Depuloxa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEPULOXA (DEPULOXA)

Composition:

Active substance: duloxetine;

1 capsule contains 30 mg or 60 mg of duloxetine (as duloxetine hydrochloride);

Excipients: spherical sugar, sucrose, carboxymethylethylcellulose, hypromellose, crospovidone, povidone, talc, Opadry White YS-1-7003 (composition: titanium dioxide (E 171), hypromellose (E 464), polyethylene glycol (E 1521), polysorbate 80 (E 433)).

Pharmaceutical form. Gastric-resistant capsules.

Main physicochemical properties:

30 mg dosage: hard gelatin capsules, size "3", with an opaque white body and an opaque blue cap, marked with golden-yellow ink "H" on the cap and "191" on the body, filled with pellets ranging from white to almost white;

60 mg dosage: hard gelatin capsules, size "1", with an opaque green body and an opaque blue cap, marked with white ink "H" on the cap and "192" on the body, filled with pellets ranging from white to almost white.

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

Pharmacological Properties

Pharmacodynamics

Duloxetine is a combined inhibitor of serotonin (5-HT) and norepinephrine (NA) reuptake. It weakly inhibits dopamine reuptake and shows no significant affinity for histaminergic, dopaminergic, cholinergic, or adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin and norepinephrine in various brain regions of animals.

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.

Clinical Efficacy and Safety

Major Depressive Disorder. 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 of 60–120 mg in five out of seven fixed-dose studies in adult outpatients with major depressive disorder.

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

In a depression relapse prevention study, relapse rates during the 6-month double-blind observation period were 17% for duloxetine and 29% for placebo, respectively.

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

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; therefore, caution is recommended when treating this population.

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

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

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

The efficacy of duloxetine 30–120 mg (flexible dosing) once daily in elderly patients (>65 years) with generalized anxiety disorder was evaluated in a study that demonstrated statistically significant improvement in HAM-A total score in patients receiving duloxetine compared to placebo. Efficacy and safety of duloxetine 30–120 mg once daily in elderly patients with generalized anxiety disorder were similar to those observed in studies involving younger adult patients. However, data on elderly patients receiving the maximum dose (120 mg daily) are limited; therefore, 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 (aged 22 to 88 years) who had experienced diabetic neuropathic pain for at least 6 months. Patients meeting diagnostic criteria for major depressive disorder were excluded from these studies. The primary outcome measure was the average 24-hour average pain score, recorded by patients in a diary using an 11-point Likert scale.

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

In a study, pain reduction was maintained over the subsequent 6 months in patients who responded to an 8-week open-label duloxetine therapy at 60 mg once daily, as determined by the Brief Pain Inventory (BPI) 24-hour average pain score.

Pharmacokinetics

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

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

Distribution. Duloxetine is highly bound to human plasma proteins (approximately 96%), including both 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. Duloxetine pharmacokinetics have not been specifically studied in poor CYP2D6 metabolizers. Some data suggest higher plasma levels of duloxetine in these patients.

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

Special Populations

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

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

Renal Function Impairment. In patients with end-stage renal disease on regular dialysis, a twofold increase in 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 Insufficiency. Moderate liver disease (Child-Pugh Class B) affects duloxetine pharmacokinetics. Compared to healthy volunteers, apparent plasma clearance of duloxetine was 79% lower, apparent elimination 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 insufficiency.

Breastfeeding. The effect of duloxetine was studied in 6 women during lactation for at least 12 weeks postpartum. Duloxetine is excreted in breast milk, with steady-state concentrations in breast milk approximately one-quarter of those 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.

Clinical characteristics.

Indications.

Treatment of major depressive disorder.

Treatment of diabetic peripheral neuropathic pain.

Treatment of generalized anxiety disorder.

Contraindications.

Hypersensitivity to duloxetine or to any of the excipients of the medicinal product.

Duloxetine must not be administered concomitantly with non-selective irreversible monoamine oxidase inhibitors (MAOIs).

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

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

Duloxetine must not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min).

Duloxetine must not be administered to patients with unstable hypertension, as this may provoke a hypertensive crisis.

Interaction with other medicinal products and other forms of interaction.

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

Inhibitors of CYP1A2. Since CYP1A2 is involved in the metabolism of duloxetine, concomitant administration of duloxetine with strong CYP1A2 inhibitors is likely to increase duloxetine concentrations. Fluvoxamine (100 mg once daily), a potent CYP1A2 inhibitor, reduces the plasma clearance of duloxetine by approximately 77% and increases AUC_0-t by 6-fold. Therefore, duloxetine must not be administered concomitantly with CYP1A2 inhibitors, including fluvoxamine.

Medicinal products acting on the CNS. When prescribing duloxetine in combination with other centrally acting medicinal products, particularly those with similar mechanisms of action, including alcohol and sedative agents (e.g., benzodiazepines, morphine-like opioids, antipsychotics, phenobarbital, sedative antihistamines), certain precautions must be taken.

Serotonergic agents. In rare cases, serotonin syndrome has been observed in patients receiving selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) in combination with serotonergic agents. Depuloxa should be prescribed with caution in combination 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.

Effect of duloxetine on other medicinal products

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

Medicinal products metabolized by CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. Administration of duloxetine at a dose of 60 mg twice daily together with a single dose of desipramine, a CYP2D6 substrate, increases the AUC of desipramine by 3-fold. 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 the 5-hydroxy metabolite; no dosage adjustments are recommended. Depuloxa should be used with caution in combination with medicinal products primarily metabolized by CYP2D6 (e.g., risperidone, tricyclic antidepressants [TCAs] such as nortriptyline, amitriptyline, and imipramine), particularly those with a narrow therapeutic index (e.g., flecainide, propafenone, and metoprolol).

Oral contraceptives and other steroid agents. In vitro data 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 administered with caution concomitantly 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 duloxetine was administered to patients receiving warfarin. However, in a clinical pharmacology study in healthy volunteers, concomitant administration of duloxetine and warfarin 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 duloxetine following a 40 mg oral dose.

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

Special precautions for use.

Epileptic seizures and mania. As with other drugs acting on the CNS, caution is advised when prescribing Depuloxa to patients with a history of epileptic seizures, mania, or bipolar disorders.

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

Arterial pressure and palpitations. Duloxetine has been associated with increased blood 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, blood pressure monitoring is recommended in patients with known arterial hypertension and/or other cardiac conditions, especially during the first month of treatment. Depuloxa should be used with caution 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"). For patients who experience persistent increases in blood pressure during treatment with Depuloxa, consideration should be given to dose reduction or gradual discontinuation (see section "Side effects"). Depuloxa 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, refer to section "Contraindications". For information on patients with mild to moderate renal dysfunction, see 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 selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, or triptans), agents that impair serotonin metabolism such as monoamine oxidase inhibitors (MAOIs), 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 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, which includes hyperthermia, muscle rigidity, elevated serum creatine kinase levels, autonomic instability with possible rapid fluctuations in vital signs, and changes in mental status.

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, particularly during initiation of treatment and dose escalation.

Herbal products containing St. John’s wort

Adverse reactions may be more common when Depuloxa is used concomitantly with 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 (including suicidal events). This 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 such improvement occurs. Clinical experience indicates that the risk of suicide may increase during the early stages of recovery.

Other psychiatric disorders for which Depuloxa may be prescribed are also associated with an increased risk of suicidal events. Additionally, these conditions may coexist with major depressive disorder. Therefore, the same precautions should be observed when treating patients with other psychiatric disorders as with those suffering from major depressive disorder.

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

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

Patients (especially those at high risk) should be closely monitored during treatment, particularly at the beginning of therapy and when dosage changes occur. Patients (and caregivers) should be informed of the need to monitor for any worsening of clinical condition, suicidal thoughts or behavior, or unusual changes in behavior, and to seek immediate medical attention if such symptoms occur.

Diabetic peripheral neuropathic pain.

Isolated cases of suicidal ideation and suicidal behavior have been reported during treatment with duloxetine or immediately after discontinuation, similar to other medicinal products with 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). Depuloxa should not be used in children and adolescents under 18 years of age.

Suicidality (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behavior, and anger) were more frequently observed in clinical trials of children and adolescents receiving antidepressants compared to those receiving placebo. If, considering clinical need, a decision to treat is made, patients should be closely monitored for the emergence of suicidal symptoms. Additionally, long-term safety data on growth, maturation, and cognitive and behavioral development in children and adolescents are lacking.

Bleeding. Bleeding disorders such as bruising, purpura, and gastrointestinal hemorrhage have been reported with SSRIs and SNRIs, including duloxetine. Duloxetine increases the risk of postpartum hemorrhage. Caution is recommended in patients taking anticoagulants and/or medicinal products that may affect platelet function (e.g., NSAIDs or acetylsalicylic acid), and in patients with known predisposition to bleeding.

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. The medicinal product should be used with caution in patients at increased risk of developing hyponatremia (e.g., elderly patients), patients with liver cirrhosis, dehydrated patients, and patients receiving diuretics.

Discontinuation syndrome. Discontinuation symptoms occur frequently, especially following abrupt discontinuation of treatment. 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 "Side effects". These symptoms are usually mild or moderate, but may be severe in some patients. They typically occur within the first few days after stopping treatment. Very rarely, such symptoms have been observed in patients who have accidentally missed a dose. These symptoms resolve spontaneously and usually 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 120 mg duloxetine in elderly patients with major depressive disorder and generalized anxiety disorder are limited. Therefore, caution is advised when using the maximum dose in elderly patients (see section "Dosage and administration").

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

Medicinal products containing duloxetine

Duloxetine is marketed under various trade 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 (see section "Side effects"). Most cases occurred during the first few months of treatment. Liver injury is usually hepatocellular in nature. Caution is advised when prescribing duloxetine to 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 "Side effects"). Reports of persistent sexual dysfunction, where symptoms persisted despite discontinuation of SSRIs/SNRIs, have been documented.

Presence of sucrose. The medicinal product must not be administered to patients with hereditary fructose intolerance, malabsorption syndrome, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have shown reproductive toxicity at duloxetine AUC levels below 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 conducted in the EU included 1,500 individuals exposed in 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 20 weeks gestational age until delivery) was associated with an increased risk of preterm birth (almost 2-fold increase, corresponding to approximately 6 additional preterm births per 100 women exposed to duloxetine in late pregnancy). Most deliveries occurred between 35 and 36 weeks of gestation. This association was not observed in the US study.

US observational data confirmed an increased risk (almost 2-fold) of postpartum hemorrhage following duloxetine use 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, given its mechanism of action (inhibition of serotonin reuptake).

As with other serotonergic medicinal products, neonates may experience symptoms of withdrawal syndrome if the mother used duloxetine prior to delivery. Symptoms of withdrawal syndrome include orthostatic hypotension, tremor, hyperreflexia, 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 medicinal product during pregnancy is recommended only if the expected benefit outweighs the potential risk. Women should be advised to inform their physician if they become pregnant or plan to become pregnant while taking duloxetine.

Breastfeeding.

According to a study conducted in 6 lactating women, duloxetine is very weakly excreted into human breast milk. The estimated infant dose calculated at 1 mg per 1 kg body weight is approximately 0.14% of the maternal dose. The safety of duloxetine in infants is unknown; therefore, breastfeeding during treatment with Depuloxa is not recommended.

Fertility. In animal studies, duloxetine did not affect male fertility, and effects in females occurred 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. Duloxetine may cause sedation and dizziness. Therefore, if sedation or dizziness occurs, patients should avoid potentially hazardous activities such as driving or operating machinery.

Dosage and Administration

Major Depressive Disorder. The initial and recommended maintenance dose is 60 mg once daily, administered independently of food intake.

Doses above 60 mg once daily, up to a maximum dose of 120 mg daily, have been evaluated in terms of safety. However, there are no clinical data demonstrating that patients who do not respond to the initial recommended dose may benefit from dose escalation.

Therapeutic response is typically observed within 2–4 weeks of treatment initiation.

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

Generalized Anxiety Disorder. The recommended initial dose is 30 mg once daily, administered independently of food intake. For patients with an inadequate response to treatment, the dose should be increased to 60 mg daily, 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 also dosing recommendations above).

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

After achieving a stable response, 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, administered independently of food intake. Doses above 60 mg once daily, up to a maximum of 120 mg daily, administered in evenly divided doses, have been evaluated for safety in clinical trials. Plasma concentrations of duloxetine exhibit considerable inter-individual variability. Therefore, some patients who do not respond adequately to 60 mg may benefit from a higher dose.

Therapeutic effect is typically observed within 2 months. Additional benefit after this period is unlikely in patients with inadequate initial response.

Therapeutic benefit should be regularly assessed (at least every 3 months).

Elderly Patients. Dose adjustment based solely on age is not recommended for elderly patients. As with any medication, caution should be exercised when treating elderly patients, particularly when using Depuloxa at a dose of 120 mg daily for major depressive disorder or generalized anxiety disorder, as data in this population are limited.

Patients with Hepatic Impairment. Depuloxa is contraindicated in patients with hepatic disease.

Patients with Renal Impairment. Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). Depuloxa should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min).

Discontinuation of Treatment. Abrupt discontinuation should be avoided. When discontinuing treatment with Depuloxa, the dose should be gradually reduced over at least 1–2 weeks to minimize the risk of discontinuation reactions. If intolerable symptoms occur following dose reduction or upon discontinuation, it is recommended to reinstitute the previously prescribed dose. The physician may then continue tapering the dose, but more gradually.

Pediatric Population.

Duloxetine should not be used in children and adolescents under 18 years of age.

Overdose.

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

Treatment of Overdose. There is no specific antidote. In cases of serotonin syndrome, specific treatment is required (cyproheptadine and/or temperature control). Airway patency must be ensured. Cardiac monitoring and continuous monitoring 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 management. Activated charcoal reduces drug absorption. Due to the large volume of distribution of duloxetine, forced diuresis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.

Adverse reactions

The most commonly reported adverse reactions in patients receiving duloxetine were nausea, headache, dry mouth, somnolence, and dizziness. However, most of the common adverse reactions were mild to moderate in severity, typically began early in therapy, and tended to resolve 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 classification: 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 the available data).

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

1 Seizures and tinnitus were observed following discontinuation of treatment.

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

3 See section "Special precautions".

4 Cases of aggression and hostility were reported at the beginning of treatment and after discontinuation of treatment.

5 Cases of suicidal ideation and suicidal behaviour have been reported at the beginning of treatment and immediately after discontinuation of treatment (see section "Special precautions").

6 The established frequency of adverse reactions from post-marketing studies not observed in placebo-controlled clinical trials.

7 Statistically no significant difference from placebo.

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

9 Expected frequency based on all clinical trial data.

10 Predicted frequency based on placebo-controlled clinical trials.

Discontinuation of duloxetine (especially abrupt discontinuation) is frequently associated with a withdrawal syndrome. The most common adverse reactions in such cases are: 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 dizziness.

For SSRIs and SNRIs, these events are usually mild or moderate and self-limiting, however, in some patients they may be severe and/or prolonged. Therefore, gradual discontinuation of therapy by dose tapering is recommended when treatment with duloxetine is no longer required (see sections "Dosage and administration" and "Special precautions").

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 levels remained stable in both patients receiving duloxetine and those receiving placebo. In the extension phase of these studies lasting up to 52 weeks, increases in HbA1c levels were observed in both the duloxetine and usual care groups, although the mean increase in the duloxetine treatment group was 0.3%. Small increases in fasting blood glucose and total cholesterol levels were also observed in patients receiving duloxetine, while slight decreases in risk factor counts were observed in these laboratory parameters.

The heart rate-corrected QT interval in patients receiving 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.

The adverse reaction profile of duloxetine in children and adolescents is similar to that observed in adults. In children, a mean decrease in body weight of 0.1 kg was observed over 10 weeks of study with duloxetine compared to a mean increase of 0.9 kg in the placebo group. Subsequently, over 4–6 months, patients on average returned to the expected baseline body weight level based on population data for age- and gender-matched peers.

In studies up to 9 months, an overall mean decrease of 1% in height growth was observed (a 2% decrease in children aged 7–11 years and a 0.3% increase in adolescents (12–17 years)) in paediatric patients treated with duloxetine.

Reporting of adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as 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. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 ºC, in a place inaccessible to children.

Packaging. 30 mg: 7 capsules in a blister, 4 blisters per pack;
60 mg: 10 capsules in a blister, 3 blisters per pack.

Prescription status. Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of its operations.

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.