1. Name Of The Medicinal Product
Cymbalta* 30 mg hard gastro-resistant capsules.
Cymbalta 60 mg hard gastro-resistant capsules.
2. Qualitative And Quantitative Composition
Each capsule contains 30 mg of duloxetine (as hydrochloride).
Excipients 30 mg: each capsule contains 8.6 mg sucrose.
Each capsule contains 60 mg of duloxetine (as hydrochloride).
Excipients 60 mg: each capsule contains 17.2 mg sucrose.
For the full list of excipients, see section 6.1.
3. Pharmaceutical Form
Hard gastro-resistant capsule.
30 mg: Opaque white body, imprinted with '30 mg' and an opaque blue cap, imprinted with '9543'.
60 mg: Opaque green body, imprinted with '60 mg' and an opaque blue cap, imprinted with '9542'.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of major depressive disorder.
Treatment of diabetic peripheral neuropathic pain.
Treatment of generalised anxiety disorder.
Cymbalta is indicated in adults.
For further information see section 5.1.
4.2 Posology And Method Of Administration
Posology
Major Depressive Disorder: The starting and recommended maintenance dose is 60 mg once daily with or without food. Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day have been evaluated from a safety perspective in clinical trials. However, there is no clinical evidence suggesting that patients not responding to the initial recommended dose may benefit from dose up-titrations.
Therapeutic response is usually seen after 2-4 weeks of treatment.
After consolidation of the antidepressive response, it is recommended to continue treatment for several months, in order to avoid relapse. In patients responding to duloxetine, and with a history of repeated episodes of major depression, further long-term treatment at a dose of 60 to 120 mg/day could be considered.
Generalised Anxiety Disorder: The recommended starting dose in patients with generalised anxiety disorder is 30 mg once daily with or without food. In patients with insufficient response, the dose should be increased to 60 mg, which is the usual maintenance dose in most patients.
In patients with co-morbid major depressive disorder, the starting and maintenance dose is 60 mg once daily (please see also dosing recommendation above).
Doses up to 120 mg per day have been shown to be efficacious and have been evaluated from a safety perspective in clinical trials. In patients with insufficient response to 60 mg, escalation up to 90 mg or 120 mg may therefore be considered. Dose escalation should be based upon clinical response and tolerability.
After consolidation of the response, it is recommended to continue treatment for several months, in order to avoid relapse.
Diabetic Peripheral Neuropathic Pain: The starting and recommended maintenance dose is 60 mg daily with or without food. Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day administered in evenly divided doses, have been evaluated from a safety perspective in clinical trials. The plasma concentration of duloxetine displays large inter-individual variability (see section 5.2). Hence, some patients that respond insufficiently to 60 mg may benefit from a higher dose.
Response to treatment should be evaluated after 2 months. In patients with inadequate initial response, additional response after this time is unlikely.
The therapeutic benefit should be reassessed regularly (at least every three months) (see section 5.1).
Elderly
No dosage adjustment is recommended for elderly patients solely on the basis of age. However, as with any medicine, caution should be exercised when treating the elderly, especially with Cymbalta 120 mg per day for major depressive disorder, for which data are limited (see sections 4.4 and 5.2).
Children and Adolescents
Duloxetine is not recommended for use in children and adolescents due to insufficient data on safety and efficacy (see section 4.4).
Hepatic Impairment
Cymbalta must not be used in patients with liver disease resulting in hepatic impairment (see sections 4.3 and 5.2).
Renal Impairment
No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80 ml/min). Cymbalta must not be used in patients with severe renal impairment (creatinine clearance <30 ml/min; see section 4.3).
Discontinuation of Treatment
Abrupt discontinuation should be avoided. When stopping treatment with Cymbalta the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.
Method of administration
For oral use.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Concomitant use of Cymbalta with non selective, irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated (see section 4.5).
Liver disease resulting in hepatic impairment (see section 5.2).
Cymbalta should not be used in combination with fluvoxamine, ciprofloxacin or enoxacin (i.e., potent CYP1A2 inhibitors), since the combination results in elevated plasma concentrations of duloxetine (see section 4.5).
Severe renal impairment (creatinine clearance <30 ml/min) (see section 4.4).
The initiation of treatment with Cymbalta is contraindicated in patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive crisis (see sections 4.4 and 4.8).
4.4 Special Warnings And Precautions For Use
Mania and Seizures
Cymbalta should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures.
Mydriasis
Mydriasis has been reported in association with duloxetine, therefore, caution should be used when prescribing Cymbalta to patients with increased intraocular pressure or those at risk of acute narrow-angle glaucoma.
Blood Pressure and Heart Rate
Duloxetine has been associated with an increase in blood pressure, and clinically significant hypertension in some patients. This may be due to the noradrenergic effect of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, especially in patients with pre-existing hypertension. Therefore, in patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended, especially during the first month of treatment. Duloxetine should be used with caution in patients whose conditions could be compromised by an increased heart rate or by an increase in 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 a sustained increase in blood pressure while receiving duloxetine, either dose reduction or gradual discontinuation should be considered (see section 4.8). In patients with uncontrolled hypertension, duloxetine should not be initiated (see section 4.3).
Renal Impairment
Increased plasma concentrations of duloxetine occur in patients with severe renal impairment on haemodialysis (creatinine clearance <30 ml/min). For patients with severe renal impairment, see section 4.3. See section 4.2 for information on patients with mild or moderate renal dysfunction.
Use With Antidepressants
Caution should be exercised when using Cymbalta in combination with antidepressants. In particular, the combination with selective reversible MAOIs is not recommended.
St John's Wort
Adverse reactions may be more common during concomitant use of Cymbalta and herbal preparations containing St John's Wort (Hypericum perforatum).
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). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric conditions for which Cymbalta is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.
Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal thoughts prior to commencement of treatment, are known to be at greater risk of suicidal thoughts or suicidal behaviour, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant medicinal products in psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.
Cases of suicidal thoughts and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation (see section 4.8).
Close supervision of patients, and in particular those at high risk, should accompany medicinal product therapy, especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about 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
As with other medicinal products with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation. Concerning risk factors for suicidality in depression, see 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
No clinical trials have been conducted with duloxetine in paediatric populations. Cymbalta should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour, and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation, and cognitive and behavioural development are lacking.
Haemorrhage
There have been reports of bleeding abnormalities, such as ecchymoses, purpura, and gastrointestinal haemorrhage, with selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs), including duloxetine. Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function (e.g., NSAIDs or acetylsalicylic acid (ASA)), and in patients with known bleeding tendencies.
Hyponatraemia
Hyponatraemia has been reported when administering Cymbalta, including cases with serum sodium lower than 110 mmol/l. Hyponatraemia may be due to a syndrome of inappropriate anti-diuretic hormone secretion (SIADH). The majority of cases of hyponatraemia were reported in the elderly, especially when coupled with a recent history of, or condition pre-disposing to, altered fluid balance. Caution is required in patients at increased risk for hyponatraemia, such as elderly, cirrhotic, or dehydrated patients, or patients treated with diuretics.
Discontinuation of Treatment
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on abrupt treatment discontinuation occurred in approximately 45% of patients treated with Cymbalta and 23% of patients taking placebo.
The risk of withdrawal symptoms seen with SSRIs and SNRIs may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. The most commonly reported reactions are listed in section 4.8. Generally, these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that duloxetine should be gradually tapered when discontinuing treatment over a period of no less than 2 weeks, according to the patient's needs (see section 4.2).
Elderly
Data on the use of Cymbalta 120 mg in elderly patients with major depressive disorders are limited. Therefore, caution should be exercised when treating the elderly with the maximum dosage (see sections 4.2 and 5.2). Data on the use of Cymbalta in elderly patients with generalised anxiety disorder are limited.
Akathisia/Psychomotor Restlessness
The use of duloxetine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Medicinal Products Containing Duloxetine
Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic pain, major depressive disorder, generalised anxiety disorder and stress urinary incontinence). The use of more than one of these products concomitantly should be avoided.
Hepatitis/Increased Liver Enzymes
Cases of liver injury, including severe elevations of liver enzymes (>10-times upper limit of normal), hepatitis, and jaundice have been reported with duloxetine (see section 4.8). Most of them occurred during the first months of treatment. The pattern of liver damage was predominantly hepatocellular. Duloxetine should be used with caution in patients treated with other medicinal products associated with hepatic injury.
Sucrose
Cymbalta hard gastro-resistant capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Monoamine Oxidase Inhibitors (MAOIs)
Due to the risk of serotonin syndrome, duloxetine should not be used in combination with non-selective, irreversible monoamine oxidase inhibitors (MAOIs) or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI (see section 4.3).
For selective, reversible MAOIs, like moclobemide, the risk of serotonin syndrome is lower. However, the concomitant use of Cymbalta with selective, reversible MAOIs is not recommended (see section 4.4).
Inhibitors of CYP1A2
Because CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine. Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77% and increased AUCo-t 6-fold. Therefore, Cymbalta should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (see section 4.3).
CNS Medicinal Products
The risk of using duloxetine in combination with other CNS-active medicinal products has not been systematically evaluated, except in the cases described in this section. Consequently, caution is advised when Cymbalta is taken in combination with other centrally-acting medicinal products or substances, including alcohol and sedative medicinal products (e.g., benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).
Serotonin Syndrome
In rare cases, serotonin syndrome has been reported in patients using SSRIs (e.g., paroxetine, fluoxetine) concomitantly with serotonergic medicinal products. Caution is advisable if Cymbalta is used concomitantly with serotonergic antidepressants like SSRIs, tricyclics like clomipramine or amitriptyline, St John's Wort (Hypericum perforatum), venlafaxine, or triptans, tramadol, pethidine, and tryptophan.
Effect of Duloxetine on Other Medicinal Products
Medicinal products metabolised by CYP1A2: The pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60 mg twice daily).
Medicinal products metabolised by CYP2D6: Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered at a dose of 60 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of duloxetine (40 mg twice daily) increases steady-state AUC of tolterodine (2 mg twice daily) by 71%, but does not affect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment is recommended. Caution is advised if Cymbalta is co-administered with medicinal products that are predominantly metabolised by CYP2D6 (risperidone, tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), particularly if they have a narrow therapeutic index (such as flecainide, propafenone, and metoprolol).
Oral contraceptives and other steroidal agents: Results of in vitro studies demonstrate that duloxetine does not induce the catalytic activity of CYP3A. Specific in vivo drug interaction studies have not been performed.
Anticoagulants and antiplatelet agents: Caution should be exercised when duloxetine is combined with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction. Furthermore, increases in INR values have been reported when duloxetine was co-administered to patients treated with warfarin. However, concomitant administration of duloxetine with warfarin under steady state conditions, in healthy volunteers, as part of a clinical pharmacology study, 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: Co-administration of duloxetine with aluminium- and magnesium-containing antacids, or duloxetine with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose.
Inducers of CYP1A2: Population pharmacokinetic analyses have shown that smokers have almost 50% lower plasma concentrations of duloxetine compared with non-smokers.
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data on the use of duloxetine in pregnant women. Studies in animals have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum clinical exposure (see section 5.3).
The potential risk for humans is unknown. Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN to SNRI treatment, this potential risk cannot be ruled out with duloxetine, taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).
As with other serotonergic medicinal products, discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. Discontinuation symptoms seen with duloxetine may include hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures. The majority of cases have occurred either at birth or within a few days of birth.
Cymbalta should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. Women should be advised to notify their physician if they become pregnant, or intend to become pregnant, during therapy.
Breast-Feeding
Duloxetine is very weakly excreted into human milk, based on a study of 6 lactating patients who did not breast-feed their children. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose (see section 5.2). As the safety of duloxetine in infants is not known, the use of Cymbalta while breast-feeding is not recommended.
4.7 Effects On Ability To Drive And Use Machines
No studies of the effects on the ability to drive and use machines have been performed. Cymbalta may be associated with sedation and dizziness. Patients should be instructed that if they experience sedation or dizziness they should avoid potentially hazardous tasks such as driving or operating machinery.
4.8 Undesirable Effects
a. Summary of the safety profile
The most commonly reported adverse reactions in patients treated with Cymbalta were nausea, headache, dry mouth, somnolence and dizziness. However, the majority of common adverse reactions were mild to moderate; they usually started early in therapy, and most tended to subside even as therapy was continued.
b. Tabulated summary of adverse reactions
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 7819 patients, 4823 on duloxetine and 2996 on placebo) in depression, generalised anxiety disorder and diabetic neuropathic pain.
Table 1: Adverse reactions
Frequency estimate: Very common (
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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1 Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation.
2 Cases of orthostatic hypotension and syncope have been reported especially at the initiation of treatment.
3 See section 4.4.
4 Cases of aggression and anger have been reported particularly early in treatment or after treatment discontinuation.
5 Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation (see section 4.4).
6 Estimated frequency of post-marketing surveillance reported adverse reactions; not observed in placebo-controlled clinical trials.
7 Not statistically significantly different from placebo.
8 Falls were more common in the elderly (65 years old).
c. Description of selected adverse reactions
Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, irritability, diarrhoea, hyperhydrosis and vertigo are the most commonly reported reactions.
Generally, for SSRIs and SNRIs, these events are mild to moderate and self-limiting; however, in some patients they may be severe and/or prolonged. It is therefore advised that when duloxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).
In the 12-week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose 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 52 weeks, there was an increase in HbA1c in both the duloxetine and routine care groups, but the mean increase was 0.3% greater in the duloxetine-treated group. There was also a small increase in fasting blood glucose and in total cholesterol in duloxetine-treated patients, while those laboratory tests showed a slight decrease in the routine care group.
The heart rate-corrected QT interval in duloxetine-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or QTcB measurements between duloxetine-treated and placebo-treated patients.
4.9 Overdose
Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of 5400 mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or in combination with other medicinal products) included somnolence, coma, serotonin syndrome, seizures, vomiting and tachycardia.
No specific antidote is known for duloxetine, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. A free airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption. Duloxetine has a large volume of distribution and forced diuresis, haemoperfusion, and exchange perfusion are unlikely to be beneficial.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Other antidepressants. ATC code: N06AX21.
Mechanism of action
Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake, with no significant affinity for histaminergic, dopaminergic, cholinergic, and adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin and noradrenaline in various brain areas of animals.
Pharmacodynamic effects
Duloxetine normalised pain thresholds in several preclinical models of neuropathic and inflammatory pain and attenuated pain behaviour in a model of persistent pain. The pain inhibitory action of duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the central nervous system.
Clinical efficacy and safety
Major Depressive Disorder
Cymbalta was studied in a clinical programme involving 3,158 patients (1,285 patient-years of exposure) meeting DSM-IV criteria for major depression. The efficacy of Cymbalta at the recommended dose of 60 mg once a day was demonstrated in three out of three randomised, double-blind, placebo-controlled, fixed-dose acute studies in adult outpatients with major depressive disorder. Overall, Cymbalta's efficacy has been demonstrated at daily doses between 60 and 120 mg in a total of five out of seven randomised, double-blind, placebo-controlled, fixed-dose acute studies in adult outpatients with major depressive disorder.
Cymbalta demonstrated statistical superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAM-D) total score (including both the emotional and somatic symptoms of depression). Response and remission rates were also statistically significantly higher with Cymbalta compared with placebo. Only a small proportion of patients included in pivotal clinical trials had severe depression (baseline HAM-D>25).
In a relapse prevention study, patients responding to 12 weeks of acute treatment with open-label Cymbalta 60 mg once daily were randomised to either Cymbalta 60 mg once daily or placebo for a further 6 months. Cymbalta 60 mg once daily demonstrated a statistically significant superiority compared to placebo (p = 0.004) on the primary outcome measure, the prevention of depressive relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind, follow-up period was 17% and 29% for duloxetine and placebo, respectively.
During 52 weeks of placebo-controlled double-blind treatment, duloxetine-treated patients with recurrent MDD had a significantly longer symptom free period (p<0.001) compared with patients randomised to placebo. All patients had previously responded to duloxetine during open-label duloxetine treatment (28 to 34 weeks) at a dose of 60 to 120 mg/day. During the 52-week placebo-controlled double-blind treatment phase, 14.4% of the duloxetine-treated patients and 33.1% of the placebo-treated patients experienced a return of their depressive symptoms (p<0.001).
The effect of Cymbalta 60 mg once a day in elderly depressed patients (
Generalised Anxiety Disorder
Cym
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