Simoda

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIMODA

Composition:

Active substance: duloxetine;

One gastro-resistant hard capsule contains duloxetine hydrochloride equivalent to duloxetine 30 mg or 60 mg;

Excipients: sugar spheres, hydroxypropylcellulose, hypromellose, hypromellose phthalate, triethyl citrate, talc.

Dosage form. Gastro-resistant hard capsules.

Main physicochemical properties:

30 mg: capsules with grey opaque body and blue opaque cap; imprint: «DLX 30» on the body and cap of the capsule;

60 mg: capsules with grey opaque body and white opaque cap; imprint: «DLX 60» on the body and cap of the capsule.

Pharmacotherapeutic group. Agents acting on the nervous system. Psycholeptics. Antidepressants. ATC code N06AX21.

Pharmacological Properties

Pharmacodynamics

Duloxetine is a combined inhibitor of serotonin and norepinephrine reuptake. It weakly inhibits dopamine reuptake and has no significant affinity for histaminergic, dopaminergic, cholinergic, or adrenergic receptors. Duloxetine also exerts analgesic effects, which are likely due to the slowing of pain impulse transmission in the central nervous system. Duloxetine dose-dependently increases extracellular levels of serotonin and norepinephrine in various regions of the animal brain.

Duloxetine normalized pain thresholds in several preclinical models of neuropathic and inflammatory pain and reduced pain-related behavior in a model of persistent pain. The inhibitory effect of duloxetine on pain 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 studied in a clinical program where the efficacy of duloxetine at the recommended dose of 60 mg once daily was demonstrated in three out of three fixed-dose studies in adult outpatients with major depressive disorder. Overall, efficacy of duloxetine was demonstrated at daily doses ranging from 60 to 120 mg.

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 included in the key clinical trials had severe depression (baseline HAM-D > 25).

In a study on prevention of depressive relapse, relapse rates were observed over a 6-month double-blind period. Duloxetine at a dose of 60 mg once daily demonstrated statistically significant superiority over placebo (p=0.004) for the primary outcome—prevention of depressive relapse—measured as time to relapse. The relapse rate during the 6-month double-blind observation period was lower for duloxetine than for placebo.

During a long-term study, patients with bipolar disorder who received duloxetine had a significantly longer period of symptom-free treatment compared to patients in the placebo group. All patients had previously responded to duloxetine during open-label treatment at doses ranging from 60 mg to 120 mg daily.

The effect of duloxetine 60 mg once daily in elderly patients with depression (≥65 years) was specifically studied in a trial that showed a statistically significant difference in reduction of 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 individuals. However, data on elderly patients receiving the maximum dose (120 mg daily) are limited, and caution is therefore recommended when treating this patient population.

Generalized Anxiety Disorder: Duloxetine demonstrated statistically significant superiority over placebo in five out of five studies, including four acute episode studies and one relapse prevention study in adult patients with generalized anxiety disorder.

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

In a relapse prevention study, patients who responded to a 6-month open-label duloxetine treatment were randomized to either continue duloxetine or switch to placebo for another 6 months. Duloxetine at doses from 60 mg to 120 mg once daily demonstrated statistically significant superiority over placebo in preventing relapse, measured as time to relapse. The relapse rate with duloxetine was lower than in the placebo group.

Efficacy of duloxetine 30–120 mg once daily in elderly patients (>65 years) with generalized anxiety disorder was evaluated in a study that demonstrated statistically significant improvement in total HAM-A score in patients receiving duloxetine compared to those receiving placebo. Efficacy and safety of duloxetine at doses of 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, so caution is recommended when using this dose in elderly patients.

Diabetic Peripheral Neuropathic Pain: The efficacy of duloxetine for the treatment of diabetic neuropathic pain was established in two fixed-dose studies involving adults who had suffered from diabetic neuropathic pain for at least 6 months. Patients meeting diagnostic criteria for major depressive disorder were excluded from these studies. In both studies, duloxetine at doses of 60 mg once daily and 60 mg twice daily significantly reduced pain compared to placebo. In some patients, the effect was noticeable within the first week of treatment.

Children

Duloxetine has not been studied in patients under 7 years of age.

Two randomized, double-blind, placebo-controlled clinical trials involving 800 children aged 7 to 17 years with major depressive disorder were conducted. These two studies included placebo, fluoxetine, and duloxetine arms. Neither duloxetine (30–120 mg) nor the active control group (fluoxetine 20–40 mg) differed statistically from placebo in change from baseline to endpoint in total score on the Children's Depression Rating Scale-Revised (CDRS-R). Discontinuation due to adverse events was higher in patients receiving duloxetine compared to those receiving fluoxetine, primarily due to nausea.

Suicidal behavior was reported during the acute treatment phase, and suicidal behavior was reported in both the duloxetine and fluoxetine groups throughout the study course. Additionally, one patient who switched from placebo to duloxetine exhibited suicidal behavior while taking duloxetine.

A study was conducted in patients aged 7–17 years with generalized anxiety disorder using a flexible dosing regimen to allow gradual dose escalation from 30 mg once daily to higher doses (maximum 120 mg once daily). Duloxetine treatment demonstrated statistically significant greater improvement in GAD symptoms. Maintenance of effect was not evaluated. There was no statistically significant difference in discontinuation due to adverse events between groups. Suicidal ideation was observed in two patients who switched from placebo to duloxetine after the acute phase, during the continuation phase while taking duloxetine. A conclusion on the overall benefit-risk ratio in this age group has not been established.

One study was conducted in pediatric patients with juvenile primary fibromyalgia syndrome (JPFS), in which the duloxetine group did not differ from the placebo group. Thus, there is no evidence of efficacy in this pediatric population. A parallel study with duloxetine was conducted in adolescents aged 13 to 18 years with JPFS. The study included randomization of patients to duloxetine 30 mg/60 mg or placebo daily.

Duloxetine did not demonstrate efficacy in reducing pain, as measured by the primary outcome of the Brief Pain Inventory (BPI). Safety results from this study were consistent with the known safety profile of duloxetine.

The European Medicines Agency has waived the obligation to submit study results for duloxetine in all pediatric subpopulations for the treatment of major depressive disorder, diabetic neuropathic pain, and generalized anxiety disorder. See section "Dosage and Administration" for information on pediatric use.

Pharmacokinetics

Duloxetine is administered as an enantiomer. Duloxetine is extensively metabolized by oxidative enzymes (CYP1A2 and polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of duloxetine show high inter-individual variability (typically 50–60%), partly due to sex, age, smoking status, and CYP2D6 metabolizer status.

Absorption. After oral administration, duloxetine is well absorbed. Maximum concentration (Cmax) is reached within 6 hours after dose administration. Absolute bioavailability after oral administration ranges from 32% to 80% (on average, 50%). Food intake delays absorption, increasing the time to reach Cmax from 6 to 10 hours, while absorption is reduced by approximately 11%. These changes have no clinical significance.

Distribution. Duloxetine is highly bound to human plasma proteins (approximately 96%), both to albumin and alpha-1-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. Based on in vitro studies, circulating metabolites of duloxetine are considered pharmacologically inactive. The pharmacokinetics of duloxetine in poor CYP2D6 metabolizers 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 (on average, 12 hours). After intravenous administration, plasma clearance of duloxetine ranges from 22 L/h to 46 L/h (on average, 36 L/h). After oral administration, apparent plasma clearance of duloxetine ranges from 33 to 261 L/h (on average, 101 L/h).

Special Populations

Sex. Pharmacokinetic differences were observed between men and women: plasma clearance is approximately 50% lower in women. However, due to the overlap in clearance ranges, sex-based pharmacokinetic differences do not justify recommending a lower dose for female patients.

Age. Pharmacokinetic differences were observed between young women and elderly women (≥65 years): AUC increases by approximately 25%, and elimination half-life is approximately 25% longer in elderly women, although the magnitude of these changes is insufficient to justify dose adjustment. According to general recommendations, caution should be exercised when treating elderly patients.

Renal Impairment. In patients with end-stage renal disease on regular dialysis, a doubling of duloxetine concentration and exposure (AUC) was observed compared to healthy volunteers. Pharmacokinetic data on duloxetine are limited in patients with mild or moderate renal impairment.

Hepatic Impairment. Moderate liver disease (Child-Pugh class B) affects the pharmacokinetics of duloxetine. Compared to healthy volunteers, apparent plasma clearance of duloxetine was 79% lower, elimination half-life was 2.3 times longer, and AUC was 3.7 times higher in patients with moderate liver disease. The pharmacokinetics of duloxetine and its metabolites have not been studied in patients with mild or severe hepatic impairment.

Lactation. The effect of duloxetine was studied in women during lactation for at least 12 weeks postpartum. Duloxetine is excreted in breast milk, and steady-state concentrations in breast milk are approximately one-quarter of those in plasma. The amount of duloxetine in breast milk is approximately 7 mcg/day at a dosage of 40 mg twice daily. Lactation does not affect the pharmacokinetics of duloxetine.

Children. The pharmacokinetics of duloxetine in pediatric patients aged 7 to 17 years with major depressive disorder after single daily oral doses of 20 to 120 mg were characterized using population modeling analysis based on data from three studies. Model-predicted steady-state plasma concentrations of duloxetine in children 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.

The medicinal product Simoda is intended for adults.

For additional information, see section "Pharmacological properties".

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Concomitant use of duloxetine with non-selective, irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Simoda should not be used in combination with fluvoxamine, ciprofloxacin, or enoxacin (strong CYP1A2 inhibitors), as such combination leads to increased plasma concentrations of duloxetine.

Severe renal impairment (creatinine clearance < 30 mL/min) (see section "Special precautions for use").

Initiation of duloxetine treatment is contraindicated in patients with uncontrolled hypertension, due to the potential risk of hypertensive crisis.

Interaction with other medicinal products and other forms of interaction.

MAO inhibitors. Due to the risk of serotonin syndrome, duloxetine must not be administered concomitantly with non-selective, irreversible MAO inhibitors or within at least 14 days after discontinuation of MAOI therapy. Because of the half-life of duloxetine, MAO inhibitors must not be initiated within at least 5 days after discontinuation of duloxetine treatment. Concomitant use of Simoda with selective, reversible MAO inhibitors such as moclobemide is not recommended. The antibiotic linezolid is a reversible non-selective MAO inhibitor and must not be administered to patients receiving Simoda (see section "Special precautions for use").

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

Medicinal products acting on the CNS. The risk of using duloxetine in combination with other centrally acting medicinal products has not been systematically evaluated, except for cases mentioned in this section. Therefore, caution should be exercised when administering duloxetine concomitantly with other medicinal products or substances affecting the central nervous system, including alcohol and sedative medicinal products (e.g., benzodiazepines, morphine-like agents, antipsychotics, phenobarbital, and sedative antihistamines).

Serotonergic agents. Serotonin syndrome has been rarely reported in patients treated with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) concomitantly with serotonergic agents. Simoda should be used with caution in combination with serotonergic agents such as SSRIs, SNRIs, tricyclic antidepressants (e.g., clomipramine or amitriptyline), moclobemide, linezolid, St. John's wort (Hypericum perforatum), triptans, tramadol, meperidine, and tryptophan.

Effect of duloxetine on other medicinal products

Medicinal products metabolized by CYP1A2. In a clinical study evaluating the concomitant administration of theophylline, a CYP1A2 substrate, with duloxetine (60 mg twice daily), no significant mutual effect on pharmacokinetics was observed.

Medicinal products metabolized by CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine 60 mg twice daily was co-administered with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased by three-fold. 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 its 5-hydroxy metabolite, and no dose adjustments are recommended. Caution is advised when using Simoda concomitantly with medicinal products primarily metabolized by CYP2D6 (e.g., risperidone, tricyclic antidepressants such as nortriptyline, amitriptyline, and imipramine), especially those with a narrow therapeutic index (e.g., flecainide, propafenone, and metoprolol).

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 antiplatelet agents. Duloxetine should be used with caution when administered concomitantly with oral anticoagulants and antiplatelet agents due to the potential increased risk of bleeding resulting from pharmacodynamic interaction. Additionally, increases in INR values have been reported in patients receiving warfarin when duloxetine was introduced. However, in a clinical pharmacology study in healthy volunteers under steady-state conditions, concomitant administration of duloxetine and warfarin did not result in clinically significant changes in INR from baseline or in the pharmacokinetics of R- or S-warfarin.

Effect of other medicinal products on duloxetine

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 a 40 mg oral dose of duloxetine.

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

Special precautions for use.

Mania and epileptic seizures. Duloxetine should be used with caution in patients with a history of mania or diagnosed bipolar disorder and/or epileptic seizures.

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

Arterial pressure and heart rate. Duloxetine is associated with increased arterial pressure and clinically significant arterial hypertension in some patients. This may be related to the noradrenergic effect of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, particularly in patients with pre-existing hypertension. Therefore, monitoring of blood pressure is recommended in patients with known arterial hypertension and/or other cardiac diseases, especially during the first month of treatment. Simoda should be used with caution in patients whose condition may be compromised by an increase in pulse rate or elevated blood pressure. Caution is also advised when using 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, consideration should be given to dose reduction or gradual discontinuation of the drug (see section "Undesirable effects"). Simoda should not be used in patients with uncontrolled arterial hypertension (see section "Contraindications").

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

Serotonin syndrome / neuroleptic malignant syndrome. As with other serotonergic agents, serotonin syndrome or neuroleptic malignant syndrome may occur during treatment with duloxetine and can potentially be life-threatening, especially when used concomitantly with other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants, or triptans), agents that impair serotonin metabolism such as MAO inhibitors, or with 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, characterized by hyperthermia, muscle rigidity, elevated serum creatine kinase levels, autonomic instability with possible rapid fluctuations in vital signs, and altered mental status.

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

Herbal products containing St. John’s wort

Adverse reactions may be more common when Simoda is used concomitantly with herbal products containing St. John’s wort (Hypericum perforatum).

Suicidality

Major depressive disorder and generalized anxiety disorder

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicidality-related phenomena). Risk persists until significant remission occurs.

Patients should be closely monitored until significant improvement is achieved, as remission may not occur within 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 Simoda is prescribed may also be associated with an increased risk of suicidal phenomena. Additionally, these psychiatric conditions may be comorbid with major depressive disorder. Therefore, similar precautions should be taken when treating patients with major depressive disorder and other psychiatric conditions. Patients with a history of suicidal behavior 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 antidepressant drugs 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 thoughts and suicidal behavior have been reported during or immediately after discontinuation of duloxetine therapy. Close monitoring of patients, especially those at risk, is necessary during therapy, particularly in the early stages, and appropriate dose adjustments should be made. Patients and caregivers should be informed of the need to monitor for any clinical worsening, emergence of suicidal thoughts or behaviors, or unusual changes in behavior, and to seek immediate medical help if these symptoms occur.

Diabetic peripheral neuropathic pain

Isolated cases of suicidal thoughts and suicidal behavior have been reported during or immediately after discontinuation of duloxetine therapy, as with other drugs having similar pharmacological effects (antidepressants). For risk factors related to suicidality in depression, see above. Physicians should inform patients of the need to report any feelings of distress.

Use in children and adolescents under 18 years of age. Simoda should not be used for the treatment of children and adolescents under 18 years of age. Suicidality-related behaviors (suicide attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behavior, and anger) were more frequently observed in clinical trials among children and adolescents receiving antidepressants compared to those receiving placebo. If treatment is clinically indicated, careful monitoring for the emergence of suicidal symptoms is required. Furthermore, long-term safety data on growth, maturation, and cognitive and behavioral development in children and adolescents are lacking (see section "Undesirable effects").

Bleeding. Bleeding events such as bruising, purpura, and gastrointestinal bleeding have been reported with SSRIs and SNRIs, including duloxetine. Duloxetine may increase the risk of postpartum hemorrhage (see section "Use during pregnancy or breastfeeding"). Caution is advised in patients taking anticoagulants and/or drugs that may affect platelet function (e.g., NSAIDs or acetylsalicylic acid) and in patients with known bleeding tendencies.

Hyponatremia. Cases of hyponatremia, including serum sodium levels below 110 mmol/L, have been reported with duloxetine use. 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. Caution is advised when prescribing the drug to patients at increased risk of hyponatremia (e.g., elderly patients), patients with hepatic cirrhosis, dehydrated patients, and patients receiving diuretics.

Discontinuation of treatment. Withdrawal symptoms commonly occur after discontinuation of treatment (especially abrupt discontinuation) (see section "Undesirable effects"). 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 withdrawal symptoms observed with SSRIs and SNRIs may depend on several factors, including duration of treatment, dose, and speed of dose reduction. The most commonly reported adverse reactions are listed in section "Undesirable effects". These symptoms are usually mild to moderate in severity but may be severe in some patients. Withdrawal symptoms typically occur within the first few days after stopping treatment, although isolated reports describe symptoms in patients who inadvertently missed a dose. Generally, these symptoms resolve spontaneously within two weeks, although in some patients they may persist longer (2–3 months or more). Therefore, when discontinuing treatment, the dose of duloxetine should be gradually reduced over at least two weeks, depending on individual patient needs (see section "Dosage and administration").

Elderly patients. Data on the use of duloxetine 120 mg in elderly patients with major depressive disorder and generalized anxiety disorder are limited. Therefore, caution is advised when using the drug at the maximum dose in elderly patients (see sections "Dosage and administration" and "Pharmacological properties").

Akathisia/psychomotor restlessness. Duloxetine use has been associated with akathisia, characterized by a subjectively unpleasant or anxious urge to move, often accompanied by an inability to sit or stand still. This phenomenon is more likely to occur during the first few weeks of treatment. Increasing the dose in patients who develop these symptoms may be harmful.

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.

Hepatitis/elevated liver enzymes. Cases of liver injury, including marked elevation of liver enzymes (>10 times the upper limit of normal), hepatitis, and jaundice, have been reported with duloxetine use (see section "Undesirable effects"). Most cases occurred within the first few months of treatment. Liver injury is most commonly hepatocellular in nature. Caution is advised when prescribing duloxetine to patients taking drugs that may cause liver injury.

Sexual dysfunction

SSRIs/SNRIs may cause symptoms of sexual dysfunction (see section "Undesirable effects"). Persistent sexual dysfunction has been reported, with symptoms continuing despite discontinuation of SSRIs/SNRIs.

Sucrose

The product contains sucrose (in the form of sugar spheres) as an excipient; therefore, patients with hereditary fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency should not take this medicine.

Use during pregnancy or breastfeeding.

Fertility

In animal studies, duloxetine did not affect male fertility, while effects in females occurred only at doses causing maternal toxicity.

Pregnancy

Animal studies have shown reproductive toxicity at duloxetine AUC levels below the maximum clinical exposure (see section "Pharmacological properties").

According to data from two large observational studies, an increased overall risk of major congenital malformations is not expected (one study conducted in the USA included 2500 individuals who used duloxetine during the first trimester, and another conducted in the EU included 1500 individuals who used duloxetine during the first trimester). Analysis of specific malformations, such as cardiac defects, did not show conclusive results.

In the EU study, exposure to duloxetine in late pregnancy (at any time from week 20 of gestation until delivery) was associated with an increased risk of preterm birth (less than two-fold increase, corresponding to approximately 6 additional preterm births per 100 women using duloxetine in late pregnancy). Most occurred between weeks 35 and 36 of gestation. This association was not observed in the US study.

US observational data indicate an increased risk (less than two-fold) of postpartum hemorrhage following duloxetine exposure within one month before delivery.

Epidemiological data suggest that the use of SSRIs during pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although the association between PPHN and SNRI use has not been studied, this potential risk cannot be excluded with duloxetine use, considering its mechanism of action (inhibition of serotonin reuptake).

As with other serotonergic medicinal products, withdrawal symptoms may occur in newborns whose mothers took duloxetine before delivery. Symptoms of duloxetine withdrawal may include hypotonia, tremor, irritability, feeding difficulties, respiratory distress syndrome, and seizures. Most cases occurred either at birth or within several days after birth. Simoda should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. Women should inform their physicians if they become pregnant or plan to become pregnant during therapy.

Lactation

Duloxetine passes into breast milk to a very low extent, as confirmed in six lactating women. The estimated daily infant dose (mg/kg) is approximately 0.14% of the maternal dose. The safety of duloxetine in infants is unknown; therefore, the use of Simoda during breastfeeding is not recommended.

Ability to affect reaction speed when driving vehicles or operating machinery.

Studies on the effect of duloxetine on reaction speed when driving vehicles or operating machinery have not been conducted. The use of Simoda is associated with sedation and dizziness. Patients should refrain from potentially hazardous activities such as driving vehicles or operating machinery if they experience sedation or dizziness.

Method of Administration and Dosage

Dosage

Major Depressive Disorder

The initial and recommended maintenance dose is 60 mg once daily. The drug should be taken regardless of food intake. Doses exceeding 60 mg once daily, up to a maximum dose of 120 mg daily divided into two doses, have been evaluated for safety in clinical trials. However, there are no clinical data demonstrating that patients who do not respond to the initial recommended dose benefit from higher titrated doses.

Therapeutic response is usually observed after 2–4 weeks of treatment.

After a sustained antidepressant effect is achieved, treatment should be continued for several months to prevent relapse. In patients who have responded well to duloxetine treatment and who experience recurrent episodes of depressive disorders, further long-term treatment may be continued at doses ranging from 60 to 120 mg daily.

Generalized Anxiety Disorder

The recommended initial dose for patients with generalized anxiety disorder is 30 mg once daily. The drug should be taken regardless of food intake. For patients with an inadequate response, the dose may be increased to 60 mg. In patients with comorbid major depressive disorder, the initial and maintenance doses are 60 mg once daily (see also dosage recommendations above). Doses up to 120 mg daily have been shown to be effective and have been evaluated for safety in clinical studies. For patients with inadequate response to the 60 mg dose, doses up to 90 mg or 120 mg daily may be considered. Dose escalation should be based on clinical response and tolerability.

After an adequate response to the drug is achieved, treatment should be continued for several months to prevent relapse.

Diabetic Peripheral Neuropathic Pain

The initial and recommended maintenance dose is 60 mg daily. The drug should be taken regardless of food intake. Doses exceeding 60 mg once daily (up to a maximum dose of 120 mg daily) should be evenly divided into multiple doses. Plasma concentrations of duloxetine exhibit high individual variability. Higher doses may be effective in patients who do not respond adequately to the 60 mg dose.

Treatment response should be evaluated after 2 months. Additional benefit after this period is unlikely in patients with an inadequate initial response.

The therapeutic effect should be reviewed regularly (no less than once every 3 months).

Special Patient Groups

Elderly Patients

Dose adjustment based solely on age is not required for elderly patients. However, as with any medicinal product, caution should be exercised in elderly patients, particularly when prescribing Simoda capsules at a dose of 120 mg daily for major depressive disorder, for which data are limited (see sections “Special Warnings and Precautions for Use” and “Pharmacological Properties”).

Hepatic Impairment

Simoda capsules are contraindicated in patients with liver disease or hepatic impairment.

Renal Impairment

Dosage adjustment is not required in patients with mild or moderate renal dysfunction (creatinine clearance from 30 to 80 mL/min). Simoda should not be administered to patients with severe renal impairment (creatinine clearance <30 mL/min).

Children

Duloxetine should not be used in children and adolescents under 18 years of age for the treatment of major depressive disorder due to lack of sufficient safety and efficacy data (see sections “Adverse Reactions” and “Pharmacological Properties”).

The safety and efficacy of duloxetine for the treatment of generalized anxiety disorder in children aged 7–17 years have not been established. Current available data are presented in the sections “Adverse Reactions” and “Pharmacological Properties”.

Discontinuation of Treatment

Abrupt discontinuation of treatment should be avoided. The dose should be gradually reduced over a period of at least one to two weeks to minimize the risk of withdrawal reactions (see sections “Special Warnings and Precautions for Use” and “Adverse Reactions”). If discontinuation symptoms occur following dose reduction or cessation of treatment, the drug may be reintroduced at previously prescribed doses. Subsequently, the physician may continue dose reduction, but more gradually.

Method of Administration

For oral use.

Children

Simoda is not indicated for use in children and adolescents (under 18 years of age).

Overdose

Symptoms. Cases of overdose with duloxetine administered at doses of up to 5400 mg, either as monotherapy or in combination with other medicinal products, have been reported. Fatal outcomes have been recorded, primarily in cases of mixed overdose, as well as with duloxetine administered at doses of approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or in combination with other medicinal products) include somnolence, coma, serotonin syndrome, seizures, vomiting, and tachycardia.

Treatment of Overdose. No specific antidotes are known. In the event of serotonin syndrome, specific treatment is required (cyproheptadine and/or temperature control). Airway patency should be ensured. Cardiac monitoring and monitoring of vital signs, along with appropriate symptomatic and supportive measures, are recommended. Gastric lavage may be appropriate if performed immediately after drug ingestion or for symptomatic therapy. Activated charcoal reduces drug absorption. Due to the large volume of distribution of duloxetine in the body, forced diuresis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.

Adverse Reactions

Short description of safety profile

The most commonly reported adverse reactions in patients receiving duloxetine were nausea, headache, dry mouth, somnolence, and dizziness. However, most common adverse reactions were mild to moderate in severity, usually occurred at the beginning of treatment, and tended to resolve over time, even with continued therapy.

General list of adverse reactions

The adverse reactions listed below were reported in spontaneous reports and during placebo-controlled clinical trials.

Frequency assessment: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Within each frequency group, adverse effects are listed in order of decreasing severity.

Infections and infestations: uncommon – laryngitis.

Immune system disorders: rare – anaphylactic reaction, hypersensitivity.

Endocrine disorders: rare – hypothyroidism.

Metabolism and nutrition disorders: common – decreased appetite; uncommon – hyperglycemia (particularly in patients with diabetes mellitus); rare – dehydration, hyponatremia, ADH deficiency\6.

Psychiatric disorders: common – insomnia, restlessness, decreased libido, anxiety, anorgasmia, unusual dreams; uncommon – suicidal ideation\5,7, sleep disorders, bruxism, disorientation, apathy; rare – suicidal behavior\5,7, mania, hallucinations, aggression and anger\4.

Nervous system disorders: very common – headache, somnolence; common – dizziness, lethargy, tremor, paresthesia; uncommon – myoclonus, akathisia\7, nervousness, attention disturbance, dysgeusia, dyskinesia, restless legs syndrome, poor sleep; rare – serotonin syndrome\6, convulsions\1, psychomotor agitation\6, extrapyramidal disorders\6.

Eye disorders: common – blurred vision; uncommon – mydriasis, visual disturbances; rare – glaucoma.

Ear and labyrinth disorders: common – tinnitus\1; uncommon – vertigo, ear pain.

Cardiac disorders: common – palpitations; uncommon – tachycardia, supraventricular arrhythmia, primarily atrial fibrillation; frequency not known – stress cardiomyopathy (Takotsubo cardiomyopathy).

Vascular disorders: common – increased blood pressure\3, hot flushes; uncommon – loss of consciousness\2, arterial hypertension\3,7, orthostatic hypotension\2, feeling of cold in extremities; rare – hypertensive crisis\3,6.

Respiratory, thoracic and mediastinal disorders: common – yawning; uncommon – laryngospasm, epistaxis; rare – interstitial lung disease\10, eosinophilic pneumonia\6.

Gastrointestinal disorders: very common – nausea, dry mouth; common – constipation, diarrhea, abdominal pain, vomiting, dyspepsia, flatulence; uncommon – gastrointestinal hemorrhage\7, gastroenteritis, eructation, gastritis, dysphagia; rare – stomatitis, blood in stool, bad breath, microscopic colitis\9.

Hepatobiliary disorders: uncommon – hepatitis\3, increased liver enzymes (ALT, AST, alkaline phosphatase), acute liver injury; rare – liver failure\6, jaundice\6.

Skin and subcutaneous tissue disorders: common – increased sweating, rash; uncommon – night sweats, urticaria, contact dermatitis, cold sweat, photosensitivity reactions, increased tendency to bruise; rare – Stevens-Johnson syndrome\6, angioedema\6; very rare – cutaneous vasculitis.

Musculoskeletal and connective tissue disorders: common – musculoskeletal pain, muscle spasm; uncommon – muscle stiffness, muscle twitching; rare – trismus.

Renal and urinary disorders: common – dysuria, urinary frequency; uncommon – urinary retention, difficulty in initiating urination, nocturia, polyuria, decreased urine flow; rare – abnormal urine odor.

Reproductive system and breast disorders: common – erectile dysfunction, ejaculation disorder, delayed ejaculation; uncommon – gynecological bleeding, menstrual disorders, sexual dysfunction, testicular pain; rare – menopausal symptoms, galactorrhea, hyperprolactinemia, postpartum hemorrhage\6.

General disorders and administration site conditions: common – fall\8, fatigue; uncommon – chest pain\7, malaise, feeling cold, thirst, chills, weakness, feeling of warmth, gait disturbance.

Additional findings in laboratory tests: common – weight decrease; uncommon – weight increase, increased blood creatine phosphokinase, increased blood potassium; rare – increased plasma cholesterol.

1 Cases of convulsions and tinnitus were also observed after discontinuation of treatment.

2 Cases of orthostatic hypotension and loss of consciousness were predominantly observed at the beginning of treatment.

3 See section "Special precautions for use".

4 Reports of aggression and anger were mainly during initiation of treatment and after discontinuation.

5 Cases of suicidal thoughts and behavior have been reported during treatment with duloxetine or immediately after discontinuation (see section "Special precautions for use").

6 Frequency of adverse reactions established from post-marketing surveillance; not observed in placebo-controlled clinical trials.

7 Statistically not significantly different from placebo.

8 Falls were more frequent in elderly patients (≥65 years).

9 Calculated frequency based on all clinical trial data.

10 Frequency estimation based on placebo-controlled clinical trials.

Discontinuation of duloxetine therapy (especially abrupt) is frequently accompanied by withdrawal syndrome. The most common adverse reactions in such cases include: sensory disturbances (including paresthesia or electric shock sensations, particularly in the head), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhea, hyperhidrosis, and dizziness.

Typically, for MDD and GAD, these events are mild to moderate and self-limiting, but in some patients they may be severe and/or prolonged. Therefore, gradual discontinuation by dose tapering is recommended when duloxetine treatment is no longer required (see sections "Special precautions for use" and "Dosage and administration").

In acute phase studies of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose levels were observed in patients receiving duloxetine. HbA1c levels remained stable in both duloxetine and placebo groups. A slight increase in fasting blood glucose and total cholesterol was also observed in patients receiving duloxetine, while in these laboratory tests a slight decrease in risk categories was observed.

The heart rate-corrected QT interval in patients taking duloxetine did not differ from those taking placebo. No clinically significant differences in QT, PR, QRS, or QTcB measurements were observed between patients receiving duloxetine and placebo.

Children

Overall, 509 children with major depressive disorder and 241 children with generalized anxiety disorder, aged 7 to 17 years, received duloxetine treatment in clinical trials. The adverse reaction profile of duloxetine in children and adolescents was generally similar to that observed in adults.

Overall, in 467 pediatric patients receiving duloxetine in clinical trials, there was an average weight decrease of 0.1 kg compared to an average increase of 0.9 kg in patients receiving placebo.

Subsequently, during extension periods of four to six months, patients tended to return toward their expected baseline weight percentile based on population data for age- and sex-matched peers.

In studies lasting up to 9 months, an overall average 1% reduction in growth was observed with duloxetine treatment (see section "Special precautions for use").

Shelf life. 24 months.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

7 gastro-resistant hard capsules in a blister made of polyvinyl chloride film and aluminum foil. 1 blister or 4 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

BALKANPHARMA-DUPNITSA AD / BALKANPHARMA-DUPNITSA AD.

Manufacturer's address and location of its operations.

3 Samokovsko Shosse Str., Dupnitsa 2600, Bulgaria / 3 Samokovsko Shosse Str., Dupnitsa 2600, Bulgaria.

Marketing Authorization Holder.

UAB “Farmlyga” / UAB “Farmlyga”.

Address of the Marketing Authorization Holder.

Antakalnio g. 48A-304, Vilnius, Republic of Lithuania / Antakalnio g. 48A-304, Vilnius, Republic of Lithuania.