Cymbalta

/ Eli Lilly

Initial Treatment UMajor Depressive DisorderU: Cymbalta should be administered at a total dose of 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.
Generalized Anxiety Disorder: For most patients, the recommended starting dose for Cymbalta is 60 mg administered 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, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated.
Diabetic Peripheral Neuropathic Pain: The recommended dose for Cymbalta is 60 mg administered 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. For patients for whom tolerability is a concern, a lower starting dose may be considered. Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment.
Fibromyalgia: The recommended dose for Cymbalta is 60 mg administered once daily. Treatment should begin 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.
Chronic Musculoskeletal Pain: The recommended dose for Cymbalta is 60 mg once daily. Dosing may be started 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.
For full details see prescribing information.

For the treatment of major depressive episodes, neuropathic pain associated with diabetic peripheral neuropathy, generalized anxiety disorder (GAD), fibromyalgia and chronic muscoskeletal pain. This has been established in studies in patients with chronic low back pain and chronic pain due to osteoarthritis when other therapies have failed or are contra-indicated.

Monoamine Oxidase Inhibitors: Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serious, sometimes fatal, drug interactions with serotonergic drugs. These interactions may include 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 an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome.

Clinical Worsening and Suicide Risk: 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. See prescribing information for full details.;

Clinical Trial Data Sources: The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=3007), GAD (N=910), OA (N=239), CLBP (N=600), DPNP (N=906), and FM (N=1139). The population studied was 17 to 91 years of age; 65.0%, 62.5%, 61.5%, 42.9%, and 94.4% female; and 82.7%, 81.2%, 86.2 %, 74.0%, and 85.7% Caucasian for MDD, GAD, OA and CLBP, DPNP, and FM, respectively. Most patients received doses of a total of 60 to 120 mg per day. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials Major Depressive Disorder:  Approximately 8.5% (256/3007) of the patients who received duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.8% (91/1883) of the patients receiving placebo. Nausea (duloxetine 1.2%, placebo 0.4%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine-treated patients and at a rate of at least twice that of placebo).
Generalized Anxiety Disorder: Approximately 13.8% (126/910) of the patients who received duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 5.3% (35/665) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.3%, placebo 0.5%), dizziness (duloxetine 1.0%, placebo 0.5%), and vomiting (duloxetine 1.0%, placebo 0.2%).
Diabetic Peripheral Neuropathic Pain: Approximately 12.9% (117/906) of the patients who received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.5%, placebo 0.7%), dizziness (duloxetine 1.2%, placebo 0.4%), and somnolence (duloxetine 1.1%, placebo 0.0%).
Fibromyalgia: Approximately 18.7% (213/1139) of the patients who received duloxetine in 3 to 6 month placebo-controlled trials for FM discontinued treatment due to an adverse reaction, compared with 10.8% (87/802) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.1%, placebo 0.5%), headache (duloxetine 1.2%, placebo 0.2%), somnolence (duloxetine 1.2%, placebo 0.0%), and fatigue (duloxetine 1.1%, placebo 0.1%).
Chronic Pain due to Osteoarthritis: Approximately 16.3% (39/239) of the patients who received duloxetine in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 5.6% (14/248) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.9%, placebo 0.8%) and asthenia (duloxetine 1.3%, placebo 0.0%).
Chronic Low Back Pain – Approximately 16.5% (99/600) of the patients who received duloxetine in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.0%, placebo 0.7%), and somnolence (duloxetine 1.0%, placebo 0.0%).
Most Pooled Trials for all Approved Indications: The most commonly observed adverse reactions in Cymbalta-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, fatigue, constipation, decreased appetite, and hyperhidrosis.
Diabetic Peripheral Neuropathic Pain: The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth. Fibromyalgia: The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation.
Chronic Pain due to Osteoarthritis: The most commonly observed adverse reactions in Cymbalta-treated patients were nausea, fatigue, and constipation.
Chronic Low Back Pain: The most commonly observed adverse reactions in Cymbalta-treated patients were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.
For full details see prescribing information.

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Inhibitors of CYP1A2 (fluvoxamine, cimetidine, quinolone). Inhibitors of CYP2D6 (paroxetine, fluoxetine, quinidine)//Dual Inhibition of CYP1A2 and CYP2D6 (fluvoxamine)//Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin). Drugs that Affect Gastric Acidity It 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, the drug, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using this drug 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 it with aluminum- and magnesium-containing antacids (51 mEq) or with famotidine, had no significant effect on the rate or extent of it absorption after administration of a 40 mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects the drug absorption. Drugs Metabolized by CYP1A2 In vitro drug interaction studies demonstrate that it 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. The drug 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 the drug (60 mg twice daily). Drugs Metabolized by CYP2D6 It is a moderate inhibitor of CYP2D6. When the drug 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.// Monoamine Oxidase Inhibitors Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including this drug, and the potential for serotonin syndrome, caution is advised when the drug is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John? Wort. The concomitant use of it with other SSRIs, SNRIs or tryptophan is not recommended.//Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of the drug with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Alcohol When the drug and ethanol were administered several hours apart so that peak concentrations of each would coincide, it did not increase the impairment of mental and motor skills caused by alcohol. In the drug clinical trials database, three patients treated by the drug 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. CNS Drugs Given the primary CNS effects of the drug, 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. Drugs Highly Bound to Plasma Protein Because duloxetine is highly bound to plasma protein, administration of the drug 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).
For full details see prescribing information.

Teratogenic Effects, Pregnancy Category C: 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 (7 times the maximum recommended human dose [MRHD, 60 mg/day] and 4 times the human dose of 120 mg/day on a mg/m2 basis, in rat; 15 times the MRHD and 7 times the human dose of 120 mg/day on a mg/m2 basis in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (2 times the MRHD and ≈1 times the human dose of 120 mg/day on a mg/m2 basis in rat; 3 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis 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 (5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis); 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. There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects – Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), 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 SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome When treating pregnant women with Cymbalta during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Cymbalta in the third trimester.
Labor and Delivery: The effect of duloxetine on labor and delivery in humans is unknown. Duloxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: 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. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics. The disposition of duloxetine was studied in 6 lactating women who were at least 12 weeks postpartum. Duloxetine 40 mg twice daily was given for 3.5 days. Like many other drugs, duloxetine is detected in breast milk, and steady state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 μg/day while on 40 mg BID dosing. The excretion of duloxetine metabolites into breast milk was not examined. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended.
Pediatric Use: Safety and effectiveness in the pediatric population have not been established. Anyone considering the use of Cymbalta in a child or adolescent must balance the potential risks with the clinical need.

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.
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. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).
See prescribing information for full details.