DRUGS & SUPPLEMENTS
1 INDICATIONS AND USAGEDuloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for:
2 DOSAGE AND ADMINISTRATION- Take Duloxetine once daily, with or without food. Swallow Duloxetine whole; do not crush or chew, do not open capsule. Take a missed dose as soon as it is remembered. Do not take two doses of Duloxetine at the same time..
2.1 Dosage for Treatment of Major Depressive DisorderAdminister Duloxetine at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated. Periodically reassess to determine the need for maintenance treatment and the appropriate dose for such treatment .
2.2 Dosage for Treatment of Generalized Anxiety DisorderAdults
For most patients, initiate Duloxetine 60 mg once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see CLINICAL STUDIES ].
Initiate Duloxetine at a dose of 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg. Thereafter, patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. Safety of doses above 120 mg once daily has not been adequately evaluated .
Children and Adolescents (7 to 17 years of age)
Initiate Duloxetine at a dose of 30 mg once daily for 2 weeks before considering an increase to 60 mg. The recommended dose range is 30 to 60 mg once daily. Some patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. The safety of doses above 120 mg once daily has not been evaluated .
2.3 Dosage for Treatment of Diabetic Peripheral Neuropathic PainAdminister Duloxetine 60 mg once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated . For patients for whom tolerability is a concern, a lower starting dose may be considered.
Since diabetes is frequently complicated by renal disease, consider a lower starting dose and gradual increase in dose for patients with renal impairment .
2.5 Dosage for Treatment of Chronic Musculoskeletal PainAdminister Duloxetine 60 mg once daily. Begin treatment at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions .
2.6 Dosing in Special PopulationsHepatic Impairment
Avoid use in patients with chronic liver disease or cirrhosis .
Severe Renal Impairment
Avoid use in patients with severe renal impairment, GFR <30 mL/min .
2.7 Discontinuing DuloxetineAdverse reactions after discontinuation of Duloxetine, after abrupt or tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible .
2.8 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric DisordersAt least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Duloxetine. Conversely, at least 5 days should be allowed after stopping Duloxetine before starting an MAOI intended to treat psychiatric disorders .
2.9 Use of Duloxetine with Other MAOIs such as Linezolid or Methylene BlueDo not start Duloxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered .
In some cases, a patient already receiving Duloxetine therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Duloxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Duloxetine may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue .
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Duloxetine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use .
3 DOSAGE FORMS AND STRENGTHS40 mg delayed-release capsules (3).
Duloxetine is available as delayed-release capsules:
40 mg: Size '2' Capsules with white cap and white body imprinted with "LU" on cap and "H25" in black ink on body, containing eight white to off white mini tablets.
The use of MAOIs intended to treat psychiatric disorders with Duloxetine or within 5 days of stopping treatment with Duloxetine is contraindicated because of an increased risk of serotonin syndrome. The use of Duloxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated .
Starting Duloxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome .
5 WARNINGS AND PRECAUTIONS
5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young AdultsPatients 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 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
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 DOSAGE AND ADMINISTRATION (2.7) and WARNINGS AND PRECAUTIONS (5.7) for descriptions of the risks of discontinuation of Duloxetine].
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 above, 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 Duloxetine 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 above 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 Duloxetine is not approved for use in treating bipolar depression.
5.2 HepatotoxicityThere have been reports of hepatic failure, sometimes fatal, in patients treated with Duloxetine. 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 with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Duloxetine 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.
Duloxetine increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% of duloxetine-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In adult placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.25% (144/11,496) of duloxetine-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In adult placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.
Because it is possible that Duloxetine and alcohol may interact to cause liver injury or that Duloxetine may aggravate pre-existing liver disease, Duloxetine should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
5.3 Orthostatic Hypotension, Falls and SyncopeOrthostatic hypotension, falls 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 falling appears to be related to the degree of orthostatic decrease in blood pressure as well as other factors that may increase the underlying risk of falls.
In an analysis of patients from all placebo-controlled trials, patients treated with Duloxetine reported a higher rate of falls compared to patients treated with placebo. Risk appears to be related to the presence of orthostatic decrease in blood pressure. The risk of blood pressure decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors and in patients taking Duloxetine at doses above 60 mg daily. Consideration should be given to dose reduction or discontinuation of Duloxetine in patients who experience symptomatic orthostatic hypotension, falls and/or syncope during Duloxetine therapy.
Risk of falling also appeared to be proportional to a patient's underlying risk for falls and appeared to increase steadily with age. As elderly patients tend to have a higher underlying risk for falls due to a higher prevalence of risk factors such as use of multiple medications, medical comorbidities and gait disturbances, the impact of increasing age by itself is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported .
5.4 Serotonin SyndromeThe development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Duloxetine, alone but particularly with concomitant use of other serotonergic drugs 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 Duloxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Duloxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Duloxetine. Duloxetine should be discontinued before initiating treatment with the MAOI .
If concomitant use of Duloxetine with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with Duloxetine and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
5.5 Abnormal BleedingSSRIs and SNRIs, including Duloxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of Duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation.
5.6 Severe Skin ReactionsSevere skin reactions, including erythema multiforme and Stevens-Johnson Syndrome, can occur with Duloxetine. The reporting rate of SJS associated with Duloxetine 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.
Duloxetine should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.
5.7 Discontinuation of Treatment with DuloxetineDiscontinuation symptoms have been systematically evaluated in patients taking Duloxetine. 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 duloxetine-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 Duloxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see DOSAGE AND ADMINISTRATION (2.7)] .
5.8 Activation of Mania/HypomaniaIn adult placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% of duloxetine-treated patients and 0.04% (1/2536) of placebo-treated patients. No activation of mania or hypomania was reported in DPNP, GAD, 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, Duloxetine should be used cautiously in patients with a history of mania.
5.9 Angle-Closure Glaucoma
5.10 SeizuresDuloxetine 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% of patients treated with Duloxetine and 0.01% (1/9513) of patients treated with placebo. Duloxetine should be prescribed with care in patients with a history of a seizure disorder.
5.11 Effect on Blood PressureIn adult placebo-controlled clinical trials across indications from baseline to endpoint, Duloxetine 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 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 twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5 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 .
5.12 Clinically Important Drug InteractionsBoth CYP1A2 and CYP2D6 are responsible for Duloxetine metabolism.
Potential for Other Drugs to Affect Duloxetine
CYP1A2 Inhibitors :
Co-administration of Duloxetine with potent CYP1A2 inhibitors should be avoided .
Because CYP2D6 is involved in Duloxetine metabolism, concomitant use of Duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of Duloxetine .
Potential for Duloxetine to Affect Other Drugs
Drugs Metabolized by CYP2D6:
Co-administration of Duloxetine 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 Duloxetine. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Duloxetine and thioridazine should not be co-administered .
Other Clinically Important Drug Interactions
Use of Duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Duloxetine should not be prescribed for patients with substantial alcohol use .
CNS Acting Drugs :
Given the primary CNS effects of Duloxetine, 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 .
5.13 HyponatremiaHyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Duloxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when Duloxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk . Discontinuation of Duloxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.
5.14 Use in Patients with Concomitant IllnessClinical experience with Duloxetine 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 Duloxetine enteric coating. In extremely acidic conditions, Duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Duloxetine in patients with conditions that may slow gastric emptying.
Duloxetine 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.
Avoid use in patients with chronic liver disease or cirrhosis .
Severe Renal Impairment
Avoid use in patients with severe renal impairment, GFR <30 mL/min. Increased plasma concentration of Duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis) .
Glycemic Control in Patients with Diabetes
As observed in DPNP trials, Duloxetine treatment worsens glycemic control in some patients with diabetes. In three clinical trials of Duloxetine 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, Duloxetine 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 Duloxetine group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the Duloxetine and by 0.2% in the routine care groups.
5.15 Urinary Hesitation and RetentionDuloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Duloxetine, 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 Duloxetine use, hospitalization and/or catheterization has been needed.
5.16 Laboratory TestsNo specific laboratory tests are recommended.
6 ADVERSE REACTIONS- Most common adverse reactions : nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis (6.3).
To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharma at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
The following serious adverse reactions are described below and elsewhere in the labeling:
6.1 Clinical Trial Data SourcesBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.
The data described below reflect exposure to Duloxetine in placebo-controlled trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), and DPNP (N=906). The population studied was 17 to 89 years of age; 65.7%, 60.8%, 60.6% and 42.9% female; and 81.8%, 72.6%, 85.3%, and 74.0% Caucasian for MDD, GAD, OA and CLBP, and DPNP, respectively. Most patients received doses of a total of 60 to 120 mg per day [see CLINICAL STUDIES (14)]. The data below do not include results of the trial examining the efficacy of Duloxetine in patients ≥ 65 years old for the treatment of generalized anxiety disorder; however, the adverse reactions observed in this geriatric sample were generally similar to adverse reactions in the overall adult population.
Children and Adolescents
The data described below reflect exposure to Duloxetine in pediatric, 10-week, placebo-controlled trials for MDD (N=341) and GAD (N=135). The population studied (N=476) was 7 to 17 years of age with 42.4% children age 7 to 11 years of age, 50.6% female, and 68.6% white. Patients received 30 to 120 mg per day during placebo-controlled acute treatment studies. Additional data come from the overall total of 822 pediatric patients (age 7 to 17 years of age) with 41.7% children age 7 to 11 years of age and 51.8% female exposed to Duloxetine in MDD and GAD clinical trials up to 36-weeks in length, in which most patients received 30 to 120 mg per day.
6.2 Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Adult Placebo-Controlled TrialsMajor Depressive Disorder
Approximately 8.4% of the patients who received Duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of the patients receiving placebo. Nausea (duloxetine 1.1%, placebo 0.4%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Duloxetine treated patients and at a rate of at least twice that of placebo).
Generalized Anxiety Disorder
Approximately 13.7% (139/1018) of the patients who received Duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.3%, placebo 0.4%), and dizziness (duloxetine 1.3%, placebo 0.4%).
Diabetic Peripheral Neuropathic Pain
Approximately 12.9% (117/906) of the patients who received Duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.5%, placebo 0.7%), dizziness (duloxetine 1.2%, placebo 0.4%), and somnolence (duloxetine 1.1%, placebo 0.0%).
Chronic Pain due to Osteoarthritis
Approximately 15.7% (79/503) of the patients who received Duloxetine in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.2%, placebo 1.0%).
Chronic Low Back Pain
Approximately 16.5% (99/600) of the patients who received Duloxetine in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.0%, placebo 0.7%), and somnolence (duloxetine 1.0%, placebo 0.0%).
6.3 Most Common Adult Adverse ReactionsPooled Trials for All Approved Indications
The most commonly observed adverse reactions in Duloxetine -treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.
Diabetic Peripheral Neuropathic Pain
The most commonly observed adverse reactions in Duloxetine -treated patients (as defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.
Chronic Pain due to Osteoarthritis
The most commonly observed adverse reactions in duloxetine-treated patients (as defined above) were nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness.
Chronic Low Back Pain
The most commonly observed adverse reactions in duloxetine-treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.
6.4 Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Adult Placebo- Controlled TrialsTable 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with Duloxetine and with an incidence greater than placebo.
6.5 Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in Adult Placebo-Controlled TrialsPooled MDD and GAD Trials
Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with Duloxetine and with an incidence greater than placebo.
Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Duloxetine (determined prior to rounding) in the premarketing acute phase of DPNP, OA, and CLBP placebo-controlled trials and with an incidence greater than placebo.
6.6 Effects on Male and Female Sexual Function in AdultsChanges in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale, 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 5 below, patients treated with Duloxetine 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 Duloxetine experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Duloxetine than on placebo as measured by ASEX total score. 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.
6.7 Vital Sign Changes in AdultsIn placebo-controlled clinical trials across approved indications for change from baseline to endpoint, Duloxetine treatment was associated with mean increases of 0.23 mm Hg in systolic blood pressure and 0.73 mm Hg in diastolic blood pressure compared to mean decreases of 1.09 mm Hg systolic and 0.55 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure .
Duloxetine treatment, for up to 26 weeks in placebo-controlled trials across approved indications, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in duloxetine-treated patients, decrease of 0.17 beats per minute in placebo-treated patients).
6.8 Laboratory Changes in AdultsDuloxetine treatment in placebo-controlled clinical trials across approved indications, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in duloxetine-treated patients when compared with placebo-treated patients . High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in Duloxetine treated patients compared to placebo.
6.9 Electrocardiogram Changes in AdultsThe effect of Duloxetine 160 mg and 200 mg administered twice daily to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female subjects. No QT interval prolongation was detected. Duloxetine appears to be associated with concentration-dependent but not clinically meaningful QT shortening.
6.10 Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine in AdultsFollowing is a list of treatment-emergent adverse reactions reported by patients treated with Duloxetine in clinical trials. In clinical trials of all indications, 34,756 patients were treated with Duloxetine. Of these, 26.9% took Duloxetine for at least 6 months, and 12.4% (4317) for at least one year. The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.
Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.
Frequent: palpitations; Infrequent: myocardial infarction and tachycardia.
Ear and Labyrinth Disorders
Frequent: vertigo; Infrequent: ear pain and tinnitus.
Frequent: vision blurred; Infrequent: diplopia, dry eye, and visual impairment.
Frequent: flatulence; Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer.
General Disorders and Administration Site Conditions
Frequent: chills/rigors; Infrequent: falls, feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance.
Infections and Infestations
Infrequent: gastroenteritis and laryngitis.
Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased.
Metabolism and Nutrition Disorders
Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia.
Musculoskeletal and Connective Tissue Disorders
Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching.
Nervous System Disorders
Frequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria.
Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide.
Renal and Urinary Disorders
Frequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal.
Reproductive System and Breast Disorders
Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder.
Respiratory, Thoracic and Mediastinal Disorders
Frequent: yawning, oropharyngeal pain; Infrequent: throat tightness.
Skin and Subcutaneous Tissue Disorders
Frequent: pruritus; Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis.
Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness.
6.11 Adverse Reactions Observed in Children and Adolescent Placebo-Controlled Clinical TrialsThe adverse drug reaction profile observed in pediatric clinical trials (children and adolescents) was consistent with the adverse drug reaction profile observed in adult clinical trials. The specific adverse drug reactions observed in adult patients can be expected to be observed in pediatric patients (children and adolescents) . The most common (≥5% and twice placebo) adverse reactions observed in pediatric clinical trials include: nausea, diarrhea, decreased weight, and dizziness.
Table 6 provides the incidence of treatment-emergent adverse reactions in MDD and GAD pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with Duloxetine and with an incidence greater than placebo.
Discontinuation-emergent symptoms have been reported when stopping Duloxetine. The most commonly reported symptoms following discontinuation of Duloxetine in pediatric clinical trials have included headache, dizziness, insomnia, and abdominal pain .
Growth (Height and Weight)
Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Pediatric patients treated with Duloxetine in clinical trials experienced a 0.1kg mean decrease in weight at 10 weeks, compared with a mean weight gain of approximately 0.9 kg in placebo-treated patients. The proportion of patients who experienced a clinically significant decrease in weight (≥3.5%) was greater in the Duloxetine group than in the placebo group (14% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension periods, duloxetine-treated patients on average trended toward recovery to their expected baseline weight percentile based on population data from age- and sex-matched peers. In studies up to 9 months, duloxetine-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in children [7 to 11 years of age] and 1.3 cm increase in adolescents [12 to 17 years of age]). While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in children [7 to 11 years of age] and increase of 0.3% in adolescents [12 to 17 years of age]). Weight and height should be monitored regularly in children and adolescents treated with Duloxetine.
6.12 Postmarketing Spontaneous ReportsThe following adverse reactions have been identified during postapproval use of Duloxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions 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, angle-closure glaucoma, extrapyramidal disorder, galactorrhea, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.
7 DRUG INTERACTIONS
7.1 Inhibitors of CYP1A2When Duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) Duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and Duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin .
7.2 Inhibitors of CYP2D6Concomitant use of Duloxetine with paroxetine (20 mg once daily) increased the concentration of Duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) .
7.3 Dual Inhibition of CYP1A2 and CYP2D6Concomitant administration of Duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in Duloxetine AUC and Cmax .
7.4 Drugs that Interfere with HemostasisSerotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2 to 9 mg once daily) under steady state conditions with Duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUCτ,ss, Cmax,ss or tmax,ss) for both R- and S-warfarin were not altered by Duloxetine. Because of the potential effect of Duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when Duloxetine is initiated or discontinued .
7.5 LorazepamUnder steady-state conditions for Duloxetine and lorazepam (2 mg Q 12 hours), the pharmacokinetics of Duloxetine were not affected by co-administration.
7.6 TemazepamUnder steady-state conditions for Duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of Duloxetine were not affected by co-administration.
7.7 Drugs that Affect Gastric AcidityDuloxetine 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, Duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Duloxetine in patients with conditions that may slow gastric emptying. Drugs that raise the gastrointestinal pH may lead to an earlier release of Duloxetine. However, co-administration of Duloxetine with aluminum- and magnesium-containing antacids (51 mEq) or Duloxetine 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 .
7.8 Drugs Metabolized by CYP1A2In vitro drug interaction studies demonstrate that Duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1% to 15%) and 20% (13% to 27%) when co-administered with Duloxetine (60 mg twice daily).
7.9 Drugs Metabolized by CYP2D6Duloxetine is a moderate inhibitor of CYP2D6. When Duloxetine was administered in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold .
7.10 Drugs Metabolized by CYP2C9Results of in vitro studies demonstrate that Duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by Duloxetine .
7.11 Drugs Metabolized by CYP3AResults of in vitro studies demonstrate that Duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates resulting from induction or inhibition is not anticipated, although clinical studies have not been performed.
7.12 Drugs Metabolized by CYP2C19Results of in vitro studies demonstrate that Duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed.
7.13 Monoamine Oxidase Inhibitors.
7.14 Serotonergic Drugs.
7.15 AlcoholWhen Duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, Duloxetine did not increase the impairment of mental and motor skills caused by alcohol.
In the Duloxetine clinical trials database, three Duloxetine -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 .
7.16 CNS Drugs.
7.17 Drugs Highly Bound to Plasma ProteinBecause Duloxetine is highly bound to plasma protein, administration of Duloxetine to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. However, co-administration of Duloxetine (60 or 120 mg) with warfarin (2 to 9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug) .
8 USE IN SPECIFIC POPULATIONS
8.1 PregnancyTeratogenic Effects, Pregnancy Category C
There are no adequate and well-controlled studies of Duloxetine administration in pregnant women. In animal studies with Duloxetine, fetal weights were decreased but there was no evidence of teratogenicity in pregnant rats and rabbits at oral doses administered during the period of organogenesis up to 4 and 7 times the maximum recommended human dose (MRHD) of 120 mg/day, respectively. When Duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD. At this dose, pup behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed. Post-weaning growth was not adversely affected. Duloxetine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Fetal/Neonatal Adverse Reaction:
Neonates exposed during pregnancy to serotonin - norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding which can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of the SNRIs or SSRIs, or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome .
In animal reproduction studies, Duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development.
When Duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (4 times the maximum recommended human dose (MRHD) of 120 mg/day on a mg/m2 basis, in rat; 7 times the MRHD in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day approximately equal to the MRHD in rats; 2 times the MRHD in rabbits).
When Duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (2 times the MRHD); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal Duloxetine treatment.
8.3 Nursing MothersRisk Summary
Duloxetine is present in human milk. In a published study, lactating women who were weaning their infants were given Duloxetine. At steady state, the concentration of Duloxetine in breast milk was approximately 25% that of maternal plasma. The estimated daily infant dose was approximately 0.14% of the maternal dose. The developmental and health benefits of human milk feeding should be considered along with the mother's clinical need for Duloxetine and any potential adverse effects on the milk-fed child from the drug or from the underlying maternal condition. Exercise caution when Duloxetine is administered to a nursing woman.
The disposition of Duloxetine was studied in 6 lactating women who were at least 12 weeks postpartum and had elected to wean their infants. The women were given 40 mg of Duloxetine twice daily for 3.5 days. The peak concentration measured in breast milk occurred at a median of 3 hours after the dose. The amount of Duloxetine in breast milk was approximately 7 mcg/day while on that dose; the estimated daily infant dose was approximately 2 mcg/kg/day. The presence of Duloxetine metabolites in breast milk was not examined.
8.4 Pediatric UseGeneralized Anxiety Disorder
In pediatric patients aged 7 to 17 years, efficacy was demonstrated in one 10-week, placebo-controlled trial. The study included 272 pediatric patients with GAD of which 47% were 7 to 11 years of age. Duloxetine demonstrated superiority over placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale for GAD severity score [see CLINICAL STUDIES (14.2)]. The safety and effectiveness in pediatric patients less than 7 years of age have not been established.
Major Depressive Disorder
Efficacy was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients with MDD, age 7 to 17. Neither Duloxetine nor an active control (indicated for treatment of pediatric depression) was superior to placebo. Thus, safety and effectiveness of Duloxetine have not been established in pediatric patients less than 18 years of age with MDD.
The most frequently observed adverse reactions in the clinical trials included nausea, headache, decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as Duloxetine [see ADVERSE REACTIONS (6.11)].
Use of Duloxetine in a child or adolescent must balance the potential risks with the clinical need .
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).
8.5 Geriatric UseOf the 2,418 patients in premarketing clinical studies of Duloxetine for MDD, 5.9% (143) were 65 years of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. In the MDD, GAD, and DPNP, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Duloxetine have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event .
In an analysis of data from all placebo-controlled-trials, patients treated with Duloxetine reported a higher rate of falls compared to patients treated with placebo. The increased risk appears to be proportional to a patient's underlying risk for falls. Underlying risk appears to increase steadily with age. As elderly patients tend to have a higher prevalence of risk factors for falls such as medications, medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during treatment with Duloxetine is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported .
The pharmacokinetics of Duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of Duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the patient is not necessary.
8.6 GenderDuloxetine's half-life is similar in men and women. Dosage adjustment based on gender is not necessary.
8.7 Smoking StatusDuloxetine bioavailability appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers.
8.8 RaceNo specific pharmacokinetic study was conducted to investigate the effects of race.
8.9 Hepatic ImpairmentPatients with clinically evident hepatic impairment have decreased Duloxetine metabolism and elimination. After a single 20 mg dose of Duloxetine, 6 cirrhotic patients with moderate liver impairment 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 .
8.10 Severe Renal ImpairmentLimited 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 to 80 mL/min) have no significant effect on Duloxetine apparent clearance .
9 DRUG ABUSE AND DEPENDENCE
9.2 AbuseIn animal studies, Duloxetine did not demonstrate barbiturate-like abuse potential.
While Duloxetine 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 Duloxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).
9.3 DependenceIn drug dependence studies, Duloxetine did not demonstrate dependence-producing potential in rats.
10.1 Signs and SymptomsIn postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with Duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.
10.2 Management of OverdoseThere is no specific antidote to Duloxetine, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug.
An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.
Activated charcoal may be useful in limiting absorption of Duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.
In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken Duloxetine and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation . The physician should consider contacting a poison control center (1-800-222-1222 or www.poison.org) for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).
11 DESCRIPTIONDuloxetine (duloxetine delayed-release capsules USP) is 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 cream colored powder, which is soluble in methanol.
Each capsule contains enteric-coated mini tablets comprising of Duloxetine hydrochloride equivalent to 40 of Duloxetine. These enteric-coated mini tablets are designed to prevent degradation of the drug in the acidic environment of the stomach. Inactive ingredients include ammonia solution, black iron oxide, croscarmellose sodium, gelatin, hypromellose, hypromellose phthalate, lactose monohydrate, magnesium stearate, polysorbate 80, potassium hydroxide, pregelatinized starch, propylene glycol, shellac, talc, titanium dioxide and triethyl citrate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of ActionAlthough 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.
12.2 PharmacodynamicsPreclinical studies have shown that Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase.
Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Duloxetine, consideration should be given to the possibility that they might be drug-related.
12.3 PharmacokineticsDuloxetine 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, CYP1A2 and CYP2D6.
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 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 CYP1A2 and CYP2D6 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% of the dose) amounts of unchanged Duloxetine are present in the urine. Most (about 70%) of the Duloxetine dose appears in the urine as metabolites of Duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of Duloxetine.
Children and Adolescents (ages 7 to 17 years)
Duloxetine steady-state plasma concentration was comparable in children (7 to 12 years of age), adolescents (13 to 17 years of age) and adults. The average steady-state Duloxetine concentration was approximately 30% lower in the pediatric population (children and adolescents) relative to the adults. The model-predicted Duloxetine steady state plasma concentrations in children and adolescents were mostly within the concentration range observed in adult patients and did not exceed the concentration range in adults.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis
Duloxetine was administered in the diet to mice and rats for 2 years.
In female mice receiving Duloxetine at 140 mg/kg/day (6 times the maximum recommended human dose (MRHD) 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 (2 times the MRHD) Tumor incidence was not increased in male mice receiving Duloxetine at doses up to 100 mg/kg/day (4 times the MRHD).
In rats, dietary doses of Duloxetine up to 27 mg/kg/day in females (2 times the MRHD) and up to 36 mg/kg/day in males (3 times the MRHD) did not increase the incidence of tumors.
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 (4 times the MRHD) did not alter mating or fertility.
14 CLINICAL STUDIESThe efficacy of Duloxetine has been established in the following adequate and well-controlled trials:
14.1 Major Depressive DisorderThe efficacy of Duloxetine as a treatment for depression was established in 4 randomized, double-blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting DSM-IV criteria for major depression. In 2 studies, patients were randomized to duloxetine 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in the third study, patients were randomized to Duloxetine 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to Duloxetine 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that doses greater than 60 mg/day confer additional benefits.
In all 4 studies, Duloxetine demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (Studies 1 to 4 in Table 7).
In all of these clinical studies, analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
14.2 Generalized Anxiety DisorderThe efficacy of Duloxetine in the treatment of generalized anxiety disorder was established in 1 fixed-dose randomized, double-blind, placebo-controlled trial and 2 flexible-dose randomized, double-blind, placebo-controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM-IV criteria for GAD.
In 1 flexible-dose study and in the fixed-dose study, the starting dose was 60 mg once daily where down titration to 30 mg once daily was allowed for tolerability reasons before increasing it to 60 mg once daily. Fifteen percent of patients were down titrated. One flexible-dose study had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily.
The 2 flexible-dose studies involved dose titration with Duloxetine doses ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10-week treatment period. The mean dose for completers at endpoint in the flexible-dose studies was 104.75 mg/day. The fixed-dose study evaluated Duloxetine doses of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9-week treatment period. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit.
In all 3 studies, Duloxetine demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score (Studies 1 to 3 in Table 8) and by the Sheehan Disability Scale (SDS) global functional impairment score. The SDS is a composite measurement of the extent emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities, and family life/home responsibilities.
In another study, 887 patients meeting DSM-IV-TR criteria for GAD received Duloxetine 60 mg to 120 mg once daily during an initial 26-week open-label treatment phase. Four hundred and twenty-nine patients who responded to open-label treatment (defined as meeting the following criteria at weeks 24 and 26: a decrease from baseline HAM-A total score by at least 50% to a score no higher than 11, and a Clinical Global Impressions of Improvement [CGI-Improvement] score of 1 or 2) were randomly assigned to continuation of Duloxetine at the same dose (N=216) or to placebo (N=213) and were observed for relapse. Of the patients randomized, 73% had been in a responder status for at least 10 weeks. Relapse was defined as an increase in CGI-Severity score at least 2 points to a score ≥4 and a MINI (Mini-International Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or discontinuation due to lack of efficacy. Patients taking Duloxetine experienced a statistically significantly longer time to relapse of GAD than did patients taking placebo (Study 4 in Figure 2).
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.
The efficacy of Duloxetine in the treatment of patients ≥65 years of age with generalized anxiety disorder was established in one 10-week flexible-dose, randomized, double-blind, placebo-controlled trial in adults ≥65 years of age meeting the DSM-IV criteria for GAD. In this study, the starting dose was 30 mg once daily for 2 weeks before further dose increases in 30 mg increments at treatment weeks 2, 4, and 7 up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dose for patients completing the 10-week acute treatment phase was 50.95 mg. Patients treated with Duloxetine (N=151) demonstrated significantly greater improvement compared with placebo (N=140) on mean change from baseline to endpoint as measured by the Hamilton Anxiety Rating Scale total score (Study 5 in Table 8).
The efficacy of Duloxetine in the treatment of pediatric patients 7 to 17 years of age with generalized anxiety disorder (GAD) was established in 1 flexible-dose randomized, double-blind, placebo-controlled trial in pediatric outpatients with GAD (based on DSM-IV criteria).
In this study, the starting dose was 30 mg once daily for 2 weeks. Further dose increases in 30 mg increments up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dose for patients completing the 10-week treatment phase was 57.6 mg/day. In this study, Duloxetine (N=135) demonstrated superiority over placebo (N=137) from baseline to endpoint as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score (Study 6 in Table 8).
14.3 Diabetic Peripheral Neuropathic PainThe efficacy of Duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients having diabetic peripheral neuropathic pain for at least 6 months. Study DPNP-1 and Study DPNP-2 enrolled a total of 791 patients of whom 592 (75%) completed the studies. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of ≥4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to Duloxetine. Patients recorded their pain daily in a diary.
Both studies compared Duloxetine 60 mg once daily or 60 mg twice daily with placebo. DPNP-1 additionally compared Duloxetine 20 mg with placebo. A total of 457 patients (342 Duloxetine, 115 placebo) were enrolled in DPNP-1 and a total of 334 patients (226 Duloxetine, 108 placebo) were enrolled in DPNP-2. Treatment with Duloxetine 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain scores from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figures 3 and 4 show the fraction of patients achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.
Figure 3: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - DPNP-1
Figure 4: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - DPNP-2
14.5 Chronic Musculoskeletal PainDuloxetine is indicated for the management of chronic musculoskeletal pain. This has been established in studies in patients with chronic low back pain and chronic pain due to osteoarthritis.
Studies in Chronic Low Back Pain
The efficacy of Duloxetine in chronic low back pain (CLBP) was assessed in two double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study CLBP-1 and Study CLBP-2), and one of 12-weeks duration (CLBP-3). CLBP-1 and CLBP-3 demonstrated efficacy of Duloxetine in the treatment of chronic low back pain. Patients in all studies had no signs of radiculopathy or spinal stenosis.
Two hundred thirty-six adult patients (N=115 on Duloxetine, N=121 on placebo) enrolled and 182 (77%) completed 13-week treatment phase. After 7 weeks of treatment, Duloxetine patients with less than 30% reduction in average daily pain and who were able to tolerate Duloxetine 60 mg once daily had their dose of Duloxetine, in a double-blinded fashion, increased to 120 mg once daily for the remainder of the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking Duloxetine 60 to 120 mg daily had a significantly greater pain reduction compared to placebo. Randomization was stratified by the patient's baseline NSAIDs use status. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.
Four hundred and four patients were randomized to receive fixed doses of Duloxetine daily or a matching placebo (N=59 on Duloxetine 20 mg, N=116 on Duloxetine 60 mg, N=112 on Duloxetine 120 mg, N=117 on placebo) and 267 (66%) completed the entire 13-week study. After 13 weeks of treatment, none of the three Duloxetine doses showed a statistically significant difference in pain reduction compared to placebo.
Four hundred and one patients were randomized to receive fixed doses of Duloxetine 60 mg daily or placebo (N=198 on Duloxetine, N=203 on placebo), and 303 (76%) completed the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 12 weeks of treatment, patients taking Duloxetine 60 mg daily had significantly greater pain reduction compared to placebo.
For various degrees of improvement in pain from baseline to study endpoint, Figures 7 and 8 show the fraction of patients in CLBP-1 and CLBP-3 achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned the value of 0% improvement.
Studies in Chronic Pain Due to Osteoarthritis
The efficacy of Duloxetine in chronic pain due to osteoarthritis was assessed in 2 double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study OA-1 and Study OA-2). All patients in both studies fulfilled the ACR clinical and radiographic criteria for classification of idiopathic osteoarthritis of the knee. Randomization was stratified by the patients' baseline NSAIDs-use status. Patients assigned to Duloxetine started treatment in both studies at a dose of 30 mg once daily for one week. After the first week, the dose of Duloxetine was increased to 60 mg once daily. After 7 weeks of treatment with Duloxetine 60 mg once daily, in OA-1 patients with sub-optimal response to treatment (<30% pain reduction) and tolerated Duloxetine 60 mg once daily had their dose increased to 120 mg. However, in OA-2, all patients, regardless of their response to treatment after 7 weeks, were re-randomized to either continue receiving Duloxetine 60 mg once daily or have their dose increased to 120 mg once daily for the remainder of the study. Patients in the placebo treatment groups in both studies received a matching placebo for the entire duration of studies. For both studies, efficacy analyses were conducted using 13-week data from the combined Duloxetine 60 mg and 120 mg once daily treatment groups compared to the placebo group.
Two hundred fifty-six patients (N=128 on Duloxetine, N=128 on placebo) enrolled and 204 (80%) completed the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking Duloxetine had significantly greater pain reduction. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.
Two hundred thirty-one patients (N=111 on Duloxetine, N=120 on placebo) enrolled and 173 (75%) completed the study. Patients had a mean baseline pain of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking Duloxetine did not show a significantly greater pain reduction.
In Study OA-1, for various degrees of improvement in pain from baseline to study endpoint, Figure 7 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned the value of 0% improvement.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How SuppliedDuloxetine is available as delayed-release capsules in the following strength, color, imprint, and presentation:
16.2 Storage and HandlingStore at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Medication Guide).
- Information on Medication Guide
Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Duloxetine and counsel them in its appropriate use. A patient Medication Guide is available for Duloxetine. Instruct patients, their families, and their caregivers to read the Medication Guide before starting Duloxetine and each time their prescription is renewed, and assist them in understanding its contents. Give patients the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Advise patients of the following issues and ask them to alert their prescriber if these occur while taking Duloxetine.
- Suicidal Thoughts and Behaviors
Encourage patients, their families, and their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.
Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication .
- Duloxetine should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating.
- Continuing the Therapy Prescribed
While patients may notice improvement with Duloxetine therapy in 1 to 4 weeks, advise patients to continue therapy as directed.
Inform patients that severe liver problems, sometimes fatal, have been reported in patients treated with Duloxetine. Instruct patients to talk to their healthcare provider if they develop itching, right upper belly pain, dark urine, or yellow skin/eyes while taking Duloxetine, which may be signs of liver problems. Instruct patients to talk to their healthcare provider about their alcohol consumption. Use of Duloxetine with heavy alcohol intake may be associated with severe liver injury .
Although Duloxetine does not increase the impairment of mental and motor skills caused by alcohol, use of Duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Duloxetine should not be prescribed for patients with substantial alcohol use .
- Orthostatic Hypotension, Falls and Syncope
Advise patients of the risk of orthostatic hypotension, falls and syncope, especially during the period of initial use and subsequent dose escalation, and in association with the use of concomitant drugs that might potentiate the orthostatic effect of Duloxetine .
- Serotonin Syndrome
Caution patients about the risk of serotonin syndrome with the concomitant use of Duloxetine and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort .
Advise patients of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Caution patients to seek medical care immediately if they experience these symptoms.
- Abnormal Bleeding
Caution patients about the concomitant use of Duloxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding .
- Severe Skin Reactions
Caution patients that Duloxetine may cause serious skin reactions. This may need to be treated in a hospital and may be life-threatening. Counsel patients to call their doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions .
- Discontinuation of Treatment
Instruct patients that discontinuation of Duloxetine may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue, and should be advised not to alter their dosing regimen, or stop taking Duloxetine without consulting their physician .
- Activation of Mania or Hypomania
Adequately screen patients with depressive symptoms for risk of bipolar disorder (e.g. family history of suicide, bipolar disorder, and depression) prior to initiating treatment with Duloxetine. Advise patients to report any signs or symptoms of a manic reaction such as greatly increased energy, severe trouble sleeping, racing thoughts, reckless behavior, talking more or faster than usual, unusually grand ideas, and excessive happiness or irritability .
- Angle-Closure Glaucoma
Advise patients that taking Duloxetine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. [See WARNINGS AND PRECAUTIONS (5.9)]
Advise patients to inform their physician if they have a history of seizure disorder .
- Effects on Blood Pressure
Caution patients that Duloxetine may cause an increase in blood pressure .
- Concomitant Medications
Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions .
Advise patients that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including Duloxetine. Advise patients of the signs and symptoms of hyponatremia .
- Concomitant Illnesses
- Advise patients to inform their physicians about all of their medical conditions .
- Duloxetine is in a class of medicines that may affect urination. Instruct patients to consult with their healthcare provider if they develop any problems with urine flow .
- Pregnancy and Nursing Mothers
Advise patients to notify their physician if they:
Safety and efficacy of Duloxetine in patients 7 to 17 years of age have been established for the treatment of GAD. The types of adverse reactions observed with Duloxetine in children and adolescents were generally similar to those observed in adults. The safety and effectiveness of Duloxetine have not been established in pediatric patients less than 18 years of age with other indications. [See USE IN SPECIFIC POPULATIONS (8.4)].
- Interference with Psychomotor Performance
Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies Duloxetine has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Therefore, caution patients about operating hazardous machinery including automobiles, until they are reasonably certain that Duloxetine therapy does not affect their ability to engage in such activities.
Baltimore, Maryland 21202
Revised: May 2015 ID#: 241554
(duloxetine delayed-release capsules USP)
Read this Medication Guide before you start taking Duloxetine and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
Talk to your healthcare provider about:
Duloxetine is a prescription medicine used to treat a certain type of depression called Major Depressive Disorder (MDD). Duloxetine belongs to a class of medicines known as SNRIs (or serotonin-norepinephrine reuptake inhibitors).
Duloxetine is also used to treat or manage:
Do Not take Duloxetine if you:
What should I tell my healthcare provider before taking Duloxetine?
Before starting Duloxetine, tell your healthcare provider if you:
Especially tell your healthcare provider if you take:
Do not take Duloxetine with any other medicine that contain Duloxetine.
How should I take Duloxetine?
Duloxetine may cause serious side effects, including: See "What is the most important information I should know about Duloxetine?"
Common possible side effects in people who take Duloxetine include:
1. liver damage. Symptoms may include:
5. severe skin reactions: Duloxetine may cause serious skin reactions that may require stopping its use. This may need to be treated in a hospital and may be life-threatening. Call your healthcare provider right away or get emergency help if you have skin blisters, peeling rash, sores in the mouth, hives or any other allergic reactions.
6. discontinuation symptoms: Do not stop Duloxetine without first talking to your healthcare provider. Stopping Duloxetine too quickly or changing from another antidepressant too quickly may result in serious symptoms including:
9. seizures or convulsions
10. low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Duloxetine. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to 1-800-FDA-1088.
How should I store Duloxetine?
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
Keep Duloxetine and all medicines out of the reach of children.
General information about the safe and effective use of Duloxetine.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Duloxetine for a condition for which it was not prescribed. Do not give Duloxetine to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Duloxetine. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about Duloxetine that is written for healthcare professionals.
For more information about Duloxetine call 1-800-399-2561 or go to www.lupinpharmaceuticals.com.
What are the ingredients in Duloxetine?
Active ingredient: Duloxetine hydrochloride
Ammonia solution, black iron oxide, croscarmellose sodium, gelatin, hypromellose, hypromellose phthalate, lactose monohydrate, magnesium stearate, polysorbate 80, potassium hydroxide, pregelatinized starch, propylene glycol, shellac, talc, titanium dioxide and triethyl citrate.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Duloxetine is a trademark of Lupin Pharma.
The brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharma. The makers of these brands are not affiliated with and do not endorse Lupin Pharma or its products.
Baltimore, Maryland 21202
Revised: May 2015 ID#: 241555
Duloxetine (Duloxetine Delayed-release Capsules USP)
40 mg - 30s Bottle
Duloxetine pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Duloxetine available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Duloxetine destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Duloxetine Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Duloxetine pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Duloxetine?
Depending on the reaction of the Duloxetine after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Duloxetine not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Duloxetine addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Duloxetine, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Duloxetine consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
Two visitors reported frequency of useHow often in a day do you take the medicine?
Are you taking the Duloxetine drug as prescribed by the doctor?
Few medications can be taken Once in a day more than prescribed when the doctor's advice mentions the medicine can be taken according to frequency or severity of symptoms. Most times, be very careful and clear about the number of times you are taking the medication. The report of sDrugs.com website users about the frequency of taking the drug Duloxetine is mentioned below.
One visitor reported dosesWhat is the dose of Duloxetine drug you are taking?
According to the survey conducted among sDrugs.com website users, the maximum number of people are using the following dose 11-50mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
The information was verified by Dr. Arunabha Ray, MD Pharmacology