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CYMBALTA (duloxetine hydrochloride) Delayed-release Capsules

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CYMBALTA (duloxetine hydrochloride) Delayed-release Capsules 1 PV 5904 AMP 1 CYMBALTA® 2 (duloxetine hydrochloride) Delayed-release Capsules 3 WARNING 4 Suicidality and Antidepressant Drugs — Antidepressants increased the risk compared to 5 placebo of suicidal thinking and behavior (suicidality) in children, a...

CYMBALTA (duloxetine hydrochloride) Delayed-release Capsules
1 PV 5904 AMP 1 CYMBALTA® 2 (duloxetine hydrochloride) Delayed-release Capsules 3 WARNING 4 Suicidality and Antidepressant Drugs — Antidepressants increased the risk compared to 5 placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young 6 adults in short-term studies of major depressive disorder (MDD) and other psychiatric 7 disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child, 8 adolescent, or young adult must balance this risk with the clinical need. Short-term studies 9 did not show an increase in the risk of suicidality with antidepressants compared to 10 placebo in adults beyond age 24; there was a reduction in risk with antidepressants 11 compared to placebo in adults aged 65 and older. Depression and certain other psychiatric 12 disorders are themselves associated with increases in the risk of suicide. Patients of all ages 13 who are started on antidepressant therapy should be monitored appropriately and 14 observed closely for clinical worsening, suicidality, or unusual changes in behavior. 15 Families and caregivers should be advised of the need for close observation and 16 communication with the prescriber. Cymbalta is not approved for use in pediatric patients. 17 (See WARNINGS, Clinical Worsening and Suicide Risk, PRECAUTIONS, Information for 18 Patients, PRECAUTIONS, Pediatric Use.) 19 DESCRIPTION 20 Cymbalta® (duloxetine hydrochloride) is a selective serotonin and norepinephrine reuptake 21 inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-(S)-N-methyl-γ-(1-22 naphthyloxy)-2-thiophenepropylamine hydrochloride. The empirical formula is 23 C18H19NOS•HCl, which corresponds to a molecular weight of 333.88. The structural formula is: 24 25 Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble 26 in water. 27 Each capsule contains enteric-coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine 28 hydrochloride equivalent to 20, 30, or 60 mg of duloxetine, respectively. These enteric-coated 29 pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. 30 Inactive ingredients include FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl 31 methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium 32 dioxide, and triethyl citrate. The 20 and 60 mg capsules also contain iron oxide yellow. 33 2 CLINICAL PHARMACOLOGY 34 Pharmacodynamics 35 Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic 36 actions of duloxetine in humans are unknown, these actions are believed to be related to its 37 potentiation of serotonergic and noradrenergic activity in the CNS. Preclinical studies have 38 shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake 39 and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for 40 dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors 41 in vitro. Duloxetine does not inhibit monoamine oxidase (MAO). Duloxetine undergoes 42 extensive metabolism, but the major circulating metabolites have not been shown to contribute 43 significantly to the pharmacologic activity of duloxetine. 44 Pharmacokinetics 45 Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its 46 pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma 47 concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly 48 through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP1A2. 49 Absorption and Distribution — Orally administered duloxetine hydrochloride is well absorbed. 50 There is a median 2-hour lag until absorption begins (Tlag), with maximal plasma 51 concentrations (Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of 52 duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally 53 decreases the extent of absorption (AUC) by about 10%. There is a 3-hour delay in absorption 54 and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to 55 a morning dose. 56 The apparent volume of distribution averages about 1640 L. Duloxetine is highly 57 bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid 58 glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not 59 been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic 60 impairment. 61 Metabolism and Elimination — Biotransformation and disposition of duloxetine in humans 62 have been determined following oral administration of 14C-labeled duloxetine. Duloxetine 63 comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes 64 extensive metabolism to numerous metabolites. The major biotransformation pathways for 65 duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. 66 Both CYP2D6 and CYP1A2 catalyze the oxidation of the naphthyl ring in vitro. Metabolites 67 found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine 68 sulfate. Many additional metabolites have been identified in urine, some representing only minor 69 pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are 70 present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites 71 of duloxetine; about 20% is excreted in the feces. 72 Special Populations 73 Gender — Duloxetine’s half-life is similar in men and women. Dosage adjustment based on 74 gender is not necessary. 75 Age — The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in 76 healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There 77 was no difference in the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and 78 3 the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses 79 suggest that the typical values for clearance decrease by approximately 1% for each year of age 80 between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage 81 of between-patient variability. Dosage adjustment based on the age of the patient is not necessary 82 (see DOSAGE AND ADMINISTRATION). 83 Smoking Status — Duloxetine bioavailability (AUC) appears to be reduced by about 84 one-third in smokers. Dosage modifications are not recommended for smokers. 85 Race — No specific pharmacokinetic study was conducted to investigate the effects of race. 86 Renal Insufficiency — Limited data are available on the effects of duloxetine in patients with 87 end-stage renal disease (ESRD). After a single 60-mg dose of duloxetine, Cmax and AUC values 88 were approximately 100% greater in patients with end-stage renal disease receiving chronic 89 intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, 90 however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy 91 duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, 92 were approximately 7- to 9-fold higher and would be expected to increase further with multiple 93 dosing. For this reason, Cymbalta is not recommended for patients with end-stage renal disease 94 (requiring dialysis) or severe renal impairment (estimated creatinine clearance [CrCl] 95 <30 mL/min) (see DOSAGE AND ADMINISTRATION). Population PK analyses suggest that 96 mild to moderate degrees of renal dysfunction (estimated CrCl 30-80 mL/min) have no 97 significant effect on duloxetine apparent clearance. 98 Hepatic Insufficiency — Patients with clinically evident hepatic insufficiency have decreased 99 duloxetine metabolism and elimination. After a single 20-mg dose of Cymbalta, 6 cirrhotic 100 patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine 101 clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in 102 mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the 103 half-life was about 3 times longer (see PRECAUTIONS). It is recommended that duloxetine not 104 be administered to patients with any hepatic insufficiency (see DOSAGE AND 105 ADMINISTRATION). 106 Nursing Mothers — The disposition of duloxetine was studied in 6 lactating women who were 107 at least 12-weeks postpartum. Duloxetine 40 mg BID was given for 3.5 days. Lactation did not 108 influence duloxetine pharmacokinetics. Like many other drugs, duloxetine is detected in breast 109 milk, and steady-state concentrations in breast milk are about one-fourth those in plasma. The 110 amount of duloxetine in breast milk is approximately 7 µg/day while on 40 mg BID dosing. The 111 excretion of duloxetine metabolites into breast milk was not examined. Because the safety of 112 duloxetine in infants is not known, nursing while on Cymbalta is not recommended (see 113 DOSAGE AND ADMINISTRATION). 114 Drug-Drug Interactions (also see PRECAUTIONS, Drug Interactions) 115 Potential for Other Drugs to Affect Duloxetine 116 Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. 117 Inhibitors of CYP1A2 — When duloxetine 60 mg was co-administered with fluvoxamine 118 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased 119 approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased 120 approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and 121 quinolone antimicrobials such as ciprofloxacin and enoxacin. 122 4 Inhibitors of CYP2D6 — Because CYP2D6 is involved in duloxetine metabolism, concomitant 123 use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in 124 higher concentrations (on average 60%) of duloxetine (see PRECAUTIONS, Drug Interactions). 125 Dual Inhibition of CYP1A2 and CYP2D6 — Concomitant administration of duloxetine 40 mg 126 BID with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer 127 subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax. 128 Studies with Benzodiazepines 129 Lorazepam — Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam 130 (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration. 131 Temazepam — Under steady-state conditions for duloxetine (20 mg qhs) and temazepam 132 (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration. 133 Potential for Duloxetine to Affect Other Drugs 134 Drugs Metabolized by CYP1A2 — In vitro drug interaction studies demonstrate that 135 duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of 136 CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, 137 although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the 138 CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence 139 interval) increase in theophylline AUC was 7% (1%-5%) and 20% (13%-27%) when 140 co-administered with duloxetine (60 mg BID). 141 Drugs Metabolized by CYP2D6 — Duloxetine is a moderate inhibitor of CYP2D6 and 142 increases the AUC and Cmax of drugs metabolized by CYP2D6 (see PRECAUTIONS). 143 Therefore, co-administration of Cymbalta with other drugs that are extensively metabolized by 144 this isozyme and that have a narrow therapeutic index should be approached with caution (see 145 PRECAUTIONS, Drug Interactions). 146 Drugs Metabolized by CYP2C9 — Duloxetine does not inhibit the in vitro enzyme activity of 147 CYP2C9. Inhibition of the metabolism of CYP2C9 substrates is therefore not anticipated, 148 although clinical studies have not been performed. 149 Drugs Metabolized by CYP3A — Results of in vitro studies demonstrate that duloxetine does 150 not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of 151 CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction 152 or inhibition is not anticipated, although clinical studies have not been performed. 153 Drugs Metabolized by CYP2C19 — Results of in vitro studies demonstrate that duloxetine 154 does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of 155 CYP2C19 substrates is therefore not anticipated, although clinical studies have not been 156 performed. 157 Studies with Benzodiazepines 158 Lorazepam — Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam 159 (2 mg Q 12 hours), the pharmacokinetics of lorazepam were not affected by co-administration. 160 Temazepam — Under steady-state conditions for duloxetine (20 mg qhs) and temazepam 161 (30 mg qhs), the pharmacokinetics of temazepam were not affected by co-administration. 162 Drugs Highly Bound to Plasma Protein — Because duloxetine is highly bound to plasma 163 protein, administration of Cymbalta to a patient taking another drug that is highly protein bound 164 may cause increased free concentrations of the other drug, potentially resulting in adverse events. 165 5 CLINICAL STUDIES 166 Major Depressive Disorder 167 The efficacy of Cymbalta as a treatment for depression was established in 4 randomized, 168 double-blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting 169 DSM-IV criteria for major depression. In 2 studies, patients were randomized to Cymbalta 60 mg 170 once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 171 9 weeks; in the third study, patients were randomized to Cymbalta 20 or 40 mg twice daily 172 (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were 173 randomized to Cymbalta 40 or 60 mg twice daily (N=95 and N=93, respectively) or 174 placebo (N=93) for 8 weeks. There is no evidence that doses greater than 60 mg/day confer any 175 additional benefit. 176 In all 4 studies, Cymbalta demonstrated superiority over placebo as measured by improvement 177 in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score. 178 Analyses of the relationship between treatment outcome and age, gender, and race did not 179 suggest any differential responsiveness on the basis of these patient characteristics. 180 Diabetic Peripheral Neuropathic Pain 181 The efficacy of Cymbalta for the management of neuropathic pain associated with diabetic 182 peripheral neuropathy (DPN) was established in 2 randomized, 12-week, double-blind, 183 placebo-controlled, fixed-dose studies in adult patients having diabetic peripheral neuropathy for 184 at least 6 months. Study 1 and 2 enrolled a total of 791 patients of whom 592 (75%) completed 185 the studies. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal 186 symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain 187 score of ≥4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients 188 were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to Cymbalta. 189 Patients recorded their pain daily in a diary. 190 Both studies compared Cymbalta 60 mg once daily or 60 mg twice daily with placebo. Study 1 191 additionally compared Cymbalta 20 mg with placebo. A total of 457 patients (342 Cymbalta, 192 115 placebo) were enrolled in Study 1 and a total of 334 patients (226 Cymbalta, 108 placebo) 193 were enrolled in Study 2. Treatment with Cymbalta 60 mg one or two times a day statistically 194 significantly improved the endpoint mean pain scores from baseline and increased the proportion 195 of patients with at least a 50% reduction in pain score from baseline. For various degrees of 196 improvement in pain from baseline to study endpoint, Figures 1 and 2 show the fraction of 197 patients achieving that degree of improvement. The figures are cumulative, so that patients 198 whose change from baseline is, for example, 50%, are also included at every level of 199 improvement below 50%. Patients who did not complete the study were assigned 0% 200 improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted 201 throughout the study. 202 6 203 204 Figure 1: Percentage of Patients Achieving Various Levels of Pain Relief 205 as Measured by 24-Hour Average Pain Severity - Study 1 206 207 Figure 2: Percentage of Patients Achieving Various Levels of Pain Relief 208 as Measured by 24-Hour Average Pain Severity - Study 2 209 210 Generalized Anxiety Disorder 211 The efficacy of Cymbalta in the treatment of generalized anxiety disorder (GAD) was 212 established in 1 fixed-dose randomized, double-blind, placebo-controlled trial and 213 2 flexible-dose randomized, double-blind, placebo-controlled trials in adult outpatients between 214 18 and 83 years of age meeting the DSM-IV criteria for GAD. 215 In 1 flexible-dose study and in the fixed-dose study, the starting dose was 60 mg once daily 216 where down titration to 30 mg once daily was allowed for tolerability reasons before increasing 217 7 it to 60 mg once daily. Fifteen percent of patients were down titrated. One flexible-dose study 218 had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily. 219 The 2 flexible-dose studies involved dose titration with Cymbalta doses ranging from 60 mg 220 once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) 221 over a 10-week treatment period. The mean dose for completers at endpoint in the flexible-dose 222 studies was 104.75 mg/day. The fixed-dose study evaluated Cymbalta doses of 60 mg once daily 223 (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9-week treatment 224 period. While a 120 mg/day dose was shown to be effective, there is no evidence that doses 225 greater than 60 mg/day confer additional benefit. 226 In all 3 studies, Cymbalta demonstrated superiority over placebo as measured by greater 227 improvement in the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability 228 Scale (SDS) global functional impairment score. The SDS is a widely used and well-validated 229 scale that measures the extent emotional symptoms disrupt patient functioning in 3 life 230 domains: work/school, social life/leisure activities and family life/home responsibilities. 231 Subgroup analyses did not indicate that there were any differences in treatment outcomes as a 232 function of age or gender. 233 INDICATIONS AND USAGE 234 Major Depressive Disorder 235 Cymbalta is indicated for the treatment of major depressive disorder (MDD). 236 The efficacy of Cymbalta has been established in 8- and 9-week placebo-controlled trials of 237 outpatients who met DSM-IV diagnostic criteria for major depressive disorder (see CLINICAL 238 STUDIES). 239 A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly 240 every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily 241 functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of 242 interest in usual activities, significant change in weight and/or appetite, insomnia or 243
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