Tuesday, November 6, 2007

Cymbalta

Here is prescribing info about Cymbalta (Duloxetine HCI)
CYMBALTA®
(duloxetine hydrochloride) Delayed-release Capsules
WARNING
Suicidality and Antidepressant Drugs — Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Order Cymbalta or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Buy Cymbalta is not approved for use in pediatric patients. (See WARNINGS, Clinical Worsening and Suicide Risk, PRECAUTIONS, Information for Patients, PRECAUTIONS, Pediatric Use.)
DESCRIPTION
Cymbalta® (duloxetine hydrochloride) 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.
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CLINICAL PHARMACOLOGY
Pharmacodynamics
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. Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Order Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Buy Duloxetine does not inhibit monoamine oxidase (MAO). Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.
Pharmacokinetics
Cheap Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP1A2.
Absorption and Distribution — Orally administered duloxetine hydrochloride is well absorbed. There is a median 2-hour lag until absorption begins (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. There is a 3-hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose.
The apparent volume of distribution averages about 1640 L. Duloxetine (Buy Cymbalta online) is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment.
Metabolism and Elimination — Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled 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 oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% n="14)" n="14)" n="123" n="128," n="122" n="139," n="86" n="91," n="89)" n="95" n="93," n="93)" n="168" n="162)" n="159" n="161)" n="168)" n="170)" n="175)">3 times
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the upper limit of normal occurred in 0.9% (8/930) of Cymbalta-treated patients and in 0.3% (2/652) of placebo-treated patients. In controlled trials in DPN, elevations of ALT to >3 times the upper limit of normal occurred in 1.68% (8/477) of Cymbalta-treated patients and in 0% (0/187) 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% (39/3732) of Cymbalta-treated patients compared to 0.2% (6/2568) 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, respectively. 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.
The combination of transaminase elevations and elevated bilirubin, without evidence of obstruction, is generally recognized as an important predictor of severe liver injury. In clinical trials, three Cymbalta online patients had elevations of transaminases and bilirubin, but also had elevation of alkaline phosphatase, suggesting an obstructive process; in these patients, there was evidence of heavy alcohol use and this may have contributed to the abnormalities seen. Two placebo-treated patients also had transaminase elevations with elevated bilirubin. Postmarketing reports indicate that elevated transaminases, bilirubin and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, Order Cymbalta should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
Orthostatic Hypotension and Syncope — Orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during duloxetine treatment, particularly after dose increases. 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 CLINICAL PHARMACOLOGY, Drug-Drug Interactions , and PRECAUTIONS, Drug Interactions ) and in patients taking duloxetine at doses above 60 mg daily. Consideration should be given to discontinuing duloxetine in patients who experience symptomatic orthostatic hypotension and/or syncope during duloxetine therapy.
Effect on Blood Pressure — In clinical trials across indications, relative to placebo, duloxetine treatment was associated with mean increases of up to 2.1 mm Hg in systolic blood pressure and up to 2.3 mm Hg in diastolic blood pressure. 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 duloxetine 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 BID. At the highest 200 mg BID dose, the increase in mean pulse rate was 5.0-6.8 bpm and increases in mean blood pressure were 4.7-6.8 mm Hg (systolic) and 4.5-7 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, Vital Sign Changes ).
Activation of Mania/Hypomania — In placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (2/2327) of
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duloxetine-treated patients and 0.1% (1/1460) of placebo-treated patients. No activation of mania or hypomania was reported in DPNP or GAD 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 major depressive disorder. As with these other agents, Cymbalta should be used cautiously in patients with a history of mania.
Seizures —Order Duloxetine online has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In placebo-controlled clinical trials, seizures/convulsions occurred in 0.04% (3/8504) of patients treated with duloxetine and 0.02% (1/6123) of patients treated with placebo. Cymbalta should be prescribed with care in patients with a history of a seizure disorder.
Hyponatremia — Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported and appeared to be reversible when Cymbalta was discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.
Controlled Narrow-Angle Glaucoma — 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 ).
Discontinuation of Treatment with Buy Cymbalta — Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. 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 duloxetine-treated patients compared to those discontinuing from placebo: dizziness; nausea; headache; paresthesia; fatigue; vomiting; irritability; nightmares; insomnia; diarrhea; anxiety; hyperhidrosis; and vertigo.
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 ).
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. As duloxetine is rapidly hydrolyzed in acidic media to 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.
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As observed in DPNP trials, Cymbalta online treatment worsens glycemic control in some patients with diabetes. In three clinical trials of Cheap 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.
Increased plasma concentrations of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis). For this reason, Buy Cymbalta is not recommended for patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min) (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).
Markedly increased exposure to duloxetine occurs in patients with hepatic insufficiency and Buy Cymbalta should not be administered to these patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Cymbalta and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Cymbalta. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given 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.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Cymbalta.
Clinical Worsening and Suicide Risk — Patients, their families, and their caregivers should be encouraged 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. Families and caregivers of patients should be advised to look 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.
Cymbalta should be swallowed whole and should not be chewed or crushed, nor should the contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating.
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, patients should be
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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.
Patients should be advised 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.
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 ordinarily not be prescribed for patients with substantial alcohol use.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Cymbalta and triptans, tramadol or other serotonergic agents.
Orthostatic Hypotension and Syncope — Patients should be advised of the risk of orthostatic hypotension 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 duloxetine.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to notify their physician if they are breast-feeding.
While patients with MDD may notice improvement with Cymbalta therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.
Laboratory Tests
No specific laboratory tests are recommended.
Drug Interactions (also see CLINICAL PHARMACOLOGY, Drug-Drug Interactions)
Potential for Other Drugs to Affect Cymbalta
Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.
Inhibitors of CYP1A2 — Concomitant use of duloxetine with fluvoxamine, an inhibitor of CYP1A2, results in approximately a 6-fold increase in AUC and about a 2.5-fold increase in Cmax of duloxetine. Some quinolone antibiotics would be expected to have similar effects and these combinations should be avoided.
Inhibitors of CYP2D6 — Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 may result in higher concentrations of duloxetine. Paroxetine (20 mg QD) increased the concentration of duloxetine (40 mg QD) 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).
Potential for Duloxetine to Affect Other Drugs
Drugs Metabolized by CYP1A2 — In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity, and it is unlikely to have a clinically significant effect on the metabolism of CYP1A2 substrates (see CLINICAL PHARMACOLOGY, Drug Interactions ).
Drugs Metabolized by CYP2D6 — Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg BID) in conjunction with a single 50-mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. Therefore, co-administration of Cymbalta with other drugs that are extensively metabolized by this isozyme and which have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines
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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.
Drugs Metabolized by CYP3A — Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity (see CLINICAL PHARMACOLOGY, Drug Interactions ).
Cymbalta May Have a Clinically Important Interaction with the Following Other Drugs:
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 PRECAUTIONS, Hepatotoxicity ).
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.
Serotonergic Drugs — Based on the mechanism of action of SNRIs and SSRIs, including Cymbalta and the potential for serotonin syndrome, caution is advised when Cymbalta is coadministered 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's Wort (see WARNINGS, Serotonin Syndrome ). The concomitant use of Cymbalta with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS, Drug Interactions ).
Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Cymbalta with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome ).
Potential for Interaction with 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.
Monoamine Oxidase Inhibitors — See CONTRAINDICATIONS and WARNINGS .
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis — Duloxetine was administered in the diet to mice and rats for 2 years.
In female mice receiving duloxetine at 140 mg/kg/day (11 times the maximum recommended human dose [MRHD, 60 mg/day] and 6 times the human dose of 120 mg/day on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2
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basis). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (8 times the MRHD and 4 times the human dose of 120 mg/day on a mg/m2 basis).
In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis) and up to 36 mg/kg/day in males (6 times the MRHD and 3 times the human dose of 120 mg/day on a mg/m2 basis) did not increase the incidence of tumors.
Mutagenesis — Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow in vivo.
Impairment of Fertility — Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (7 times the maximum recommended human dose of 60 mg/day and 4 times the human dose of 120 mg/day on a mg/m2 basis) did not alter mating or fertility.
Pregnancy
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
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discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS, Monoamine Oxidase Inhibitors ). 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 ).
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.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk ). Anyone considering the use of Cymbalta in a child or adolescent must balance the potential risks with the clinical need.
Geriatric Use
Of the 2418 patients in premarketing clinical studies of Cymbalta for MDD, 5.9% (143) were 65 years of age or over. Of the 1074 patients in the DPN premarketing studies, 33% (357) were 65 years of age or over. Premarketing clinical studies of GAD did not include sufficient numbers of subjects age 65 or over to determine whether they respond differently from younger subjects. In the MDD and DPN studies, 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. As with other antidepressants, Cymbalta has been associated with cases of clinically significant hyponatremia (see Hyponatremia, under PRECAUTIONS ).
ADVERSE REACTIONS
Cymbalta has been evaluated for safety in 2418 patients diagnosed with major depressive disorder who participated in multiple-dose premarketing trials, representing 1099 patient-years of exposure. Among these 2418 Cymbalta-treated patients, 1139 patients participated in eight 8- or 9-week, placebo-controlled trials at doses ranging from 40 to 120 mg/day, while the remaining 1279 patients were followed for up to 1 year in an open-label safety study using flexible doses from 80 to 120 mg/day. Two placebo-controlled studies with doses of 80 and 120 mg/day had 6-month maintenance extensions. Of these 2418 patients, 993 Cymbalta-treated patients were exposed for at least 180 days and 445 Cymbalta-treated patients were exposed for at least 1 year.
Cymbalta has also been evaluated for safety in 1074 patients with diabetic peripheral neuropathy representing 472 patient-years of exposure. Among these 1074 Cymbalta-treated patients, 568 patients participated in two 12- to 13-week, placebo-controlled trials at doses ranging from 20 to 120 mg/day. An additional 449 patients were enrolled in an open-label safety study using 120 mg/day for a duration of 6 months. Another 57 patients, originally treated with placebo, were exposed to Cymbalta for up to 12 months at 60 mg twice daily in an extension phase. Among these 1074 patients, 484 had 6 months of exposure to Cymbalta, and 220 had 12 months of exposure.
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Cymbalta has also been evaluated for safety in 668 patients with generalized anxiety disorder representing 95 patient-years of exposure. These 668 patients participated in 9- or 10-week placebo-controlled trials at doses ranging from 60 mg once daily to 120 mg once daily. Of these 668 patients, 449 were exposed for at least 2 months to Cymbalta.
In the full cohort of placebo-controlled clinical trials for any indication, safety has been evaluated in 8504 patients treated with duloxetine and 6123 patients treated with placebo. In clinical trials, a total of 23,983 patients have been exposed to duloxetine. In duloxetine clinical trials, adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.
Clinical investigators recorded adverse events using descriptive terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing adverse events, grouping similar types of events into a smaller number of standardized event categories is necessary. In the tables and tabulations that follow, MedDRA terminology has been used to classify reported adverse events.
The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Events reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.
The cited figures provide the prescriber with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators.
Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials
Major Depressive Disorder
Approximately 10% of the 1139 patients who received Cymbalta in the MDD placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% of the 777 patients receiving placebo. Nausea (Cymbalta 1.4%, placebo 0.1%) was the only common adverse event reported as reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Cymbalta-treated patients and at a rate of at least twice that of placebo).
Diabetic Peripheral Neuropathic Pain
Approximately 14% of the 568 patients who received Cymbalta in the DPN placebo-controlled trials discontinued treatment due to an adverse event, compared with 7% of the 223 patients receiving placebo. Nausea (Cymbalta 3.5%, placebo 0.4%), dizziness (Cymbalta 1.6%, placebo 0.4%), somnolence (Cymbalta 1.6%, placebo 0%) and fatigue (Cymbalta 1.1%, placebo 0%) were the common adverse events reported as reasons for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Cymbalta-treated patients and at a rate of at least twice that of placebo).
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Generalized Anxiety Disorder
Approximately 16% of the 668 patients who received Cymbalta in the GAD placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% of the 495 patients receiving placebo. Nausea (Cymbalta 3.7%, placebo 0.2%), vomiting (Cymbalta 1.4%, placebo 0%) and dizziness (Cymbalta 1.2%, placebo 0.2%) were the common adverse events reported as reasons for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Cymbalta-treated patients and at a rate of at least twice that of placebo).
Adverse Events Occurring at an Incidence of 2% or More Among Cymbalta-Treated Patients in Placebo-Controlled Trials
Major Depressive Disorder
Table 2 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of MDD placebo-controlled trials and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta-treated MDD patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; dry mouth; constipation; decreased appetite; fatigue; somnolence; and increased sweating (see Table 2 ).
Table 2: Treatment-Emergent Adverse Events Incidence in MDD Placebo-Controlled Trials1
Percentage of Patients Reporting Event
System Organ Class / Adverse Event
Cymbalta (N=1139)
Placebo (N=777)
Gastrointestinal Disorders
Nausea
20
7
Dry mouth
15
6
Constipation
11
4
Diarrhea
8
6
Vomiting
5
3
Metabolism and Nutrition Disorders
Appetite decreased2
8
2
Investigations
Weight decreased
2
1
General Disorders and Administration Site Conditions
Fatigue
8
4
Nervous System Disorders
Dizziness
9
5
Somnolence
7
3
Tremor
3
1
Skin and Subcutaneous Tissue Disorders
Sweating increased
6
2
Vascular Disorders
Hot flushes
2
1
Eye Disorders
Vision blurred
4
1
Psychiatric Disorders
Insomnia3
11
6
Anxiety
3
2
Libido decreased
3
1
20
Orgasm abnormal4
3
1
Reproductive System and Breast Disorders
Erectile dysfunction5
4
1
Ejaculation delayed5
3
1
Ejaculatory dysfunction5, 6
3
1
1 Events reported by at least 2% of patients treated with Cymbalta and more often with placebo. The following events were reported by at least 2% of patients treated with Cymbalta for MDD and had an incidence equal to or less than placebo: upper abdominal pain, palpitations, dyspepsia, back pain, arthralgia, headache, pharyngitis, cough, nasopharyngitis, and upper respiratory tract infection.
2 Term includes anorexia.
3 Term includes middle insomnia.
4 Term includes anorgasmia.
5 Male patients only.
6 Term includes ejaculation disorder and ejaculation failure.
Diabetic Peripheral Neuropathic Pain
Table 3 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of DPN placebo-controlled trials (doses of 20 to 120 mg/day) and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta-treated DPN patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; somnolence; dizziness; constipation; dry mouth; hyperhidrosis; decreased appetite; and asthenia (see Table 3 ).
Table 3: Treatment-Emergent Adverse Events Incidence in DPN Placebo-Controlled Trials1
Percentage of Patients Reporting Event
System Organ Class / Adverse Event
Cymbalta 60 mg BID (N=225)
Cymbalta 60 mg QD (N=228)
Cymbalta 20 mg QD (N=115)
Placebo (N=223)
Gastrointestinal Disorders
Nausea
30
22
14
9
Constipation
15
11
5
3
Diarrhea
7
11
13
6
Dry mouth
12
7
5
4
Vomiting
5
5
6
4
Dyspepsia
4
4
4
3
Loose stools
2
3
2
1
General Disorders and Administration Site Conditions
Fatigue
12
10
2
5
Asthenia
8
4
2
1
Pyrexia
3
1
2
1
Infections and Infestations
Nasopharyngitis
9
7
9
5
Metabolism and Nutrition Disorders
Decreased appetite
11
4
3
<1
Anorexia
5
3
3
<1
Musculoskeletal and Connective Tissue Disorders
Muscle cramp
4
4
5
3
Myalgia
4
1
3
<1
Nervous System Disorders
Somnolence
21
15
7
5
21
Headache
15
13
13
10
Dizziness
17
14
6
6
Tremor
5
1
0
0
Psychiatric Disorders
Insomnia
13
8
9
7
Renal and Urinary Disorders
Pollakiuria
5
1
3
2
Reproductive System and Breast Disorders
Erectile dysfunction2
4
1
0
0
Respiratory, Thoracic and Mediastinal Disorders
Cough
5
3
6
4
Pharyngolaryngeal pain
6
1
3
1
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis
8
6
6
2
1 Events reported by at least 2% of patients treated with Cymbalta and more often than placebo. The following events were reported by at least 2% of patients treated with Cymbalta for DPN and had an incidence equal to or less than placebo: edema peripheral, influenza, upper respiratory tract infection, back pain, arthralgia, pain in extremity, and pruritus.
2 Male patients only.
Generalized Anxiety Disorder
Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of GAD placebo-controlled trials (doses of 60 to 120 mg once daily) and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta-treated GAD patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; fatigue; dry mouth; somnolence; constipation; insomnia; appetite decreased; hyperhidrosis; libido decreased; vomiting; ejaculation delayed; and erectile dysfunction (see Table 4 ).
Table 4: Treatment-Emergent Adverse Events Incidence in GAD Placebo-Controlled Trials1
Percentage of Patients Reporting Event
System Organ Class / Adverse Event
Cymbalta (N=668)
Placebo (N=495)
Eye Disorders
Vision blurred
4
2
Gastrointestinal Disorders
Nausea
38
10
Dry mouth
12
4
Constipation
10
3
Diarrhea
8
6
Vomiting
5
2
Abdominal pain2
4
3
Dyspepsia3
4
3
General Disorders and Administration Site Conditions
Fatigue4
13
5
Metabolism and Nutrition Disorders
Appetite decreased5
8
3
Nervous System Disorders
22
Dizziness
15
8
Somnolence6
12
3
Tremor
4
1
Paraesthesia7
2
1
Psychiatric Disorders
Insomnia8
9
4
Libido decreased9
7
2
Agitation10
4
2
Orgasm abnormal11
3
0
Reproductive System and Breast Disorders
Ejaculation delayed12
5
1
Erectile dysfunction12
5
1
Respiratory, Thoracic and Mediastinal Disorders
Yawning
3
0
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis
7
2
Vascular Disorders
Hot flushes
3
1
1 Events reported by at least 2% of patients treated with Cymbalta and more often with placebo. The following events were reported by at least 2% of patients treated with Cymbalta for GAD and had an incidence equal to or less than placebo: nasopharyngitis, upper respiratory tract infection, headache, pollakiuria, and musculoskeletal pain (includes myalgia, neck pain).
2 Term includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain.
3 Term includes stomach discomfort.
4 Term includes asthenia.
5 Term includes anorexia.
6 Term includes hypersomnia and sedation.
7 Term includes hypoaesthesia.
8 Term includes initial insomnia, middle insomnia, and early morning awakening.
9 Term includes loss of libido.
10 Term includes feeling jittery, nervousness, restlessness, tension, and psychomotor agitation.
11 Term includes anorgasmia.
12 Male patients only.
Adverse events seen in men and women were generally similar except for effects on sexual function (described below). Clinical studies of Cymbalta did not suggest a difference in adverse event rates in people over or under 65 years of age. There were too few non-Caucasian patients studied to determine if these patients responded differently from Caucasian patients.
Effects on Male and Female Sexual Function
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. Table 5 displays the incidence of sexual side effects spontaneously reported by at least 2% of either male or female patients taking Cymbalta in MDD placebo-controlled trials.
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Table 5: Treatment-Emergent Sexual Dysfunction-Related Adverse Events Incidence in MDD Placebo-Controlled Trials1
Percentage of Patients Reporting Event4
% Male Patients
% Female Patients
Adverse Event
Cymbalta (N=378)
Placebo (N=247)
Cymbalta (N=761)
Placebo (N=530)
Orgasm abnormal2
4
1
2
0
Ejaculatory dysfunction3
3
1
NA
NA
Libido decreased
6
2
1
0
Erectile dysfunction
4
1
NA
NA
Ejaculation delayed
3
1
NA
NA
1 Events reported by at least 2% of patients treated with Cymbalta and more often than with placebo.
2 Term includes anorgasmia.
3 Term includes ejaculation disorder and ejaculation failure.
4 NA=Not applicable.
Because adverse sexual events are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in Table 6 below, patients treated with Cymbalta experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Cymbalta experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Cymbalta than on placebo as measured by ASEX total score. These studies did not, however, include an active control drug with known effects on female sexual dysfunction, so that there is no evidence that its effects differ from other antidepressants. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects.
Table 6: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials
Male Patients***
Female Patients***
Cymbalta (n***=175)
Placebo (n=83)
Cymbalta (n=241)
Placebo (n=126)
ASEX Total (Items 1-5)
0.56*
-1.07
-1.15
-1.07
Item 1 — Sex drive
-0.07
-0.12
-0.32
-0.24
Item 2 — Arousal
0.01
-0.26
-0.21
-0.18
Item 3 — Ability to achieve erection (men); Lubrication (women)
0.03
-0.25
-0.17
-0.18
Item 4 — Ease of reaching orgasm
0.40**
-0.24
-0.09
-0.13
Item 5 — Orgasm satisfaction
0.09
-0.13
-0.11
-0.17
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*** n=Number of patients with non-missing change score for ASEX total.
* p=0.013 versus placebo.
** p<0.001 versus placebo.
Urinary Hesitation
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.
Laboratory Changes
Cymbalta treatment, for up to 9-weeks in MDD, 9-10 weeks in GAD or 13-weeks in DPN placebo-controlled clinical trials, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Cymbalta-treated patients when compared with placebo-treated patients (see PRECAUTIONS ).
Vital Sign Changes
In clinical trials across indications, relative to placebo, duloxetine treatment was associated with mean increases of up to 2.1 mm Hg in systolic blood pressure and up to 2.3 mm Hg in diastolic blood pressure, averaging up to 2 mm Hg. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure (see PRECAUTIONS ).
Duloxetine treatment, for up to 13-weeks in placebo-controlled trials typically caused a small increase in heart rate compared to placebo of up to 3 beats per minute.
Weight Changes
In placebo-controlled clinical trials, MDD and GAD patients treated with Cymbalta for up to 10-weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In DPN placebo-controlled clinical trials, patients treated with Cymbalta for up to 13-weeks experienced a mean weight loss of approximately 1.1 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients.
Electrocardiogram Changes
Electrocardiograms were obtained from duloxetine-treated patients and placebo-treated patients in clinical trials lasting up to 13-weeks. No clinically significant differences were observed for QTc, QT, PR, and QRS intervals between duloxetine-treated and placebo-treated patients. There were no differences in clinically meaningful QTcF elevations between duloxetine and placebo. In a positive-controlled study in healthy volunteers using duloxetine up to 200 mg BID, no prolongation of the corrected QT interval was observed.
Other Adverse Events Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine
Following is a list of MedDRA terms that reflect treatment-emergent adverse events as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with duloxetine at multiple doses throughout the dose range studied during any phase of a clinical trial within the premarketing and postmarketing database (23,983 patients, 10,649.5 patient-years of exposure). The events included are those not already listed in Tables 2 through 4 and not considered in the WARNINGS and PRECAUTIONS sections. The events were reported by more than one patient, are not common as background events and/or were considered possibly drug related (e.g., because of the drug’s pharmacology) or potentially important.
25
It is important to emphasize that, although the events reported occurred during treatment with Cymbalta, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Blood and Lymphatic System Disorders — Infrequent: anemia and lymphadenopathy; Rare: leukopenia and thrombocytopenia.
Cardiac Disorders — Frequent: palpitations; Infrequent: atrial fibrillation, coronary artery disease, myocardial infarction, and tachycardia; Rare: bundle branch block right, cardiac failure, and cardiac failure congestive.
Ear and Labyrinth Disorders — Frequent: vertigo; Infrequent: ear pain and tinnitus.
Eye Disorders — Frequent: vision blurred; Infrequent: conjunctivitis, diplopia, and visual disturbance; Rare: glaucoma, macular degeneration, maculopathy, photopsia, and retinal detachment.
Gastrointestinal Disorders — Frequent: abdominal pain and flatulence; Infrequent: dysphagia, eructation, gastritis, halitosis, irritable bowel syndrome, and stomatitis; Rare: aphthous stomatitis, colitis, esophageal stenosis, gastric ulcer, gingivitis, hematochezia, impaired gastric emptying, and melena.
General Disorders and Administration Site Conditions — Frequent: chills/rigors; Infrequent: edema, edema peripheral, feeling abnormal, feeling hot and/or cold, influenza-like illness, malaise, and thirst; Rare: face edema, gait disturbance, and sluggishness.
Hepato-biliary Disorders — Rare: hepatic steatosis.
Infections and Infestations — Infrequent: gastroenteritis and laryngitis; Rare: diverticulitis.
Investigations — Frequent: weight decreased and weight increased; Infrequent: blood cholesterol increased; Rare: blood creatinine increased, urine output decreased, and white blood cell count increased.
Metabolism and Nutrition Disorders — Infrequent: dehydration, hypercholesterolemia, hyperlipidemia, hypoglycemia, and increased appetite; Rare: dyslipidemia and hypertriglyceridemia.
Musculoskeletal and Connective Tissue Disorders — Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching; Rare: muscular weakness.
Nervous System Disorders — Frequent: dysgeusia, lethargy, and parasthesia/hypoesthesia; Infrequent: coordination abnormal, disturbance in attention, dyskinesia, hypersomnia, myoclonus, and poor quality sleep; Rare: dysarthria.
Psychiatric Disorders — Frequent: agitation, anxiety, libido decreased, nervousness, nightmare/abnormal dreams, and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, restlessness, suicide attempt, and tension; Rare: completed suicide, mania, and pressure of speech.
Renal and Urinary Disorders — Infrequent: dysuria, micturition urgency, nocturia, polyuria, urinary hesitation, urinary incontinence, urinary retention, urine flow decreased, and urine odor abnormal; Rare: nephropathy.
Reproductive System and Breast Disorders — Frequent: anorgasmia/orgasm abnormal, ejaculation delayed, and ejaculation disorder; Infrequent: menopausal symptoms and sexual dysfunction.
26
Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning; Infrequent: throat tightness; Rare: pharyngeal edema.
Skin and Subcutaneous Tissue Disorders — Frequent: pruritus and rash; Infrequent: acne, alopecia, cold sweat, dermatitis contact, eczema, erythema, increased tendency to bruise, night sweats, photosensitivity reaction, and skin ulcer; Rare: dermatitis exfoliative, ecchymosis, and hyperkeratosis.
Vascular Disorders — Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness; Rare: hypertensive crisis and phlebitis.
Postmarketing Spontaneous Reports
Adverse events reported since market introduction that were temporally related to duloxetine therapy and not mentioned elsewhere in labeling include: anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, erythema multiforme, extrapyramidal disorder, glaucoma, hallucinations, hyperglycemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, Stevens-Johnson Syndrome, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
Duloxetine is not a controlled substance.
Physical and Psychological Dependence
In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential. In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.
While Cymbalta has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing 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 behavior).
OVERDOSAGE
There is limited clinical experience with duloxetine overdose in humans. In clinical trials, cases of acute ingestions up to 3000 mg, alone or in combination with other drugs, were reported with none being fatal. However, 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 approximately 1000 mg. Signs and symptoms of overdose (mostly with mixed drugs) included serotonin syndrome, somnolence, vomiting, and seizures.
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
27
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 PRECAUTIONS, Drug Interactions ). 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).
DOSAGE AND ADMINISTRATION
Initial Treatment
Major Depressive Disorder
Cymbalta should be administered at a total dose of 40 mg/day (given as 20 mg BID) to 60 mg/day (given either once a day or as 30 mg BID) without regard to meals.
There is no evidence that doses greater than 60 mg/day confer any additional benefits.
Diabetic Peripheral Neuropathic Pain
Cymbalta should be administered at a total dose of 60 mg/day given once a day, without regard to meals.
While a 120 mg/day dose was shown to be safe and effective, 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 (see CLINICAL PHARMACOLOGY, Special Populations and below ).
Generalized Anxiety Disorder
For most patients, the recommended starting dose for Cymbalta is 60 mg administered once daily without regard to meals. 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 once daily 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.
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder
It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. There is insufficient evidence available to answer the question of how long a patient should continue to be treated with Cymbalta. Patients should be
28
periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
Diabetic Peripheral Neuropathic Pain
As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Cymbalta must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials, but a one-year open-label safety study was conducted.
Generalized Anxiety Disorder
Generalized anxiety disorder is generally recognized as a chronic condition. The effectiveness of Cymbalta in long-term use for GAD, that is, for more than 10 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use Cymbalta for extended periods should periodically evaluate the long-term usefulness of the drug for the individual patient.
Special Populations
Dosage for Renally Impaired Patients — Cymbalta is not recommended for patients with end-stage renal disease (requiring dialysis) or in severe renal impairment (estimated creatinine clearance <30 mL/min) (see CLINICAL PHARMACOLOGY ).
Dosage for Hepatically Impaired Patients — It is recommended that Cymbalta not be administered to patients with any hepatic insufficiency (see CLINICAL PHARMACOLOGY and PRECAUTIONS ).
Dosage for Elderly Patients — No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose.
Treatment of Pregnant Women During the Third Trimester — Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS ). 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.
Dosage for Nursing Mothers — Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended (see CLINICAL PHARMACOLOGY ).
Discontinuing Cymbalta
Symptoms associated with discontinuation of Cymbalta and other SSRIs and SNRIs have been reported (see PRECAUTIONS ). Patients should be monitored for these symptoms when discontinuing treatment. 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.
Switching Patients to or from a Monoamine Oxidase Inhibitor
At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI (see CONTRAINDICATIONS and WARNINGS ).
29
HOW SUPPLIED
Cymbalta® (duloxetine hydrochloride) Delayed-release Capsules are available in 20, 30, and 60 mg strengths.
The 20 mg* capsule has an opaque green body and cap, and is imprinted with “20 mg” on the body and “LILLY 3235” on the cap:
NDC 0002-3235-60 (PU3235) — Bottles of 60
NDC 0002-3235-33 (PU3235) — (ID†100) Blisters
The 30 mg* capsule has an opaque white body and opaque blue cap, and is imprinted with “30 mg” on the body and “LILLY 3240” on the cap:
NDC 0002-3240-30 (PU3240) — Bottles of 30
NDC 0002-3240-90 (PU3240) — Bottles of 90
NDC 0002-3240-04 (PU3240) — Bottles of 1000
NDC 0002-3240-33 (PU3240) — (ID†100) Blisters
The 60 mg* capsule has an opaque green body and opaque blue cap, and is imprinted with “60 mg” on the body and “LILLY 3237” on the cap:
NDC 0002-3237-30 (PU3237) — Bottles of 30
NDC 0002-3237-90 (PU3237) — Bottles of 90
NDC 0002-3237-04 (PU3237) — Bottles of 1000
NDC 0002-3237-33 (PU3237) — (ID†100) Blisters
* equivalent to duloxetine base.
†Identi-Dose® (unit dose medication, Lilly).
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Literature revised October 24, 2007
Eli Lilly and Company
Indianapolis, IN 46285, USA
www.Cymbalta.com
Copyright © 2004, 2007, Eli Lilly and Company. All rights reserved.
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PRINTED IN USA
Medication Guide
Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions
Read the Medication Guide that comes with your or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
30
What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
• Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?
31
• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.

This Medication Guide has been approved by the US Food and Drug Administration for all antidepressants.
Patient Information revised June 21, 2007
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