APO- DULOXETINE ENTERIC CAPSULES. (+)-(S)-N-methyl-γ-(1-naphthalenyloxy)-2-thiophenepropylamine hydrochloride - PDF

APO- DULOXETINE ENTERIC CAPSULES NAME OF THE MEDICINE Duloxetine hydrochloride Chemical Name: (+)-(S)-N-methyl-γ-(1-naphthalenyloxy)-2-thiophenepropylamine hydrochloride Structural Formula: Molecular Formula:

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APO- DULOXETINE ENTERIC CAPSULES NAME OF THE MEDICINE Duloxetine hydrochloride Chemical Name: (+)-(S)-N-methyl-γ-(1-naphthalenyloxy)-2-thiophenepropylamine hydrochloride Structural Formula: Molecular Formula: C 18 H 19 NOS HCl Molecular Weight: CAS Registry Number: DESCRIPTION Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water. Each capsule contains enteric-coated pellets of duloxetine hydrochloride, equivalent to 30 mg or 60 mg duloxetine, that are designed to prevent degradation of the drug in the acidic environment of the stomach. In addition, each capsule contains Sugar Spheres (ARTG ID 2535), hypromellose, purified talc, purified water, sucrose, hypromellose phthalate, triethyl citrate, gelatin, titanium dioxide, brilliant blue FCF, iron oxide yellow (60 mg capsule only), Tekprint SB-4020 Green Ink (ARTG ID 2652; 30 mg capsule only) and TekPrint SW-0012 White Ink (ARTG ID 13175; 60 mg capsule only). PHARMACOLOGY Pharmacological Actions Duloxetine is a selective serotonin and noradrenaline reuptake inhibitor, and weakly inhibits dopamine uptake with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors. Although the mechanism of the antidepressant action of duloxetine in humans is unknown, it is believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Duloxetine dose-dependently increased extracellular levels of serotonin and noradrenaline in selected brain areas of animals, and neurochemical and behavioural studies in animals indicate an enhancement of central serotonin and noradrenaline neurotransmission. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine. Duloxetine displayed analgesic activity in rodent models of persistent, inflammatory pain, but not acute or arthritic pain. Pharmacokinetics In a study comparing this product with the reference product, the two products were shown to be bioequivalent under fasting and fed conditions. Under fasting conditions, the 90% confidence intervals for the ratio of AUC 0-t and C max were found to be between 93.28% and % and 90.02% and % respectively. Under fed conditions, the 90% confidence intervals for the ratio of AUC 0-t and C max were found to be between % and % and 86.81% and % respectively. APO- Duloxetine Enteric Capsules Page 1 Absorption In humans, orally administered duloxetine hydrochloride is well absorbed with maximal plasma concentrations (C max ) of duloxetine occurring 6 hours post dose. Food does not affect the C max of duloxetine, however food can delay the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 11%. Duloxetine plasma exposure increases in proportion to dose for doses up to 60 mg twice a day. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Based upon AUC, multiple once daily doses of 60 mg produce steady-state concentrations that are approximately 1.5 times higher than that predicted from a 60 mg single dose. Average minimum and maximum steadystate concentrations for the 60 mg once daily dose are 27.0 and 89.5 ng/ml, respectively. There is no clinically important difference in the pharmacokinetic parameters of morning and evening doses. Distribution Following oral administration, the apparent volume of distribution of duloxetine averages 1640 L. Duloxetine is highly protein bound ( 90%) to plasma proteins but protein binding is not affected by renal or hepatic impairment. Duloxetine binds to both albumin and α1-acid glycoprotein. Metabolism Duloxetine undergoes extensive metabolism. The 2 major metabolites found in plasma and urine are the glucuronide conjugate of 4-hydroxy duloxetine, and the sulfate conjugate of 5-hydroxy, 6-methoxy duloxetine. Both CYP2D6 and CYP1A2 catalyse the formation of the initial oxidation steps to form 4-, 5- and 6-hydroxy duloxetine. The metabolites circulating in plasma are in the conjugated form and are not pharmacologically active. Excretion The half-life of duloxetine (unchanged drug) is 12.1 hours. Apparent plasma clearance of duloxetine after an oral dose is 101 L/hr. The majority (70%) of the duloxetine dose is recovered in the urine as conjugated metabolites of oxidative metabolites of duloxetine. Approximately 20% of the dose is recovered in the faeces as unchanged drug, unconjugated metabolites, or unidentified compounds. Only trace ( 1% of the dose) amounts of unchanged duloxetine are present in the urine. Special Populations Gender Apparent plasma clearance was lower in females, however this difference in clearance values does not appear to be clinically significant. The mean half-life of duloxetine was similar between males and females. Dosage adjustment based on gender is not necessary. Elderly Population pharmacokinetic analyses suggest no significant effect of age on the pharmacokinetics of duloxetine in adult male and female patients with major depressive disorder. Dosage adjustment based on age is not necessary for elderly patients. Children and Adolescents 18 years old Duloxetine is not indicated for use in patients under 18 years of age. Race No specific pharmacokinetic study was conducted to investigate the effects of race. Due to large interpatient variability, clinically significant differences in drug level exposure among ethnic groups are not likely. Smoking Status Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. modifications are not recommended for smokers. Dosage Renal Impairment Duloxetine C max and AUC values were approximately 2-fold higher in patients with end stage renal disease (ESRD) receiving chronic intermittent dialysis, compared with subjects with normal renal function. In contrast, the elimination half-life was similar in both groups. A lower dose should be used for patients with ESRD (see DOSAGE AND ADMINISTRATION). Population pharmacokinetic APO- Duloxetine Enteric Capsules Page 2 analyses suggest that mild renal dysfunction has no significant effect on apparent plasma clearance of duloxetine. Hepatic Impairment Mean duloxetine apparent plasma clearance of patients with moderate cirrhosis of the liver was approximately 15% of that of healthy subjects. The C max was similar but the half-life was 34 hours longer. Duloxetine is contraindicated in patients with hepatic impairment (see CONTRAINDICATIONS). CLINICAL TRIALS Acute treatment of depression The efficacy of duloxetine has been evaluated in six double-blind, placebo-controlled acute Phase 3 studies of 8 9 weeks duration in 1978 adult outpatients (18 to 83 years) meeting the DSM-IV criteria for major depression at doses of 40 mg to 120 mg daily. In four of these studies, duloxetine was significantly superior to placebo as measured by the mean change in the 17 item Hamilton Depression Rating Scale (HAMD 17 ) total score from baseline to endpoint. Duloxetine doses in these four studies were: 60 mg once daily (two studies) 20 mg twice daily and 40 mg twice daily (one study) 40 mg twice daily and 60 mg twice daily (one study) In the remaining two studies duloxetine showed numerically superior mean change compared with placebo. The duloxetine doses in these two studies were: 20 mg twice daily and 40 mg twice daily 40 mg twice daily and 60 mg twice daily In both of these latter studies, the active comparator paroxetine also did not separate significantly from placebo on the primary outcome measure. Response ( 50% reduction in HAMD 17 total score) and remission (HAMD 17 total score 7) were also significantly higher with duloxetine compared with placebo in five out of six and three out of six acute studies, respectively. While results were positive for improvement in the HAMD 17 at a dose of 20 mg twice daily in one of two studies, this dose did not demonstrate statistical superiority on any other measure including response or remission. Table 1: HAMD 17 Total, Response, and Remission Rates Placebo-Controlled Duloxetine 60 mg Once Daily Studies HMBHa HMBHb Placebo (n = 115) Duloxetine (n = 121) P- Value 4 Placebo (n = 136) Duloxetine (n = 123) P- Value 4 HAMD 17 Total Response 2 27 (23%) 55 (45%) (35%) 62 (50%) Remission 3 17 (15%) 38 (31%) (24%) 39 (32%) Least-squares mean change from baseline 2 Response = 50% reduction in HAMD17 total score from baseline to endpoint 3 Remission = HAMD17 total score 7 at endpoint 4 P-values for the HAMD 17 Total are from analysis of covariance and for response and remission are from Fisher's exact test In addition to the HAMD 17 total score, several other measures were included in the evaluation of efficacy of duloxetine. HAMD 17 Depressed Mood Item (Item 1), the Anxiety Subfactor of the HAMD 17, the Patient Global Impressions (PGI) Improvement Score, bodily pain as measured by Visual Analog Scale (VAS), and the Quality of Life in Depression rating scales were also examined. In the four studies where duloxetine demonstrated statistical superiority over placebo as measured by improvement in the HAMD 17 total score, results were also positive for the additional measures at doses of 60 mg to 120 mg per day. APO- Duloxetine Enteric Capsules Page 3 In each study and in pooled data, the effectiveness of duloxetine was similar regardless of age, gender or racial origin. Prevention of depressive relapse Patients responding to 12 weeks of acute treatment with open-label duloxetine at a dose of 60 mg once daily were randomly assigned to either duloxetine 60 mg once daily or placebo for a further 6 months (continuation phase) and time to relapse in each group was compared. Of 533 subjects who enrolled in the study, 278 responded and were randomised to duloxetine 60 mg once daily (n = 136) or placebo (n = 142). The estimated probability of depressive relapse at 6 months for placebo was 38.3% and for duloxetine 60 mg once daily was 19.7% (p = 0.004). During the 6- month continuation therapy phase of this study, 17.4% of duloxetine-treated patients met the a priori-defined criteria for relapse compared with 28.5% on placebo (p = 0.042). Of 88 patients who relapsed during the continuation phase, 87 received double-blind rescue therapy. The patients who relapsed on placebo (n = 58) were treated with duloxetine at a dose of 60 mg once daily, and those relapsing on duloxetine 60 mg once daily (n = 29) were treated with duloxetine 60 mg twice daily. Of those patients relapsing on placebo and treated with duloxetine 60 mg once daily, response (50% reduction in HAMD 17 total score) occurred in 77% and remission (HAMD 17 total score 7) occurred in 57% at the end of 12 further weeks of treatment. Of those patients who relapsed on duloxetine 60 mg once daily and who were treated with an increased dose of 60 mg twice daily, 62% met response criteria and 38% met remission criteria. Use in elderly patients with depression The efficacy and safety of duloxetine 60 mg once daily (n = 207) and placebo (n = 104) have been compared in the acute treatment (study duration 8 weeks) of elderly patients with MDD ( 65 years of age, mean age 72.9 years). Duloxetine treated patients experienced improvement in depressive symptoms, as assessed by the Geriatric Depression Scale, from week 1, with least-squares mean changes from baseline to endpoint of for placebo-treated patients and for duloxetinetreated patients (p 0.001). On the Hamilton Depression Rating Scale, least squares mean changes from baseline to endpoint for total HAMD score were for placebo-treated patients and for duloxetine-treated patients (p 0.001). Duloxetine-treated patients also experienced a greater improvement in composite cognitive score than the placebo-treated patients. The least-squares mean change from baseline to endpoint for the composite cognitive score was 0.76 in placebo-treated patients and 1.95 for duloxetine-treated patients (p = 0.013). General Anxiety Disorder The efficacy of duloxetine has been established in 5 Phase 3 clinical trials. Four of the studies were acute placebo-controlled studies and the fifth was a relapse prevention study. Of the four placebo controlled studies one was a fixed dose study while the other three were flexible dose studies. Study HMBR (fixed dose) was a randomised double blind trial designed to assess whether duloxetine 120 mg once daily (QD) was superior to placebo in the treatment of GAD as measured by the mean change in Hamilton Anxiety Depression Rating Scale (HAMA) during the 9-week, double-blind, acute therapy phase. A key secondary objective was to assess whether duloxetine 60 mg QD was superior to placebo in the treatment of GAD during the 9-week, double blind acute therapy phase. Studies HMDT, HMDU and HMDW, respectively, were Phase 3 (flexible dose) randomised doubleblind placebo-controlled studies that used the same primary objective: to assess whether duloxetine flexibly dosed from 60 mg to 120 mg QD was superior to placebo in the treatment of GAD as measured by mean change in HAMA total score over 10 weeks. Venlafaxine 75 mg to 225 mg QD was used as an active comparator in studies HMDU and HMDW and data from these trials was combined (designed a priori) to have sufficient power for non-inferiority comparison of duloxetine with venlafaxine. For all 3 studies doses were increased at specified visits if the CGI-Improvement score remained at 3 or below or minimally improved. In all 4 acute placebo controlled studies the mean decrease in HAMA total score was significantly greater for duloxetine-treated patients compared with placebo treated patients as shown in Table 2. APO- Duloxetine Enteric Capsules Page 4 Study/ duration Table 2: Summary of Primary Efficacy in acute placebo-controlled GAD studies Treatment Group N Baseline Endpoint LSMean Change p-value vs placebo HMBR Duloxetine 60 mg QD weeks Duloxetine 120 mg QD Placebo HMDT Duloxetine 60 to 120 mg QD weeks Placebo HMDU Duloxetine 60 to 120 mg QD weeks Venlafaxine 75 to 225 mg QD Placebo HMDW Duloxetine 20 mg QD weeks Duloxetine 60 to 120 mg QD Venlafaxine 75 to 225 mg QD Placebo QD = once daily Duloxetine at the recommended dose of 60 mg to 120 mg once daily 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 study HMDV, 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 month double-blind follow-up period was 14% for duloxetine and 42% for placebo. INDICATIONS Treatment of major depressive disorder (MDD). Treatment of generalised anxiety disorder (GAD). CONTRAINDICATIONS Patients with hypersensitivity to duloxetine or to any of the excipients in the formulation. Use in combination with monoamine oxidase inhibitors (MAOI) or the reversible MAOI (RIMA), moclobemide, or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 5 days should be allowed after stopping duloxetine, before starting a MAOI. Cases of serious reactions, such as potentially life threatening serotonin syndrome (characterised by neuromuscular excitation, altered mental status and autonomic dysfunction) have been reported in patients receiving an SNRI in combination with MAOIs and RIMA, and in patients who have recently discontinued an SNRI and have been started on a MAOI (see PRECAUTIONS, Serotonin Syndrome). Patients with liver disease resulting in hepatic impairment (see PHARMACOLOGY, Pharmacokinetics). Use in combination with potent CYP1A2 inhibitors (see INTERACTIONS WITH OTHER MEDICINES). APO- Duloxetine Enteric Capsules Page 5 PRECAUTIONS Clinical Worsening and Suicide Risk Product Information - Australia The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. This risk must be considered in all depressed patients. Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient s presenting symptoms. Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Patients with co-morbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality. Pooled analyses of 24 short-term (4 to 16 weeks), placebo-controlled trials of nine antidepressant medicines (SSRIs and others) in 4400 children and adolescents with major depressive disorder (16 trials), obsessive compulsive disorder (4 trials) or other psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4% compared with 2% of patients given placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards and increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder trials, but there were signals of risk arising from trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medications in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non- SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine). Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality. Families and caregivers of children and adolescents being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or nonpsychiatric) should be informed about t
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