Duloxetine: prescribing information – dosing, contraindications, interactions, side effects

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.

Posology

Major depressive disorder
The starting and recommended maintenance dose is 60 mg once daily with or without food. Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day have been evaluated from a safety perspective in clinical trials. However, there is no clinical evidence suggesting that patients not responding to the initial recommended dose may benefit from dose up-titrations.

Therapeutic response is usually seen after 2-4 weeks of treatment.

After consolidation of the antidepressive response, it is recommended to continue treatment for several months, in order to avoid relapse. In patients responding to duloxetine, and with a history of repeated episodes of major depression, further long-term treatment at a dose of 60 to 120 mg/day could be considered.

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

In patients with co-morbid major depressive disorder, the starting and maintenance dose is 60 mg once daily (please see also dosing recommendation above).

Doses up to 120 mg per day have been shown to be efficacious and have been evaluated from a safety perspective in clinical trials. In patients with insufficient response to 60 mg, escalation up to 90 mg or 120 mg may therefore be considered. Dose escalation should be based upon clinical response and tolerability.

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

Diabetic peripheral neuropathic pain
The starting and recommended maintenance dose is 60 mg daily with or without food. Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day administered in evenly divided doses, have been evaluated from a safety perspective in clinical trials. The plasma concentration of duloxetine displays large inter-individual variability (see section 5.2). Hence, some patients that respond insufficiently to 60 mg may benefit from a higher dose.

Response to treatment should be evaluated after 2 months. In patients with inadequate initial response, additional response after this time is unlikely.

The therapeutic benefit should be reassessed regularly (at least every three months) (see section 5.1).

Special populations

Elderly
No dosage adjustment is recommended for elderly patients solely on the basis of age. However, as with any medicine, caution should be exercised when treating the elderly, especially with Cymbalta 120 mg per day for major depressive disorder or generalised anxiety disorder, for which data are limited (see sections 4.4 and 5.2).

Hepatic impairment
Cymbalta must not be used in patients with liver disease resulting in hepatic impairment (see sections 4.3 and 5.2).

Renal impairment
No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80 ml/min). Cymbalta must not be used in patients with severe renal impairment (creatinine clearance <30 ml/min; see section 4.3).

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

The safety and efficacy of duloxetine for the treatment of generalised anxiety disorder in paediatric patients aged 7-17 years have not been established. Current available data are described in sections 4.8, 5.1 and 5.2.

The safety and efficacy of duloxetine for the treatment of diabetic peripheral neuropathic pain has not been studied. No data are available.

Discontinuation of treatment
Abrupt discontinuation should be avoided. When stopping treatment with Cymbalta the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.
Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

Method of administration
For oral use.

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 (see section 4.5).

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

The initiation of treatment with Cymbalta is contraindicated in patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive crisis (see sections 4.4 and 4.8).

a. Summary of the safety profile
The most commonly reported adverse reactions in patients treated with Cymbalta were nausea, headache, dry mouth, somnolence, and dizziness. However, the majority of common adverse reactions were mild to moderate, they usually started early in therapy, and most tended to subside even as therapy was continued.

b. Tabulated summary of adverse reactions
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials.

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 the available data).

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

Very common
Common
Uncommon
Rare
Very rare
Not known
Infections and infestations

Laryngitis

Immune system disorders

Anaphylactic reaction
Hyper- sensitivity disorder

Very common
Common
Uncommon
Rare
Very rare
Not known
Endocrine disorders

Hypo- thyroidism

Metabolism and nutrition disorders

Decreased
Appetite
Hyperglycaemia
(reported especially in diabetic patients)
Dehydration
Hyponatraemia
SIADH6

Psychiatric disorders

Insomnia
Agitation
Libido decreased
Anxiety
Orgasm abnormal
Abnormal dreams
Suicidal ideation5,7
Sleep disorder
Bruxism
Disorientation
Apathy
Suicidal behaviour5,7
Mania
Hallucinations
Aggression and anger4

Nervous system disorders

Headache
Somnolence
Dizziness
Lethargy
Tremor
Paraesthesi a

Myoclonus
Akathisia7
Nervousness
Disturbance in attention
Dysgeusia
Dyskinesia
Restless legs syndrome
Poor quality sleep
Serotonin syndrome6
Convulsion1
Psychomotor restlessness6
Extra-pyramidal symptoms6

Eye disorders

Blurred vision
Mydriasis
Visual impairment
Glaucoma

Ear and labyrinth disorders

Tinnitus1
Vertigo
Ear pain

Cardiac disorders

Palpitation s
Tachycardia
Supra- ventricular arrhythmia, mainly atrial fibrillation

Stress cardiomyopathy
(Takotsubo cardiomyopathy)
Vascular disorders

Blood pressure increase3
Flushing
Syncope2
Hypertension3,7
Orthostatic hypotension2
Peripheral coldness
Hypertensive crisis3,6

Very common
Common
Uncommon
Rare
Very rare
Not known
Respiratory, thoracic and mediastinal disorders

Yawning
Throat tightness
Epistaxis
Interstitial lung disease10
Eosinophilic pneumonia6

Gastrointestinal disorders

Nausea
Dry mouth
Constipatio n
Diarrhoea
Abdominal pain
Vomiting
Dyspepsia
Flatulence
Gastrointestinal haemorrhage7
Gastroenteritis
Eructation
Gastritis
Dysphagia
Stomatitis
Haematochezia
Breath odour
Microscopic colitis9

Hepato-biliary disorders

Hepatitis3
Elevated liver enzymes (ALT,
AST, alkaline phosphatase)
Acute liver injury
Hepatic failure6
Jaundice6

Skin and subcutaneous tissue disorders

Sweating increased
Rash
Night sweats
Urticaria
Dermatitis contact
Cold sweat
Photo- sensitivity reactions
Increased tendency to bruise
Stevens-Johnson
Syndrome6
Angio-neurotic oedema6
Cutaneous vasculitis

Musculoskeletal and connective tissue disorders

Musculo- skeletal pain
Muscle spasm
Muscle tightness
Muscle twitching
Trismus

Renal and urinary disorders

Dysuria
Pollakiuria
Urinary retention
Urinary hesitation
Nocturia
Polyuria
Urine flow decreased
Urine odour abnormal

Reproductive system and breast disorders

Erectile dysfunctio n
Gynaecological haemorrhage
Menstrual disorder
Menopausal symptoms
Galactorrhoea

Very common
Common
Uncommon
Rare
Very rare
Not known
Ejaculation disorder
Ejaculation delayed
Sexual dysfunction
Testicular pain
Hyperprolactina emia
Postpartum haemorrhage6
General disorders and administration site conditions

Falls8
Fatigue
Chest pain7
Feeling abnormal
Feeling cold
Thirst
Chills
Malaise
Feeling hot
Gait disturbance

Investigations

Weight decrease
Weight increase
Blood creatine phosphokinase increased
Blood potassium increased
Blood cholesterol increased

1 Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation.
2 Cases of orthostatic hypotension and syncope have been reported especially at the initiation of treatment.
3 See section 4.4.
4 Cases of aggression and anger have been reported particularly early in treatment or after treatment discontinuation.
5 Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation (see section 4.4).
6 Estimated frequency of post-marketing surveillance reported adverse reactions; not observed in placebo-controlled clinical trials.
7 Not statistically significantly different from placebo.
8 Falls were more common in the elderly (≥65 years old).
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, particularly in 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, in some patients they may be severe and/or prolonged. It is therefore advised that when duloxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

In the 12 week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine- treated patients. HbA1c was stable in both duloxetine-treated and placebo-treated patients. In the extension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in both the duloxetine and routine care groups, but the mean increase was 0.3% greater in the duloxetine-

treated group. There was also a small increase in fasting blood glucose and in total cholesterol in duloxetine-treated patients while those laboratory tests showed a slight decrease in the routine care group.

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

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

A total of 467 paediatric patients initially randomized to duloxetine in clinical trials experienced a 0.1 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 average trended toward recovery to their expected baseline weight percentile based on population data from age- and gender-matched peers.

In studies of up to 9 months an overall mean decrease of 1% in height percentile (decrease of 2% in children (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 of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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

Mydriasis
Mydriasis has been reported in association with duloxetine, therefore, caution should be used when prescribing Cymbalta to patients with increased intraocular pressure, or those at risk of acute narrow- angle glaucoma.

Blood pressure and heart rate
Duloxetine has been associated with an increase in blood pressure and clinically significant hypertension in some patients. This may be due to the noradrenergic effect of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, especially in patients with pre-existing hypertension. Therefore, in patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended, especially during the first month of treatment. Duloxetine should be used with caution in patients whose conditions could be compromised by an increased heart rate or by an increase in blood pressure. Caution should also be exercised when duloxetine is used with medicinal products that may impair its metabolism (see section 4.5). For patients who experience a sustained increase in blood pressure while receiving duloxetine either dose reduction or gradual discontinuation should be considered (see section 4.8). In patients with uncontrolled hypertension duloxetine should not be initiated (see section 4.3).

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

Serotonin syndrome/ Neuroleptic malignant syndrome
As with other serotonergic agents, serotonin syndrome or neuroleptic malignant syndrome (NMS), a potentially life-threatening condition, may occur with duloxetine treatment, particularly with concomitant use of other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants or triptans), with agents that impair metabolism of serotonin such as MAOIs, or with antipsychotics or other dopamine antagonists 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), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). Serotonin syndrome in its most severe form can resemble NMS, which includes hyperthermia, muscle rigidity, elevated serum creatine kinase levels, autonomic instability with possible rapid fluctuation of vital signs and mental status changes.

If concomitant treatment with duloxetine and other serotonergic/neuroleptic agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of 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 preparations containing St John’s wort (Hypericum perforatum).

Suicide
Major Depressive Disorder and Generalised Anxiety Disorder: Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which Cymbalta is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal thoughts prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicidal behaviour, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant medicinal products in psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

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

Close supervision of patients and in particular those at high risk should accompany medicinal product therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Diabetic Peripheral Neuropathic Pain: As with other medicinal products with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviours

have been reported during duloxetine therapy or early after treatment discontinuation. Concerning risk factors for suicidality in depression, see above. Physicians should encourage patients to report any distressing thoughts or feelings at any time.

Use in children and adolescents under 18 years of age
Cymbalta should not be used in the treatment of children and adolescents under the age of 18 years.
Suicide-related behaviours (suicide attempts and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger), were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms (see section 5.1). In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking (see section 4.8).

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

Hyponatraemia
Hyponatraemia has been reported when administering Cymbalta, including cases with serum sodium lower than 110 mmol/l. Hyponatraemia may be due to a syndrome of inappropriate anti-diuretic hormone secretion (SIADH). The majority of cases of hyponatraemia were reported in the elderly, especially when coupled with a recent history of, or condition pre-disposing to, altered fluid balance.
Caution is required in patients at increased risk for hyponatraemia, such as elderly, cirrhotic, or dehydrated patients or patients treated with diuretics.

Discontinuation of treatment
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials adverse events seen on abrupt treatment discontinuation occurred in approximately 45% of patients treated with Cymbalta and 23% of patients taking placebo.
The risk of withdrawal symptoms seen with SSRI’s and SNRI’s may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. The most commonly reported reactions are listed in section 4.8. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that duloxetine should be gradually tapered when discontinuing treatment over a period of no less than 2 weeks, according to the patient’s needs (see section 4.2).

Elderly
Data on the use of Cymbalta 120 mg in elderly patients with major depressive disorder and generalised anxiety disorder are limited. Therefore, caution should be exercised when treating the elderly 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 a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Medicinal products containing duloxetine
Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic pain, major depressive disorder, generalised anxiety disorder and stress urinary incontinence). The use of more than one of these products concomitantly should be avoided.

Hepatitis/increased liver enzymes
Cases of liver injury, including severe elevations of liver enzymes (>10 times upper limit of normal), hepatitis and jaundice have been reported with duloxetine (see section 4.8). Most of them occurred during the first months of treatment. The pattern of liver damage was predominantly hepatocellular.
Duloxetine should be used with caution in patients treated with other medicinal products associated with hepatic injury.

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-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRIs.

Sucrose
Cymbalta hard gastro-resistant capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Sodium
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 not be used in combination with non-selective irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI (see section 4.3).

The concomitant use of Cymbalta with selective, reversible MAOIs, like moclobemide, is not recommended (see section 4.4). The antibiotic linezolid is a reversible non-selective MAOI and should not be given to patients treated with Cymbalta (see section 4.4).

Inhibitors of CYP1A2: Because CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine.
Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77% and increased AUCo-t 6-fold. Therefore Cymbalta should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (see section 4.3).

CNS medicinal products: The risk of using duloxetine in combination with other CNS-active medicinal products has not been systematically evaluated, except in the cases described in this section.
Consequently, caution is advised when Cymbalta is taken in combination with other centrally acting medicinal products or substances, including alcohol and sedative medicinal products (e.g.
benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

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 used concomitantly with serotonergic agents like SSRIs, SNRIs, tricyclic antidepressants like clomipramine or amitriptyline, MAOIs like moclobemide or linezolid, St John’s wort (Hypericum perforatum) or triptans, 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 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of duloxetine (40 mg twice daily) increases steady state AUC of tolterodine (2 mg twice daily) by 71 %, but does not affect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment is recommended. Caution is advised if Cymbalta is co-administered with medicinal products that are predominantly metabolised by CYP2D6 (risperidone, tricyclic antidepressants [TCAs] such as nortriptyline, amitriptyline, and imipramine) particularly if they have a narrow therapeutic index (such as flecainide, propafenone and metoprolol).

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

Anticoagulants and antiplatelet agents: Caution should be exercised when duloxetine is combined with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction. Furthermore, increases in INR values have been reported when duloxetine was co-administered to patients treated with warfarin. However, concomitant administration of duloxetine with warfarin under steady state conditions, in healthy volunteers, as part of a clinical pharmacology study, did not result in a clinically significant change in INR from baseline or in the pharmacokinetics of R- or S-warfarin.

Effects of other medicinal products on duloxetine
Antacids and H2 antagonists: Co-administration of duloxetine with aluminium- and magnesium- containing antacids or duloxetine with famotidine had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose.

Inducers of CYP1A2: Population pharmacokinetic analyses have shown that smokers have almost 50% lower plasma concentrations of duloxetine compared with non-smokers.

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

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

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

In the EU study, maternal exposure to duloxetine during late pregnancy (at any time from 20 weeks gestational 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 duloxetine late in pregnancy). The majority occurred between 35 and 36 weeks of gestation. This association was not seen in the US study.

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

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late

pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN).
Although no studies have investigated the association of PPHN to SNRI treatment, this potential risk cannot be ruled out with duloxetine taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).

As with other serotonergic medicinal products, discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. Discontinuation symptoms seen with duloxetine may include hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures. The majority of cases have occurred either at birth or within a few days of birth.

Cymbalta should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. Women should be advised to notify their physician if they become pregnant, or intend to become pregnant, during therapy.

Breast feeding
Duloxetine is very weakly excreted into human milk based on a study of 6 lactating patients, who did not breast feed their children. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose (see section 5.2). As the safety of duloxetine in infants is not known, the use of Cymbalta while breast-feeding is not recommended.

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

Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of 5400 mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or in combination with other medicinal products) included somnolence, coma, serotonin syndrome, seizures, vomiting and tachycardia.

No specific antidote is known for duloxetine but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. A free airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption.
Duloxetine has a large volume of distribution and forced diuresis, haemoperfusion, and exchange perfusion are unlikely to be beneficial.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other antidepressants. ATC code: N06AX21.

Mechanism of action
Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic

and adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin and noradrenaline in various brain areas of animals.

Pharmacodynamic effects
Duloxetine normalised pain thresholds in several preclinical models of neuropathic and inflammatory pain and attenuated pain behaviour in a model of persistent pain. The pain inhibitory action of duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the central nervous system.

Clinical efficacy and safety
Major Depressive Disorder: Cymbalta was studied in a clinical programme involving 3,158 patients (1,285 patient-years of exposure) meeting DSM-IV criteria for major depression. The efficacy of Cymbalta at the recommended dose of 60 mg once a day was demonstrated in three out of three randomised, double-blind, placebo-controlled, fixed dose acute studies in adult outpatients with major depressive disorder. Overall, Cymbalta’s efficacy has been demonstrated at daily doses between 60 and 120 mg in a total of five out of seven randomised, double-blind, placebo-controlled, fixed dose acute studies in adult outpatients with major depressive disorder.

Cymbalta demonstrated statistical superiority over placebo as measured by improvement in the 17- item Hamilton Depression Rating Scale (HAM-D) total score (including both the emotional and somatic symptoms of depression). Response and remission rates were also statistically significantly higher with Cymbalta compared with placebo. Only a small proportion of patients included in pivotal clinical trials had severe depression (baseline HAM-D>25).

In a relapse prevention study, patients responding to 12-weeks of acute treatment with open-label Cymbalta 60 mg once daily were randomised to either Cymbalta 60 mg once daily or placebo for a further 6-months. Cymbalta 60 mg once daily demonstrated a statistically significant superiority compared to placebo (p=0.004) on the primary outcome measure, the prevention of depressive relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow-up period was 17% and 29% for duloxetine and placebo, respectively.

Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolised by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of 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 post dose. The absolute oral bioavailability of duloxetine ranged from 32% to 80% (mean of 50%). Food delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11 %). These changes do not have any clinical significance.

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

Biotransformation: Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. Both cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites glucuronide conjugate of 4-hydroxy duloxetine and sulfate conjugate of 5-hydroxy 6-methoxy duloxetine. Based upon in vitro studies, the circulating metabolites of duloxetine are considered pharmacologically inactive. 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 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 of 36 l/hr). After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/hr (mean 101 l/hr).

Special populations

Treatment of major depressive disorder.
Treatment of diabetic peripheral neuropathic pain.
Treatment of generalised anxiety disorder.

Duloxetine Lilly is indicated in adults.
For further information see section 5.1.

Posology
Major depressive disorder
The starting and recommended maintenance dose is 60 mg once daily with or without food. Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day have been evaluated from a safety perspective in clinical trials. However, there is no clinical evidence suggesting that patients not responding to the initial recommended dose may benefit from dose up-titrations.

Therapeutic response is usually seen after 2-4 weeks of treatment.

After consolidation of the antidepressive response, it is recommended to continue treatment for several months, in order to avoid relapse. In patients responding to duloxetine, and with a history of repeated episodes of major depression, further long-term treatment at a dose of 60 to 120 mg/day could be considered.

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

In patients with co-morbid major depressive disorder, the starting and maintenance dose is 60 mg once daily (please see also dosing recommendation above).

Doses up to 120 mg per day have been shown to be efficacious and have been evaluated from a safety perspective in clinical trials. In patients with insufficient response to 60 mg, escalation up to 90 mg or 120 mg may therefore be considered. Dose escalation should be based upon clinical response and tolerability.

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

Diabetic peripheral neuropathic pain
The starting and recommended maintenance dose is 60 mg daily with or without food. Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day administered in evenly divided doses, have been evaluated from a safety perspective in clinical trials. The plasma concentration of duloxetine displays large inter-individual variability (see section 5.2). Hence, some patients that respond insufficiently to 60 mg may benefit from a higher dose.

Response to treatment should be evaluated after 2 months. In patients with inadequate initial response, additional response after this time is unlikely.

The therapeutic benefit should be reassessed regularly (at least every three months) (see section 5.1).

Special populations

Elderly
No dosage adjustment is recommended for elderly patients solely on the basis of age. However, as with any medicine, caution should be exercised when treating the elderly, especially with Duloxetine Lilly 120 mg per day for major depressive disorder or generalised anxiety disorder, for which data are limited (see sections 4.4 and 5.2).

Hepatic impairment
Duloxetine Lilly must not be used in patients with liver disease resulting in hepatic impairment (see sections 4.3 and 5.2).

Renal impairment
No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80 ml/min). Duloxetine Lilly must not be used in patients with severe renal impairment (creatinine clearance <30 ml/min; see section 4.3).

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

The safety and efficacy of duloxetine for the treatment of generalised anxiety disorder in paediatric patients aged 7-17 years have not been established. Current available data are described in sections 4.8, 5.1 and 5.2.

The safety and efficacy of duloxetine for the treatment of diabetic peripheral neuropathic pain has not been studied. No data are available.

Discontinuation of treatment
Abrupt discontinuation should be avoided. When stopping treatment with Duloxetine Lilly the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

Method of administration
For oral use.

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

Concomitant use of Duloxetine Lilly with nonselective, irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated (see section 4.5).

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

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

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

The initiation of treatment with Duloxetine Lilly is contraindicated in patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive crisis (see sections 4.4 and 4.8).

a. Summary of the safety profile
The most commonly reported adverse reactions in patients treated with Duloxetine Lilly were nausea, headache, dry mouth, somnolence, and dizziness. However, the majority of common adverse reactions were mild to moderate, they usually started early in therapy, and most tended to subside even as therapy was continued.

b. Tabulated list of adverse reactions
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical 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 the available data).

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

Very common
Common
Uncommon
Rare
Very rare
Not known
Infections and infestations

Laryngitis

Immune system disorders

Anaphylactic reaction

Very common
Common
Uncommon
Rare
Very rare
Not known
Hyper- sensitivity disorder
Endocrine disorders

Hypo- thyroidism

Metabolism and nutrition disorders

Decreased
Appetite
Hyperglycaemia
(reported especially in diabetic patients)
Dehydration
Hyponatraemi a
SIADH6

Psychiatric disorders

Insomnia
Agitation
Libido decreased
Anxiety
Orgasm abnormal
Abnormal dreams
Suicidal ideation5,7
Sleep disorder
Bruxism
Disorientation
Apathy
Suicidal behaviour5,7
Mania
Hallucinations
Aggression and anger4

Nervous system disorders

Headache
Somnolence
Dizziness
Lethargy
Tremor
Paraesthesia

Myoclonus
Akathisia7
Nervousness
Disturbance in attention
Dysgeusia
Dyskinesia
Restless legs syndrome
Poor quality sleep
Serotonin syndrome6
Convulsion1
Psychomotor restlessness6
Extra- pyramidal symptoms6

Eye disorders

Blurred vision
Mydriasis
Visual impairment
Glaucoma

Ear and labyrinth disorders

Tinnitus1
Vertigo
Ear pain

Cardiac disorders

Palpitations
Tachycardia
Supra- ventricular arrhythmia, mainly atrial fibrillation

Stress cardiomyopathy
(Takotsubo cardiomyopathy)
Vascular disorders

Blood pressure increase3
Flushing
Syncope2
Hypertension3,7
Orthostatic hypotension2
Hypertensive crisis3,6

Very common
Common
Uncommon
Rare
Very rare
Not known
Peripheral coldness
Respiratory, thoracic and mediastinal disorders

Yawning
Throat tightness
Epistaxis
Interstitial lung disease10
Eosinophilic pneumonia6

Gastrointestinal disorders

Nausea
Dry mouth
Constipatio n Diarrhoea
Abdominal pain
Vomiting
Dyspepsia
Flatulence
Gastrointestinal haemorrhage7
Gastroenteritis
Eructation
Gastritis
Dysphagia
Stomatitis
Haematochezi a
Breath odour
Microscopic colitis9

Hepato-biliary disorders

Hepatitis3
Elevated liver enzymes (ALT,
AST, alkaline phosphatase)
Acute liver injury
Hepatic failure6
Jaundice6

Skin and subcutaneous tissue disorders

Sweating increased
Rash
Night sweats
Urticaria
Dermatitis contact
Cold sweat
Photo- sensitivity reactions
Increased tendency to bruise
Stevens-
Johnson
Syndrome6
Angio- neurotic oedema6
Cutaneous vasculitis

Musculoskeletal and connective tissue disorders

Musculo- skeletal pain
Muscle spasm
Muscle tightness
Muscle twitching
Trismus

Renal and urinary disorders

Dysuria
Pollakiuria
Urinary retention
Urinary hesitation
Nocturia
Polyuria
Urine flow decreased
Urine odour abnormal

Reproductive system and breast disorders

Erectile dysfunction
Gynaecological haemorrhage
Menstrual
Menopausal symptoms
Galactorrhoea

Very common
Common
Uncommon
Rare
Very rare
Not known
Ejaculation disorder
Ejaculation delayed disorder
Sexual dysfunction
Testicular pain
Hyperprolactin aemia
Postpartum haemorrhage6
General disorders and administration site conditions

Falls8
Fatigue
Chest pain7
Feeling abnormal
Feeling cold
Thirst
Chills
Malaise
Feeling hot
Gait disturbance

Investigations

Weight decrease
Weight increase
Blood creatine phosphokinase increased
Blood potassium increased
Blood cholesterol increased

1 Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation.
2 Cases of orthostatic hypotension and syncope have been reported especially at the initiation of treatment.
3 See section 4.4.
4 Cases of aggression and anger have been reported particularly early in treatment or after treatment discontinuation.
5 Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation (see section 4.4).
6 Estimated frequency of post-marketing surveillance reported adverse reactions; not observed in placebo-controlled clinical trials.
7 Not statistically significantly different from placebo.
8 Falls were more common in the elderly (≥65 years old).
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, particularly in 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, in some patients they may be severe and/or prolonged. It is therefore advised that when duloxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

In the 12 week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine- treated patients. HbA1c was stable in both duloxetine-treated and placebo-treated patients. In the extension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in both the duloxetine and routine care groups, but the mean increase was 0.3% greater in the duloxetine-

treated group. There was also a small increase in fasting blood glucose and in total cholesterol in duloxetine-treated patients while those laboratory tests showed a slight decrease in the routine care group.

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

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

A total of 467 paediatric patients initially randomized to duloxetine in clinical trials experienced a 0.1 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 average trended toward recovery to their expected baseline weight percentile based on population data from age- and gender-matched peers.

In studies of up to 9 months an overall mean decrease of 1% in height percentile (decrease of 2% in children (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 of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Mania and seizures
Duloxetine Lilly should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures.

Mydriasis
Mydriasis has been reported in association with duloxetine, therefore, caution should be used when prescribing Duloxetine Lilly to patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma.

Blood pressure and heart rate
Duloxetine has been associated with an increase in blood pressure and clinically significant hypertension in some patients. This may be due to the noradrenergic effect of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, especially in patients with pre-existing hypertension. Therefore, in patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended, especially during the first month of treatment. Duloxetine should be used with caution in patients whose conditions could be compromised by an increased heart rate or by an increase in blood pressure. Caution should also be exercised when duloxetine is used with medicinal products that may impair its metabolism (see section 4.5). For patients who experience a sustained increase in blood pressure while receiving duloxetine either dose reduction or gradual discontinuation should be considered (see section 4.8). In patients with uncontrolled hypertension duloxetine should not be initiated (see section 4.3).

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

Serotonin syndrome/ Neuroleptic malignant syndrome
As with other serotonergic agents, serotonin syndrome or neuroleptic malignant syndrome (NMS), a potentially life-threatening condition, may occur with duloxetine treatment, particularly with concomitant use of other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants or triptans), with agents that impair metabolism of serotonin such as MAOIs, or with antipsychotics or other dopamine antagonists 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), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). Serotonin syndrome in its most severe form can resemble NMS, which includes hyperthermia, muscle rigidity, elevated serum creatine kinase levels, autonomic instability with possible rapid fluctuation of vital signs and mental status changes.

If concomitant treatment with duloxetine and other serotonergic/neuroleptic agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of 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 Duloxetine Lilly and herbal preparations containing St John’s wort (Hypericum perforatum).

Suicide
Major Depressive Disorder and Generalised Anxiety Disorder: Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which Duloxetine Lilly is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal thoughts prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicidal behaviour, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant medicinal products in psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

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

Close supervision of patients and in particular those at high risk should accompany medicinal product therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Diabetic Peripheral Neuropathic Pain: As with other medicinal products with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviours

have been reported during duloxetine therapy or early after treatment discontinuation. Concerning risk factors for suicidality in depression, see above. Physicians should encourage patients to report any distressing thoughts or feelings at any time.

Use in children and adolescents under 18 years of age
Duloxetine Lilly should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempts and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger), were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms (see section 5.1). In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking (see section 4.8).

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

Hyponatraemia
Hyponatraemia has been reported when administering Duloxetine Lilly, including cases with serum sodium lower than 110 mmol/l. Hyponatraemia may be due to a syndrome of inappropriate anti- diuretic hormone secretion (SIADH). The majority of cases of hyponatraemia were reported in the elderly, especially when coupled with a recent history of, or condition pre-disposing to, altered fluid balance. Caution is required in patients at increased risk for hyponatraemia, such as elderly, cirrhotic, or dehydrated patients or patients treated with diuretics.

Discontinuation of treatment
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials adverse events seen on abrupt treatment discontinuation occurred in approximately 45% of patients treated with Duloxetine Lilly and 23% of patients taking placebo. The risk of withdrawal symptoms seen with SSRI’s and SNRI’s may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. The most commonly reported reactions are listed in section 4.8. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that duloxetine should be gradually tapered when discontinuing treatment over a period of no less than 2 weeks, according to the patient’s needs (see section 4.2).

Elderly
Data on the use of Duloxetine Lilly 120 mg in elderly patients with major depressive disorder and generalised anxiety disorder are limited. Therefore, caution should be exercised when treating the elderly 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 a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Medicinal products containing duloxetine
Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic pain, major depressive disorder, generalised anxiety disorder and stress urinary incontinence). The use of more than one of these products concomitantly should be avoided.

Hepatitis/increased liver enzymes
Cases of liver injury, including severe elevations of liver enzymes (>10 times upper limit of normal), hepatitis and jaundice have been reported with duloxetine (see section 4.8). Most of them occurred during the first months of treatment. The pattern of liver damage was predominantly hepatocellular.
Duloxetine should be used with caution in patients treated with other medicinal products associated with hepatic injury.

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-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRIs.

Sucrose
Duloxetine Lilly hard gastro-resistant capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Sodium
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 not be used in combination with non-selective irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping Duloxetine Lilly before starting an MAOI (see section 4.3).

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

Inhibitors of CYP1A2: Because CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine.
Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77% and increased AUCo-t 6-fold. Therefore Duloxetine Lilly should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (see section 4.3).

CNS medicinal products: The risk of using duloxetine in combination with other CNS-active medicinal products has not been systematically evaluated, except in the cases described in this section.
Consequently, caution is advised when Duloxetine Lilly is taken in combination with other centrally acting medicinal products or substances, including alcohol and sedative medicinal products (e.g.
benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

Serotonergic agents: In rare cases, serotonin syndrome has been reported in patients using SSRIs/SNRIs concomitantly with serotonergic agents. Caution is advisable if Duloxetine Lilly is used concomitantly with serotonergic agents like SSRIs, SNRIs, tricyclic antidepressants like clomipramine or amitriptyline, MAOIs like moclobemide or linezolid, St John’s wort (Hypericum perforatum) or triptans, 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 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of duloxetine (40 mg twice daily) increases steady state AUC of tolterodine (2 mg twice daily) by 71 %, but does not affect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment is recommended. Caution is advised if Duloxetine Lilly is co-administered with medicinal products that are predominantly metabolised by CYP2D6 (risperidone, tricyclic antidepressants [TCAs] such as nortriptyline, amitriptyline, and imipramine) particularly if they have a narrow therapeutic index (such as flecainide, propafenone and metoprolol).

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

Anticoagulants and antiplatelet agents: Caution should be exercised when duloxetine is combined with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction. Furthermore, increases in INR values have been reported when duloxetine was co-administered to patients treated with warfarin. However, concomitant administration of duloxetine with warfarin under steady state conditions, in healthy volunteers, as part of a clinical pharmacology study, did not result in a clinically significant change in INR from baseline or in the pharmacokinetics of R- or S-warfarin.

Effects of other medicinal products on duloxetine
Antacids and H2 antagonists: Co-administration of duloxetine with aluminium- and magnesium- containing antacids or duloxetine with famotidine had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose.

Inducers of CYP1A2: Population pharmacokinetic analyses have shown that smokers have almost 50% lower plasma concentrations of duloxetine compared with non-smokers.

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

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

In the EU study, maternal exposure to duloxetine during late pregnancy (at any time from 20 weeks gestational 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 duloxetine late in pregnancy). The majority occurred between 35 and 36 weeks of gestation. This association was not seen in the US study.

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

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN).
Although no studies have investigated the association of PPHN to SNRI treatment, this potential risk

cannot be ruled out with duloxetine taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).

As with other serotonergic medicinal products, discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. Discontinuation symptoms seen with duloxetine may include hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures. The majority of cases have occurred either at birth or within a few days of birth.

Duloxetine Lilly should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. Women should be advised to notify their physician if they become pregnant, or intend to become pregnant, during therapy.

Breast feeding
Duloxetine is very weakly excreted into human milk based on a study of 6 lactating patients, who did not breast feed their children. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose (see section 5.2). As the safety of duloxetine in infants is not known, the use of Duloxetine Lilly while breast-feeding is not recommended.

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

Duloxetine Lilly may have a mild to moderate influence on the ability to drive and use machines.
Duloxetine Lilly may be associated with sedation and dizziness. Patients should be instructed that if they experience sedation or dizziness they should avoid potentially hazardous tasks such as driving or operating machinery.

Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of 5400 mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or in combination with other medicinal products) included somnolence, coma, serotonin syndrome, seizures, vomiting and tachycardia.

No specific antidote is known for duloxetine but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. A free airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption.
Duloxetine has a large volume of distribution and forced diuresis, haemoperfusion, and exchange perfusion are unlikely to be beneficial.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: psychoanaleptics, antidepressants, other antidepressants. ATC code:
N06AX21.

Mechanism of action
Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic

and adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin and noradrenaline in various brain areas of animals.

Pharmacodynamic effects
Duloxetine normalised pain thresholds in several preclinical models of neuropathic and inflammatory pain and attenuated pain behaviour in a model of persistent pain. The pain inhibitory action of duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the central nervous system.

Clinical efficacy and safety
Major Depressive Disorder: Duloxetine Lilly 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 Duloxetine Lilly at the recommended dose of 60 mg once a day was demonstrated in three out of three randomised, double-blind, placebo-controlled, fixed dose acute studies in adult outpatients with major depressive disorder. Overall, Duloxetine Lilly’s efficacy has been demonstrated at daily doses between 60 and 120 mg in a total of five out of seven randomised, double-blind, placebo-controlled, fixed dose acute studies in adult outpatients with major depressive disorder.

Duloxetine Lilly demonstrated statistical superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAM-D) total score (including both the emotional and somatic symptoms of depression). Response and remission rates were also statistically significantly higher with Duloxetine Lilly compared with placebo. Only a small proportion of patients included in pivotal clinical trials had severe depression (baseline HAM-D>25).

In a relapse prevention study, patients responding to 12-weeks of acute treatment with open-label Duloxetine Lilly 60 mg once daily were randomised to either Duloxetine Lilly 60 mg once daily or placebo for a further 6-months. Duloxetine Lilly 60 mg once daily demonstrated a statistically significant superiority compared to placebo (p=0.004) on the primary outcome measure, the prevention of depressive relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow-up period was 17% and 29% for duloxetine and placebo, respectively.

Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolised by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of 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 post dose. The absolute oral bioavailability of duloxetine ranged from 32% to 80% (mean of 50%). Food delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11 %). These changes do not have any clinical significance.

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

Biotransformation
Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. Both cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites glucuronide conjugate of 4-hydroxy duloxetine and sulfate conjugate of 5-hydroxy 6-methoxy duloxetine. Based upon in vitro studies, the circulating metabolites of duloxetine are considered pharmacologically inactive. 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 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 of 36 l/hr).
After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/hr (mean 101 l/hr).

Special populations

Gender

YENTREVE is indicated for women for the treatment of moderate to severe Stress Urinary Incontinence (SUI).

YENTREVE is indicated in adults.
For further information see section 5.1.

Posology

The recommended dose of YENTREVE is 40 mg twice daily without regard to meals. After 2-4 weeks of treatment, patients should be re-assessed in order to evaluate the benefit and tolerability of the therapy. Some patients may benefit from starting treatment at a dose of 20 mg twice daily for two weeks before increasing to the recommended dose of 40 mg twice daily. Dose escalation may decrease, though not eliminate, the risk of nausea and dizziness.

However, limited data are available to support the efficacy of YENTREVE 20 mg twice daily.

The efficacy of YENTREVE has not been evaluated for longer than 3 months in placebo-controlled studies. The benefit of treatment should be re-assessed at regular intervals.

Combining YENTREVE with a pelvic floor muscle training (PFMT) programme may be more effective than either treatment alone. It is recommended that consideration be given to concomitant PFMT.

Hepatic impairment
YENTREVE must not be used in women with liver disease resulting in hepatic impairment (see sections 4.3 and 5.2).

Renal impairment
No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80 ml/min). YENTREVE must not be used in patients with severe renal impairment (creatinine clearance <30 ml/min; see section 4.3).

Paediatric population

The safety and efficacy of duloxetine for the treatment of stress urinary incontinence has not been studied. No data are available.

Special populations

Elderly
Caution should be exercised when treating the elderly.

Discontinuation of treatment
Abrupt discontinuation should be avoided. When stopping treatment with YENTREVE the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

Method of administration
For oral use.

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

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

YENTREVE should not be used in combination with nonselective, irreversible monoamine oxidase inhibitors - MAOIs (see section 4.5).

YENTREVE should not be used in combination with CYP1A2 inhibitors, like fluvoxamine, ciprofloxacin or enoxacin since the combination results in elevated plasma concentrations of duloxetine (see section 4.5).

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

The initiation of treatment with YENTREVE is contraindicated in patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive crisis (see sections 4.4 and 4.8).

a. Summary of the safety profile
The most commonly reported adverse events in patients treated with YENTREVE in clinical trials in SUI and other lower urinary tract disorders were nausea, dry mouth fatigue and constipation. The data analysis of four 12-week, placebo-controlled clinical trials in patients with SUI, including 958 duloxetine-treated and 955 placebo-treated patients, showed that the onset of the reported adverse events typically occurred in the first week of therapy. However, the majority of the most frequent adverse events were mild to moderate and resolved within 30 days of occurrence (e.g. nausea).

b. Tabulated summary of adverse reactions
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical 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 the available data).

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

Very common
Common
Uncommon
Rare
Very rare
Not known
Infections and infestations

Laryngitis

Immune system disorders

Hyper- sensitivity disorder
Anaphylactic reaction

Endocrine disorders

Hypo- thyroidism

Metabolism and nutrition disorders

Appetite decreased
Dehydration
Hyperglycaemi a (reported especially in diabetic patients)
Hyponatraemia
SIADH6

Psychiatric disorders

Insomnia
Agitation
Libido decreased
Anxiety
Sleep disorder

Bruxism
Disorientation
Apathy
Orgasm abnormal
Abnormal dreams
Suicidal behaviour5,6
Suicidal ideation5,7
Mania6
Hallucinations
Aggression and anger4,6

Nervous system disorders

Headache
Dizziness
Lethargy
Somnolence
Tremor
Paraesthesia
Nervousness
Disturbance in attention
Dysgeusia
Poor quality sleep

Serotonin syndrome6
Convulsions1,6
Myoclonus
Akathisia6
Psychomotor restlessness6
Extra- pyramidal symptoms6
Dyskinesia
Restless legs syndrome

Eye disorders

Blurred vision
Mydriasis
Visual impairment
Dry eye
Glaucoma

Ear and labyrinth disorders

Vertigo
Tinnitus1
Ear pain

Cardiac disorders

Palpitations
Tachycardia
Supra- ventricular arrhythmia,

Stress cardiomyopathy
(Takotsubo cardiomyopathy)

Very common
Common
Uncommon
Rare
Very rare
Not known mainly atrial fibrillation6
Vascular disorders

Hypertensio n3,7
Flushing
Syncope2
Blood pressure increase3
Hypertensive crisis3
Orthostatic hypotension2
Peripheral coldness

Respiratory, thoracic and mediastinal disorders

Yawning
Throat tightness
Epistaxis
Interstitial lung disease10
Eosinophilic pneumonia6

Gastrointestinal disorders

Nausea
Dry mouth
Constipation
Diarrhoea
Abdominal pain
Vomiting
Dyspepsia
Gastrointestin al haemorrhage7
Gastroenteriti s
Stomatitis
Eructation
Gastritis
Dysphagia
Flatulence
Breath odour
Haematochezia
Microscopic colitis9

Hepato-biliary disorders

Hepatitis3
Elevated liver enzymes
(ALT, AST, alkaline phosphatase)
Acute liver injury
Hepatic failure6
Jaundice6

Skin and subcutaneous tissue disorders

Sweating increased
Rash
Night sweats
Urticaria
Dermatitis contact
Cold sweat
Increased tendency to bruise
Stevens-
Johnson
Syndrome6
Angio-neurotic oedema6
Photo- sensitivity reactions
Cutaneous vasculitis

Musculoskeletal and connective tissue disorders

Musculo- skeletal pain
Muscle tightness
Muscle spasm
Muscle twitching

Very common
Common
Uncommon
Rare
Very rare
Not known
Trismus
Renal and urinary disorders

Urinary hesitation
Dysuria
Nocturia
Pollakiuria
Urine odour abnormal
Urinary retention6
Polyuria
Urine flow decreased

Reproductive system and breast disorders

Gynaecologic al haemorrhage
Menopausal symptoms

Menstrual disorder
Galactorrhoea
Hyperprolactin aemia
Postpartum haemorrhage6

General disorders and administration site conditions

Fatigue
Asthenia
Chills
Chest pain7
Falls8
Feeling abnormal
Feeling cold
Thirst
Malaise
Feeling hot
Gait disturbance

Investigations

Weight decrease
Weight increase
Blood cholesterol increased
Blood creatine phosphokinas e increased
Blood potassium increased

1 Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation.
2 Cases of orthostatic hypotension and syncope have been reported especially at the initiation of treatment.
3 See section 4.4.
4 Cases of aggression and anger have been reported particularly early in treatment or after treatment discontinuation.
5 Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation (see section 4.4).
6 Estimated frequency of post-marketing surveillance reported adverse reactions; not observed in placebo-controlled clinical trials.
7 Not statistically significantly different from placebo.
8 Falls were more common in the elderly (≥65 years old).
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, particularly in 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, in some patients they may be severe and/or prolonged. It is therefore advised that when duloxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

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

In the 12 week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine- treated patients. HbA1c was stable in both duloxetine-treated and placebo-treated patients. In the extension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in both the duloxetine and routine care groups, but the mean increase was 0.3% greater in the duloxetine- treated group. There was also a small increase in fasting blood glucose and in total cholesterol in duloxetine-treated patients while those laboratory tests showed a slight decrease in the routine care group.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Mania and seizures
YENTREVE should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures.

Serotonin syndrome/ Neuroleptic malignant syndrome
As with other serotonergic agents, serotonin syndrome or neuroleptic malignant syndrome (NMS), a potentially life-threatening condition, may occur with duloxetine treatment, particularly with concomitant use of other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants or triptans), with agents that impair metabolism of serotonin such as MAOIs, or with antipsychotics or other dopamine antagonists 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), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). Serotonin syndrome in its most severe form can resemble NMS, which includes hyperthermia, muscle rigidity, elevated serum creatine kinase levels, autonomic instability with possible rapid fluctuation of vital signs and mental status changes.

If concomitant treatment with duloxetine and other serotonergic/neuroleptic agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems in clinically warranted, careful observation of 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 YENTREVE and herbal preparations containing St John’s wort (Hypericum perforatum).

Mydriasis
Mydriasis has been reported in association with duloxetine, therefore, caution should be used when prescribing duloxetine in patients with increased intraocular pressure, or those at risk of acute narrow- angle glaucoma.

Blood pressure and heart rate
Duloxetine has been associated with an increase in blood pressure and clinically significant hypertension in some patients. This may be due to the noradrenergic effect of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, especially in patients with pre-existing hypertension. Therefore, in patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended, especially during the first month of treatment. Duloxetine should be used with caution in patients whose conditions could be compromised by an increased heart rate or by an increase in blood pressure. Caution should also be exercised when duloxetine is used with medicinal products that may impair its metabolism (see section 4.5). For patients who experience a sustained increase in blood pressure while receiving duloxetine either dose reduction or gradual discontinuation should be considered (see section 4.8). In patients with uncontrolled hypertension duloxetine should not be initiated (see section 4.3).

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

Haemorrhage
There have been reports of bleeding abnormalities, such as ecchymoses, purpura and gastrointestinal haemorrhage with selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs), including duloxetine. Duloxetine may increase the risk of postpartum haemorrhage (see section 4.6). Caution is advised in patients taking anticoagulants and/or medicinal

products known to affect platelet function (e.g. NSAIDs or acetylsalicylic acid (ASA)), and in patients with known bleeding tendencies.

Discontinuation of treatment
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In a clinical trial, adverse events seen on abrupt treatment discontinuation occurred in approximately 44% of patients treated with YENTREVE and 24% of patients taking placebo.

The risk of withdrawal symptoms seen with SSRI’s and SNRI’s may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. The most commonly reported reactions are listed in section 4.8. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that duloxetine should be gradually tapered when discontinuing treatment over a period of no less than 2 weeks, according to the patient’s needs (see section 4.2).

Hyponatraemia
Hyponatraemia has been reported when administering YENTREVE, including cases with serum sodium lower than 110 mmol/l. Hyponatraemia may be due to a syndrome of inappropriate anti- diuretic hormone secretion (SIADH). The majority of cases of hyponatraemia were reported in the elderly, especially when coupled with a recent history of, or condition pre-disposing to, altered fluid balance. Caution is required in patients at increased risk for hyponatraemia, such as elderly, cirrhotic, or dehydrated patients or patients treated with diuretics.

Depression, suicidal ideation and behaviour
Although YENTREVE is not indicated for the treatment of depression, its active ingredient (duloxetine) also exists as an antidepressant medicinal product. Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal thoughts prior to commencement of treatment are known to be at a greater risk of suicidal thoughts or suicidal behaviour, and should receive careful monitoring during treatment. A meta-analysis of placebo- controlled clinical trials of antidepressant medicinal products in psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Cases of suicidal thoughts and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation (see section 4.8). Physicians should encourage patients to report any distressing thoughts or feelings or depressive symptoms at any time. If while on YENTREVE therapy, the patient develops agitation or depressive symptoms, specialised medical advice should be sought, as depression is a serious medical condition. If a decision to initiate antidepressant pharmacological therapy is taken, the gradual discontinuation of YENTREVE is recommended (see section 4.2).

Use in children and adolescents under 18 years of age
YENTREVE should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempts and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger), were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in

children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Medicinal products containing duloxetine
Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic pain, major depressive disorder, generalised anxiety disorder and stress urinary incontinence). The use of more than one of these products concomitantly should be avoided.

Hepatitis/increased liver enzymes
Cases of liver injury, including severe elevations of liver enzymes (>10 times upper limit of normal), hepatitis and jaundice have been reported with duloxetine (see section 4.8). Most of them occurred during the first months of treatment. The pattern of liver damage was predominantly hepatocellular.
Duloxetine should be used with caution in patients treated with other medicinal products associated with hepatic injury.

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

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-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRIs.

Sucrose
YENTREVE hard gastro-resistant capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Sodium
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 not be used in combination with non-selective irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping YENTREVE before starting an MAOI (see section 4.3).

The concomitant use of YENTREVE with selective, reversible MAOIs, like moclobemide, is not recommended (see section 4.4). The antibiotic linezolid is a reversible non-selective MAOI and should not be given to patients treated with YENTREVE (see section 4.4).

Inhibitors of CYP1A2: Because CYP1A2 is involved in duloxetine metabolism, concomitant use of YENTREVE with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine. Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77% and increased AUC0-t 6-fold. Therefore YENTREVE should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (see section 4.3).

CNS medicinal products: Caution is advised when YENTREVE is taken in combination with other centrally acting medicinal products or substances, including alcohol and sedative medicinal products (e.g. benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

Serotonergic agents: In rare cases, serotonin syndrome has been reported in patients using SSRIs/SNRIs concomitantly with serotonergic agents. Caution is advisable if YENTREVE is used concomitantly with serotonergic agents like SSRIs, SNRIs, tricyclic antidepressants like clomipramine or amitriptyline, MAOIs like moclobemide or linezolid, St John’s wort (Hypericum perforatum) or triptans, 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 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of duloxetine (40 mg twice daily) increases steady state AUC of tolterodine (2 mg twice daily) by 71 %, but does not affect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment is recommended. Caution is advised if YENTREVE is co-administered with medicinal products that are predominantly metabolised by CYP2D6 (risperidone, tricyclic antidepressants [TCAs] such as nortriptyline, amitriptyline, and imipramine) particularly if they have a narrow therapeutic index (such as flecainide, propafenone and metoprolol).

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

Anticoagulants and antiplatelet agents: Caution should be exercised when duloxetine is combined with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction. Furthermore, increases in INR values have been reported when duloxetine was co-administered to patients treated with warfarin. However, concomitant administration of duloxetine with warfarin under steady state conditions, in healthy volunteers, as part of a clinical pharmacology study, did not result in a clinically significant change in INR from baseline or in the pharmacokinetics of R- or S-warfarin.

Effects of other medicinal products on duloxetine
Antacids and H2 antagonists: Co-administration of YENTREVE with aluminium- and magnesium- containing antacids or with famotidine had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose.

Inducers of CYP1A2: Population pharmacokinetic studies analyses have shown that smokers have almost 50% lower plasma concentrations of duloxetine compared with non-smokers.

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

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

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

In the EU study, maternal exposure to duloxetine during late pregnancy (at any time from 20 weeks gestational 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 duloxetine late in pregnancy). The majority occurred between 35 and 36 weeks of gestation. This association was not seen in the US study.

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

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN).
Although no studies have investigated the association of PPHN to SNRI treatment, this potential risk cannot be ruled out with duloxetine taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).

As with other serotonergic medicinal products, discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. Discontinuation symptoms seen with duloxetine may include hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures. The majority of cases have occurred either at birth or within a few days of birth.

YENTREVE should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. Women should be advised to notify their physician if they become pregnant, or intend to become pregnant, during therapy.

Breast feeding
Duloxetine is very weakly excreted into human milk based on a study of 6 lactating patients, who did not breast feed their children. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose (see section 5.2). As the safety of duloxetine in infants is not known, the use of YENTREVE while breast-feeding is not recommended.

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

Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of 5400 mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or in combination with other medicinal products) included somnolence, coma, serotonin syndrome, seizures, vomiting and tachycardia.

No specific antidote is known for duloxetine but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. A free airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption.
Duloxetine has a large volume of distribution and forced diuresis, haemoperfusion, and exchange perfusion are unlikely to be beneficial.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other antidepressants. ATC code: N06AX21.

Mechanism of action
Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors.

Pharmacodynamic effects
In animal studies, increased levels of 5-HT and NE in the sacral spinal cord, lead to increased urethral tone via enhanced pudendal nerve stimulation to the urethral striated sphincter muscle only during the storage phase of the micturition cycle. A similar mechanism in women is believed to result in stronger urethral closure during urine storage with physical stress that could explain the efficacy of duloxetine in the treatment of women with SUI.

Clinical efficacy and safety
The efficacy of duloxetine 40 mg given twice daily in the treatment of SUI was established in four double-blind, placebo-controlled studies that randomised 1913 women (22 to 83 years) with SUI; of these, 958 patients were randomised to duloxetine and 955 to placebo. The primary efficacy measures were Incontinence Episode Frequency (IEF) from diaries and an incontinence specific quality of life questionnaire score (I-QOL).

Incontinence Episode Frequency: In all four studies the duloxetine-treated group had a 50% or greater median decrease in IEF compared with 33% in the placebo-treated group. Differences were observed at each visit after 4 weeks (duloxetine 54% and placebo 22%), 8 weeks (52% and 29%), and 12 weeks (52% and 33%) of medication.

In an additional study limited to patients with severe SUI, all responses with duloxetine were achieved within 2 weeks.

The efficacy of YENTREVE has not been evaluated for longer than 3 months in placebo-controlled studies. The clinical benefit of YENTREVE compared with placebo has not been demonstrated in women with mild SUI, defined in randomised trials as those with IEF < 14 per week. In these women, YENTREVE may provide no benefit beyond that afforded by more conservative behavioural interventions.

Quality of Life: Incontinence Quality of Life (I-QOL) questionnaire scores were significantly improved in the duloxetine-treated patient group compared with the placebo-treated group (9.2 versus 5.9 score improvement, p<0.001). Using a global improvement scale (PGI), significantly more women using duloxetine considered their symptoms of stress incontinence to be improved with treatment compared with women using placebo (64.6% versus 50.1%, p<0.001).

YENTREVE and Prior Continence Surgery: There are limited data that suggest that the benefits of YENTREVE are not diminished in women with stress urinary incontinence who have previously undergone continence surgery.

Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolised by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of 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 post dose. The absolute oral bioavailability of duloxetine ranged from 32% to 80% (mean of 50%). Food delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11 %). These changes do not have any clinical significance.

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

Biotransformation: Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. Both cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites glucuronide conjugate of 4-hydroxy duloxetine and sulfate conjugate of 5-hydroxy 6-methoxy duloxetine. Based upon in vitro studies, the circulating metabolites of duloxetine are considered pharmacologically inactive. 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 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 of 36 l/hr). After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/hr (mean 101 l/hr).

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