Instructions Symbia capsules 60 mg No. 28
Composition
active ingredient: duloxetine;
1 capsule contains 33.7 mg or 67.3 mg of duloxetine hydrochloride, equivalent to 30 mg or 60 mg of duloxetine;
excipients: spherical sugar, hydroxypropyl cellulose, hypromellose, hypromellose phthalate (HP-55), triethyl citrate, talc;
capsule shell (for 30 mg dosage): titanium dioxide (E 171), diamond blue FCF (E 133), hypromellose (E 464), black iron oxide (E 172);
capsule shell (for 60 mg dosage): titanium dioxide (E 171), hypromellose (E 464), black iron oxide (E 172).
Dosage form
Enteric-coated hard capsules.
Main physicochemical properties:
30 mg capsules: capsules with an opaque gray body and an opaque blue cap, marked “DLX 30”;
60 mg capsules: capsules with an opaque gray body and an opaque white cap, marked "DLX 60".
Pharmacotherapeutic group
Antidepressants. ATX code N06A X21.
Pharmacological properties
Pharmacodynamics.
Duloxetine is a combined serotonin and norepinephrine reuptake inhibitor. It has little dopamine reuptake inhibition and has low affinity for histamine, dopamine, cholinergic, and adrenergic receptors. The mechanism of action of duloxetine in the treatment of depression is due to inhibition of serotonin and norepinephrine reuptake and, as a result, increased serotonergic and noradrenergic neurotransmission in the central nervous system. Duloxetine also has analgesic effects, which are likely to be the result of slowing the transmission of pain impulses in the central nervous system.
Pharmacokinetics.
Absorption: Duloxetine is well absorbed after oral administration. Peak concentrations are reached 6 hours after dosing. Food intake delays absorption, increasing the time to peak concentration from 6 to 10 hours and decreasing absorption (approximately 11%).
Distribution: Duloxetine is highly bound to serum proteins (approximately 96%) to both albumin and α1-acid glycoprotein. Protein binding is not affected by hepatic or renal impairment.
Metabolism: Duloxetine is metabolized by CYP2D6 and CYP1A2 isoenzymes. The metabolites formed are pharmacologically inactive.
Elimination: The elimination half-life of duloxetine is 12 hours. The mean plasma clearance of duloxetine is 101 L/hour.
Renal impairment: In patients with end-stage renal disease undergoing dialysis, duloxetine exposure and AUC were increased two-fold compared to healthy volunteers. Therefore, a lower starting dose should be considered in patients with chronic renal failure. Pharmacokinetic data on duloxetine are limited in patients with mild to moderate renal impairment.
Liver failure
Moderate hepatic disease (Child-Pugh Class B) affected the pharmacokinetics of duloxetine. Compared to healthy volunteers, the apparent plasma clearance of duloxetine was 79% lower, the apparent half-life was 2.3-fold longer, and the AUC was 3.7-fold higher in patients with moderate hepatic disease. The pharmacokinetics of duloxetine and its metabolites have not been studied in patients with mild or severe hepatic impairment.
Indication
Treatment of major depressive disorder.
Treatment of diabetic peripheral neuropathic pain.
Treatment of generalized anxiety disorder.
Contraindication
A contraindication to the use of the drug is hypersensitivity to duloxetine or to any of the excipients of the drug.
Duloxetine should not be administered concomitantly with non-selective, irreversible monoamine oxidase (MAO) inhibitors or for at least 14 days after discontinuation of MAO inhibitors. Given the half-life of duloxetine, MAO inhibitors should not be administered for at least 5 days after discontinuation of duloxetine.
Symbia® should not be prescribed to patients with unstable hypertension, as it may trigger a hypertensive crisis.
The drug should not be prescribed to patients with end-stage renal failure (creatinine clearance up to 30 ml/min).
Symbia® should not be prescribed to patients with liver disease as it may cause liver failure.
Duloxetine is not recommended for use in children due to insufficient data on its safety and efficacy in this age group.
Symbia® should 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 types of interactions
CYP1A2 inhibitors. Since CYP1A2 is involved in the metabolism of duloxetine, concomitant use of duloxetine with potent CYP1A2 inhibitors is likely to result in increased duloxetine concentrations. Fluvoxamine (100 mg once daily), a potent CYP1A2 inhibitor, reduced duloxetine plasma clearance by approximately 77% and increased AUC0-t by 6-fold. Therefore, Symbia® should not be administered concomitantly with CYP1A2 inhibitors, including fluvoxamine.
Medicinal products metabolised 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 3-fold. Co-administration of duloxetine (40 mg twice daily) increased the steady-state AUC of tolterodine (2 mg twice daily) by 71% but did not affect the pharmacokinetics of the 5-hydroxy metabolite, and no dosage adjustment is recommended. Caution is advised when using Symbia® with medicinal products that are predominantly metabolised by CYP2D6 (risperidone, tricyclic antidepressants [TCAs] such as nortriptyline, amitriptyline and imipramine), especially if they have a narrow therapeutic index (e.g. flecainide, propafenone and metoprolol).
Medicinal products acting on the central nervous system: Caution should be exercised when prescribing duloxetine in combination with other medicinal products and substances acting on the central nervous system, particularly those with a similar mechanism of action, including alcohol and sedative medicinal products (e.g. benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).
MAO inhibitors. Duloxetine should not be administered with non-selective, irreversible MAO inhibitors due to the risk of serotonin syndrome. When taking reversible, selective MAO inhibitors, such as moclobemide, the risk of serotonin syndrome is lower, but the use of this combination is not recommended. The antibiotic linezolid is a reversible, non-selective MAO inhibitor and should not be administered to patients receiving Symbia® (see section "Special warnings and precautions for use").
Serotonin syndrome. Symbia® should be used with caution in combination with serotonergic and tricyclic antidepressants such as clomipramine or amitriptyline, together with moclobemide or linezolid, St. John's wort (Hypericum perforatum) preparations or triptans, tramadol, peptidyne, tryptophan.
Oral contraceptives and other steroidal agents: In vitro studies indicate that duloxetine does not induce CYP3A catalytic activity. Specific in vivo drug interaction studies have not been performed.
Anticoagulants and antithrombotic agents. Duloxetine should be used with caution in combination with oral anticoagulants and antithrombotic agents due to the increased risk of bleeding due to pharmacodynamic interactions. In addition, increases in INR have been observed when duloxetine was administered to patients receiving warfarin. However, concomitant administration of duloxetine and warfarin in a clinical pharmacology study in healthy volunteers did not result in a clinically significant change in INR from baseline or in the pharmacokinetics of R- or S-warfarin.
Medicinal products containing duloxetine: Concomitant use with other medicinal products containing duloxetine should be avoided.
Medicines containing St. John's wort herb. Adverse reactions often occur when used together.
Antacids and H2 antagonists: Co-administration of duloxetine with antacids containing aluminum and magnesium, or duloxetine with famotidine, did not affect the rate or extent of absorption of duloxetine following a 40 mg oral dose.
CYP1A2 inducers: A population pharmacokinetic analysis showed that smokers have almost 50% lower plasma concentrations of duloxetine compared to non-smokers.
Application features
WARNING
Patients at high risk of suicide should be closely monitored during treatment, as the possibility of a suicide attempt cannot be ruled out until significant remission occurs.
Duloxetine hydrochloride has not been studied in patients under 18 years of age and is therefore not indicated for use in this age group.
Seizures and mania: As with other drugs that act on the central nervous system, duloxetine should be used with caution in patients with a history of seizures, mania, or bipolar disorder.
Blood pressure and palpitations. In some patients, duloxetine has been associated with an increase in blood pressure and clinically significant hypertension. Monitoring of blood pressure is recommended in patients with hypertension and/or other cardiac disease. This may be related to the noradrenergic effects of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, particularly in patients with hypertensive disease. Therefore, monitoring of blood pressure is recommended in patients with known hypertension and/or other cardiac disease, particularly during the first month of treatment. Symbia® should be used with caution in patients who may be at risk from increased heart rate or increased blood pressure. Duloxetine should also be used with caution with medicinal products that may impair its metabolism (see section 4.5). For patients who experience persistent elevations in blood pressure while taking Symbia
®, consideration should be given to reducing the dose or gradually discontinuing the drug (see section "Adverse Reactions"). Symbia® should not be used in patients with uncontrolled hypertension (see section "Contraindications").
Renal impairment: Increased plasma concentrations of duloxetine have been observed in patients with severe renal impairment on haemodialysis (creatinine clearance <30 ml/min). For patients with severe renal impairment, see section 4.3. For patients with mild to moderate renal impairment, see section 4.4.
Haemorrhage: Bleeding disorders such as bruising, including purpura, and gastrointestinal bleeding have been reported with selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs), including duloxetine. Caution is advised in patients taking anticoagulants and/or medicinal products that may affect platelet function (e.g. non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid) and in patients with a known tendency to bleed.
Serotonin syndrome.
As with other serotonergic agents, serotonin syndrome may be potentially life-threatening with duloxetine, especially 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 4.3 and 4.5).
Symptoms of serotonin syndrome may include altered mental status (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoherence), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
If concomitant treatment with duloxetine and other serotonergic agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, close patient monitoring is recommended, particularly during treatment initiation and dose increases.
Hyponatremia: Cases of hyponatremia, including cases with serum sodium levels below 110 mmol/L, have been reported with duloxetine. Hyponatremia may be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Most cases of hyponatremia have been reported in the elderly, especially in combination with conditions that alter fluid balance. Caution should be exercised in patients at increased risk of hyponatremia (e.g., the elderly), patients with cirrhosis, dehydrated patients, and patients receiving diuretics.
Preparations containing St. John's wort herb.
Adverse reactions may be more common with concomitant use of Symbia® and preparations containing St. John's wort (Hypericum perforatum).
Withdrawal syndrome.
Withdrawal symptoms are common, especially when treatment is stopped abruptly. The risk of withdrawal symptoms with SSRIs and SNRIs depends on several factors, including the duration and dose of therapy and the rate of dose reduction. The most frequently reported reactions are listed in the Adverse Reactions section. These symptoms are usually mild or moderate, but in some patients they may be severe, usually occurring within the first few days after stopping treatment. Very rarely, such symptoms have been observed in patients who accidentally missed a dose. These symptoms are self-limiting and usually resolve within 2 weeks, although in some individuals they may be prolonged (2
Akathisia/psychomotor restlessness: Symptoms of akathisia (characterized by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still) occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be harmful.
Liver enzyme elevations: Cases of liver injury, including severe elevations of liver enzymes (>10 times the upper limit of normal), hepatitis and jaundice have been reported with duloxetine (see section 4.8). These events have been reported most frequently during the first months of treatment. Liver injury is most often hepatocellular in nature. Caution should be exercised when prescribing duloxetine to patients taking medicinal products that may cause liver injury.
Sexual dysfunction.
SSRIs/SNRIs may cause symptoms of sexual dysfunction (see section 4.8). Long-term sexual dysfunction has been reported where symptoms persist despite discontinuation of SSRIs/SNRIs.
Suicide.
Major depressive disorder and generalised anxiety disorder. Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). The risk persists until significant remission is achieved. The patient should be closely monitored until significant improvement is achieved, as remission may not occur during the first few weeks or more of treatment. It is common clinical experience that the risk of suicide is increased during the initial stages of treatment.
Other psychiatric conditions for which Symbia® is prescribed are also associated with an increased risk of suicidality. In addition, these psychiatric conditions may be comorbid if they accompany major depressive disorder. Therefore, caution should be exercised when treating patients with both major depressive disorder and other psychiatric conditions. Patients with a history of suicidal ideation or a significant level of suicidal ideation are at greater risk of suicidal behavior and should be monitored closely during treatment. Suicidal ideation and suicidal behavior have been reported during duloxetine therapy or early after discontinuation. Patients should be closely monitored during therapy, particularly those at risk, and the dosage should be adjusted accordingly. Patients and caregivers should be informed of the need to monitor for any clinical worsening, suicidal behavior or thoughts, and unusual changes in behavior and to seek medical advice immediately if they occur.
Diabetic peripheral neuropathic pain: Isolated cases of suicidal ideation and suicidal behaviour have been reported during or early after treatment with duloxetine, as with other medicinal products with similar pharmacological effects (antidepressants). Physicians should advise patients to report any feelings of distress.
Elderly: Data on the use of Symbia® 120 mg in elderly patients with major depressive disorder and generalized anxiety disorder are limited.
Therefore, caution should be exercised when using the drug in elderly patients at the maximum dosage (see section "Method of administration and dosage").
Serious skin reactions: The following skin reactions have been reported very rarely in post-marketing experience: angioedema, contusion, hemorrhage, Stevens-Johnson syndrome, bruising, urticaria.
Medicines containing duloxetine. Duloxetine is used under different brand names for several indications (diabetic neuropathic pain, major depressive disorder, generalised anxiety disorder and stress urinary incontinence). The use of more than one of these medicines at the same time should be avoided.
Presence of sucrose. Symbia® enteric-coated capsules should not be prescribed to patients with hereditary fructose intolerance, malabsorption syndrome, or sucrase-isomaltase insufficiency.
Use during pregnancy or breastfeeding
Fertility
In animal studies, duloxetine did not affect male fertility, and effects in females were only evident at doses that caused maternal toxicity.
There are no adequate and well-controlled studies in pregnant women, therefore its use during pregnancy is not recommended. There are no adequate data from the use of duloxetine in pregnant women. Animal studies have shown reproductive toxicity at systemic exposure (AUC) of duloxetine below the maximum clinical exposure. The potential risk for humans is unknown. Epidemiological data suggest that the use of SSRIs during pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension of the newborn (PPHN). Although the association of PPHN with SSRI treatment has not been studied, this potential risk cannot be excluded with duloxetine given its mechanism of action (inhibition of serotonin reuptake). As with other serotonergic drugs, withdrawal symptoms may occur in infants whose mothers have used duloxetine before delivery. Withdrawal symptoms include orthostatic hypotension, tremor, hyperexcitability, difficulty swallowing, sucking, respiratory distress, and seizures. In most cases, these symptoms have occurred immediately after birth or within the first few days of life. Women taking duloxetine should be advised to inform their doctor if they become pregnant or plan to become pregnant.
The use of the drug during pregnancy is recommended only if the expected effect outweighs the risk.
Breastfeeding period
Duloxetine is poorly excreted in breast milk. The approximate dose received by the child (based on 1 mg per 1 kg of body weight) is 0.14% of the maternal dose. The safety of duloxetine in children is unknown, so breastfeeding while taking duloxetine is not recommended.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect of duloxetine on the speed of reaction when driving vehicles or using other mechanisms have not been conducted. The drug may cause sedation and dizziness. During treatment, patients should refrain from potentially hazardous activities that require increased attention and speed of psychomotor reactions.
Method of administration and doses
Major depressive disorder. The recommended starting and maintenance dose is 60 mg once daily, administered without regard to meals. Doses above 60 mg once daily up to a maximum dose of 120 mg daily have been evaluated for safety. However, there is no clinical evidence that dose escalation is effective in patients who do not respond to the initial recommended dose.
A therapeutic response is usually observed after 2-4 weeks of treatment.
After a sustained antidepressant effect, it is recommended to continue treatment for several months to avoid relapse. In patients who respond to duloxetine and have a history of recurrent major depressive episodes, further long-term treatment at a dose of 60-120 mg per day should be considered.
Diabetic peripheral neuropathic pain. The recommended starting dose is 60 mg once daily, without regard to meals. In some patients, a daily dose above 60 mg may be prescribed, up to a maximum dose of 120 mg per day, given in 2 divided doses.
The therapeutic effect of treatment is evident within 2 months. In patients with an inadequate initial response, an additional response after this period is unlikely. The therapeutic benefit should be assessed regularly (at least every 3 months).
Generalized anxiety disorder. The recommended starting dose is 30 mg once daily, without regard to meals. In case of insufficient response to treatment, the dose should be increased to 60 mg daily. In case of insufficient response to treatment at a dose of 60 mg, an increase in the dose to 90 or 120 mg daily may be considered.
The therapeutic effect of treatment is evident within 2–4 weeks. After the response is established, it is recommended to continue treatment for several months to avoid relapse.
Patients with renal insufficiency. No dose adjustment is required for patients with mild to moderate renal insufficiency (creatinine clearance 30–80 ml/min). Symbia® is not indicated for the treatment of patients with end-stage renal disease (creatinine clearance <30 ml/min).
Patients with hepatic insufficiency. The drug should not be prescribed to patients with liver disease or hepatic insufficiency.
Elderly patients. Dose adjustment based on age alone is not recommended for elderly patients. As with any drug, caution should be exercised when treating the elderly, especially when using Symbia® at a dose of 120 mg per day for major depressive disorder or generalized anxiety disorder.
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 reduce the risk of withdrawal reactions. If intolerable symptoms occur after dose reduction or after discontinuation of treatment, the drug can be resumed at the previously prescribed dose. Subsequently, the doctor may continue to reduce the dose, but more gradually.
Clinical studies on the use of duloxetine in children (under 18 years of age) have not been conducted, therefore it is not used in pediatric practice.
Overdose
Clinical data on overdose with duloxetine are limited. Cases of overdose have been reported with duloxetine at a dose of 5400 mg as monotherapy or in combination with other drugs. Fatalities have been reported, primarily with mixed overdoses, and with duloxetine at a dose of approximately 1000 mg.
Symptoms: Symptoms of overdose (mainly in combination with other drugs) have included drowsiness, coma, serotonin syndrome, convulsions, seizures, vomiting, and tachycardia.
Treatment of overdose. Specific antidotes are not known, and specific treatment (cyproheptadine and/or temperature control) is necessary if serotonin syndrome occurs. Airway patency should be checked. Cardiac monitoring and vital signs should be monitored, along with appropriate symptomatic and supportive measures. Gastric lavage may be appropriate if performed immediately after ingestion or in patients with symptoms of overdose. Activated charcoal reduces the absorption of the drug. Duloxetine has a large volume of distribution, so forced diuresis, hemoperfusion, and exchange perfusion are unlikely to be useful.
Adverse reactions
Dizziness, nausea and headache (>5%) have been reported as adverse reactions on discontinuation of duloxetine. Disturbances of sensation, sleep disturbances, agitation or anxiety, tremor, irritability, diarrhoea and hyperhidrosis have also been observed on discontinuation of the drug. The table below lists the adverse reactions with duloxetine from spontaneous reports and placebo-controlled clinical trials.
Frequency estimate: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%), very rare (<0.01%).
| Very often | Often | Infrequently | Rarely | Very rare |
| From the organs of vision | | | | |
| Blurry image | Mydriasis, visual disturbances, dry eyes | Glaucoma | | |
| From the side of the organs of hearing and vestibular apparatus | | | | |
| Ringing in the ears1 | Dizziness, earache | | | |
| Respiratory, thoracic and mediastinal disorders | | | | |
| Yawning, oropharyngeal pain | Feeling of tightness in the throat, nosebleeds | | | |
| Gastrointestinal tract | | | | |
| Nausea (24.3%), dry mouth (12.8%) | Constipation, diarrhea, vomiting, dyspepsia, flatulence, abdominal pain | Gastrointestinal bleeding7, gastroenteritis, eructation, gastritis | Stomatitis, bad breath, blood in stool, microscopic colitis | |
| Liver and biliary tract | | | | |
| Elevated liver enzymes (ALT, AST, alkaline phosphatase), hepatitis3, acute liver injury | Jaundice6, liver failure6 | | | |
| Renal and urinary disorders | | | | |
| Dysuria | Urinary retention, difficulty initiating urination, nocturia, polyuria, decreased urine flow | Abnormal urine odor | | |
| From the endocrine system | | | | |
| Hypothyroidism | | | | |
| From the side of metabolism, metabolism | | | | |
| Decreased appetite | Hyperglycemia (especially in patients with diabetes) | Dehydration, hyponatremia, SNSADH | | |
| From the nervous system | | | | |
Headache (14.3%), drowsiness (10.7%), dizziness (10.2%) | Tremor, paresthesia | Myoclonus, akathisia7, nervousness, disturbance in attention, lethargy, dyskinesia, dysgeusia, restless legs syndrome, poor sleep | Serotonin syndrome6, seizures1, psychomotor restlessness6, extrapyramidal disorders6 | |
| From the psyche | | | | |
| Insomnia, agitation, decreased libido, anxiety, abnormal visions and abnormal orgasm | Sleep disorders, bruxism, disorientation, apathy, suicidal ideation5,7 | Mania, hallucinations, aggression and hostility4, suicidal behavior5,7 | | |
| Cardiovascular system | | | | |
| Feeling of palpitations, hot flashes | Tachycardia, supraventricular arrhythmia, fibrillation, most often atrial. Arterial hypertension3,7, increased blood pressure3, orthostatic hypotension2, loss of consciousness2, feeling cold in the extremities | Hypertensive crisis3,6 | | |
| On the part of the immune system | | | | |
| Anaphylactic reactions, hypersensitivity | | | | |
| Skin and subcutaneous tissue disorders | | | |
Increased sweating, rash | Night sweats, contact dermatitis, hives, cold sweat, photosensitivity, increased tendency to bruise | Angioedema6, Stevens-Johnson syndrome6 | Cutaneous vasculitis | |
| Musculoskeletal and connective tissue disorders | | | | |
| Musculoskeletal pain, muscle spasm | Muscle twitching, feeling of muscle stiffness | Trismus | | |
| Reproductive system and mammary gland function | | | | |
| Erectile dysfunction, impaired or delayed ejaculation | Menstrual disorders, sexual disorders, gynecological bleeding | Menopausal symptoms, galactorrhea, hyperprolactinemia | | |
| General disorders and administration site conditions | | | | |
| Fatigue | Chest pain7; fall8; feeling unwell, feeling cold, feeling of “crawling” (pins and needles), thirst, malaise, feeling hot, gait disturbance | | | |
| Infections and infestations | | | | |
| Laryngitis | | | | |
| Laboratory indicators | | | | |
| Weight loss | Weight gain, increased creatine phosphokinase levels | Increased blood cholesterol levels | | |
1 Cases of seizures and tinnitus have been observed after discontinuation of treatment.
2 Cases of orthostatic hypotension and loss of consciousness were observed mainly at the beginning of treatment.
3 Patients who experience persistent elevations in blood pressure while taking duloxetine should have their dose reduced or their drug therapy gradually discontinued.
4 Cases of aggression and anger have been reported at the start of treatment and after treatment discontinuation.
5 Cases of suicidal ideation and suicidal behaviour have been reported early in treatment and early after treatment discontinuation.
6 The frequency of adverse reactions identified from post-marketing studies that were not observed in placebo-controlled clinical trials.
7 Not statistically significantly different from placebo.
8 Falls were more common in older people (≥65 years).
Discontinuation of therapy (especially abrupt discontinuation) is often accompanied by a withdrawal syndrome. The most common adverse reactions in this case are dizziness, somnolence, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and severe delusions), weakness, anxiety or aggression, nausea and/or vomiting, tremor, headache, irritability, diarrhoea, hyperhidrosis and vertigo. Gradual discontinuation of therapy is recommended. Usually for SSRIs and SNRIs these events are mild to moderate and self-limiting, but in some patients they may be severe and/or prolonged. Therefore, gradual discontinuation of therapy by dose reduction is recommended when duloxetine treatment is no longer required (see sections 4.4 and 4.2).
In the 12-week acute phase of duloxetine studies in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose were observed in patients treated with duloxetine. HbA1c was stable in both duloxetine and placebo-treated patients. In the extension phase of these studies, which lasted up to 52 weeks, increases in HbA1c were observed in both the duloxetine and usual care groups, but the mean increase in the duloxetine group was 0.3%. There were also small increases in fasting blood glucose and total cholesterol in patients treated with duloxetine, while these laboratory studies showed small decreases in the risk groups.
The QT interval with heart rate correction in patients taking duloxetine did not differ from patients taking placebo. No clinically significant differences in QT, PR, QRS, or QTcB measurements were observed between patients taking duloxetine and placebo.
Kidney failure.
In patients with severe renal impairment (creatinine clearance <30 mL/min) undergoing hemodialysis, increased levels of duloxetine have been observed.
