Defacto 60

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEFAXTO 30, DEFAXTO 60 (DEFAXTO 30, DEFAXTO 60)

Composition:

Active substance: duloxetine hydrochloride;

One capsule contains duloxetine hydrochloride 67.3 mg equivalent to duloxetine 60 mg, or duloxetine hydrochloride 33.7 mg equivalent to duloxetine 30 mg;

Excipients: hypromellose, spherical sugar, talc, sucrose, hypromellose phthalate, triethyl citrate;

For 30 mg – gelatin capsule size "3" (titanium dioxide (E 171), FD&C Blue #2 (E132), gelatin, sodium lauryl sulfate);

For 60 mg – gelatin capsule size "1" [(titanium dioxide (E 171), FD&C Blue #2 (E132), gelatin, sodium lauryl sulfate, iron oxide yellow (E 172)].

Pharmaceutical form. Modified-release hard capsules.

Main physicochemical properties.

For 30 mg – size "3" capsules with an opaque blue cap and an opaque white body, marked with green ink "157" on the body and "A" on the cap, containing granules of white to greyish color.

For 60 mg – size "1" capsules with an opaque blue cap and an opaque green body, marked with white ink "157" on the body and "A" on the cap, containing granules of white to greyish color.

Pharmacotherapeutic group. Antidepressants. Other 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 CNS. Duloxetine also exerts analgesic effects, which are likely due to the inhibition of pain impulse transmission in the central nervous system.

Pharmacokinetics.

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

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

Metabolism. Duloxetine is metabolized by the CYP2D6 and CYP1A2 isoenzymes. The resulting metabolites 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 exposure (AUC) was observed compared to healthy subjects. Therefore, patients with chronic renal impairment 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.

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

Duloxetine must not be administered concomitantly with non-selective, irreversible monoamine oxidase inhibitors (MAOIs), and at least 14 days must elapse after discontinuation of MAOI therapy before starting duloxetine. Due to the half-life of duloxetine, MAOIs must not be initiated within at least 5 days after discontinuation of duloxetine.

Defacto must not be prescribed to patients with unstable hypertension, as it may provoke a hypertensive crisis.

Defacto must not be prescribed to patients with end-stage renal disease (creatinine clearance below 30 mL/min).

Defacto must not be prescribed to patients with hepatic disease, as it may lead to liver failure.

Defacto is not used in pediatric practice.

Defacto must not be administered 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 clinical studies, co-administration of theophylline, a CYP1A2 substrate, with duloxetine (60 mg twice daily) did not result in significant pharmacokinetic interactions.

Inhibitors of CYP1A2. Since CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with strong 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, Defacto must not be co-administered with CYP1A2 inhibitors.

Medicinal products metabolized by CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine 60 mg twice daily was co-administered with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 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 with CYP2D6 inhibitors that have a narrow therapeutic index.

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

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

Serotonin syndrome. Defacto must be used cautiously in combination with serotonergic agents and tricyclic antidepressants, St. John's wort preparations, tramadol, meperidine, and tryptophan.

Anticoagulants and antiplatelet agents. Duloxetine should be used cautiously with oral anticoagulants and antiplatelet agents due to the potential increased risk of bleeding resulting from pharmacodynamic interactions.

MEDICINAL PRODUCTS CONTAINING DULOXETINE.

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

PREPARATIONS CONTAINING ST. JOHN'S WORT.

Adverse reactions frequently occur when used concomitantly with Defacto.

Special precautions for use.

WARNING

Patients at high risk of suicide must be under close supervision during treatment, as suicide attempts may still occur before significant remission is achieved.

The use of duloxetine hydrochloride in patients under 18 years of age has not been studied; therefore, the drug is not intended for this age group.

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

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

Arterial pressure and heart rate. In some patients, duloxetine may cause increased arterial pressure. Hypertensive crises have been reported during duloxetine treatment in patients with known arterial hypertension. Patients with known arterial hypertension and/or other heart conditions should have their blood pressure monitored. In patients with persistently elevated blood pressure, dose reduction or gradual discontinuation of the drug may be necessary. Treatment of patients with unstable hypertension is not recommended.

Patients with renal impairment

In patients with renal impairment (creatinine clearance ≤30 mL/min), increased plasma concentrations of duloxetine are observed. Dosage recommendations for patients with mild to moderate renal impairment are provided in the section "Dosage and administration". Duloxetine is contraindicated in patients with end-stage renal disease; see section "Contraindications".

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome—a potentially life-threatening condition—may occur during treatment with duloxetine, especially when used concomitantly with other serotonergic agents (including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and triptans), or with other drugs affecting serotonin metabolism such as monoamine oxidase inhibitors (MAOIs), antipsychotics, or dopamine antagonists that may affect serotonergic neurotransmitter systems (see sections "Interaction with other medicinal products and other forms of interaction" and "Contraindications").

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

If concomitant use of duloxetine with other serotonergic agents is clinically necessary, close monitoring of the patient is required, especially at the beginning of treatment and during dose escalation.

St. John’s wort

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

Suicide

Major depressive disorder and generalized anxiety disorder

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

Other psychiatric conditions for which Defacto is prescribed may also be associated with an increased risk of suicide-related phenomena. In addition, 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 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. Clinical studies have shown 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 therapy. Close monitoring of patients, particularly those at risk, is necessary throughout therapy, especially in the early stages, and appropriate dose adjustments should be made. Patients and caregivers should be warned to monitor for worsening symptoms, suicidal thoughts or behaviors, and unusual changes in behavior, and to report these immediately to the physician.

Diabetic peripheral neuropathic pain

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

Children

Defacto should not be used in the treatment of children under 18 years of age. Suicidal behavior (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behavior, and anger) were observed more frequently in clinical trials involving children and adolescents receiving antidepressants compared to those receiving placebo.

Hemorrhage Cases of hemorrhage, including ecchymoses, purpura, gastrointestinal bleeding, and hemorrhages, have been reported during treatment with serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (including duloxetine). Particular caution is required when treating patients taking anticoagulants and/or drugs affecting platelet function (e.g., nonsteroidal anti-inflammatory drugs or acetylsalicylic acid), and patients with a predisposition to bleeding.

Hyponatremia Cases of hyponatremia have been reported with duloxetine use, including cases with serum sodium levels as low as 110 mmol/L. Hyponatremia may be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Most cases of hyponatremia occurred in elderly patients, particularly those with a history of fluid imbalance. Duloxetine should be prescribed cautiously in patients at increased risk of hyponatremia: elderly patients, patients with antidiuretic hormone deficiency, and patients with liver cirrhosis.

Discontinuation syndrome Discontinuation symptoms are relatively common, especially after abrupt discontinuation (see section "Dosage and administration"). The risk of discontinuation syndrome with serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors depends on the duration of treatment, dosage, and rate of dose reduction. The most common adverse reactions are listed in the section "Adverse reactions". These symptoms are usually mild to moderate in severity, but in some patients may be severe. Discontinuation symptoms typically occur within the first few days after stopping treatment and, rarely, after missing a dose. Symptoms usually resolve spontaneously within 2 weeks, but in some patients may persist for 2–3 months or longer. Discontinuation of treatment should be carried out gradually over a period of at least 2 weeks.

Elderly patients

Data on the use of Defacto at a dose of 120 mg in elderly patients with major depressive disorder and generalized anxiety disorder are limited. Therefore, duloxetine should be used with caution in these patients, especially at the maximum dose (see section "Dosage and administration").

Akathisia/psychomotor agitation Akathisia may occur during duloxetine treatment, characterized by a subjectively distressing sense of restlessness and an urge to move constantly, often accompanied by an inability to sit or stand still. These symptoms typically appear within the first few weeks of treatment. Dose escalation may be harmful in patients experiencing such symptoms.

Other medicinal products containing duloxetine Duloxetine is marketed under different brand names for several indications (treatment of diabetic peripheral neuropathic pain, major depressive disorder, generalized anxiety disorder, and stress urinary incontinence). Concomitant use of more than one of these products should be avoided.

Elevated liver enzymes Marked elevations in liver enzymes (more than 10 times the upper limit of normal) or liver injury with cholestasis, or marked 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 cautiously in patients taking medications that may cause liver injury.

Presence of sucrose Modified-release hard capsules Defacto 30 and Defacto 60 contain sucrose. Defacto should not be administered to patients with hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Serious skin reactions

In post-marketing studies of duloxetine, very rare cases of serious skin reactions have been reported, including angioedema, contusion, hemorrhage, Stevens-Johnson syndrome, ecchymosis, and urticaria.

Use during pregnancy or breastfeeding

Adequate controlled studies in pregnant women have not been conducted; therefore, the drug is not recommended during pregnancy. Reproductive toxicity of duloxetine has been demonstrated in animal studies at systemic exposures lower than the maximum clinical exposure.

Potential risks to humans are unknown. Although studies have not established a link between persistent pulmonary hypertension of the newborn and treatment with serotonin-norepinephrine reuptake inhibitors, the risk cannot be excluded with duloxetine use due to its mechanism of action (serotonin reuptake inhibition). Neonates may experience discontinuation syndrome symptoms if the mother used duloxetine prior to delivery. Discontinuation syndrome symptoms may include orthostatic hypotension, tremor, increased neuromuscular reflex excitability, difficulty in swallowing, sucking, respiratory disturbances, and epileptic seizures. These symptoms are usually observed immediately after birth or within the first few days of life. The use of the drug during pregnancy is recommended only if the expected benefit outweighs the potential risk.

Women taking duloxetine should be advised to inform their physician if they become pregnant or plan to become pregnant.

Duloxetine is weakly excreted into breast milk. The estimated 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

During treatment, patients should refrain from potentially hazardous activities requiring heightened attention and rapid psychomotor reactions.

Dosage and Administration

Major Depressive Disorder: Duloxetine is administered at a dose of 60 mg once daily, independent of food intake.

In some patients, dose escalation up to the maximum of 120 mg daily, divided into two doses, may be considered. Doses exceeding 120 mg daily have not been systematically evaluated.

Therapeutic effects of treatment typically emerge within 2–4 weeks.

After the antidepressant effect is achieved, treatment should be continued for several months to prevent relapse. For patients with a history of recurrent major depressive disorder who respond to duloxetine therapy, long-term treatment with a dosage of 60–120 mg daily may be recommended.

Generalized Anxiety Disorder: The recommended initial dose is 30 mg once daily, independent of food intake. In patients with an inadequate response to treatment, the dose should be increased to 60 mg daily. For patients with comorbid major depressive disorder, the starting and maintenance dose is 60 mg (see recommendations above). Clinical trials have demonstrated efficacy and evaluated safety of doses up to 120 mg of duloxetine daily.

If there is insufficient response to a 60 mg dose, dose escalation to 90 or 120 mg daily may be considered. Dose increases should be based on clinical response and tolerability.

After the antidepressant effect is achieved, 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. In some patients, dose escalation up to a maximum of 120 mg daily, divided into two doses, may be considered.

Therapeutic effects of treatment typically emerge within 2 months. In patients who do not respond within 2 months, clinical benefit beyond this time is unlikely. Treatment efficacy should be evaluated regularly (at least every three months).

Elderly Patients: Dose adjustment is not recommended based on age alone in elderly patients. However, as with any other medicinal product, caution should be exercised when treating elderly patients, particularly when using Defacto at a dose of 120 mg daily for major depressive disorder or generalized anxiety disorder.

Patients with Hepatic Impairment: Defacto must not be prescribed 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 drug is not recommended for use in patients with end-stage renal disease (creatinine clearance < 30 mL/min).

Discontinuation of Treatment: Abrupt discontinuation should be avoided. When discontinuing treatment with Defacto, the dose should be gradually reduced over a period of at least one to two weeks to minimize the risk of discontinuation reactions. If intolerable symptoms occur after dose reduction or upon discontinuation, the previously prescribed dose may be reinstated. Subsequently, the physician may continue tapering the dose, but more gradually.

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

Overdose

Data regarding duloxetine overdose are limited. Large doses (up to 1400 mg) of duloxetine, administered either as monotherapy or in combination with other medicinal products, have been reported without fatal outcomes. Symptoms of overdose (mostly following co-ingestion with other drugs) included somnolence, coma, serotonin syndrome, seizures, vomiting, and tachycardia.

Treatment of Overdose: There are no known specific antidotes. In cases of serotonin syndrome, specific treatment is required (cyproheptadine and/or temperature control). Airway patency should 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 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, and headache (> 5%) have been reported as adverse symptoms upon discontinuation of duloxetine. Upon discontinuation, disturbances in sensation, sleep disturbances, agitation or anxiety, tremor, irritability, diarrhea, and hyperhidrosis have also been reported. The table lists adverse reactions observed during duloxetine treatment, 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%).

• 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.
    • Patients experiencing persistent increase in blood pressure during duloxetine treatment should have their dose reduced or the therapy tapered off gradually.
      • Cases of aggression and irritability have been reported at the beginning of treatment and after discontinuation of treatment.
        • Cases of suicidal ideation and suicidal behavior have been reported at the beginning of treatment and immediately after discontinuation of treatment.
          • The frequency of adverse reactions established from post-marketing data not observed in placebo-controlled clinical trials.
            • Statistically not significantly different from placebo.

8 Cases of falls were more frequent in elderly patients (*≥* 65 years of age and older).

Discontinuation of therapy (especially abrupt discontinuation) is frequently accompanied by withdrawal symptoms. The most common adverse reactions in such cases are: dizziness, somnolence, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), fatigue, anxiety or agitation, nausea and/or vomiting, tremor, headache, irritability, diarrhea, hyperhidrosis, and vertigo. Gradual discontinuation of therapy is recommended.

Renal impairment.

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

Hepatitis/elevated liver enzymes.

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

Minor increases in blood potassium levels have been reported. Transient abnormal potassium levels were infrequently observed in patients treated with duloxetine compared to placebo.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30°C.

Keep out of reach of children.

Packaging. 8 capsules per blister pack. 10 blister packs per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Alembic Pharmaceuticals Limited.

Manufacturer's address and site of operations.

Panelav, P.V. Tajpura, District Halol, Taluka Panchmahal, Gujarat – 389 350, India.