Nexetin

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

Composition:

Active ingredient: duloxetine;

1 capsule contains duloxetine hydrochloride equivalent to 20 mg or 40 mg of duloxetine;

Excipients: spherical sugar (neutral pellets), hypromellose, sucrose, talc, triethyl citrate, hypromellose acetate succinate, concentrated ammonia solution, Opadry White 02A28361 coating: hypromellose, titanium dioxide (E 171), talc;

Capsule shell composition for 20 mg: gelatin, indigocarmine (E 132), titanium dioxide (E 171);

Capsule shell composition for 40 mg: gelatin, indigocarmine (E 132), red iron oxide (E 172), yellow iron oxide (E 172), titanium dioxide (E 171).

Pharmaceutical form. Hard enteric-coated capsules.

Main physicochemical properties:

20 mg capsules: hard gelatin capsules with an opaque blue body and an opaque blue cap, containing pellets ranging from white to yellowish;

40 mg capsules: hard gelatin capsules with an opaque orange body and an opaque blue cap, containing pellets ranging from white to yellowish.

Pharmacotherapeutic group.

Antidepressants. ATC code N06AX21.

Pharmacological Properties

Pharmacodynamics

Duloxetine is a combined inhibitor of serotonin and norepinephrine reuptake. It weakly inhibits dopamine reuptake and has negligible affinity for histaminergic and dopaminergic, cholinergic, and adrenergic receptors.

The mechanism of action of duloxetine in the treatment of stress urinary incontinence in women is likely related to increased levels of serotonin and norepinephrine, which in turn enhances stimulation of the pudendal nerve at the level of the urethral sphincter. Thus, the use of duloxetine promotes strengthening of urethral tone during urine retention, particularly under conditions of physical exertion.

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 by the CYP2D6 and CYP1A2 isoenzymes. The metabolites formed are pharmacologically inactive.

Elimination. The mean elimination half-life of duloxetine is 12 hours. The mean 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 subjects. Therefore, patients with chronic renal impairment should be started on a lower dose.

Clinical characteristics.

Indications.

Treatment of moderate to severe stress urinary incontinence in women.

The drug is intended for adults.

Contraindications.

Hypersensitivity to duloxetine or to any of the excipients of the drug.

Concomitant use with fluvoxamine, ciprofloxacin, or enoxacin (strong CYP1A2 inhibitors) – due to increased plasma concentration of duloxetine.

End-stage renal disease (creatinine clearance < 30 mL/min).

Unstable arterial hypertension, which may provoke a hypertensive crisis.

Concomitant use with non-selective irreversible monoamine oxidase inhibitors (MAOIs), and use of duloxetine at least within 14 days after discontinuation of MAOI therapy. Due to the half-life of duloxetine, MAOIs must not be used at least within 5 days after discontinuation of duloxetine treatment.

Liver disease, which may lead to hepatic failure.

Not recommended for children due to insufficient data on safety and efficacy of duloxetine in this age group.

Interaction with other medicinal products and other types of interactions.

Monoamine oxidase inhibitors (MAOIs). Due to the risk of serotonin syndrome, duloxetine must not be used in combination with non-selective irreversible MAOIs or at least within 14 days after discontinuation of MAOI therapy. Due to the half-life of duloxetine, MAOIs must not be used at least within 5 days after discontinuation of duloxetine (see section "Contraindications").

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

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

Medicinal products acting on the central nervous system. Duloxetine should be used with caution in combination with other medicinal products acting on the central nervous system, especially those with similar mechanisms of action, including alcohol and sedative agents (e.g., benzodiazepines, morphine-like drugs, neuroleptics, phenobarbital, sedatives, antihistamines).

Serotonin syndrome. Serotonin syndrome has been rarely reported in patients taking SSRIs/SNRIs concomitantly with serotonergic agents. The drug is not recommended to be used concomitantly with serotonergic antidepressants such as SSRIs/SNRIs, tricyclic antidepressants (e.g., clomipramine or amitriptyline), MAOIs (e.g., moclobemide or linezolid), St. John's wort (Hypericum perforatum), triptans, tramadol, meperidine, and tryptophan (see section "Special precautions for use").

Effect of duloxetine on other medicinal products

Drugs metabolized by CYP1A2. In a clinical study of concomitant administration of theophylline, a CYP1A2 substrate, with duloxetine (60 mg twice daily), the pharmacokinetics of each were not significantly affected by the other.

Drugs 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 its 5-hydroxy metabolite; therefore, dose adjustment is not recommended. Therefore, caution is required when using duloxetine with CYP2D6 inhibitors (risperidone, tricyclic antidepressants [TCAs] such as nortriptyline, amitriptyline, and imipramine) that have a narrow therapeutic index (e.g., flecainide, propafenone, and metoprolol).

Oral contraceptives and other steroid medicinal products. In vitro studies have shown 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 used with caution when co-administered with oral anticoagulants and antithrombotic agents due to the potential increased risk of bleeding via pharmacodynamic interaction. In addition, an increase in international normalized ratio (INR) has been reported when patients received warfarin concomitantly with duloxetine. However, in a clinical pharmacology study, concomitant administration of duloxetine and warfarin to healthy volunteers under controlled conditions did not result in clinically significant changes in INR compared to 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 aluminum- and magnesium-containing antacids or with famotidine does not significantly affect the rate and extent of absorption of duloxetine after oral administration of a 40 mg dose.

Inducers of CYP1A2. Pharmacokinetic studies 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 used with caution in patients with a history of mania or diagnosed bipolar disorder and/or seizures.

Serotonin syndrome/Malignant neuroleptic syndrome

As with other serotonergic agents, serotonin syndrome or malignant neuroleptic syndrome (NMS), potentially life-threatening conditions, may occur during treatment with duloxetine, particularly when used concomitantly with other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants, or triptans), with agents that impair serotonin metabolism such as monoamine oxidase inhibitors (MAOIs), or with antipsychotic drugs or other dopamine antagonists that may affect serotonergic neurotransmitter systems (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

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

If concomitant treatment with duloxetine and other serotonergic drugs affecting serotonergic and/or dopaminergic neurotransmitter systems is clinically justified, careful monitoring of patients is recommended, especially at the beginning of therapy and during dose escalation.

St. John's wort (Hypericum perforatum)

Adverse reactions may occur more frequently when duloxetine is used concomitantly with herbal preparations containing St. John's wort (Hypericum perforatum).

Mydriasis

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

Blood pressure and heart rate

In some patients, duloxetine may cause increases in blood pressure and clinically significant arterial hypertension. This may be related to the noradrenergic effect of duloxetine. Cases of hypertensive crisis have been reported during duloxetine treatment, especially in patients with hypertensive disease. Patients with arterial hypertension and/or other heart diseases should have their blood pressure monitored, particularly during the first month of treatment. Duloxetine should be used with caution in patients whose underlying medical conditions may be compromised by increases in heart rate or blood pressure. Caution is also advised when prescribing 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 (see section "Undesirable effects"). Treatment should not be initiated in patients with unstable hypertension (see section "Contraindications").

Renal function

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

Haemorrhage

Disorders of haemostasis such as ecchymosis, purpura, and gastrointestinal bleeding have been observed during treatment with SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), including duloxetine. Duloxetine may increase the risk of postpartum haemorrhage (see subsection "Use during pregnancy or breastfeeding"). The drug should be used with caution in patients taking anticoagulants and/or drugs affecting platelet function (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs] or acetylsalicylic acid), as well as in patients with a predisposition to bleeding.

Discontinuation of treatment

Upon discontinuation of treatment (particularly abrupt discontinuation), withdrawal symptoms frequently occur (see section "Undesirable effects"). In clinical trials, adverse events observed after abrupt discontinuation occurred in approximately 44% of patients taking duloxetine and in 24% of patients taking placebo.

The risk of withdrawal symptoms observed with SSRIs and SNRIs may depend on several factors, including duration of treatment, dose, and speed of dose reduction. The most commonly occurring adverse reactions are listed in section "Undesirable effects". These symptoms are usually mild to moderate in severity, but in some patients may be severe. Withdrawal symptoms typically occur within the first few days after discontinuation of treatment, although isolated reports have described such symptoms in patients who inadvertently missed a dose. Generally, these symptoms resolve spontaneously within two weeks, although in some patients they may persist longer (2–3 months or more). Therefore, when discontinuing treatment, the dose of duloxetine should be gradually reduced over at least two weeks, depending on the patient's needs.

Hyponatraemia

Cases of hyponatraemia, including cases with serum sodium levels below 110 mmol/L, have been reported during duloxetine treatment. Hyponatraemia may be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Most cases of hyponatraemia were observed in elderly patients, particularly in combination with conditions leading to fluid imbalance. The drug should be prescribed with caution to patients at increased risk of developing hyponatraemia (e.g., elderly patients), patients with liver cirrhosis, patients with dehydration, or patients receiving diuretics.

Depression, suicidal thoughts and behaviour

Although the medicinal product Nexitin is not indicated for the treatment of depression, its active ingredient (duloxetine) is also used as an antidepressant. Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related 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 in the early stages of recovery. Patients with a history of suicide attempts or those exhibiting a significant degree of suicidal ideation prior to treatment initiation are at greater risk of suicidal thoughts or suicidal behaviour and should therefore be closely monitored during treatment.

Cases of suicidal thoughts and suicidal behaviour have been reported during duloxetine therapy or immediately after discontinuation of treatment (see section "Special precautions for use"). Physicians should encourage patients to report any distressing thoughts, feelings, or symptoms of depression at any time. If a patient develops agitation or symptoms of depression during Nexitin therapy, consultation with a specialist should be sought, as depression is a serious condition. If a decision is made to initiate pharmacological antidepressant therapy, gradual discontinuation of Nexitin is recommended (see section "Dosage and administration").

Use in children and adolescents under 18 years of age

Duloxetine should not be used in the treatment of children under 18 years of age. Suicidal behaviour (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour, and anger) were observed more frequently in clinical trials involving children and adolescents receiving antidepressants compared to those receiving placebo. If, based on clinical need, a decision to treat is made, careful monitoring for the emergence of suicidal symptoms is required. In addition, long-term safety data on growth, puberty, cognitive, and behavioural development in children and adolescents are lacking.

Medicinal products containing duloxetine

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

Hepatitis/elevated liver enzymes

Cases of liver injury, including marked elevations in liver enzymes (>10 times the upper limit of normal), hepatitis, and jaundice have been reported during duloxetine treatment (see section "Undesirable effects"). Most cases occurred within the first few months of treatment. Liver injury is most commonly hepatocellular in nature. Duloxetine should be prescribed with caution in patients taking drugs that may cause liver damage.

Akathisia/psychomotor restlessness

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

Sexual dysfunction

SSRIs/SNRIs may cause symptoms of sexual dysfunction (see section "Undesirable effects"). Prolonged sexual dysfunction has been reported, with symptoms persisting despite discontinuation of SSRIs/SNRIs.

Sucrose intolerance

The product must not be given to patients with hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding

Studies on the use of duloxetine in pregnant women have not been conducted; therefore, the drug is not prescribed during pregnancy. As with other serotonergic medicinal products, neonates may exhibit symptoms of withdrawal syndrome if the mother used duloxetine prior to delivery. Symptoms of withdrawal syndrome include orthostatic hypotension, tremor, hyperreflexia syndrome, difficulty swallowing, sucking difficulties, respiratory disorders, and epileptic 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.

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 during treatment with duloxetine is not recommended.

Ability to affect reaction speed when driving or operating machinery

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

Dosage and Administration

The recommended dose of the drug is 40 mg twice daily, regardless of food intake. After 2–4 weeks of treatment, patients should undergo a medical evaluation to assess the therapeutic response. Some patients may experience improvement at the beginning of treatment with a dose of 20 mg twice daily for 2 weeks before increasing to the recommended dose of 40 mg twice daily. Dose escalation may reduce the risk of nausea and dizziness.

Capsules with a dosage of 20 mg may also be used.

Combining the use of the drug with pelvic floor muscle training may be more effective than treatment with duloxetine alone. A pelvic floor training program is recommended to be considered.

Patients with hepatic impairment. The drug must not be administered to patients with liver disease.

Patients with renal impairment. Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance of 30–80 mL/min). The use of the drug is contraindicated in patients with end-stage renal disease (creatinine clearance < 30 mL/min).

Elderly patients. The medicinal product should be used with caution in elderly patients.

Children

The safety and efficacy of duloxetine in children (under 18 years of age) have not been established; therefore, the drug should not be prescribed to this age group.

Withdrawal syndrome. Withdrawal symptoms are quite common, especially following abrupt discontinuation of treatment. Discontinuation of treatment should be carried out over a period of at least 2 weeks by gradually reducing the dose.

Overdose.

Data regarding duloxetine overdose are limited. Cases of ingestion of large doses (up to 5400 mg) of duloxetine have been reported. Fatal outcomes have been reported following ingestion of the drug alone at a dose of approximately 1000 mg or in combination with other medicinal products. Symptoms of overdose (either alone or in combination with other medicinal products) included somnolence, coma, serotonin syndrome, seizures, vomiting, and tachycardia.

Treatment. Specific antidotes are not known. In case of serotonin syndrome, specific treatment is required (administration of cyproheptadine and/or temperature control). Airway patency should be ensured. Continuous cardiac monitoring and vital signs surveillance, along with appropriate symptomatic and supportive measures, are recommended. Gastric lavage may be beneficial if performed soon after drug ingestion or for symptomatic purposes. 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

According to study data, the most commonly observed adverse events were nausea, dry mouth, fatigue, and constipation.

The following classification was used to assess the frequency of various adverse reactions:

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

1 Seizures and tinnitus were also observed after discontinuation of treatment.

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

3 Patients who experience persistent increase in blood pressure during duloxetine treatment require dose reduction or gradual discontinuation of therapy.

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 behavior were reported during treatment and immediately after discontinuation of treatment.

6 The frequency established from post-marketing studies, which were not observed in placebo-controlled clinical trials.

7 Statistically not significantly different from those observed with placebo.

8 Falls were most frequently observed in elderly patients (≥ 65 years of age).

9 Calculated frequency based on all clinical study data.

10 Frequency estimation based on placebo-controlled clinical trials.

Discontinuation of therapy (especially abrupt discontinuation) is often accompanied by withdrawal syndrome. The most common adverse reactions in such cases are dizziness, sensory disturbances (including paresthesia or electric shock sensations, particularly in the head), sleep disturbances (including insomnia and vivid dreams), fatigue, somnolence, weakness, agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhea, hyperhidrosis, and vertigo. Gradual discontinuation of therapy is recommended.

For SSRIs and SNRIs, these events are usually mild or moderate and resolve spontaneously; 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 "Special precautions" 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, although 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 slight decreases in risk group counts were observed in these laboratory parameters.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is important. 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, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

14 capsules in a blister. 2 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and location of its business activity.

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