DULOXETINE ZENTIVA 60mg gastro-resistant capsules medication leaflet

Duloxetine Zentiva 30 mg gastro-resistant hard capsules

Duloxetine Zentiva 60 mg gastro-resistant hard capsules

Duloxetine Zentiva 30 mg gastro-resistant hard capsules

Each capsule contains duloxetine hydrochloride equivalent to 30 mg duloxetine.

Each capsule contains 42.26 - 46.57 mg of sucrose.

Duloxetine Zentiva 60 mg gastro-resistant hard capsules

Each capsule contains duloxetine hydrochloride equivalent to 60 mg duloxetine.

Each capsule contains 84.51 - 93.14 mg of sucrose.

For the full list of excipients, see section 6.1.

Gastro-resistant hard capsule

Duloxetine Zentiva 30 mg gastro-resistant hard capsules

Hard opaque gelatin capsules of length approx. 15.9 mm with white opaque body and light-blueopaque cap which contain off-white to light-brown-yellow spherical pellets.

Duloxetine Zentiva 60 mg gastro-resistant hard capsules

Hard opaque gelatin capsules of length approx. 19.4 mm with ivory opaque body and light-blueopaque cap which contain off-white to light-brown-yellow spherical pellets.

Treatment of major depressive disorder.

Treatment of diabetic peripheral neuropathic pain.

Treatment of generalised anxiety disorder.

Duloxetine Zentiva 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 duloxetine120 mg per day for major depressive disorder or generalised anxiety disorder, for which data arelimited (see sections 4.4 and 5.2).

Duloxetine Zentiva must not be used in patients with liver disease resulting in hepatic impairment (seesections 4.3 and 5.2).

No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinineclearance 30 to 80 ml/min). Duloxetine Zentiva must not be used in patients with severe renalimpairment (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 Duloxetine Zentiva the doseshould be gradually reduced over a period of at least one to two weeks in order to reduce the risk ofwithdrawal reactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease inthe dose or upon discontinuation of treatment, then resuming the previously prescribed dose may beconsidered. 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 Duloxetine Zentiva with nonselective, irreversible monoamine oxidase inhibitors(MAOIs) is contraindicated (see section 4.5).

Liver disease resulting in hepatic impairment (see section 5.2).

Duloxetine Zentiva should not be used in combination with fluvoxamine, ciprofloxacin or enoxacin(i.e. potent CYP1A2 inhibitors) since the combination results in elevated plasma concentrations ofduloxetine (see section 4.5).

Severe renal impairment (creatinine clearance <30 ml/min) (see section 4.4).

The initiation of treatment with Duloxetine Zentiva is contraindicated in patients with uncontrolledhypertension that could expose patients to a potential risk of hypertensive crisis (see sections 4.4 and4.8).

Mania and seizures

Duloxetine 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 Duloxetine Zentiva to patients with increased intraocular pressure, or those at risk of acutenarrow-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, with antipsychotics or otherdopamine antagonists or with opioids such as buprenorphine (with or without naloxone), tramadol andpethidine that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 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.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy shouldbe considered depending on the severity of the symptoms.

St. John’s wort

Adverse reactions may be more common during concomitant use of Duloxetine Zentiva and herbalpreparations 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 occurduring the first few weeks or more of treatment, patients should be closely monitored until suchimprovement occurs. It is general clinical experience that the risk of suicide may increase in the earlystages of recovery.

Other psychiatric conditions for which duloxetine is prescribed can also be associated with anincreased risk of suicide-related events. In addition, these conditions may be co-morbid with majordepressive disorder. The same precautions observed when treating patients with major depressivedisorder 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 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 similar pharmacological action (antidepressants), isolated casesof suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early aftertreatment discontinuation. Concerning risk factors for suicidality in depression, see above. Physiciansshould encourage patients to report any distressing thoughts or feelings at any time.

Use in children and adolescents under 18 years of age

Duloxetine should not be used in the treatment of children 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 duloxetine, 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 duloxetine 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 within2 weeks, 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 duloxetine 120 mg in elderly patients with major depressive disorder andgeneralised anxiety disorder are limited. Therefore, caution should be exercised when treating theelderly with the maximum 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

Duloxetine Zentiva gastro-resistant hard capsules contain sucrose. Patients with rare hereditaryproblems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiencyshould not take this medicine.

Monoamine oxidase inhibitors (MAOIs)

Due to the risk of serotonin syndrome, duloxetine should not be used in combination withnon-selective irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days ofdiscontinuing treatment with an MAOI. Based on the half-life of duloxetine, at least 5 days should beallowed after stopping Duloxetine Zentiva before starting an MAOI (see section 4.3).

The concomitant use of Duloxetine Zentiva with selective, reversible MAOIs, like moclobemide, isnot recommended (see section 4.4). The antibiotic linezolid is a reversible non-selective MAOI andshould not be given to patients treated with duloxetine (see section 4.4).

Inhibitors of CYP1A2

Because CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with potentinhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine. Fluvoxamine (100 mgonce daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine byabout 77% and increased AUCo-t 6-fold. Therefore Duloxetine Zentiva should not be administered incombination 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 beensystematically evaluated, except in the cases described in this section. Consequently, caution isadvised when duloxetine is taken in combination with other centrally acting medicinal products orsubstances, 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 withserotonergic agents. Caution is advisable if duloxetine is used concomitantly with serotonergic agentslike SSRIs, SNRIs, tricyclic antidepressants like clomipramine or amitriptyline, MAOIs likemoclobemide or linezolid, St. John’s wort (Hypericum perforatum) or triptans, buprenorphine,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 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 mgtwice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased3-fold. The co-administration of duloxetine (40 mg twice daily) increases steady state AUC oftolterodine (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 duloxetine is co-administered with medicinal products that are predominantly metabolised by CYP2D6 (risperidone,tricyclic antidepressants [TCAs] such as nortriptyline, amitriptyline, and imipramine) particularly ifthey 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 antiplateletagents 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 topatients treated with warfarin. However, concomitant administration of duloxetine with warfarin understeady state conditions, in healthy volunteers, as part of a clinical pharmacology study, did not resultin 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 duloxetinewith famotidine had no significant effect on the rate or extent of duloxetine absorption afteradministration of a 40 mg oral dose.

Inducers of CYP1A2

Population pharmacokinetic analyses have shown that smokers have almost 50% lower plasmaconcentrations 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.

Duloxetine 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.

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 duloxetine while breast-feeding is not recommended.

No studies on the effects on the ability to drive and use machines have been performed. Duloxetinemay be associated with sedation and dizziness. Patients should be instructed that if they experiencesedation or dizziness they should avoid potentially hazardous tasks such as driving or operatingmachinery.

The most commonly reported adverse reactions in patients treated with duloxetine 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.

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

Table 1: Adverse reactions

Frequency es 1/100 to < 1/1,000 to< 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated fromthe available data).

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

Very common Common Uncommon Rare Very Not knownrare

Laryngitis

Anaphylacticreaction

Hyper-sensitivitydisorder

Hypo-thyroidism

Very common Common Uncommon Rare Very Not knownrare

Decreased Hyperglycaemi Dehydrationappetite a (reported Hyponatraemiespecially in adiabetic SIADH6patients)

Insomnia Suicidal Suicidal

Agitation ideation5,7 behaviour5,7

Libido Sleep disorder Maniadecreased Bruxism Hallucinations

Anxiety Disorientation Aggression

Orgasm Apathy and anger4abnormal

Abnormaldreams

Headache Dizziness Myoclonus Serotonin

Somnolence Lethargy Akathisia7 syndrome6

Tremor Nervousness Convulsion1

Paraesthesia Disturbance in Psychomotorattention restlessness6

Dysgeusia Extra-

Dyskinesia pyramidal

Restless legs symptoms6syndrome

Poor qualitysleep

Blurred vision Mydriasis Glaucoma

Visualimpairment

Ear and labyrinth disorders

Tinnitus1 Vertigo

Ear pain

Palpitations Tachycardia Stress

Supra- cardiomyopathyventricular (Takotsuboarrhythmia, cardiomyopathy)mainly atrialfibrillation

Blood pressure Syncope2 Hypertensiveincrease3 Hypertension3,7 crisis3,6

Flushing Orthostatichypotension2

Peripheralcoldness

Yawning Throat Interstitialtightness lung disease10

Epistaxis Eosinophilicpneumonia6

Very common Common Uncommon Rare Very Not knownrare

Nausea Constipation Gastrointestinal Stomatitis

Dry mouth Diarrhoea haemorrhage7 Haematochezi

Abdominal Gastroenteritis apain Eructation Breath odour

Vomiting Gastritis Microscopic

Dyspepsia Dysphagia colitis9

Flatulence

Hepato-biliary disorders

Hepatitis3 Hepatic

Elevated liver failure6enzymes (ALT, Jaundice6

AST, alkalinephosphatase)

Acute liverinjury

Sweating Night sweats Stevens- Cutaneoincreased Urticaria Johnson us

Rash Dermatitis Syndrome6 vasculiticontact Angio- s

Cold sweat neurotic

Photo- oedema6sensitivityreactions

Increasedtendency tobruise

Musculo- Muscle Trismusskeletal pain tightness

Muscle spasm Muscletwitching

Dysuria Urinary Urine odour

Pollakiuria retention abnormal

Urinaryhesitation

Nocturia

Polyuria

Urine flowdecreased

Erectile Gynaecological Menopausaldysfunction haemorrhage symptoms

Ejaculation Menstrual Galactorrhoeadisorder disorder Hyperprolactin

Ejaculation Sexual aemiadelayed dysfunction Postpartum

Testicular pain haemorrhage6

Falls8 Chest pain7

Fatigue Feelingabnormal

Feeling cold

Very common Common Uncommon Rare Very Not knownrare

Thirst

Chills

Malaise

Feeling hot

Gaitdisturbance

Weight Weight Blooddecrease increase cholesterol

Blood creatine increasedphosphokinaseincreased

Bloodpotassiumincreased1 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 treatmentdiscontinuation.5 Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early aftertreatment 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 65 years old)9 Estimated frequency based on all clinical trial data.10Estimated frequency based on placebo-controlled clinical trials.

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.

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 a0.1 kg mean decrease in weight at 10-weeks compared with a 0.9 kg mean increase in 353 placebo-treated patients. Subsequently, over the four- to six-month extension period, patients on averagetrended toward recovery to their expected baseline weight percentile based on population data fromage- and gender-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

Duloxetine was studied in a clinical programme involving 3,158 patients (1,285 patient-years ofexposure) meeting DSM-IV criteria for major depression. The efficacy of duloxetine at therecommended 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, duloxetine’s efficacy has been demonstrated at daily doses between 60 and 120 mg in a totalof five out of seven randomised, double-blind, placebo-controlled, fixed dose acute studies in adultoutpatients with major depressive disorder.

Duloxetine 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 duloxetine 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-labelduloxetine 60 mg once daily were randomised to either duloxetine 60 mg once daily or placebo for afurther 6-months. Duloxetine 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 duloxetine 60 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 duloxetine 60 mg once dailyin elderly patients was comparable to that seen in the younger adults. However, data on elderlypatients exposed to the maximum dose (120 mg per day) are limited and thus, caution is recommendedwhen treating this population.

Generalised Anxiety Disorder

Duloxetine demonstrated statistically significant superiority over placebo in five out of five studiesincluding four randomised, double-blind, placebo-controlled acute studies and a relapse preventionstudy in adult patients with generalised anxiety disorder.

Duloxetine demonstrated statistically significant superiority over placebo as measured byimprovement in the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability Scale(SDS) global functional impairment score. Response and remission rates were also higher withduloxetine compared to placebo. Duloxetine showed comparable efficacy results to venlafaxine interms of improvements on the HAM-A total score.

In a relapse prevention study, patients responding to 6 months of acute treatment with open-labelduloxetine were randomised to either duloxetine or placebo for a further 6-months. Duloxetine 60 mgto 120 mg once daily demonstrated statistically significant superiority compared to placebo(p < 0.001) on the prevention of relapse, as measured by time to relapse. The incidence of relapseduring the 6-months double-blind follow-up period was 14% for duloxetine and 42% for placebo.

The efficacy of duloxetine 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 duloxetine 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 duloxetine as a treatment for diabetic neuropathic pain was established in 2randomised, 12-week, double-blind, placebo-controlled, fixed dose studies in adults (22 to 88 years)having diabetic neuropathic pain for at least 6 months. Patients meeting diagnostic criteria for majordepressive disorder were excluded from these trials. The primary outcome measure was the weeklymean of 24-hour average pain, which was collected in a daily diary by patients on an 11-point Likertscale.

In both studies, duloxetine 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 duloxetine 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 once daily).

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 in 184adolescents 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 thereference medicinal product containing duloxetine in all subsets of the paediatric population in thetreatment of major depressive disorder, diabetic neuropathic pain and generalised anxiety disorder. Seesection 4.2 for information on paediatric 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.

Duloxetine is well absorbed after oral administration with a Cmax occurring 6 hours post dose. Theabsolute oral bioavailability of duloxetine ranged from 32% to 80% (mean of 50%). Food delays thetime to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent ofabsorption (approximately 11 %). These changes do not have any clinical significance.

Duloxetine is approximately 96% bound to human plasma proteins. Duloxetine binds to both albuminand alpha-l acid glycoprotein. Protein binding is not affected by renal or hepatic impairment.

Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. Bothcytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites glucuronideconjugate of 4-hydroxy duloxetine and sulphate conjugate of 5-hydroxy 6-methoxy duloxetine. Basedupon in vitro studies, the circulating metabolites of duloxetine are considered pharmacologicallyinactive. The pharmacokinetics of duloxetine in patients who are poor metabolisers with respect to

CYP2D6 has not been specifically investigated. Limited data suggest that the plasma levels ofduloxetine are higher in these patients.

The elimination half-life of duloxetine ranges from 8 to 17 hours (mean of 12 h). After an intravenousdose the plasma clearance of duloxetine ranges from 22 l/h to 46 l/h (mean of 36 l/h). After an oraldose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/h (mean 101 l/h).

Pharmacokinetic differences have been identified between males and females (apparent plasmaclearance is approximately 50% lower in females). Based upon the overlap in the range of clearance,gender-based pharmacokinetic differences do not justify the recommendation for using a lower dosefor female patients.

Age65 years)(AUC increases by about 25% and half-life is about 25% longer in the elderly), although themagnitude of these changes is not sufficient to justify adjustments to the dose. As a generalrecommendation, caution should be exercised when treating the elderly (see sections 4.2 and 4.4).

End stage renal disease (ESRD) patients receiving dialysis had 2-fold higher duloxetine Cmax and AUCvalues compared with healthy subjects. Pharmacokinetic data on duloxetine is limited in patients withmild or moderate renal impairment.

Moderate liver disease (Child Pugh Class B) affected the pharmacokinetics of duloxetine. Comparedwith healthy subjects, the apparent plasma clearance of duloxetine was 79% lower, the apparentterminal half-life was 2.3 times longer, and the AUC was 3.7 times higher in patients with moderateliver disease. The pharmacokinetics of duloxetine and its metabolites have not been studied in patientswith mild or severe hepatic insufficiency.

The disposition of duloxetine was studied in 6 lactating women who were at least 12-weekspostpartum. Duloxetine is detected in breast milk, and steady-state concentrations in breast milk areabout one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7while on 40 mg twice daily dosing. Lactation did not influence duloxetine pharmacokinetics.

Pharmacokinetics of duloxetine in paediatric patients aged 7 to 17 years with major depressivedisorder following oral administration of 20 to 120 mg once daily dosing regimen was characterizedusing population modelling analyses based on data from 3 studies. The model-predicted duloxetinesteady state plasma concentrations in paediatric patients were mostly within the concentration rangeobserved 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 at45 mg/kg/day. The general toxicity profile of duloxetine in juvenile rats was similar to that in adultrats. The no-adverse effect level was determined to be 20 mg/kg/day.

Sucrose

Maize starch

Hypromellose

Talc

Hypromellose acetate succinate

Triethyl citrate

Duloxetine Zentiva 30 mg gastro-resistant hard capsules

Indigo carmine (E132)

Titanium dioxide (E171)

Gelatin

Titanium dioxide (E171)

Gelatin

Duloxetine Zentiva 60 mg gastro-resistant hard capsules

Indigo carmine (E132)

Titanium dioxide (E171)

Gelatin

Yellow iron oxide (E172)

Titanium dioxide (E171)

Gelatin

Not applicable.

2 years

Store below 30 °C. Store in the original package in order to protect from moisture.

Opaque PVC/PCTFE/Alu blisters or transparent PVC/PVDC/Alu blisters.

Duloxetine Zentiva 30 mg gastro-resistant hard capsules7, 28, 56, 84 and 98 capsules

Duloxetine Zentiva 60 mg gastro-resistant hard capsules14, 28, 56, 84 and 98 capsules

Not all pack sizes may be marketed.

No special requirements.

Zentiva, k.s.

U Kabelovny 130102 37 Prague 10

Czech Republic

Duloxetine Zentiva 30 mg gastro-resistant hard capsules

EU/1/15/1028/001

EU/1/15/1028/002

EU/1/15/1028/003

EU/1/15/1028/008

EU/1/15/1028/009

EU/1/15/1028/010

EU/1/15/1028/011

EU/1/15/1028/012

EU/1/15/1028/013

EU/1/15/1028/014

Duloxetine Zentiva 60 mg gastro-resistant hard capsules

EU/1/15/1028/004

EU/1/15/1028/005

EU/1/15/1028/006

EU/1/15/1028/007

EU/1/15/1028/015

EU/1/15/1028/016

EU/1/15/1028/017

EU/1/15/1028/018

EU/1/15/1028/019

EU/1/15/1028/020

Date of first authorisation: 20/08/2015

Date of latest renewal: 13/08/2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.