Generic Name: DULOXETINE HYDROCHLORIDE
Brand Name: Cymbalta
- Substance Name(s):
- DULOXETINE HYDROCHLORIDE
DRUG INTERACTIONS
7 Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Potent inhibitors of CYP1A2 should be avoided (7.1). Potent inhibitors of CYP2D6 may increase CYMBALTA concentrations (7.2). CYMBALTA is a moderate inhibitor of CYP2D6 (7.9). 7.1 Inhibitors of CYP1A2 When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see Warnings and Precautions (5.12)]. 7.2 Inhibitors of CYP2D6 Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see Warnings and Precautions (5.12)]. 7.3 Dual Inhibition of CYP1A2 and CYP2D6 Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax. 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUCτ,ss, Cmax,ss or tmax,ss) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued [see Warnings and Precautions (5.5)]. 7.5 Lorazepam Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration. 7.6 Temazepam Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration. 7.7 Drugs that Affect Gastric Acidity CYMBALTA has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, CYMBALTA, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using CYMBALTA in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of CYMBALTA with aluminum- and magnesium-containing antacids (51 mEq) or CYMBALTA with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption [see Warnings and Precautions (5.14)]. 7.8 Drugs Metabolized by CYP1A2 In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily). 7.9 Drugs Metabolized by CYP2D6 Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold [see Warnings and Precautions (5.12)]. 7.10 Drugs Metabolized by CYP2C9 Results of in vitro studies demonstrate that duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine [see Drug Interactions (7.4)]. 7.11 Drugs Metabolized by CYP3A Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed. 7.12 Drugs Metabolized by CYP2C19 Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed. 7.13 Monoamine Oxidase Inhibitors (MAOIs) [See Dosage and Administration (2.8, 2.9), Contraindications (4), and Warnings and Precautions (5.4)]. 7.14 Serotonergic Drugs [See Dosage and Administration (2.8, 2.9), Contraindications (4), and Warnings and Precautions (5.4)]. 7.15 Alcohol When CYMBALTA and ethanol were administered several hours apart so that peak concentrations of each would coincide, CYMBALTA did not increase the impairment of mental and motor skills caused by alcohol. In the CYMBALTA clinical trials database, three CYMBALTA-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen [see Warnings and Precautions (5.2, 5.12)]. 7.16 CNS Drugs [See Warnings and Precautions (5.12)]. 7.17 Drugs Highly Bound to Plasma Protein Because duloxetine is highly bound to plasma protein, administration of CYMBALTA to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. However, co-administration of duloxetine (60 or 120 mg) with warfarin (2-9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug) [see Drug Interactions (7.4)].
OVERDOSAGE
10 10.1 Signs and Symptoms In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting. 10.2 Management of Overdose There is no specific antidote to CYMBALTA, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken CYMBALTA and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Warnings and Precautions (5.4) and Drug Interactions (7)]. The physician should consider contacting a poison control center (1-800-222-1222 or www.poison.org) for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).
DESCRIPTION
11 CYMBALTA® (duloxetine delayed-release capsules) is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride. The empirical formula is C18H19NOS•HCl, which corresponds to a molecular weight of 333.88. The structural formula is: Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water. Each capsule contains enteric-coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride equivalent to 20, 30, or 60 mg of duloxetine, respectively. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. Inactive ingredients include FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate. The 20 and 60 mg capsules also contain iron oxide yellow. Structural Formula
CLINICAL STUDIES
14 The efficacy of CYMBALTA has been established in the following adequate and well-controlled trials: Major Depressive Disorder (MDD): 4 short-term and 1 maintenance trial in adults [see Clinical Studies (14.1)]. Generalized Anxiety Disorder (GAD): 3 short-term trials in adults, 1 maintenance trial in adults, and 1 short-term trial in children and adolescents [see Clinical Studies (14.2)]. Diabetic Peripheral Neuropathic Pain (DPNP): Two 12-week trials in adults [see Clinical Studies (14.3)]. Fibromyalgia (FM): Two trials in adults (one of 3 months duration and one of 6 months duration) [see Clinical Studies (14.4)]. Chronic Musculoskeletal Pain: Two 12- to 13-week trials in adult patients with chronic low back pain (CLBP) and one 13-week trial in adult patients with chronic pain due to osteoarthritis [see Clinical Studies (14.5)]. 14.1 Major Depressive Disorder The efficacy of CYMBALTA as a treatment for depression was established in 4 randomized, double-blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting DSM-IV criteria for major depression. In 2 studies, patients were randomized to CYMBALTA 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in the third study, patients were randomized to CYMBALTA 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to CYMBALTA 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that doses greater than 60 mg/day confer additional benefits. In all 4 studies, CYMBALTA demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (Studies 1-4 in Table 7). In all of these clinical studies, analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics. Table 7: Summary of the Primary Efficacy Results for Studies in Major Depressive Disorder SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in trials where multiple dose groups were included. a Difference (drug minus placebo) in least-squares mean change from baseline. b Doses statistically significantly superior to placebo. Study Number Treatment Group Primary Efficacy Measure: HAMD-17 Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) Study 1 CYMBALTA (60 mg/day)b 21.5 (4.10) -10.9 (0.70) -4.9 (-6.8, -2.9) Placebo 21.1 (3.71) -6.1 (0.69) — Study 2 CYMBALTA (60 mg/day)b 20.3 (3.32) -10.5 (0.71) -2.2 (-4.0, -0.3) Placebo 20.5 (3.42) -8.3 (0.67) — Study 3 CYMBALTA (20 mg BID)b 18.6 (5.85) -7.4 (0.80) -2.4 (-4.7, -0.2) CYMBALTA (40 mg BID)b 18.1 (4.52) -8.6 (0.81) -3.6 (-5.9, -1.4) Placebo 17.2 (5.11) -5.0 (0.81) — Study 4 CYMBALTA (40 mg BID)b 19.9 (3.54) -11.0 (0.49) -2.2 (-3.6, -0.9) CYMBALTA (60 mg BID)b 20.2 (3.41) -12.1 (0.49) -3.3 (-4.7, -1.9) Placebo 19.9 (3.58) -8.8 (0.50) — In another study, 533 patients meeting DSM-IV criteria for MDD received CYMBALTA 60 mg once daily during an initial 12-week open-label treatment phase. Two hundred and seventy-eight patients who responded to open label treatment (defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not meeting the DSM-IV criteria for MDD) were randomly assigned to continuation of CYMBALTA at the same dose (N=136) or to placebo (N=142) for 6 months. Patients on CYMBALTA experienced a statistically significantly longer time to relapse of depression than did patients on placebo (Study 5 in Figure 1). Relapse was defined as an increase in the CGI-S score of ≥2 points compared with that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-week temporal criterion had to be satisfied at only the second visit. The effectiveness of CYMBALTA in hospitalized patients with major depressive disorder has not been studied. Figure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (MDD Study 5) Figure 1 14.2 Generalized Anxiety Disorder The efficacy of CYMBALTA in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed-dose randomized, double-blind, placebo-controlled trial and 2 flexible-dose randomized, double-blind, placebo-controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM-IV criteria for GAD. In 1 flexible-dose study and in the fixed-dose study, the starting dose was 60 mg once daily where down titration to 30 mg once daily was allowed for tolerability reasons before increasing it to 60 mg once daily. Fifteen percent of patients were down titrated. One flexible-dose study had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily. The 2 flexible-dose studies involved dose titration with CYMBALTA doses ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10-week treatment period. The mean dose for completers at endpoint in the flexible-dose studies was 104.75 mg/day. The fixed-dose study evaluated CYMBALTA doses of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9-week treatment period. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. In all 3 studies, CYMBALTA demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score (Studies 1-3 in Table 8) and by the Sheehan Disability Scale (SDS) global functional impairment score. The SDS is a composite measurement of the extent emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities, and family life/home responsibilities. In another study, 887 patients meeting DSM-IV-TR criteria for GAD received CYMBALTA 60 mg to 120 mg once daily during an initial 26-week open-label treatment phase. Four hundred and twenty-nine patients who responded to open-label treatment (defined as meeting the following criteria at weeks 24 and 26: a decrease from baseline HAM-A total score by at least 50% to a score no higher than 11, and a Clinical Global Impressions of Improvement [CGI-Improvement] score of 1 or 2) were randomly assigned to continuation of CYMBALTA at the same dose (N=216) or to placebo (N=213) and were observed for relapse. Of the patients randomized, 73% had been in a responder status for at least 10 weeks. Relapse was defined as an increase in CGI-Severity score at least 2 points to a score ≥4 and a MINI (Mini-International Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or discontinuation due to lack of efficacy. Patients taking CYMBALTA experienced a statistically significantly longer time to relapse of GAD than did patients taking placebo (Study 4 in Figure 2). Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. The efficacy of CYMBALTA in the treatment of patients ≥65 years of age with generalized anxiety disorder was established in one 10-week flexible-dose, randomized, double-blind, placebo-controlled trial in adults ≥65 years of age meeting the DSM-IV criteria for GAD. In this study, the starting dose was 30 mg once daily for 2 weeks before further dose increases in 30 mg increments at treatment weeks 2, 4, and 7 up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dose for patients completing the 10-week acute treatment phase was 50.95 mg. Patients treated with CYMBALTA (N=151) demonstrated significantly greater improvement compared with placebo (N=140) on mean change from baseline to endpoint as measured by the Hamilton Anxiety Rating Scale total score (Study 5 in Table 8). The efficacy of CYMBALTA in the treatment of pediatric patients 7 to 17 years of age with generalized anxiety disorder (GAD) was established in 1 flexible-dose randomized, double-blind, placebo-controlled trial in pediatric outpatients with GAD (based on DSM-IV criteria). In this study, the starting dose was 30 mg once daily for 2 weeks. Further dose increases in 30 mg increments up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dose for patients completing the 10-week treatment phase was 57.6 mg/day. In this study, CYMBALTA (N=135) demonstrated superiority over placebo (N=137) from baseline to endpoint as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score (Study 6 in Table 8). Table 8: Summary of the Primary Efficacy Results for Studies in General Anxiety Disorder SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in trials where multiple dose groups were included. a Difference (drug minus placebo) in least squares mean change from baseline. b Dose statistically significantly superior to placebo. Study Number Treatment Group Primary Efficacy Measure Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) Study 1 (HAM-A) CYMBALTA (60 mg/day)b 25.1 (7.18) -12.8 (0.68) -4.4 (-6.2, -2.5) CYMBALTA (120 mg/day)b 25.1 (7.24) -12.5 (0.67) -4.1 (-5.9, -2.3) Placebo 25.8 (7.66) -8.4 (0.67) — Study 2 (HAM-A) CYMBALTA (60-120 mg/day)b 22.5 (7.44) -8.1 (0.70) -2.2 (-4.2, -0.3) Placebo 23.5 (7.91) -5.9 (0.70) — Study 3 (HAM-A) CYMBALTA (60-120 mg/day)b 25.8 (5.66) -11.8 (0.69) -2.6 (-4.5, -0.7) Placebo 25.0 (5.82) -9.2 (0.67) — Study 5 (Elderly) (HAM-A) CYMBALTA (60-120 mg/day)b 24.6 (6.21) -15.9 (0.63) -4.2 (-5.9, -2.5) Placebo 24.5 (7.05) -11.7 (0.67) — Study 6 (Pediatric) CYMBALTA (30-120 mg/day)b 17.5 (1.98) -9.7 (0.50) -2.7 (-4.0, -1.3) (PARS for GAD) Placebo 17.4 (2.24) -7.1 (0.50) — Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (GAD Study 4) Figure 2 14.3 Diabetic Peripheral Neuropathic Pain The efficacy of CYMBALTA for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients having diabetic peripheral neuropathic pain for at least 6 months. Study DPNP-1 and Study DPNP-2 enrolled a total of 791 patients of whom 592 (75%) completed the studies. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of ≥4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to CYMBALTA. Patients recorded their pain daily in a diary. Both studies compared CYMBALTA 60 mg once daily or 60 mg twice daily with placebo. DPNP-1 additionally compared CYMBALTA 20 mg with placebo. A total of 457 patients (342 CYMBALTA, 115 placebo) were enrolled in DPNP-1 and a total of 334 patients (226 CYMBALTA, 108 placebo) were enrolled in DPNP-2. Treatment with CYMBALTA 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain scores from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figures 3 and 4 show the fraction of patients achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study. Figure 3: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – DPNP-1 Figure 4: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – DPNP-2 Figure 3 Figure 4 14.4 Fibromyalgia The efficacy of CYMBALTA for the management of fibromyalgia was established in two randomized, double-blind, placebo-controlled, fixed-dose studies in adult patients meeting the American College of Rheumatology criteria for fibromyalgia (a history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). Study FM-1 was three months in duration and enrolled female patients only. Study FM-2 was six months in duration and enrolled male and female patients. Approximately 25% of participants had a comorbid diagnosis of major depressive disorder (MDD). FM-1 and FM-2 enrolled a total of 874 patients of whom 541 (62%) completed the studies. The patients had a baseline pain score of 6.5 on an 11-point scale ranging from 0 (no pain) to 10 (worse possible pain). Both studies compared CYMBALTA 60 mg once daily or 120 mg daily (given in divided doses in FM-1 and as a single daily dose in FM-2) with placebo. FM-2 additionally compared CYMBALTA 20 mg with placebo during the initial three months of a six-month study. A total of 354 patients (234 CYMBALTA, 120 placebo) were enrolled in FM-1 and a total of 520 patients (376 CYMBALTA, 144 placebo) were enrolled in FM-2 (5% male, 95% female). Treatment with CYMBALTA 60 mg or 120 mg daily statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Pain reduction was observed in patients both with and without comorbid MDD. However, the degree of pain reduction may be greater in patients with comorbid MDD. For various degrees of improvement in pain from baseline to study endpoint, Figures 5 and 6 show the fraction of patients achieving that degree of improvement. The figures are cumulative so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study. Improvement was also demonstrated on measures of function (Fibromyalgia Impact Questionnaires) and patient global impression of change (PGI). Neither study demonstrated a benefit of 120 mg compared to 60 mg, and a higher dose was associated with more adverse reactions and premature discontinuations of treatment. Figure 5: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – FM-1 Figure 6: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – FM-2 Additionally, the benefit of up-titration in non-responders to CYMBALTA at 60 mg/day was evaluated in a separate study. Patients were initially treated with CYMBALTA 60 mg once daily for eight weeks in open-label fashion. Subsequently, completers of this phase were randomized to double-blind treatment with CYMBALTA at either 60 mg once daily or 120 mg once daily. Those patients who were considered non-responders, where response was defined as at least a 30% reduction in pain score from baseline at the end of the 8-week treatment, were no more likely to meet response criteria at the end of 60 weeks of treatment if blindly titrated to CYMBALTA 120 mg as compared to those who were blindly continued on CYMBALTA 60 mg. Figure 5 Figure 6 14.5 Chronic Musculoskeletal Pain CYMBALTA is indicated for the management of chronic musculoskeletal pain. This has been established in studies in patients with chronic low back pain and chronic pain due to osteoarthritis. Studies in Chronic Low Back Pain The efficacy of CYMBALTA in chronic low back pain (CLBP) was assessed in two double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study CLBP-1 and Study CLBP-2), and one of 12-weeks duration (CLBP-3). CLBP-1 and CLBP-3 demonstrated efficacy of CYMBALTA in the treatment of chronic low back pain. Patients in all studies had no signs of radiculopathy or spinal stenosis. Study CLBP-1: Two hundred thirty-six adult patients (N=115 on CYMBALTA, N=121 on placebo) enrolled and 182 (77%) completed 13-week treatment phase. After 7 weeks of treatment, CYMBALTA patients with less than 30% reduction in average daily pain and who were able to tolerate CYMBALTA 60 mg once daily had their dose of CYMBALTA, in a double-blinded fashion, increased to 120 mg once daily for the remainder of the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking CYMBALTA 60-120 mg daily had a significantly greater pain reduction compared to placebo. Randomization was stratified by the patients’ baseline NSAIDs-use status. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use. Study CLBP-2: Four hundred and four patients were randomized to receive fixed doses of CYMBALTA daily or a matching placebo (N=59 on CYMBALTA 20 mg, N=116 on CYMBALTA 60 mg, N=112 on CYMBALTA 120 mg, N=117 on placebo) and 267 (66%) completed the entire 13-week study. After 13 weeks of treatment, none of the three CYMBALTA doses showed a statistically significant difference in pain reduction compared to placebo. Study CLBP-3: Four hundred and one patients were randomized to receive fixed doses of CYMBALTA 60 mg daily or placebo (N=198 on CYMBALTA, N=203 on placebo), and 303 (76%) completed the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 12 weeks of treatment, patients taking CYMBALTA 60 mg daily had significantly greater pain reduction compared to placebo. For various degrees of improvement in pain from baseline to study endpoint, Figures 7 and 8 show the fraction of patients in CLBP-1 and CLBP-3 achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned the value of 0% improvement. Figure 7: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – CLBP-1 Figure 8: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – CLBP-3 Figure 7 Figure 8 Studies in Chronic Pain Due to Osteoarthritis The efficacy of CYMBALTA in chronic pain due to osteoarthritis was assessed in 2 double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study OA-1 and Study OA-2). All patients in both studies fulfilled the ACR clinical and radiographic criteria for classification of idiopathic osteoarthritis of the knee. Randomization was stratified by the patients’ baseline NSAIDs-use status. Patients assigned to CYMBALTA started treatment in both studies at a dose of 30 mg once daily for one week. After the first week, the dose of CYMBALTA was increased to 60 mg once daily. After 7 weeks of treatment with CYMBALTA 60 mg once daily, in OA-1 patients with sub-optimal response to treatment (<30% pain reduction) and tolerated CYMBALTA 60 mg once daily had their dose increased to 120 mg. However, in OA-2, all patients, regardless of their response to treatment after 7 weeks, were re-randomized to either continue receiving CYMBALTA 60 mg once daily or have their dose increased to 120 mg once daily for the remainder of the study. Patients in the placebo treatment groups in both studies received a matching placebo for the entire duration of studies. For both studies, efficacy analyses were conducted using 13-week data from the combined CYMBALTA 60 mg and 120 mg once daily treatment groups compared to the placebo group. Study OA-1: Two hundred fifty-six patients (N=128 on CYMBALTA, N=128 on placebo) enrolled and 204 (80%) completed the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking CYMBALTA had significantly greater pain reduction. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use. Study OA-2: Two hundred thirty-one patients (N=111 on CYMBALTA, N=120 on placebo) enrolled and 173 (75%) completed the study. Patients had a mean baseline pain of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking CYMBALTA did not show a significantly greater pain reduction. In Study OA-1, for various degrees of improvement in pain from baseline to study endpoint, Figure 7 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned the value of 0% improvement. Figure 9: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – OA-1 Figure 9
HOW SUPPLIED
Product: 68151-4734 NDC: 68151-4734-6 1 CAPSULE, DELAYED RELEASE in a PACKAGE
RECENT MAJOR CHANGES
Boxed Warning: Suicidal Thoughts and Behaviors 10/2014 Indications and Usage (1) 10/2014 Dosage and Administration: Dosage for Treatment of Generalized Anxiety Disorder (2.2) 10/2014 Contraindications: Uncontrolled Narrow-Angle Glaucoma (4.2) Removed 07/2014 Warnings and Precautions: Orthostatic Hypotension, Falls and Syncope (5.3) 11/2014 Angle-Closure Glaucoma (5.9) 07/2014
GERIATRIC USE
8.5 Geriatric Use Of the 2,418 patients in premarketing clinical studies of CYMBALTA for MDD, 5.9% (143) were 65 years of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. Of the 1,761 patients in FM premarketing studies, 7.9% (140) were 65 years of age or over. In the MDD, GAD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including CYMBALTA have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.13)]. In an analysis of data from all placebo-controlled-trials, patients treated with CYMBALTA reported a higher rate of falls compared to patients treated with placebo. The increased risk appears to be proportional to a patient’s underlying risk for falls. Underlying risk appears to increase steadily with age. As elderly patients tend to have a higher prevalence of risk factors for falls such as medications, medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during treatment with CYMBALTA is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported [see Warnings and Precautions (5.3) and Adverse Reactions (6.10)]. The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the patient is not necessary.
MECHANISM OF ACTION
12.1 Mechanism of Action Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.
INDICATIONS AND USAGE
1 CYMBALTA® is indicated for the treatment of: Major Depressive Disorder [see Clinical Studies (14.1 )] Generalized Anxiety Disorder [see Clinical Studies (14.2 )] Diabetic Peripheral Neuropathy [see Clinical Studies (14.3 )] Fibromyalgia [see Clinical Studies (14.4 )] Chronic Musculoskeletal Pain [see Clinical Studies (14.5 )] CYMBALTA® is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for: Major Depressive Disorder (MDD) (1) Generalized Anxiety Disorder (GAD) (1) Diabetic Peripheral Neuropathic Pain (DPNP) (1) Fibromyalgia (FM) (1) Chronic Musculoskeletal Pain (1)
PEDIATRIC USE
8.4 Pediatric Use Generalized Anxiety Disorder — In pediatric patients aged 7 to 17 years, efficacy was demonstrated in one 10-week, placebo-controlled trial. The study included 272 pediatric patients with GAD of which 47% were 7 to 11 years of age. CYMBALTA demonstrated superiority over placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score [see Clinical Studies (14.2)]. The safety and effectiveness in pediatric patients less than 7 years of age have not been established. Major Depressive Disorder — Efficacy was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients with MDD, age 7-17. Neither CYMBALTA nor an active control (indicated for treatment of pediatric depression) was superior to placebo. The safety and effectiveness in pediatric patients less than 7 years of age have not been established. The most frequently observed adverse reactions in the clinical trials included nausea, headache, decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as CYMBALTA [see Adverse Reactions (6.11)]. Use of CYMBALTA in a child or adolescent must balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions (5.1)]. Animal Data — Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug treatment was discontinued. These effects were observed at the high dose of 45 mg/kg/day (2 times the MRHD, for a child); the no-effect-level was 20 mg/kg/day (≈1 times the MRHD, for a child).
PREGNANCY
8.1 Pregnancy Pregnancy Category C Pregnancy Exposure Registry — There is a pregnancy registry that monitors the pregnancy outcomes in women exposed to CYMBALTA during pregnancy. To enroll, contact the CYMBALTA Pregnancy Registry at 1-866-814-6975 or www.cymbaltapregnancyregistry.com. Risk Summary — There are no adequate and well-controlled studies of CYMBALTA administration in pregnant women. In animal studies with duloxetine, fetal weights were decreased but there was no evidence of teratogenicity in pregnant rats and rabbits at oral doses administered during the period of organogenesis up to 4 and 7 times the maximum recommended human dose (MRHD) of 120 mg/day, respectively. When duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD. At this dose, pup behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed. Post-weaning growth was not adversely affected. CYMBALTA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reaction — Neonates exposed during pregnancy to serotonin – norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding which can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of the SNRIs or SSRIs, or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.4)]. Data Animal Data — In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development. When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (4 times the maximum recommended human dose (MRHD) of 120 mg/day on a mg/m2 basis, in rat; 7 times the MRHD in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day approximately equal to the MRHD in rats; 2 times the MRHD in rabbits). When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (2 times the MRHD); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment.
NUSRING MOTHERS
8.3 Nursing Mothers Risk Summary CYMBALTA is present in human milk. In a published study, lactating women who were weaning their infants were given CYMBALTA. At steady state, the concentration of CYMBALTA in breast milk was approximately 25% that of maternal plasma. The estimated daily infant dose was approximately 0.14% of the maternal dose. The developmental and health benefits of human milk feeding should be considered along with the mother’s clinical need for CYMBALTA and any potential adverse effects on the milk-fed child from the drug or from the underlying maternal condition. Exercise caution when CYMBALTA is administered to a nursing woman. Data The disposition of CYMBALTA was studied in 6 lactating women who were at least 12 weeks postpartum and had elected to wean their infants. The women were given 40 mg of CYMBALTA twice daily for 3.5 days. The peak concentration measured in breast milk occurred at a median of 3 hours after the dose. The amount of CYMBALTA in breast milk was approximately 7 mcg/day while on that dose; the estimated daily infant dose was approximately 2 mcg/kg/day. The presence of CYMBALTA metabolites in breast milk was not examined.
BOXED WARNING
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.1)]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1)]. WARNING: SUICIDALTHOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants (5.1) Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1)
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported in patients treated with CYMBALTA. CYMBALTA should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. CYMBALTA should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease (5.2) Orthostatic Hypotension, Falls and Syncope: Cases have been reported with CYMBALTA therapy (5.3) Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including with CYMBALTA, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John’s Wort). If such symptoms occur, discontinue CYMBALTA and initiate supportive treatment. If concomitant use of CYMBALTA with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.4) Abnormal Bleeding: CYMBALTA may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with the concomitant use of CYMBALTA and NSAIDs, aspirin, or other drugs that affect coagulation (5.5, 7.4) Severe Skin Reactions: Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with CYMBALTA. CYMBALTA should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified. (5.6) Discontinuation: May result in symptoms, including dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue (5.7) Activation of mania or hypomania has occurred (5.8) Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.9) Seizures: Prescribe with care in patients with a history of seizure disorder (5.10) Blood Pressure: Monitor blood pressure prior to initiating treatment and periodically throughout treatment (5.11) Inhibitors of CYP1A2 or Thioridazine: Should not administer with CYMBALTA (5.12) Hyponatremia: Cases of hyponatremia have been reported (5.13) Glucose Control in Diabetes: In diabetic peripheral neuropathic pain patients, small increases in fasting blood glucose, and HbA1c have been observed (5.14) Conditions that Slow Gastric Emptying: Use cautiously in these patients (5.14) Urinary Hesitation and Retention (5.15) 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo 3 times the upper limit of normal occurred in 1.25% (144/11,496) of CYMBALTA-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In adult placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively. Because it is possible that CYMBALTA and alcohol may interact to cause liver injury or that CYMBALTA may aggravate pre-existing liver disease, CYMBALTA should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. 5.3 Orthostatic Hypotension, Falls and Syncope Orthostatic hypotension, falls and syncope have been reported with therapeutic doses of CYMBALTA. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during CYMBALTA treatment, particularly after dose increases. The risk of falling appears to be related to the degree of orthostatic decrease in blood pressure as well as other factors that may increase the underlying risk of falls. In an analysis of patients from all placebo-controlled trials, patients treated with CYMBALTA reported a higher rate of falls compared to patients treated with placebo. Risk appears to be related to the presence of orthostatic decrease in blood pressure. The risk of blood pressure decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors [see Warnings and Precautions (5.12) and Drug Interactions (7.1)] and in patients taking CYMBALTA at doses above 60 mg daily. Consideration should be given to dose reduction or discontinuation of CYMBALTA in patients who experience symptomatic orthostatic hypotension, falls and/or syncope during CYMBALTA therapy. Risk of falling also appeared to be proportional to a patient’s underlying risk for falls and appeared to increase steadily with age. As elderly patients tend to have a higher underlying risk for falls due to a higher prevalence of risk factors such as use of multiple medications, medical comorbidities and gait disturbances, the impact of increasing age by itself is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported [see Adverse Reactions (6.10) and Patient Counseling Information (17)]. 5.4 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including CYMBALTA, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of CYMBALTA with MAOIs intended to treat psychiatric disorders is contraindicated. CYMBALTA should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking CYMBALTA. CYMBALTA should be discontinued before initiating treatment with the MAOI [see Dosage and Administration (2.8, 2.9), and Contraindications (4)]. If concomitant use of CYMBALTA with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with CYMBALTA and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. 5.5 Abnormal Bleeding SSRIs and SNRIs, including CYMBALTA, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of CYMBALTA and NSAIDs, aspirin, or other drugs that affect coagulation. 5.6 Severe Skin Reactions Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with CYMBALTA. The reporting rate of SJS associated with CYMBALTA use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting. CYMBALTA should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified. 5.7 Discontinuation of Treatment with CYMBALTA Discontinuation symptoms have been systematically evaluated in patients taking CYMBALTA. Following abrupt or tapered discontinuation in adult placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in CYMBALTA-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Patients should be monitored for these symptoms when discontinuing treatment with CYMBALTA. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. 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 [see Dosage and Administration (2.7)]. 5.8 Activation of Mania/Hypomania In adult placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (4/3779) of CYMBALTA-treated patients and 0.04% (1/2536) of placebo-treated patients. No activation of mania or hypomania was reported in DPNP, GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, CYMBALTA should be used cautiously in patients with a history of mania. 5.9 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including CYMBALTA may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.10 Seizures CYMBALTA has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In adult placebo-controlled clinical trials, seizures/convulsions occurred in 0.02% (3/12,722) of patients treated with CYMBALTA and 0.01% (1/9513) of patients treated with placebo. CYMBALTA should be prescribed with care in patients with a history of a seizure disorder. 5.11 Effect on Blood Pressure In adult placebo-controlled clinical trials across indications from baseline to endpoint, CYMBALTA treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.3 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of CYMBALTA on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment [see Adverse Reactions (6.7)]. 5.12 Clinically Important Drug Interactions Both CYP1A2 and CYP2D6 are responsible for CYMBALTA metabolism. Potential for Other Drugs to Affect CYMBALTA CYP1A2 Inhibitors — Co-administration of CYMBALTA with potent CYP1A2 inhibitors should be avoided [see Drug Interactions (7.1)]. CYP2D6 Inhibitors — Because CYP2D6 is involved in CYMBALTA metabolism, concomitant use of CYMBALTA with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of CYMBALTA [see Drug Interactions (7.2)]. Potential for CYMBALTA to Affect Other Drugs Drugs Metabolized by CYP2D6 — Co-administration of CYMBALTA with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with CYMBALTA. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, CYMBALTA and thioridazine should not be co-administered [see Drug Interactions (7.9)]. Other Clinically Important Drug Interactions Alcohol — Use of CYMBALTA concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, CYMBALTA should not be prescribed for patients with substantial alcohol use [see Warnings and Precautions (5.2) and Drug Interactions (7.15)]. CNS Acting Drugs — Given the primary CNS effects of CYMBALTA, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action [see Warnings and Precautions (5.12) and Drug Interactions (7.16)]. 5.13 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including CYMBALTA. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when CYMBALTA was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of CYMBALTA should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.14 Use in Patients with Concomitant Illness Clinical experience with CYMBALTA in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of CYMBALTA’s enteric coating. In extremely acidic conditions, CYMBALTA, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using CYMBALTA in patients with conditions that may slow gastric emptying (e.g., some diabetics). CYMBALTA has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing. Hepatic Impairment — Avoid use in patients with chronic liver disease or cirrhosis [see Dosage and Administration (2.6), Warnings and Precautions (5.2), and Use in Specific Populations (8.9)]. Severe Renal Impairment — Avoid use in patients with severe renal impairment, GFR <30 mL/min. Increased plasma concentration of CYMBALTA, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis) [see Dosage and Administration (2.6) and Use in Specific Populations (8.10)]. Glycemic Control in Patients with Diabetes — As observed in DPNP trials, CYMBALTA treatment worsens glycemic control in some patients with diabetes. In three clinical trials of CYMBALTA for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12-week acute treatment phase of these studies, CYMBALTA was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the CYMBALTA group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the CYMBALTA and by 0.2% in the routine care groups. 5.15 Urinary Hesitation and Retention CYMBALTA is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with CYMBALTA, consideration should be given to the possibility that they might be drug-related. In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with CYMBALTA use, hospitalization and/or catheterization has been needed. 5.16 Laboratory Tests No specific laboratory tests are recommended.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Information on Medication Guide — Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with CYMBALTA and counsel them in its appropriate use. A patient Medication Guide is available for CYMBALTA. Instruct patients, their families, and their caregivers to read the Medication Guide before starting CYMBALTA and each time their prescription is renewed, and assist them in understanding its contents. Give patients the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Advise patients of the following issues and ask them to alert their prescriber if these occur while taking CYMBALTA. Suicidal Thoughts and Behaviors — Encourage patients, their families, and their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Boxed Warning, and Warnings and Precautions (5.1)]. CYMBALTA should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Continuing the Therapy Prescribed — While patients may notice improvement with CYMBALTA therapy in 1 to 4 weeks, advise patients to continue therapy as directed. Hepatotoxicity — Inform patients that severe liver problems, sometimes fatal, have been reported in patients treated with CYMBALTA. Instruct patients to talk to their healthcare provider if they develop itching, right upper belly pain, dark urine, or yellow skin/eyes while taking CYMBALTA, which may be signs of liver problems. Instruct patients to talk to their healthcare provider about their alcohol consumption. Use of CYMBALTA with heavy alcohol intake may be associated with severe liver injury [see Warnings and Precautions (5.2)]. Alcohol — Although CYMBALTA does not increase the impairment of mental and motor skills caused by alcohol, use of CYMBALTA concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, CYMBALTA should not be prescribed for patients with substantial alcohol use [see Warnings and Precautions (5.2) and Drug Interactions (7.15)]. Orthostatic Hypotension, Falls and Syncope — Advise patients of the risk of orthostatic hypotension, falls and syncope, especially during the period of initial use and subsequent dose escalation, and in association with the use of concomitant drugs that might potentiate the orthostatic effect of CYMBALTA [see Warnings and Precautions (5.3)]. Serotonin Syndrome — Caution patients about the risk of serotonin syndrome with the concomitant use of CYMBALTA and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John’s Wort [see Contraindications (4), Warnings and Precautions (5.4), and Drug Interactions (7.14)]. Advise patients of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Caution patients to seek medical care immediately if they experience these symptoms. Abnormal Bleeding — Caution patients about the concomitant use of CYMBALTA and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [see Warnings and Precautions (5.5)]. Severe Skin Reactions — Caution patients that CYMBALTA may cause serious skin reactions. This may need to be treated in a hospital and may be life-threatening. Counsel patients to call their doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions [see Warnings and Precautions (5.6)]. Discontinuation of Treatment — Instruct patients that discontinuation of CYMBALTA may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue, and should be advised not to alter their dosing regimen, or stop taking CYMBALTA without consulting their physician [see Warnings and Precautions (5.7)]. Activation of Mania or Hypomania — Adequately screen patients with depressive symptoms for risk of bipolar disorder (e.g. family history of suicide, bipolar disorder, and depression) prior to initiating treatment with CYMBALTA. Advise patients to report any signs or symptoms of a manic reaction such as greatly increased energy, severe trouble sleeping, racing thoughts, reckless behavior, talking more or faster than usual, unusually grand ideas, and excessive happiness or irritability [see Warnings and Precautions (5.8)]. Angle-Closure Glaucoma — Advise patients that taking CYMBALTA can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. [See Warnings and Precautions (5.9)]. Seizures — Advise patients to inform their physician if they have a history of seizure disorder [see Warnings and Precautions (5.10)]. Effects on Blood Pressure — Caution patients that CYMBALTA may cause an increase in blood pressure [see Warnings and Precautions (5.11)]. Concomitant Medications — Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions [see Dosage and Administration (2.8, 2.9), Contraindications (4), Warnings and Precautions (5.4, 5.12), and Drug Interactions (7)]. Hyponatremia — Advise patients that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including CYMBALTA. Advise patients of the signs and symptoms of hyponatremia [see Warnings and Precautions (5.13)]. Concomitant Illnesses — Advise patients to inform their physicians about all of their medical conditions [see Warnings and Precautions (5.14)]. CYMBALTA is in a class of medicines that may affect urination. Instruct patients to consult with their healthcare provider if they develop any problems with urine flow [see Warnings and Precautions (5.15)]. Pregnancy and Nursing Mothers Advise patients to notify their physician if they: become pregnant during therapy intend to become pregnant during therapy are nursing [see Use in Specific Populations (8.1, 8.3)]. Pediatric Use — Safety and efficacy of CYMBALTA in patients 7 to 17 years of age have been established for the treatment of GAD. The types of adverse reactions observed with CYMBALTA in children and adolescents were generally similar to those observed in adults. The safety and effectiveness of CYMBALTA have not been established in pediatric patients less than 18 years of age with other indications. [See Use in Specific Populations (8.4)]. Interference with Psychomotor Performance — Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies CYMBALTA has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Therefore, caution patients about operating hazardous machinery including automobiles, until they are reasonably certain that CYMBALTA therapy does not affect their ability to engage in such activities. Literature revised June 2015 Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2004, 2015, Eli Lilly and Company. All rights reserved. CYM-0006-USPI-20150618
DOSAGE AND ADMINISTRATION
2 Swallow CYMBALTA whole. Do not chew or crush. Do not open the capsule and sprinkle its contents on food or mix with liquids. All of these might affect the enteric coating. CYMBALTA can be given without regard to meals. If a dose of CYMBALTA is missed, take the missed dose as soon as it is remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time. Do not take two doses of CYMBALTA at the same time. Take CYMBALTA once daily, with or without food. Swallow CYMBALTA whole; do not crush or chew, do not open capsule. Take a missed dose as soon as it is remembered. Do not take two doses of CYMBALTA at the same time. (2) Indication Starting Dose Target Dose Maximum Dose MDD (2.1) 40 mg/day to 60 mg/day Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance Treatment: 60 mg/day 120 mg/day GAD (2.2) Adults 60 mg/day 60 mg/day (once daily) 120 mg/day Elderly 30 mg/day 60 mg/day (once daily) 120 mg/day Children and Adolescents (7 to 17 years of age) 30 mg/day 30 to 60 mg/day (once daily) 120 mg/day DPNP (2.3) 60 mg/day 60 mg/day (once daily) 60 mg/day FM (2.4) 30 mg/day 60 mg/day (once daily) 60 mg/day Chronic Musculoskeletal Pain (2.5) 30 mg/day 60 mg/day (once daily) 60 mg/day Some patients may benefit from starting at 30 mg once daily (2) There is no evidence that doses greater than 60 mg/day confers additional benefit, while some adverse reactions were observed to be dose-dependent (2) Discontinuing CYMBALTA: Gradually reduce dosage to avoid discontinuation symptoms (2.7, 5.7) Hepatic Impairment: Avoid use in patients with chronic liver disease or cirrhosis (5.14) Renal Impairment: Avoid use in patients with severe renal impairment, GFR <30 mL/min (5.14) 2.1 Dosage for Treatment of Major Depressive Disorder Administer CYMBALTA at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated. Periodically reassess to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.1)]. 2.2 Dosage for Treatment of Generalized Anxiety Disorder Adults — For most patients, initiate CYMBALTA 60 mg once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)]. Elderly — Initiate CYMBALTA at a dose of 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg. Thereafter, patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. Safety of doses above 120 mg once daily has not been adequately evaluated [see Clinical Studies (14.2)]. Children and Adolescents (7 to 17 years of age) — Initiate CYMBALTA at a dose of 30 mg once daily for 2 weeks before considering an increase to 60 mg. The recommended dose range is 30 to 60 mg once daily. Some patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. The safety of doses above 120 mg once daily has not been evaluated [see Clinical Studies (14.2)]. 2.3 Dosage for Treatment of Diabetic Peripheral Neuropathic Pain Administer CYMBALTA 60 mg once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see Clinical Studies (14.3)]. For patients for whom tolerability is a concern, a lower starting dose may be considered. Since diabetes is frequently complicated by renal disease, consider a lower starting dose and gradual increase in dose for patients with renal impairment [see Dosage and Administration (2.6), Use in Specific Populations (8.10), and Clinical Pharmacology (12.3)]. 2.4 Dosage for Treatment of Fibromyalgia Administer CYMBALTA 60 mg once daily. Begin treatment at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence that doses greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.4)]. 2.5 Dosage for Treatment of Chronic Musculoskeletal Pain Administer CYMBALTA 60 mg once daily. Begin treatment at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.5)]. 2.6 Dosing in Special Populations Hepatic Impairment — Avoid use in patients with chronic liver disease or cirrhosis [see Warnings and Precautions (5.14) and Use in Specific Populations (8.9)]. Severe Renal Impairment — Avoid use in patients with severe renal impairment, GFR <30 mL/min [see Warnings and Precautions (5.14) and Use in Specific Populations (8.10)]. 2.7 Discontinuing CYMBALTA Adverse reactions after discontinuation of CYMBALTA, after abrupt or tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions (5.7)]. 2.8 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with CYMBALTA. Conversely, at least 5 days should be allowed after stopping CYMBALTA before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4)]. 2.9 Use of CYMBALTA with Other MAOIs such as Linezolid or Methylene Blue Do not start CYMBALTA in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4)]. In some cases, a patient already receiving CYMBALTA therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, CYMBALTA should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with CYMBALTA may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.4)]. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with CYMBALTA is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.4)].