increased, and the body weight of pups in the first 4 days of life decreased. The reduction in pup survival was due to in utero exposure to sertraline. However, the clinical significance of these effects is unclear.
Carcinogenicity: Lifetime carcinogenicity studies were conducted in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day (approximately 1 and 2 times the MRHD in mg/m2, respectively). A dose-related increase in hepatic adenomas was observed in male mice at doses ranging from 10 to 40 mg/kg (approximately 0.25-1 times the MRHD in mg/m2), but no increase in hepatic adenomas was observed in female mice or rats, and no increase in hepatocellular carcinomas was observed. the spontaneous rate of hepatic adenomas in CD-1 mice is fluctuating, and the significance of this result for humans is unclear. Female rats at a dose of 40 mg/kg showed an increase in thyroid follicular adenomas without thyroid hyperplasia. Increased uterine adenomas were observed in rats in the 10-40 mg/kg (in mg/m2, approximately 0.5-2 times the MRHD, respectively) administration group compared to the control group, but the relevance of this finding to the drug is not clear.
Dependence: Animal studies have not shown a potential for excitatory effects or barbiturate-like (central depressant) abuse of this product.
Juvenile Animal Toxicity: Delayed sexual maturation was observed in young rats given sertraline 10, 40, and 80 mg/kg/day orally from postnatal day 21 to day 56, and in male rats at 80 mg/kg/day and female rats ≥10 mg/kg/day, with the exception of a reduced auditory startle reflex in female rats at 40 and 80 mg/kg/day at the end of dosing (no effect was seen after discontinuation). No effects on fertility and neurobehavioral development were observed in males and females. The high dose (80 mg/kg/day) produced sertraline plasma levels (AUC) equivalent to 5 times that of MRHD given to pediatric patients (6-17 years old).
[Pharmacokinetics].
In males, sertraline was administered orally once daily at 50-200 mg. Sertraline exhibited pharmacokinetic properties proportional to the dose administered, with peak human blood concentrations (Cmax) at 4.5-8.4 hours of dosing for 14 consecutive days. Pharmacokinetic parameters in adolescents and the elderly were not significantly different from those in adults between the ages of 18 and 65. The mean half-life of sertraline is 22-36 hours. Consistent with the terminal clearance half-life, steady-state concentrations are reached after one week of once-daily dosing, during which there is a twofold accumulation of concentrations. The plasma protein binding rate of sertraline is 98%. Results from animal studies indicate that sertraline has a large volume of distribution.
Sertraline is primarily metabolized first by the liver, and the pharmacological activity of N-desmethyl sertraline, the major metabolite in plasma, is significantly lower than sertraline in vitro, about 1/20th that of sertraline, and there is no evidence of pharmacological activity in antidepressant models in vivo; its half-life is 62-104 hours. The final metabolites of sertraline and N-desmethyl sertraline are excreted in moderate amounts from feces and urine, and only a small amount (<0.2%) of sertraline is excreted from urine in its original form.
Food has no significant effect on the bioavailability of sertraline tablets.
Storage】 Keep sealed.
Package】 Double aluminum package, 14 tablets/box; 28 tablets/box.
Expiration date】 24 months
Execution Standard
Approval number】 State Drug Administration H20080141
[Drug Marketing Licensee
Name: Zhejiang Huahai Pharmaceutical Co.
Address: Flood Bridge, Linhai City, Zhejiang Province
Manufacturer
Company Name: Zhejiang Huahai Pharmaceutical Co.
Production Address: Flood Bridge, Linhai City, Zhejiang Province
Postal code：317024
Telephone number: 0576-85010288
Fax number: 0576-85016013
Website: www.huahaipharm.com