Instructions for Duloxin capsules 30 mg No. 28
Composition
1 capsule contains 33.7 mg of duloxetine hydrochloride, equivalent to 30 mg of duloxetine;
excipients: spherical sugar, hydroxypropyl methylcellulose, polyethylene glycol 6000, talc, sucrose, hydroxydipropyl methylcellulose acetate succinate, triethyl citrate;
hard gelatin capsule No. 3 (for 30 mg capsules);
capsule shell composition: titanium dioxide (E 171), indigotine blue (E 132), gelatin.
Dosage form
Enteric-coated hard capsules.
Main physicochemical properties: hard gelatin capsule No. 3, blue body, white cap. Capsule contents: white or almost white pellets.
Pharmacotherapeutic group
Other 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 (CNS). Duloxetine also has analgesic effects, which are likely to be the result of slowing the transmission of pain impulses in the CNS.
Pharmacokinetics
Duloxetine is well absorbed after oral administration. Peak plasma concentrations are reached 6 hours after administration. Food intake delays absorption, increasing the time to Cmax from 6 to 10 hours and decreasing absorption (approximately 11%).
Distribution: Duloxetine is highly bound to serum proteins (>90%).
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.
Indication
Treatment of major depressive disorder.
Treatment of diabetic peripheral neuropathic pain.
Treatment of generalized anxiety disorders.
Contraindication
Hypersensitivity to the active substance or to any of the excipients of the drug.
The concomitant use of duloxetine with non-selective, irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated.
Liver diseases that can cause liver failure.
Duloxetine should not be used in combination with fluvoxamine, ciprofloxacin or enoxacin (strong CYP1A2 inhibitors) as the combination leads to increased plasma concentrations of duloxetine.
Severe renal failure (creatinine clearance < 30 ml/min).
Initiation of duloxetine treatment is contraindicated in patients with uncontrolled hypertension, as this 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 of stopping their use. Based on the half-life of duloxetine, MAOIs should not be started until 5 days after stopping duloxetine (see section 4.3).
The combined use of duloxetine with selective reversible MAOIs such as moclobemide is not recommended (see section 4.4). The antibiotic linezolid is a reversible non-selective MAOI and should not be given to patients taking duloxetine (see section 4.4).
CYP1A2 inhibitors: Since CYP1A2 is involved in the metabolism of duloxetine, concomitant use of duloxetine with strong CYP1A2 inhibitors is likely to result in increased duloxetine concentrations. Fluvoxamine (100 mg once daily), a strong CYP1A2 inhibitor, decreased duloxetine plasma clearance by approximately 77% and AUC by 6-fold. Therefore, duloxetine should not be administered in combination with strong CYP1A2 inhibitors such as fluvoxamine (see section 4.4).
Serotoninergic agents: Serotonin syndrome has been reported rarely in patients receiving selective serotonin reuptake inhibitors/serotonin norepinephrine reuptake inhibitors (SSRIs/SNRIs) in combination with serotonergic agents. Caution is advised when duloxetine is used concomitantly with serotonergic agents such as SSRIs, SNRIs, tricyclic antidepressants such as clomipramine or amitriptyline, MAOIs such as moclobemide or linezolid, St. John's wort (Hypericum perforatum) or triptans, tramadol, pethidine and tryptophan (see section 4.4).
Effects of duloxetine on other medicinal products
Drugs metabolized by CYP1A2: The pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60 mg twice daily).
Drugs metabolized by CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine 60 mg twice daily was administered with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold.
Co-administration of duloxetine (40 mg twice daily) increases the steady-state exposure (AUC) of tolterodine (2 mg twice daily) by 71%, but does not affect the pharmacokinetics of its active 5-hydroxyl metabolite and does not require dose adjustment.
Caution is advised when duloxetine is used concomitantly with drugs that are predominantly metabolized by CYP2D6 (risperidone, tricyclic antidepressants such as nortriptyline, amitriptyline and imipramine), especially if they have a narrow therapeutic index (flecainide, propafenone and metoprolol).
Oral contraceptives and other steroids: In vitro studies indicate that duloxetine does not induce CYP3A catalytic activity. Specific in vivo drug interaction studies have not been conducted.
Anticoagulants and antithrombotic agents. Duloxetine should be used with caution in combination with oral anticoagulants and antithrombotic agents due to the potential for increased bleeding risk due to pharmacodynamic interactions. Additionally, increases in international normalized ratio (INR) have been observed when warfarin was administered concomitantly with duloxetine. However, co-administration of duloxetine and warfarin in a clinical pharmacology study in healthy volunteers under inpatient conditions did not result in a clinically meaningful change in INR from baseline or in the pharmacokinetics of R- or S-warfarin.
Effects of other drugs on duloxetine
Antacids and H2 antagonists: Co-administration of duloxetine with aluminum- and magnesium-containing antacids or with famotidine did not affect the rate or extent of absorption of duloxetine following a 40 mg oral dose.
CYP1A2 inducer. Population pharmacokinetic analysis showed that smokers have almost 50% lower plasma concentrations of duloxetine compared to non-smokers.
Application features
Mania and epileptic seizures
Duloxetine should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder and/or epileptic seizures.
Mydriasis
Cases of mydriasis have been reported in association with duloxetine, therefore duloxetine should be used with caution in patients with elevated intraocular pressure or at risk of acute narrow-angle glaucoma.
Blood pressure and palpitations
In some patients, duloxetine has been associated with increases in blood pressure and clinically significant hypertension. This may be related to the noradrenergic effects of duloxetine. Hypertensive crisis has been reported with duloxetine, particularly in patients with pre-existing hypertension. Monitoring of blood pressure is recommended in patients with known hypertension and/or other heart failure, particularly during the first month of treatment. Duloxetine should be used with caution in patients whose underlying disease may be compromised by an increase in heart rate or blood pressure. Caution should be exercised when duloxetine is co-administered with medicinal products that may impair its metabolism (see section 4.5). For patients who experience persistent increases in blood pressure while taking duloxetine, dose reduction or gradual discontinuation should be considered (see section 4.8). Treatment should not be initiated in patients with unstable hypertension (see section "Contraindications").
Kidney failure
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 or moderate renal impairment, see section 4.4.
As with other serotonergic agents, serotonin syndrome, which is potentially life-threatening, may occur with duloxetine treatment, especially when used concomitantly with other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants or triptans), with 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 changes in the patient's mental status (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
If concomitant treatment with duloxetine and other serotonergic drugs that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, close monitoring of patients is recommended, especially at the start of treatment and during dose increases.
St. John's wort (Hypericum perforatum)
Adverse reactions may occur more frequently when duloxetine is used concomitantly with herbal preparations containing St. John's wort (Hypericum perforatum).
Suicide
Major depressive disorder and generalized anxiety disorder.
Depression is associated with an increased risk of thoughts of harming oneself and of suicide (suicidality). The risk persists until significant remission occurs. As improvement may not occur during the first few weeks of treatment or longer, patients should be closely monitored until improvement occurs. It is common clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric disorders for which duloxetine is indicated may also be associated with an increased risk of suicidal behaviour. In addition, these conditions may coexist with major depressive disorder. Therefore, the precautions recommended for patients with major depressive disorder should be applied to patients with other psychiatric disorders.
Patients with a history of suicidal ideation or who demonstrate a significant degree of suicidal ideation prior to initiation of treatment are at increased risk of suicidal thoughts or behavior and should receive careful monitoring 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 with placebo in patients under 25 years of age.
Cases of suicidal ideation and behaviour have been reported during treatment with duloxetine or early after treatment discontinuation (see section 4.8).
Close monitoring of patients, especially those at high risk, should be undertaken in conjunction with drug therapy, particularly early in treatment and after dose adjustments. Patients and caregivers should be informed of the need to monitor for any clinical worsening, suicidal behaviour or thoughts, and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
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). For risk factors for suicidality in depression, see section above. Physicians should encourage patients to report any distressing thoughts or feelings at any time.
Use in children and adolescents under 18 years of age
Duloxetine should not be used in the treatment of children under 18 years of age. Suicidal behaviour (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were observed more frequently in clinical trials in children and adolescents treated with antidepressants compared to those treated with placebo.
Bleeding
Haemostatic disorders such as ecchymosis, purpura and gastrointestinal bleeding have been reported with SSRIs and SNRIs, including duloxetine. Duloxetine may increase the risk of postpartum haemorrhage (see section 4.6). Caution should be exercised in patients taking anticoagulants and/or medicinal products known to affect platelet function (e.g. non-steroidal anti-inflammatory drugs or acetylsalicylic acid) and in patients with known bleeding diathesis.
Hyponatraemia has been reported in patients treated with duloxetine, including cases with serum sodium levels below 110 mmol/L. Hyponatraemia may be associated with the syndrome of inappropriate antidiuretic hormone secretion. Most cases of hyponatraemia have been observed in elderly patients, especially those with a recent history or condition causing fluid imbalance. Caution should be exercised in patients at increased risk of hyponatraemia (elderly patients, patients with cirrhosis and dehydration, patients taking diuretics).
Treatment discontinuation
Withdrawal symptoms are common after discontinuation of treatment (especially if discontinued abruptly) (see section 4.8). In clinical trials, adverse events observed with abrupt discontinuation of treatment occurred in approximately 45% of patients treated with duloxetine and 23% of patients treated with placebo. The risk of withdrawal symptoms seen with SSRIs and SNRIs may depend on several factors, including duration of treatment and dose, and the rate of dose reduction. The most frequently occurring adverse reactions are listed in section 4.8. These symptoms are usually mild to moderate in severity, but may be severe in some patients. Withdrawal symptoms usually occur within the first few days of discontinuation of treatment, but there have been isolated reports of such symptoms in patients who inadvertently missed a dose. These symptoms generally resolve spontaneously within two weeks, although in some patients they may persist for longer (2-3 months or longer). Therefore, when discontinuing treatment, the dose of duloxetine should be gradually reduced over a period of at least two weeks, depending on the patient's needs (see section 4.2).
Elderly patients
Data on the use of 120 mg duloxetine in elderly patients with major depressive disorder and generalized anxiety disorder are limited. Therefore, caution should be exercised when treating elderly patients with the maximum dosage (see sections 5.2 and 5.2).
Akathisia/psychomotor agitation
Duloxetine has been associated with the development of akathisia, a subjectively unpleasant or distressing restlessness and need to move frequently, accompanied by an inability to sit or stand still. This phenomenon is more likely to occur during the first few weeks of treatment. In patients who develop these symptoms, increasing the dose of the drug may be harmful.
Medicines containing duloxetine
Duloxetine is used under different brand names for different indications (treatment of diabetic neuropathic pain, major depressive disorder, generalized anxiety disorder, and stress urinary incontinence). The use of more than one of these drugs at the same time should be avoided.
Hepatitis/increased liver enzymes
Cases of liver injury, including marked elevations of liver enzymes (>10 times the upper limit of normal), hepatitis and jaundice have been reported with duloxetine (see section 4.8). Most of these have occurred within 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
Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-term sexual dysfunction, with symptoms persisting despite discontinuation of SSRIs/SNRIs.
Saccharose
Duloxetine hard enteric-coated capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies on the effects on the ability to drive and use machines have been performed. Duloxetine may be associated with sedation and dizziness. Therefore, if sedation or dizziness occurs, patients should avoid potentially hazardous activities such as driving or operating machinery.
Use during pregnancy or breastfeeding
Pregnancy
There are no adequate data from the use of duloxetine in pregnant women. Animal studies have shown reproductive toxicity at AUCs of duloxetine lower than the maximum clinical exposure.
The potential risk to humans is unknown.
Epidemiological data have shown that the use of SSRIs during pregnancy, especially in late pregnancy, may increase the risk of developing persistent pulmonary hypertension of the newborn (PPHN).
As with other serotonergic drugs, withdrawal symptoms may occur in infants whose mothers have used duloxetine before delivery. Withdrawal symptoms seen with duloxetine include hypotension, tremor, hyperexcitability, difficulty swallowing, respiratory depression, and seizures. In most cases, these symptoms have occurred immediately after birth or within the first few days of life.
Observational data suggest an increased risk (less than 2-fold) of postpartum hemorrhage after use of duloxetine within the month before delivery.
Duloxetine should be used during pregnancy only if the expected benefit to the mother justifies the potential risk to the fetus. Women taking duloxetine should inform their doctor if they become pregnant or plan to become pregnant.
Breast-feeding
Duloxetine is excreted in human milk in a study of six lactating mothers who did not breastfeed their infants. The established dose for the infant on a mg/kg basis is 0.14% of the maternal dose (see section 5.2). The safety of duloxetine in infants is unknown, and breastfeeding is not recommended while taking duloxetine.
Fertility
Duloxetine had no effect on male fertility. Effects in women were evident only at doses that caused maternal toxicity.
Method of administration and doses
Method of application
Duloxetine is for oral use.
Doses
Major depressive disorder
The initial and recommended maintenance dose is 60 mg once daily, without regard to meals. Doses above 60 mg once daily up to a maximum dose of 120 mg daily have been evaluated for safety in clinical trials. However, there is no clinical evidence that patients who do not respond to the initial recommended dose may benefit from an increase in dose.
Therapeutic results are usually observed after 2-4 weeks of treatment.
After consolidation of the antidepressant response, it is recommended to continue treatment for several months to avoid relapse. In patients who respond to duloxetine and have a history of previous recurrent major depressive episodes, further long-term treatment at a dose of 60-120 mg per day may be considered.
Generalized anxiety disorders
The recommended starting dose for patients with generalized anxiety disorder is 30 mg once daily, without regard to meals. In patients with inadequate response, the dose should be increased to 60 mg, 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 dosing recommendations above).
Doses up to 120 mg/day have been shown to be effective and are being evaluated for safety in clinical trials. Therefore, for those patients who do not respond adequately to the 60 mg dose, an increase in dose to 90 or 120 mg may be considered. Dose increases should be based on clinical response and tolerability.
After consolidation of the response, it is recommended to continue treatment for several months to avoid relapse.
Diabetic peripheral neuropathic pain
The initial and recommended maintenance dose is 60 mg once daily, without regard to food intake. Doses above 60 mg once daily, up to a maximum of 120 mg daily, given in equally divided doses, have been evaluated for safety in clinical trials. Plasma concentrations of duloxetine show wide interindividual variability (see section 5.2). Therefore, some patients who do not respond adequately to the 60 mg dose may be given a higher dose.
The outcome of treatment should be assessed after 2 months. In patients with an inadequate initial response, an additional response after this time is unlikely.
Therapeutic benefit should be reassessed (at least every 3 months) (see Pharmacodynamics).
Special populations
Elderly patients
No dose adjustment is recommended for elderly patients based solely on age. However, caution should be exercised when treating the elderly, especially when using duloxetine at a dose of 120 mg/day in major depressive disorder, for which data are limited (see sections 5.2 and 4.4).
Liver failure
Duloxetine should not be used in patients with liver disease that may lead to hepatic failure (see sections 5.2 and 4.3).
Kidney failure
For patients with mild to moderate renal impairment (creatinine clearance 30 to 80 mL/min). Duloxetine should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min, see section 4.3).
Abrupt discontinuation of treatment should be avoided. When discontinuing treatment with duloxetine, the dose should be gradually reduced over at least 1–2 weeks to reduce the risk of withdrawal symptoms (see sections 4.4 and 4.8). If intolerable symptoms develop after dose reduction or discontinuation, the previously prescribed dose may be resumed. Your doctor may then continue to reduce the dose more gradually.
Children
The safety and efficacy of duloxetine in children under 18 years of age have not been studied, so the drug should not be prescribed to this age group of patients.
Overdose
Overdoses of duloxetine alone or in combination with other drugs have been reported at doses of up to 5400 mg. Some fatalities have been reported following overdoses of duloxetine, mostly in combination with other drugs, and with duloxetine alone at doses of approximately 1000 mg. Signs and symptoms of overdose (alone or in combination with other drugs) have included somnolence, coma, serotonin syndrome, seizures, vomiting, and tachycardia.
There are no specific antidotes to duloxetine; if serotonin syndrome occurs, specific treatment (cyproheptadine and/or temperature control) is necessary. A patent airway should be maintained. Cardiac monitoring and vital signs should be monitored, along with appropriate symptomatic and supportive measures. Gastric lavage may be considered immediately after ingestion or in symptomatic patients. Activated charcoal may be useful to limit absorption. Duloxetine has a large volume of distribution, and forced diuresis, hemoperfusion, and exchange perfusion are unlikely to be of benefit.
Adverse reactions
Brief description of the safety profile
The most commonly reported adverse reactions in patients treated with duloxetine were nausea, headache, dry mouth, somnolence and dizziness. However, most of the common adverse reactions were mild or moderate in severity, usually occurred early in treatment, and most tended to resolve, even with continued therapy.
Tabulated list of adverse reactions
The following are adverse reactions observed in self-reported and placebo-controlled clinical trials in patients with depression, generalized anxiety disorder, and diabetic neuropathic pain (including a total of 9 4 5 4 patients, of whom 5 70 3 received duloxetine and 3 7 5 1 received placebo).
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).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Infections and infestations: uncommon – laryngitis.
On the part of the immune system: rarely - anaphylactic reaction, hypersensitivity.
On the part of the endocrine system: rarely - hypothyroidism.
Metabolism and nutrition disorders: often - decreased appetite; infrequently - hyperglycemia (especially in patients with diabetes mellitus); rarely - dehydration, hyponatremia, ADH deficiency 6.
Psychiatric disorders: common: insomnia, agitation, decreased libido, anxiety, anorgasmia, abnormal dreams; uncommon: suicidal ideation 5, 7, sleep disorders, bruxism, disorientation, apathy; rare: suicidal behavior 5, 7, mania, hallucinations, aggression and malice 4.
Nervous system disorders: very common – headache, drowsiness; common – dizziness, lethargy, tremor, paresthesia; uncommon – myoclonus, akathisia 7, nervousness, disturbance in attention, dysgeusia, dyskinesia, restless legs syndrome, poor sleep; rare – serotonin syndrome 6, convulsions 1, psychomotor agitation 6, extrapyramidal disorders 6.
On the part of the organs of vision: often - blurred vision; infrequently - mydriasis, visual disturbances; rarely - glaucoma.
From the side of the organs of hearing and labyrinth: often - tinnitus 1; infrequently - vertigo, earache.
Cardiac disorders: often - palpitations; infrequently - tachycardia, supraventricular arrhythmia, mainly atrial fibrillation.
From the vascular system: often - increased blood pressure 3, hot flashes; infrequently - loss of consciousness 2, arterial hypertension 3, 7, orthostatic hypotension 2, feeling of coldness in the extremities; rarely - hypertensive crisis 3, 6.
Respiratory, thoracic and mediastinal disorders: common: yawning; uncommon: laryngospasm, epistaxis; rare: interstitial lung disease 10, eosinophilic pneumonia 6.
From the digestive tract: very often - nausea, dry mouth; often - constipation, diarrhea, abdominal pain, vomiting, dyspepsia, flatulence; infrequently - gastrointestinal bleeding 7, gastroenteritis, belching, gastritis, dysphagia; rarely - stomatitis, blood in the stool, bad breath, microscopic colitis 9.
Skin and subcutaneous tissue disorders: common: increased sweating, rash; uncommon: night sweats, urticaria, contact dermatitis, cold sweat, photosensitivity reactions, increased tendency to bruise; rare: Stevens-Johnson syndrome 6, angioedema 6, cutaneous vasculitis.
Musculoskeletal and connective tissue disorders: common: musculoskeletal pain, muscle spasm; uncommon: muscle stiffness, muscle twitching; rare: trismus.
On the part of the kidneys and urinary tract: often - dysuria, frequent urination, pollakiuria; infrequently - urinary retention, difficulty starting urination, nocturia, polyuria, decreased urine flow; rarely - abnormal urine odor.
3 Reproductive system and breast disorders: common: erectile dysfunction, ejaculation disorder, ejaculation delay; uncommon: gynecological bleeding, menstrual disorders, sexual dysfunction, testicular pain; rare: menopausal symptoms, galactorrhea, hyperprolactinemia, postpartum hemorrhage 6.
General disorders and administration site conditions: common – fall 8, fatigue; uncommon – chest pain 7, malaise, feeling cold, thirst, chills, weakness, feeling hot, gait disturbance.
Additional changes in tests: often - weight loss; infrequently - weight gain, increased blood creatinine phosphokinase, increased blood potassium; rarely - increased plasma cholesterol.
1 Cases of seizures and tinnitus have also been observed after discontinuation of treatment.
2 Cases of orthostatic hypotension and loss of consciousness were observed mainly at the beginning of treatment.
3 See section "Application features".
4 Cases of aggression and anger were mainly reported at the beginning of treatment and after treatment discontinuation.
5 Cases of suicidal ideation and behaviour have been reported during duloxetine treatment or early after treatment discontinuation (see section 4.4).
6 The frequency of adverse reactions is determined from post-marketing studies; not observed in placebo-controlled clinical trials.
7 Statistically not significantly different from placebo.
8 Falls were more common in older people (≥ 65 years).
9 Estimated frequency based on all clinical trial data.
10 Frequency estimate based on placebo-controlled clinical trials.
Description of selected adverse reactions
Discontinuation of duloxetine treatment (especially abrupt) is often associated with withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia or electric shock sensations, particularly in the head), sleep disturbances (including insomnia and severe delusions), fatigue, somnolence, restlessness or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhoea, hyperhidrosis and dizziness are the most commonly reported reactions.
Typically, for SSRIs and SNRIs, these events were mild to moderate in intensity and self-limiting; however, in some patients they may be severe and/or prolonged. Therefore, if continued treatment with duloxetine is no longer required, gradual discontinuation by dose tapering is recommended (see sections 4.4 and 4.2).
In the 1–2 week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose were observed with duloxetine. HbA1c levels were stable in both the duloxetine and placebo groups. In the extension phase of these studies, which lasted up to 5–2 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 with duloxetine, whereas these laboratory tests showed small decreases in the usual care group.
The heart rate-adjusted QT interval in patients taking duloxetine did not differ from that in patients taking placebo. There were no clinically significant differences in QT, PR, QRS, or QTcB measurements between patients taking duloxetine and placebo.
Children
It is known that the profile of adverse reactions when using a doula
