Ducset

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

Composition:

Active substance: duloxetine;

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

Excipients: spherical sugar, hypromellose 603, sucrose, talc, triethyl citrate, hypromellose acetate succinate (AS-LF), ammonium hydroxide solution 25 %, Opadry White 02A28361: hypromellose, titanium dioxide (E 171), talc;

composition of gelatin capsule №3 for 30 mg: titanium dioxide (E 171), indigocarmine (E 132), gelatin;

composition of gelatin capsule №1 for 60 mg: titanium dioxide (E 171), indigocarmine (E 132), yellow iron oxide (E 172), gelatin.

Pharmaceutical form. Enteric-coated capsules.

Main physicochemical properties:

30 mg: hard gelatin capsules with an opaque white body and an opaque dark blue cap, containing white or almost white pellets;

60 mg: hard gelatin capsules with an opaque green body and an opaque dark blue cap, containing white or almost white pellets.

Pharmacotherapeutic group.

Antidepressants. ATC code N06AX21.

Pharmacological properties.

Pharmacodynamics.

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

Pharmacokinetics.

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

Distribution. Duloxetine is highly bound to plasma proteins (> 90%).

Metabolism. Duloxetine is metabolized via the CYP2D6 and CYP1A2 isoenzymes. The metabolites formed are pharmacologically inactive.

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

Renal impairment. In patients with end-stage renal disease undergoing regular dialysis, a twofold increase in duloxetine concentration and area under the concentration-time curve (AUC) has been observed compared to healthy volunteers. Therefore, patients with chronic renal insufficiency require a lower initial dose.

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 drug.
• Concomitant use with non-selective irreversible monoamine oxidase inhibitors (MAOIs) or within at least 14 days after discontinuation of MAOI therapy. Due to the half-life of duloxetine, MAOIs should not be initiated at least 5 days after stopping duloxetine treatment.
• Concomitant use with fluvoxamine, ciprofloxacin, or enoxacin (strong CYP1A2 inhibitors) due to increased plasma concentrations of duloxetine.
• Unstable arterial hypertension, which may provoke a hypertensive crisis.
• End-stage renal disease (creatinine clearance < 30 mL/min).
• Hepatic disorders that may lead to liver failure.
• Pediatric age.

Interaction with other medicinal products and other forms of interaction.

Medicinal products metabolized by CYP1A2. During clinical studies of concomitant administration of theophylline, a CYP1A2 substrate, with duloxetine (60 mg twice daily), no significant effect on the pharmacokinetics of these drugs was observed.

Inhibitors of CYP1A2. Since CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with potent CYP1A2 inhibitors is likely to increase duloxetine concentrations. Fluvoxamine (100 mg once daily), a potent CYP1A2 inhibitor, reduces plasma clearance of duloxetine by approximately 77%. Therefore, Duxet should not be co-administered with CYP1A2 inhibitors.

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 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 5-hydroxy metabolite. Therefore, caution is required when prescribing duloxetine together with CYP2D6 substrates that have a narrow therapeutic index.

Medicinal products acting on the central nervous system. Caution is required when administering duloxetine in combination with other centrally acting medicinal products, especially those with similar mechanisms of action, including alcohol and sedative agents.

MAO inhibitors. Duloxetine should not be administered concomitantly with non-selective irreversible monoamine oxidase inhibitors (MAOIs) due to the risk of serotonin syndrome. The risk of serotonin syndrome is lower with reversible selective MAOIs such as moclobemide; however, the use of such combinations is not recommended.

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

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 orally administered 40 mg doses of duloxetine.

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

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

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

Medicinal products containing duloxetine.

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

Medicinal products containing St. John's wort.

The combination with Duxet is frequently associated with adverse reactions.

Special precautions for use.

Warning

Patients with a high risk of suicide must be under close supervision during treatment, as suicide attempts are still possible until significant remission occurs.

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

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

Blood pressure and heart rate. In some patients, duloxetine may cause increased blood pressure and clinically significant arterial hypertension. Blood pressure monitoring is recommended in patients with arterial hypertension and/or other heart diseases. This effect may be related to the noradrenergic activity of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, particularly in patients with hypertensive disease. Therefore, blood pressure monitoring is recommended in patients with known arterial hypertension and/or other cardiac conditions, especially during the first month of treatment. The medicinal product Duxet should be used with caution in patients whose condition may be compromised by increased pulse rate or elevated blood pressure. Duloxetine should also be used cautiously with medicinal products that may impair its metabolism (see section "Interaction with other medicinal products and other forms of interaction"). In patients experiencing persistent increase in blood pressure during Duxet treatment, dose reduction or gradual discontinuation of the drug should be considered (see section "Adverse reactions"). Duxet 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 dysfunction undergoing hemodialysis (creatinine clearance <30 mL/min). For patients with severe renal impairment, see section "Contraindications". Information regarding patients with mild to moderate renal dysfunction is provided in section "Dosage and administration".

Hemorrhage. Bleeding disorders such as bruising, including purpura, and gastrointestinal bleeding have been reported with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including duloxetine. Caution is recommended in patients taking anticoagulants and/or medicinal products that may affect platelet function (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid) and in patients with known predisposition to bleeding.

Serotonin syndrome / neuroleptic malignant syndrome. As with other serotonergic agents, serotonin syndrome or neuroleptic malignant syndrome (NMS) may occur during treatment with duloxetine and may 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, antipsychotics, or other dopamine antagonists that may affect serotonergic neurotransmitter systems (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). In its most severe form, serotonin syndrome may resemble NMS, characterized by hyperthermia, muscle rigidity, elevated serum creatine kinase levels, autonomic instability with possible rapid fluctuations in vital signs, and mental status changes.

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

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 drug should be prescribed with caution in patients at increased risk of hyponatremia (e.g., elderly patients), patients with liver cirrhosis, dehydrated patients, and patients receiving diuretics.

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

Discontinuation syndrome. Discontinuation symptoms occur frequently, especially after abrupt cessation 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 "Adverse reactions". These symptoms are usually mild or moderate, but in some patients they may be severe and typically occur within the first few days after stopping treatment. Very rarely, such symptoms have been observed in patients who accidentally missed a dose. These symptoms spontaneously resolve and usually disappear within 2 weeks, although in some individuals they may persist longer (2–3 months or more). Therefore, it is recommended to gradually reduce the dose of duloxetine when discontinuing treatment over a period of at least 2 weeks according to patient needs (see section "Dosage and administration").

Akathisia/psychomotor restlessness. Akathisia (characterized by a subjectively unpleasant or anxious restlessness and a need 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.

Elevated liver enzymes. Marked elevations in liver enzymes (more than 10 times the upper limit of normal) or liver injury with cholestasis, or significant enzyme elevations together with liver injury, have occurred rarely. Most reports occurred during the first months of treatment. Liver injury is most commonly hepatocellular in nature. Duloxetine should be prescribed with caution in patients taking medicinal products that may cause liver injury.

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

Sucrose content. Enteric-coated capsules of Duxet must not be administered to patients with hereditary fructose intolerance, malabsorption syndrome, or sucrase-isomaltase deficiency.

Suicide.

Major depressive disorder and generalized anxiety disorder.

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

The psychiatric conditions for which Duxet is prescribed may also be associated with an increased risk of suicide-related events. In addition, these psychiatric conditions may be comorbid when accompanying major depressive disorder. Therefore, the same precautionary measures should be observed when treating patients with major depressive disorder as well as other psychiatric conditions. Patients with a history of suicide-related events or significant suicidal ideation are at higher risk of suicidal behavior and require closer monitoring during treatment. Cases of suicidal ideation and suicidal behavior have been reported during or immediately after discontinuation of duloxetine therapy. Close monitoring of patients, especially those at risk, is required during therapy, particularly in the early stages, along with appropriate dose adjustments. Patients and caregivers should be informed about the need to monitor for any clinical worsening, suicidal thoughts or behaviors, or unusual changes in behavior and to seek immediate medical attention if these occur.

Diabetic peripheral neuropathic pain.

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

Elderly patients.

Data on the use of Duxet 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 maximum dose in elderly patients (see section "Dosage and administration").

Serious skin reactions.

Very rare cases of skin reactions such as angioneurotic edema, petechiae, Stevens-Johnson syndrome, ecchymoses, and urticaria have been reported.

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 concomitant use of multiple such products should be avoided.

Sucrose.

If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

Fertility

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

Pregnancy

Adequate and well-controlled studies on the effects of the drug in pregnant women have not been conducted; therefore, the use of the drug during pregnancy is not recommended. There are insufficient data on the use of duloxetine in pregnant women. Animal studies have shown that reproductive toxicity occurs at systemic exposure (AUC) lower than the maximum clinical exposure. The potential risk to humans is unknown. 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 treatment has not been studied, this potential risk cannot be excluded with duloxetine use due to 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 may include orthostatic hypotension, tremor, syndrome of increased nervous-reflex excitability, difficulty in swallowing, sucking, respiratory disorders, and seizures. In most cases, these symptoms were observed immediately after birth or within the first few days of life. Women should be advised to inform their physician if they become pregnant or plan to become pregnant while taking duloxetine.

The use of the drug during pregnancy is recommended only if the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Breastfeeding period

Duloxetine is weakly excreted into breast milk. The approximate infant dose (calculated as 1 mg per 1 kg of body weight) is 0.14% of the maternal dose. The safety of duloxetine in infants is unknown; therefore, breastfeeding during duloxetine treatment is not recommended.

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 may cause sedative effects and dizziness. During treatment, patients should refrain from potentially hazardous activities requiring heightened attention and rapid psychomotor responses.

Dosage and Administration

Major Depressive Disorder. The initial and recommended maintenance dose is 60 mg once daily, administered independently of food intake. Doses exceeding 60 mg once daily up to a maximum of 120 mg daily have been evaluated regarding safety. However, there are no clinical data demonstrating that dose escalation is effective in patients who do not respond to the initial recommended dose.

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

After achieving a sustained antidepressant effect, 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.

Diabetic Peripheral Neuropathic Pain. The recommended initial dose is 60 mg once daily, independent of food intake. Some patients may be prescribed a daily dose higher than 60 mg, up to a maximum of 120 mg daily, divided into two doses.

Therapeutic effect is typically observed within 2 months. Additional therapeutic response after this period is unlikely in patients with inadequate initial response. Therapeutic benefit should be regularly assessed (at least every 3 months).

Generalized Anxiety Disorder. The recommended initial dose is 30 mg once daily, independent of food intake. For patients with insufficient treatment response, the dose should be increased to 60 mg daily. If there is inadequate response to 60 mg daily, dose escalation to 90 or 120 mg daily may be considered.

Therapeutic effect typically emerges within 2–4 weeks. After response stabilization, treatment should be continued for several months to prevent relapse.

Patients with Renal Impairment. Dose adjustment is not required in patients with mild to moderate renal impairment. DUXET is contraindicated in patients with end-stage renal disease (creatinine clearance < 30 mL/min).

Patients with Hepatic Impairment. DUXET must not be administered to patients with hepatic disease.

Elderly Patients. Dose adjustment based solely on age is not recommended in elderly patients. As with any medicinal product, caution should be exercised when treating elderly patients, particularly when administering DUXET at a dose of 120 mg daily for major depressive disorder or generalized anxiety disorder.

Discontinuation of Treatment. Abrupt discontinuation should be avoided. The dose should be gradually reduced over a period of at least one to two weeks to minimize the risk of withdrawal reactions. If intolerable symptoms occur following dose reduction or upon discontinuation, the previous dose may be reinstated. Subsequently, the physician may continue tapering the dose, but more gradually.

Pediatric Population.

The safety and efficacy of duloxetine in children have not been established; therefore, the product is contraindicated in this patient population.

Overdose.

Clinical data on duloxetine overdose are limited. Cases of overdose have been reported with doses of up to 5400 mg of duloxetine, either as monotherapy or in combination with other medicinal products. Fatalities have been reported, primarily in cases of mixed overdose, as well as with duloxetine doses of approximately 1000 mg.

Symptoms. Symptoms of overdose (mostly in combination with other medicinal products) include somnolence, coma, serotonin syndrome, seizures, vomiting, and tachycardia.

Treatment. No specific antidotes are known. In cases of serotonin syndrome, specific treatment is required (administration of cyproheptadine and/or temperature control). Airway patency must be ensured. Continuous 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. Activated charcoal reduces drug absorption. Due to the large volume of distribution of duloxetine in the body, forced diuresis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.

Adverse Reactions.

Dizziness, nausea, and headache (>5%) have been reported as adverse symptoms upon discontinuation of duloxetine. Upon discontinuation of the drug, sensory disturbances, sleep disturbances, agitation or anxiety, tremor, irritability, diarrhea, and hyperhidrosis have also been observed. The table below presents adverse reactions associated with duloxetine administration based on data from spontaneous reports and placebo-controlled clinical trials.

Frequency assessment: very common (≥10%), common (≥1% to <10%), uncommon (≥0.1% to <1%), rare (≥0.01% to <0.1%), very rare (<0.01%).

Infections and infestations: laryngitis.

Endocrine system disorders: hypothyroidism.

Immune system disorders: anaphylactic reactions, hypersensitivity.

Metabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydration, hyponatremia, syndrome of inappropriate antidiuretic hormone secretion⁶.

Psychiatric disorders: insomnia, agitation, decreased libido, anxiety, abnormal visions and abnormal orgasm, sleep disorders, bruxism, confusion, apathy, suicidal ideation^5,7, mania, hallucinations, aggression and hostility⁴, suicidal behavior^5,7.

Nervous system disorders: headache, somnolence, dizziness, tremor, paresthesia, myoclonus, akathisia⁷, restlessness, attention disorders, lethargy, dyskinesia, taste disturbances, restless legs syndrome, poor sleep, serotonin syndrome⁶, convulsions¹, psychomotor agitation⁶, extrapyramidal disorders⁶.

Eye disorders: blurred vision, mydriasis, visual disturbances, dry eyes, glaucoma.

Ear and labyrinth disorders: tinnitus¹, vertigo, ear pain.

Cardiac disorders: palpitations; tachycardia; hot flushes; supraventricular arrhythmia; fibrillation, mostly atrial; stress cardiomyopathy (Takotsubo cardiomyopathy) (frequency unknown); arterial hypertension^3,7; increased blood pressure³; orthostatic hypotension²; loss of consciousness²; cold sensation in extremities; hypertensive crisis^3,6.

Respiratory, thoracic and mediastinal disorders: yawning, oropharyngeal pain, throat tightness, epistaxis, interstitial lung disease¹⁰, eosinophilic pneumonia⁶.

Gastrointestinal disorders: nausea, vomiting, dyspepsia, flatulence, abdominal pain, constipation, diarrhea, gastrointestinal hemorrhage⁷, gastroenteritis, belching, gastritis, stomatitis, bad breath, blood in stool, dry mouth, dysphagia, microscopic colitis⁹.

Hepatobiliary disorders: elevated liver enzymes (ALT, AST, alkaline phosphatase), hepatitis³, acute liver injury, jaundice⁶, liver failure⁶.

Skin and subcutaneous tissue disorders: increased sweating, rash, night sweats, contact dermatitis, urticaria, cold sweat, photosensitivity, increased tendency to bruising, angioedema⁶, Stevens-Johnson syndrome⁶, skin vasculitis.

Musculoskeletal and connective tissue disorders: musculoskeletal pain, muscle spasm, muscle twitching, muscle stiffness, trismus.

Renal and urinary disorders: dysuria, urinary retention, difficulty initiating urination, nocturia, polyuria, decreased urine stream, abnormal urine odor.

Reproductive system and breast disorders: erectile dysfunction, ejaculation disorder or delay, menstrual disorders, sexual dysfunction, gynecological bleeding, menopausal symptoms, galactorrhea, hyperprolactinemia, postpartum hemorrhage⁶, testicular pain.

General disorders and administration site conditions: fatigue, chest pain⁷, falls⁸, malaise, cold sensation, "pins and needles" sensation, thirst, feeling unwell, hot sensation, gait disturbances.

Investigations: decreased body weight, increased body weight, increased creatine phosphokinase levels, increased blood cholesterol levels, increased blood potassium levels.

• Cases of convulsions and tinnitus were observed after discontinuation of treatment.
  • Cases of orthostatic hypotension and loss of consciousness were primarily observed at the beginning of treatment.
    • Patients experiencing persistent increases in blood pressure during duloxetine treatment should have their dose reduced or the therapy tapered off gradually.
      • Cases of aggression and hostility were reported at the beginning of treatment and after discontinuation.
        • Cases of suicidal ideation and suicidal behavior were reported at the beginning of treatment and immediately after discontinuation.
          • Frequency established from post-marketing surveillance data.
            • Statistically not significantly different from placebo.
              • Falls were more frequent in elderly patients (≥ 65 years).
                • Approximate frequency based on data from all clinical trials.
                  • Approximate frequency based on data from placebo-controlled clinical trials.

Discontinuation of therapy (especially abrupt discontinuation) is frequently accompanied by withdrawal syndrome. The most common adverse reactions in such cases include: dizziness, somnolence, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), weakness, anxiety or aggression, nausea and/or vomiting, tremor, headache, irritability, diarrhea, hyperhidrosis, and dizziness. Gradual discontinuation of therapy is recommended. For SSRIs and SNRIs, these events are usually mild or moderate and self-limiting, but in some patients they may be severe and/or prolonged. Therefore, gradual discontinuation by dose reduction is recommended when treatment with duloxetine is no longer required (see sections "Special Instructions" and "Dosage and Administration").

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 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 treatment group was 0.3%. Small increases in fasting blood glucose and total cholesterol were also observed in patients receiving duloxetine, while these laboratory parameters showed slight decreases in the risk group counts.

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

Renal impairment.

In patients with severe renal impairment (creatinine clearance <30 mL/min) undergoing hemodialysis, increased plasma levels of duloxetine have been observed. Use is contraindicated.

Hepatitis/Elevated liver enzymes.

Cases of liver injury have been reported, including marked elevations in liver enzymes (increases up to 10 times the upper limit of normal), hepatitis, and jaundice. Most of these events occurred within the first month of treatment. Liver injury is most commonly hepatocellular in nature. Duloxetine should be used with caution in patients taking medications that may cause liver injury.

Mild increases in blood potassium levels have been reported. Transient abnormal potassium levels were uncommonly observed in patients receiving duloxetine compared to placebo.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25°C in the original packaging.

Keep out of reach and sight of children.

Packaging.

14 capsules in a blister; 2 blisters in a cardboard package.

Prescription status.

Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and location of business operations.

Sankaklar Quarter, Eskisehir Yolu Akcakoca Highway No:299, 81100 Duzce, Turkey.