Discontinuation symptoms have been systematically evaluated in patients taking CYMBALTA. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at a rate greater than or equal to 1% and at a significantly higher rate in CYMBALTA-treated patients compared with those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, nightmare, fatigue, insomnia, diarrhea, anxiety, hyperhidrosis, and vertigo. Although these events are generally self-limiting, some have been reported to be severe. (See Warnings and Precautions, Discontinuation of Treatment and Dosage and Administration.) CYMBALTA is in a class of drugs known to affect urethral resistance during the filling stage of the bladder. In placebo-controlled clinical trials in patients with MDD and DPN, urinary hesitation on voiding was reported in <1% of female patients and approximately 1% of male patients. If symptoms of urinary hesitation develop during treatment with CYMBALTA, consideration should be given to the possibility that they might be drug-related. In one fibromyalgia study the most common adverse events that occurred in the duloxetine 120 mg QD group at an incidence rate that was 5% or greater, and approximately twice that of the duloxetine 60 mg/day group included the following: constipation (21.1% vs. 10.0%; p=.01) and somnolence (15.0% vs. 7.3%, p=.043). In another fibromyalgia study somnolence was the most common adverse event that occurred in the duloxetine 60 mg BID group at an incidence rate that was 5% or greater, and approximately twice that of the duloxetine 60 mg QD group (12.1% vs. 5.1%, p=.064). In DPN trials, CYMBALTA treatment worsened glycemic control in some diabetic patients. In three clinical trials of CYMBALTA for the management of pain associated with DPN, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 9.8 mmol/L (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 0.67 mmol/L (12 mg/dL) in the CYMBALTA group and decreased by 0.64 mmol/L (11.5 mg/dL) in the routine care group, which was statistically different. HbA1c increased by 0.5% in the CYMBALTA group and by 0.2% in the routine care groups. Post-marketing surveillance has identified reports of hepatic injury, including hepatocellular, pure cholestatic and mixed injury ranging from mild elevations in laboratory values to more severe clinical signs and symptoms of liver injury. Isolated cases of liver failure, including fatal cases, have been reported. Most of these cases have been reported in patients with past or current medical and other risk factors for liver injury, including alcohol abuse, hepatitis, or exposure to drugs with known adverse effects on the liver and it is unclear to what extent duloxetine may have played a contributing role (see Contraindications and Warnings and Precautions, Hepatotoxicity).
Indications and Clinical UseCYMBALTA is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN). CYMBALTA (duloxetine hydrochloride) is indicated for the symptomatic relief of major depressive disorder (MDD). The efficacy of CYMBALTA in maintaining an antidepressant response for up to 6 months in patients who have shown initial treatment response following 12 weeks of open label acute treatment was demonstrated in a placebo-controlled trial. The efficacy of CYMBALTA in hospitalized patients with MDD has not been studied. The safety and efficacy of CYMBALTA in paediatric patients (<18 years of age) have not been established and its use in this patient population is not indicated. See Warnings and Precautions, General, Potential Association with Behavioural And Emotional Changes, Including Self-Harm; see also Dosage and Administration. CYMBALTA is indicated for the symptomatic relief of anxiety causing clinically significant distress in patients with generalized anxiety disorder (GAD). The efficacy of CYMBALTA in maintaining anxiolytic response for up to 6 months in patients with GAD was demonstrated in a long-term placebo-controlled trial in patients who had initially responded to CYMBALTA during a 6-month open-label phase. CYMBALTA is indicated for the management of pain associated with fibromyalgia (FM). The effectiveness of CYMBALTA in long-term use (i.e. more than 6 months in patients with MDD, and 12 weeks in patients with DPN or FM) has not been systematically evaluated in controlled clinical trials. The physician who elects to use CYMBALTA for extended periods in any indication should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Pharmacokinetic results suggest no overall differences between these subjects and younger subjects. 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 (see Warnings and Precautions, Special Populations, Geriatrics (≥65 years of age) and Action and Clinical Pharmacology, Special Populations and Conditions).
OverdosageIn animal studies, the major signs of overdose toxicity related to the central nervous and gastrointestinal systems. These included central nervous system effects such as tremors, clonic convulsions, ataxia, emesis, and decreased appetite. In clinical trials, cases of acute ingestions above 3000 mg, alone or in combination with other drugs, were reported, with none being fatal. However, in post marketing experience fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, serotonin syndrome, seizures, vomiting, and tachycardia. No specific antidote is known, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. An airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption. Duloxetine has a large volume of distribution and forced diuresis, hemoperfusion, and exchange perfusion are unlikely to be beneficial. In managing overdose, consider the possibility of multiple drug involvement. A specific caution involves patients who are taking or have recently taken duloxetine and might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation 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 Drug Interactions).
Dosage Forms, Composition and PackagingEach opaque green body and opaque blue cap, delayed-release capsule, imprinted “60 mg” on the body and “9542” on the cap contains: duloxetine HCl 60 mg. Nonmedicinal ingredients: FD&C Blue No. 2, gelatin, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate and yellow iron oxide. Blisters of 7 and 28. Each opaque white body and opaque blue cap, delayed-release capsule, imprinted “30 mg” on the body and “9543” on the cap contains: duloxetine HCl 30 mg. Nonmedicinal ingredients: FD&C Blue No. 2, gelatin, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide and triethyl citrate. Blisters of 7 and 28.
Warnings and PrecautionsIncreased plasma concentrations of duloxetine occur in patients with end-stage renal disease (requiring dialysis). For this reason CYMBALTA is not recommended for patients with end-stage renal disease or severe renal impairment (see Action and Clinical Pharmacology, Renal Insufficiency; and Dosage and Administration, Dosage for Patients with Renal Impairment). Recent analyses of placebo-controlled clinical trial safety databases from selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo. The small denominators in the clinical trials database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs. Post-marketing reports indicate that some neonates exposed to SSRIs or newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications 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 SSRIs and other newer antidepressants or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Contraindications, Monoamine Oxidase Inhibitors (MAOIs)). When treating a pregnant woman with CYMBALTA during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Dosage and Administration, Treatment of Pregnant Women During the Third Trimester). There are no adequate and well-controlled studies in pregnant women. In animal reproductive studies, duloxetine has been shown to have adverse effects on embryo/fetal and post-natal development. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Clinical experience with CYMBALTA in patients with concomitant systemic illnesses is limited. Caution is advisable when using CYMBALTA in patients with diseases or conditions that produce altered metabolism or hemodynamic responses. For example, caution should be exercised in using CYMBALTA in patients with conditions that slow gastric emptying (e.g., some patients with diabetic gastroparesis) (see Drug Interactions, Potential for Interaction with Drugs that Affect Gastric Acidity). On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment with SSRIs, particularly when given in combination with other serotonergic and/or neuroleptic drugs. Serotonin syndrome symptoms may include mental status changes (e.g., confusion, irritability, extreme agitation progressing to delirium and coma), autonomic instability with rapid fluctuations of vital signs (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., rigidity, myoclonus, hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). As these syndromes may result in potentially life-threatening conditions, treatment with CYMBALTA should be discontinued if such events occur and supportive symptomatic treatment should be initiated. CYMBALTA should not be used in combination with MAOIs (including linezolid, an antibiotic which is a non-selective reversible MAOI) or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, tramadol, St. John’s Wort) due to the risk of serotonergic syndrome (see Contraindications and Drug Interactions). There have been reports of bleeding abnormalities with selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs), including very rare cases of ecchymoses and gastrointestinal bleeding reported with CYMBALTA (see Adverse Reactions, Post-Market Adverse Drug Reactions). While a causal relationship to CYMBALTA has not been established, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences. Skin and other mucous membrane bleedings have been reported following treatment with CYMBALTA. Thus, caution is advised in patients taking anticoagulants (e.g. warfarin) and/or medicinal products known to affect platelet function (e.g. nonsteroidal anti-inflammatories and ASA), and in patients with known tendency for bleeding or those with predisposing conditions. Safe use of CYMBALTA during pregnancy has not been established. Therefore, CYMBALTA should not be administered to pregnant women or those intending to become pregnant, unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible hazards to the fetus. Because CYP1A2 is involved in duloxetine metabolism, the potential exists for increased concentrations of duloxetine when co-administered with a CYP1A2 inhibitor. Fluvoxamine (100 mg QD), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77%. CYMBALTA should not be used concomitantly with potent CYP1A2 inhibitors (e.g. fluvoxamine) and some quinolone antibiotics (e.g. ciprofloxacin, or enoxacine). See Contraindications and Drug Interactions. CYMBALTA increases the risk of elevation of serum aminotransferase levels. In clinical trials, the median time to detection of the aminotransferase elevation was about two months. In these patients, these were usually transient and self-limiting with continued use, or resolved upon discontinuation of CYMBALTA. Liver aminotransferase elevations resulted in the discontinuation of 0.3% (73/23 983) of CYMBALTA-treated patients. In placebo-controlled trials in MDD, elevations of alanine aminotransferase (ALT) to >3 times the upper limit of normal occurred in 0.4% (8/1902) of CYMBALTA-treated patients and in 0.2% (2/1200) of placebo-treated patients. In placebo-controlled trials in DPN, elevations of ALT to >3 times the upper limit of normal occurred in 2% (13/662) of CYMBALTA-treated patients and in 0% (0/281) of placebo-treated patients. In the full cohort of placebo-controlled trials in any indication, elevation of ALT >3 times the upper limit of normal occurred in 1.1% (75/6871) of CYMBALTA-treated patients compared with 0.3% (13/5036) of placebo-treated patients. In 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. Postmarketing reports have described cases of hepatitis with abdominal pain, hepatomegaly and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported (see Adverse Reactions, Post-Market Adverse Drug Reactions, Hepatic). The combination of aminotransferase elevations and elevated bilirubin, without evidence of cholestasis, is generally recognized as an important predictor of severe liver injury. In clinical trials, 7 CYMBALTA patients had elevations of aminotransferase and bilirubin, but 5 of 7 also had elevation of alkaline phosphatase, suggesting an obstructive process; in 3 of these 7 patients, there was evidence of heavy alcohol use and this may have contributed to the abnormalities seen. Two placebo-treated patients also had aminotransferase elevations with elevated bilirubin. Post-marketing reports indicate that elevated aminotransferase, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Severe elevations of liver enzymes (>10 times the upper limit of normal) or liver injury with a cholestatic or mixed pattern have been rarely reported, in some cases associated with excessive alcohol use or pre-existing liver disease. Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, CYMBALTA should ordinarily not be prescribed to patients with substantial alcohol use (see Special Populations, Use In Patients with Substantial Alcohol Use). CYMBALTA should not be used in patients with any liver disease resulting in hepatic impairment (see Contraindications, Hepatic Impairment). CYMBALTA should be used with caution in patients treated with other drugs associated with hepatic injury (see Adverse Reactions, Post-Market Adverse Drug Reactions, Hepatic). Physicians should be aware of the signs and symptoms of liver damage (e.g. pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu-like” symptoms) and should investigate such symptoms promptly. CYMBALTA should be discontinued and should not be restarted in patients with jaundice. In patients receiving a serotonin reuptake inhibitor in combination with a MAOI, there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and are then started on a MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. The effects of combined use of CYMBALTA (duloxetine hydrochloride) and MAOIs have not been evaluated in humans or animals. Therefore, because CYMBALTA is an inhibitor of both serotonin and norepinephrine reuptake, it is recommended that CYMBALTA not be used in combination with a MAOI (including linezolid, an antibiotic which is a non-selective reversible MAOI), or within at least 14 days of discontinuing treatment with a MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping CYMBALTA before starting a MAOI (see Contraindications, Monoamine Oxidase Inhibitors (MAOIs); and Drug Interactions). The safety and efficacy of CYMBALTA in paediatric patients (<18 years of age) have not been established and its use in this patient population is not indicated. See Warnings and Precautions, General, Potential Association with Behavioural And Emotional Changes, Including Self-Harm. See also Dosage and Administration, Dosage for Pediatric Patients; and Indications and Clinical Use, Pediatrics (<18 years of age). Refer to Adverse Reactions, Sexual Function. CYMBALTA capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine. Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant treatment with CYMBALTA and a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. See Warnings and Precautions,Serotonin Syndrome/Neuroleptic Malignant Syndrome, and Drug Interactions, Triptans (5HT1 Agonists). CYMBALTA has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s pre-marketing testing. However, electrocardiograms of 321 patients who received CYMBALTA in MDD placebo-controlled clinical trials and 728 patients who received CYMBALTA in DPN placebo-controlled clinical trials were evaluated; CYMBALTA was not associated with the development of clinically significant ECG abnormalities (see Adverse Reactions, Electrocardiogram Changes). Additionally a clinical pharmacology study was conducted to assess the safety of duloxetine at the highest tolerable level of exposure of duloxetine (200 mg BID) and to measure QT interval. QT interval at doses up to 200 mg BID was not prolonged (see Action and Clinical Pharmacology, Clinical Safety Pharmacology). In MDD and DPN placebo-controlled clinical trials, CYMBALTA-treated patients did not develop abnormal ECGs at a rate different from that in placebo-treated patients (see Adverse Reactions, Electrocardiogram Changes). CYMBALTA has been associated with an increase in blood pressure and clinically significant hypertension in some patients. This may be due to the noradrenergic effect of duloxetine. In clinical trials across indications, relative to placebo, CYMBALTA treatment was associated with a mean increase of approximately 1 mm Hg in both systolic and diastolic blood pressure. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure (see Adverse Reactions, Vital Sign Changes). There was no significant difference between treatment groups in the rate of discontinuation due to elevated blood pressure. CYMBALTA treatment, for up to 26 weeks in placebo-controlled trials typically caused a small mean increase in heart rate compared to placebo of up to 3-4 beats per minute. Cases of hypertensive crisis have been reported very rarely with CYMBALTA, especially in patients with pre-existing hypertension. CYMBALTA should be used with caution in patients with uncontrolled hypertension as it may expose them to hypertensive crisis (see Adverse Reactions, Post-Market Adverse Drug Reactions). Blood pressure and heart rate should be evaluated prior to initiating treatment and periodically measured throughout treatment, especially in patients with known hypertension and/or other cardiac disease. CYMBALTA should be used with caution in patients whose conditions could be compromised by an increased heart rate or by an increase in blood pressure. Caution should also be exercised when CYMBALTA is used with drugs that may impair its metabolism (see Drug Interactions). For patients who experience a sustained increase in blood pressure while receiving CYMBALTA either dose reduction or gradual discontinuation should be considered. There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, and depersonalization. In some cases, the events occurred within several weeks of starting treatment. Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes. Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This effect appears to be dose-related. An in vivo study suggests that drugs which inhibit P4502D6, including certain SSRIs such as paroxetine, fluoxetine, and fluvoxamine, will elevate plasma levels of thioridazine. Therefore, as CYMBALTA is a moderate inhibitor of CYP2D6 and increases the AUC and Cmax of drugs metabolized by CYP2D6, CYMBALTA should not be used in combination with thioridazine. See Contraindications and Drug Interactions. Discontinuation symptoms have been systematically evaluated in patients taking CYMBALTA. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at a rate greater than or equal to 1% and at a significantly higher rate in CYMBALTA-treated patients compared with those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, nightmare, fatigue, insomnia, diarrhoea, anxiety, hyperhidrosis, and vertigo. 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, dose titration should be managed on the basis of the patient’s clinical response (see Adverse Reactions, Adverse Events Following Discontinuation of Treatment; and Dosage and Administration, Discontinuation of Treatment). Any psychoactive drug may impair judgment, thinking, or motor skills. CYMBALTA may be associated with undesirable effects such as sedation and dizziness. Therefore, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that CYMBALTA therapy does not affect their ability to engage in such activities. Use of CYMBALTA in patients who consume substantial amounts of alcohol may be associated with severe liver injury. Isolated cases of liver failure, including fatal cases, have been reported. CYMBALTA should only be used in exceptional circumstances and with extreme caution in these patients (see Warnings and Precautions, Hepatotoxicity, and Adverse Reactions, Post-Market Adverse Drug Reactions, Hepatic). Patients with clinically evident hepatic impairment have decreased duloxetine metabolism and elimination. After a single non-therapeutic (20 mg) dose of CYMBALTA, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer. CYMBALTA is contraindicated in patients with any liver disease resulting in hepatic impairment (see Contraindications, Hepatic Impairment; Action and Clinical Pharmacology, Hepatic Insufficiency; and Dosage and Administration, Dosage for Patients with Hepatic Impairment). In placebo-controlled trials in patients with MDD, activation of mania or hypomania was reported in 0.1% (2/2489) of CYMBALTA-treated patients and 0.1% (1/1625) of placebo-treated patients. No activation of mania or hypomania was reported in DPN, GAD or FM placebo-controlled trials. Activation of mania/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 MDD. As with similar CNS active drugs, CYMBALTA should be used cautiously in patients with a history of mania. A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should be made only after patients have been adequately assessed to determine if they are at risk for bipolar disorder. Of the 2418 CYMBALTA-treated patients in the MDD clinical studies 5.9% (143) were 65 years of age or over. Of the 1429 CYMBALTA-treated patients in the DPN studies, 31.9% (456) were 65 years of age or over. Of the 1226 CYMBALTA-treated patients in FM studies, 7.9% (97) were 65 years of age or over. No overall differences in safety or effectiveness were 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. The effect of duloxetine on labour and delivery in humans is unknown. However, because duloxetine and/or its metabolites cross the placenta in rats and because of the possibility that duloxetine and/or its metabolites may have adverse effects on the newborn, duloxetine should be used during labour and delivery only if the potential benefit justifies the potential risk to the fetus. Patients currently taking SSRIs or newer antidepressants should not be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended (see Warnings and Precautions, Dependence, Discontinuation of Treatment; Adverse Reactions, Adverse Events Following Discontinuation of Treatment; and Dosage and Administration, Discontinuation of Treatment). In clinical trials, CYMBALTA was associated with an increased risk of mydriasis; therefore it should be used cautiously in patients with controlled narrow-angle glaucoma (see Contraindications, Uncontrolled Narrow-Angle Glaucoma). 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. 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 (see Adverse Reactions, Post-Market Adverse Drug Reactions). In animal studies, duloxetine did not demonstrate stimulant or barbiturate-like (depressant) abuse potential. Duloxetine did produce reductions in activity in rodents and monkeys. In drug dependence studies, duloxetine did not demonstrate any dependence-producing potential in monkeys or rats. While CYMBALTA has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behaviour in the clinical trials. However, it is not possible to predict on the basis of pre-marketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of CYMBALTA (e.g. development of tolerance, incrementation of dose, drug-seeking behaviour). Although anticonvulsant effects of duloxetine have been observed in animal studies, CYMBALTA has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product’s premarketing testing. In placebo-controlled clinical trials across all indications, seizures/convulsions occurred in 0.03% (3/9445) of patients treated with duloxetine and 0.01% (1/6770) of patients treated with placebo. As with other CNS active drugs, CYMBALTA should be used with caution in patients with a history of a seizure disorder. No specific laboratory tests are recommended. The possibility of a suicide attempt is inherent in MDD and other psychiatric disorders and may persist until significant remission occurs. As with other drugs with similar pharmacological action (inhibitor of serotonin reuptake [SSRI] or inhibitor of serotonin and norepinephrine reuptake [SNRI]), isolated cases of suicidal ideation and suicidal behaviours have been reported during CYMBALTA therapy or early after treatment discontinuation. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions should be written for the smallest quantity consistent with good patient management, in order to reduce the risk of overdose (see Warnings and Precautions, General, Potential Association with Behavioural And Emotional Changes, Including Self-Harm; Adverse Reactions, Adverse Events Following Discontinuation of Treatment; and Dosage and Administration, Discontinuation of Treatment). Because of the well established comorbidity between depression and other psychiatric disorders, the same precautions observed when treating patients with depression should be observed when treating patients with other psychiatric disorders (see Warnings and Precautions, General, Potential Association with Behavioural And Emotional Changes, Including Self-Harm). Physicians should encourage patients to report any distressing thoughts or feelings at any time. In DPN trials, CYMBALTA treatment worsened glycemic control in some diabetic patients. In three clinical trials of CYMBALTA for the management of pain associated with DPN, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 9.8 mmol/L (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 0.67 mmol/L (12 mg/dL) in the CYMBALTA group and decreased by 0.64 mmol/L (11.5 mg/dL) in the routine care group, which was statistically significantly different. HbA1c increased by 0.5% in the CYMBALTA group and by 0.2% in the routine care groups. Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose. Because the safety of duloxetine in infants is not known, nursing while on CYMBALTA is not recommended. Patients should be advised to notify their physician if they are breast-feeding.
Storage and StabilityStore between 15 and 30°C. Action and Clinical PharmacologyPatients with clinically evident hepatic impairment have decreased duloxetine metabolism and elimination. After a single, non-therapeutic (20 mg) dose of CYMBALTA, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer. CYMBALTA is contraindicated in patients with any liver disease resulting in hepatic impairment (see Contraindications, Hepatic Impairment; Warnings and Precautions, Hepatic Impairment; and Dosage and Administration, Dosage for Patients with Hepatic Impairment). The pharmacokinetics of duloxetine after a single dose of 40 mg were evaluated in 12 healthy elderly females (65 to 77 years) and 12 healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was 24% higher and the half-life 4.3 hours longer in the elderly females. Pharmacokinetic results suggest no overall differences between these subjects and younger subjects. 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. Dosage adjustment based on the age of the patient is not necessary (see Dosage and Administration, Dosage for Elderly Patients). The apparent volume of distribution ranges from 701 to 3800 L (5th to 95th percentile, mean of 1640 L). Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment. In humans, orally administered duloxetine hydrochloride is well absorbed, with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of duloxetine. However, food delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11%). Duloxetine plasma exposure increases in proportion to dose for doses up to 60 mg twice a day. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Based upon AUC, multiple once daily doses of 60 mg produce steady-state concentrations that are approximately 1.5 times higher than that predicted from a 60 mg single dose. Average minimum and maximum steady-state concentrations for the 60 mg QD dose are 27.0 and 89.5 ng/mL, respectively. There is no clinically important difference in the pharmacokinetic parameters of morning and evening doses. CYMBALTA (duloxetine hydrochloride) is a serotonin and norepinephrine reuptake inhibitor, and weakly inhibits dopamine uptake with no significant affinity for histaminergic, dopaminergic, cholinergic, and adrenergic receptors. Duloxetine is also a potent in vitro inhibitor of transporter binding, with 5-HT and transporter NE inhibition constants (Ki) of 0.8 and 7.5 nM, respectively. Duloxetine dose-dependently increased extracellular levels of serotonin and norepinephrine in various brain areas of animals. It is chemically unrelated to other SNRIs, tricyclic, tetracyclic, or other available drugs effective in the treatment of MDD. A clinical pharmacology study was conducted to assess the safety of duloxetine at the highest tolerable level of exposure of duloxetine and measure QT interval. Of the 117 subjects enrolled, 84 were available for statistical analysis at the maximum dosage of 200 mg BID, and 91 on placebo. Seventy subjects (approximately 60%) completed the entire protocol. Compared with placebo, the mean change in the QTcF interval decreased at each time point with duloxetine 200 mg BID, ranging between −3.0 and −6.4 msec. The upper limit of the two-sided 90% confidence intervals was less than 5 msec at each time point, indicating no clinically relevant increase in the QTcF interval. Similar results were found with the covariance approach and the individual correction method. No individual QTcF exceeded 470 msec on either duloxetine or placebo, and only 2 subjects had a categorical QTcF increase >30 msec at either 160 mg BID or 200 mg BID dosages (n=84), compared with 6 subjects (n=97) at placebo. Furthermore, no subject had a maximal QTc interval greater than 450 msec based on the average of replicate QTcF and QTcI values on day four of duloxetine 200 mg BID. The ability to detect relevant changes in QTc intervals in this study was confirmed by observing significant differences in the QTc interval at two time points (mean change in QTcF=6.7 msec at 2 hours, p<0.0001 and 2.7 msec at 6 hours, p=0.0186) with moxifloxacin as compared with placebo. QT interval at doses up to 200 mg BID were not prolonged. No specific pharmacokinetic study was conducted to investigate the effects of race. Due to large interpatient variability, clinically significant differences in drug level exposure among ethnic groups are not likely. The elimination half-life of duloxetine ranges from 8.1 to 17.4 hours (5th to 95th percentile, mean of 12.1 hours) and the apparent plasma clearance ranges from 33 to 261 L/hr (5th to 95th percentile, mean of 101 L/hr). Apparent plasma clearance of duloxetine does not differ between once daily and twice daily dosing. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine following single dose administration of 14C-labelled duloxetine. The majority (72%) of the duloxetine dose is recovered in the urine as metabolites of duloxetine and approximately 19% is recovered in the feces. Duloxetine Cmax and AUC values were approximately 2-fold higher in patients with end stage renal disease (ESRD) receiving chronic intermittent hemodialysis, compared with subjects with normal renal function. In contrast, the elimination half-life was similar in both groups. Studies have not been conducted in patients with a moderate degree of renal dysfunction. Population PK analyses suggest that mild renal dysfunction has no significant effect on duloxetine apparent clearance. CYMBALTA is not recommended for patients with end-stage renal disease or severe renal impairment (see Contraindications; Warnings and Precautions, Renal; and Dosage and Administration, Dosage for Patients with Renal Impairment). In clinical pharmacology studies, the mean apparent clearance of duloxetine was 9 to 55% lower in females as compared with males. In these studies, duloxetine half-life was similar between males and females. A similar effect of gender on the apparent plasma clearance was identified in patients with MDD. Since exposure in males and females spans a similar range, these differences in average clearance values do not appear to be clinically significant. Dosage adjustment based on gender is not necessary. Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labelled duloxetine. Integrated over time, duloxetine comprises about 3% of the total radiolabelled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP2D6 and CYP1A2 catalyze the formation of 2 major metabolites found in plasma and urine (glucuronide conjugate of 4-hydroxy duloxetine, and the sulfate conjugate of 5-hydroxy, 6-methoxy duloxetine). The major circulating metabolites are not pharmacologically active. The effectiveness of duloxetine in the treatment of MDD is presumed to be linked to its inhibition of central nervous system (CNS) neuronal uptake of serotonin and norepinephrine, and a resultant increase in serotonin and norepinephrine neurotransmission. The pain inhibitory action of duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the central nervous system. Studies at clinically relevant doses in humans (i.e., 40-60 mg BID) have shown that duloxetine decreases 5-hydroxytryptamine concentration in the blood and decreases the urinary excretion of norepinephrine and its metabolites, consistent with blockade of serotonin and norepinephrine uptake processes, respectively. Duloxetine undergoes extensive metabolism; however, the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine. Neurochemical and behavioural studies in laboratory animals showed an enhancement of both serotonin and norepinephrine neurotransmission in the CNS. Responses consistent with enhanced serotonergic and noradrenergic neurotransmission include lowered food intake, body weight, and alcohol intake. Duloxetine also normalized pain thresholds in several preclinical models of neuropathic [L5/L6 spinal nerve ligation model and partial sciatic nerve ligation model] and inflammatory pain [carrageenan model and acetic-acid induced writhing model] and attenuated pain behaviour in a model of persistent pain [formalin model, late phase] at doses that are consistent with in vivo blockade of 5HT and NE reuptake sites]. Duloxetine’s affinity for dopamine uptake sites is low. Nevertheless, animal studies have shown increases in extracellular levels of dopamine in prefrontal cortex in addition to increases in norepinephrine and serotonin levels. This is presumed to be associated with the known propensity of cortical norepinephrine transporters to take up dopamine as well as norepinephrine, rather than an effect on dopamine transporters themselves. Safety and efficacy in pediatric patients have not been established. Duloxetine bioavailability appears to be about 34% lower in smokers than in nonsmokers, although dosage modifications are not routinely recommended.
ContraindicationsCYMBALTA is contraindicated in patients with severe renal impairment (i.e. creatinine clearance <30 mL/min) or end-stage renal disease (see Warnings and Precautions, Renal). CYMBALTA is contraindicated in patients with any liver disease resulting in hepatic impairment (see Warnings and Precautions, General, Hepatic Impairment; and Dosage and Administration, Dosage for Patients with Hepatic Impairment). CYMBALTA (duloxetine hydrochloride) is contraindicated in patients with a known hypersensitivity to the drug or the other components of the product. Concomitant use of CYMBALTA and thioridazine is contraindicated (see Warnings and Precautions, General, Thioridazine). CYMBALTA should not be used concomitantly with potent CYP1A2 inhibitors (e.g. fluvoxamine) and some quinolone antibiotics (e.g. ciprofloxacin, or enoxacine) (see Drug Interactions). In clinical trials, CYMBALTA was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma (see Warnings and Precautions, General, Controlled Narrow-Angle Glaucoma). CYMBALTA should not be used concomitantly with a monoamine oxidase inhibitor (MAOI), including linezolid, an antibiotic which is a non-selective reversible MAOI or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping CYMBALTA before starting an MAOI (see Warnings and Precautions, General, Monoamine Oxidase Inhibitors (MAOI)).
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