Aleval (Tablets) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

N06AB06 (Sertraline)

Active Substance

Sertraline (Rec.INN registered by WHO)

Dosage Forms

	Aleval	Film-coated tablets, 25 mg: 14 and 28 pcs.
		Film-coated tablets, 50 mg: 14 and 28 pcs.
		Film-coated tablets, 100 mg: 14 and 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets are blue, round, biconvex, with a score on one side; the core is white on the break.

Excipients: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, corn starch, hypromellose 2910, purified talc, magnesium stearate, colloidal anhydrous silicon dioxide, crospovidone, indigo carmine.

Film coating composition: hypromellose 2910, macrogol 6000, purified talc, titanium dioxide, indigo carmine.

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

Film-coated tablets are blue, round, biconvex, with a score on one side; the core is white on the break.

Excipients: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, corn starch, hypromellose 2910, purified talc, titanium dioxide, magnesium stearate, colloidal silicon dioxide, crospovidone, indigo carmine.

Film coating composition: hypromellose 2910, macrogol 6000, purified talc, titanium dioxide, indigo carmine.

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

Film-coated tablets are blue, round, biconvex, with a score on one side; the core is white on the break.

Excipients: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, corn starch, hypromellose 2910, purified talc, magnesium stearate, colloidal silicon dioxide, crospovidone, indigo carmine.

Film coating composition: hypromellose 2910, macrogol 6000, purified talc, titanium dioxide, indigo carmine.

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

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Antidepressant

Pharmacological Action

Antidepressant, a selective serotonin reuptake inhibitor (5-HT). It has a very weak effect on the reuptake of norepinephrine and dopamine. At therapeutic doses, Sertraline blocks serotonin uptake in human platelets.

It does not have stimulant, sedative, or anticholinergic effects. Sertraline has no affinity for muscarinic cholinergic receptors, adrenergic receptors, serotonin, dopamine, histamine receptors, GABA- or benzodiazepine receptors.

The antidepressant effect is noted by the end of the second week of regular Sertraline administration, while the maximum effect is achieved only after 6 weeks. Sertraline does not cause mental or physical drug dependence.

Pharmacokinetics

When taken orally, absorption from the gastrointestinal tract is significant but slow. C_max in blood plasma is reached 4.5-8.4 hours after oral administration. Steady-state plasma concentrations of sertraline are achieved within one week with once-daily administration. When the drug is taken with food, bioavailability increases by 25%, and the time to reach C_max decreases.

Distribution

The overall binding of sertraline to plasma proteins is 98%. V_d > 20 L/kg.

Sertraline is excreted in breast milk. There are no data on the ability of sertraline to cross the blood-brain barrier.

Metabolism and Excretion

Sertraline is extensively metabolized during first-pass metabolism in the liver, undergoing N-demethylation. Its main metabolite, N-desmethylsertraline, is less active than the parent compound. Metabolites are excreted in urine and feces in equal amounts. About 0.2% of sertraline is excreted unchanged in the urine. T_1/2 of the drug is 22-36 hours and does not depend on age or gender. For N-desmethylsertraline, this figure is 62-104 hours.

Pharmacokinetics in Special Clinical Situations

T_1/2 and AUC of sertraline increase in patients with impaired liver function.

Regardless of the severity of renal failure, the pharmacokinetics of sertraline during its constant use do not change.

Sertraline is not dialyzable.

Indications

• Depression of various etiologies (treatment and prevention);
• Obsessive-compulsive disorder (OCD);
• Panic disorder (with or without agoraphobia);
• Post-traumatic stress disorder (PTSD).

ICD codes

Dosage Regimen

The drug is administered orally, once a day in the morning or evening. Sertraline tablets can be taken with or without food.

For depression and OCD in adults, the initial dose is 50 mg once a day. The dose can be gradually increased at intervals of no more than once a week to a maximum daily dose of 200 mg.

The initial therapeutic effect may appear within 7 days, but the full effect is usually achieved after 2-4 weeks (or even longer for OCD). The maintenance dose for long-term treatment should be the minimum effective dose with appropriate adjustments depending on the therapeutic effect.

For OCD in children aged 6 to 12 years, the initial dose is 25 mg. After one week, the dose can be increased to 50 mg.

For children aged 12 to 17 years, the initial dose is 50 mg. The daily dose can be gradually increased from 50 mg to a maximum of 200 mg, no sooner than after one week. To avoid overdose, the lower body weight of children compared to adults should be taken into account; when increasing the dose above 50 mg/day, careful monitoring of this category of patients is necessary, and at the first signs of overdose, the drug should be discontinued.

For panic disorder and PTSD, the drug is prescribed to adults. The initial dose is 25 mg. Taking into account tolerability, the dose can be gradually increased to a maximum of 200 mg no more than once a week by 25 mg, until the desired therapeutic effect is achieved.

A satisfactory therapeutic result is usually achieved within 7 days from the start of treatment. However, to achieve the full therapeutic effect, regular use of the drug for 2-4 weeks is required. The minimum dose that provides a therapeutic effect is subsequently maintained as a maintenance dose.

In elderly patients and patients with impaired renal function, special dose adjustment is not required.

In patients with severe hepatic impairment, the dose of the drug should be reduced or the intervals between doses should be increased.

Adverse Reactions

From the digestive system: dyspeptic symptoms (flatulence, nausea, vomiting, diarrhea), abdominal pain, pancreatitis, dry mouth, hepatitis, jaundice, hepatic failure, decreased appetite up to anorexia; rarely – increased appetite.

From the cardiovascular system: palpitations, tachycardia, decreased blood pressure.

From the musculoskeletal system: arthralgia, muscle cramps.

From the central and peripheral nervous system: extrapyramidal disorders (dyskinesia, akathisia, teeth grinding, gait disturbance), involuntary muscle contractions, paresthesia, fainting, drowsiness, headache, migraine, dizziness, tremor, insomnia, anxiety, agitation, tremor, convulsions, manic disorders, hallucinations, euphoria, nightmares, psychosis, decreased libido, suicide, coma.

From the respiratory system: bronchospasm, yawning.

From the urinary system: enuresis, urinary incontinence or retention.

From the reproductive system: sexual dysfunction (delayed ejaculation, decreased potency), galactorrhea, gynecomastia, menstrual cycle disorders, priapism.

From the sensory organs: visual impairment, mydriasis, periorbital edema, tinnitus.

From the endocrine system: hyperprolactinemia, hypothyroidism, syndrome of inappropriate ADH secretion.

Dermatological reactions: skin redness or facial flushing, alopecia, photosensitivity, purpura, increased sweating; rarely – Stevens-Johnson syndrome, toxic epidermal necrolysis.

Allergic reactions: urticaria, itching, anaphylactoid reaction, angioedema, facial edema.

Laboratory data: rarely, with long-term use – asymptomatic increase in serum transaminase activity. Discontinuation of the drug in this case leads to normalization of enzyme activity. The development of leukopenia and thrombocytopenia, as well as an increase in serum cholesterol concentration, is possible.

Other: weakness, decrease or increase in body weight, bleeding (including nasal, gastrointestinal or hematuria), peripheral edema.

When discontinuing treatment with sertraline, in rare cases – withdrawal syndrome: paresthesia, hypesthesia, symptoms of depression, hallucinations, aggressive reactions, psychomotor agitation, anxiety, or symptoms of psychosis that cannot be distinguished from the symptoms of the underlying disease may occur.

Contraindications

• Uncontrolled epilepsy;
• Concomitant use with MAO inhibitors and pimozide (when switching from one drug to another, a 14-day interval without antidepressant use should be observed);
• Concomitant use of sertraline with tryptophan or fenfluramine;
• Children under 6 years of age for depression and OCD;
• Children and adolescents under 18 years of age for panic disorder and PTSD;
• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to the components of the drug.

Use with caution in organic brain diseases (including mental retardation), manic states, epilepsy, hepatic and/or renal failure, decreased body weight, in children over 6 years of age with depression and OCD.

Use in Pregnancy and Lactation

The use of the drug is contraindicated during pregnancy and lactation (breastfeeding).

There are no controlled results of the use of sertraline in pregnant women.

Women of reproductive age who are planned to be prescribed Sertraline should use effective methods of contraception.

Sertraline is excreted in breast milk. There are no reliable data on the safety of the drug during breastfeeding. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

In the case of using sertraline during pregnancy and breastfeeding, some newborns whose mothers took antidepressants from the group of selective serotonin reuptake inhibitors, including sertraline, may experience symptoms similar to the drug withdrawal reaction.

Use in Hepatic Impairment

The drug should be used with caution in hepatic insufficiency.

In patients with severe hepatic impairment, the dose of the drug should be reduced or the intervals between doses should be increased.

Use in Renal Impairment

The drug should be used with caution in renal insufficiency.

In patients with impaired renal function, special dose adjustment is not required.

Pediatric Use

Contraindicated in children under 6 years of age for depression and OCD; in children and adolescents under 18 years of age for panic disorder and PTSD.

In children and adolescents with depression and other mental disorders, antidepressants, compared with placebo, increase the risk of suicidal thoughts and suicidal behavior. Therefore, when prescribing the drug Aleval or any other antidepressants to children, adolescents, and young people under 24 years of age, the risk of suicide and the benefits of their use should be weighed.

Geriatric Use

In elderly patients, special dose adjustment is not required.

In elderly patients during treatment with sertraline, transient hyponatremia may occur. This side effect is associated with the syndrome of inappropriate ADH secretion. If symptomatic hyponatremia develops, Sertraline should be discontinued and adequate therapy aimed at correcting blood sodium levels should be prescribed. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, weakness and unsteadiness, which can lead to falls. In more severe cases, hallucinations, fainting, convulsions, coma, respiratory arrest, and death may occur.

Special Precautions

Aleval should not be prescribed concomitantly with MAO inhibitors, or within 14 days after discontinuation of MAO inhibitor treatment. Similarly, MAO inhibitors should not be prescribed within 14 days after discontinuation of Aleval.

Cases of serotonin syndrome and neuroleptic malignant syndrome (NMS) have been reported with the use of selective serotonin reuptake inhibitors (SSRIs), the risk of which increases when SSRIs are combined with other serotonergic agents (including triptans), as well as drugs that affect serotonin metabolism (including MAO inhibitors), antipsychotics and other dopamine receptor antagonists. Manifestations of serotonin syndrome may include mental status changes (in particular, agitation, hallucinations, coma), autonomic instability (tachycardia, blood pressure fluctuations, hyperthermia), neuromuscular transmission changes (hyperreflexia, impaired coordination) and/or gastrointestinal disorders (nausea, vomiting, and diarrhea). Some manifestations of serotonin syndrome, including hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuations in vital signs, and mental status changes, may resemble symptoms developing in NMS.

Caution should be exercised when co-administering sertraline with other drugs that enhance serotonergic neurotransmission, such as tryptophan, fenfluramine, or serotonin 5-HT receptor agonists. Such co-administration should be avoided if possible, given the likelihood of pharmacodynamic interaction.

Experience from clinical trials aimed at determining the optimal time required to switch patients from other antidepressants and agents used for OCD to Sertraline is limited. Caution should be exercised during such a switch, especially from long-acting drugs, such as fluoxetine. The required interval between discontinuation of one SSRI and initiation of another similar drug has not been established.

It should be noted that there is insufficient experience with the use of sertraline in patients undergoing electroconvulsive therapy. The potential success or risk of such combination therapy has not been studied.

There is no experience with the use of sertraline in patients with convulsive syndrome, so the use of the drug should be avoided in patients with unstable epilepsy, and patients with controlled epilepsy should be carefully monitored during treatment. If seizures occur, the drug should be discontinued.

During clinical trials prior to the marketing of sertraline, manic disorders were observed in approximately 0.4% of patients taking Sertraline. Cases of activation of manic disorders have also been described in a small proportion of patients with manic-depressive psychosis receiving other antidepressant or anti-OCD agents.

Sertraline is actively biotransformed in the liver. According to a pharmacokinetic study, with multiple doses of sertraline in patients with stable mild liver cirrhosis, an increase in T_1/2 of the drug and an increase in C_max and AUC by almost 3 times compared to these indicators in healthy people were observed. There were no significant differences in plasma protein binding between the two groups. Sertraline should be used with caution in patients with liver disease. When prescribing the drug to a patient with impaired liver function, the advisability of reducing the dose or increasing the interval between doses of the drug should be discussed.

Sertraline is excreted in the urine in insignificant amounts unchanged. In patients with mild to moderate renal failure (CrCl 30-60 ml/min) and patients with severe renal failure (CrCl ≤10-29 ml/min and less), the pharmacokinetic parameters (C_max and AUC_0-24) of sertraline during its multiple administration did not differ significantly from the control group. In all groups, T_1/2 of the drug was the same, and there were no differences in plasma protein binding. The results of this study indicate that, as expected given the insignificant renal excretion of sertraline, no dose adjustment depending on the severity of renal failure is required.

It is recommended to exercise caution when prescribing SSRIs in combination with drugs with a known ability to alter platelet function, as well as in patients with a history of hemorrhagic diseases.

Transient hyponatremia may occur during treatment with sertraline. This develops more often in elderly patients, as well as when taking diuretics or a number of other drugs. This side effect is associated with the syndrome of inappropriate antidiuretic hormone secretion. If symptomatic hyponatremia develops, Sertraline should be discontinued and adequate therapy aimed at correcting blood sodium concentration should be prescribed. Signs and symptoms of hyponatremia include headache, impaired concentration, memory impairment, weakness and unsteadiness, which can lead to falls. In more severe cases, hallucinations, fainting, seizures, coma, respiratory arrest and death may occur.

Risk of Suicide Attempts

Patients with depression are at risk for suicide attempts. This risk persists until remission develops. Therefore, from the start of treatment until the optimal clinical effect is achieved, patients should be under constant medical supervision.

In children, adolescents, and young adults under 24 years of age with depression and other psychiatric disorders, antidepressants, compared with placebo, increase the risk of suicidal thoughts and suicidal behavior. Therefore, when prescribing the drug Aleval or any other antidepressants to children, adolescents, and young adults under 24 years of age, the risk of suicide and the benefit of their use should be weighed. In short-term studies in people over 24 years of age, the risk of suicide was not increased, and in people over 65 years of age it was somewhat reduced. Any depressive disorder itself increases the risk of suicide. Therefore, during treatment with antidepressants, all patients should be monitored for early detection of behavioral disturbances or changes, as well as suicidal tendencies.

Effect on Ability to Drive and Operate Machinery

During treatment with the drug Aleval, patients are not recommended to drive vehicles, special equipment, or engage in activities associated with increased risk.

Overdose

Symptoms: severe symptoms of sertraline overdose have not been identified even when the drug was administered in high doses. However, with simultaneous administration with other drugs or ethanol, severe poisoning, up to coma and death, is possible. Overdose can cause serotonin syndrome with nausea, vomiting, drowsiness, tachycardia, agitation, dizziness, psychomotor agitation, diarrhea, increased sweating, myoclonus, and hyperreflexia.

Treatment: there are no specific antidotes. Intensive supportive therapy and constant monitoring of vital body functions are required. Inducing vomiting is not recommended. Administration of activated charcoal may be more effective than gastric lavage. Airway patency must be maintained. Sertraline has a large V_d, therefore, increased diuresis, dialysis, hemoperfusion, or blood transfusion may be ineffective.

Drug Interactions

When sertraline and pimozide were used concomitantly, an increase in pimozide concentration was observed with its single administration at a low dose (2 mg). The increase in pimozide concentration was not associated with any changes in the ECG. Since the mechanism of this interaction is unknown and pimozide has a narrow therapeutic index, the concomitant use of pimozide and sertraline is contraindicated.

Severe complications are observed with the simultaneous use of sertraline and MAO inhibitors (including the selective selegiline, the reversible-acting MAO inhibitor moclobemide, as well as linezolid). The development of serotonin syndrome is possible (hyperthermia, rigidity, myoclonus, lability of the autonomic nervous system (rapid fluctuations in respiratory and cardiovascular parameters), changes in mental status, including increased irritability, marked agitation, confusion, which in some cases may progress to delirium or coma). Similar complications, sometimes fatal, occur when MAOIs are prescribed during or immediately after treatment with antidepressants that inhibit neuronal monoamine reuptake.

Combined use of sertraline and drugs that have a depressant effect on the central nervous system requires careful monitoring. Alcohol consumption is prohibited during the treatment period. No potentiation of the effect of carbamazepine, haloperidol, or phenytoin, as well as ethanol, on cognitive and psychomotor function in healthy people was noted.

When indirect anticoagulants (warfarin) are co-administered with sertraline, a slight but statistically significant increase in prothrombin time is observed – in these cases, it is recommended to monitor prothrombin time at the beginning of sertraline treatment and after its discontinuation.

When switching from one serotonin neuronal reuptake inhibitor to another, a “washout period” is not necessary. However, caution is required when changing the course of treatment. Concomitant administration of tryptophan or fenfluramine with sertraline should be avoided.

Sertraline causes minimal induction of hepatic microsomal enzymes. Concomitant administration of sertraline and phenazone at a dose of 200 mg leads to a significant decrease in the T_1/2 of phenazone, although this occurs in only 5% of cases.

When co-administered, Sertraline does not alter the beta-adrenergic blocking effect of atenolol.

No drug interaction with glibenclamide and digoxin was detected when sertraline was administered at a daily dose of 200 mg.

Long-term use of Sertraline at a dose of 200 mg/day does not have a clinically significant effect and does not suppress the metabolism of phenytoin. Despite this, careful monitoring of plasma phenytoin concentration from the start of sertraline treatment with appropriate adjustment of the phenytoin dose is recommended.

Extremely rare cases of weakness, increased tendon reflexes, confusion, anxiety, and agitation have been reported in patients simultaneously taking Sertraline and sumatriptan. Monitoring of patients who have appropriate clinical grounds for simultaneous use of sertraline and sumatriptan is recommended.

Pharmacokinetic Interaction

Sertraline binds to plasma proteins. Therefore, the possibility of its interaction with other drugs that bind to plasma proteins (for example, diazepam and tolbutamide) must be taken into account.

When used concomitantly with cimetidine, concomitant use significantly reduces the clearance of sertraline.

Long-term treatment with sertraline at a dose of 50 mg/day increases the plasma concentration of concomitantly used drugs metabolized by the isoenzyme CYP2D6 (tricyclic antidepressants, class I C antiarrhythmic drugs – propafenone, flecainide).

In experimental in vitro interaction studies, it was shown that beta-hydroxylation of endogenous cortisol, which occurs with the participation of isoenzymes CYP3A3/4, as well as the metabolism of carbamazepine and terfenadine, do not change during long-term use of sertraline at a dose of 200 mg/day. Plasma concentrations of tolbutamide, phenytoin, and warfarin also do not change during long-term administration of sertraline at the same dose. Therefore, it is believed that Sertraline does not inhibit the CYP2C9 isoenzyme.

When taken concomitantly, Sertraline reduces the clearance of tolbutamide (blood glucose control is necessary).

Sertraline does not affect the serum concentration of diazepam, which indicates the absence of inhibition of the CYP2C19 isoenzyme. According to in vitro studies, Sertraline has virtually no or minimal inhibitory effect on the CYP1A2 isoenzyme.

The pharmacokinetics of lithium do not change with concomitant administration of sertraline. However, tremor is observed more frequently with their concomitant use. Particular caution is required when using sertraline (like other SSRIs) concomitantly with drugs affecting serotonergic transmission (e.g., lithium).

Storage Conditions

The drug should be stored out of the reach of children, in a dry place, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.