CYMBALTA 60mg gastro-resistant capsules medication leaflet

Cymbalta 30 mg hard gastro-resistant capsules

Cymbalta 60 mg hard gastro-resistant capsules

Cymbalta 30 mg

Each capsule contains 30 mg of duloxetine (as hydrochloride).

Each capsule may contain up to 56 mg sucrose.

Cymbalta 60 mg

Each capsule contains 60 mg of duloxetine (as hydrochloride).

Each capsule may contain up to 111 mg sucrose.

For the full list of excipients, see section 6.1.

Hard gastro-resistant capsule.

Cymbalta 30 mg

Opaque white body, imprinted with ‘30 mg’ and an opaque blue cap, imprinted with ‘9543’.

Cymbalta 60 mg

Opaque green body, imprinted with ‘60 mg’ and an opaque blue cap, imprinted with ‘9542’.

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.

Major depressive disorder

The starting and recommended maintenance dose is 60 mg once daily with or without food. Dosagesabove 60 mg once daily, up to a maximum dose of 120 mg per day have been evaluated from a safetyperspective in clinical trials. However, there is no clinical evidence suggesting that patients notresponding 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 severalmonths, in order to avoid relapse. In patients responding to duloxetine, and with a history of repeatedepisodes of major depression, further long-term treatment at a dose of 60 to 120 mg/day could beconsidered.

The recommended starting dose in patients with generalised anxiety disorder is 30 mg once daily withor without food. In patients with insufficient response the dose should be increased to 60 mg, which isthe usual maintenance dose in most patients.

In patients with co-morbid major depressive disorder, the starting and maintenance dose is 60 mg oncedaily (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 safetyperspective in clinical trials. In patients with insufficient response to 60 mg, escalation up to 90 mg or120 mg may therefore be considered. Dose escalation should be based upon clinical response andtolerability.

After consolidation of the response, it is recommended to continue treatment for several months, inorder to avoid relapse.

Diabetic peripheral neuropathic pain

The starting and recommended maintenance dose is 60 mg daily with or without food. Dosages above60 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 ofduloxetine displays large inter-individual variability (see section 5.2). Hence, some patients thatrespond 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).

No dosage adjustment is recommended for elderly patients solely on the basis of age. However, aswith any medicine, caution should be exercised when treating the elderly, especially with Cymbalta120 mg per day for major depressive disorder or generalised anxiety disorder, for which data arelimited (see sections 4.4 and 5.2).

Cymbalta must not be used in patients with liver disease resulting in hepatic impairment (see sections4.3 and 5.2).

No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinineclearance 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).

Duloxetine should not be used in children and adolescents under the age of 18 years for the treatmentof major depressive disorder because of safety and efficacy concerns (see sections 4.4, pct. 4.8 and 5.1).

The safety and efficacy of duloxetine for the treatment of generalised anxiety disorder in paediatricpatients aged 7-17 years have not been established. Current available data are described in sections4.8, 5.1 and 5.2.

The safety and efficacy of duloxetine for the treatment of diabetic peripheral neuropathic pain has notbeen studied. No data are available.

Abrupt discontinuation should be avoided. When stopping treatment with Cymbalta the dose should begradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawalreactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose orupon 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.

For oral use.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant use of Cymbalta with nonselective, 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 (seesection 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 hypertensionthat could expose patients to a potential risk of hypertensive crisis (see sections 4.4 and 4.8).

Mania and seizures

Cymbalta should be used with caution in patients with a history of mania or a diagnosis of bipolardisorder, and/or seizures.

Mydriasis

Mydriasis has been reported in association with duloxetine, therefore, caution should be used whenprescribing 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 significanthypertension in some patients. This may be due to the noradrenergic effect of duloxetine. Cases ofhypertensive crisis have been reported with duloxetine, especially in patients with pre-existinghypertension. Therefore, in patients with known hypertension and/or other cardiac disease, bloodpressure monitoring is recommended, especially during the first month of treatment. Duloxetineshould be used with caution in patients whose conditions could be compromised by an increased heartrate or by an increase in blood pressure. Caution should also be exercised when duloxetine is usedwith medicinal products that may impair its metabolism (see section 4.5). For patients who experiencea sustained increase in blood pressure while receiving duloxetine either dose reduction or gradualdiscontinuation should be considered (see section 4.8). In patients with uncontrolled hypertensionduloxetine should not be initiated (see section 4.3).

Increased plasma concentrations of duloxetine occur in patients with severe renal impairment onhaemodialysis (creatinine clearance <30 ml/min). For patients with severe renal impairment, seesection 4.3. See section 4.2 for information on patients with mild or moderate renal dysfunction.

Serotonin syndrome/ Neuroleptic malignant syndrome

As with other serotonergic agents, serotonin syndrome or neuroleptic malignant syndrome (NMS), apotentially life-threatening condition, may occur with duloxetine treatment, particularly withconcomitant use of other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants ortriptans), with agents that impair metabolism of serotonin such as MAOIs, or with antipsychotics orother dopamine antagonists that may affect the serotonergic neurotransmitter systems (see sections 4.3and 4.5).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscularaberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea,vomiting, diarrhoea). Serotonin syndrome in its most severe form can resemble NMS, which includeshyperthermia, muscle rigidity, elevated serum creatine kinase levels, autonomic instability withpossible rapid fluctuation of vital signs and mental status changes.

If concomitant treatment with duloxetine and other serotonergic/neuroleptic agents that may affect theserotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observationof the patient is advised, particularly during treatment initiation and dose increases.

St John’s wort

Adverse reactions may be more common during concomitant use of Cymbalta and herbal preparationscontaining St John’s wort (Hypericum perforatum).

Suicide

Major Depressive Disorder and Generalised Anxiety Disorder: Depression is associated with anincreased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persistsuntil significant remission occurs. As improvement may not occur during the first few weeks or moreof treatment, patients should be closely monitored until such improvement occurs. It is general clinicalexperience 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 increasedrisk of suicide-related events. In addition, these conditions may be co-morbid with major depressivedisorder. The same precautions observed when treating patients with major depressive disorder shouldtherefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidalthoughts prior to commencement of treatment are known to be at greater risk of suicidal thoughts orsuicidal behaviour, and should receive careful monitoring during treatment. A meta-analysis ofplacebo-controlled clinical trials of antidepressant medicinal products in psychiatric disorders showedan increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than25 years old.

Cases of suicidal thoughts and suicidal behaviours have been reported during duloxetine therapy orearly after treatment discontinuation (see section 4.8).

Close supervision of patients and in particular those at high risk should accompany medicinal producttherapy 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 thoughtsand unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Diabetic Peripheral Neuropathic Pain: As with other medicinal products with similarpharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviourshave been reported during duloxetine therapy or early after treatment discontinuation. Concerning riskfactors for suicidality in depression, see above. Physicians should encourage patients to report anydistressing thoughts or feelings at any time.

Use in children and adolescents under 18 years of age

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 (predominantlyaggression, oppositional behaviour and anger), were more frequently observed in clinical trials amongchildren and adolescents treated with antidepressants compared to those treated with placebo. If, basedon clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored forthe appearance of suicidal symptoms (see section 5.1). In addition, long-term safety data in childrenand adolescents concerning growth, maturation and cognitive and behavioural development arelacking (see section 4.8).

There have been reports of bleeding abnormalities, such as ecchymoses, purpura and gastrointestinalhaemorrhage with selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenalinereuptake inhibitors (SNRIs), including duloxetine. Duloxetine may increase the risk of postpartumhaemorrhage (see section 4.6). Caution is advised in patients taking anticoagulants and/or medicinalproducts known to affect platelet function (e.g. NSAIDs or acetylsalicylic acid (ASA)), and in patientswith known bleeding tendencies.

Hyponatraemia

Hyponatraemia has been reported when administering Cymbalta, including cases with serum sodiumlower than 110 mmol/l. Hyponatraemia may be due to a syndrome of inappropriate anti-diuretichormone 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, ordehydrated patients or patients treated with diuretics.

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation isabrupt (see section 4.8). In clinical trials adverse events seen on abrupt treatment discontinuationoccurred in approximately 45% of patients treated with Cymbalta and 23% of patients taking placebo.

The risk of withdrawal symptoms seen with SSRI’s and SNRI’s may be dependent on several factorsincluding the duration and dose of therapy and the rate of dose reduction. The most commonlyreported 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 ofdiscontinuing treatment, but there have been very rare reports of such symptoms in patients who haveinadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2weeks, though in some individuals they may be prolonged (2-3 months or more). It is thereforeadvised that duloxetine should be gradually tapered when discontinuing treatment over a period of noless than 2 weeks, according to the patient’s needs (see section 4.2).

Data on the use of Cymbalta 120 mg in elderly patients with major depressive disorder and generalisedanxiety disorder are limited. Therefore, caution should be exercised when treating the elderly with themaximum dosage (see sections 4.2 and 5.2).

Akathisia/psychomotor restlessness

The use of duloxetine has been associated with the development of akathisia, characterised by asubjectively unpleasant or distressing restlessness and need to move often accompanied by an inabilityto sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients whodevelop these symptoms, increasing the dose may be detrimental.

Medicinal products containing duloxetine

Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathicpain, major depressive disorder, generalised anxiety disorder and stress urinary incontinence). The useof 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 occurredduring 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 associatedwith hepatic 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-lastingsexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRIs.

Sucrose

Cymbalta hard gastro-resistant capsules contain sucrose. Patients with rare hereditary problems offructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should nottake this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially‘sodium-free’.

Monoamine oxidase inhibitors (MAOIs): Due to the risk of serotonin syndrome, duloxetine should notbe used in combination with non-selective irreversible monoamine oxidase inhibitors (MAOIs), orwithin 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).

The concomitant use of Cymbalta with selective, reversible MAOIs, like moclobemide, is notrecommended (see section 4.4). The antibiotic linezolid is a reversible non-selective MAOI and shouldnot be given to patients treated with Cymbalta (see section 4.4).

Inhibitors of CYP1A2: Because CYP1A2 is involved in duloxetine metabolism, concomitant use ofduloxetine 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 plasmaclearance of duloxetine by about 77% and increased AUCo-t 6-fold. Therefore Cymbalta should not beadministered 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-activemedicinal 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 actingmedicinal products or substances, including alcohol and sedative medicinal products (e.g.benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

Serotonergic agents: In rare cases, serotonin syndrome has been reported in patients using

SSRIs/SNRIs concomitantly with serotonergic agents. Caution is advisable if Cymbalta is usedconcomitantly with serotonergic agents like SSRIs, SNRIs, tricyclic antidepressants like clomipramineor amitriptyline, MAOIs like moclobemide or linezolid, St John’s wort (Hypericum perforatum) ortriptans, tramadol, pethidine and tryptophan (see section 4.4).

Effect of duloxetine on other medicinal products

Medicinal products metabolised by CYP1A2: The pharmacokinetics of theophylline, a CYP1A2substrate, 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. Whenduloxetine 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 (40mg twice daily) increases steady state AUC of tolterodine (2 mg twice daily) by 71 %, but does notaffect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment isrecommended. Caution is advised if Cymbalta is co-administered with medicinal products that arepredominantly metabolised by CYP2D6 (risperidone, tricyclic antidepressants [TCAs] such asnortriptyline, amitriptyline, and imipramine) particularly if they have a narrow therapeutic index (suchas flecainide, propafenone and metoprolol).

Oral contraceptives and other steroidal agents: Results of in vitro studies demonstrate that duloxetinedoes not induce the catalytic activity of CYP3A. Specific in vivo drug interaction studies have notbeen performed.

Anticoagulants and antiplatelet agents: Caution should be exercised when duloxetine is combinedwith oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributableto a pharmacodynamic interaction. Furthermore, increases in INR values have been reported whenduloxetine was co-administered to patients treated with warfarin. However, concomitantadministration of duloxetine with warfarin under steady state conditions, in healthy volunteers, as partof a clinical pharmacology study, did not result in a clinically significant change in INR from baselineor 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 ofduloxetine 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.

In animal studies, duloxetine had no effect on male fertility, and effects in females were only evidentat doses that caused maternal toxicity.

Studies in animals have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetinelower than the maximum clinical exposure (see section 5.3).

Two large observational studies do not suggest an overall increased risk of major congenitalmalformation (one from the US including 2,500 exposed to duloxetine during the first trimester andone from the EU including 1,500 exposed to duloxetine during the first trimester). The analysis onspecific malformations such as cardiac malformations shows inconclusive results.

In the EU study, maternal exposure to duloxetine during late pregnancy (at any time from 20 weeksgestational age to delivery) was associated with an increased risk for preterm birth (less than 2-fold,corresponding to approximately 6 additional premature births per 100 women treated with duloxetinelate in pregnancy). The majority occurred between 35 and 36 weeks of gestation. This association wasnot seen in the US study.

The US observational data have provided evidence of an increased risk (less than 2-fold) ofpostpartum haemorrhage following duloxetine exposure within the month prior to birth.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in latepregnancy, 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 riskcannot be ruled out with duloxetine taking into account the related mechanism of action (inhibition ofthe re-uptake of serotonin).

As with other serotonergic medicinal products, discontinuation symptoms may occur in the neonateafter maternal duloxetine use near term. Discontinuation symptoms seen with duloxetine may includehypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures. The majority ofcases 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 thefoetus. Women should be advised to notify their physician if they become pregnant, or intend tobecome pregnant, during therapy.

Breast feeding

Duloxetine is very weakly excreted into human milk based on a study of 6 lactating patients, who didnot breast feed their children. The estimated daily infant dose on a mg/kg basis is approximately0.14% of the maternal dose (see section 5.2). As the safety of duloxetine in infants is not known, theuse of Cymbalta while breast-feeding is not recommended.

No studies on the effects on the ability to drive and use machines have been performed. Cymbalta maybe associated with sedation and dizziness. Patients should be instructed that if they experience sedationor dizziness they should avoid potentially hazardous tasks such as driving or operating machinery.

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 reactionswere mild to moderate, they usually started early in therapy, and most tended to subside even astherapy was continued.

b. Tabulated summary of adverse reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlledclinical trials.

Table 1: Adverse reactions

Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to<1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from theavailable data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very Common Uncommon Rare Very rare Not knowncommon

Laryngitis

Anaphylacticreaction

Hyper-sensitivitydisorder

Very Common Uncommon Rare Very rare Not knowncommon

Hypo-thyroidism

Decreased Hyperglycaemia Dehydration

Appetite (reported Hyponatraemiaespecially in SIADH6diabeticpatients)

Insomnia Suicidal Suicidal

Agitation ideation5,7 behaviour5,7

Libido Sleep disorder Maniadecreased Bruxism Hallucinations

Anxiety Disorientation Aggression and

Orgasm Apathy anger4abnormal

Abnormaldreams

Headache Dizziness Myoclonus Serotonin

Somnolence Lethargy Akathisia7 syndrome6

Tremor Nervousness Convulsion1

Paraesthesi Disturbance in Psychomotora attention restlessness6

Dysgeusia Extra-pyramidal

Dyskinesia symptoms6

Restless legssyndrome

Poor qualitysleep

Blurred Mydriasis Glaucomavision Visualimpairment

Ear and labyrinth disorders

Tinnitus1 Vertigo

Ear pain

Palpitation Tachycardia Stresss Supra- cardiomyopathyventricular (Takotsuboarrhythmia, cardiomyopathy)mainly atrialfibrillation

Blood Syncope2 Hypertensivepressure Hypertension3,7 crisis3,6increase3 Orthostatic

Flushing hypotension2

Peripheralcoldness

Very Common Uncommon Rare Very rare Not knowncommon

Yawning Throat tightness Interstitial lung

Epistaxis disease10

Eosinophilicpneumonia6

Nausea Constipatio Gastrointestinal Stomatitis

Dry mouth n haemorrhage7 Haematochezia

Diarrhoea Gastroenteritis Breath odour

Abdominal Eructation Microscopicpain Gastritis colitis9

Vomiting Dysphagia

Dyspepsia

Flatulence

Hepato-biliary disorders

Hepatitis3 Hepatic failure6

Elevated liver Jaundice6enzymes (ALT,

AST, alkalinephosphatase)

Acute liverinjury

Sweating Night sweats Stevens-Johnson Cutaneousincreased Urticaria Syndrome6 vasculitis

Rash Dermatitis Angio-neuroticcontact oedema6

Cold sweat

Photo-sensitivityreactions

Increasedtendency tobruise

Musculo- Muscle tightness Trismusskeletal Musclepain twitching

Musclespasm

Dysuria Urinary Urine odour

Pollakiuria retention abnormal

Urinaryhesitation

Nocturia

Polyuria

Urine flowdecreased

Erectile Gynaecological Menopausaldysfunctio haemorrhage symptomsn Menstrual Galactorrhoeadisorder

Very Common Uncommon Rare Very rare Not knowncommon

Ejaculation Sexual Hyperprolactinadisorder dysfunction emia

Ejaculation Testicular pain Postpartumdelayed haemorrhage6

Falls8 Chest pain7

Fatigue Feelingabnormal

Feeling cold

Thirst

Chills

Malaise

Feeling hot

Gait disturbance

Weight Weight increase Blooddecrease Blood creatine cholesterolphosphokinase increasedincreased

Blood potassiumincreased1 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 oftreatment.3 See section 4.4.4 Cases of aggression and anger have been reported particularly early in treatment or after treatmentdiscontinuation.5 Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy orearly after treatment discontinuation (see section 4.4).6 Estimated frequency of post-marketing surveillance reported adverse reactions; not observed inplacebo-controlled clinical trials.7 Not statistically significantly different from placebo.8 Falls were more common in the elderly (≥65 years old).9 Estimated frequency based on all clinical trial data.10Estimated frequency based on placebo-controlled clinical trials.

c. Description of selected adverse reactions

Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms.

Dizziness, sensory disturbances (including paraesthesia or electric shock-like sensations, particularlyin the head), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence,agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, 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, insome patients they may be severe and/or prolonged. It is therefore advised that when duloxetinetreatment is no longer required, gradual discontinuation by dose tapering should be carried out (seesections 4.2 and 4.4).

In the 12 week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathicpain, 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 theextension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in boththe 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 induloxetine-treated patients while those laboratory tests showed a slight decrease in the routine caregroup.

The heart rate-corrected QT interval in duloxetine-treated patients did not differ from that seen inplacebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or

QTcB measurements between duloxetine-treated and placebo-treated patients.

d. Paediatric population

A total of 509 paediatric patients aged 7 to 17 years with major depressive disorder and 241 paediatricpatients aged 7 to 17 years with generalised anxiety disorder were treated with duloxetine in clinicaltrials. In general, the adverse reaction profile of duloxetine in children and adolescents was similar tothat seen for adults.

A total of 467 paediatric patients initially randomized to duloxetine in clinical trials experienced a 0.1kg mean decrease in weight at 10-weeks compared with a 0.9 kg mean increase in 353 placebo-treatedpatients. Subsequently, over the four- to six-month extension period, patients on average trendedtoward recovery to their expected baseline weight percentile based on population data from age- andgender-matched peers.

In studies of up to 9 months an overall mean decrease of 1% in height percentile (decrease of 2% inchildren (7-11 years) and increase of 0.3% in adolescents (12-17 years)) was observed in duloxetine-treated paediatric patients (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of5400 mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also withduloxetine alone at a dose of approximately 1000 mg. Signs and symptoms of overdose (duloxetinealone or in combination with other medicinal products) included somnolence, coma, serotoninsyndrome, 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 beestablished. Monitoring of cardiac and vital signs is recommended, along with appropriatesymptomatic and supportive measures. Gastric lavage may be indicated if performed soon afteringestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption.

Duloxetine has a large volume of distribution and forced diuresis, haemoperfusion, and exchangeperfusion are unlikely to be beneficial.

Pharmacotherapeutic group: Other antidepressants. ATC code: N06AX21.

Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weaklyinhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergicand adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin andnoradrenaline in various brain areas of animals.

Duloxetine normalised pain thresholds in several preclinical models of neuropathic and inflammatorypain and attenuated pain behaviour in a model of persistent pain. The pain inhibitory action ofduloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within thecentral nervous system.

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 threerandomised, double-blind, placebo-controlled, fixed dose acute studies in adult outpatients with majordepressive disorder. Overall, Cymbalta’s efficacy has been demonstrated at daily doses between 60and 120 mg in a total of five out of seven randomised, double-blind, placebo-controlled, fixed doseacute 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 andsomatic symptoms of depression). Response and remission rates were also statistically significantlyhigher with Cymbalta compared with placebo. Only a small proportion of patients included in pivotalclinical 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 afurther 6-months. Cymbalta 60 mg once daily demonstrated a statistically significant superioritycompared 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-upperiod was 17% and 29% for duloxetine and placebo, respectively.

During 52 weeks of placebo-controlled double blind treatment, duloxetine-treated patients withrecurrent MDD had a significantly longer symptom free period (p<0.001) compared with patientsrandomised to placebo. All patients had previously responded to duloxetine during open-labelduloxetine 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 theplacebo-treated patients experience a return of their depressive symptoms (p<0.001).

The effect of Cymbalta 60 mg once a day in elderly depressed patients (≥65 years) was specificallyexamined in a study that showed a statistically significant difference in the reduction of the HAMD17score for duloxetine-treated patients compared to placebo. Tolerability of Cymbalta 60 mg once dailyin elderly patients was comparable to that seen in the younger adults. However, data on elderlypatients exposed to the maximum dose (120mg per day) are limited and thus, caution is recommendedwhen treating this population.

Generalised Anxiety Disorder: Cymbalta demonstrated statistically significant superiority overplacebo in five out of five studies including four randomised, double-blind, placebo-controlled acutestudies and a relapse prevention study in adult patients with generalised anxiety disorder.

Cymbalta demonstrated statistically significant superiority over placebo as measured by improvementin the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability Scale (SDS) globalfunctional impairment score. Response and remission rates were also higher with Cymbalta comparedto placebo. Cymbalta showed comparable efficacy results to venlafaxine in terms of improvements onthe HAM-A total score.

In a relapse prevention study, patients responding to 6 months of acute treatment with open-label

Cymbalta were randomised to either Cymbalta or placebo for a further 6-months. Cymbalta 60 mg to120 mg once daily demonstrated statistically significant superiority compared to placebo (p<0.001) onthe prevention of relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow-up period was 14% for Cymbalta and 42% for placebo.

The efficacy of Cymbalta 30-120 mg (flexible dosing) once a day in elderly patients (>65 years) withgeneralised anxiety disorder was evaluated in a study that demonstrated statistically significantimprovement in the HAM-A total score for duloxetine treated patients compared to placebo treatedpatients. The efficacy and safety of Cymbalta 30-120 mg once daily in elderly patients withgeneralised anxiety disorder was similar to that seen in studies of younger adult patients. However,data on elderly patients exposed to the maximum dose (120 mg per day) are limited and, thus, cautionis recommended when using this dose with the elderly population.

Diabetic Peripheral Neuropathic Pain: The efficacy of Cymbalta as a treatment for diabeticneuropathic pain was established in 2 randomised, 12-week, double-blind, placebo-controlled, fixeddose studies in adults (22 to 88 years) having diabetic neuropathic pain for at least 6 months. Patientsmeeting diagnostic criteria for major depressive disorder were excluded from these trials. The primaryoutcome measure was the weekly mean of 24-hour average pain, which was collected in a daily diaryby patients on an 11-point Likert scale.

In both studies, Cymbalta 60 mg once daily and 60 mg twice daily significantly reduced paincompared with placebo. The effect in some patients was apparent in the first week of treatment. Thedifference in mean improvement between the two active treatment arms was not significant. At least30% reported pain reduction was recorded in approximately 65% of duloxetine treated patients versus40% for placebo. The corresponding figures for at least 50% pain reduction were 50% and 26%respectively. Clinical response rates (50% or greater improvement in pain) were analysed according towhether or not the patient experienced somnolence during treatment. For patients not experiencingsomnolence, clinical response was observed in 47% of patients receiving duloxetine and 27% ofpatients on placebo. Clinical response rates in patients experiencing somnolence were 60% onduloxetine and 30% on placebo. Patients not demonstrating a pain reduction of 30% within 60 days oftreatment were unlikely to reach this level during further treatment.

In an open label long-term uncontrolled study, the pain reduction in patients responding to 8-weeks ofacute treatment of Cymbalta 60 mg once daily was maintained for a further 6-months as measured bychange on the Brief Pain Inventory (BPI) 24-hour average pain item.

Duloxetine has not been studied in patients under the age of 7.

Two randomized, double-blind, parallel clinical trials were performed in 800 paediatric patients aged 7to 17 years with major depressive disorder (see section 4.2). These two studies included a 10 weekplacebo and active (fluoxetine) controlled acute phase followed by six months period of activecontrolled extension treatment. Neither duloxetine (30-120 mg) nor the active control arm (fluoxetine20-40 mg) statistically separated from placebo on change from baseline to endpoint in the Children´s

Depression Rating Scale-Revised (CDRS-R) total score. Discontinuation due to adverse events washigher in patients taking duloxetine compared with those treated with fluoxetine, mostly due to nausea.

During the 10-week acute treatment period, suicidal behaviours were reported (duloxetine 0/333 [0%],fluoxetine 2/225 [0.9%], placebo 1/220 [0.5%]). Over the entire 36-week course of the study, 6 out of333 patients initially randomized to duloxetine and 3 out of 225 patients initially randomized tofluoxetine experienced suicidal behaviour (exposure adjusted incidence 0.039 events per patient yearfor duloxetine and 0.026 for fluoxetine). In addition, one patient who transitioned from placebo toduloxetine experienced a suicidal behaviour while taking duloxetine.

A randomised, double-blind, placebo-controlled study was performed in 272 patients aged 7-17 yearswith generalised anxiety disorder. The study included a 10 week placebo-controlled acute phase,followed by an 18 week extension treatment period. A flexible dose regimen was used in this study, toallow for slow dose escalation from 30 mg once daily to higher doses (maximum 120 mg oncedaily). Treatment with duloxetine showed a statistically significantly greater improvement in GADsymptoms, as measured by PARS severity score for GAD (mean difference between duloxetine andplacebo of 2.7 points [95% CI 1.3-4.0]), after 10 weeks of treatment. The maintenance of the effecthas not been evaluated. There was no statistically significant difference in discontinuation due toadverse events between duloxetine and placebo groups during the 10 week acute treatment phase. Twopatients who transitioned from placebo to duloxetine after the acute phase experienced suicidalbehaviours while taking duloxetine during the extension phase. A conclusion on the overallbenefit/risk in this age group has not been established (see also sections 4.2 and 4.8).

A single study has been performed in paediatric patients with juvenile primary fibromyalgia syndrome(JPFS) in which the duloxetine-treated group did not separate from placebo group for the primaryefficacy measure. Therefore, there is no evidence of efficacy in this paediatric patient population. Therandomised, double-blind, placebo-controlled, parallel study of duloxetine was conducted in184 adolescents aged 13 to 18 years (mean age 15.53 years) with JPFS. The study included a 13-weekdouble-blind period where patients were randomised to duloxetine 30 mg/60 mg, or placebo daily.

Duloxetine did not show efficacy in reducing pain as measured by primary outcome measure of Brief

Pain Inventory (BPI) average pain score endpoint: least squares (LS) mean change from baseline in

BPI average pain score at 13 weeks was -0.97 in the placebo group, compared with -1.62 in theduloxetine 30/60 mg group (p = 0.052). The safety results from this study were consistent with theknown safety profile of duloxetine.

The European Medicines Agency has waived the obligation to submit the results of studies with

Cymbalta in all subsets of the paediatric population in the treatment of major depressive disorder,diabetic neuropathic pain and generalised anxiety disorder. See section 4.2 for information onpaediatric use.

Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolised by oxidativeenzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokineticsof duloxetine demonstrate large intersubject variability (generally 50-60%), partly due to gender, age,smoking status and CYP2D6 metaboliser status.

Absorption: Duloxetine is well absorbed after oral administration with a Cmax occurring 6 hours postdose. The absolute oral bioavailability of duloxetine ranged from 32% to 80% (mean of 50%). Fooddelays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases theextent of absorption (approximately 11 %). These changes do not have any clinical significance.

Distribution: Duloxetine is approximately 96% bound to human plasma proteins. Duloxetine binds toboth albumin and alpha-l acid glycoprotein. Protein binding is not affected by renal or hepaticimpairment.

Biotransformation: Duloxetine is extensively metabolised and the metabolites are excreted principallyin urine. Both cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolitesglucuronide conjugate of 4-hydroxy duloxetine and sulfate conjugate of 5-hydroxy 6-methoxyduloxetine. Based upon in vitro studies, the circulating metabolites of duloxetine are consideredpharmacologically inactive. The pharmacokinetics of duloxetine in patients who are poor metaboliserswith respect to CYP2D6 has not been specifically investigated. Limited data suggest that the plasmalevels of duloxetine are higher in these patients.

Elimination: The elimination half-life of duloxetine ranges from 8 to 17 hours (mean of 12 hours).

After an intravenous dose the plasma clearance of duloxetine ranges from 22 l/hr to 46 l/hr (mean of36 l/hr). After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/hr(mean 101 l/hr).

Gender: Pharmacokinetic differences have been identified between males and females (apparentplasma clearance is approximately 50% lower in females). Based upon the overlap in the range ofclearance, gender-based pharmacokinetic differences do not justify the recommendation for using alower dose for female patients.

Age: Pharmacokinetic differences have been identified between younger and elderly females (≥65 years)(AUC increases by about 25% and half-life is about 25% longer in the elderly), although the magnitudeof these changes is not sufficient to justify adjustments to the dose. As a general recommendation,caution should be exercised when treating the elderly (see sections 4.2 and 4.4).

Renal impairment: End stage renal disease (ESRD) patients receiving dialysis had 2-fold higherduloxetine Cmax and AUC values compared with healthy subjects. Pharmacokinetic data on duloxetineis limited in patients with mild or moderate renal impairment.

Hepatic impairment: Moderate liver disease (Child Pugh Class B) affected the pharmacokinetics ofduloxetine. Compared with healthy subjects, the apparent plasma clearance of duloxetine was 79%lower, the apparent terminal half-life was 2.3 times longer, and the AUC was 3.7 times higher inpatients with moderate liver disease. The pharmacokinetics of duloxetine and its metabolites have notbeen studied in patients with mild or severe hepatic insufficiency.

Breast-feeding mothers: The disposition of duloxetine was studied in 6 lactating women who were atleast 12-weeks postpartum. Duloxetine is detected in breast milk, and steady-state concentrations inbreast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk isapproximately 7 µg/day while on 40 mg twice daily dosing. Lactation did not influence duloxetinepharmacokinetics.

Paediatric population: Pharmacokinetics of duloxetine in paediatric patients aged 7 to 17 years withmajor depressive disorder following oral administration of 20 to 120 mg once daily dosing regimenwas characterized using population modelling analyses based on data from 3 studies. The model-predicted duloxetine steady state plasma concentrations in paediatric patients were mostly within theconcentration range observed in adult patients.

Duloxetine was not genotoxic in a standard battery of tests and was not carcinogenic in rats.

Multinucleated cells were seen in the liver in the absence of other histopathological changes in the ratcarcinogenicity study. The underlying mechanism and the clinical relevance are unknown. Femalemice receiving duloxetine for 2 years had an increased incidence of hepatocellular adenomas andcarcinomas at the high dose only (144 mg/kg/day), but these were considered to be secondary tohepatic microsomal enzyme induction. The relevance of this mouse data to humans is unknown.

Female rats receiving duloxetine (45 mg/kg/day) before and during mating and early pregnancy had adecrease in maternal food consumption and body weight, oestrous cycle disruption, decreased livebirth indices and progeny survival, and progeny growth retardation at systemic exposure levelsestimated to be at the most at maximum clinical exposure (AUC). In an embryotoxicity study in therabbit, a higher incidence of cardiovascular and skeletal malformations was observed at systemicexposure levels below the maximum clinical exposure (AUC). No malformations were observed inanother study testing a higher dose of a different salt of duloxetine. In prenatal/postnatal toxicitystudies in the rat, duloxetine induced adverse behavioural effects in the offspring at exposures belowmaximum clinical exposure (AUC).

Studies in juvenile rats reveal transient effects on neurobehaviour, as well as significantly decreasedbody weight and food consumption; hepatic enzyme induction; and hepatocellular vacuolation at 45mg/kg/day. The general toxicity profile of duloxetine in juvenile rats was similar to that in adult rats.

The no-adverse effect level was determined to be 20 mg/kg/day.

Hypromellose

Hypromellose acetate succinate

Sucrose

Sugar spheres

Talc

Titanium dioxide (E171)

Triethyl citrate

Cymbalta 30 mg

Gelatin

Sodium lauryl sulfate

Titanium dioxide (E171)

Indigo carmine (E132)

Edible green ink

Edible green ink contains:

Black iron oxide - synthetic (E172)

Yellow iron oxide - synthetic (E172)

Shellac

Cymbalta 60 mg

Gelatin

Sodium lauryl sulfate

Titanium dioxide (E171)

Indigo carmine (E132)

Yellow iron oxide (E172)

Edible white ink

Edible white ink contains:

Titanium dioxide (E171)

Shellac

Povidone

Not applicable.

3 years.

Store in the original package in order to protect from moisture. Do not store above 30º C.

Polyvinylchloride (PVC), polyethylene (PE), and polychlorotrifluoroethylene (PCTFE) blister sealedwith an aluminium foil.

Cymbalta 30 mg

Cymbalta 30 mg is available in packs of 7, 28 and 98 hard gastro-resistant capsules.

Cymbalta 60 mg

Cymbalta 60 mg is available in packs of 28, 56, 84 and 98 hard gastro-resistant capsules and inmultipacks containing 100 (5 packs of 20) and 500 (25 packs of 20) hard gastro-resistant capsules.

Not all pack sizes may be marketed.

No special requirements.

Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands.

EU/1/04/296/001

EU/1/04/296/002

EU/1/04/296/003

EU/1/04/296/004

EU/1/04/296/005

EU/1/04/296/006

EU/1/04/296/007

EU/1/04/296/008

EU/1/04/296/009

Date of first authorisation: 17 December 2004

Date of latest renewal: 24 June 2009

Detailed information on this medicine is available on the European Medicines Agency (EMA) website: http://www.ema.europa.eu