Dulocem 60

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DULOKEM 30 DULOKEM 60

Composition:

Active substance: duloxetine;

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

Excipients (hard enteric-coated capsules 30 mg): spherical sugar, hypromellose, hydroxypropylcellulose, crospovidone, talc, triethyl citrate, titanium dioxide (E 171), hypromellose phthalate, gelatin capsule No. 2*

capsule shell composition: gelatin, titanium dioxide (E 171), indigocarmine (E 132), sodium lauryl sulfate;

Excipients (hard enteric-coated capsules 60 mg): spherical sugar, hypromellose, hydroxypropylcellulose, crospovidone, talc, triethyl citrate, titanium dioxide (E 171), hypromellose phthalate, gelatin capsule No. 0*

capsule shell composition: gelatin, titanium dioxide (E 171), indigocarmine (E 132), yellow iron oxide (E 172), sodium lauryl sulfate.

Pharmaceutical form. Hard enteric-coated capsules.

Main physicochemical characteristics:

Hard enteric-coated capsules 30 mg: hard gelatin capsules with a white body and a blue cap, marked with white ink "Dulox" on the cap and black ink "30 mg" on the body, containing pellets from white to almost white;

Hard enteric-coated capsules 60 mg: hard gelatin capsules with a green body and a blue cap, marked with white ink "Dulox" on the cap and "60 mg" on the body, containing pellets from white to almost white.

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 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, resulting in enhanced serotonergic and noradrenergic neurotransmission in the central nervous system. Duloxetine also exerts analgesic effects, which are likely due to the slowing of pain impulse transmission in the central nervous system.

Pharmacokinetics.

After oral administration, duloxetine is well absorbed. Maximum concentration is reached 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 elimination half-life of duloxetine is 12 hours. The average plasma clearance of duloxetine is 101 L/h.

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

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

Interaction with other medicinal products and other forms of interaction.

Drugs metabolized by CYP1A2. In a clinical study, co-administration of theophylline, a CYP1A2 substrate, with duloxetine (60 mg twice daily) did not significantly affect their pharmacokinetics.

Inhibitors of CYP1A2. Since CYP1A2 is involved in the metabolism of duloxetine, concomitant use of duloxetine with strong CYP1A2 inhibitors 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, Dulokem must not be prescribed together with such inhibitors.

Drugs metabolized by CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. Administration of duloxetine 60 mg twice daily together with a single dose of desipramine, a CYP2D6 substrate, increases the AUC of desipramine by threefold. Concomitant administration of duloxetine (40 mg twice daily) increases the steady-state AUC of tolterodine (2 mg twice daily) by 71%, but does not affect the pharmacokinetics of its 5-hydroxy metabolite. Therefore, caution is required when prescribing duloxetine together with CYP2D6 inhibitors that have a narrow therapeutic index.

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

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

Serotonin syndrome. The medicinal product should be used with caution 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 with caution in combination with oral anticoagulants and antiplatelet agents due to the potential for increased risk of bleeding via pharmacodynamic interaction.

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 duloxetine.

Special precautions for use.

Warning

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

Seizures and mania. As with other centrally acting agents, duloxetine should be prescribed with caution in patients with a history of seizures, mania, or bipolar disorder.

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

Blood pressure and heart rate. In some patients, duloxetine may increase blood pressure. Patients with known hypertension and/or other cardiac conditions should have their blood pressure monitored. Patients with sustained high blood pressure may require dose reduction or gradual discontinuation of the drug. Treatment of patients with unstable hypertension is not recommended.

Hemorrhage. There have been reports of hemorrhagic events, including purpura, gastrointestinal bleeding, and ecchymosis.

Hyponatremia. Use with caution in patients at increased risk of hyponatremia: elderly patients, patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH), and those with liver cirrhosis.

Discontinuation syndrome. Discontinuation symptoms are relatively common, especially following abrupt cessation of treatment. Discontinuation should be carried out over at least two weeks by gradually reducing the dose.

Akathisia/psychomotor agitation. Such symptoms may occur within the first few weeks of treatment.

Elevated liver enzymes. Marked increases in liver enzymes (more than 10 times the upper limit of normal) or liver injury with cholestasis, or significant enzyme elevations combined with liver injury, have occurred rarely. Most cases were reported during the first few months of treatment. Liver injury is most commonly hepatocellular in nature. Duloxetine should be used with caution in patients taking medications that may cause liver damage.

Presence of sucrose. This medicinal product is contraindicated in patients with hereditary fructose intolerance, malabsorption syndrome, or sucrase-isomaltase deficiency.

Suicide.

Major depressive disorder and generalized anxiety disorder.

Depression is associated with an increased risk of suicidal ideation, self-harm, and suicide (suicide-related events). Risk persists until significant remission occurs. Patients should be closely monitored until significant improvement is achieved, as remission may not occur during the first several weeks of treatment or longer. Clinical experience indicates that the risk of suicide may be increased 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 events. Moreover, these psychiatric conditions may be comorbid with major depressive disorder. Therefore, similar precautionary measures should be followed when treating patients with major depressive disorder as well as other psychiatric conditions. Patients with a history of suicide-related events or high levels of suicidal ideation are at greater risk of suicidal behavior and require closer monitoring during treatment. Cases of suicidal ideation and suicidal behavior have been reported during or immediately following duloxetine therapy. Close monitoring of patients, particularly those at risk, is essential throughout therapy, especially in the early stages, along with appropriate dose adjustments.

Diabetic peripheral neuropathic pain.

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

Elderly patients.

Data on the use of the 120 mg dose in elderly patients with major depressive disorder and generalized anxiety disorder are limited.

Serious skin reactions.

Very rare cases of serious skin reactions such as angioedema, ecchymosis, Stevens-Johnson syndrome, petechiae, and urticaria have been reported.

Use during pregnancy or breastfeeding.

Adequate and well-controlled studies of the drug in pregnant women have not been conducted; therefore, use during pregnancy is not recommended. As with other serotonergic medicinal products, neonates may experience symptoms of withdrawal syndrome if the mother used duloxetine prior to delivery. Symptoms of withdrawal syndrome may include orthostatic hypotension, tremor, hyperreflexia, difficulty in swallowing and sucking, respiratory disorders, and seizures. In most cases, these symptoms occurred immediately after birth or within the first few days of life. Women should be advised to inform their physician if they become pregnant or are planning to become pregnant while taking duloxetine.

The use of the drug during pregnancy should only be considered if the expected benefit to the mother outweighs the potential risk to the fetus.

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 responses.

Dosage and Administration

Major Depressive Disorder. The recommended dose is 60 mg once daily, administered regardless of food intake.

Some patients may benefit from doses higher than 60 mg, up to a maximum daily dose of 120 mg, divided into two doses. Doses exceeding 120 mg have not been systematically evaluated.

Diabetic Peripheral Neuropathic Pain. The recommended initial dose is 60 mg once daily, administered regardless of food intake. For some patients, the dose may be increased above 60 mg once daily, up to a maximum daily dose of 120 mg, divided into two doses.

The therapeutic effect of treatment becomes apparent within 2 months.

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

The therapeutic effect of treatment becomes apparent within 2–4 weeks.

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

Patients with Hepatic Impairment. Duloxetine is contraindicated in patients with hepatic disease.

Elderly Patients. No dosage adjustment is required when administering the drug to elderly patients.

Pediatric Patients.

The safety and efficacy of duloxetine in pediatric patients have not been established; therefore, the drug should not be administered to this age group.

Overdose.

Data regarding duloxetine overdose are limited. There have been reports of ingestion of large doses (up to 1400 mg) of duloxetine, alone or in combination with other drugs, without fatal outcomes. Symptoms of overdose (mostly in combination with other drugs) included somnolence, coma, serotonin syndrome, seizures, vomiting, and tachycardia.

Treatment. There are no specific antidotes. If serotonin syndrome occurs, specific treatment is required (administration of cyproheptadine and/or temperature control). Airway patency must be assessed. Continuous cardiac monitoring and vital signs surveillance are recommended, along with appropriate symptomatic and supportive measures. 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 have been reported as adverse symptoms upon discontinuation of duloxetine. Upon discontinuation of duloxetine, sensory disturbances, sleep disturbances, agitation or anxiety, tremor, irritability, diarrhea, and hyperhidrosis have also been reported.

Infections and infestations: laryngitis.

Endocrine system disorders: hypothyroidism.

Immune system disorders: anaphylactic reactions, hypersensitivity.

Metabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydration, hyponatremia, SIADH⁶.

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

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

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

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

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

Respiratory, thoracic and mediastinal disorders: yawning, oropharyngeal pain, throat tightness, epistaxis.

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

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

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

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

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

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

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

Investigations: weight decrease, weight increase, increased creatine phosphokinase, increased blood cholesterol.

• Seizures and tinnitus have been observed after discontinuation of treatment.
  • Orthostatic hypotension and loss of consciousness have been observed mainly at the beginning of treatment.
    • Patients experiencing persistent increase in blood pressure during duloxetine treatment should have their dose reduced or treatment gradually discontinued.
      • Cases of aggression and hostility have been reported at the beginning of treatment and after discontinuation.
        • Cases of suicidal ideation and suicidal behavior have been reported at the beginning of treatment and immediately after discontinuation.
          • Frequency established from post-marketing studies.
            • Statistically not significantly different from placebo.
              • Falls were more frequent in elderly patients (≥ 65 years).

Discontinuation of therapy (especially abrupt interruption) is frequently associated with withdrawal syndrome. The most common adverse reactions in such cases are: dizziness, somnolence, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), weakness, anxiety or aggressiveness, nausea and/or vomiting, tremor, headache, irritability, diarrhea, hyperhidrosis, and dizziness. Gradual discontinuation 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. Use is contraindicated.

Hepatitis/elevated liver enzymes.

Cases of liver damage 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 is hepatocellular. Duloxetine should be prescribed with caution in patients taking medicinal products that may cause liver damage.

Slight increases in blood potassium levels have been reported. Transient abnormal potassium levels were infrequently observed in patients receiving duloxetine treatment compared to placebo.

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 per blister. 1 blister per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Alkem Laboratories Ltd.

Manufacturer's address and place of business.

167 Mahatma Gandhi, Udio Nagar, Dabhel, Daman, 396210, India.