Duloxetine Delayed-release

Duloxetine Delayed-release Capsules should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Duloxetine Delayed-release Capsules can be given without regard to meals.

2.1Initial Treatment

Major Depressive Disorder — Duloxetine Delayed-release Capsules should be administered 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 [see Clinical Studies (14.1)].

Generalized Anxiety Disorder — For most patients, the recommended starting dose for Duloxetine Delayed-release Capsules is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated [see Clinical Studies (14.2)].

Diabetic Peripheral Neuropathic Pain — The recommended dose for Duloxetine Delayed-release Capsules is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see Clinical Studies (14.3)]. For patients for whom tolerability is a concern, a lower starting dose may be considered.

Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.10), and Clinical Pharmacology (12.3)].

Chronic Musculoskeletal Pain — The recommended dose for Duloxetine Delayed-release Capsules is 60 mg once daily. Dosing may be started at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.5)].

2.2Maintenance/Continuation/Extended Treatment

Major Depressive Disorder — It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with Duloxetine Delayed-release Capsules as monotherapy. Duloxetine Delayed-release Capsules should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.1)].

Generalized Anxiety Disorder — It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with Duloxetine Delayed-release Capsules as monotherapy. Duloxetine Delayed-release Capsules should be administered in a dose range of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)].

Diabetic Peripheral Neuropathic Pain — As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Duloxetine Delayed-release Capsules must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.

Chronic Musculoskeletal Pain — The efficacy of Duloxetine Delayed-release Capsules has not been established in placebo-controlled studies beyond 13 weeks.

2.3Dosing in Special Populations

Hepatic Insufficiency — It is recommended that Duloxetine Delayed-release Capsules should ordinarily not be administered to patients with any hepatic insufficiency [see Warnings and Precautions (5.13) and Use in Specific Populations (8.9)].

Severe Renal Impairment — Duloxetine Delayed-release Capsules are not recommended for patients with end-stage renal disease or severe renal impairment (estimated creatinine clearance <30 mL/min) [see Warnings and Precautions (5.13) and Use in Specific Populations (8.10)].

Elderly Patients — No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose [see Use in Specific Populations (8.5)].

Pregnant Women — There are no adequate and well-controlled studies in pregnant women; therefore, Duloxetine Delayed-release Capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].

Nursing Mothers — Because the safety of duloxetine in infants is not known, nursing while on Duloxetine Delayed-release Capsules is not recommended [see Use in Specific Populations (8.3)].

2.4Discontinuing Duloxetine Delayed-release Capsules

Symptoms associated with discontinuation of Duloxetine Delayed-release Capsules and other SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions (5.7)].

2.5Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Duloxetine Delayed-release Capsules. Conversely, at least 5 days should be allowed after stopping Duloxetine Delayed-release Capsules before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].

2.6Use of Duloxetine Delayed-release Capsules with Other MAOIs such as Linezolid or Methylene Blue

Do not start Duloxetine Delayed-release Capsules 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 [see Contraindications (4.1)]

In some cases, a patient already receiving Duloxetine Delayed-release Capsules 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 Delayed-release Capsules 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 Delayed-release Capsules may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.4)].

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 Delayed-release Capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.4)].

2.1 Hypertension

The dose of nebivolol must be individualized to the needs of the patient. For most patients, the recommended starting dose is 5 mg once daily, with or without food, as monotherapy or in combination with other agents. For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial.

Renal Impairment

In patients with severe renal impairment (ClCr less than 30 mL/min) the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. Nebivolol has not been studied in patients receiving dialysis [see Clinical Pharmacology (12.4) ].

Hepatic Impairment

In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. Nebivolol has not been studied in patients with severe hepatic impairment and therefore it is not recommended in that population [see Clinical Pharmacology (12.4) ].

2.2 Subpopulations

Geriatric Patients

It is not necessary to adjust the dose in the elderly [see use in Specific Populations (8.5) ].

CYP2D6 Polymorphism

No dose adjustments are necessary for patients who are CYP2D6 poor metabolizers. The clinical effect and safety profile observed in poor metabolizers were similar to those of extensive metabolizers [see Clinical Pharmacology (12.3) ].

Duloxetine Delayed-release Capsules should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Duloxetine Delayed-release Capsules can be given without regard to meals.

2.1 Initial Treatment

Major Depressive Disorder — Duloxetine Delayed-release Capsules should be administered 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 [see Clinical Studies (14.1)].

Generalized Anxiety Disorder — For most patients, the recommended starting dose for Duloxetine Delayed-release Capsules is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated [see Clinical Studies (14.2)].

Diabetic Peripheral Neuropathic Pain — The recommended dose for Duloxetine Delayed-release Capsules is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see Clinical Studies (14.3)]. For patients for whom tolerability is a concern, a lower starting dose may be considered.

Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.10), and Clinical Pharmacology (12.3)].

Chronic Musculoskeletal Pain — The recommended dose for Duloxetine Delayed-release Capsules is 60 mg once daily. Dosing may be started at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.5)].

2.2 Maintenance/Continuation/Extended Treatment

Major Depressive Disorder — It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with Duloxetine Delayed-release Capsules as monotherapy. Duloxetine Delayed-release Capsules should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.1)].

Generalized Anxiety Disorder — It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with Duloxetine Delayed-release Capsules as monotherapy. Duloxetine Delayed-release Capsules should be administered in a dose range of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)].

Diabetic Peripheral Neuropathic Pain — As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Duloxetine Delayed-release Capsules must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.

Chronic Musculoskeletal Pain — The efficacy of Duloxetine Delayed-release Capsules has not been established in placebo-controlled studies beyond 13 weeks.

2.3 Dosing in Special Populations

Hepatic Insufficiency — It is recommended that Duloxetine Delayed-release Capsules should ordinarily not be administered to patients with any hepatic insufficiency [see Warnings and Precautions (5.13) and Use in Specific Populations (8.9)].

Severe Renal Impairment — Duloxetine Delayed-release Capsules are not recommended for patients with end-stage renal disease or severe renal impairment (estimated creatinine clearance <30 mL/min) [see Warnings and Precautions (5.13) and Use in Specific Populations (8.10)].

Elderly Patients — No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose [see Use in Specific Populations (8.5)].

Pregnant Women — There are no adequate and well-controlled studies in pregnant women; therefore, Duloxetine Delayed-release Capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].

Nursing Mothers — Because the safety of duloxetine in infants is not known, nursing while on Duloxetine Delayed-release Capsules is not recommended [see Use in Specific Populations (8.3)].

2.4 Discontinuing Duloxetine Delayed-release Capsules

Symptoms associated with discontinuation of Duloxetine Delayed-release Capsules and other SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions (5.7)].

2.5 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Duloxetine Delayed-release Capsules. Conversely, at least 5 days should be allowed after stopping Duloxetine Delayed-release Capsules before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].

2.6 Use of Duloxetine Delayed-release Capsules with Other MAOIs such as Linezolid or Methylene Blue

Do not start Duloxetine Delayed-release Capsules 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 [see Contraindications (4.1)]

In some cases, a patient already receiving Duloxetine Delayed-release Capsules 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 Delayed-release Capsules 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 Delayed-release Capsules may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.4)].

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 Delayed-release Capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.4)].

Duloxetine Delayed-release Capsules should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Duloxetine Delayed-release Capsules can be given without regard to meals.

2.1 Initial Treatment

— Duloxetine Delayed-release Capsules should be administered 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 . Major Depressive Disorder[see ] Clinical Studies (14.1)

— For most patients, the recommended starting dose for Duloxetine Delayed-release Capsules is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated . Generalized Anxiety Disorder[see ] Clinical Studies (14.2)

— The recommended dose for Duloxetine Delayed-release Capsules is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated . For patients for whom tolerability is a concern, a lower starting dose may be considered. Diabetic Peripheral Neuropathic Pain[see ] Clinical Studies (14.3)

Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment [see , , and ]. Dosage and Administration (2.3)Use in Specific Populations (8.10)Clinical Pharmacology (12.3)

— The recommended dose for Duloxetine Delayed-release Capsules is 60 mg once daily. Dosing may be started at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions . Chronic Musculoskeletal Pain[see ] Clinical Studies (14.5)

2.2 Maintenance/Continuation/Extended Treatment

— It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with Duloxetine Delayed-release Capsules as monotherapy. Duloxetine Delayed-release Capsules should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment . Major Depressive Disorder[see ] Clinical Studies (14.1)

— It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with Duloxetine Delayed-release Capsules as monotherapy. Duloxetine Delayed-release Capsules should be administered in a dose range of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment . Generalized Anxiety Disorder[see ] Clinical Studies (14.2)

— As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Duloxetine Delayed-release Capsules must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials. Diabetic Peripheral Neuropathic Pain

— The efficacy of Duloxetine Delayed-release Capsules has not been established in placebo-controlled studies beyond 13 weeks. Chronic Musculoskeletal Pain

2.3 Dosing in Special Populations

— It is recommended that Duloxetine Delayed-release Capsules should ordinarily not be administered to patients with any hepatic insufficiency . Hepatic Insufficiency[see and ] Warnings and Precautions (5.13)Use in Specific Populations (8.9)

— Duloxetine Delayed-release Capsules are not recommended for patients with end-stage renal disease or severe renal impairment (estimated creatinine clearance <30 mL/min) . Severe Renal Impairment[see and ] Warnings and Precautions (5.13)Use in Specific Populations (8.10)

— No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose . Elderly Patients[see ] Use in Specific Populations (8.5)

— There are no adequate and well-controlled studies in pregnant women; therefore, Duloxetine Delayed-release Capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus . Pregnant Women[see ] Use in Specific Populations (8.1)

— Because the safety of duloxetine in infants is not known, nursing while on Duloxetine Delayed-release Capsules is not recommended . Nursing Mothers[see ] Use in Specific Populations (8.3)

2.4 Discontinuing Duloxetine Delayed-release Capsules

Symptoms associated with discontinuation of Duloxetine Delayed-release Capsules and other SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible . [see ] Warnings and Precautions (5.7)

2.5 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Duloxetine Delayed-release Capsules. Conversely, at least 5 days should be allowed after stopping Duloxetine Delayed-release Capsules before starting an MAOI intended to treat psychiatric disorders [see ]. Contraindications (4.1)

2.6 Use of Duloxetine Delayed-release Capsules with Other MAOIs such as Linezolid or Methylene Blue

Do not start Duloxetine Delayed-release Capsules 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 [see ] Contraindications (4.1)

In some cases, a patient already receiving Duloxetine Delayed-release Capsules 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 Delayed-release Capsules 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 Delayed-release Capsules may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see ]. Warnings and Precautions (5.4)

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 Delayed-release Capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use . [see ] Warnings and Precautions (5.4)