Revival®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT REVIVAL® (REVIVAL)

Composition:

Active substance: duloxetine hydrochloride;

One gastro-resistant hard capsule contains duloxetine hydrochloride 33.68 mg, equivalent to duloxetine 30 mg, or duloxetine hydrochloride 67.35 mg, equivalent to duloxetine 60 mg;

Excipients: spherical sugar (sucrose, corn starch), hypromellose 2910/5 mPa·s, crospovidone type A, sucrose, hypromellose acetate succinate, triethyl citrate (E 1505), talc, macrogol 8000, titanium dioxide (E 171);

Capsule shell (for 30 mg capsules):
Composition of capsule shell: titanium dioxide (E 171), gelatin, patent blue V (E 131), sodium lauryl sulfate, carmoisine (E 122), purified water;

Capsule shell (for 60 mg capsules):
Composition of capsule shell: titanium dioxide (E 171), gelatin, sodium lauryl sulfate, erythrosine (E 127), iron oxide red (E 172), iron oxide black (E 172), purified water.

Pharmaceutical form. Gastro-resistant hard capsules.

Main physicochemical properties:

30 mg capsules: hard gelatin capsules size "3" with white body and blue cap, containing almost white-colored pellets;

60 mg capsules: hard gelatin capsules size "0" with light grey body and pink cap, containing almost white-colored pellets.

Pharmacotherapeutic group. Other antidepressants. ATC code N06AX21.

Pharmacological Properties

Pharmacodynamics

Duloxetine is a combined inhibitor of serotonin (5-HT) and norepinephrine (NA) reuptake. It weakly inhibits dopamine reuptake and has negligible affinity for histaminergic and dopaminergic, cholinergic, and adrenergic receptors. In a dose-dependent manner, duloxetine increases extracellular levels of serotonin and norepinephrine in various regions of the brain in animals.

Pharmacodynamic effects. Duloxetine normalizes the pain threshold. Duloxetine also exerts analgesic effects, which are likely due to slowing the transmission of pain impulses in the central nervous system (CNS).

Clinical efficacy and safety

Major Depressive Disorder (MDD): The efficacy of duloxetine was demonstrated in studies evaluating fixed-dose effects of the drug in adult patients with MDD. Duloxetine showed statistically significant superiority over placebo. Response and remission rates were also statistically significantly higher with duloxetine compared to placebo. In a study evaluating the efficacy of duloxetine in preventing relapse, the drug demonstrated statistically significant advantage over placebo. Patients with recurrent MDD receiving duloxetine had a significantly longer symptom-free period compared to those receiving placebo. Studies on the efficacy of duloxetine in elderly patients (≥65 years) with depression showed statistically significant differences compared to placebo.

Generalized Anxiety Disorder (GAD): In clinical trials, duloxetine demonstrated statistically significant superiority over placebo in both acute treatment and prevention of relapse in adult patients with GAD.

Response and remission rates were also higher with duloxetine compared to placebo. In a relapse prevention study in elderly patients (≥65 years) with GAD, the efficacy of duloxetine compared to placebo was demonstrated. The efficacy and safety of duloxetine in elderly patients were similar to those observed in younger adult patients.

Diabetic peripheral neuropathic pain: The efficacy of duloxetine was established in studies evaluating treatment of diabetic neuropathic pain. Duloxetine significantly reduced pain compared to placebo. The effect was evident in some patients as early as the first week of treatment. In these same studies, the occurrence of somnolence in patients during treatment was also analyzed. Clinical response was more frequent among patients who did not experience somnolence when treated with duloxetine compared to those receiving placebo.

Children. The use of duloxetine in patients under 7 years of age has not been studied. Studies conducted in children aged 7 to 17 years with MDD showed that neither duloxetine nor the main control group differed statistically from placebo.

Discontinuation due to adverse effects was higher in patients taking duloxetine compared to those receiving fluoxetine, primarily due to nausea. Suicidal behavior was also reported during duloxetine use. Treatment with duloxetine demonstrated statistically more significant improvement in patients with GAD. Duloxetine did not demonstrate efficacy in reducing pain as measured by the primary endpoint of average pain score on the Brief Pain Inventory (BPI).

Pharmacokinetics

Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolized by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of duloxetine show high inter-individual variability (typically 50–60%), partly due to sex, age, smoking, and CYP2D6 metabolizer status.

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

Distribution. Approximately 96% of duloxetine is protein-bound in human plasma. Duloxetine binds to both albumin and α1-acid glycoprotein. Renal or hepatic impairment does not affect plasma protein binding.

Metabolism. Duloxetine is extensively metabolized, with metabolites primarily excreted in urine. Both cytochrome P450-2D6 and 1A2 catalyze the formation of two major metabolites: the glucuronide conjugate of 4-hydroxyduloxetine and the sulfate conjugate of 5-hydroxy-6-methoxyduloxetine. According to in vitro studies, circulating metabolites of duloxetine are considered pharmacologically inactive. The pharmacokinetics of duloxetine in patients who are poor metabolizers via CYP2D6 have not been specifically studied. Limited data suggest higher plasma levels of duloxetine in these patients.

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

Special patient populations

Sex. Pharmacokinetic differences were observed between men and women (apparent plasma clearance is approximately 50% lower in women). However, due to overlap in the clearance range, pharmacokinetic differences related to sex do not justify using a lower dose in female patients.

Age. Pharmacokinetic differences were observed between younger women and elderly women (≥65 years): AUC increases by approximately 25%, and elimination half-life is about 25% longer in elderly women. However, the magnitude of these changes is insufficient to justify dose adjustment. As a general recommendation, caution should be exercised when treating elderly patients (see sections "Dosage and administration" and "Special precautions").

Renal impairment. In patients with end-stage renal disease on regular dialysis, a twofold increase in duloxetine concentration and area under the pharmacokinetic concentration-time curve (AUC) was observed compared to healthy volunteers. Pharmacokinetic data on duloxetine are limited in patients with mild or moderate renal impairment.

Hepatic impairment. Moderate hepatic impairment (Child-Pugh class B) affects the pharmacokinetics of duloxetine. Compared to healthy volunteers, apparent plasma clearance of duloxetine was 79% lower, terminal elimination half-life was 2.3 times longer, and AUC was 3.7 times higher in patients with moderately severe liver disease. The pharmacokinetics of duloxetine and its metabolites have not been studied in patients with mild or severe hepatic impairment.

Breastfeeding women. Distribution of duloxetine was studied in breastfeeding women at least 12 weeks postpartum. Duloxetine is excreted in breast milk, and steady-state concentration in breast milk is approximately one-quarter of that in plasma. The amount of duloxetine in breast milk is approximately 7 mcg/day when administering 40 mg twice daily. Lactation does not affect the pharmacokinetics of duloxetine.

Children. The pharmacokinetics of duloxetine in pediatric patients aged 7 to 17 years with MDD after oral administration of 20 to 120 mg once daily were characterized using population modeling analysis based on data from three studies. Model-predicted steady-state plasma concentrations of duloxetine in children were predominantly within the range observed in adult patients.

Clinical characteristics.

Indications.

Treatment of major depressive disorder.

Treatment of diabetic peripheral neuropathic pain.

Treatment of generalized anxiety disorder.

The medicinal product Revival® is intended for adult patients.

For additional information, see section "Pharmacological properties".

Contraindications.

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

Concomitant use with non-selective irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated. Liver disease that may lead to hepatic failure.

Duloxetine should not be used in combination with fluvoxamine, ciprofloxacin, or enoxacin (strong CYP1A2 inhibitors) due to increased plasma concentration of duloxetine. Severe renal impairment (creatinine clearance < 30 mL/min). Initiation of duloxetine treatment is contraindicated in patients with uncontrolled hypertension, as it may lead to a potential risk of hypertensive crisis.

Interaction with other medicinal products and other types of interactions.

MAOIs. Due to the risk of serotonin syndrome, duloxetine should not be used in combination with non-selective irreversible MAOIs or within 14 days after discontinuation of such agents. Because of the half-life of duloxetine, MAO inhibitors should not be initiated for at least 5 days after discontinuation of duloxetine treatment (see section "Contraindications"). Concomitant use of Revival® with selective reversible MAO inhibitors, such as moclobemide, is not recommended (see section "Special precautions for use"). Linezolid—an antibiotic and a reversible non-selective MAO inhibitor—should not be administered to patients receiving Revival® (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 AUC0-t by 6 times. Therefore, duloxetine should not be co-administered with CYP1A2 inhibitors, including fluvoxamine (see section "Special precautions for use").

Medicinal products acting on the central nervous system. The risk of using duloxetine in combination with other centrally acting medicinal products has not been systematically evaluated, except for cases mentioned in this section. Therefore, caution should be exercised when taking duloxetine in combination with other agents or substances affecting the CNS, including alcohol and sedative medicinal products (e.g., benzodiazepines, morphine-like agents, antipsychotics, phenobarbital, sedative antihistamines).

Serotonin syndrome. Serotonin syndrome rarely occurs in patients treated with selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) in combination with serotonergic agents. Duloxetine should be used with caution in combination with serotonergic agents such as SSRIs, SNRIs, tricyclic antidepressants (e.g., clomipramine or amitriptyline), MAO inhibitors (e.g., moclobemide or linezolid), St. John’s wort (Hypericum perforatum), triptans, tramadol, pethidine, and tryptophan (see section "Special precautions for use").

Effect of duloxetine on other medicinal products.

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

Medicinal products metabolized by CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. Administration of duloxetine at a dose of 60 mg twice daily 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 active 5-hydroxy metabolite and does not require dose adjustment. Revival® should be used with caution together 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).

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

Anticoagulants and antithrombotic agents. Duloxetine should be used with caution together with oral anticoagulants and antithrombotic agents due to the potential increased risk of bleeding via pharmacodynamic interaction. In addition, increased international normalized ratio (INR) values have been reported when patients received warfarin concomitantly with 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 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 antacids containing aluminum and magnesium or with famotidine did not affect the rate or extent of absorption of duloxetine after a single 40 mg oral dose.

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

Special precautions for use.

Mania and epileptic seizures. Duloxetine should be used with caution in patients with a history of mania or diagnosed bipolar disorder and/or epileptic seizures.

Mydriasis. Cases of mydriasis have been reported in association with duloxetine use; therefore, Revival® should be administered with caution to 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. This may be related to the noradrenergic effect of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, particularly in patients with pre-existing hypertension. Therefore, blood pressure monitoring is recommended in patients with known arterial hypertension and/or other cardiac diseases, especially during the first month of treatment. Revival® 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"). For patients who experience persistent elevation in blood pressure during treatment with Revival®, consideration should be given to dose reduction or gradual discontinuation of treatment (see section "Adverse reactions"). Revival® should not be used in patients with uncontrolled arterial hypertension (see section "Contraindications").

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

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

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

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

St. John’s wort (Hypericum perforatum). Adverse reactions may be more frequent when Revival® is used concomitantly with herbal preparations containing St. John’s wort (Hypericum perforatum).

Suicidality.

Major depressive disorder and generalized anxiety disorder. Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicidal behaviors). The 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 improvement occurs. Clinical experience indicates that the risk of suicide may increase during the early stages of recovery.

Other psychiatric disorders for which duloxetine is indicated may also be associated with an increased risk of suicidal events. In addition, these conditions may accompany major depressive disorder. Therefore, precautions applied to patients with major depressive disorder should also be applied to patients with other psychiatric disorders. Patients with a history of suicidal behavior or those exhibiting marked suicidal ideation prior to initiation of treatment are at increased risk of developing suicidal thoughts or suicidal behavior and should be closely monitored 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 behavior have been reported during treatment with duloxetine or immediately after discontinuation of treatment (see section "Adverse reactions"). Close monitoring of patients, especially those at high risk, is necessary throughout therapy, particularly at the beginning of treatment and when dosage is changed. Patients and caregivers should be informed of the need to monitor for any clinical worsening, emergence of suicidal thoughts or behaviors, or unusual changes in behavior, and to seek immediate medical attention if these symptoms occur.

Diabetic peripheral neuropathic pain. Isolated cases of suicidal ideation and suicidal behavior have been reported during treatment with duloxetine or immediately after discontinuation, as with other medicinal products with similar pharmacological action (antidepressants). For information on risk factors for suicidality in depression, see the section above. Physicians should inform patients of the need to report any feelings of concern.

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 behavior (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behavior, and anger) were more frequently observed in clinical trials involving children and adolescents receiving antidepressants compared to those receiving placebo.

Bleeding. Disorders of hemostasis such as bruising, including purpura, and gastrointestinal bleeding have been reported with SSRIs and SNRIs, including duloxetine. Duloxetine may increase the risk of postpartum hemorrhage (see subsection "Use during pregnancy or breastfeeding"). Caution should be exercised in patients taking anticoagulants and/or medicinal products that may affect platelet function (e.g., NSAIDs or acetylsalicylic acid), and in patients with known hemorrhagic diathesis.

Hyponatremia. Cases of hyponatremia, including serum sodium levels below 110 mmol/L, have been observed with duloxetine use. Hyponatremia may be associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Most cases of hyponatremia were observed 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 (elderly patients, patients with liver cirrhosis and dehydration, patients receiving diuretics).

Discontinuation syndrome. Discontinuation symptoms occur frequently, especially following abrupt discontinuation of treatment (see section "Adverse reactions"). The risk of discontinuation symptoms with SSRIs and SNRIs depends on several factors, including duration and dose of therapy and the speed of dose reduction. The most common adverse reactions are listed in section "Adverse reactions". These symptoms are usually mild to moderate in severity, but in some patients they may be severe. They typically occur within the first few days after discontinuation of treatment, although isolated reports describe symptoms occurring in patients who inadvertently missed a dose. Generally, these symptoms resolve spontaneously within two weeks, although in some patients they may last longer (2–3 months or more). Therefore, it is recommended to gradually reduce the dose of duloxetine over a period of at least two weeks when discontinuing treatment, depending on patient needs (see section "Dosage and administration").

Akathisia / psychomotor agitation. Use of duloxetine has been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and a need to move, often 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, dose escalation may be harmful.

Sexual dysfunction. Selective serotonin reuptake inhibitors (SSRIs) / serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section "Adverse reactions"). Cases of persistent sexual dysfunction, where symptoms persisted despite discontinuation of SSRI/SNRI therapy, have been reported.

Hepatitis / elevated liver enzymes. Cases of liver injury, including marked increases in liver enzyme levels (>10 times the upper limit of normal), hepatitis, and jaundice have been reported with duloxetine use (see section "Adverse reactions"). Most cases occurred within the first months of treatment. Liver injury is most often hepatocellular in nature. Duloxetine should be prescribed with caution in patients taking medicinal products that may cause liver injury.

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

Misuse of duloxetine-containing medicinal products. Duloxetine is marketed under various trade names for several indications (diabetic neuropathic pain, major depressive disorder, generalized anxiety disorder, and stress urinary incontinence). The simultaneous use of multiple duloxetine-containing medicinal products should be avoided.

Presence of sucrose. This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this product.

Use during pregnancy or breastfeeding.

Fertility. In animal studies, duloxetine did not affect male fertility, and effects in females were observed only at doses causing toxic effects in the mother.

Pregnancy. Animal studies showed reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum clinical exposure. Studies investigating the effects of duloxetine on the fetus during the first trimester of pregnancy did not provide convincing evidence of an increased risk of serious specific congenital malformations, including cardiac defects. It is known that the use of duloxetine in late pregnancy (at any time from 20 weeks of gestation to delivery) has been associated with an increased risk of preterm birth. Observational data indicate an increased risk (less than two-fold) of postpartum hemorrhage if duloxetine is used within one month before delivery. Epidemiological data suggest that the use of SSRIs during pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although the association between PPHN and SNRI treatment has not been studied, this potential risk cannot be excluded for duloxetine due to its relevant mechanism of action (inhibition of serotonin reuptake).

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 hypotonia, tremor, increased nervous excitability, difficulty in sucking, respiratory depression, and epileptic seizures. In most cases, these symptoms were observed immediately after birth or within the first few days of life. Duloxetine should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. Women taking duloxetine should inform their physician if they become pregnant or plan to become pregnant.

Lactation period. According to a study conducted in six lactating mothers who were not breastfeeding their infants, duloxetine passes into human breast milk to a very low extent. The estimated infant dose calculated at 1 mg per 1 kg body weight is approximately 0.14% of the maternal dose (see section "Pharmacokinetics"). The safety of duloxetine in infants is unknown; therefore, the use of Revival® during breastfeeding is not recommended.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of duloxetine on reaction speed while driving or operating machinery have not been conducted. Revival® may cause sedation and dizziness. Therefore, patients experiencing sedation or dizziness should avoid potentially hazardous activities such as driving or operating machinery.

Method of Administration and Dosage.

Major Depressive Disorder. The initial and recommended maintenance dose is 60 mg once daily, regardless of food intake. Doses above 60 mg once daily, up to a maximum dose of 120 mg per day, have been evaluated for safety. However, there are no clinical data demonstrating that patients who do not respond to the initial recommended dose may benefit from dose escalation.

Therapeutic response is usually 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, continuation of long-term treatment at a dose of 60–120 mg per day should be considered.

Generalized Anxiety Disorder. The recommended initial dose is 30 mg once daily, regardless of food intake. In patients with an inadequate treatment response, the dose should be increased to 60 mg per day, which is the usual maintenance dose in most patients.

In patients with comorbid major depressive disorder, both the initial and maintenance dose is 60 mg once daily (see dosage recommendations above).

Doses up to 120 mg per day have demonstrated efficacy and have been evaluated for safety in clinical trials. Therefore, in patients with an inadequate response to a 60 mg dose, dose escalation to 90 or 120 mg may be considered.

Dose increases should be based on clinical response and tolerability. After response consolidation, treatment should be continued for several months to prevent relapse.

Diabetic Peripheral Neuropathic Pain. The initial and recommended maintenance dose is 60 mg once daily, regardless of food intake. Administration of the drug at doses above 60 mg once daily, up to a maximum of 120 mg per day, administered in evenly divided doses, has been evaluated for safety in clinical trials. Plasma concentrations of duloxetine show high inter-individual variability (see section "Pharmacokinetics"). Therefore, some patients who do not respond adequately to a 60 mg dose may benefit from a higher dose. Treatment response should be evaluated after 2 months. Additional therapeutic benefit after this period in patients with inadequate initial response is unlikely.

Therapeutic benefit should be regularly reassessed (at least every 3 months) (see section "Pharmacodynamics").

Elderly Patients. Dose adjustment is not recommended solely on the basis of age in elderly patients. However, caution should be exercised when treating elderly patients, particularly when using Revival® at a dose of 120 mg per day for major depressive disorder or generalized anxiety disorder, as data in these populations are limited (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Patients with Hepatic Impairment. Revival® should not be prescribed to patients with liver disease that may cause hepatic impairment (see sections "Pharmacokinetics" and "Contraindications").

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

Discontinuation of Treatment. Abrupt discontinuation of treatment 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 symptoms. If intolerable symptoms occur following dose reduction or upon discontinuation, re-initiation of the drug at the previously established dose may be considered. Subsequently, the physician may continue tapering the dose, but more gradually.

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 patient population.

Overdose.

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

Treatment. There are no known 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 surveillance of vital signs, along with appropriate symptomatic and supportive measures, are recommended. Gastric lavage may be appropriate if performed soon after ingestion or for symptomatic management. 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

The most commonly reported adverse reactions were nausea, headache, dry mouth, somnolence, and dizziness. Most common adverse reactions were of mild to moderate intensity. They usually occurred at the beginning of treatment, and most tended to diminish over time, even with continued therapy.

Listed below are the adverse reactions reported in spontaneous reports and during placebo-controlled clinical trials. Frequency assessment: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), not known (cannot be estimated from available data). Within each frequency category, adverse effects are presented in order of decreasing severity.

Infections and infestations: uncommon – laryngitis.

Endocrine system disorders: rare – hypothyroidism.

Immune system disorders: rare – anaphylactic reactions, hypersensitivity.

Metabolism and nutrition disorders: common – decreased appetite; uncommon – hyperglycaemia (particularly in patients with diabetes mellitus); rare – dehydration, hyponatraemia, syndrome of inappropriate antidiuretic hormone secretion^6.

Psychiatric disorders: common – insomnia, agitation, decreased libido, anxiety, abnormal vision and abnormal orgasm, unusual dreams; uncommon – suicidal ideation^5,7, sleep disorders, bruxism, disorientation, apathy; rare – suicidal behaviour^5,7, mania, hallucinations, aggression and anger^4.

Nervous system disorders: very common – headache, somnolence; common – dizziness, lethargy, tremor, paraesthesia; uncommon – myoclonus, akathisia^7, restlessness, attention disorders, dysgeusia, dyskinesia, restless legs syndrome, poor sleep; rare – serotonin syndrome^6, seizures^1, psychomotor agitation^6, extrapyramidal disorders^6.

Eye disorders: common – blurred vision; uncommon – mydriasis, visual disturbances; rare – glaucoma.

Ear and labyrinth disorders: common – tinnitus^1; uncommon – dizziness, ear pain.

Cardiac disorders: common – palpitations; uncommon – tachycardia, supraventricular arrhythmia, mainly atrial fibrillation; not known – stress cardiomyopathy (Takotsubo cardiomyopathy).

Vascular disorders: common – increased blood pressure^3, hot flushes; uncommon – arterial hypertension^3,7, orthostatic hypotension^2, loss of consciousness^2, cold sensation in extremities; rare – hypertensive crisis^3,6.

Respiratory, thoracic and mediastinal disorders: common – yawning; uncommon – laryngospasm, epistaxis; rare – interstitial lung disease^10, eosinophilic pneumonia^6.

Gastrointestinal disorders: very common – nausea, dry mouth; common – vomiting, dyspepsia, flatulence, abdominal pain, constipation, diarrhoea; uncommon – gastrointestinal haemorrhage^7, gastroenteritis, belching, gastritis, dysphagia; rare – stomatitis, malodour, blood in stool, microscopic colitis^9.

Hepatobiliary disorders: uncommon – increased liver enzymes (ALT, AST, alkaline phosphatase), hepatitis^3, acute liver injury; rare – jaundice^6, hepatic failure^6.

Skin and subcutaneous tissue disorders: common – increased sweating, rash; uncommon – night sweats, contact dermatitis, urticaria, cold sweat, photosensitivity, increased bruising tendency; rare – angioedema^6, Stevens-Johnson syndrome^6; very rare – cutaneous vasculitis.

Musculoskeletal and connective tissue disorders: common – musculoskeletal pain, muscle spasms; uncommon – muscle twitching, feeling of muscle stiffness; rare – trismus.

Renal and urinary disorders: common – dysuria, pollakiuria; uncommon – urinary retention, difficulty in initiating micturition, nocturia, polyuria, decreased urine flow; rare – abnormal odour of urine.

Reproductive system and breast disorders: common – erectile dysfunction, impaired or delayed ejaculation; uncommon – menstrual disorders, sexual dysfunction, gynaecological bleeding, testicular pain; rare – menopausal symptoms, galactorrhoea, hyperprolactinaemia, postpartum haemorrhage^6.

General disorders: common – fatigue, falls^8; uncommon – chest pain^7, malaise, cold sensation, chills, thirst, weakness, feeling of warmth, gait disturbance.

Investigations: common – weight decreased; uncommon – weight increased, increased blood creatine phosphokinase, increased blood potassium; rare – increased blood cholesterol.

1 Seizures and tinnitus were observed after discontinuation of treatment.

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

3 See section "Special warnings and precautions for use".

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

5 Cases of suicidal ideation and behaviour were reported during treatment with duloxetine or immediately after discontinuation (see section "Special warnings and precautions for use").

6 Frequency established from post-marketing data not observed in placebo-controlled clinical trials.

7 Statistically not significantly different from placebo.

8 Fall incidents were more frequent in elderly patients (≥65 years).

9 Calculated frequency based on all clinical trial data.

10 Frequency estimation based on placebo-controlled clinical trials.

Description of selected adverse reactions. Discontinuation of duloxetine therapy (especially abrupt discontinuation) frequently leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia or electric shock sensations, particularly in the head), sleep disturbances (including insomnia and vivid dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhoea, and hyperhidrosis are the most commonly reported reactions.

Typically, for SSRIs and SNRIs, these phenomena were of mild or moderate intensity and resolved spontaneously; however, in some patients, they could be severe and/or prolonged. Therefore, if further treatment with duloxetine is not required, gradual discontinuation is recommended by tapering the dose (see sections "Dosage and administration" and "Special warnings and precautions for use").

In the 12-week acute phase of three clinical trials 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 the duloxetine and placebo groups. In the extension phase of these trials 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 group was 0.3%. Small increases in fasting blood glucose and total cholesterol were also observed in patients receiving duloxetine, whereas slight decreases were observed in these laboratory parameters in the usual care group. 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 intervals were observed between patients receiving duloxetine and placebo.

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

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

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging to protect from moisture, in a place inaccessible to children.

Packaging. 10 capsules in a blister; 3 or 9 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Medocemie Limited / Medochemie Limited.

Manufacturer's address and location of operations.
Konstantinoupoleos 1-10, Limassol, 3011, Cyprus /
Konstantinoupoleos 1-10, Limassol, 3011, Cyprus.