Depratal

I N S T R U C T I O N for medical use of the medicinal product Depretal (Depratal)

Composition:

active substance: duloxetine hydrochloride;

one enteric-coated tablet contains duloxetine hydrochloride equivalent to 30 mg or 60 mg of duloxetine;

excipients: compressed sugar, maize starch, magnesium stearate;

coating composition: methacrylic acid-ethyl acrylate copolymer (1:1), 30% dispersion; triethyl citrate; talc; titanium dioxide (E 171); simethicone emulsion.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties:

30 mg dosage: white to almost white, round, biconvex, coated tablets with engraving ’)’ on one side.

60 mg dosage: white to almost white, round, biconvex, coated tablets.

Pharmacotherapeutic group. Other antidepressants. ATC code N06A X21.

Pharmacological Properties

Pharmacodynamics

Duloxetine is a combined inhibitor of serotonin and norepinephrine reuptake. It weakly inhibits dopamine reuptake and has no significant affinity for histaminergic and dopaminergic, cholinergic, or adrenergic receptors. The mechanism of action of duloxetine in the treatment of depression is attributed to inhibition of the reuptake of serotonin and norepinephrine, resulting in enhanced serotonergic and noradrenergic neurotransmission in the central nervous system (CNS). Duloxetine also exerts analgesic effects, which are likely due to the slowing of pain impulse transmission in the CNS.

Pharmacokinetics

Absorption

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

Distribution

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

Metabolism

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

Elimination

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

Non-clinical Safety Data

Duloxetine did not show genotoxicity in a standard battery of tests and did not demonstrate carcinogenicity in rats. Multinucleated hepatocytes were observed in the liver without other histopathological changes in a carcinogenicity study in rats. The primary mechanism and clinical significance are unknown. In female mice treated with duloxetine for 2 years, an increased incidence of hepatocellular adenomas and carcinomas was observed only at a high dose (144 mg/kg/day), but these were considered secondary to the induction of hepatic microsomal enzymes. The relevance of findings from mouse studies to humans is unknown.

In a study in female rats treated with duloxetine (45 mg/kg/day) before and during mating and in early pregnancy, reduced maternal food consumption and body weight, disruption of the estrous cycle, reduced offspring live birth and survival rates, and delayed offspring growth were observed at systemic exposure levels estimated to be up to the highest at maximum clinical exposure (AUC). In an embryotoxicity study in rabbits, a higher incidence of cardiovascular and skeletal developmental abnormalities was observed at systemic exposure levels lower than the maximum clinical exposure (AUC). No developmental abnormalities were observed in another study testing a higher dose of a different duloxetine salt. In prenatal/postnatal toxicity studies in rats, duloxetine caused adverse behavioral effects in offspring at doses below the maximum clinical exposure (AUC). Studies in young rats revealed a transient effect on neurobehavior, as well as significant reduction in body weight and food consumption, induction of hepatic enzymes, and hepatocellular vacuolization at a dose of 45 mg/kg/day. The overall toxicity profile of duloxetine in young rats was similar to that in adult rats. The no-observed-adverse-effect level (NOAEL) for duloxetine in young rats was determined to be 20 mg/kg/day.

Clinical Characteristics.

Indications.

Treatment of major depressive disorder.

Treatment of diabetic peripheral neuropathic pain.

Treatment of generalized anxiety disorder.

Contraindications.

Contraindications for the use of the drug include 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 must not be prescribed to patients with unstable hypertension, as this may provoke a hypertensive crisis.

Duloxetine must not be prescribed to patients with end-stage renal failure (creatinine clearance < 30 mL/min).

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

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

Interaction with other medicinal products and other forms of interaction.

Medicinal products metabolized by CYP1A2. In a clinical study, no significant pharmacokinetic interaction was observed when theophylline, a CYP1A2 substrate, was co-administered with duloxetine (60 mg twice daily).

Inhibitors of CYP1A2. Since CYP1A2 is involved in the metabolism of duloxetine, concomitant use of duloxetine with strong inhibitors of CYP1A2 is likely to increase duloxetine concentrations. Fluvoxamine (100 mg once daily), a potent CYP1A2 inhibitor, reduces the plasma clearance of duloxetine by approximately 77%. Therefore, duloxetine must not be prescribed together with CYP1A2 inhibitors, particularly fluvoxamine.

Medicinal products metabolized by CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine 60 mg twice daily was administered with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased threefold. Concomitant administration of duloxetine (40 mg twice daily) increased the steady-state AUC of tolterodine (2 mg twice daily) by 71%, but did not affect the pharmacokinetics of the 5-hydroxy metabolite; therefore, no dosage adjustments are recommended.

Caution is recommended when using duloxetine concomitantly with medicinal products primarily metabolized by CYP2D6 (e.g., risperidone, tricyclic antidepressants such as nortriptyline, amitriptyline, and imipramine), especially those with a narrow therapeutic index (e.g., flecainide, propafenone, and metoprolol).

Medicinal products acting on the CNS. Precautions are necessary when prescribing duloxetine in combination with other medicinal products and substances acting on the central nervous system, particularly those with similar mechanisms of action, including alcohol and sedative agents (e.g., benzodiazepines, opioid analgesics, antidepressants, phenobarbital, sedating antihistamines).

MAO inhibitors. Duloxetine must not be prescribed concomitantly with non-selective irreversible MAO inhibitors due to the risk of serotonin syndrome, and at least 14 days must elapse after discontinuation of MAO inhibitors before starting duloxetine. Considering the half-life of duloxetine, MAO inhibitors must not be prescribed until at least 5 days after discontinuation of duloxetine. The risk of serotonin syndrome is lower when reversible selective MAO inhibitors (e.g., moclobemide), triptans, tramadol, meperidine, tryptophan, or buprenorphine are used, but such combinations are not recommended. Linezolid, an antibiotic and a reversible non-selective MAOI, should not be prescribed to patients taking duloxetine (see section "Special precautions for use").

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

Anticoagulants and antithrombotic agents. Duloxetine should be prescribed with caution together with oral anticoagulants and antithrombotic agents due to an increased risk of bleeding resulting from pharmacodynamic interaction. Increased international normalized ratio (INR) values have been reported in patients taking warfarin who started taking duloxetine. However, in a clinical pharmacology study, concomitant administration of duloxetine and warfarin in healthy volunteers under controlled conditions 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.

Products containing St. John's wort. Adverse reactions commonly occur when used concomitantly with duloxetine.

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

Inducers of CYP1A2: pharmacokinetic analyses have shown that smokers have plasma concentrations of duloxetine nearly 50% lower than non-smokers.

Special precautions for use.

Seizures and mania. Duloxetine should be prescribed with caution in patients with a history of seizures, mania, or bipolar disorder.

Mydriasis. Cases of mydriasis have been reported in association with duloxetine use; therefore, duloxetine should be prescribed 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 increase arterial blood pressure. This may be related to the noradrenergic effect of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, especially in patients with pre-existing hypertension. Patients with arterial hypertension and/or other cardiac conditions should have their blood pressure monitored, particularly during the first month of treatment. Duloxetine should be used with caution in patients at risk of cardiac arrhythmias or increased blood pressure. Caution is also advised when using duloxetine with medicinal products that may impair its metabolism (see section "Interaction with other medicinal products and other forms of interaction"). Patients with persistently elevated blood pressure may require dose reduction or gradual discontinuation of the drug. Treatment of patients with unstable hypertension is not recommended.

Renal impairment. Increased plasma concentrations of duloxetine have been observed in patients with end-stage renal disease undergoing chronic hemodialysis (creatinine clearance < 30 mL/min). For patients with end-stage renal disease, see section "Contraindications"; for patients with mild or moderate renal impairment, see section "Posology and method of administration".

Serotonin syndrome and neuroleptic malignant syndrome. Treatment with duloxetine may lead to potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome, 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), antidepressants, or other dopamine antagonists that may affect serotonergic and/or dopaminergic neurotransmitter systems.

Serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

In its most severe form, serotonin syndrome may resemble neuroleptic malignant syndrome, which is characterized by hyperthermia, muscle rigidity, elevated serum creatine kinase, autonomic instability with possible rapid fluctuations in vital signs, and mental status changes.
If concomitant treatment with duloxetine and other serotonergic agents and/or neuroleptics affecting serotonergic and/or dopaminergic neurotransmitter systems is clinically justified, careful patient monitoring is recommended, especially at the beginning of treatment and during dose escalation.

If serotonin syndrome is suspected, consideration should be given to reducing the dose or discontinuing treatment, depending on the severity of symptoms.

Bleeding. Abnormal bleeding, including ecchymoses, purpura, gastrointestinal bleeding, and hemorrhage, has been reported with the use of SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), including duloxetine. The drug should be prescribed with caution in patients taking anticoagulants and/or medicinal products affecting platelet function (e.g., nonsteroidal anti-inflammatory drugs or acetylsalicylic acid), as well as in patients with a predisposition to bleeding. Duloxetine increases the risk of postpartum hemorrhage (see section "Use during pregnancy or breastfeeding").

Hyponatremia. Hyponatremia, including cases with serum sodium levels below 110 mmol/L, has been reported with the use of the medicinal product Depretal. Hyponatremia may be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Most of these cases were reported in elderly patients, particularly those with a history of hyponatremia or conditions that may alter fluid balance. The drug should be prescribed with caution in elderly patients, patients with cirrhosis, patients with dehydration, or patients receiving diuretics.

Discontinuation syndrome. Discontinuation symptoms occur quite frequently, especially following abrupt cessation of treatment (see section "Adverse reactions"). In clinical trials, adverse reactions upon abrupt discontinuation were observed in approximately 45% of patients receiving duloxetine and in 23% of patients receiving placebo.

The risk of discontinuation symptoms with SSRIs and SNRIs depends on several factors, including duration of therapy, dosage, and rate of dose reduction. These symptoms are usually mild or moderate, but in some patients they may be severe. They typically appear within the first few days after stopping treatment, although very rare reports describe such symptoms in patients who accidentally missed a dose. These symptoms are usually self-limiting and resolve within 2 weeks, although in some individuals they may persist longer (2–3 months or more). Therefore, it is recommended that discontinuation of duloxetine be carried out gradually over a period of at least 2 weeks, according to individual patient needs.

Akathisia/psychomotor agitation. The use of duloxetine has been associated with akathisia, characterized by subjective distressing psychomotor restlessness and an urge to move, often accompanied by an inability to sit or stand still. This phenomenon occurs within the first few weeks of treatment. In patients who develop these symptoms, dose escalation may be harmful.

Hepatitis/elevated liver enzymes. Cases of hepatic injury, including marked increases in liver enzymes (up to 10 times the upper limit of normal), hepatitis, and jaundice, have been reported (see section "Adverse reactions"). Most of these events occurred within the first month of treatment. Hepatic injury was predominantly hepatocellular in nature. Duloxetine should be prescribed with caution in patients taking medicinal products that may cause hepatic 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 and/or SNRIs.

Sucrose content. Depretal enteric-coated tablets 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 thoughts, self-harm, and suicide (suicide-related phenomena). The risk persists until significant remission occurs. Patients should be closely monitored until significant 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 in the early stages of treatment.

Other psychiatric conditions for which duloxetine is prescribed may also be associated with an increased risk of suicide-related phenomena. Additionally, these psychiatric conditions may be comorbid with major depressive disorder. Therefore, similar precautions should be taken when treating patients with major depressive disorder and other psychiatric disorders. 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. 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 ideation and suicidal behavior have been reported during treatment with duloxetine or immediately after discontinuation.

During treatment, especially in the early stages and after dose changes, patients should be closely monitored, particularly those at high risk. Patients (and their caregivers) should be informed of the need to monitor for any clinical worsening, suicidal behavior or thoughts, and unusual changes in behavior, and to contact their physician immediately 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 its discontinuation, as with 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). Duloxetine should not be used for the treatment of children and adolescents (under 18 years of age). Suicidal-related behavior (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behavior, and anger) were observed more frequently in clinical trials among children and adolescents receiving antidepressants compared to those receiving placebo. If, considering clinical need, a decision is made to initiate treatment, the patient should be closely monitored for the emergence of suicidal symptoms. Additionally, long-term safety data regarding growth, maturation, and cognitive and behavioral development in children and adolescents are lacking (see section "Adverse reactions").

Elderly patients. Data on the use of the medicinal product Depretal at a dose of 120 mg in elderly patients with major depressive disorder and generalized anxiety disorder are limited. Therefore, caution should be exercised when treating elderly patients with the maximum dose.

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies have demonstrated reproductive toxicity when systemic exposure (AUC) to duloxetine was lower than the maximum clinical exposure (see section "Preclinical safety data").

Results from two large observational studies (one conducted in the United States involving 2,500 women, and one conducted in the European Union involving 1,500 women who took duloxetine during the first trimester of pregnancy) did not indicate an overall increased risk of major congenital malformations. Analyses of individual malformations, such as cardiac defects, were inconclusive.

In the European Union study, the use of duloxetine in patients during late pregnancy (at any time from 20 weeks of gestation to delivery) was associated with an increased risk of preterm birth (nearly two-fold, corresponding to approximately 6 additional preterm births per 100 women). Most preterm births occurred between 35 and 36 weeks of gestation. No such association was observed in the U.S. study.

Observational data from the United States show an increased risk (nearly two-fold) of postpartum hemorrhage with duloxetine use within one month before delivery.

Epidemiological data suggest that the use of SSRIs during pregnancy, particularly in late pregnancy, increases the risk of persistent pulmonary hypertension in newborns.

Although no study has specifically examined the association between persistent pulmonary hypertension and SSRI treatment, this potential risk cannot be excluded with duloxetine use, considering its related mechanism of action (inhibition of serotonin reuptake).

As with other serotonergic medicinal products, newborns exposed to maternal duloxetine use may develop withdrawal symptoms shortly after birth. These symptoms may include hypotonia, tremor, agitation, feeding difficulties, respiratory distress, and seizures. In most cases, withdrawal symptoms occurred either at birth or within a few days after delivery.

Medicinal products containing duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to inform their physician if they become pregnant or plan to become pregnant during therapy.

Breastfeeding

Duloxetine is weakly excreted into 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 duloxetine treatment is not recommended.

Fertility

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

Ability to influence 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 use may be associated with sedation and dizziness. During treatment, patients may experience sedative effects or dizziness. In such cases, patients should refrain from potentially hazardous activities requiring heightened attention and psychomotor speed.

Dosage and Administration

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

The safety of doses ranging from 60 mg once daily up to the maximum dose of 120 mg per day has been evaluated in clinical trials. However, there are no clinical data demonstrating that patients who do not respond to the initial recommended dose will benefit from dose escalation.

Therapeutic effect develops within 2–4 weeks.

After achieving a response to antidepressant treatment, it is recommended to continue therapy for several months to prevent relapse. For patients who respond to duloxetine and have a history of recurrent episodes of major depressive disorder, long-term continuation therapy at a dose of 60–120 mg daily should be considered.

Generalized Anxiety Disorder. The recommended initial dose is 30 mg once daily, independent of food intake. If an inadequate response to treatment is observed, the dose may be increased to 60 mg daily, which is the usual maintenance dose for most patients. For patients with comorbid major depressive disorder, the recommended initial and maintenance dose is 60 mg once daily (see dosage recommendations above).

Efficacy and safety of doses up to 120 mg have been demonstrated in clinical trials. Therefore, for patients with inadequate response to a 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 therapeutic effect, treatment should be continued for several months to prevent relapse.

Diabetic Peripheral Neuropathic Pain. The recommended initial dose is 60 mg once daily, independent of food intake. Some patients may benefit from dose escalation up to a maximum of 120 mg daily, administered in two divided doses. This dosage regimen has been evaluated for safety in clinical trials. Plasma concentrations of duloxetine show high interindividual variability; therefore, some patients who do not respond adequately to a 60 mg dose may benefit from a higher dose.

Therapeutic effect develops within 2 months.

In patients with inadequate initial response, further dose increases beyond this point are unlikely to be justified.
Therapeutic benefits should be regularly assessed (at least every 3 months).

Patients with Renal Impairment. Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance of 30–80 mL/min). This medicinal product is contraindicated in patients with end-stage renal disease (creatinine clearance < 30 mL/min).

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

Elderly Patients. Dose adjustment is not required when administering the drug to elderly patients. However, as with any medicinal product, Depretil should be used with caution in elderly patients, particularly when using duloxetine at a dose of 120 mg daily for major depressive disorder or generalized anxiety disorder, for which data are limited (see section "Special Warnings and Precautions for Use").

Discontinuation of Treatment

Abrupt discontinuation of the medicinal product should be avoided. When stopping treatment with duloxetine, the dose should be gradually reduced over a period of at least 1 to 2 weeks to minimize the risk of withdrawal symptoms (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions"). If intolerable symptoms occur after dose reduction or upon discontinuation, reinitiation of the previously prescribed dose may be considered. The physician may then continue tapering the dose at a slower rate.

Pediatric Population

The medicinal product is not used in pediatric practice.

Overdose

Symptoms. Cases of overdose with duloxetine, both as monotherapy and in combination with other medicinal products, have been reported. The highest documented single dose was 5400 mg. Several fatal cases have occurred, primarily following mixed overdoses; however, fatal outcomes have also been reported after administration of duloxetine alone at doses of approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or in combination with other drugs) included somnolence, coma, serotonin syndrome, seizures, vomiting, and tachycardia. Common symptoms of overdose (mostly following concomitant use with other medications) included somnolence, coma, serotonin syndrome, epileptic seizures, vomiting, and tachycardia.

There are no specific antidotes. In cases of serotonin syndrome, specific treatment is required (cyproheptadine and/or temperature control). Airway patency must be ensured. Continuous cardiac monitoring and vital signs surveillance, along with appropriate symptomatic and supportive measures, are recommended. Gastric lavage may be considered if performed soon after ingestion or for symptomatic reasons. 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.

Dizziness, nausea, headache, dry mouth, and somnolence have been most frequently reported as adverse symptoms during duloxetine treatment. However, most adverse reactions were mild to moderate in severity, typically beginning early in the course of therapy, and the majority resolved 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 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000).

• 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".
      • Reports of aggression and hostility were observed at the beginning of treatment and after discontinuation of treatment.
        • Reports of suicidal ideation and suicidal behaviour were observed at the beginning of treatment and immediately after discontinuation of treatment.
          • Frequency established from post-marketing data not observed in placebo-controlled clinical trials.
            • Statistically not significantly different from placebo.
              • Falls were more frequent in elderly patients (≥ 65 years).
                • Calculated frequency is based on all clinical trial data.
                  • Approximate frequency based on placebo-controlled clinical trials.

Description of selected adverse reactions

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

Typically, when treating with SSRIs and SNRIs, these reactions are mild or moderate and resolve spontaneously; however, in some patients they may be severe and/or prolonged. Therefore, if treatment with duloxetine is no longer required, gradual discontinuation by dose tapering is recommended (see sections "Special precautions" and "Dosage and administration").

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

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

In patients with end-stage renal disease (creatinine clearance < 30 mL/min) undergoing haemodialysis, increased plasma levels of duloxetine are observed.

Slight increases in serum potassium levels have been reported. Transient abnormal potassium values were infrequently observed in patients taking duloxetine compared to placebo.

Reporting suspected adverse reactions

If adverse effects occur or if you have any questions regarding the safety of this medicinal product, please contact the representative office of "Adamed Pharma S.A." at 23 Lesi Ukrainky Blvd, Office 2, Kyiv, 01133, Tel: +38 044 374 67 55.

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

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. 7 enteric-coated tablets per blister; 1 or 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Adamed Pharma S.A., Poland.

Manufacturer's address and location of operations. ul. Marsz. J. Piłsudskiego 5, 95-200 Pabianice, Poland.