Duloxenta

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

Composition:

Active substance: duloxetine hydrochloride;

1 hard enteric-coated capsule contains 30 mg or 60 mg of duloxetine as duloxetine hydrochloride;

Excipients: spherical sugar (sucrose, corn starch), hypromellose, sucrose, hypromellose phthalate, talc, triethyl citrate;

capsule shell for 30 mg dosage: titanium dioxide (E 171), indigo carmine (E 132), gelatin, printing ink (shellac, black iron oxide (E 172));

capsule shell for 60 mg dosage: titanium dioxide (E 171), indigo carmine (E 132), yellow iron oxide (E 172), gelatin, printing ink (shellac, black iron oxide (E 172)).

Pharmaceutical form. Hard enteric-coated capsules.

Main physicochemical properties:

30 mg dosage: white to almost white pellets in a hard gelatin capsule size № 3 with a white body and a dark blue cap; "30" printed in black on the body;

60 mg dosage: white to almost white pellets in a hard gelatin capsule size № 1 with a yellowish-green body and a dark blue cap; "60" printed in black on the body.

Pharmacotherapeutic group. Psycholeptics. Other antidepressants. ATC code N06AX21.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Duloxetine is a combined inhibitor of serotonin (5-HT) and norepinephrine (NE) reuptake. It weakly inhibits dopamine reuptake, with no significant affinity for histaminergic, dopaminergic, cholinergic, or adrenergic receptors.

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 analgesic effect of duloxetine is believed to result from potentiation of descending inhibitory pain pathways in the central nervous system.

Pharmacokinetics.

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

Absorption

After oral administration, duloxetine is well absorbed. Maximum concentration is reached 6 hours after drug intake. Absolute bioavailability of duloxetine after oral administration ranges from 32% to 80% (on average, 50%). Food intake delays absorption time, increasing the time to maximum concentration from 6 to
10 hours, while reducing absorption by approximately 11%. These changes are not clinically significant.

Distribution

Duloxetine is highly bound to human plasma proteins (approximately 96%), both to albumin and to alpha-1-acid glycoprotein. Hepatic or renal impairment does not affect protein binding.

Biotransformation

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 patients who are poor metabolizers of CYP2D6 have not been specifically studied. Limited data suggest that plasma duloxetine levels are higher in these patients.

Elimination

The elimination half-life of duloxetine is 12 hours. Mean plasma clearance of duloxetine is 101 L/h.

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 patient populations

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

Age: Pharmacokinetic differences were observed between younger and elderly women (≥ 65 years of age) (AUC increases by approximately 25%, and elimination half-life is approximately 25% longer in elderly patients), 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 chronic dialysis, a doubling of duloxetine concentration and exposure (AUC) was observed compared to healthy subjects. 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, 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. The effect of duloxetine was studied in 6 lactating women who were at least 12 weeks postpartum. Duloxetine is excreted in breast milk, with a steady-state concentration in breast milk approximately one-quarter of that in plasma. The amount of duloxetine in breast milk is approximately 7 μg/day at a dosage of 40 mg twice daily. Lactation did not affect the pharmacokinetics of duloxetine.

Pediatric population. The pharmacokinetics of duloxetine in children aged 7 to 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 3 studies. Model-predicted plasma concentrations of duloxetine in pediatric patients were predominantly within the range of concentrations observed in adult patients.

Clinical characteristics.

Indications.

Treatment of major depressive disorder.

Treatment of diabetic peripheral neuropathic pain.

Treatment of generalized anxiety disorder.

Duloxenta® is indicated for adults.

For additional information, see section "Pharmacological properties".

Contraindications.

Contraindications for the use of the drug include hypersensitivity to duloxetine or to any of its excipients.

Duloxetine must not be administered concomitantly with non-selective irreversible monoamine oxidase inhibitors (MAOIs) (see section "Interaction with other medicinal products and other forms of interaction").

Duloxetine should not be administered to patients with hepatic disease, as this may lead to liver failure (see section "Pharmacokinetics").

Duloxetine should not be administered in combination with fluvoxamine, ciprofloxacin, or enoxacin (strong CYP1A2 inhibitors) due to increased plasma concentrations of duloxetine (see section "Interaction with other medicinal products and other forms of interaction").

Duloxetine must not be administered to patients with end-stage renal disease (creatinine clearance <30 mL/min) (see section "Special precautions for use").

Duloxetine must not be administered to patients with unstable hypertension, as this may provoke a hypertensive crisis (see section "Special precautions for use" and "Adverse reactions").

Interaction with other medicinal products and other forms of interaction.

MAO inhibitors. Duloxetine should not be used in combination with non-selective irreversible monoamine oxidase inhibitors (MAOIs) or within at least 14 days after discontinuation of MAOI therapy due to the risk of serotonin syndrome. Based on the elimination half-life of duloxetine, at least 5 days should elapse after discontinuation of Duloxenta® before initiating MAOI therapy (see section "Special precautions for use").

The risk of serotonin syndrome is lower when using reversible selective MAO inhibitors such as moclobemide; however, the use of such combinations is not recommended. Linezolid, an antibiotic, is a reversible non-selective MAO inhibitor and should not be administered to patients receiving Duloxenta® (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 the plasma clearance of duloxetine by approximately 77% and increases AUC_0–t by 6-fold. Therefore, duloxetine must not be co-administered with CYP1A2 inhibitors, particularly fluvoxamine.

Medicinal products acting on the central nervous system.

The risk of using duloxetine in combination with other centrally acting medicinal products has not been systematically evaluated, except for cases described in this section. Therefore, caution is advised when using Duloxenta® in combination with other medicinal products or substances acting on the CNS, including alcohol and sedative agents (e.g., benzodiazepines, morphine-like analgesics, neuroleptics, phenobarbital, sedative antihistamines).

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

Effect of duloxetine on other medicinal products

MEDICINAL PRODUCTS METABOLIZED BY CYP1A2: Concomitant administration of duloxetine (60 mg twice daily) did not significantly affect the pharmacokinetics of theophylline, a CYP1A2 substrate.

MEDICINAL PRODUCTS METABOLIZED BY CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. Administration of duloxetine at 60 mg twice daily together with a single dose of desipramine, a CYP2D6 substrate, increased desipramine AUC by 3-fold. Concomitant administration of duloxetine (40 mg twice daily) increased steady-state AUC of tolterodine (2 mg twice daily) by 71%, but did not affect the pharmacokinetics of its 5-hydroxy metabolite; therefore, no dose adjustment is recommended. Caution is advised when using duloxetine concomitantly with medicinal products primarily metabolized by CYP2D6 (e.g., risperidone, tricyclic antidepressants [TCAs] 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 study results 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 when co-administered with oral anticoagulants and antithrombotic agents due to the potential for increased risk of bleeding resulting from pharmacodynamic interaction. Additionally, increases in INR values have been observed in patients receiving warfarin when duloxetine was introduced. However, in a clinical pharmacology study, concomitant administration of duloxetine and warfarin in healthy volunteers under steady-state conditions 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 concentrations of duloxetine nearly 50% lower than non-smokers.

Special precautions for use.

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

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

Arterial 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. Cases of hypertensive crisis have been reported during duloxetine treatment, particularly in patients with pre-existing hypertension. Therefore, blood pressure monitoring is recommended in patients with known arterial hypertension and/or other cardiac conditions, especially during the first month of treatment. Duloxetine should be used cautiously in patients whose condition may be compromised by increased heart 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").

Patients who experience persistent increases in blood pressure during duloxetine treatment should consider dose reduction or gradual discontinuation (see section "Adverse reactions"). Duloxetine should not be initiated in patients with uncontrolled hypertension (see section "Contraindications").

Renal impairment. Increased plasma concentrations of duloxetine have been observed in patients with severe renal impairment on hemodialysis (creatinine clearance <30 mL/min). For patients with severe renal impairment, see section "Contraindications". Information regarding patients with mild or moderate renal dysfunction is provided in section "Dosage and administration".

Serotonin syndrome/Malignant Neuroleptic Syndrome (MNS). As with other serotonergic agents, serotonin syndrome or malignant neuroleptic syndrome may occur during treatment with duloxetine and can be potentially life-threatening, particularly 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, or buprenorphine, which may affect serotonergic neurotransmitter systems (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

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

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, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). In its most severe form, serotonin syndrome may resemble MNS, including hyperthermia, muscle rigidity, elevated serum creatine kinase levels, autonomic instability with possible rapid fluctuations in vital signs, and mental status changes.

Herbal products containing St. John's wort. Adverse reactions may be more frequent when the medicinal product Duloxenta® is used concomitantly with herbal preparations 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). Risk persists until significant remission occurs. Patients should be closely monitored until substantial 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 disorders for which Duloxenta® is indicated may also be associated with an increased risk of suicidality. Additionally, these psychiatric conditions may be comorbid when accompanying major depressive disorder. Therefore, similar precautions should be taken when treating patients with major depressive disorder or other psychiatric conditions. Patients with a history of suicidal behavior or significant suicidal ideation are at higher risk of developing 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 thoughts and suicidal behavior have been reported during or immediately after discontinuation of duloxetine therapy (see section "Adverse reactions").

During therapy, especially in the early stages and during dosage adjustments, patients—particularly those at risk—should be closely observed, and appropriate dosage modifications should be made. Patients and caregivers should be informed of the need to monitor for any clinical worsening, suicidal thoughts or behavior, or unusual changes in behavior, and to seek medical help immediately if such 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 medicinal products having similar pharmacological action (antidepressants). Physicians should inform patients of the need to report any feelings of distress.

Use in children and adolescents under 18 years of age.

Duloxenta® 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 (primarily aggression, oppositional behavior, and anger) were observed more frequently in clinical trials among children and adolescents receiving antidepressants compared to those receiving placebo. If treatment is clinically warranted, patients should be closely monitored for the emergence of suicidal symptoms (see section "Pharmacodynamics"). Furthermore, long-term safety data on growth, maturation, and cognitive and behavioral development in children and adolescents are lacking (see section "Adverse reactions").

Bleeding. Cases of bleeding, including ecchymoses, purpura, and gastrointestinal hemorrhage, have been reported with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (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 medicinal products that may affect platelet function (e.g., NSAIDs or acetylsalicylic acid) and in patients with known bleeding tendencies.

Hyponatremia. Cases of hyponatremia, including instances with 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. The drug should be used cautiously in patients at increased risk of hyponatremia (e.g., elderly patients), patients with liver cirrhosis, dehydrated patients, and patients receiving diuretics.

Discontinuation syndrome. Discontinuation symptoms are relatively common, especially following abrupt discontinuation (see section "Adverse reactions"). In clinical trials, adverse events following abrupt discontinuation occurred in approximately 45% of patients receiving duloxetine and 23% of those receiving placebo. The risk of discontinuation symptoms with SSRIs and SNRIs depends on several factors, including duration and dose of therapy and the rate of dose reduction. The most commonly reported reactions are listed in section "Adverse reactions". These symptoms are usually mild or moderate but may be severe in some patients and typically occur within the first few days after discontinuation. Very rarely, such symptoms have been observed in patients who missed a dose. Symptoms usually resolve spontaneously and disappear 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 over at least 2 weeks when discontinuing treatment, according to patient needs (see section "Dosage and administration").

Elderly patients. Data on the use of duloxetine at a dose of 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 "Pharmacokinetics").

Akathisia/psychomotor agitation. Duloxetine may cause akathisia, characterized by subjective distress or anxiety and an urge to move, often accompanied by an inability to sit or stand still. Such symptoms typically occur within the first few weeks of treatment. Increasing the dose in patients developing 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.

Elevated liver enzymes. Marked elevations in liver enzymes (more than 10 times the upper limit of normal) or hepatocellular injury with cholestasis, or significant enzyme elevations with liver injury, have occurred rarely (see section "Adverse reactions"). Most reports occurred within the first months of treatment. Liver injury is predominantly hepatocellular in nature. Duloxetine should be used cautiously in patients taking medicinal products that may cause liver injury.

Sexual dysfunction. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section "Adverse reactions"). Persistent sexual dysfunction has been reported, with symptoms continuing despite discontinuation of SSRIs/SNRIs.

Presence of sucrose. Duloxenta® contains sucrose. The hard gastro-resistant capsules Duloxenta® should not be administered to patients with hereditary fructose intolerance, malabsorption syndrome, or sucrase-isomaltase deficiency. If a patient has 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 (AUC) lower than the maximum clinical exposure.

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 2,500 individuals exposed to duloxetine in the first trimester, and another in the EU included 1,500 individuals exposed in the first trimester). Analysis of specific malformations, such as cardiac defects, showed inconclusive results.

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

Observational data suggest an increased risk (less than two-fold) of postpartum hemorrhage following exposure to duloxetine within one month before delivery.

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

As with other serotonergic medicinal products, newborns exposed to duloxetine near delivery may exhibit symptoms of discontinuation syndrome. Symptoms include hypotonia, tremor, syndrome of increased neuromuscular excitability, difficulty in swallowing and sucking, respiratory disturbances, and seizures. In most cases, these symptoms occurred immediately after birth or within the first few days of life.

The use of the drug during pregnancy is recommended only if the expected benefit outweighs the potential risk to the fetus. Women taking duloxetine should be advised to inform their physician if they become pregnant or plan to become pregnant.

Breastfeeding

Duloxetine is weakly excreted into breast milk, based on data from a study of 6 lactating patients who did not breastfeed their infants. The calculated infant dose of 1 mg per 1 kg body weight corresponds to approximately 0.14% of the maternal dose. The safety of duloxetine in infants is unknown; therefore, breastfeeding during duloxetine treatment is not recommended.

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 of duloxetine on reaction speed when driving or operating machinery have not been conducted. The medicinal product Duloxenta® may cause sedation and dizziness. Patients should be informed that if they experience sedation or dizziness, they should refrain from potentially hazardous activities such as driving or operating machinery.

Method of Administration and Dosage.

For oral use

Major Depressive Disorder: The initial and recommended maintenance dose of duloxetine is 60 mg once daily, regardless of food intake. Doses above 60 mg once daily may be increased up to a maximum dose of 120 mg per day, divided into equal doses. Doses exceeding 120 mg per day have not been systematically evaluated in clinical trials. However, there are no clinical data indicating that increasing the dose will be effective for patients who do not respond to the initial recommended dose.

Therapeutic effect becomes apparent within 2–4 weeks.

After achieving a sustained antidepressant effect, treatment should be continued for several months to prevent relapse. For patients who respond to duloxetine and have a history of recurrent episodes of major depression, long-term maintenance treatment with a dose of 60–120 mg daily should be considered.

Generalized Anxiety Disorder: The recommended starting dose is 30 mg once daily, regardless of food intake. For patients with an inadequate response to treatment, the dose should be increased to 60 mg, which is the usual maintenance dose for most patients.

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

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

After achieving a sustained therapeutic effect, 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. Doses exceeding 60 mg once daily, up to a maximum of 120 mg per day divided into equal doses, have been evaluated for safety in clinical studies. Plasma concentrations of duloxetine show considerable inter-individual variability (see section "Pharmacokinetics"). Therefore, some patients with an inadequate response to the 60 mg dose may benefit from a higher dose.

Therapeutic effect becomes apparent within 2 months. In patients with inadequate initial response, additional benefit after this period is unlikely. The therapeutic effect should be regularly re-evaluated (at least every 3 months) (see section "Pharmacodynamics").

Special Patient Populations

Elderly Patients: Dose adjustment is not recommended solely on the basis of age. However, as with any medicinal product, caution should be exercised when treating elderly patients, particularly when using Duloxenta***®*** at a dose of 120 mg daily for the treatment of major depressive disorder or generalized anxiety disorder, for which data are limited (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Patients with Hepatic Impairment: Duloxenta***®*** must not be administered to patients with hepatic diseases causing impaired liver function (see sections "Contraindications" and "Pharmacokinetics").

Patients with Renal Impairment: Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance from 30 to 80 mL/min). The use of duloxetine is not recommended in patients with end-stage renal disease (creatinine clearance <30 mL/min) (see section "Contraindications").

Children.

Duloxetine should not be used in children and adolescents under 18 years of age for the treatment of major depressive disorder due to safety and efficacy concerns (see sections "Special Warnings and Precautions for Use", "Adverse Reactions", and "Pharmacodynamics").

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 described in the sections "Adverse Reactions", "Pharmacodynamics", and "Pharmacokinetics".

The safety and efficacy of duloxetine for the treatment of diabetic peripheral neuropathic pain have not been studied. Data are lacking.

Discontinuation of Treatment.

Abrupt discontinuation should be avoided. After stopping treatment with Duloxenta***®***, the dose should be gradually reduced over a period of at least one to two weeks to reduce the risk of withdrawal reactions (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions"). If intolerable symptoms occur after dose reduction or upon discontinuation, consideration may be given to reinstating the previously prescribed dose. Subsequently, the physician may continue tapering the dose, but more gradually.

Children.

Clinical studies on the use of duloxetine in children have not been conducted; therefore, it is not used in pediatric practice.

Overdose.

Cases of ingestion of large doses (up to 5400 mg) of the drug, either as monotherapy or in combination with other medicinal products, have been reported. There have been some fatal cases, mostly due to mixed overdoses, but also with duloxetine alone at a dose of approximately 1000 mg. Symptoms of overdose (duloxetine alone or in combination with other drugs) included somnolence, coma, serotonin syndrome, seizures, vomiting, and tachycardia.

There are no specific antidotes. Specific treatment (cyproheptadine and/or temperature control) is required if serotonin syndrome occurs. Airway patency must be ensured. Cardiac monitoring and surveillance of vital signs, along with appropriate symptomatic and supportive measures, are recommended. Gastric lavage may be appropriate if performed immediately after ingestion or for symptomatic reasons. Activated charcoal reduces drug absorption. Duloxetine has a large volume of distribution, making forced diuresis, hemoperfusion, and exchange transfusion unlikely to be beneficial.

Adverse Reactions

The most common adverse reactions in patients receiving duloxetine were nausea, headache, dry mouth, somnolence, and dizziness. However, most of the commonly observed adverse reactions were of mild to moderate severity, usually began early in therapy, and tended to diminish even with continued treatment.

The table below lists adverse reactions observed during duloxetine administration, based on data from spontaneous reports and 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), not known (cannot be estimated from available data).

Within each frequency category, adverse reactions are listed in order of decreasing prominence.

Very common	Common	Uncommon	Rare	Very rare	Not known
Infections and infestations
		Laryngitis.
Endocrine system disorders
			Hypothyroidism.
Immune system disorders
			Anaphylactic reactions, hypersensitivity.
Metabolism and nutrition disorders
	Decreased appetite.	Hyperglycemia (especially in patients with diabetes mellitus).	Dehydration, hyponatremia, ADH deficiency6.
Psychiatric disorders
	Insomnia, agitation, decreased libido, anxiety, abnormal orgasm and abnormal dreams.	Suicidal ideation5,7, sleep disorders, bruxism, disorientation, apathy.	Suicidal behavior5,7, mania, hallucinations, aggression and anger4.
Nervous system disorders
Headache Drowsiness	Dizziness, lethargy, tremor, paresthesia.	Myoclonus, akathisia7, nervousness, attention disorders, dysgeusia, dyskinesia, restless legs syndrome, poor sleep.	Serotonin syndrome6, seizures1, psychomotor restlessness6, extrapyramidal disorders6.
Eye disorders
	Blurred vision.	Mydriasis, visual disturbances.	Glaucoma.
Ear and labyrinth disorders
	Tinnitus1.	Dizziness, ear pain.
Cardiac disorders
	Palpitations.	Tachycardia, supraventricular arrhythmia, fibrillation mostly atrial.			Stress cardiomyopathy (Takotsubo cardiomyopathy)
Vascular disorders
	Increased blood pressure3, flushing.	Arterial hypertension3,7, orthostatic hypotension2, loss of consciousness2, cold sensation in limbs.	Hypertensive crisis3,6.
Respiratory system disorders
	Yawning.	Throat tightness, epistaxis.	Interstitial lung disease10, eosinophilic pneumonia6.
Gastrointestinal disorders
Nausea Dry mouth	Constipation, diarrhea, abdominal pain, vomiting, dyspepsia, flatulence.	Gastrointestinal hemorrhage7, gastroenteritis, belching, gastritis, dysphagia.	Stomatitis, blood in stool, bad breath, microscopic colitis9.
Hepatobiliary disorders
		Hepatitis3, elevated liver enzymes (ALT, AST, alkaline phosphatase), acute liver injury.	Liver failure6, jaundice6.
Skin and subcutaneous tissue disorders
	Increased sweating, rash.	Night sweats, urticaria, contact dermatitis, cold sweat, photosensitivity, increased tendency to bruising.	Stevens-Johnson syndrome6, angioneurotic edema6.	Skin vasculitis.
Musculoskeletal and connective tissue disorders
	Musculoskeletal pain, muscle spasm.	Muscle stiffness, muscle twitching.	Trismus.
Renal and urinary disorders
	Dysuria, pollakiuria.	Urinary retention, difficulty initiating micturition, nocturia, polyuria, decreased urine flow.	Abnormal urine odor.
Reproductive system and breast disorders
	Erectile dysfunction, ejaculation disorder, delayed ejaculation.	Gynecological bleeding, menstrual disorders, sexual disorders, testicular pain.	Menopausal symptoms, galactorrhea, hyperprolactinemia, postpartum hemorrhage6.
General disorders
	Fatigue.	Chest pain7, fall8, malaise, cold sensation, thirst, chills, feeling unwell, hot flushes, gait disturbance.
Investigations
	Decreased body weight.	Increased body weight, elevated blood creatine phosphokinase, increased blood potassium.	Elevated blood cholesterol.

• Seizures and tinnitus were observed after discontinuation of treatment.
  • Cases of orthostatic hypotension and loss of consciousness were observed predominantly at the beginning of treatment.
    • See section "Special precautions for use".
      • Cases of aggression and hostility were reported at the beginning of treatment and after discontinuation of treatment.
        • Cases of suicidal ideation and suicidal behavior were reported at the beginning of treatment and immediately after discontinuation of treatment.
          • Frequency established from post-marketing studies, not observed in placebo-controlled clinical trials.
            • Statistically not significantly different from placebo.
              • Falls were more frequent in elderly patients (aged ≥ 65 years).
                • Frequency established based on data from all clinical trials.
                  • Frequency established based on data from placebo-controlled clinical trials.

Discontinuation of duloxetine (especially abrupt) usually leads to withdrawal symptoms. The most common adverse reactions in such cases are: dizziness, sensory disturbances (including paresthesia or electric shock-like 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, diarrhea, hyperhidrosis, and vertigo.

For SSRIs and SNRIs, these phenomena are usually mild or moderate and self-limiting; however, in some patients, they may be severe and/or prolonged. Therefore, it is recommended to gradually discontinue therapy by tapering the dose when treatment with duloxetine is no longer required (see sections "Dosage and administration" and "Special precautions for use").

In 12-week 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 remained stable in both patients receiving duloxetine and those receiving placebo. In the extension phase of these studies, lasting up to 52 weeks, an increase in HbA1c levels was observed in both the duloxetine and usual care groups, although the mean increase in the duloxetine treatment group was 0.3%. A slight increase in fasting blood glucose and total cholesterol levels was also observed in patients taking duloxetine, whereas a slight decrease in risk factor groups was observed in these laboratory parameters.

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

In clinical trials, 509 pediatric patients aged 7 to 17 years with major depressive disorder and 241 pediatric patients aged 7 to 17 years with generalized anxiety disorder were treated with duloxetine. Overall, the adverse reaction profile of duloxetine in children and adolescents was similar to that observed in adults.

Overall, 467 pediatric patients randomized to duloxetine in clinical trials experienced a mean weight loss of 0.1 kg over 10 weeks, compared to a mean weight gain of 0.9 kg in 353 patients receiving placebo. Subsequently, during continuation of the study over a four- to six-month period, patients tended to regain toward the expected baseline body weight percentile based on population data for age- and sex-matched peers.

In studies lasting up to 9 months, children receiving duloxetine showed an overall reduction in growth velocity of 1% (a 2% reduction in children aged 7–11 years and a 0.3% increase in adolescents aged 12–17 years) (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. 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 the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 25°C in the original packaging to protect from moisture.

Keep out of reach of children.

Packaging. 10 enteric-coated hard capsules in a blister; 3 or 6 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address and location of operations.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.