Duloxin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DULOXIN® (DULOXIN)

Composition:

Active substance: duloxetine hydrochloride;

Each capsule contains 33.7 mg of duloxetine hydrochloride, equivalent to 30 mg of duloxetine, or 67.4 mg of duloxetine hydrochloride, equivalent to 60 mg of duloxetine;

Excipients: sucrose spheres, hydroxypropylmethylcellulose, polyethylene glycol 6000, talc, sucrose, hydroxypropylmethylcellulose acetate succinate, triethyl citrate;

hard gelatin capsule size № 3 (for 30 mg capsules);

Capsule shell composition: titanium dioxide (E 171), indigo carmine (E 132), gelatin;

hard gelatin capsule size № 1 (for 60 mg capsules);

Capsule shell composition: titanium dioxide (E 171), indigo carmine (E 132), quinoline yellow (E 104), erythrosine (E 127), gelatin.

Pharmaceutical form. Hard enteric-coated capsules.

Main physicochemical properties:

30 mg: hard gelatin capsule size № 3, blue cap, white body. The capsule contents – white or almost white pellets;

60 mg: hard gelatin capsule size № 1, blue cap, ivory body. The capsule contents – white or almost white pellets.

Pharmacotherapeutic group.
Other antidepressants. ATC code N06AX21.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Duloxetine is a combined inhibitor of serotonin (5-HT) and norepinephrine (NA) reuptake. It weakly inhibits dopamine reuptake and has negligible affinity for histaminergic, dopaminergic, cholinergic, and adrenergic receptors. In a dose-dependent manner, duloxetine increases extracellular levels of serotonin and norepinephrine in various regions of the animal brain.

Pharmacodynamic effects

Duloxetine normalizes pain threshold. The inhibitory effect of duloxetine is believed to result from potentiation of descending pain inhibition pathways in the central nervous system.

Clinical efficacy and safety

Major depressive disorder (MDD): The efficacy of duloxetine was demonstrated in studies evaluating fixed doses of the drug in adult patients with major depressive disorder. Duloxetine showed statistically significant superiority over placebo. Response and remission rates were also statistically significantly higher with duloxetine compared to placebo.

In a study evaluating the efficacy of duloxetine in preventing relapses, the drug demonstrated statistically significant advantage compared to placebo. Patients with recurrent MDD receiving duloxetine had a significantly longer symptom-free period compared to those receiving placebo.

Studies on the efficacy of duloxetine in elderly patients (≥65 years) with depression showed statistically significant differences compared to placebo.

Generalized anxiety disorder (GAD): In clinical trials, duloxetine demonstrated statistically significant superiority over placebo when used in the acute phase and for relapse prevention in adult patients with GAD.

Response and remission rates were also higher with duloxetine compared to placebo.

In a relapse prevention study in elderly patients (≥65 years) with GAD, the efficacy of duloxetine compared to placebo was demonstrated. The efficacy and safety of duloxetine in elderly patients were similar to those observed in younger adult patients.

Diabetic peripheral neuropathic pain. The efficacy of duloxetine was established in studies evaluating treatment of diabetic neuropathic pain.

Duloxetine significantly reduced pain compared to placebo. The effect was evident in some patients within the first week of treatment.

In these same studies, the occurrence of somnolence during treatment was also analyzed. Among patients who did not experience somnolence, clinical response was more frequently observed with duloxetine than with placebo.

Children

The use of duloxetine in patients under 7 years of age has not been studied. A study involving children aged 7 to 17 years with MDD showed that treatment outcomes with duloxetine and in the control group did not differ statistically from placebo.

Discontinuation due to adverse effects was higher in patients receiving duloxetine compared to those receiving fluoxetine, primarily due to nausea. Suicidal behavior was also reported with duloxetine use.

Treatment with duloxetine demonstrated statistically greater improvement in patients with GAD.

Duloxetine did not demonstrate efficacy in reducing pain as measured by the primary endpoint of average pain score on the Brief Pain Inventory (BPI).

Pharmacokinetics.

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

Absorption. After oral administration, duloxetine is well absorbed, with peak plasma concentration reached approximately 6 hours after dosing. Absolute oral bioavailability of duloxetine ranges from 32% to 80% (mean value 50%). Food intake delays absorption, increasing the time to Cmax from 6 to 10 hours, and reduces absorption by approximately 11%. These changes are not clinically significant.

Distribution. Approximately 96% of duloxetine is protein-bound in human plasma. Duloxetine binds to both albumin and alpha-1 acid glycoprotein. Renal or hepatic impairment does not affect plasma protein binding.

Metabolism. Duloxetine is extensively metabolized, with metabolites 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. According to in vitro studies, circulating metabolites of duloxetine are considered pharmacologically inactive. The pharmacokinetics of duloxetine in patients who are poor metabolizers via CYP2D6 have not been specifically studied. Limited data suggest higher plasma duloxetine levels in these patients.

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

Special patient groups

Sex. Pharmacokinetic differences were observed between men and women (apparent plasma clearance approximately 50% lower in women). However, due to overlap in clearance ranges, sex-related pharmacokinetic differences do not justify using a lower dose in female patients.

Age. Pharmacokinetic differences were observed between younger women and elderly women (≥65 years) (AUC increased by approximately 25%, and elimination half-life approximately 25% longer in elderly women), although the magnitude of these changes is insufficient to justify dose adjustment. As a general recommendation, caution should be exercised when treating elderly patients (see sections "Dosage and administration" and "Special precautions").

Renal impairment. In patients with end-stage renal disease on regular dialysis, a twofold increase in duloxetine concentration and area under the pharmacokinetic concentration-time curve (AUC) was observed compared to healthy volunteers. Pharmacokinetic data on duloxetine use in patients with mild or moderate renal impairment are limited.

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

Lactating women. Distribution of duloxetine was studied in women who were at least 12 weeks postpartum and breastfeeding. Duloxetine is excreted into breast milk, with steady-state concentration in breast milk approximately one-quarter of that in plasma. The amount of duloxetine in breast milk is approximately 7 mcg/day when 40 mg twice daily is administered. 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 oral doses of 20 to 120 mg once daily 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 disorders.

Treatment of diabetic peripheral neuropathic pain.

Treatment of generalized anxiety disorders.

The medicinal product DULOXETINE® is intended for adult patients.

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 types of interactions").

Hepatic diseases that may lead to hepatic failure.

Duloxetine should not be used in combination with fluvoxamine, ciprofloxacin, or enoxacin (strong CYP1A2 inhibitors), as such combinations lead to increased plasma concentrations of duloxetine (see section "Interaction with other medicinal products and other types of interactions").

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

Initiation of duloxetine treatment is contraindicated in patients with uncontrolled arterial hypertension, as this may lead to a potential risk of hypertensive crisis (see sections "Interaction with other medicinal products and other types of interactions" and "Adverse reactions").

Interaction with other medicinal products and other types of interactions.

Monoamine oxidase inhibitors (MAOIs). Due to the risk of serotonin syndrome, duloxetine should not be used in combination with non-selective, irreversible MAOIs or within 14 days after discontinuation of such agents. Considering the half-life of duloxetine, MAOIs should not be initiated earlier than 5 days after discontinuation of duloxetine (see section "Contraindications").

Combination of duloxetine with selective reversible MAOIs, such as moclobemide, is not recommended (see section "Special precautions for use"). Linezolid, a reversible non-selective MAOI, should not be administered to patients receiving duloxetine (see section "Special precautions for use").

Inhibitors of CYP1A2. Since CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with strong CYP1A2 inhibitors is likely to increase duloxetine concentrations. Fluvoxamine (100 mg once daily), a strong CYP1A2 inhibitor, reduces plasma clearance of duloxetine by approximately 77% and increases AUC 0-t by 6-fold. Therefore, duloxetine should not be co-administered with strong CYP1A2 inhibitors such as fluvoxamine (see section "Special precautions for use").

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

Serotonergic medicinal products. In rare cases, serotonin syndrome has been reported in patients receiving selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) together with serotonergic agents. Caution is recommended when duloxetine is used concomitantly with serotonergic agents such as SSRIs, SNRIs, tricyclic antidepressants (e.g., clomipramine or amitriptyline), MAOIs (e.g., moclobemide or linezolid), St. John's wort (Hypericum perforatum), triptans, tramadol, meperidine, and tryptophan (see section "Special precautions for use").

Effect of duloxetine on other medicinal products

Drugs metabolized by CYP1A2. The pharmacokinetics of theophylline, a CYP1A2 substrate, is not significantly affected by co-administration with duloxetine (60 mg twice daily).

Drugs 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 threefold.

Concomitant administration of duloxetine (40 mg twice daily) increases the steady-state AUC of tolterodine (2 mg twice daily) by 71%, but does not affect the pharmacokinetics of its active 5-hydroxy metabolite and does not require dose adjustment.

Duloxetine should be used with caution when co-administered 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 drug interaction studies have not been conducted.

Anticoagulants and antithrombotic agents. Duloxetine should be prescribed with caution together with oral anticoagulants and antithrombotic agents due to the potential increased risk of bleeding resulting from pharmacodynamic interaction. Additionally, increases in international normalized ratio (INR) have been reported when patients received warfarin concomitantly with duloxetine. However, co-administration of duloxetine and warfarin in a clinical pharmacology study in healthy volunteers did not result in clinically significant changes in INR compared to baseline or in the pharmacokinetics of R- or S-warfarin.

Effect of other drugs on duloxetine

Antacids and H2 antagonists. Co-administration of duloxetine with antacids containing aluminum and magnesium or with famotidine does not affect the rate or extent of absorption of duloxetine after a 40 mg oral dose.

Inducer of CYP1A2. Population pharmacokinetic analysis showed that smokers have plasma concentrations of duloxetine 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 used cautiously in patients with elevated intraocular pressure or at risk of acute angle-closure glaucoma.

Arterial pressure and palpitations

In some patients, duloxetine use has been associated with increased blood pressure and clinically significant arterial hypertension. This may be related to the noradrenergic effect of duloxetine. Cases of hypertensive crisis have been reported during duloxetine treatment, particularly in patients with pre-existing hypertension. Patients with known arterial hypertension and/or other cardiovascular disorders should have their blood pressure monitored, especially during the first month of treatment. Duloxetine should be used with caution in patients whose underlying medical conditions may be compromised by increased heart rate or blood pressure. Caution is required when prescribing 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 duloxetine treatment, consideration should be given to dose reduction or gradual discontinuation of the drug (see section "Undesirable effects"). Treatment with duloxetine should not be initiated in patients with unstable 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 impairment, see section "Posology and method of administration".

Serotonin syndrome / neuroleptic malignant syndrome

As with other serotonergic agents, serotonin syndrome or neuroleptic malignant syndrome (NMS), a potentially life-threatening condition, may occur during treatment with duloxetine, particularly when used concomitantly with other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants, or triptans), agents that impair serotonin metabolism such as monoamine oxidase inhibitors (MAOIs), or with antipsychotic medicinal products 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 changes in mental status (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, lack of coordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). In its most severe form, serotonin syndrome may resemble NMS, which includes 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/neuroleptic medicinal products affecting serotonergic and/or dopaminergic neurotransmitter systems is clinically justified, careful monitoring of patients is recommended, particularly at the beginning of treatment and during dose escalation.

St. John’s wort (Hypericum perforatum)

Adverse reactions may occur more frequently when duloxetine is used concomitantly with herbal medicinal 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 and suicide (suicidal behaviour). The risk persists until significant remission occurs. Since improvement may not occur during the first few weeks of treatment or longer, patients should be closely monitored until improvement occurs. Clinical experience indicates that the risk of suicide may increase during the early stages of recovery.

Other psychiatric disorders for which duloxetine is indicated may also be associated with an increased risk of suicidal behaviour. Additionally, these conditions may coexist with major depressive disorder. Therefore, precautions recommended for patients with major depressive disorder should also be applied to patients with other psychiatric disorders.

Patients with a history of suicidal behaviour or those exhibiting pronounced suicidal ideation prior to initiation of treatment are at increased risk of suicidal thoughts or suicidal behaviour during treatment and should be closely monitored. A meta-analysis of placebo-controlled clinical trials of antidepressants in psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients under 25 years of age.

Cases of suicidal ideation and behaviour have been reported during treatment with duloxetine or immediately after discontinuation of treatment (see section "Undesirable effects").

Close monitoring of patients, especially those at high risk, should accompany pharmacological treatment, particularly in the early stages of treatment and after dosage changes. Patients and caregivers should be informed of the need to monitor for any clinical worsening, emergence of suicidal thoughts or behaviour, or unusual changes in behaviour, and to seek immediate medical attention if such symptoms occur.

Diabetic peripheral neuropathic pain.

Isolated cases of suicidal ideation and suicidal behaviour have been reported during or immediately after discontinuation of duloxetine therapy, as with other medicinal products with similar pharmacological action (antidepressants). For risk factors related to suicidality in depression, see the section above. Physicians should encourage patients to report any distressing thoughts or feelings at any time.

Use in children and adolescents under 18 years of age

Duloxetine should not be used for the treatment of children under 18 years of age. Suicidal behaviour (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour, and anger) were more frequently observed in clinical trials involving children and adolescents receiving antidepressants compared to those receiving placebo.

Haemorrhage

Disorders of haemostasis such as ecchymosis, purpura, and gastrointestinal bleeding have been reported with the use of SSRIs and SNRIs, including duloxetine. Duloxetine may increase the risk of postpartum haemorrhage (see subsection "Use during pregnancy or breastfeeding"). Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function (e.g., non-steroidal anti-inflammatory drugs or acetylsalicylic acid) and in patients with known haemorrhagic diathesis.

Hyponatraemia

Hyponatraemia has been reported in patients treated with duloxetine, including cases with serum sodium levels below 110 mmol/L. Hyponatraemia may be associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Most cases of hyponatraemia occurred in elderly patients, particularly in association with recent history or conditions causing fluid imbalance. Caution is advised in patients at increased risk of hyponatraemia (elderly patients, patients with cirrhosis or dehydration, and patients taking diuretics).

Discontinuation of treatment

Withdrawal symptoms frequently occur after discontinuation of treatment (especially abrupt discontinuation) (see section "Undesirable effects"). In clinical trials, adverse events observed upon 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 rate 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 discontinuation of treatment, although isolated reports have described such symptoms in patients who inadvertently missed a dose. Generally, these symptoms resolve spontaneously within two weeks, although in some patients they may persist longer (up to 2–3 months). Therefore, when discontinuing treatment, the dose of duloxetine should be gradually reduced over at least two weeks, depending on individual patient needs (see section "Posology and method of administration").

Elderly patients

Data on the use of 120 mg duloxetine in elderly patients with major depressive disorder and generalized anxiety disorder are limited. Therefore, caution should be exercised when treating elderly patients with the maximum dose (see sections "Pharmacokinetics" and "Posology and method of administration").

Akathisia/psychomotor agitation

Duloxetine use has been associated with the development of akathisia, characterized by a subjectively unpleasant or anxiety-inducing restlessness and a need to move frequently, accompanied by an inability to sit or stand still. This phenomenon is more likely to occur during the first few weeks of treatment. In patients who develop these symptoms, increasing the dose of the drug may be harmful.

Medicinal products containing duloxetine

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

Hepatitis/elevated liver enzymes

Cases of liver injury, including marked elevations in liver enzyme levels (>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 of hepatocellular type. Caution is required when prescribing duloxetine to patients taking medicinal products that may cause liver injury.

Sexual dysfunction

Selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section "Undesirable effects"). Reports of persistent sexual dysfunction, in which symptoms persisted despite discontinuation of SSRI/SNRI therapy, have been received.

Sucrose

If a patient has been diagnosed with intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.

Use during pregnancy or breastfeeding

Pregnancy

Animal studies have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum clinical exposure level.

Studies investigating the effect of duloxetine on the fetus during the first trimester of pregnancy have not provided conclusive evidence of an increased risk of serious specific congenital malformations, including cardiac defects.

It is known that the use of duloxetine in late pregnancy (at any time from 20 weeks of gestation until delivery) has been associated with an increased risk of preterm birth.

Observational data indicate an increased risk (less than two-fold) of postpartum haemorrhage when duloxetine is used within one month prior to 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 no studies have specifically investigated the association between PPHN and SSRI treatment, this potential risk cannot be excluded for duloxetine, considering its similar mechanism of action (inhibition of serotonin reuptake).

As with other serotonergic medicinal products, neonates may experience withdrawal syndrome symptoms if the mother used duloxetine prior to delivery. Withdrawal symptoms associated with duloxetine use include hypotonia, tremor, increased irritability, difficulty feeding, respiratory depression, and seizures. In most cases, these symptoms were observed immediately after birth or within the first few days of life.

Duloxetine should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. Women should inform their physician if they become pregnant or plan to become pregnant while taking duloxetine.

Breastfeeding

Data from a study in six non-nursing lactating women indicate that duloxetine is very weakly excreted into human breast milk. The calculated infant dose is 0.14% of the maternal dose per mg/kg body weight (see section "Pharmacokinetics"). The safety of duloxetine in infants is unknown; therefore, breastfeeding is not recommended during treatment with duloxetine.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

Studies on the effect on the ability to drive or operate machinery have not been conducted. Duloxetine may be associated with sedation and dizziness. Therefore, patients experiencing sedation or dizziness should avoid potentially hazardous activities such as driving or operating machinery.

Method of Administration and Dosage

Method of Administration

Duloxetine is intended for oral use.

Dosage

Major Depressive Disorder

The initial and recommended maintenance dose is 60 mg once daily, regardless of food intake. Doses exceeding 60 mg once daily, up to a maximum dose of 120 mg per day, have been evaluated for safety in clinical trials. However, there are no clinical data indicating that patients who do not respond to the initial recommended dose may benefit from dose escalation.

Therapeutic effect is usually observed within 2–4 weeks of treatment.

After consolidation of the antidepressant response, treatment should be continued for several months to prevent relapse. In patients who respond to duloxetine and have a history of previous recurrent major depressive episodes, long-term continuation therapy at a dose of 60–120 mg daily may be considered.

Doses up to 120 mg daily have demonstrated efficacy and have been evaluated for safety in clinical trials. Therefore, in patients with an inadequate response to a 60 mg dose, dose escalation to 90 or 120 mg may be considered. Dose increases should be based on clinical response and tolerability.

After response consolidation, treatment should be continued for several months to prevent relapse.

Generalized Anxiety Disorder

The recommended initial dose for patients with generalized anxiety disorder is 30 mg once daily, regardless of food intake. In patients with an inadequate response, the dose should be increased to 60 mg, which is the usual maintenance dose for most patients.

In patients with comorbid major depressive disorder, both the initial and maintenance dose is 60 mg once daily (see dosage recommendations above).

Doses up to 120 mg daily have been shown to be effective and have been evaluated for safety in clinical trials. Therefore, in patients with an inadequate response to a 60 mg dose, dose escalation to 90 or 120 mg may be considered. Dose increases should be based on clinical response and tolerability.

After response consolidation, treatment should be continued for several months to prevent relapse.

Diabetic Peripheral Neuropathic Pain

The initial and recommended maintenance dose is 60 mg once daily, regardless of food intake. Administration of the drug at doses exceeding 60 mg once daily, up to a maximum dose of 120 mg daily administered in evenly divided doses, has been evaluated for safety in clinical trials. Plasma concentrations of duloxetine show high individual variability (see section "Pharmacokinetics"). Therefore, some patients with an inadequate response to 60 mg doses may benefit from higher doses.

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

Therapeutic benefit should be re-evaluated periodically (at least every 3 months) (see section "Pharmacodynamics").

Special Populations

Elderly Patients

Dose adjustment is not recommended solely on the basis of age in elderly patients. However, caution should be exercised when treating elderly patients, particularly when using duloxetine at a dose of 120 mg daily for major depressive disorder or GAD, as data are limited in these populations (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Hepatic Impairment

Duloxetine should not be used in patients with liver disease that may lead to hepatic failure (see sections "Pharmacokinetics" and "Contraindications").

Renal Impairment

No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance of 30–80 mL/min). Duloxetine should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min; see section "Contraindications").

Discontinuation of Treatment

Abrupt discontinuation of treatment should be avoided. When stopping duloxetine therapy, the dose should be gradually reduced over at least 1–2 weeks to minimize the risk of withdrawal symptoms (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions"). If intolerable symptoms occur following dose reduction or discontinuation, the previously prescribed dose may be reinstated. The physician may then continue tapering the dose, but more gradually.

Pediatric Population

The medicinal product should not be administered to children and adolescents under 18 years of age.

Overdose.

Cases of duloxetine overdose, alone or in combination with other medicinal products, with doses up to 5400 mg have been reported. Fatal outcomes have been reported following duloxetine overdose, primarily in combination with other drugs, but also with duloxetine alone at doses of approximately 1000 mg. Signs and symptoms of overdose (alone or in combination with other drugs) included somnolence, coma, serotonin syndrome, seizures, vomiting, and tachycardia.

There are no specific antidotes for duloxetine. In cases of serotonin syndrome, specific treatment is required (cyproheptadine and/or temperature control). Airway patency must be ensured. Continuous cardiac monitoring and vital sign surveillance should be performed, along with appropriate symptomatic and supportive measures. Gastric lavage may be considered immediately after drug ingestion or in patients exhibiting symptoms. Activated charcoal may be useful in limiting absorption. Duloxetine has a large volume of distribution, making forced diuresis, hemoperfusion, and exchange transfusion 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 of mild or moderate severity, usually occurred at the beginning of treatment, and most tended to diminish over time, even with continued therapy.

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 (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Within each frequency group, adverse effects are listed in decreasing order of 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 – hyperglycaemia (particularly in patients with diabetes mellitus); rare – dehydration, hyponatraemia, 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 behaviour^5,7, mania, hallucinations, aggression and anger^4.

Nervous system disorders: very common – headache, somnolence; common – dizziness, lethargy, tremor, paraesthesia; 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, predominantly 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, diarrhoea, abdominal pain, vomiting, dyspepsia, flatulence; uncommon – gastrointestinal haemorrhage^7, gastroenteritis, belching, 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 bruising; rare – Stevens-Johnson syndrome^6, angioneurotic oedema^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 initiating micturition, nocturia, polyuria, decreased urine stream; rare – abnormal urine odour.

Reproductive system and breast disorders: common – erectile dysfunction, ejaculation disorder, delayed ejaculation; uncommon – gynaecological bleeding, menstrual disorders, sexual dysfunction, testicular pain; rare – menopausal symptoms, galactorrhoea, hyperprolactinaemia, postpartum haemorrhage^6.

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

Investigations: common – weight decreased; uncommon – weight increased, 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 mainly observed at the beginning of treatment.

^3 See section "Special precautions".

^4 Reports of aggression and anger were mainly observed at the beginning of treatment and after discontinuation of treatment.

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

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

^7 Statistically not significantly different from placebo.

^8 Cases of falls were more frequent in elderly patients (≥65 years).

^9 Estimated frequency based on all clinical trial data.

^10 Frequency assessment based on placebo-controlled clinical trials.

Description of selected adverse reactions

Discontinuation of duloxetine (especially abrupt) often leads to the occurrence of withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia or electric shock sensations, particularly in the head), sleep disturbances (including insomnia and vivid dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhoea, hyperhidrosis, and vertigo are the most commonly reported reactions.

Typically, for SSRIs and SNRIs, these events were of mild or moderate intensity and resolved spontaneously; however, in some patients, they could be severe and/or prolonged. Therefore, if further treatment with duloxetine is not required, gradual discontinuation is recommended by gradually reducing the dose (see sections "Special precautions" and "Dosage and administration").

In the 12-week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose levels were observed with duloxetine. HbA1c levels remained stable in both the duloxetine and placebo groups. In the extension phase of these studies, lasting up to 52 weeks, increases in HbA1c were observed in both the duloxetine and usual care groups, but the mean increase in the duloxetine group was 0.3%. Small increases in fasting blood glucose and total cholesterol were also observed in patients receiving duloxetine, whereas these laboratory parameters showed slight decreases in the usual care group.

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

Paediatric population

The adverse reaction profile in children and adolescents with MDD and GAD treated with duloxetine was similar to that observed in adults.

During treatment with duloxetine, an average weight loss of 0.1 kg over 10 weeks was observed. Subsequently, patients showed a tendency to return to their baseline weight percentiles based on demographic data for age- and sex-matched peers.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

Store out of reach and sight of children in the original packaging at a temperature not exceeding 30°C.

Packaging

For 30 mg capsules:

7 capsules in a blister; 1 or 4 blisters in a cardboard box.

For 60 mg capsules:

7 capsules in a blister; 4 blisters in a cardboard box.

Prescription status

Prescription-only.

Manufacturer

Laboratorios Normon, S.A.
Ronda de Valdecarrizo, 6, Tres Cantos, 28760 Madrid, Spain.

Marketing authorization holder

ASINO UKRAINE LLC

Address of the marketing authorization holder

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

In case of adverse reactions or questions regarding the safety and efficacy of the medicine, please contact the Pharmacovigilance Department of ASINO UKRAINE LLC at: 8 Vatslava Havela Boulevard, Kyiv, 03124, Tel/Fax: +380442812333.