Zalox
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZALOX (ZALOX)
Composition:
Active substance: sertraline in the form of sertraline hydrochloride;
1 capsule contains 50 mg of sertraline in the form of sertraline hydrochloride;
Excipients: anhydrous lactose, corn starch, sodium lauryl sulfate, magnesium stearate;
Capsule shell composition: gelatin, quinoline yellow dye (E 104), yellow FCF dye (E 110), titanium dioxide (E 171).
Pharmaceutical form. Capsules.
Main physicochemical properties:
hard gelatin capsules Conisnap #4 filled with white or almost white powder. On the white body of the capsule, "Sertraline" is printed, with "50 mg" beneath it. "Sertraline" is underlined. On the yellow cap of the capsule, "Р" is printed. The inscriptions are black.
Pharmacotherapeutic group. Antidepressants. Selective serotonin reuptake inhibitors. ATC code N06AB06.
Pharmacological Properties.
Pharmacodynamics.
The mechanism of action of sertraline is related to its ability to inhibit the reuptake of serotonin (5-HT) in neurons. The drug exhibits weak effects on the reuptake of norepinephrine and dopamine in neurons. Within the range of clinically relevant doses, sertraline also blocks serotonin uptake in platelets.
Like many other antidepressants, sertraline leads to downregulation of norepinephrine and serotonin receptors in the brain. Receptor binding studies have shown that sertraline has no significant affinity for adrenergic (alpha 1, alpha 2, and beta), cholinergic, gamma-aminobutyric acid (GABA), dopaminergic, histaminergic, serotonergic (5-HT1A, 5-HT1B, 5-HT2), or benzodiazepine receptors.
In placebo-controlled clinical trials under strictly controlled conditions, sertraline was shown not to exert sedative effects and not to affect the patient's psychomotor functions.
Pharmacokinetics.
With prolonged oral administration of the drug at a dose of 200 mg per day, the peak plasma concentration averages 0.19 µg/mL and is reached within 4.5–8.4 hours after dosing. The elimination half-life of sertraline ranges from 22 to 36 hours. Due to its long elimination half-life, approximately twofold accumulation of the drug occurs until steady-state concentrations are achieved after one week of daily dosing.
Within the dose range of 50 to 200 mg per day, the pharmacokinetics of sertraline are dose-dependent.
Sertraline is extensively metabolized in the liver to an N-demethylated derivative, which is practically devoid of pharmacological activity. Both sertraline and its N-demethylated metabolite undergo oxidative deamination followed by conjugation, hydroxylation, and glucuronidation. Metabolites are excreted in equal amounts in feces and urine. Unchanged sertraline is excreted in urine in negligible amounts.
Approximately 98% of sertraline in plasma is protein-bound. The interaction of sertraline with other drugs that also have high protein-binding capacity has not yet been fully elucidated.
The pharmacokinetics of sertraline in young and elderly individuals, as well as in men and women, do not differ significantly.
Clinical characteristics.
Indications.
− Major depressive episodes. Prevention of relapse of major depressive episodes.
− Panic disorder with or without agoraphobia.
− Obsessive-compulsive disorder (OCD) in adults and children aged 6–17 years.
− Social anxiety disorder.
− Post-traumatic stress disorder (PTSD).
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Concomitant use with irreversible monoamine oxidase inhibitors (MAOIs) due to the risk of developing serotonin syndrome, manifested by symptoms such as agitation, tremor, and flushing. Sertraline therapy must not be initiated within at least 14 days after discontinuation of irreversible MAOI treatment. Sertraline use must be discontinued at least 7 days prior to starting therapy with an irreversible MAOI.
Concomitant use of sertraline and pimozide is contraindicated (see "Interaction with other medicinal products and other forms of interaction").
Interaction with other medicinal products and other forms of interaction.
Concomitant use with sertraline is contraindicated.
Monoamine oxidase inhibitors (MAOIs).
Irreversible MAOIs (e.g., selegiline)
Concomitant use of sertraline with irreversible MAOIs such as selegiline is contraindicated. Sertraline must not be administered within at least 14 days after discontinuation of irreversible MAOI therapy. Sertraline treatment must be discontinued at least 7 days before initiating therapy with an irreversible MAOI (see "Contraindications").
Reversible selective MAO-A inhibitors (moclobemide).
Due to the risk of serotonin syndrome, sertraline should not be used in combination with reversible selective MAOIs such as moclobemide. After discontinuation of reversible MAOIs, the interval before starting sertraline therapy may be shorter than 14 days. It is recommended to discontinue sertraline at least 7 days before initiating therapy with a reversible MAOI (see "Contraindications").
Reversible non-selective MAOIs (linezolid).
The antibiotic linezolid is a weak, non-selective reversible MAOI and should not be administered to patients receiving sertraline (see "Contraindications").
Severe adverse reactions have been reported in patients who recently discontinued MAOI therapy (e.g., methylene blue) and started sertraline, or who discontinued sertraline shortly before starting MAOI therapy. These reactions included tremor, myoclonus, excessive sweating, nausea, vomiting, flushing, dizziness, hyperthermia with symptoms resembling neuroleptic malignant syndrome, seizures, and fatal outcomes.
Pimozide.
In a study with a single low dose of pimozide (2 mg), pimozide levels increased by approximately 35%. This increase in levels was not accompanied by any changes in ECG parameters.
The mechanism of interaction between sertraline and pimozide is unknown; however, concomitant use is contraindicated due to the narrow therapeutic index of pimozide (see "Contraindications").
Concomitant use with sertraline is not recommended.
Central nervous system (CNS) depressants and alcohol.
Concomitant administration of sertraline at a dose of 200 mg/day did not potentiate the effects of alcohol, carbamazepine, haloperidol, or phenytoin on cognitive and psychomotor functions in healthy study participants. However, concomitant use of sertraline with alcohol is not recommended.
Other serotonergic medicinal products.
(See section "Special warnings and precautions for use").
Caution is required when co-administering sertraline with fentanyl (used primarily during general anesthesia and chronic pain therapy), other serotonergic agents (including other serotonergic antidepressants, triptans), and other opioids.
Special precautions are required during concomitant use.
Drugs that prolong the QT interval
The risk of QTc interval prolongation and/or ventricular arrhythmias (e.g., torsades de pointes) increases when sertraline is used concomitantly with other drugs that prolong the QTc interval (e.g., certain antipsychotics and antibiotics) (see section "Special warnings and precautions for use").
Lithium.
In a study, concomitant administration of sertraline and lithium did not significantly alter lithium pharmacokinetics but resulted in increased tremor compared to placebo, suggesting a possible pharmacodynamic interaction. Appropriate monitoring of patients is required when sertraline and lithium are used concomitantly.
Phenytoin.
Plasma phenytoin concentration monitoring is recommended during the initial phase of sertraline therapy, with appropriate dose adjustments of phenytoin. Additionally, concomitant use of sertraline with phenytoin may lead to decreased plasma concentrations of sertraline.
A reduction in sertraline plasma levels cannot be excluded under the influence of CYP3A4 inducers such as phenobarbital, carbamazepine, St. John’s wort, and rifampicin.
Triptans.
There have been isolated reports of weakness, hyperreflexia, incoordination, confusion, anxiety, and agitation following concomitant use of sertraline and sumatriptan. Serotonin syndrome symptoms may also occur with other drugs of this class (triptans). If concomitant treatment with sertraline and triptans is clinically necessary, appropriate patient monitoring should be ensured (see section "Special warnings and precautions for use").
Warfarin.
Concomitant use of sertraline at a dose of 200 mg/day and warfarin resulted in a small but statistically significant increase in prothrombin time, which may in rare cases lead to disturbances in the international normalized ratio (INR). Therefore, prothrombin time should be carefully monitored at the beginning of sertraline therapy and upon its discontinuation.
Interaction with other medicinal products, digoxin, atenolol, cimetidine.
Concomitant use with cimetidine resulted in a significant reduction in sertraline clearance. The clinical significance of these changes is not established. Sertraline does not affect the beta-blocking properties of atenolol. No interaction was observed when sertraline at a dose of 200 mg/day was administered concomitantly with digoxin.
Neuromuscular blocking agents
Selective serotonin reuptake inhibitors (SSRIs) may reduce plasma cholinesterase activity, potentially leading to prolonged neuromuscular blockade with mivacurium or other neuromuscular blocking agents.
Medicinal products affecting platelet function.
The risk of bleeding increases when SSRIs, including sertraline, are used concomitantly with medicinal products affecting platelet function (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, and ticlopidine), or other medicinal products that increase bleeding risk (see section "Special warnings and precautions for use").
Drugs metabolized by cytochrome P450.
Sertraline may act as a weak or moderate inhibitor of the CYP2D6 isoenzyme.
Clinically significant interactions may occur with other CYP2D6 substrates having narrow therapeutic ranges, such as class 1C antiarrhythmics (e.g., propafenone and flecainide), tricyclic antidepressants, and typical antipsychotics, particularly when sertraline is used at higher doses.
Sertraline is not a clinically significant inhibitor of the CYP3A4, CYP2C9, CYP2C19, or CYP1A2 isoenzymes. This is supported by in vivo drug interaction study results using CYP3A4 substrates (endogenous cortisol, carbamazepine, terfenadine, alprazolam), the CYP2C19 substrate diazepam, and CYP2C9 substrates (tolbutamide, glyburide, and phenytoin). In vitro study results indicate that sertraline has very low or no potential to inhibit CYP1A2.
Daily consumption of three glasses of grapefruit juice increased plasma sertraline levels by nearly 100% in a crossover study involving 8 healthy Japanese subjects. Therefore, grapefruit juice consumption should be avoided during sertraline therapy (see section "Special warnings and precautions for use").
Based on the grapefruit juice interaction study results, a substantially greater increase in sertraline exposure cannot be excluded when sertraline is used concomitantly with potent CYP3A4 inhibitors, including protease inhibitors, ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, and nefazodone. This also applies to moderate CYP3A4 inhibitors: aprepitant, erythromycin, fluconazole, verapamil, and diltiazem. Concomitant use of potent CYP3A4 inhibitors should be avoided during sertraline therapy.
In individuals with slow CYP2C19 metabolism, plasma sertraline levels are increased by approximately 50% compared to individuals with rapid CYP2C19 metabolism. A drug interaction cannot be excluded with potent CYP2C19 inhibitors such as omeprazole, lansoprazole, pantoprazole, rabeprazole, fluoxetine, and fluvoxamine.
Special precautions for use.
In adults and children treated with antidepressants, symptoms such as restlessness, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, psychomotor agitation, hypomania, and mania have been observed. These symptoms may precede the emergence of suicidal tendencies. Consideration should be given to changing the therapeutic regimen or discontinuing the medication if depressive symptoms progressively worsen, suicidal ideation emerges, or symptoms of increased suicidality occur. If a decision is made to discontinue treatment, the drug should be tapered gradually as quickly as possible, but it should be remembered that abrupt discontinuation may be accompanied by withdrawal syndrome.
Prior to initiating treatment, patients should be evaluated to determine the risk of developing bipolar disorder. This includes a thorough psychiatric history, including family history of suicide, bipolar disorders, and depression. Zalox is not indicated for the treatment of bipolar depression.
Sexual dysfunction
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section "Adverse reactions"). Reports have been received regarding persistent sexual dysfunction, with symptoms continuing despite discontinuation of SSRIs/SNRIs.
Serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS).
Life-threatening syndromes such as serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS) have been reported during treatment with SSRIs, including sertraline. The risk increases when serotonergic agents (including triptans and fentanyl) are used concomitantly with agents affecting serotonin metabolism (including MAO inhibitors, e.g., methylene blue), antipsychotics, and other dopamine antagonists, as well as opioids. Serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic dysfunction (tachycardia, fluctuations in blood pressure, hyperthermia), neuromuscular abnormalities (hyperreflexia, incoordination), and/or gastrointestinal disturbances (nausea, vomiting, diarrhea). Some manifestations of serotonin syndrome, including hyperthermia, muscle rigidity, autonomic instability, and mental status changes, resemble those of neuroleptic malignant syndrome. Patients should be monitored for signs and symptoms of SS or NMS (see "Contraindications").
Switching from SSRIs, antidepressants, or anti-obsessive agents.
Data from controlled studies on the optimal timing for switching from SSRIs, antidepressants, or anti-obsessive agents to sertraline are limited. Caution should be exercised when making such treatment changes, especially when switching from long-acting agents such as fluoxetine.
Other serotonergic agents, e.g., tryptophan, fenfluramine, and 5-HT agonists.
Concomitant use of sertraline with other agents that enhance serotonergic neurotransmission, such as tryptophan, fenfluramine, fentanyl, 5-HT agonists, or herbal preparations containing St. John's wort (Hypericum perforatum), should be done with caution. In general, such combination therapy should be avoided (potential pharmacodynamic interaction).
Prolonged QTc interval/ventricular tachycardia of the "torsades de pointes" type
Cases of prolonged QTc interval and ventricular tachycardia of the "torsades de pointes" type have been reported during post-marketing use of sertraline, mostly in patients with other risk factors for prolonged QTc interval/ventricular tachycardia of the "torsades de pointes" type. Therefore, sertraline should be used with caution in patients with risk factors for prolonged QTc interval.
Exacerbation of hypomania or mania.
Exacerbation of manic/hypomanic symptoms has been reported in a small percentage of patients receiving approved antidepressants and anti-obsessive agents, including sertraline. Therefore, sertraline should be used cautiously in patients with a history of mania/hypomania. Close medical supervision is required. Treatment should be discontinued if signs of a manic episode appear.
Schizophrenia.
Psychotic symptoms may worsen in patients with schizophrenia during treatment with the drug.
Seizures.
Seizures may occur during sertraline therapy. Sertraline should not be prescribed to patients with unstable epilepsy, and patients with controlled epilepsy require careful monitoring during sertraline treatment. The drug should be discontinued in patients who experience seizures.
Suicide/suicidal thoughts/suicide attempts or clinical worsening.
Patients with depression have an increased risk of developing suicidal thoughts, self-harm, and suicide attempts (suicidal behaviors and manifestations). This risk persists until significant remission occurs. Since improvement may take several weeks or longer, patients should remain under close supervision until improvement occurs. Clinical experience generally indicates that the risk of suicide increases in the early stages of recovery.
Other psychiatric disorders treated with sertraline may also be associated with a risk of developing suicidal behaviors and manifestations. Additionally, these conditions may coexist with major depressive disorder. Therefore, similar precautionary measures applicable to the treatment of patients with major depressive disorder are necessary when treating patients with other psychiatric disorders.
Patients with a history of suicidal behaviors or manifestations, or patients who exhibit pronounced suicidal ideation before starting therapy, have a higher risk of developing suicidal thoughts and attempts during treatment and therefore require close monitoring during treatment.
Close monitoring is indicated for patients at high risk of developing suicidality during treatment with this medicinal product, especially at the beginning of therapy and after any dosage adjustments. Patients (and caregivers) should be advised to monitor for any signs of clinical worsening, emergence of suicidal behavior or suicidal thoughts, or any changes in behavior, and to seek immediate medical help.
Use in children.
Sertraline should not be used for the treatment of children, except for patients aged 6–17 years with obsessive-compulsive disorder. In clinical trials involving children and adolescents receiving antidepressants, suicidal behavior (suicide attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behavior, and anger) occurred more frequently compared to patients receiving placebo.
If, based on clinical need, the decision is made to prescribe this medication, careful monitoring for signs of suicidal symptoms is required. Long-term safety data on the use of this medication in children, regarding its impact on growth, maturation, and cognitive and behavioral development, are lacking. In long-term therapy of pediatric patients, physicians should monitor for deviations from normal development of organ systems.
Abnormal bleeding/bruising.
Cases of pathological skin hemorrhagic phenomena such as ecchymoses and purpura, as well as other hemorrhagic events such as gastrointestinal or gynecological bleeding, including fatal outcomes, have been reported during SSRI use. Caution is recommended when using SSRIs, particularly when used concomitantly with drugs affecting platelet function (anticoagulants, atypical antipsychotics, phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, and nonsteroidal anti-inflammatory drugs), and in patients with a history of hemorrhagic disorders (see "Interaction with other medicinal products and other types of interactions").
Hyponatremia.
Hyponatremia may develop during treatment with SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs), including sertraline. In many cases, hyponatremia is due to the syndrome of inappropriate antidiuretic hormone secretion. Serum sodium levels below 110 mmol/L have been reported. Elderly patients are at higher risk of developing hyponatremia when using SSRIs and SNRIs. The risk of this complication is also increased in patients taking diuretics and in patients with hypovolemia of any origin (see section "Use in elderly patients").
If symptomatic hypovolemia develops in a patient, discontinuation of sertraline therapy should be considered, and appropriate medical intervention should be initiated.
Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and loss of physical balance, which may lead to falls. In more severe and/or acute episodes of hyponatremia, hallucinations, syncope, seizures, coma, respiratory arrest, and fatal outcomes are possible.
Withdrawal symptoms observed upon discontinuation of sertraline therapy.
Withdrawal symptoms are common upon discontinuation of the drug, especially in cases of abrupt cessation (see section "Adverse reactions").
The risk of developing withdrawal syndrome depends on several factors: duration of therapy, dosage, and rate of dose reduction. The most frequently reported reactions include dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor, and headache. Generally, these symptoms are mild to moderate in severity, although they may be severe in some patients. They usually appear within the first few days after discontinuation of therapy; very rarely, such symptoms have been observed in patients who accidentally missed a dose. In most cases, these symptoms resolve spontaneously within 2 weeks, although they may occasionally persist longer (2–3 months or more). Therefore, it is recommended to gradually reduce the dose of the drug when discontinuing therapy—over several weeks or months, depending on patient needs (see section "Dosage and administration").
Akathisia/psychomotor restlessness.
Sertraline use has been associated with akathisia, characterized by subjective distress or inability to remain still and an urge to move, often accompanied by inability to sit or stand quietly. The risk of such complications is highest during the first two weeks of therapy. Increasing the dose may be harmful for patients who develop these symptoms.
Use in hepatic impairment.
Sertraline is extensively metabolized in the liver. Pharmacokinetic studies with multiple dosing in patients with stable mild cirrhosis showed a prolongation of elimination half-life and approximately a threefold increase in AUC and Cmax compared to individuals with normal liver function. No significant differences in plasma protein binding between these two groups were observed. Caution should be exercised when administering sertraline to patients with liver disease. When prescribing sertraline to patients with impaired liver function, consideration should be given to reducing the dose or frequency of administration. The drug should not be prescribed to patients with severe hepatic impairment (see "Dosage and administration").
Use in renal impairment.
Sertraline is extensively metabolized, and excretion of unchanged compound in urine is a minor elimination pathway. In studies involving patients with mild to moderate (creatinine clearance 30–60 mL/min) or moderate to severe (creatinine clearance 10–29 mL/min) renal impairment, pharmacokinetic parameters (AUC0-24 and Cmax) after multiple dosing were not statistically significantly different from those in the control group. Dose adjustment based on the degree of renal impairment is not necessary.
Use in elderly patients.
In studies, the nature and frequency of adverse reactions in elderly patients were similar to those observed in younger patients.
However, use of SSRIs and SNRIs, including sertraline, has been associated with cases of clinically significant hyponatremia in elderly patients, who are at higher risk of developing this adverse effect (see "Hyponatremia" in the "Special precautions for use" section).
Diabetes mellitus.
New-onset diabetes has been reported in patients receiving SSRI therapy, including sertraline, as well as loss of glycemic control, including both hyperglycemia and hypoglycemia, in patients with and without diabetes. Therefore, monitoring of glucose levels in patients is recommended. Patients with diabetes should carefully monitor their glucose levels, as dose adjustments of insulin and/or other oral hypoglycemic agents may be required.
Electroconvulsive therapy.
Clinical studies investigating the risks or benefits of combined use of electroconvulsive therapy and sertraline have not been conducted.
Grapefruit juice
Concomitant use of sertraline with grapefruit juice is not recommended (see section "Interaction with other medicinal products and other types of interactions").
Urine screening test
Reports have been received regarding false-positive immunological urine screening tests for benzodiazepines in patients taking sertraline. False-positive results are due to the low specificity of the laboratory test and may persist for several days after discontinuation of sertraline.
Differentiation of sertraline from benzodiazepines in urine can be achieved by confirmatory tests such as gas chromatography/mass spectrometry.
Angle-closure glaucoma.
SSRI-class drugs, including sertraline, may affect pupil size, leading to mydriasis. This effect may cause narrowing of the anterior chamber angle, resulting in increased intraocular pressure and development of angle-closure glaucoma, particularly in predisposed patients. Sertraline should be used with caution in patients with angle-closure glaucoma or a history of glaucoma.
Excipients.
Zalox contains lactose. Therefore, if a patient has intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.
Zalox contains the colorant Yellow FCF, which may cause allergic reactions.
Use during pregnancy or breastfeeding.
Pregnancy.
There is no experience with the use of this medicinal product in this patient population; therefore, sertraline use during pregnancy is not recommended except when the woman's clinical condition justifies the use, and the expected benefits outweigh the potential risks.
Women of reproductive age should use appropriate contraceptive methods during treatment with this drug.
Use of sertraline during pregnancy has been reported to cause symptoms similar to withdrawal reactions in some newborns (whose mothers took sertraline). This symptom has also been observed with other SSRIs.
Newborns should be monitored if the mother continues sertraline use in late pregnancy, especially in the third trimester. After sertraline use in late pregnancy, newborns may develop symptoms such as respiratory distress syndrome, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, tremor, syndrome of increased neuromuscular excitability, irritability, lethargy/apathy, persistent crying, somnolence, and difficulty falling asleep. These symptoms may be due to other serotonergic effects or withdrawal symptoms. In most cases, these complications occur immediately after delivery or shortly thereafter (within 24 hours).
According to study data, use of SSRIs during pregnancy, particularly in late pregnancy, increases the risk of developing persistent pulmonary hypertension in the newborn.
Breastfeeding.
Published data on sertraline levels in breast milk indicate that sertraline and its metabolite N-desmethylsertraline are excreted in breast milk in small amounts. Low or undetectable concentrations of the drug have been found in infant serum, except in one case where the drug concentration in infant serum was approximately 50% of the concentration in maternal serum (but without any noticeable effect on the infant's health). To date, no adverse effects of the drug on the health of breastfed infants have been reported, but this risk cannot be excluded.
Use of the drug during breastfeeding is not recommended, except when, in the physician's opinion, the benefit of taking the drug outweighs the potential risk.
Fertility
Data obtained from animal studies did not reveal any effect of sertraline on fertility parameters. Reports from human studies using some SSRIs suggest that effects on sperm quality are reversible. To date, no effect on human fertility has been identified.
Effect on the ability to drive or operate machinery.
Clinical-pharmacological studies indicate no effect of sertraline on psychomotor functions. However, patients should exercise caution, as the drug may impair mental or physical reactions affecting the ability to drive a car or operate machinery.
Method of Administration and Dosage.
Zalox is administered orally once daily (in the morning or evening). Capsules may be taken regardless of food intake.
Initiation of treatment.
Depression and OCD: Initial dose is 50 mg/day.
Panic disorders, PTSD, and social anxiety disorder: Initial dose is 25* mg/day; after 1 week, the dose should be increased to 50 mg once daily. This dosing regimen has been shown to reduce the incidence of adverse effects typical of panic disorders during the initial phase of treatment.
Dose titration.
Depression, OCD, panic disorders, social anxiety disorder, and PTSD.
In patients who do not respond to a 50 mg dose, therapeutic effect may be achieved by increasing the dose. Dose adjustments should not begin earlier than 1 week after starting treatment, with gradual increments of 50 mg at intervals of at least one week. The maximum dose should not exceed 200 mg/day. Dose adjustments should not occur more frequently than once per week, considering the elimination half-life of sertraline, which is 24 hours.
Initial signs of therapeutic effect may appear within 7 days of treatment. However, achieving a full therapeutic response usually requires a longer period, especially in patients with OCD.
Maintenance dose.
During long-term therapy, the dose should be maintained at the lowest effective level, with subsequent adjustments based on therapeutic response.
Depression.
Long-term therapy may also be used to prevent relapse of major depressive episodes (MDE). In most cases, the recommended dose for preventing MDE relapse is the same as the dose used during treatment of the depressive episode. Patients with depression should continue therapy for a sufficient duration—at least 6 months—to ensure complete symptom remission.
Panic disorders and OCD.
During long-term therapy in patients with panic disorders and OCD, regular re-evaluation of treatment is recommended, as the efficacy of the drug in preventing relapses of these disorders has not been demonstrated.
Use in children.
Children with obsessive-compulsive disorder (OCD).
Children aged 13–17 years: Initial dose is 50 mg once daily.
Children aged 6–12 years: Initial dose is 25* mg once daily. After 1 week, the dose may be increased to 50 mg once daily.
If the desired effect is not achieved with a 50 mg/day dose, the dose may be further increased by increments of up to 50 mg per day over several weeks. The maximum dose is 200 mg/day.
However, when increasing the dose beyond 50 mg in pediatric patients, lower body weight compared to adults should be taken into account. Dose adjustments should not occur more frequently than once per week.
The efficacy of the drug in children with major depressive disorder has not been established. Data on use in children under 6 years of age are lacking (see "Special Instructions").
Use in elderly patients.
The drug should be used with caution in elderly patients, as they are at increased risk of developing hyponatremia (see "Special Instructions").
Use in hepatic impairment.
Caution should be exercised when administering sertraline to patients with liver disease. In patients with impaired liver function, the dose or frequency of administration should be reduced.
The drug should not be used in patients with severe hepatic impairment, as clinical data on its use in such patients are lacking (see "Special Instructions").
Use in renal impairment.
Dosage adjustment is not required in patients with impaired renal function (see "Special Instructions").
Withdrawal symptoms observed upon discontinuation of sertraline therapy.
Abrupt discontinuation of the drug should be avoided. When stopping sertraline treatment, the dose should be gradually reduced over at least 1–2 weeks to minimize the risk of withdrawal reactions (see "Special Instructions" and "Adverse Reactions"). If intolerable symptoms occur after dose reduction or discontinuation, resuming treatment at the previously prescribed dose may be considered. The physician may then continue tapering the dose, but more gradually.
*To achieve this dosage strength, sertraline in another dosage form should be used.
Children.
The drug should not be used for the treatment of children, except for children with obsessive-compulsive disorder aged 6 years and older (see "Method of Administration and Dosage").
Overdose.
Toxicity.
Sertraline has a safety margin that depends on the patient population and/or concomitant use of other drugs. Fatal outcomes have been reported following sertraline overdose, both as monotherapy and in combination with other agents and/or alcohol. Therefore, every case of overdose requires intensive management. Cases of overdose with sertraline monotherapy have been reported at doses up to 13.5 g.
Symptoms.
Symptoms of overdose include serotonin-mediated adverse effects, such as: drowsiness, gastrointestinal disturbances (including nausea and vomiting), tachycardia, tremor, agitation, and dizziness. Coma has been reported less frequently.
Prolongation of the QTc interval and ventricular tachycardia of the "torsades de pointes" type have been reported following sertraline overdose; therefore, ECG monitoring is recommended in all cases of sertraline overdose.
Treatment.
There are no specific antidotes for sertraline. Airway patency, adequate oxygenation, and ventilation should be ensured and maintained as necessary. In managing overdose, administration of activated charcoal (which may be used with a laxative) may be as effective or more effective than gastric lavage. Induction of emesis is not recommended. Recommended monitoring includes cardiac monitoring (e.g., ECG) and other vital signs, along with symptomatic and supportive therapy. Due to the large volume of distribution of sertraline, forced diuresis, dialysis, hemoperfusion, or exchange transfusion are unlikely to be beneficial.
Adverse Reactions
The most commonly observed adverse effect is nausea.
In men treated for social anxiety disorder, sexual dysfunction (ejaculation disorders) was reported. These adverse effects are dose-dependent and often resolve spontaneously with continued therapy.
Below are combined data on adverse reactions observed during clinical trials involving patients with depression, OCD, panic disorders, PTSD, and social anxiety disorders. Some of these may decrease in intensity and frequency with prolonged treatment and do not necessarily lead to discontinuation of therapy.
Infections and infestations: pharyngitis, upper respiratory tract infections, rhinitis, diverticulitis, gastroenteritis, otitis media.
Benign and malignant neoplasms (including cysts and polyps): neoplasm (one case reported in a patient receiving sertraline, compared to no cases in the placebo group).
Blood and lymphatic system disorders: lymphadenopathy, leukopenia, thrombocytopenia.
Immune system disorders: anaphylactoid reaction, allergic reaction, allergy.
Endocrine disorders: hyperprolactinemia, hypothyroidism, syndrome of inappropriate antidiuretic hormone secretion (SIADH).
M metabolism and nutrition disorders: decreased appetite, increased appetite, hypercholesterolemia, hypoglycemia, hyponatremia. Diabetes mellitus and hyperglycemia have also been reported.
Psychiatric disorders: insomnia, depression, depersonalization, nightmares, anxiety, agitation, nervousness, decreased libido, bruxism, hallucinations, euphoric mood, apathy, pathological thinking, conversion disorder, drug dependence, psychotic disorder, aggression, paranoia, suicidal ideation/behavior [only in patients with OCD during or shortly after discontinuation of sertraline therapy (see "Special precautions")], somnambulism, premature ejaculation, paroniria.
Nervous system disorders: dizziness, somnolence, headache, paresthesia, tremor, hypertonia, dysgeusia, attention disturbance, seizures, involuntary muscle contractions, coordination disorder, hyperkinesia, amnesia, hypoesthesia, speech disorder, postural dizziness, migraine, coma, choreoathetosis, dyskinesia, hyperesthesia, sensory disturbances, movement disorders (including extrapyramidal symptoms such as hyperkinesia, hypertonia, dystonia, jaw spasms, or gait disturbances), syncope.
Symptoms of serotonin syndrome or neuroleptic malignant syndrome have also been reported, in some cases associated with concomitant use of serotonergic agents, including agitation, confusion, excessive sweating, diarrhea, elevated body temperature, hypertension, rigidity, tachycardia, akathisia, and psychomotor agitation (see "Special precautions"), cerebral vasospasm (including reversible cerebral vasoconstriction syndrome and Call-Fleming syndrome).
Eye disorders: vision blurred, glaucoma, lacrimation disorders, scotoma, diplopia, photophobia, hyphema, mydriasis, visual disturbances, anisocoria. Frequency unknown: maculopathy.
Ear and labyrinth disorders: tinnitus, ear pain.
Cardiac disorders: palpitations, tachycardia, myocardial infarction, bradycardia, cardiac arrhythmia, QTc interval prolongation, torsades de pointes ventricular tachycardia.
Vascular disorders: hot flushes, hypertension, hyperemia, peripheral ischemia, pathological hemorrhagic events (such as epistaxis, gastrointestinal bleeding, or hematuria).
Respiratory, thoracic and mediastinal disorders: yawning, bronchospasm, dyspnea, epistaxis, laryngospasm, hyperventilation, hypoventilation, stridor, dystonia, hiccup, interstitial lung disease.
Gastrointestinal disorders: diarrhea, nausea, dry mouth, abdominal pain, vomiting, constipation, dyspepsia, flatulence, esophagitis, dysphagia, hemorrhoids, hypersalivation, tongue changes, eructation, melena, hematochezia, stomatitis, tongue ulcers, dental disorders, glossitis, oral mucosal ulcers, pancreatitis. Frequency unknown: microscopic colitis.
Hepatobiliary disorders: liver function abnormalities, hepatic failure, rarely leading to fatal outcome; fulminant hepatitis; necrotic hepatitis; cholestatic jaundice.
Skin and subcutaneous tissue disorders: rash, hyperhidrosis, periorbital edema, purpura, alopecia, cold sweat, dry skin, urticaria, dermatitis, bullous dermatitis, vesicular rash, abnormal hair texture changes, unusual skin odor, rare cases of severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis), angioneurotic edema, facial swelling, photosensitivity reactions, skin reactions, pruritus.
Musculoskeletal and connective tissue disorders: myalgia, osteoarthritis, muscle weakness, back pain, muscle twitching, bone disorders, arthralgia, muscle spasms. A reaction similar to multiple acyl-CoA dehydrogenase deficiency (MADD)* reported with "unknown" frequency.
*Adverse reaction identified in the post-marketing period.
Renal and urinary disorders: nocturia, urinary retention, polyuria, pollakiuria, micturition disorder, oliguria, urinary incontinence, difficulty initiating urination.
Reproductive system and breast disorders: ejaculation disorder, sexual dysfunction, erectile dysfunction, vaginal bleeding, female sexual dysfunction, menorrhagia, atrophic vulvovaginitis, balanoposthitis, genital discharge, priapism, galactorrhea, gynecomastia, irregular menstrual cycle.
Injury. Epidemiological studies have shown that treatment with certain antidepressants, including selective serotonin/norepinephrine reuptake inhibitors (SSRIs/SNRIs), is associated with an increased risk of bone fractures. This should be particularly considered at the beginning of treatment, although the elevated risk persists at later stages of treatment. This risk should also be considered when using sertraline. Elderly patients and those with risk factors for bone fractures should be warned of the danger, as dizziness and orthostatic hypotension may occur at the beginning of treatment or immediately after discontinuation, increasing the likelihood of falls and fractures. Observational data suggest an association between the use of these drugs and decreased bone mineral density in elderly men and women. Therefore, this effect cannot be excluded, particularly with sertraline treatment.
General disorders: fatigue, chest pain, malaise, chills, pyrexia, asthenia, thirst, hernia, fibrosis, drug intolerance, gait disturbance, unspecified events, peripheral edema.
Investigations:
Weight loss, weight gain, increased alanine aminotransferase levels, increased aspartate aminotransferase levels, impaired sperm quality, abnormal clinical laboratory test results, altered platelet function, increased serum cholesterol concentration.
Surgical and interventional procedures: vasodilation procedure.
Withdrawal syndrome observed upon discontinuation of sertraline.
Discontinuation of sertraline therapy (especially abrupt) usually leads to withdrawal symptoms. The most commonly reported adverse events include dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor, and headache. These adverse events are usually mild or moderate and resolve spontaneously; however, in some patients they may be severe and/or prolonged. Therefore, when sertraline therapy is no longer required, gradual discontinuation by stepwise dose reduction is recommended (see "Dosage and administration").
Use in elderly patients.
Use of selective serotonin reuptake inhibitors (SSRIs) or norepinephrine and serotonin reuptake inhibitors (SNRIs), including sertraline, has been associated with clinically significant cases of hyponatremia in elderly patients who are at increased risk of developing this adverse reaction (see "Special precautions").
Use in children.
In children receiving sertraline, the overall adverse event profile was generally similar to that observed in adult patients.
In controlled clinical trials, the following adverse reactions were reported (number of patients receiving sertraline: 281):
Very common (≥ 1/10): headache (22%), insomnia (21%), diarrhea (11%), nausea (15%).
Common (≥ 1/100 to < 1/10): chest pain, mania, pyrexia, vomiting, anorexia, affective lability, aggression, agitation, nervousness, attention disturbance, dizziness, hyperkinesia, migraine, somnolence, tremor, visual disturbance, dry mouth, dyspepsia, nightmares, fatigue, urinary incontinence, rash, acne, epistaxis, flatulence.
Uncommon (≥ 1/1,000 to < 1/100): QT interval prolongation on ECG, suicide attempts, seizures, extrapyramidal disorder, paresthesia, depression, hallucinations, purpura, hyperventilation, anemia, liver function abnormalities, increased alanine aminotransferase levels, cystitis, herpes simplex, otitis externa, ear pain, eye pain, mydriasis, malaise, hematuria, pustular rash, rhinitis, injury, weight loss, muscle twitching, unusual dreams, apathy, albuminuria, pollakiuria, polyuria, breast pain, menstrual cycle disturbance, alopecia, dermatitis, skin disorder, unusual skin odor, urticaria, bruxism, hot flushes.
Frequency unknown: enuresis.
Effects typical of this class of medicinal products
Epidemiological studies, primarily involving patients aged 50 years and older, have shown an increased risk of bone fractures in patients receiving SSRIs and tricyclic antidepressants. The mechanism underlying this increased risk is unknown.
Shelf life. 5 years.
Storage conditions.
Store at temperatures not exceeding 30°C, in a place inaccessible to children.
Packaging.
10 capsules per blister, 3 blisters per cardboard box; 250 capsules in bottles.
Prescription status.
Prescription only.
Manufacturer.
Pharmascience Inc.
Manufacturer's address.
6111 Royalmount Avenue, Suite 100, Montreal, Quebec H4P 2T4, Canada.