Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults:
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 3. (See Table 3.)
Click on icon to see table/diagram/image
No suicides occurred in any of the pediatric CYMBALTA trials. There were suicides in the adult CYMBALTA trials, but the number was not sufficient to reach any conclusion about CYMBALTA effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms [see Discontinuing CYMBALTA under Dosage & Administration and Discontinuation of Treatment with CYMBALTA as follows for descriptions of the risks of discontinuation of CYMBALTA].
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described previously, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for CYMBALTA should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described previously represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that CYMBALTA is not approved for use in treating bipolar depression.
There have been reports of hepatic failure, sometimes fatal, in patients treated with CYMBALTA. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal (ULN) with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. CYMBALTA should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.
Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis.
CYMBALTA increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (92/34,756) of CYMBALTA-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In adult placebo-controlled trials, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the ULN occurred in 1.25% (144/11,496) of CYMBALTA-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In adult placebo-controlled studies using a fixed dose design, there was evidence of a CYMBALTA dose response relationship for ALT and AST elevation of >3 times the ULN and >5 times the ULN, respectively.
Because it is possible that CYMBALTA and alcohol may interact to cause liver injury or that CYMBALTA may aggravate pre-existing liver disease, CYMBALTA should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
Orthostatic Hypotension, Falls and Syncope:
Orthostatic hypotension, falls and syncope have been reported in patients treated with the recommended CYMBALTA dosages. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during CYMBALTA treatment, particularly after dose increases. The risk of falling appears to be related to the degree of orthostatic decrease in blood pressure (BP) as well as other factors that may increase the underlying risk of falls.
In an analysis of patients from all placebo-controlled trials, patients treated with CYMBALTA reported a higher rate of falls compared to patients treated with placebo. Risk appears to be related to the presence of orthostatic decrease in BP. The risk of BP decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors [see Clinically Important Drug Interactions as follows and Inhibitors of CYP1A2 under Interactions] and in patients taking CYMBALTA at doses above 60 mg daily. Consideration should be given to dose reduction or discontinuation of CYMBALTA in patients who experience symptomatic orthostatic hypotension, falls and/or syncope during CYMBALTA therapy.
Risk of falling also appeared to be proportional to a patient's underlying risk for falls and appeared to increase steadily with age. As geriatric patients tend to have a higher underlying risk for falls due to a higher prevalence of risk factors such as use of multiple medications, medical comorbidities and gait disturbances, the impact of increasing age by itself is unclear. Falls with serious consequences including fractures and hospitalizations have been reported with CYMBALTA use [see Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of CYMBALTA in Adults under Adverse Reactions and Patient Counselling Information].
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including CYMBALTA, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of CYMBALTA with MAOI antidepressants is contraindicated. CYMBALTA should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking CYMBALTA. CYMBALTA should be discontinued before initiating treatment with the MAOI [see Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders and Use of CYMBALTA with Other MAOIs such as Linezolid or Methylene Blue under Dosage & Administration and Contraindications].
If concomitant use of CYMBALTA with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with CYMBALTA and any concomitant serotonergic agents, should be discontinued immediately if the previously mentioned events occur and supportive symptomatic treatment should be initiated.
Increased Risk of Bleeding:
Drugs that interfere with serotonin reuptake inhibition, including CYMBALTA, may increase the risk of bleeding events. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. A post-marketing study showed a higher incidence of postpartum hemorrhage in mothers taking CYMBALTA. Other bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anti-coagulants may add to this risk.
Inform patients about the risk of bleeding associated with the concomitant use of CYMBALTA and NSAIDs, aspirin, or other drugs that affect coagulation [see Interactions].
Severe Skin Reactions:
Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with CYMBALTA. The reporting rate of SJS associated with CYMBALTA use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting.
CYMBALTA should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.
Discontinuation of Syndrome:
Discontinuation symptoms have been systematically evaluated in patients taking CYMBALTA. Following abrupt or tapered discontinuation in adult placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in CYMBALTA-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.
During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.
Patients should be monitored for these symptoms when discontinuing treatment with CYMBALTA. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose but at a more gradual rate [see Discontinuing CYMBALTA under Dosage & Administration].
Activation of Mania/Hypomania:
In adult placebo-controlled trials in patients with MDD, activation of mania or hypomania was reported in 0.1% (4/3779) of CYMBALTA-treated patients and 0.04% (1/2536) of placebo-treated patients. No activation of mania or hypomania was reported in DPNP, GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, CYMBALTA should be used cautiously in patients with a history of mania.
The pupillary dilation that occurs following use of many antidepressant drugs including CYMBALTA may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
CYMBALTA has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In adult placebo-controlled clinical trials, seizures/convulsions occurred in 0.02% (3/12,722) of patients treated with CYMBALTA and 0.01% (1/9513) of patients treated with placebo. CYMBALTA should be prescribed with care in patients with a history of a seizure disorder.
Increases in Blood Pressure:
In adult placebo-controlled clinical trials across the approved adult populations from baseline to endpoint, CYMBALTA treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.3 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of CYMBALTA on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily (approximately 3.3 times the maximum recommended dosage). At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing.
Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment [see Vital Sign Changes in Adults under Adverse Reactions].
Clinically Important Drug Interactions:
Both CYP1A2 and CYP2D6 are responsible for CYMBALTA metabolism.
Potential for Other Drugs to Affect CYMBALTA: CYP1A2 Inhibitors: Co-administration of CYMBALTA with potent CYP1A2 inhibitors should be avoided [see Inhibitors of CYP1A2 under Interactions].
CYP2D6 Inhibitors: Because CYP2D6 is involved in CYMBALTA metabolism, concomitant use of CYMBALTA with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of CYMBALTA [see Inhibitors of CYP2D6 under Interactions].
Potential for CYMBALTA to Affect Other Drugs: Drugs Metabolized by CYP2D6: Co-administration of CYMBALTA with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with CYMBALTA. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, CYMBALTA and thioridazine should not be co-administered [see Drugs Metabolized by CYP2D6 under Interactions].
Other Clinically Important Drug Interactions: Alcohol: Use of CYMBALTA concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, CYMBALTA should not be prescribed for patients with substantial alcohol use [see Hepatotoxicity as previously mentioned and Alcohol under Interactions].
CNS Acting Drugs: Given the primary CNS effects of CYMBALTA, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action [see CNS Drugs under Interactions].
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 with CYMBALTA use and appeared to be reversible when CYMBALTA was discontinued. Geriatric patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Elderly as follows]. 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.
Use in Patients with Concomitant Illness:
Clinical experience with CYMBALTA in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of CYMBALTA's enteric coating. In extremely acidic conditions, CYMBALTA, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using CYMBALTA in patients with conditions that may slow gastric emptying (e.g., some diabetics).
CYMBALTA has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing.
Hepatic Impairment: Avoid use in patients with chronic liver disease or cirrhosis [see Dosing in Special Populations under Dosage & Administration, Hepatotoxicity as previously mentioned and Hepatic Impairment as follows].
Severe Renal Impairment: Avoid use in patients with severe renal impairment, GFR <30 mL/minute. Increased plasma concentration of CYMBALTA, and especially of its metabolites, occurred in patients with end-stage renal disease (requiring dialysis) [see Dosing in Special Populations under Dosage & Administration and Severe Renal Impairment as follows].
Glycemic Control in Patients with Diabetes: As observed in DPNP trials, CYMBALTA treatment worsened glycemic control in some patients with diabetes. In three clinical trials of CYMBALTA for the management of neuropathic pain associated with diabetic peripheral neuropathy [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions], 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
) 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 group and by 0.2% in the routine care group.
Urinary Hesitation and Retention:
CYMBALTA is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with CYMBALTA, consideration should be given to the possibility that they might be drug-related.
In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with CYMBALTA use, hospitalization and/or catheterization has been needed.
Use of SNRIs, including CYMBALTA, may cause symptoms of sexual dysfunction [see Adverse Reactions]. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm.
It is important for prescribers to inquire about sexual function prior to initiation of CYMBALTA and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.
Duloxetine's half-life is similar in men and women. Dosage adjustment based on gender is not necessary.
Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers.
No specific pharmacokinetic study was conducted to investigate the effects of race.
Patients with clinically evident hepatic impairment have decreased duloxetine metabolism and elimination. After a single 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 [see Dosing in Special Populations under Dosage & Administration and Use in Patients with Concomitant Illness as previously mentioned].
Severe Renal Impairment:
Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60 mg dose of duloxetine, Cmax
and AUC values were approximately 100% greater in patients with end-stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. Population PK analyses suggest that mild to moderate degrees of renal impairment (estimated CrCl 30-80 mL/min) have no significant effect on duloxetine apparent clearance [see Dosing in Special Populations under Dosage & Administration and Use in Patients with Concomitant Illness as previously mentioned].
Drug Abuse and Dependence:
Abuse: In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential.
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).
Dependence: In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.
Use in Children: Major Depressive Disorder:
The safety and effectiveness of CYMBALTA have not been established in pediatric patients for the treatment of MDD. Efficacy of CYMBALTA was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients aged 7 to 17 years old with MDD (MDD-6 and MDD-7). Neither CYMBALTA nor an active control (approved for treatment of pediatric MDD) was superior to placebo.
The most frequently observed adverse reactions in the MDD pediatric clinical trials included nausea, headache, decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs.
Juvenile Animal Toxicology Data:
Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug treatment was discontinued. These effects were observed at the high dose of 45 mg/kg/day (2 times the MRHD, for a child); the no-effect-level was 20 mg/kg/day (≈1 times the MRHD, for a child).
Use in the Elderly: Geriatric Exposure in Premarketing Clinical Trials of CYMBALTA:
Of the 2,418 patients in MDD trials, 6% (143) were 65 years of age or over.
Of the 1041 patients in CLBP trials, 21% (221) were 65 years of age or over.
Of the 487 patients in OA trials, 41% (197) were 65 years of age or over.
Of the 1,074 patients in the DPNP trials, 33% (357) were 65 years of age or over.
Of the 1,761 patients in FM trials, 8% (140) were 65 years of age or over.
In the MDD, GAD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between these geriatric and younger adult patients, but greater sensitivity of some older patients cannot be ruled out.
SSRIs and SNRIs, including CYMBALTA have been associated with clinically significant hyponatremia in geriatric patients, who may be at greater risk for this adverse reaction [see Precautions].
In an analysis of data from all placebo-controlled-trials, CYMBALTA-treated patients reported a higher rate of falls compared to placebo-treated patients. The increased risk appears to be proportional to a patient's underlying risk for falls. Underlying risk appears to increase steadily with age. As geriatric patients tend to have a higher prevalence of risk factors for falls such as medications, medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during CYMBALTA treatment is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported with CYMBALTA use [see Precautions and Adverse Reactions].
The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the Cmax
, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the adult patient is not necessary.