- Approval Id
- d57bbf3f4ba236b6
- Drug Approval Emc Name
- Duloxetine 60 mg gastro resistant capsules
- Drug Name
- Duloxetine 60 mg gastro resistant capsules
- Company Address
- First Floor, Andrews House, College Road, Guildford, Surrey, GU1 4QB, UK
- Company Website
- https://www.zentiva.co.uk/contact/mi-form
- Company Medical Info Direct Line
- +44 (0)800 090 2408
- Company Medical Info Email
- [email protected]
- Company Customer Care Direct Line
- +44 (0)844 8793 188
- Atc Code
- N06AX21
- Legal Category
- Prescription only medicine
- Authorisation Holder
- 7. Marketing authorisation holder Zentiva Pharma UK Limited, 12 New Fetter Lane, London, EC4A 1JP, UK
- Authorisation Number
- 8. Marketing authorisation number(s) PLGB 17780/1048
- Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation 01/01/2021
- Instruction Authorisation Holder
- 7. Marketing authorisation holder Zentiva Pharma UK Limited, 12 New Fetter Lane, London, EC4A 1JP, UK
- Instruction Authorisation Number
- 8. Marketing authorisation number(s) PLGB 17780/1048
- Instruction Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation 01/01/2021
- Instruction Composition
- 2. Qualitative and quantitative composition Each capsule contains duloxetine hydrochloride equivalent to 60 mg duloxetine. Excipient(s) with known effect Each capsule contains 84.51 - 9
- Instruction Dosage Form
- 3. Pharmaceutical form Gastro-resistant hard capsule Hard opaque gelatin capsules of length approx. 19.4 mm with ivory opaque body and light-blue opaque cap which contain off-white to light-brown-yellow spherical pellets.
- Instruction Clinical Particulars
- 4. Clinical particulars 4.1 Therapeutic indications • Treatment of major depressive disorder. • Treatment of diabetic peripheral neuropathic pain. • Treatment of generalised anxiety disorder. Duloxetine Zentiva is indicated in adults. For further information see section
- Instruction Pharmacology
- 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other antidepressants, ATC code: N06AX21 Mechanism of action Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin and noradrenaline in various brain areas of animals. Pharmacodynamic effects Duloxetine normalised pain thresholds in several preclinical models of neuropathic and inflammatory pain and attenuated pain behaviour in a model of persistent pain. The pain inhibitory action of duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the central nervous system. Clinical efficacy and safety Major Depressive Disorder Duloxetine 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 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'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 demonstrated statistical superiority over placebo as measured by improvement in the 17item 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 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 60 mg once daily were randomised to either duloxetine 60 mg once daily or placebo for a further 6-months. Duloxetine 60 mg once daily demonstrated a statistically significant superiority compared to placebo (p=0.004) on the primary outcome measure, the prevention of depressive relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow-up period was 17% and 29% for duloxetine and placebo, respectively. During 52 weeks of placebo-controlled double blind treatment, duloxetine-treated patients with recurrent MDD had a significantly longer symptom free period (p < 0.001) compared with patients randomised to placebo. All patients had previously responded to duloxetine during open-label duloxetine treatment (28 to 34 weeks) at a dose of 60 to 120 mg/day. During the 52-week placebo-controlled double blind treatment phase 14.4% of the duloxetine-treated patients and 33.1% of the placebo-treated patients experience a return of their depressive symptoms (p < 0.001). The effect of duloxetine 60 mg once a day in elderly depressed patients (≥ 65 years) was specifically examined in a study that showed a statistically significant difference in the reduction of the HAMD17 score for duloxetine-treated patients compared to placebo. Tolerability of duloxetine 60 mg once daily in elderly patients was comparable to that seen in the younger adults. However, data on elderly patients exposed to the maximum dose (120 mg per day) are limited and thus, caution is recommended when treating this population. Generalised Anxiety Disorder Duloxetine demonstrated statistically significant superiority over placebo in five out of five studies including four randomised, double-blind, placebo-controlled acute studies and a relapse prevention study in adult patients with generalised anxiety disorder. Duloxetine demonstrated statistically significant superiority over placebo as measured by improvement in the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability Scale (SDS) global functional impairment score. Response and remission rates were also higher with duloxetine compared to placebo. Duloxetine showed comparable efficacy results to venlafaxine in terms of improvements on the HAM-A total score. In a relapse prevention study, patients responding to 6 months of acute treatment with open-label duloxetine were randomised to either duloxetine or placebo for a further 6-months. Duloxetine 60 mg to 120 mg once daily demonstrated statistically significant superiority compared to placebo (p < 0.001) on the prevention of relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow-up period was 14% for duloxetine and 42% for placebo. The efficacy of duloxetine 30-120 mg (flexible dosing) once a day in elderly patients (>65 years) with generalised anxiety disorder was evaluated in a study that demonstrated statistically significant improvement in the HAM-A total score for duloxetine treated patients compared to placebo treated patients. The efficacy and safety of duloxetine 30-120 mg once daily in elderly patients with generalised anxiety disorder was similar to that seen in studies of younger adult patients. However, data on elderly patients exposed to the maximum dose (120 mg per day) are limited and, thus, caution is recommended when using this dose with the elderly population. Diabetic Peripheral Neuropathic Pain The efficacy of duloxetine as a treatment for diabetic neuropathic pain was established in 2 randomised, 12-week, double-blind, placebo-controlled, fixed dose studies in adults (22 to 88 years) having diabetic neuropathic pain for at least 6 months. Patients meeting diagnostic criteria for major depressive disorder were excluded from these trials. The primary outcome measure was the weekly mean of 24-hour average pain, which was collected in a daily diary by patients on an 11-point Likert scale. In both studies, duloxetine 60 mg once daily and 60 mg twice daily significantly reduced pain compared with placebo. The effect in some patients was apparent in the first week of treatment. The difference in mean improvement between the two active treatment arms was not significant. At least 30% reported pain reduction was recorded in approximately 65% of duloxetine treated patients versus 40% for placebo. The corresponding figures for at least 50% pain reduction were 50% and 26% respectively. Clinical response rates (50% or greater improvement in pain) were analysed according to whether or not the patient experienced somnolence during treatment. For patients not experiencing somnolence, clinical response was observed in 47% of patients receiving duloxetine and 27% of patients on placebo. Clinical response rates in patients experiencing somnolence were 60% on duloxetine and 30% on placebo. Patients not demonstrating a pain reduction of 30% within 60 days of treatment were unlikely to reach this level during further treatment. In an open label long-term uncontrolled study, the pain reduction in patients responding to 8-weeks of acute treatment of duloxetine 60 mg once daily was maintained for a further 6-months as measured by change on the Brief Pain Inventory (BPI) 24-hour average pain item. Paediatric population Duloxetine has not been studied in patients under the age of 7. Two randomized, double-blind, parallel clinical trials were performed in 800 paediatric patients aged 7 to 17 years with major depressive disorder (see section 4.2). These two studies included a 10 week placebo and active (fluoxetine) controlled acute phase followed by six months period of active controlled extension treatment. Neither duloxetine (30-120 mg) nor the active control arm (fluoxetine 20-40 mg) statistically separated from placebo on change from baseline to endpoint in the Children´s Depression Rating Scale-Revised (CDRS-R) total score. Discontinuation due to adverse events was higher in patients taking duloxetine compared with those treated with fluoxetine, mostly due to nausea. During the 10-week acute treatment period, suicidal behaviours were reported (duloxetine 0/333 [0%], fluoxetine 2/225 [0.9%], placebo 1/220 [0.5%]). Over the entire 36-week course of the study, 6 out of 333 patients initially randomized to duloxetine and 3 out of 225 patients initially randomized to fluoxetine experienced suicidal behaviour (exposure adjusted incidence 0.039 events per patient year for duloxetine, and 0.026 for fluoxetine). In addition, one patient who transitioned from placebo to duloxetine experienced a suicidal behaviour while taking duloxetine. A randomised, double-blind, placebo-controlled study was performed in 272 patients aged 7-17 years with generalised anxiety disorder. The study included a 10 week placebo-controlled acute phase, followed by an 18 week extension treatment period. A flexible dose regimen was used in this study, to allow for slow dose escalation from 30 mg once daily to higher doses (maximum 120 mg once daily). Treatment with duloxetine showed a statistically significantly greater improvement in GAD symptoms, as measured by PARS severity score for GAD (mean difference between duloxetine and placebo of 2.7 points [95% CI 1.3-4.0]), after 10 weeks of treatment. The maintenance of the effect has not been evaluated. There was no statistically significant difference in discontinuation due to adverse events between duloxetine and placebo groups during the 10 week acute treatment phase. Two patients who transitioned from placebo to duloxetine after the acute phase experienced suicidal behaviours while taking duloxetine during the extension phase. A conclusion on the overall benefit/risk in this age group has not been established (see also sections 4.2 and 4.8). A single study has been performed in paediatric patients with juvenile primary fibromyalgia syndrome (JPFS) in which the duloxetine-treated group did not separate from placebo group for the primary efficacy measure. Therefore, there is no evidence of efficacy in this paediatric patient population. The randomised, double-blind, placebo-controlled, parallel study of duloxetine was conducted in 184 adolescents aged 13 to 18 years (mean age 15.53 years) with JPFS. The study included a 13- week double-blind period where patients were randomised to duloxetine 30 mg/60 mg, or placebo daily. Duloxetine did not show efficacy in reducing pain as measured by primary outcome measure of Brief Pain Inventory (BPI) average pain score endpoint: least squares (LS) mean change from baseline in BPI average pain score at 13 weeks was -0.97 in the placebo group, compared with -1.62 in the duloxetine 30/60 mg group (p = 0.052). The safety results from this study were consistent with the known safety profile of duloxetine. The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing duloxetine in all subsets of the paediatric population in the treatment of major depressive disorder, diabetic neuropathic pain and generalised anxiety disorder. See section 4.2 for information on paediatric use. 5.2 Pharmacokinetic properties 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 sulphate 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 h). After an intravenous dose the plasma clearance of duloxetine ranges from 22 l/h to 46 l/h (mean of 36 l/h). After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/h (mean 101 l/h). Special populations Gender Pharmacokinetic differences have been identified between males and females (apparent plasma clearance is approximately 50% lower in females). Based upon the overlap in the range of clearance, gender-based pharmacokinetic differences do not justify the recommendation for using a lower dose for female patients. Age Pharmacokinetic differences have been identified between younger and elderly females (≥ 65 years) (AUC increases by about 25% and half-life is about 25% longer in the elderly), although the magnitude of these changes is not sufficient to justify adjustments to the dose. As a general recommendation, caution should be exercised when treating the elderly (see sections 4.2 and 4.4). Renal impairment End stage renal disease (ESRD) patients receiving dialysis had 2-fold higher duloxetine Cmax and AUC values compared with healthy subjects. Pharmacokinetic data on duloxetine is limited in patients with mild or moderate renal impairment. Hepatic impairment Moderate liver disease (Child Pugh Class B) affected the pharmacokinetics of duloxetine. Compared with healthy subjects, the apparent plasma clearance of duloxetine was 79% lower, the apparent terminal half-life was 2.3 times longer, and the AUC was 3.7 times higher in patients with moderate liver disease. The pharmacokinetics of duloxetine and its metabolites have not been studied in patients with mild or severe hepatic insufficiency. Breast-feeding mothers The disposition of duloxetine was studied in 6 lactating women who were at least 12-weeks postpartum. Duloxetine is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 μg/day while on 40 mg twice daily dosing. Lactation did not influence duloxetine pharmacokinetics. Paediatric population Pharmacokinetics of duloxetine in paediatric patients aged 7 to 17 years with major depressive disorder following oral administration of 20 to 120 mg once daily dosing regimen was characterized using population modelling analyses based on data from 3 studies. The model-predicted duloxetine steady state plasma concentrations in paediatric patients were mostly within the concentration range observed in adult patients. 5.3 Preclinical safety data Duloxetine was not genotoxic in a standard battery of tests and was not carcinogenic in rats. Multinucleated cells were seen in the liver in the absence of other histopathological changes in the rat carcinogenicity study. The underlying mechanism and the clinical relevance are unknown. Female mice receiving duloxetine for 2 years had an increased incidence of hepatocellular adenomas and carcinomas at the high dose only (144 mg/kg/day), but these were considered to be secondary to hepatic microsomal enzyme induction. The relevance of this mouse data to humans is unknown. Female rats receiving duloxetine (45 mg/kg/day) before and during mating and early pregnancy had a decrease in maternal food consumption and body weight, oestrous cycle disruption, decreased live birth indices and progeny survival, and progeny growth retardation at systemic exposure levels estimated to be at the most at maximum clinical exposure (AUC). In an embryotoxicity study in the rabbit, a higher incidence of cardiovascular and skeletal malformations was observed at systemic exposure levels below the maximum clinical exposure (AUC). No malformations were observed in another study testing a higher dose of a different salt of duloxetine. In prenatal/postnatal toxicity studies in the rat, duloxetine induced adverse behavioural effects in the offspring at exposures below maximum clinical exposure (AUC). Studies in juvenile rats reveal transient effects on neurobehaviour, as well as significantly decreased body weight and food consumption; hepatic enzyme induction; and hepatocellular vacuolation at 45 mg/kg/day. The general toxicity profile of duloxetine in juvenile rats was similar to that in adult rats. The no-adverse effect level was determined to be 20 mg/kg/day.
- Instruction Pharmaceutical Particulars
- 6. Pharmaceutical particulars 6.1 List of excipients Capsule content Sucrose Maize starch Hypromellose Talc Hypromellose acetate succinate Triethyl citrate Capsule shell Capsule cap - Indigo carmine (E132) - Titanium dioxide (E171) - Gelatin Capsule body - Yellow iron oxide (E172) - Titanium dioxide (E171) - Gelatin 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage Store below 30 °C. Store in the original package in order to protect from moisture. 6.5 Nature and contents of container Opaque PVC/PCTFE/Alu blisters or transparent PVC/PVDC/Alu blisters. Pack size: 14, 28, 56, 84 and 98 capsules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements.
- Instruction Content
- ## Composition
2. Qualitative and quantitative composition Each capsule contains duloxetine hydrochloride equivalent to 60 mg duloxetine. Excipient(s) with known effect Each capsule contains 84.51 - 9
## Pharmaceutical Form
3. Pharmaceutical form Gastro-resistant hard capsule Hard opaque gelatin capsules of length approx. 19.4 mm with ivory opaque body and light-blue opaque cap which contain off-white to light-brown-yellow spherical pellets.
## Clinical Particulars
4. Clinical particulars 4.1 Therapeutic indications • Treatment of major depressive disorder. • Treatment of diabetic peripheral neuropathic pain. • Treatment of generalised anxiety disorder. Duloxetine Zentiva is indicated in adults. For further information see section
## Pharmacological Properties
5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other antidepressants, ATC code: N06AX21 Mechanism of action Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin and noradrenaline in various brain areas of animals. Pharmacodynamic effects Duloxetine normalised pain thresholds in several preclinical models of neuropathic and inflammatory pain and attenuated pain behaviour in a model of persistent pain. The pain inhibitory action of duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the central nervous system. Clinical efficacy and safety Major Depressive Disorder Duloxetine 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 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'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 demonstrated statistical superiority over placebo as measured by improvement in the 17item 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 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 60 mg once daily were randomised to either duloxetine 60 mg once daily or placebo for a further 6-months. Duloxetine 60 mg once daily demonstrated a statistically significant superiority compared to placebo (p=0.004) on the primary outcome measure, the prevention of depressive relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow-up period was 17% and 29% for duloxetine and placebo, respectively. During 52 weeks of placebo-controlled double blind treatment, duloxetine-treated patients with recurrent MDD had a significantly longer symptom free period (p < 0.001) compared with patients randomised to placebo. All patients had previously responded to duloxetine during open-label duloxetine treatment (28 to 34 weeks) at a dose of 60 to 120 mg/day. During the 52-week placebo-controlled double blind treatment phase 14.4% of the duloxetine-treated patients and 33.1% of the placebo-treated patients experience a return of their depressive symptoms (p < 0.001). The effect of duloxetine 60 mg once a day in elderly depressed patients (≥ 65 years) was specifically examined in a study that showed a statistically significant difference in the reduction of the HAMD17 score for duloxetine-treated patients compared to placebo. Tolerability of duloxetine 60 mg once daily in elderly patients was comparable to that seen in the younger adults. However, data on elderly patients exposed to the maximum dose (120 mg per day) are limited and thus, caution is recommended when treating this population. Generalised Anxiety Disorder Duloxetine demonstrated statistically significant superiority over placebo in five out of five studies including four randomised, double-blind, placebo-controlled acute studies and a relapse prevention study in adult patients with generalised anxiety disorder. Duloxetine demonstrated statistically significant superiority over placebo as measured by improvement in the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability Scale (SDS) global functional impairment score. Response and remission rates were also higher with duloxetine compared to placebo. Duloxetine showed comparable efficacy results to venlafaxine in terms of improvements on the HAM-A total score. In a relapse prevention study, patients responding to 6 months of acute treatment with open-label duloxetine were randomised to either duloxetine or placebo for a further 6-months. Duloxetine 60 mg to 120 mg once daily demonstrated statistically significant superiority compared to placebo (p < 0.001) on the prevention of relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow-up period was 14% for duloxetine and 42% for placebo. The efficacy of duloxetine 30-120 mg (flexible dosing) once a day in elderly patients (>65 years) with generalised anxiety disorder was evaluated in a study that demonstrated statistically significant improvement in the HAM-A total score for duloxetine treated patients compared to placebo treated patients. The efficacy and safety of duloxetine 30-120 mg once daily in elderly patients with generalised anxiety disorder was similar to that seen in studies of younger adult patients. However, data on elderly patients exposed to the maximum dose (120 mg per day) are limited and, thus, caution is recommended when using this dose with the elderly population. Diabetic Peripheral Neuropathic Pain The efficacy of duloxetine as a treatment for diabetic neuropathic pain was established in 2 randomised, 12-week, double-blind, placebo-controlled, fixed dose studies in adults (22 to 88 years) having diabetic neuropathic pain for at least 6 months. Patients meeting diagnostic criteria for major depressive disorder were excluded from these trials. The primary outcome measure was the weekly mean of 24-hour average pain, which was collected in a daily diary by patients on an 11-point Likert scale. In both studies, duloxetine 60 mg once daily and 60 mg twice daily significantly reduced pain compared with placebo. The effect in some patients was apparent in the first week of treatment. The difference in mean improvement between the two active treatment arms was not significant. At least 30% reported pain reduction was recorded in approximately 65% of duloxetine treated patients versus 40% for placebo. The corresponding figures for at least 50% pain reduction were 50% and 26% respectively. Clinical response rates (50% or greater improvement in pain) were analysed according to whether or not the patient experienced somnolence during treatment. For patients not experiencing somnolence, clinical response was observed in 47% of patients receiving duloxetine and 27% of patients on placebo. Clinical response rates in patients experiencing somnolence were 60% on duloxetine and 30% on placebo. Patients not demonstrating a pain reduction of 30% within 60 days of treatment were unlikely to reach this level during further treatment. In an open label long-term uncontrolled study, the pain reduction in patients responding to 8-weeks of acute treatment of duloxetine 60 mg once daily was maintained for a further 6-months as measured by change on the Brief Pain Inventory (BPI) 24-hour average pain item. Paediatric population Duloxetine has not been studied in patients under the age of 7. Two randomized, double-blind, parallel clinical trials were performed in 800 paediatric patients aged 7 to 17 years with major depressive disorder (see section 4.2). These two studies included a 10 week placebo and active (fluoxetine) controlled acute phase followed by six months period of active controlled extension treatment. Neither duloxetine (30-120 mg) nor the active control arm (fluoxetine 20-40 mg) statistically separated from placebo on change from baseline to endpoint in the Children´s Depression Rating Scale-Revised (CDRS-R) total score. Discontinuation due to adverse events was higher in patients taking duloxetine compared with those treated with fluoxetine, mostly due to nausea. During the 10-week acute treatment period, suicidal behaviours were reported (duloxetine 0/333 [0%], fluoxetine 2/225 [0.9%], placebo 1/220 [0.5%]). Over the entire 36-week course of the study, 6 out of 333 patients initially randomized to duloxetine and 3 out of 225 patients initially randomized to fluoxetine experienced suicidal behaviour (exposure adjusted incidence 0.039 events per patient year for duloxetine, and 0.026 for fluoxetine). In addition, one patient who transitioned from placebo to duloxetine experienced a suicidal behaviour while taking duloxetine. A randomised, double-blind, placebo-controlled study was performed in 272 patients aged 7-17 years with generalised anxiety disorder. The study included a 10 week placebo-controlled acute phase, followed by an 18 week extension treatment period. A flexible dose regimen was used in this study, to allow for slow dose escalation from 30 mg once daily to higher doses (maximum 120 mg once daily). Treatment with duloxetine showed a statistically significantly greater improvement in GAD symptoms, as measured by PARS severity score for GAD (mean difference between duloxetine and placebo of 2.7 points [95% CI 1.3-4.0]), after 10 weeks of treatment. The maintenance of the effect has not been evaluated. There was no statistically significant difference in discontinuation due to adverse events between duloxetine and placebo groups during the 10 week acute treatment phase. Two patients who transitioned from placebo to duloxetine after the acute phase experienced suicidal behaviours while taking duloxetine during the extension phase. A conclusion on the overall benefit/risk in this age group has not been established (see also sections 4.2 and 4.8). A single study has been performed in paediatric patients with juvenile primary fibromyalgia syndrome (JPFS) in which the duloxetine-treated group did not separate from placebo group for the primary efficacy measure. Therefore, there is no evidence of efficacy in this paediatric patient population. The randomised, double-blind, placebo-controlled, parallel study of duloxetine was conducted in 184 adolescents aged 13 to 18 years (mean age 15.53 years) with JPFS. The study included a 13- week double-blind period where patients were randomised to duloxetine 30 mg/60 mg, or placebo daily. Duloxetine did not show efficacy in reducing pain as measured by primary outcome measure of Brief Pain Inventory (BPI) average pain score endpoint: least squares (LS) mean change from baseline in BPI average pain score at 13 weeks was -0.97 in the placebo group, compared with -1.62 in the duloxetine 30/60 mg group (p = 0.052). The safety results from this study were consistent with the known safety profile of duloxetine. The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing duloxetine in all subsets of the paediatric population in the treatment of major depressive disorder, diabetic neuropathic pain and generalised anxiety disorder. See section 4.2 for information on paediatric use. 5.2 Pharmacokinetic properties 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 sulphate 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 h). After an intravenous dose the plasma clearance of duloxetine ranges from 22 l/h to 46 l/h (mean of 36 l/h). After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/h (mean 101 l/h). Special populations Gender Pharmacokinetic differences have been identified between males and females (apparent plasma clearance is approximately 50% lower in females). Based upon the overlap in the range of clearance, gender-based pharmacokinetic differences do not justify the recommendation for using a lower dose for female patients. Age Pharmacokinetic differences have been identified between younger and elderly females (≥ 65 years) (AUC increases by about 25% and half-life is about 25% longer in the elderly), although the magnitude of these changes is not sufficient to justify adjustments to the dose. As a general recommendation, caution should be exercised when treating the elderly (see sections 4.2 and 4.4). Renal impairment End stage renal disease (ESRD) patients receiving dialysis had 2-fold higher duloxetine Cmax and AUC values compared with healthy subjects. Pharmacokinetic data on duloxetine is limited in patients with mild or moderate renal impairment. Hepatic impairment Moderate liver disease (Child Pugh Class B) affected the pharmacokinetics of duloxetine. Compared with healthy subjects, the apparent plasma clearance of duloxetine was 79% lower, the apparent terminal half-life was 2.3 times longer, and the AUC was 3.7 times higher in patients with moderate liver disease. The pharmacokinetics of duloxetine and its metabolites have not been studied in patients with mild or severe hepatic insufficiency. Breast-feeding mothers The disposition of duloxetine was studied in 6 lactating women who were at least 12-weeks postpartum. Duloxetine is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 μg/day while on 40 mg twice daily dosing. Lactation did not influence duloxetine pharmacokinetics. Paediatric population Pharmacokinetics of duloxetine in paediatric patients aged 7 to 17 years with major depressive disorder following oral administration of 20 to 120 mg once daily dosing regimen was characterized using population modelling analyses based on data from 3 studies. The model-predicted duloxetine steady state plasma concentrations in paediatric patients were mostly within the concentration range observed in adult patients. 5.3 Preclinical safety data Duloxetine was not genotoxic in a standard battery of tests and was not carcinogenic in rats. Multinucleated cells were seen in the liver in the absence of other histopathological changes in the rat carcinogenicity study. The underlying mechanism and the clinical relevance are unknown. Female mice receiving duloxetine for 2 years had an increased incidence of hepatocellular adenomas and carcinomas at the high dose only (144 mg/kg/day), but these were considered to be secondary to hepatic microsomal enzyme induction. The relevance of this mouse data to humans is unknown. Female rats receiving duloxetine (45 mg/kg/day) before and during mating and early pregnancy had a decrease in maternal food consumption and body weight, oestrous cycle disruption, decreased live birth indices and progeny survival, and progeny growth retardation at systemic exposure levels estimated to be at the most at maximum clinical exposure (AUC). In an embryotoxicity study in the rabbit, a higher incidence of cardiovascular and skeletal malformations was observed at systemic exposure levels below the maximum clinical exposure (AUC). No malformations were observed in another study testing a higher dose of a different salt of duloxetine. In prenatal/postnatal toxicity studies in the rat, duloxetine induced adverse behavioural effects in the offspring at exposures below maximum clinical exposure (AUC). Studies in juvenile rats reveal transient effects on neurobehaviour, as well as significantly decreased body weight and food consumption; hepatic enzyme induction; and hepatocellular vacuolation at 45 mg/kg/day. The general toxicity profile of duloxetine in juvenile rats was similar to that in adult rats. The no-adverse effect level was determined to be 20 mg/kg/day.
## Pharmaceutical Particulars
6. Pharmaceutical particulars 6.1 List of excipients Capsule content Sucrose Maize starch Hypromellose Talc Hypromellose acetate succinate Triethyl citrate Capsule shell Capsule cap - Indigo carmine (E132) - Titanium dioxide (E171) - Gelatin Capsule body - Yellow iron oxide (E172) - Titanium dioxide (E171) - Gelatin 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage Store below 30 °C. Store in the original package in order to protect from moisture. 6.5 Nature and contents of container Opaque PVC/PCTFE/Alu blisters or transparent PVC/PVDC/Alu blisters. Pack size: 14, 28, 56, 84 and 98 capsules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements.
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