Zoloft^® (Tablets) Instructions for Use

Marketing Authorization Holder

Viatris Specialty, LLC (USA)

Manufactured By

Pfizer Manufacturing Deutschland, GmbH (Germany)

ATC Code

N06AB06 (Sertraline)

Active Substance

Sertraline (Rec.INN registered by WHO)

Dosage Forms

	Zoloft®	Film-coated tablets, 50 mg: 14 or 28 pcs.
		Film-coated tablets, 100 mg: 14 or 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, oval, biconvex, engraved with “Pfizer” on one side and “ZLT” with the number “50”, separated by a score, on the other.

Excipients: calcium hydrogen phosphate dihydrate, microcrystalline cellulose (PH102), hypromellose, sodium starch glycolate, magnesium stearate.

Film coating composition:
Opadry white (contains hypromellose, titanium dioxide, macrogol 400, polysorbate 80);
Opadry clear (contains hypromellose, macrogol 400/8000).

14 pcs. – blisters (1) – cardboard packs^×.
14 pcs. – blisters (2) – cardboard packs^×.

^× with or without first opening control.

Film-coated tablets white, oval, biconvex, engraved with “Pfizer” on one side and “ZLT” with the number “100” on the other.

Excipients: calcium hydrogen phosphate dihydrate, microcrystalline cellulose (PH102), hypromellose, sodium starch glycolate, magnesium stearate.

Film coating composition:
Opadry white (contains hypromellose, titanium dioxide, macrogol 400, polysorbate 80);
Opadry clear (contains hypromellose, macrogol 400/8000).

14 pcs. – blisters (1) – cardboard packs^×.
14 pcs. – blisters (2) – cardboard packs^×.

^× with or without first opening control.

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Psychoanaleptics; antidepressants; selective serotonin reuptake inhibitors

Pharmacological Action

Sertraline is a potent and selective in vitro inhibitor of neuronal serotonin (5-HT) reuptake, which enhances the psychological effects of 5-HT in animals. It has only a very weak effect on neuronal reuptake of norepinephrine and dopamine. At clinical doses, Sertraline blocks the uptake of serotonin into human platelets. The drug has no stimulant, sedative, or anticholinergic effects, and does not exhibit cardiotoxic effects in animal studies. In controlled studies in healthy volunteers, Sertraline did not cause sedation and did not affect psychomotor activity. Consistent with selective inhibition of 5-HT reuptake, Sertraline does not affect catecholaminergic activity. Sertraline has no affinity for muscarinic (cholinergic), serotonergic, dopaminergic, adrenergic, histaminergic, GABA-ergic, and benzodiazepine receptors. Long-term administration of sertraline in animals was accompanied by a decrease in the activity of brain norepinephrine receptors, which is also observed with the use of other clinically effective antidepressant and anti-obsessional drugs.

Sertraline does not cause drug dependence. In a placebo-controlled, double-blind, randomized study comparing the addictive potential of sertraline, alprazolam, and d-amphetamine in humans, Sertraline did not produce positive subjective effects indicative of addictive potential. In contrast, patients rated both alprazolam and d-amphetamine significantly higher than placebo on measures such as drug liking, euphoria, and addictive potential. Sertraline did not produce the stimulant or anxiogenic effects characteristic of d-amphetamine administration, or the sedative effects and psychomotor impairment characteristic of alprazolam administration. Sertraline does not serve as a positive reinforcing stimulus in rhesus monkeys trained to self-administer cocaine, nor does it substitute as a discriminative stimulus for either d-amphetamine or pentobarbital in rhesus monkeys.

Clinical Efficacy and Safety

Major Depressive Disorder

A study was conducted involving outpatients with depression who responded to treatment with sertraline at a dose of 50-200 mg/day by the end of an initial 8-week open-label treatment phase. These patients (N=295) were randomized to continue treatment with sertraline at a dose of 50-200 mg/day or placebo for 44 weeks in a double-blind manner. Patients taking Sertraline had a statistically significantly lower relapse rate than patients taking placebo. The average dose of the drug in patients who completed the course of treatment was 70 mg/day. The proportion of patients who responded to treatment (response to treatment was defined as absence of relapse) was 83.4% in the sertraline group and 60.8% in the placebo group.

Post-Traumatic Stress Disorder (PTSD)

Pooled data from three studies of PTSD in the general population showed that the treatment response rate in men was lower than in women. In two general population studies with positive results, the treatment effect rates in men and women in the sertraline and placebo groups were comparable (women: 57.2% vs. 34.5%; men: 53.9% vs. 38.2%). The pooled general population of studies included 184 men and 430 women. Therefore, treatment outcomes in women are more reliable, while in men there was a dependence of treatment outcomes on baseline characteristics (higher frequency of substance abuse, longer duration of illness, cause of trauma, etc.), which correlated with reduced therapy effectiveness.

Cardiac Electrophysiology

In a specific, well-designed QTc interval study using supratherapeutic doses at steady state in healthy volunteers (receiving 400 mg/day, twice the recommended daily dose), the upper bound of the two-sided 90% CI for the corresponding time-matched least squares mean difference in QTcF values between sertraline and placebo (11.666 ms) was greater than the pre-specified threshold of 10 ms at the 4-hour post-dose time point. An exposure-response analysis indicated a slight positive relationship between QTcF duration and plasma sertraline concentration (0.036 ms/(ng/ml); p< 0.0001). Based on the exposure model, the threshold for a clinically significant QTcF prolongation (i.e., for a predicted 90% CI exceeding 10 ms) is at least 2.6 times the mean Cmax (86 ng/ml) after the highest recommended dose of sertraline (200 mg/day) (see sections "Special Instructions", "Drug Interactions", "Adverse Reactions", "Overdose").

Pediatric Patients with OCD

The safety and efficacy of sertraline (at a dose of 50-200 mg/day) were studied in the treatment of outpatient pediatric patients (6 to 12 years) and adolescents (13 to 17 years) with obsessive-compulsive disorder (OCD) without manifestations of depression. After completing a one-week single-blind placebo lead-in period, patients were randomized to receive flexible-dose sertraline or placebo for 12 weeks. For children aged 6 to 12 years, the initial dose of the drug was 25 mg. Patients randomized to the sertraline group showed significantly greater improvement compared to patients receiving placebo, as evidenced by scores on the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) (p=0.005), the National Institute of Mental Health (NIMH) Global Obsessive-Compulsive Scale (p=0.019), and the Improvement subscale of the Clinical Global Impression (CGI) scale (p=0.002). In addition, there was a trend towards greater improvement in the sertraline group compared to the placebo group when assessed by the Severity subscale of the CGI scale (p=0.089). In the placebo group, the mean baseline CY-BOCS score was 22.25±6.15, and the change from baseline was -3.4±0.82, while in the sertraline group these values were 23.36±4.56 and -6.8±0.87, respectively. According to a retrospective analysis, the proportion of patients who responded to treatment was 53% in the sertraline group compared to 37% in the placebo group (p=0.03). Response to treatment was defined as a reduction of at least 25% from baseline in the CY-BOCS score, the primary efficacy measure, at the endpoint.

Long-term clinical studies evaluating efficacy in pediatric patients have not been conducted.

Children

There are no data on the use of the drug in children under 6 years of age.

Post-Marketing Safety Study SPRITES

A post-marketing observational safety study was conducted involving 941 patients aged 6 to 16 years to evaluate the long-term safety of treatment with sertraline (with or without psychotherapy) compared to psychotherapy in terms of cognitive, emotional, physical, and pubertal maturation for up to 3 years. This study was also conducted in a clinical practice setting in children and adolescents with a primary diagnosis of OCD, depression, or other anxiety disorders, and it assessed cognitive function [score on the Digit Symbol Substitution Test (Part B) and the Metacognition Index from the Behavior Rating Inventory of Executive Function (BRIEF)], behavioral/emotional control (score on the Behavioral Regulation Index from the BRIEF questionnaire), and physical/pubertal maturation [score on standardized height/weight/body mass index (BMI) and Tanner stage)]. Sertraline is approved for use in pediatric patients only for children aged 6 years and older with OCD (see section “Indications”).

Standardization for each primary efficacy criterion based on gender- and age-specific normative values showed that overall results were consistent with normal development. There were no statistically significant differences for the primary efficacy criteria, except for body weight. A statistically significant change for standardized body weight was observed in comparative analyses, but the magnitude of the body weight change was small [mean (SD) change in standardized z-scores <0.5 SD]. Body weight increased in a dose-dependent manner.

Pharmacokinetics

Absorption

With daily oral administration of sertraline at a dose of 50 mg to 200 mg once daily for 14 days, the Cmax of sertraline in plasma was reached 4.5-8.4 hours after administration.

Distribution

Approximately 98% of sertraline is bound to plasma proteins.

Metabolism

Sertraline undergoes extensive first-pass metabolism in the liver.

Clinical data and in vitro study data indicate that Sertraline is metabolized by multiple pathways, including those involving the CYP3A4, CYP2C19, and CYP2B6 isoenzymes. In vitro, Sertraline and its primary metabolite (desmethylsertraline) are also substrates of P-glycoprotein.

Elimination

The mean T1/2 of sertraline is about 26 hours (range from 22 to 36 hours). Consistent with the terminal T1/2 values, there is an approximate doubling of sertraline accumulation until steady-state concentration is reached, which is achieved after one week of once-daily administration. The T1/2 of N-desmethylsertraline ranges from 62 to 104 hours. Sertraline and N-desmethylsertraline are extensively metabolized in the human body, with the final metabolites excreted equally in feces and urine. Only a small portion of sertraline (<0.2%) is excreted unchanged in the urine.

Linearity/Non-linearity

In the dose range from 50 to 200 mg, the pharmacokinetics of sertraline are proportional to the administered dose of sertraline.

Pharmacokinetics in Special Patient Groups

Pediatric patients with obsessive-compulsive disorder. The pharmacokinetics of sertraline were studied in a group of 29 patients aged 6 to 12 years and 32 adolescents aged 13 to 17 years. The initial dose of the drug, which was 25 or 50 mg/day, was gradually increased (in increments of 25 or 50 mg, respectively) over 32 days to 200 mg/day. These dosing regimens (with 25 mg and 50 mg increments) were equally well tolerated. At a dose of 200 mg, the steady-state plasma concentration of sertraline in the 6-12 year old patient group was approximately 35% higher than in the 13-17 year old patient group and 21% higher than in the adult comparison group. There were no statistically significant differences in drug clearance between boys and girls. Therefore, when using the drug in children, it is recommended to start treatment with a low dose and increase it in 25 mg increments, especially in children with low body weight. In adolescents, the same doses as for adults can be used.

Adolescents and elderly patients. The pharmacokinetic profile in adolescents and elderly patients does not differ from the pharmacokinetic profile in patients aged 18 to 65 years.

Use in hepatic impairment. In patients with liver damage, the T1/2 of sertraline is increased and the AUC value is increased 3-fold.

Use in renal impairment. In patients with moderate and severe renal impairment, no significant accumulation of sertraline was observed.

Pharmacogenomics. In patients with low CYP2C19 enzyme metabolizing activity, the plasma concentration of sertraline was approximately 50% higher than in patients with high metabolizing activity. The clinical significance of these data is not defined.

Preclinical Safety Data

Data from preclinical studies on pharmacological safety, repeated dose toxicity, genotoxicity, and carcinogenic potential did not reveal any special hazard for humans. Reproductive toxicity studies in animals did not reveal teratogenic properties of the drug; no adverse effects on male fertility were identified in these studies either. The observed manifestations of fetotoxicity may be due to toxic effects on the maternal organism. Reduced offspring survival in the postnatal period and reduced pup body weight were noted only on the first day after birth. Evidence was obtained that offspring death in the early postnatal period was due to drug exposure in utero during development after the 15th day of pregnancy. Delayed postnatal development in the offspring of females administered the drug may be due to the effect of the drug on the maternal organism, and therefore these changes do not pose a risk to humans.

Studies in rodents and other animals did not reveal a significant effect of the drug on fertility.

Studies in Young Animals

A toxicological study was conducted in young rats in which Sertraline was administered orally to male and female rats from postnatal day 21 to day 56 inclusive (at doses of 10, 40, or 80 mg/kg/day) with a drug-free recovery phase until postnatal day 196. Delayed puberty was recorded in males and females at various doses (in males at a dose of 80 mg/kg, and in females at a dose of >10 mg/kg), but despite this, there was no sertraline-related effect on any evaluable reproductive endpoints in males or females. In addition, dehydration, chromorhinorrhea, and decreased mean body weight gain were also observed from postnatal day 21 to day 56. All the aforementioned effects attributed to sertraline administration were reversible at some point during the drug-free recovery phase. The clinical significance of these effects observed in rats administered Sertraline has not been established.

Indications

• Episodes of major depressive disorder and prevention of relapse of major depressive disorder episodes in adults aged 18 years and older;
• Panic disorder with or without agoraphobia in adults aged 18 years and older;
• Obsessive-compulsive disorder (OCD) in adults and children aged 6 years and older;
• Social anxiety disorder in adults aged 18 years and older;
• Post-traumatic stress disorder (PTSD) in adults aged 18 years and older.

ICD codes

Dosage Regimen

Orally, once a day, in the morning or evening, regardless of meals.

Initial Therapy

Depression and OCD initial dose – 50 mg/day.

Panic disorder, PTSD and social anxiety disorder: treatment should be started with a dose of 25 mg/day. After one week of administration, the dose should be increased to 50 mg once a day. This dosing regimen has been shown to reduce the frequency of early adverse effects developing during treatment and characteristic of panic disorder.

Dose Titration

Depression, OCD, panic disorder, social anxiety disorder and PTSD for patients not responding to a 50 mg dose, a dose increase may be necessary. The dose should be adjusted in 50 mg increments at intervals of at least one week up to the maximum dose of 200 mg/day. Given that the T_1/2 of sertraline is 24 hours, changing the dose more frequently than once a week is not recommended.

An initial therapeutic effect may be observed within 7 days. However, longer periods are usually required to demonstrate a therapeutic response, especially in OCD.

Maintenance Therapy

During long-term therapy, the dose of the drug should be maintained at the minimum effective level. Subsequently, dose adjustment may be required depending on the patient’s therapeutic response.

Depression a long-term course of the drug may also be indicated for the prevention of relapse of major depressive disorder (MDD) episodes. In most cases, the dose recommended for the prevention of MDD relapse is similar to the dose prescribed for the treatment of an acute episode. Treatment of patients with depression should be continued for a sufficient period of time (at least 6 months) to ensure the absence of disease symptoms.

Panic disorder and OCD in case of long-term use of the drug for panic disorder and OCD, treatment results should be regularly assessed, as the efficacy of the drug for preventing relapse of such disorders has not been proven.

Special patient groups

In elderly patients the drug should be used with caution due to the increased risk of hyponatremia. The drug is used in the same dose range as in younger people.

In patients with impaired renal function no dose adjustment of the drug is required.

Patients with hepatic impairment

Sertraline should be used with caution in patients with liver disease. In patients with hepatic impairment, the dose of sertraline should be reduced or the frequency of administration decreased. Sertraline should not be used for the treatment of patients with severe hepatic impairment, as clinical data for this category of patients are lacking.

Children and adolescents with OCD

Aged 13-17 years initial dose – 50 mg/day.

Aged 6-12 years initial dose 25 mg once a day. After one week of taking the drug, the dose can be increased to 50 mg once a day.

If necessary, if the response to treatment is less than expected, the drug dose can be further increased in 50 mg/day increments over several weeks. The maximum daily dose is 200 mg. However, when increasing the dose above 50 mg, body weight should be taken into account, as it is generally lower in children than in adult patients. The time interval until the next dose change should be at least one week.

The efficacy of sertraline for the treatment of major depressive disorder in children has not been proven.

Data on use in children under 6 years of age are not available.

Withdrawal symptoms upon discontinuation of sertraline therapy

Abrupt discontinuation of the drug should be avoided. If sertraline therapy needs to be discontinued, the dose should be gradually reduced over at least one or two weeks to reduce the risk of withdrawal reactions. If intolerable adverse reactions occur during the dose reduction period or after discontinuation of sertraline, consideration should be given to resuming therapy at the previous dose. Subsequently, the physician may resume dose reduction, but at longer intervals.

Adverse Reactions

Summary of the safety profile

The most frequent adverse reaction is nausea. In the treatment of social anxiety disorder, sexual dysfunction (absent ejaculation) was noted in men in 14% of cases with sertraline use, compared to 0% with placebo. These adverse reactions are dose-dependent and usually resolve with continued therapy.

An increase in BP may occur with the use of the drug.

The profile of adverse reactions most frequently observed in double-blind, placebo-controlled studies in patients with OCD, panic disorder, PTSD and social anxiety disorder does not differ from that in clinical studies in patients with depression.

Table 1 provides information on adverse reactions observed with sertraline use, based on data obtained during post-marketing (frequency unknown) and placebo-controlled clinical studies (studies involving 2542 patients receiving Sertraline and 2145 patients receiving placebo). These studies were conducted in patients with depression, OCD, panic disorder, PTSD or social anxiety disorder.

Some of the adverse reactions listed in Table 1 may decrease in intensity and frequency with continued therapy and, in general, do not lead to discontinuation of therapy.

Tabulated summary of adverse reactions

The table presents adverse reactions by system organ class and frequency. Within each frequency group, adverse reactions are presented in descending order of severity.

Frequency is defined as: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000) and frequency unknown (cannot be estimated from the available data).

Table 1. Frequency of adverse reactions in placebo-controlled clinical studies in depression, OCD, panic disorder, PTSD and social anxiety disorder. Pooled analysis and post-marketing experience

^* Adverse reactions identified during the post-marketing period.

^§ The frequency of adverse reactions is presented as the upper threshold value calculated at a 95% confidence interval using the "rule of three" (rule for finding an unknown proportion term).

^† This phenomenon has been reported within the therapeutic class of SSRIs/SNRIs.

Withdrawal symptoms upon discontinuation of sertraline therapy

Discontinuation of sertraline treatment (especially abrupt) often leads to the development of a withdrawal syndrome. The most frequently reported symptoms are: dizziness, sensory disturbances (including paresthesias), sleep disorders (including insomnia and vivid dreams), agitation or psychomotor agitation, nausea and/or vomiting, tremor and headache. In general, these symptoms are mild, moderate and self-limiting. However, in some patients they can be severe and persist for a long time. Therefore, if the patient does not require continued sertraline treatment, the drug should be discontinued gradually by smoothly reducing the dose.

Elderly patients

The use of SSRIs and SNRIs, including sertraline, has in some cases been associated with the development of serious hyponatremia in elderly patients, who may be at increased risk of this complication (see section "Special warnings and precautions for use").

Children

In more than 600 pediatric patients treated with sertraline, the overall profile of adverse reactions was generally similar to the safety profile in adult patients. In controlled studies (with 281 patients receiving Sertraline), the following adverse reactions were noted.

Very common (≥1/10): headache (22%), insomnia (21%), diarrhea (11%), nausea (15%).

Common (≥1/100, but <1/10): chest pain, mania, pyrexia, vomiting, anorexia, affective lability, aggressive behavior, agitation, increased excitability, attention disturbance, dizziness, hyperkinesia, migraine, somnolence, tremor, vision blurred, dry mouth, dyspepsia, nightmare, increased fatigue, urinary incontinence, rash, acne, epistaxis, flatulence.

Uncommon (≥1/1000, but <1/100): prolonged QT interval on ECG, suicide attempt, convulsions, extrapyramidal disorders, paresthesia, depressive symptoms, hallucinations, purpura, hyperventilation, anemia, hepatic function abnormal, increased ALT, cystitis, herpes simplex, otitis, ear pain, eye pain, mydriasis, malaise, hematuria, pustular rash, rhinitis, injuries, decreased body weight, involuntary muscle contractions, abnormal dreams, apathy, albuminuria, pollakiuria, polyuria, chest pain, menstrual disorder, alopecia, dermatitis, skin lesions, skin odor abnormal, urticaria, sleep bruxism, flushing.

Unknown (frequency cannot be estimated from the available data): enuresis.

Class effects

According to epidemiological studies, conducted mainly in patients aged 50 years and older, an increased risk of bone fractures was noted in patients taking SSRIs and tricyclic antidepressants. The mechanism of this adverse effect is unknown.

Contraindications

• Hypersensitivity to sertraline or to any of the excipients of the used medicinal product;
• Concomitant use of sertraline with irreversible MAO inhibitors due to the risk of developing serotonin syndrome with symptoms such as agitation, tremor, and hyperthermia. Sertraline should be administered no earlier than 14 days after discontinuation of therapy with irreversible MAO inhibitors. Therapy with sertraline must be discontinued no later than 7 days before starting treatment with irreversible MAO inhibitors;
• Concomitant use with pimozide;
• Children under 6 years of age (for OCD);
• Age under 18 years (for other indications);

Use in Pregnancy and Lactation

Pregnancy

No controlled studies have been conducted in pregnant women. However, a large amount of data suggests that taking sertraline does not lead to congenital malformations. Animal studies have shown a possible effect of sertraline on reproductive function, likely related to maternal toxicity caused by the pharmacodynamic effects of the active substance and/or a direct pharmacodynamic effect of the drug on the fetus.

Some newborns whose mothers took Sertraline during pregnancy exhibited symptoms similar to withdrawal reactions. This phenomenon has also been observed with the use of other antidepressants of the SSRI group. It is not recommended to use Sertraline during pregnancy, except in cases where the intended treatment benefit for the mother outweighs the potential risk to the fetus.

Observational data indicate an increased (less than 2-fold) risk of postpartum hemorrhage after the use of SSRI/SNRI group drugs within one month before delivery.

Newborns whose mothers continued to take Sertraline in late pregnancy (especially in the third trimester) should be monitored. Newborns whose mothers took Sertraline in late pregnancy may exhibit the following symptoms: respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, tremor, muscle twitching, increased excitability, lethargy, prolonged crying, drowsiness, and difficulty falling asleep. These symptoms may be related to direct serotonergic effects or may be symptoms of drug withdrawal. In most cases, these symptoms begin immediately or soon (within 24 hours) after birth.

Epidemiological studies suggest that the use of SSRIs during pregnancy (especially in late stages) may increase the risk of persistent pulmonary hypertension of the newborn (PPHN). The observed incidence of PPHN was approximately 5 cases per 1000 newborns. In the general population, PPHN occurs with a frequency of 1-2 cases per 1000 pregnancies.

Lactation period

According to published data, Sertraline and its metabolite N-desmethylsertraline pass into breast milk in small amounts. However, these substances were not detected in the child’s blood serum or their concentrations were negligible. In only one case, the concentration in the infant’s serum was about 50% of the maternal serum concentration (with no visible negative impact on the child’s health observed). Currently, there is no data indicating that breastfeeding while taking sertraline negatively affects the child’s health. Nevertheless, the risk cannot be completely ruled out. Therefore, the use of the drug in nursing mothers is not recommended (except in cases where the benefit, in the doctor’s opinion, outweighs the risk).

Fertility

Data obtained from animal studies indicate that Sertraline does not affect fertility indicators (see the “Preclinical Safety Data” subsection).

According to described clinical cases, the use of some SSRIs affects sperm quality, but this effect is reversible. To date, no effect of sertraline on human fertility has been observed.

Use in Hepatic Impairment

Sertraline should be used with caution in patients with liver diseases. In patients with hepatic insufficiency, the dose of the drug should be reduced or the frequency of administration decreased. Sertraline should not be used to treat patients with severe hepatic insufficiency, as clinical data for this category of patients are lacking.

Use in Renal Impairment

Caution should be exercised when using sertraline in patients with renal insufficiency; dose adjustment is not required.

Pediatric Use

Contraindicated for use in children under 6 years of age (for obsessive-compulsive disorders) and under 18 years of age (for other indications).

Geriatric Use

Use with caution in elderly patients due to an increased risk of developing hyponatremia. Sertraline is used in the same dose range as in younger people.

Special Precautions

Serotonin syndrome (SS) and malignant neuroleptic syndrome (MNS)

Cases of potentially life-threatening syndromes – serotonin syndrome (SS) and malignant neuroleptic syndrome (MNS) – have been reported with the use of SSRIs, including Sertraline.

The risk of serotonin syndrome or MNS during SSRI treatment increases with the concomitant use of sertraline with other serotonergic drugs (including other serotonergic antidepressants, amphetamines, and triptans), with drugs that impair serotonin metabolism (including MAOIs, e.g., methylene blue), antipsychotic drugs and other dopamine antagonists, as well as with opioids. Patients should be monitored for the development of signs and symptoms of serotonin syndrome or MNS.

Transition from selective serotonin reuptake inhibitors (SSRIs), antidepressants, or anti-obsessional drugs

There is only limited controlled study experience regarding the optimal timing of switching from SSRIs, antidepressants, and anti-obsessional drugs to Sertraline. Therefore, caution should be exercised and decisions should be based on a thorough medical assessment when switching drugs, especially long-acting drugs such as fluoxetine.

Other serotonergic drugs such as tryptophan, fenfluramine, and 5-HT receptor agonists

Concomitant administration of sertraline and other drugs that enhance serotonergic neurotransmission effects, such as amphetamines, tryptophan, fenfluramine, 5-HT receptor agonists, or the herbal remedy St. John’s wort ( Hypericum perforatum ), should be done with caution, and such use should be avoided if possible due to the potential risk of pharmacodynamic interaction.

QT_c interval prolongation/Polymorphic ventricular tachycardia of the "torsades de pointes" type

Cases of torsades de pointes ventricular tachycardia and QT_c interval prolongation have been recorded during post-marketing use of sertraline. Most cases were reported in patients with an increased risk of QT_c interval prolongation/development of torsades de pointes ventricular tachycardia. The effect on QT_c interval prolongation was confirmed in a thorough QT_c study involving healthy volunteers, which showed a statistically significant positive exposure-response relationship. Thus, in patients with additional risk factors for QT_c interval prolongation, such as cardiovascular disease, hypokalemia or hypomagnesemia, family history of QT_c interval prolongation, bradycardia, and concomitant use of drugs that prolong the QT_c interval, Sertraline should be used with caution.

Activation of manic or hypomanic state

The emergence of manic or hypomanic state symptoms has been reported in a small percentage of patients receiving marketed antidepressants and anti-obsessional drugs, including Sertraline. Therefore, Sertraline should be used with caution in patients with a history of manic/hypomanic state. During treatment, careful medical supervision of patients is necessary. If the disease transitions into a manic phase, sertraline therapy should be discontinued.

Schizophrenia

In patients suffering from schizophrenia, psychotic symptoms may intensify.

Seizures

Seizures may occur during treatment with sertraline; therefore, the use of the drug should be avoided in patients with unstable epilepsy, and patients with controlled epilepsy should be carefully monitored. If seizures develop, sertraline therapy should be discontinued.

Suicide/Suicidal thoughts/Suicide attempts or clinical worsening

In depression, the likelihood of suicidal thoughts increases, and the risk of self-harm and suicide (suicidal actions and manifestations) increases. This risk persists until significant symptom improvement occurs. Since improvement may not occur during the first few weeks of treatment, patients should be closely monitored until improvement occurs. Current clinical experience indicates that the risk of suicide may increase during the initial stages of treatment.

In other mental disorders for which Sertraline is intended, the risk of suicidal actions and manifestations may also be increased. These disorders may also be comorbid with depression (major depressive disorder). Therefore, when treating patients with other mental illnesses, the same precautions should be taken as when treating patients with major depressive disorder.

If there is a history of suicidal actions and manifestations, as well as significant manifestations of suicidal thinking before starting treatment, the likelihood of suicidal thoughts and suicide attempts during treatment increases. In such cases, particularly careful monitoring of the patient’s condition during treatment is necessary. A meta-analysis of results from placebo-controlled clinical trials on the use of antidepressants in adult patients under 25 years of age with mental disorders demonstrated an increased likelihood of suicidal behavior when taking antidepressants compared to placebo.

During drug therapy, especially at the initial stage and after dose changes, the patient’s condition must be carefully monitored, primarily in patients at high risk of suicide. Patients (and their caregivers) should be warned to monitor for any signs of clinical worsening, suicidal behavior or thoughts, and unusual changes in behavior. If these symptoms appear, immediate medical attention should be sought.

Sexual dysfunction

SSRIs may cause symptoms of sexual dysfunction. There have been reports of persistent sexual dysfunction where symptoms persisted despite discontinuation of the SSRI.

Use in children and adolescents under 18 years of age

Sertraline should not be used to treat children and adolescents under 18 years of age, except for patients with OCD aged 6 years and older. In clinical trials, suicidal tendencies (suicide attempts and suicidal thoughts) and hostility (predominantly aggressiveness, oppositional behavior, and anger) were observed more frequently in patients receiving antidepressant therapy than in patients receiving placebo. If, based on a clinical assessment of the patient, a decision is made to conduct therapy, the patient should be carefully monitored for symptoms of suicidal behavior, especially at the beginning of therapy.

The long-term safety regarding cognitive, emotional, physical, and pubertal maturation in children and adolescents aged 6 to 16 years was assessed in a long-term observational study lasting up to 3 years. Several cases of growth retardation and delayed puberty were reported during the post-marketing period. The clinical significance and causal relationship remain unclear. During long-term therapy in pediatric patients, physicians should monitor for developmental abnormalities.

Abnormal bleeding/hemorrhage

Cases of abnormal bleeding, including skin hemorrhages (ecchymoses and purpura) and other hemorrhagic phenomena such as gastrointestinal bleeding and genital bleeding (in women), including fatal bleeding, have been reported with the use of SSRIs. The use of SSRI/SNRI group drugs may increase the risk of postpartum hemorrhage. Caution is recommended when using SSRIs in patients, especially when used concomitantly with drugs known to affect platelet function (e.g., anticoagulants, atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and NSAIDs), as well as in patients with a history of bleeding disorders.

Hyponatremia

Hyponatremia may develop as a result of treatment with SSRIs or SNRIs, including Sertraline. In many cases, hyponatremia appears to be a consequence of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases of serum sodium levels falling below 110 mmol/L have been reported.

In elderly patients, the risk of developing hyponatremia when taking SSRIs and SNRIs may be increased. Patients taking diuretics or who are dehydrated for other reasons may also be at increased risk. In patients with symptomatic hyponatremia, discontinuation of sertraline therapy should be considered; they should receive appropriate medical care. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may lead to falls. Signs and symptoms associated with more severe and/or acute cases included hallucination, syncope, seizures, coma, respiratory arrest, and death.

Withdrawal symptoms upon discontinuation of sertraline therapy

After discontinuation of sertraline, especially in case of abrupt cessation, withdrawal syndrome often develops. In clinical studies, the incidence of withdrawal symptoms was 23% in patients who discontinued the drug, compared to 12% in patients who continued sertraline therapy.

The likelihood of developing withdrawal symptoms may depend on a number of factors, including the dose and duration of treatment, as well as the rate of dose reduction. The most common reactions include dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor, and headache. Typically, these are mild or moderate symptoms, but in some cases they can be severe. These symptoms usually develop within the first few days after discontinuation of treatment, but very rare cases of these symptoms occurring after accidental missed doses have been reported. Withdrawal symptoms usually resolve without treatment within 2 weeks, but in some patients they may persist for a longer period (2-3 months or longer). Therefore, when discontinuing therapy, it is recommended to gradually reduce the dose of sertraline over several weeks or months, depending on the patient’s condition.

Akathisia/Psychomotor agitation

The use of sertraline has in some cases been accompanied by the development of akathisia, a condition characterized by an unpleasant or distressing feeling of restlessness and a need to move, combined with an inability to sit or stand still. The likelihood of developing these changes is higher during the first few weeks of treatment. Increasing the dose of sertraline in the presence of these symptoms may lead to a worsening of the patient’s condition.

Impaired liver function

Sertraline undergoes extensive metabolic transformation in the liver. According to a pharmacokinetic study using multiple doses in patients with mild compensated liver cirrhosis, an increase in the T_1/2 of sertraline and an approximately threefold increase in AUC and C_max values were observed compared to patients without liver function impairment. No significant differences in the degree of drug binding to plasma proteins were noted between these two groups. Sertraline should be used with caution in patients with liver diseases. In patients with hepatic insufficiency, the dose of sertraline should be reduced or the frequency of administration decreased. Sertraline is not recommended for patients with severe liver function impairment.

Impaired renal function

Sertraline undergoes extensive metabolic transformation, and the excretion of unchanged sertraline in the urine is an additional elimination pathway. In studies involving patients with mild to moderate renal impairment (CrCl 30-60 ml/min) or moderate to severe renal impairment (CrCl 10-29 ml/min), the main pharmacokinetic parameters after multiple doses (AUC_0-24 and C_max) did not significantly differ from patients with normal renal function. Dose adjustment of sertraline based on the degree of renal impairment is not required.

Use in elderly patients

More than 700 elderly patients (>65 years) participated in clinical studies. The nature and frequency of adverse reactions in elderly patients were similar to those in younger patients.

However, cases of clinically significant decreases in blood sodium levels have been noted with the use of SSRIs and SNRIs, including sertraline, in elderly patients who may be at risk of developing hyponatremia.

Diabetes mellitus

In patients with diabetes mellitus, SSRIs may impair glycemic control. Such patients may require adjustment of the insulin dose and/or oral hypoglycemic agent.

Electroconvulsive therapy (ECT)

No clinical studies have been conducted to assess the risk and possible benefit of combined use of ECT and sertraline.

Grapefruit juice

It is not recommended to consume grapefruit juice during treatment with sertraline.

Effect on urine screening test results

False-positive results in screening immunoassays for benzodiazepines have been recorded in patients taking Sertraline. This was due to insufficient specificity of the enzyme immunoassay screening tests. False-positive test results can be expected for several days after discontinuation of sertraline therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will help differentiate Sertraline from benzodiazepines.

Angle-closure glaucoma

SSRIs, including Sertraline, may affect pupil size, causing mydriasis. This mydriatic effect can lead to narrowing of the eye angle, causing increased intraocular pressure and angle-closure glaucoma, especially in patients with a corresponding predisposition. Therefore, Sertraline should be used with caution in patients with angle-closure glaucoma or a history of glaucoma. Sertraline can cause narrowing of the anterior chamber angle, which can lead to increased intraocular pressure and the development of angle-closure glaucoma.

Effect on the Ability to Drive Vehicles and Operate Machinery

Clinical pharmacological studies have shown that Sertraline does not affect psychomotor functions.

However, patients should be cautioned that psychotropic drugs may negatively affect the mental or physical reactions required to perform potentially hazardous tasks, such as driving vehicles or operating machinery.

Drug Interactions

MAO Inhibitors

Irreversible MAO inhibitors (e.g., selegiline)

Sertraline should not be used concurrently with irreversible (non-selective) MAO inhibitors, such as selegiline.

Sertraline should be administered no earlier than 14 days after discontinuation of irreversible MAO inhibitors.

Administration of sertraline should be discontinued at least 7 days before initiating therapy with irreversible MAO inhibitors.

Reversible selective MAO inhibitors (moclobemide)

Due to the risk of serotonin syndrome, the concomitant use of reversible selective MAO inhibitors, such as moclobemide, and Sertraline is not recommended.

A shorter period than 14 days may be observed after the use of reversible MAO inhibitors before starting sertraline.

Sertraline should be discontinued at least 7 days before initiating therapy with reversible MAO inhibitors.

Reversible non-selective MAO inhibitors (linezolid)

The antibiotic linezolid is a weak reversible non-selective MAO inhibitor.

It should not be used in patients receiving sertraline therapy.

Severe adverse reactions have been observed in patients who recently discontinued MAO inhibitor therapy and started taking sertraline (e.g., methylene blue) or who recently discontinued sertraline and started MAO inhibitor therapy.

These reactions included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with symptoms resembling neuroleptic malignant syndrome, seizures, and death.

Pimozide

According to a conducted study, a single low-dose (2 mg) administration of pimozide concomitantly with sertraline increased the concentration of pimozide by approximately 35%.

This was not associated with any ECG changes.

Since the mechanism of this interaction is unknown and pimozide has a narrow therapeutic index, the concomitant use of pimozide and sertraline is contraindicated.

CNS Depressants and Alcohol

In healthy individuals, the concomitant use of sertraline at a dose of 200 mg daily did not potentiate the effects of alcohol, carbamazepine, haloperidol, or phenytoin on cognitive and psychomotor performance.

Nevertheless, the consumption of alcohol during treatment with sertraline is not recommended.

Other Serotonergic Drugs

Caution should be exercised when sertraline is used concomitantly with other drugs that enhance serotonergic neurotransmission, such as tryptophan, fenfluramine, 5-HT agonists, tramadol, or St. John’s wort.

Such concomitant use should preferably be avoided, considering the possibility of pharmacodynamic interaction.

Opioids (e.g., fentanyl [used during anesthesia or for chronic pain management]) and other serotonergic drugs (including serotonergic antidepressants, amphetamines, triptans) should be prescribed with caution.

Drugs that Prolong the QT Interval

The risk of QT_c interval prolongation and/or the development of ventricular arrhythmias (e.g., torsades de pointes) may increase with the concomitant use of sertraline and other drugs that prolong the QT_c interval (e.g., some antipsychotics and antibiotics).

Lithium

According to a placebo-controlled study in healthy volunteers, the pharmacokinetics of lithium were not significantly altered when used concomitantly with sertraline.

However, an increase in tremor (compared to placebo) was noted, which may indicate a possible pharmacodynamic interaction.

Patients should be continuously monitored when sertraline is used concomitantly with lithium preparations.

Phenytoin

Results from a placebo-controlled study in healthy volunteers suggest that long-term use of sertraline at a dose of 200 mg/day does not cause clinically significant inhibition of phenytoin metabolism.

However, there are isolated reports of increased phenytoin concentrations with concomitant use of sertraline.

Therefore, it is recommended to monitor plasma phenytoin concentrations from the initiation of sertraline with appropriate dose adjustment.

Furthermore, during therapy with phenytoin and known inducers of CYP3A4, plasma levels of sertraline may decrease.

Metamizole

Concomitant use of sertraline with metamizole, which is an inducer of metabolizing enzymes, including CYP2B6 and CYP3A4, may lead to a decrease in plasma sertraline concentration with a potential reduction in the drug’s clinical efficacy.

In this regard, caution is recommended when using metamizole and sertraline concomitantly; if necessary, the clinical response and/or drug concentration should be monitored.

Triptans

During post-marketing use of the drug, rare cases of weakness, hyperreflexia, impaired coordination, confusion, anxiety, and agitation have been reported in patients taking Sertraline and sumatriptan concomitantly.

Symptoms of serotonin syndrome may also occur with the concomitant use of sertraline with other drugs of this class.

If there is a clinical indication for the concomitant use of sertraline and triptans, appropriate patient monitoring is recommended.

Warfarin

Concomitant use of sertraline at a dose of 200 mg/day with warfarin resulted in a small but statistically significant increase in prothrombin time, which in some cases could lead to an imbalance in INR values.

Therefore, prothrombin time should be carefully monitored during the initiation of sertraline therapy and during its discontinuation.

Other Drug Interactions (Digoxin, Atenolol, Cimetidine)

Concomitant use of sertraline and cimetidine significantly reduces the clearance of sertraline.

The clinical significance of these changes is unknown.

Sertraline did not affect the beta-blocking action of atenolol.

No drug interaction was found between sertraline (200 mg/day) and digoxin.

Drugs Affecting Platelet Function

Concomitant use of SSRIs, including Sertraline, and drugs that affect platelet function (e.g., NSAIDs, acetylsalicylic acid, and ticlopidine) or drugs that may increase the risk of bleeding may be associated with an increased risk of bleeding.

Muscle Relaxants

SSRIs may reduce plasma cholinesterase activity, leading to an increased duration of action of muscle relaxants, such as mivacurium or other neuromuscular blockers, on neuromuscular transmission.

Drugs Metabolized by Cytochrome P450 Isoenzymes

Sertraline may mildly to moderately inhibit the CYP2D6 isoenzyme.

Long-term treatment with sertraline at a dose of 50 mg/day has been shown to increase (on average by 23-37%) the steady-state plasma concentration of desipramine (a marker of CYP2D6 isoenzyme activity).

Clinically significant interaction is also observed with the concomitant use of drugs with a narrow therapeutic index that are metabolized by the CYP2D6 isoenzyme (e.g., tricyclic antidepressants, typical antipsychotics, and class IC antiarrhythmic drugs – propafenone, flecainide).

Sertraline does not clinically significantly inhibit the CYP3A4, CYP2C9, CYP2C19, and CYP1A2 isoenzymes.

This is confirmed by in vivo interaction studies with CYP3A4 substrates (endogenous cortisol, carbamazepine, terfenadine, alprazolam), CYP2C19 (diazepam), and CYP2C9 (tolbutamide, glibenclamide, and phenytoin).

Results from in vitro studies indicate that Sertraline has little or no inhibitory effect on CYP1A2 activity.

Ingestion of 3 glasses of grapefruit juice daily increases the plasma concentration of sertraline by approximately 100% (according to a crossover study involving eight healthy Japanese individuals).

Therefore, the concomitant intake of sertraline and grapefruit juice should be avoided.

Based on studies of the interaction between sertraline and grapefruit juice, it cannot be excluded that the concomitant use of sertraline and potent inhibitors of the CYP3A4 isoenzyme (e.g., protease inhibitors, ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, and nefazodone) may lead to an even greater increase in sertraline exposure.

This also applies to moderate inhibitors of the CYP3A4 isoenzyme (such as aprepitant, erythromycin, fluconazole, verapamil, and diltiazem).

Thus, the use of potent CYP3A4 isoenzyme inhibitors during sertraline therapy should be avoided.

The ability of other inducers of the CYP3A4 isoenzyme (e.g., phenobarbital, carbamazepine, St. John’s wort preparations, rifampicin) to reduce the plasma concentration of sertraline cannot be excluded either.

In patients who are slow metabolizers of the CYP2C19 isoenzyme, plasma sertraline concentrations are 50% higher than in patients who are rapid metabolizers of this enzyme.

An interaction between potent inhibitors of the CYP2C19 isoenzyme (such as omeprazole, lansoprazole, pantoprazole, rabeprazole, fluoxetine, and fluvoxamine) and sertraline cannot be excluded.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.