Instructions for use Shimoda gastro-resistant capsules 60 mg blister No. 28
Composition
active ingredient: duloxetine;
1 gastro-resistant hard capsule contains duloxetine hydrochloride, equivalent to duloxetine 60 mg;
excipients: sugar spheres, hydroxypropylcellulose, hypromellose, hypromellose phthalate, triethyl citrate, talc.
Dosage form
Gastro-resistant hard capsules.
Main physicochemical properties: capsules with a gray opaque body and a white opaque cap; marking: “DLX 60” on the capsule body and cap.
Pharmacotherapeutic group
Agents acting on the nervous system. Psychoanaleptics. Antidepressants. ATC 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 concentrations are reached 6 hours after administration. 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 (>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/h.
Renal impairment: In patients with end-stage renal disease undergoing dialysis, duloxetine concentrations and exposure (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 peripheral neuropathic pain in diabetes.
Treatment of generalized anxiety disorder.
Contraindication
A contraindication for the use of the drug is hypersensitivity to duloxetine or to any of the drug's excipients.
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.
Shimoda 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).
Shimoda 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.
Also, the drug should not be prescribed 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, decreased duloxetine plasma clearance by approximately 77% and increased AUC0-t by 6-fold. Therefore, duloxetine should not be co-administered with CYP1A2 inhibitors, including fluvoxamine.
MAO inhibitors: Due to the risk of serotonin syndrome, duloxetine should not be administered concomitantly with non-selective, irreversible MAO inhibitors or for at least 14 days after discontinuation of treatment with MAO inhibitors. Given the half-life of duloxetine, MAO inhibitors should not be administered for at least 5 days after discontinuation of treatment with duloxetine. Concomitant use of Simoda with selective, reversible MAO inhibitors such as moclobemide is not recommended. The antibiotic linezolid is a reversible, non-selective MAO inhibitor and should not be administered to patients receiving Simoda (see section 4.4).
Serotoninergic agents: Serotonin syndrome has been reported rarely in patients receiving selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-norepinephrine reuptake inhibitors (SNRIs) in combination with serotonergic agents. Caution should be exercised when prescribing Simoda in combination with serotonergic agents, tricyclic antidepressants such as clomipramine or amitriptyline, moclobemide or linezolid, St. John's wort (Hypericum perforatum) or triptans, tramadol, pethidine and tryptophan.
Effects of duloxetine on other medicinal products
Drugs metabolized by CYP1A2: In a clinical study of concomitant administration of theophylline, a CYP1A2 substrate, with duloxetine (60 mg twice daily), no significant pharmacokinetic interaction was observed.
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) 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 Simoda with drugs that are primarily metabolized by CYP2D6 (risperidone, tricyclic antidepressants such as nortriptyline, amitriptyline, and imipramine), especially if they have a narrow therapeutic index (e.g., flecainide, propafenone, and metoprolol).
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 administered with caution with oral anticoagulants and antithrombotic agents due to the potential for increased bleeding risk 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 under inpatient conditions did not result in a clinically significant change in INR from baseline or in the pharmacokinetics of R- or S-warfarin.
Effects of other medicinal products on duloxetine
Antacids and H2 antagonists: Coadministration 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.
Preparations containing St. John's wort herb
Adverse reactions often occur when used together with Shimoda.
Application features
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 not indicated for this age group.
Seizures and mania: As with other CNS-active drugs, duloxetine should be used with caution in patients with a history of seizures, mania, or bipolar disorder.
Blood pressure and palpitations. Duloxetine has been associated with increases in blood pressure and clinically significant hypertension in some patients. This may be due to the noradrenergic effects of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, particularly in patients with pre-existing hypertension. Therefore, monitoring of blood pressure is recommended in patients with known hypertension and/or other cardiac disease, particularly during the first month of treatment. Simoda should be used with caution in patients whose condition may be compromised by an increase in heart rate or blood pressure. Caution should also be exercised when duloxetine is used with medicinal products that may impair its metabolism (see section 4.5). For patients who experience persistent increases in blood pressure while taking the drug, consideration should be given to reducing the dose or gradually discontinuing the drug (see section 4.8). Patients with uncontrolled hypertension should not use Shimoda (see 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.
Serotonin syndrome: As with other serotonergic agents, serotonin syndrome may be potentially life-threatening with duloxetine, 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 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.
Preparations containing St. John's wort herb
Adverse reactions may be more common with simultaneous use of Shimoda and preparations containing St. John's wort (Hypericum perforatum).
Suicide
Major depressive disorder and generalized anxiety disorder
Depression is associated with an increased risk of suicidal 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 within the first few weeks of treatment or longer. It is common clinical experience that the risk of suicide is increased in the initial stages of treatment.
Other psychiatric conditions for which Shimoda is prescribed may also be associated with an increased risk of suicidal behaviour. In addition, these psychiatric conditions may
be comorbid if they accompany major depressive disorder. Therefore, the same precautions should be observed when treating patients with major depressive disorder as with other psychiatric conditions. Patients with a history of suicidality or a significant level of suicidal ideation are at greater risk of suicidal behavior and therefore require closer 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 suicidal behavior have been reported during duloxetine therapy or early after its discontinuation. Close monitoring of patients, especially those at risk, is necessary during therapy, especially in the early stages, and appropriate dosage adjustments should be made. Patients (and caregivers of patients) 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 occur.
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.
Haemorrhage: Bleeding events such as bruising, 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 is advised in patients taking anticoagulants and/or medicinal products that may affect platelet function (e.g. NSAIDs or acetylsalicylic acid) and in patients with a known tendency to bleed.
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.
Withdrawal symptoms. Withdrawal symptoms are quite 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 section “Adverse reactions”. These symptoms are usually mild or moderate, but in some patients they may be severe. They usually occur 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 disappear within 2 weeks, although in some individuals they may be prolonged (2-3 months or more). Therefore, it is recommended that the dose of duloxetine be gradually reduced when stopping treatment over a period of at least 2 weeks according to the patient's needs (see section “Method of administration and dosage”).
Akathisia/psychomotor restlessness: Akathisia (characterized by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still) has been reported to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be harmful.
Hepatitis/increased liver enzymes: 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). Most of these have occurred within the first few 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.
Elderly patients
Data on the use of Simoda at a dosage of 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").
Medicines containing duloxetine
Duloxetine is used under different brand names for several indications (diabetic neuropathic pain, major depressive disorder, generalized anxiety disorder, and stress urinary incontinence). The use of more than one of these medications at the same time should be avoided.
Serious skin reactions
In post-marketing studies, the following skin reactions have been reported very rarely: angioedema, contusion, hemorrhage, Stevens-Johnson syndrome, bruising, urticaria.
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.
Saccharose
The drug contains sucrose (in the composition of sugar spheres) as an excipient, therefore patients with hereditary fructose intolerance, malabsorption syndrome, sucrase-isomaltase insufficiency should not use the drug.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect of duloxetine on the ability to drive or use machines have not been conducted. The use of Simoda is associated with sedation and dizziness. Patients should refrain from potentially hazardous activities, such as driving or operating machinery, if they experience sedation or dizziness.
Use during pregnancy or breastfeeding
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 in the newborn. Although studies have not been conducted in the presence of pulmonary hypertension and concomitant use of SSRIs, a potential risk cannot be excluded given its mechanism of action (inhibition of serotonin reuptake).
There is no overall increased risk of major birth defects in 2 large observational studies (one in the US involving 2500 subjects exposed to duloxetine in the first trimester; the other in the EU involving 1500 subjects exposed to duloxetine in the first trimester). Analysis of specific birth defects, such as heart defects, has been inconclusive.
In a study conducted in the EU, maternal exposure to duloxetine in late pregnancy (any time from 20 weeks of gestation until delivery) was associated with an increased risk of preterm birth (less than 2-fold, corresponding to approximately 6 additional preterm births for every 100 women exposed to duloxetine in late pregnancy). The majority of these occurred between 35 and 36 weeks of gestation. This association was not observed in a study conducted in the US.
Observational data suggest an increased risk (less than 2-fold) of postpartum hemorrhage following exposure to duloxetine within the month before delivery (see section 4.4).
As with other serotonergic drugs, withdrawal symptoms may occur in newborns whose mothers have taken duloxetine. Symptoms of withdrawal from duloxetine may include hypotension, tremor, nervousness, difficulty feeding, respiratory distress syndrome, and seizures. Most cases have occurred either at birth or within a few days of birth. Simmod should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. Women should inform their doctors if they become pregnant or plan to become pregnant during therapy.
Breastfeeding period
Duloxetine is excreted in human milk to a very low extent, as confirmed by 6 patients who were capable of breastfeeding but did not breastfeed. The estimated daily dose to the infant (mg/kg) was approximately 0.14% of the maternal dose. The safety of duloxetine in infants is unknown, therefore, the use of Simoda during breastfeeding is not recommended.
Fertility
In animal studies, duloxetine did not affect male fertility, and effects in females were only evident at doses that caused maternal toxicity.
Method of administration and doses
Major depressive disorder
The initial and recommended maintenance dose is 60 mg once daily. The drug should be taken without regard to meals. Doses exceeding 60 mg once daily, up to a maximum dose of 120 mg daily, divided into 2 doses, have been evaluated for safety in clinical trials. However, there is no clinical data to suggest that patients do not respond to the initial recommended dose, which is preferable to a higher titer dose.
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 for whom treatment with duloxetine has been effective and who have recurrent episodes of depressive disorders, further long-term treatment can be carried out at a dose of 60 to 120 mg per day.
Generalized anxiety disorder
The recommended starting dose for patients with generalized anxiety disorder is 30 mg once daily. The drug should be taken without regard to meals. In patients with inadequate response, the dose should be increased to 60 mg. In patients with comorbid major depressive disorder, the initial and maintenance doses are 60 mg once daily (see also dosage recommendations above). Doses up to 120 mg daily have been effective and have been evaluated for safety in clinical studies. For patients with inadequate response to 60 mg, doses up to 90 mg or 120 mg daily may be considered. Dose increases should be based on clinical response and tolerability.
After an increased response to the drug, it is recommended to continue treatment for several months to prevent relapse.
Peripheral neuropathic pain in diabetes
Response to treatment should be assessed after 2 months. In patients with an inadequate initial response, further response is unlikely after this period.
The therapeutic effect should be reviewed regularly (at least once every 3 months).
Elderly patients
There is no dose adjustment for elderly patients based solely on age. However, as with any drug, caution should be exercised in elderly patients, especially when prescribing Simoda capsules at a dose of 120 mg per day for major depressive disorder, for which data are limited.
Liver failure
Shimoda capsules should not be prescribed to patients with liver disease or liver failure.
Kidney failure
No dosage adjustment is required for patients with mild to moderate renal dysfunction (creatinine clearance 30 to 80 mL/min). Simmod should not be administered to patients with severe renal impairment (creatinine clearance <30 mL/min).
Treatment discontinuation
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 withdrawal symptoms occur after dose reduction or after discontinuation of treatment, the drug can be resumed at the previously prescribed dose. Over time, the doctor may continue to reduce the dose, but more gradually.
Children
Shimoda is not used to treat children and adolescents (under 18 years of age).
Overdose
Symptoms: Cases of overdose with duloxetine at a dose of 5400 mg as monotherapy or in combination with other drugs have been reported. Fatal cases have been recorded, primarily with mixed overdose, and with duloxetine at a dose of approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or in combination with other drugs): drowsiness, coma, serotonin syndrome, seizures, vomiting and tachycardia.
Treatment of overdose. Specific antidotes are not known. If serotonin syndrome occurs, specific treatment (cyproheptadine and/or temperature control) is necessary. The airway should be checked. Monitoring of cardiac activity and vital signs is recommended, together with appropriate symptomatic and supportive measures. Gastric lavage may be appropriate if performed immediately after ingestion or for symptomatic treatment. Activated charcoal reduces the absorption of the drug. Duloxetine has a large volume of distribution in the body, and forced diuresis, hemoperfusion, and exchange perfusion are unlikely to be useful.
Adverse reactions
The most commonly reported adverse reactions were nausea, headache, dry mouth, drowsiness, and dizziness. Most of the common adverse reactions were mild to moderate in intensity. They were usually observed at the beginning of therapy and decreased with continued therapy.
The following are adverse reactions associated with duloxetine based on 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%).
Infections and infestations:
uncommon: laryngitis.
From the endocrine system:
Rare: hypothyroidism.
On the part of the immune system:
Rare: anaphylactic reactions, hypersensitivity.
Metabolism and nutrition:
common: decreased appetite;
infrequently: hyperglycemia (especially in patients with diabetes mellitus);
Rare: dehydration, hyponatremia, ADH deficiency 6.
From the psyche:
common: insomnia, agitation, decreased libido, anxiety, abnormal visions and abnormal orgasm;
uncommon: sleep disorders, bruxism, disorientation, apathy, suicidal ideation 5, 7;
Rare: mania, hallucinations, aggression and malice 4, suicidal behavior 5, 7.
From the nervous system:
very common: headache, drowsiness;
common: tremor, paresthesia, dizziness, lethargy;
uncommon: myoclonus, akathisia 7, nervousness, disturbance in attention, lethargy, dyskinesia, taste disturbance, 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:
common: blurred image;
uncommon: mydriasis, visual disturbances;
Rare: glaucoma.
On the part of the organs of hearing and balance:
common: tinnitus1;
uncommon: vertigo, earache.
From the heart:
common: feeling of palpitations;
uncommon: tachycardia, supraventricular arrhythmia, fibrillation (predominantly atrial).
From the vascular side:
common: increased blood pressure 3, hot flashes;
uncommon: arterial hypertension 3, 7, orthostatic hypotension 2, loss of consciousness 2, feeling of coldness in the extremities, syncope;
Rare: hypertensive crisis 3, 6.
On the part of the respiratory system:
common: yawning;
uncommon: feeling of tightness in the throat, nosebleed;
rare: interstitial lung disease 10, eosinophilic pneumonia 6.
From the digestive system:
very common: nausea, dry mouth;
common: constipation, diarrhea, vomiting, dyspepsia, flatulence, abdominal pain;
uncommon: gastrointestinal bleeding 7, gastroenteritis, eructation, gastritis, dysphagia;
Rare: stomatitis, bad breath, blood in stools, microscopic colitis 9.
uncommon: increased liver enzymes (ALT, AST, alkaline phosphatase), hepatitis 3, acute liver injury;
Rare: jaundice 6, hepatic failure 6.
On the part of the skin and its derivatives:
common: increased sweating, rash;
uncommon: night sweats, contact dermatitis, urticaria, cold sweat, photosensitivity, increased tendency to bruise;
rare: angioedema 6, Stevens-Johnson syndrome 6;
very rare: cutaneous vasculitis.
Musculoskeletal and connective tissue disorders:
common: musculoskeletal pain, muscle spasm;
infrequently: muscle twitching, feeling of muscle stiffness;
Rare: trismus.
From the kidneys and urinary tract:
common: dysuria, pollakiuria;
infrequently: urinary retention, difficulty in initiating urination, nocturia, polyuria, decreased urine flow;
Rare: abnormal urine odor.
From the reproductive system:
common: erectile dysfunction, impaired or delayed ejaculation;
uncommon: menstrual disorders, sexual disorders, gynecological bleeding, testicular pain;
Rare: menopausal symptoms, galactorrhea, hyperprolactinemia, postpartum hemorrhage 6.
General disorders:
common: fall 8, fatigue;
uncommon: chest pain 7 feeling unwell, feeling cold, feeling of "pins and needles", thirst, malaise, feeling hot, gait disturbance.
Research conducted:
common: weight loss;
uncommon: weight gain, increased creatinine phosphokinase levels, increased blood potassium levels;
Rare: 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 therapy gradually discontinued.
4 Cases of aggression and hostility 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 Statistically significant compared to placebo.
8 Falls were more common in older patients (aged 65 years and older).
9 The frequency of adverse reactions is based on data from all clinical trials.
10 The frequency of adverse reactions observed in placebo-controlled clinical trials has been established.
Discontinuation of duloxetine therapy (especially abrupt) is often accompanied by a withdrawal syndrome. The most common adverse reactions in this case are: sensory disturbances (including paraesthesia or electric shock sensations, especially in the head), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhoea, hyperhidrosis and dizziness.
These events are usually mild to moderate and self-limiting for SSRIs and SNRIs, but in some patients they may be severe and/or prolonged. Therefore, gradual discontinuation by dose reduction is recommended when duloxetine treatment is no longer required (see sections 4.4 and 4.2).
In the 1–2-week acute phase of duloxetine studies in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine-treated patients. HbA1c was stable in both duloxetine-treated and placebo-treated patients. 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-treated group was 0.3%. There were also small increases in fasting blood glucose and total cholesterol in duloxetine-treated patients, whereas 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.
The adverse reaction profile of duloxetine in children and adolescents is similar to that seen in adults. Children taking duloxetine experienced a mean weight loss of 0.1 kg over the 10-week study period compared with a mean weight gain of 0.9 kg in patients on placebo. Subsequently, patients returned to their expected baseline weight within 4 to 6 months, on average, based on age- and sex-matched population data.
In studies up to 9 months, there was an overall mean decrease of 1% in height (a decrease of 2% in children aged 7-11 years and an increase of
