Symbia®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Symbia®

Composition:

Active substance: duloxetine;

1 capsule contains 33.7 mg or 67.3 mg of duloxetine hydrochloride, equivalent to 30 mg or 60 mg of duloxetine;

Excipients: sucrose spheres, hydroxypropylcellulose, hypromellose, hypromellose phthalate (HP-55), triethyl citrate, talc;

Capsule shell (for 30 mg dosage): titanium dioxide (E 171), indigo carmine (E 133), hypromellose (E 464), iron oxide black (E 172);

Capsule shell (for 60 mg dosage): titanium dioxide (E 171), hypromellose (E 464), iron oxide black (E 172).

Dosage form. Hard enteric-coated capsules.

Main physicochemical properties:

30 mg capsules: capsules with an opaque grey body and an opaque blue cap, marked «DLX 30»;

60 mg capsules: capsules with an opaque grey body and an opaque white cap, marked «DLX 60».

Pharmacotherapeutic group. Antidepressants. ATC code N06AX21.

Pharmacological Properties

Pharmacodynamics

Duloxetine is a combined inhibitor of serotonin and norepinephrine reuptake. It weakly inhibits dopamine reuptake and has negligible affinity for histaminergic and dopaminergic, cholinergic, and adrenergic receptors. The mechanism of action of duloxetine in the treatment of depression is attributed to the inhibition of serotonin and norepinephrine reuptake, thereby enhancing serotonergic and noradrenergic neurotransmission in the central nervous system. Duloxetine also exerts analgesic effects, which are likely due to the attenuation of pain signal transmission in the central nervous system.

Duloxetine dose-dependently increases extracellular levels of serotonin and norepinephrine in various regions of the brain in animals.

Duloxetine normalized pain thresholds in several preclinical models of neuropathic and inflammatory pain and reduced pain-related behaviors in a persistent pain model. The analgesic effect of duloxetine is believed to result from potentiation of descending inhibitory pain pathways in the central nervous system.

Clinical Efficacy and Safety

Major Depressive Disorder. Duloxetine was evaluated in a clinical program involving 3,158 patients (1,285 patient-years of exposure) meeting DSM-IV criteria for major depressive disorder. The efficacy of duloxetine at the recommended dose of 60 mg once daily was demonstrated in three out of three randomized, double-blind, placebo-controlled, fixed-dose trials in adult outpatients with major depressive disorder. Overall, efficacy was confirmed at daily doses of 60–120 mg in five out of seven randomized, double-blind, placebo-controlled, fixed-dose trials in adult outpatients with major depressive disorder.

Duloxetine demonstrated statistically significant superiority over placebo on the 17-item Hamilton Depression Rating Scale (HAM-D), which includes both emotional and somatic symptoms of depression. Response and remission rates were also statistically significantly higher with duloxetine compared to placebo. Only a small proportion of patients enrolled in the key clinical trials had severe depression (baseline HAM-D > 25).

In a relapse prevention study, patients who responded to 12 weeks of treatment with duloxetine 60 mg once daily were randomized to continue duloxetine 60 mg once daily or switch to placebo for the next 6 months. Duloxetine 60 mg once daily demonstrated statistically significant superiority over placebo (p = 0.004) on the primary outcome measure—prevention of depressive relapse, measured as time to relapse. Relapse rates during the 6-month double-blind observation period were 17% in the duloxetine group and 29% in the placebo group.

Over 52 weeks of a placebo-controlled, double-blind study, patients with recurrent major depressive disorder receiving duloxetine had a significantly longer time in remission (p < 0.001) compared to those randomized to placebo. All patients had previously responded to duloxetine during open-label treatment (28–34 weeks) at doses of 60–120 mg daily. During the 52-week placebo-controlled, double-blind treatment phase, 14.4% of patients receiving duloxetine and 33.1% of those receiving placebo experienced a return of depressive symptoms (p < 0.001).

The effect of duloxetine 60 mg once daily in elderly patients with depression (≥ 65 years) was specifically studied in a trial that demonstrated a statistically significant reduction in HAM-D17 scores in patients receiving duloxetine compared to placebo. Tolerability of duloxetine 60 mg once daily in elderly patients was comparable to that in younger adults. However, data on elderly patients receiving the maximum dose (120 mg daily) are limited, and caution is recommended when treating this population.

Generalized Anxiety Disorder. Duloxetine demonstrated statistically significant superiority over placebo in all five studies, including four randomized, double-blind, placebo-controlled trials of acute episodes and one relapse prevention study in adult patients with generalized anxiety disorder.

Duloxetine showed statistically significant superiority over placebo, as measured by improvement in the total Hamilton Anxiety Rating Scale (HAM-A) score and the Sheehan Disability Scale (SDS) total score. Response and remission rates were also higher with duloxetine compared to placebo. Duloxetine demonstrated improvement in HAM-A total scores comparable to that of venlafaxine.

In a relapse prevention study, patients who responded to 6 months of open-label duloxetine therapy were randomized to continue duloxetine or switch to placebo for an additional 6 months. Duloxetine at doses of 60–120 mg once daily demonstrated statistically significant superiority over placebo (p < 0.001) in preventing relapse, measured as time to relapse. Relapse rates during the 6-month double-blind observation period were 14% in the duloxetine group and 42% in the placebo group.

The efficacy of duloxetine 30–120 mg (flexible dosing) once daily in elderly patients (> 65 years) with generalized anxiety disorder was evaluated in a study that demonstrated statistically significant improvement in HAM-A total scores in patients receiving duloxetine compared to placebo. The efficacy and safety of duloxetine 30–120 mg once daily in elderly patients with generalized anxiety disorder were similar to those observed in studies involving younger adult patients. However, data on elderly patients receiving the maximum dose (120 mg daily) are limited, and caution is recommended when using this dose in elderly patients.

Diabetic Peripheral Neuropathic Pain. The efficacy of duloxetine in the treatment of diabetic neuropathic pain was established in two randomized, 12-week, double-blind, placebo-controlled, fixed-dose trials in adults (aged 22–88 years) with diabetic neuropathic pain lasting at least 6 months. Patients meeting diagnostic criteria for major depressive disorder were excluded from these trials. The primary outcome measure was the average 24-hour pain score, recorded by patients in a diary using an 11-point Likert scale.

In both trials, duloxetine 60 mg once daily and 60 mg twice daily significantly reduced pain compared to placebo. In some patients, the effect was evident within the first week of treatment. The difference in mean improvement between the two active treatment groups was minimal. At least a 30% reduction in pain was reported in approximately 65% of patients receiving duloxetine compared to 40% of those receiving placebo. Similar rates of at least a 50% reduction in pain were 50% and 26%, respectively. Clinical response rates (≥ 50% pain reduction) were analyzed based on whether patients experienced somnolence during treatment. Among patients who did not experience somnolence, clinical response occurred in 47% of those receiving duloxetine and 27% of those receiving placebo. Among patients who experienced somnolence, clinical response rates were 60% with duloxetine and 30% with placebo. Patients who did not achieve at least a 30% reduction in pain within 60 days of treatment were unlikely to reach this level with continued therapy.

In an open-label, long-term, uncontrolled trial, pain reduction was maintained over the subsequent 6 months in patients who responded to an 8-week open-label treatment with duloxetine 60 mg once daily, as assessed by the Brief Pain Inventory (BPI) 24-hour average pain score.

Pediatric Population. The use of duloxetine has not been studied in patients under 7 years of age. Two randomized, double-blind, parallel, placebo- and fluoxetine-controlled clinical trials were conducted in 800 pediatric patients aged 7–17 years with major depressive disorder. These trials included a 10-week acute phase followed by a 6-month active-controlled extension phase. Neither duloxetine (30–120 mg) nor fluoxetine (20–40 mg) differed statistically from placebo in change from baseline to endpoint in the Children's Depression Rating Scale-Revised (CDRS-R) total score. Discontinuation due to adverse events was higher in patients receiving duloxetine than in those receiving fluoxetine, primarily due to nausea. Suicidal behavior was reported during the 10-week treatment period (duloxetine 0/333 [0%], fluoxetine 2/225 [0.9%], placebo 1/220 [0.5%]). Over the entire 36-week study period, 6 of 333 patients initially randomized to duloxetine and 3 of 225 initially randomized to fluoxetine exhibited suicidal behavior (exposure-adjusted incidence rates were 0.039 and 0.026 events per patient-year, respectively). Additionally, one patient who switched from placebo to duloxetine exhibited suicidal behavior while on duloxetine.

A randomized, double-blind, placebo-controlled trial was conducted in 272 patients aged 7–17 years with generalized anxiety disorder. The study included a 10-week placebo-controlled acute phase followed by an 18-week continuation phase. Flexible dosing was used, allowing gradual dose increases from 30 mg once daily to higher doses (maximum 120 mg once daily). After 10 weeks of treatment, duloxetine provided statistically significant greater improvement in symptoms of generalized anxiety disorder (GAD), measured by the Pediatric Anxiety Rating Scale (PARS): mean difference between duloxetine and placebo was 2.7 points [95% CI (confidence interval) 1.3–4.0]. Maintenance of effect was not assessed. During the 10-week acute phase, there was no statistically significant difference in discontinuation due to adverse events between duloxetine and placebo groups. Two patients who switched from placebo to duloxetine after the acute phase exhibited suicidal behavior during the maintenance phase. A conclusion on overall benefit-risk in this age group was not established.

In one study conducted in pediatric patients with juvenile primary fibromyalgia syndrome (JPFS), no statistically significant difference in primary efficacy outcomes was observed between the duloxetine and placebo groups. Therefore, there is no evidence of efficacy in the pediatric population. A randomized, double-blind, placebo-controlled, parallel-group trial of duloxetine was conducted in 184 adolescents aged 13–18 years (mean age 15.53 years) with JPFS. The study included a 13-week double-blind period during which patients were randomized to receive daily duloxetine 30 mg/60 mg or placebo. Duloxetine did not demonstrate efficacy in reducing pain, as measured by the primary endpoint—the mean change in the Brief Pain Inventory (BPI) pain score: at 13 weeks, the mean reduction in pain score (least squares, LS) was –0.97 in the placebo group compared to –1.62 in the duloxetine 30/60 mg group (p = 0.052). Safety findings from this study were consistent with the known safety profile of duloxetine.

Pharmacokinetics

Duloxetine is extensively metabolized by oxidative enzymes (CYP1A2 and polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of duloxetine are characterized by substantial inter-individual variability (typically 50–60%), partly due to sex, age, smoking, and CYP2D6 enzyme activity.

Absorption. After oral administration, duloxetine is well absorbed. Maximum concentration is reached 6 hours after dosing. Food intake delays absorption, increasing the time to maximum concentration from 6 to 10 hours, and reduces absorption (by approximately 11%).

Distribution. Duloxetine is highly bound to plasma proteins (approximately 96%), both to albumin and α1-acid glycoprotein. Hepatic or renal impairment does not affect protein binding.

Biological Transformation. Duloxetine is extensively metabolized, and metabolites are primarily excreted in urine. Both cytochrome P450-2D6 and 1A2 catalyze the formation of two major metabolites: the glucuronide conjugate of 4-hydroxyduloxetine and the sulfate conjugate of 5-hydroxy-6-methoxyduloxetine. In vitro studies indicate that circulating metabolites of duloxetine are pharmacologically inactive. The pharmacokinetics of duloxetine in patients with reduced CYP2D6 activity have not been specifically studied. Some data suggest that plasma levels of duloxetine are higher in these patients.

Elimination. The elimination half-life of duloxetine ranges from 8 to 17 hours (mean 12 hours). After intravenous administration, plasma clearance of duloxetine ranges from 22 to 46 L/h (mean 36 L/h). After oral administration, apparent plasma clearance ranges from 33 to 261 L/h (mean 101 L/h).

Special Populations

Sex. Pharmacokinetic differences between men and women have been observed: plasma clearance is approximately 50% lower in women. However, due to the overlap in clearance ranges, sex-based pharmacokinetic differences do not require dose adjustment in women.

Age. Pharmacokinetic differences have been observed between younger and older women (≥ 65 years): AUC is approximately 25% higher and elimination half-life approximately 25% longer in elderly women. However, the magnitude of these differences is not sufficient to justify dose adjustment. In accordance with general recommendations, caution should be exercised when treating elderly patients.

Renal Impairment. In patients with end-stage renal disease on dialysis, duloxetine concentrations and the area under the plasma concentration-time curve (AUC) were doubled compared to healthy volunteers. Therefore, a lower initial dose is recommended for patients with chronic renal impairment. Pharmacokinetic data on duloxetine in patients with mild or moderate renal impairment are limited.

Hepatic Impairment. Moderate hepatic impairment (Child-Pugh class B) affects the pharmacokinetics of duloxetine. In patients with moderate hepatic dysfunction, apparent plasma clearance of duloxetine was reduced by 79%, elimination half-life was prolonged by 2.3-fold, and AUC increased by 3.7-fold compared to healthy volunteers. The pharmacokinetics of duloxetine and its metabolites have not been studied in patients with mild or severe hepatic impairment.

Lactating Women. The effect of duloxetine was studied in 6 women during lactation for at least 12 weeks postpartum. Duloxetine passes into breast milk, where steady-state concentrations are approximately one-quarter of those in plasma. The amount of duloxetine in breast milk is approximately 7 µg/day at a dose of 40 mg twice daily. Lactation does not affect the pharmacokinetics of duloxetine.

Pediatric Population. The pharmacokinetics of duloxetine in pediatric patients aged 7–17 years with major depressive disorder after oral administration of 20–120 mg once daily were characterized using population modeling analysis based on data from three studies. Plasma concentrations of duloxetine in pediatric patients were predominantly within the range observed in adult patients.

Clinical Characteristics

Indications

Treatment of major depressive disorder.

Treatment of diabetic peripheral neuropathic pain.

Treatment of generalized anxiety disorder.

Contraindications

Contraindications for the use of the medicinal product include hypersensitivity to duloxetine or to any of the excipients of the medicinal product.

Duloxetine must not be administered together with non-selective, irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days after discontinuation of MAOI therapy. Due to the half-life of duloxetine, MAOIs must not be initiated within at least 5 days after discontinuation of duloxetine treatment.

Duloxetine must not be prescribed to patients with unstable hypertension, as it may provoke hypertensive crisis.

The medicinal product must not be administered to patients with end-stage renal failure (creatinine clearance <30 mL/min).

Duloxetine should not be prescribed to patients with hepatic disease, as it may lead to liver failure.

Duloxetine is not recommended for use in children due to insufficient data on safety and efficacy in this age group.

Duloxetine should not be administered in combination with fluvoxamine, ciprofloxacin, or enoxacin (strong CYP1A2 inhibitors) due to increased plasma concentrations of duloxetine.

Interaction with other medicinal products and other forms of interaction

Medicinal products metabolized by CYP1A2. In a clinical study, concomitant administration of theophylline, a CYP1A2 substrate, with duloxetine (60 mg twice daily) did not cause significant changes in the pharmacokinetics of either drug.

Inhibitors of CYP1A2. Since CYP1A2 is involved in the metabolism of duloxetine, co-administration of duloxetine with strong CYP1A2 inhibitors is likely to increase duloxetine concentrations. Fluvoxamine (100 mg once daily), a potent CYP1A2 inhibitor, reduces the plasma clearance of duloxetine by approximately 77% and increases AUC0–t by 6-fold. Therefore, Symbia® must not be co-administered with CYP1A2 inhibitors, particularly fluvoxamine.

Medicinal products metabolized by CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered at a dose of 60 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased threefold. Concomitant administration of duloxetine (40 mg twice daily) increased the steady-state AUC of tolterodine (2 mg twice daily) by 71%, but did not affect the pharmacokinetics of the 5-hydroxy metabolite; therefore, dose adjustment is not required. Caution is recommended when using Symbia® together with medicinal products primarily metabolized by CYP2D6 (risperidone, tricyclic antidepressants such as nortriptyline, amitriptyline, and imipramine), especially those with a narrow therapeutic index (e.g., flecainide, propafenone, and metoprolol).

Medicinal products acting on the central nervous system. Caution is required when prescribing duloxetine in combination with other medicinal products and substances acting on the central nervous system, particularly those with similar mechanisms of action, including alcohol and sedative medicinal products (e.g., benzodiazepines, morphine-like agents, antipsychotics, phenobarbital, sedative antihistamines).

MAO inhibitors. Duloxetine must not be administered together with non-selective, irreversible MAO inhibitors due to the risk of serotonin syndrome. The use of reversible selective MAO inhibitors, such as moclobemide, carries a lower risk of serotonin syndrome, but such combination is not recommended. The antibiotic linezolid is a reversible non-selective MAO inhibitor and therefore must not be administered to patients receiving duloxetine (see section "Special precautions for use").

Serotonin syndrome. Symbia® should be prescribed with caution in combination with serotonergic agents and tricyclic antidepressants such as clomipramine or amitriptyline, as well as with moclobemide or linezolid, preparations of St. John's wort (Hypericum perforatum), or triptans, tramadol, meperidine, and tryptophan.

Oral contraceptives and other steroid agents. In vitro studies indicate that duloxetine does not induce the catalytic activity of CYP3A. Specific in vivo interaction studies have not been conducted.

Anticoagulants and antithrombotic agents. Duloxetine should be used with caution in combination with oral anticoagulants and antithrombotic agents due to an increased risk of bleeding resulting from pharmacodynamic interaction. Additionally, an increase in the international normalized ratio (INR) has been reported when duloxetine was administered to patients receiving warfarin. However, in a clinical pharmacology study in healthy volunteers, concomitant administration of duloxetine and warfarin under controlled conditions did not result in clinically significant changes in INR from baseline or in the pharmacokinetics of R- or S-warfarin.

Medicinal products containing duloxetine. Concomitant use with other medicinal products containing duloxetine should be avoided.

Medicinal products containing St. John's wort. Adverse reactions frequently occur with concomitant use.

Antacids and H2 antagonists. Concomitant administration of duloxetine with antacids containing aluminum and magnesium or with famotidine did not affect the rate or extent of absorption of duloxetine following a 40 mg oral dose.

Inducers of CYP1A2. Population pharmacokinetic analysis has shown that smokers have plasma concentrations of duloxetine nearly 50% lower than non-smokers.

Special precautions for use

Seizures and mania. As with other medicinal products acting on the central nervous system, duloxetine should be prescribed with caution to patients with a history of seizures, mania, or bipolar disorder.

Mydriasis. Cases of mydriasis have been reported in association with duloxetine use; therefore, duloxetine should be administered with caution to patients with elevated intraocular pressure or at risk of acute angle-closure glaucoma.

Blood pressure and heart rate. In some patients, duloxetine may cause increased blood pressure and clinically significant arterial hypertension. This may be related to the noradrenergic effect of duloxetine. Patients with arterial hypertension and/or other cardiac diseases should be monitored for blood pressure, especially during the first month of treatment. Cases of hypertensive crisis associated with duloxetine have been reported, most frequently in patients with pre-existing hypertension. The medicinal product Symbia® should be used with caution in patients for whom an increase in pulse rate or blood pressure may be hazardous. Caution is also advised when administering duloxetine concomitantly with medicinal products that may impair its metabolism (see section "Interaction with other medicinal products and other forms of interaction"). For patients who experience persistent increases in blood pressure during treatment with Symbia®, consideration should be given to dose reduction or gradual discontinuation of the drug (see section "Adverse reactions"). Symbia® should not be used in patients with uncontrolled arterial hypertension (see section "Contraindications").

Renal impairment. Elevated plasma concentrations of duloxetine have been observed in patients with severe renal impairment undergoing hemodialysis (creatinine clearance <30 mL/min). For patients with severe renal impairment, see section "Contraindications". For patients with mild or moderate renal dysfunction, refer to section "Dosage and administration".

Serotonin syndrome / Neuroleptic malignant syndrome. As with other serotonergic agents, serotonin syndrome may be life-threatening during treatment with duloxetine, particularly when used concomitantly with other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants, or triptans), agents affecting serotonin metabolism such as MAO inhibitors, antipsychotics, or other dopamine antagonists that may affect serotonergic neurotransmitter systems (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

In its most severe form, serotonin syndrome may resemble neuroleptic malignant syndrome, which is characterized by hyperthermia, muscle rigidity, elevated serum creatine kinase, autonomic instability with possible rapid fluctuations in vital signs, and mental status changes.

If concomitant treatment with duloxetine and other serotonergic/neuroleptic agents affecting serotonergic and/or dopaminergic neurotransmitter systems is clinically justified, careful monitoring of the patient is recommended, particularly during initiation of therapy and dose escalation.

If serotonin syndrome is suspected, consideration should be given to reducing the dose or discontinuing treatment, depending on the severity of symptoms.

Bleeding. Abnormal bleeding, such as ecchymosis, purpura, gastrointestinal hemorrhage, and hemorrhage, has been reported during treatment with SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), including duloxetine. The medicinal product should be prescribed with caution to patients receiving anticoagulants and agents affecting platelet function (e.g., nonsteroidal anti-inflammatory drugs or acetylsalicylic acid), as well as to patients with a predisposition to bleeding. Duloxetine increases the risk of postpartum hemorrhage (see section "Use during pregnancy or breastfeeding").

Hyponatremia. Cases of hyponatremia, including cases with serum sodium levels below 110 mmol/L, have been reported during duloxetine treatment. Hyponatremia may be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Most cases of hyponatremia occurred in elderly patients, particularly in combination with conditions leading to fluid imbalance. The drug should be prescribed with caution to patients at increased risk of developing hyponatremia (e.g., elderly patients), patients with liver cirrhosis, dehydrated patients, and patients receiving diuretics.

Products containing St. John’s wort. Adverse reactions may be more frequent when Symbia® is used concomitantly with products containing St. John’s wort (Hypericum perforatum).

Discontinuation syndrome. Discontinuation symptoms occur frequently, particularly after abrupt cessation of treatment. In clinical trials, adverse events following abrupt discontinuation occurred in approximately 45% of patients taking duloxetine and in 23% of patients taking placebo.

The risk of discontinuation symptoms with SSRIs and SNRIs depends on several factors, including duration of therapy, dose, and rate of dose reduction. The most common reactions are listed in section "Adverse reactions". These symptoms are usually mild or moderate, but in some patients they may be severe. They typically occur within the first few days after discontinuation of treatment. Very rarely, such symptoms have been observed in patients who accidentally missed a dose. Discontinuation symptoms usually resolve spontaneously within 2 weeks, although in some individuals they may persist for longer (2–3 months or more). Therefore, it is recommended to gradually reduce the dose of duloxetine when discontinuing treatment over a period of at least 2 weeks, according to individual patient needs (see section "Dosage and administration").

Akathisia / psychomotor restlessness. Akathisia (characterized by subjective distress or anxiety and an urge to move, often accompanied by inability to sit or stand still) may occur within the first few weeks of treatment. For patients who develop these symptoms, dose escalation may be harmful.

Elevated liver enzymes. Cases of hepatic dysfunction, including marked elevation of liver enzymes (more than 10 times the upper limit of normal), hepatitis, and jaundice, have been reported during duloxetine treatment (see section "Adverse reactions"). These events were most frequently reported during the first months of treatment. Liver injury is usually of hepatocellular type. Duloxetine should be prescribed with caution to patients taking medicinal products that may cause liver injury.

Sexual dysfunction. SSRIs/SNRIs may cause symptoms of sexual dysfunction (see section "Adverse reactions"). Long-lasting sexual dysfunction has been reported, with symptoms persisting despite discontinuation of SSRIs/SNRIs.

Suicidality

Major depressive disorder and generalized anxiety disorder. Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). Risk persists until significant remission occurs. Patients should be closely monitored until significant improvement is achieved, as remission may not occur during the first few weeks of treatment or longer. Clinical experience indicates that the risk of suicide may increase during the early stages of treatment.

Other psychiatric conditions for which Symbia® is prescribed are also associated with an increased risk of suicide-related events. In addition, these psychiatric conditions may be comorbid with major depressive disorder. Therefore, precautions should be taken when treating patients with major depressive disorder as well as other psychiatric conditions. Patients with a history of suicide-related events or significant suicidal ideation are at higher risk of suicidal behavior and require closer monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in psychiatric disorders showed an increased risk of suicidal behavior with antidepressants compared to placebo in patients under 25 years of age.

Cases of suicidal ideation and suicidal behavior have been reported during or immediately after discontinuation of duloxetine therapy. Patients should be closely monitored throughout therapy, especially in the early stages and particularly those at risk, and appropriate dose adjustments should be made. Patients and caregivers should be informed of the need to monitor for any clinical worsening, suicidal thoughts or behavior, unusual changes in behavior, and to seek immediate medical attention if these occur.

Diabetic peripheral neuropathic pain. Isolated cases of suicidal ideation and suicidal behavior have been reported during or immediately after duloxetine therapy, as with other medicinal products with similar pharmacological action (antidepressants). Physicians should inform patients of the need to report any feelings of distress.

Elderly patients. Data on the use of Symbia® at a dose of 120 mg in elderly patients with major depressive disorder and generalized anxiety disorder are limited. Therefore, caution should be exercised when using the maximum dose in elderly patients (see sections "Dosage and administration", "Pharmacological properties").

Serious skin reactions. In post-marketing surveillance, very rare cases of the following skin reactions have been reported: angioneurotic edema, ecchymosis, hemorrhage, Stevens-Johnson syndrome, bruising, urticaria.

Medicinal products containing duloxetine. Duloxetine is marketed under various brand names for several indications (diabetic neuropathic pain, major depressive disorder, generalized anxiety disorder, and stress urinary incontinence). The simultaneous use of multiple such medicinal products should be avoided.

Presence of sucrose. Symbia® enteric-coated capsules should not be administered to patients with hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding

Fertility

In animal studies, duloxetine did not affect male fertility, while effects in female animals were observed only at doses causing maternal toxicity.