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DULOXETINE HYDROCHLORIDE is a brand name for Duloxetine. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE Duloxetine delayed-release capsules are indicated for the treatment of: Major depressive disorder in adults Generalized anxiety disorder in adults and pediatric patients 7 years of age and older Diabetic peripheral neuropathic pain in adults Fibromyalgia in adults Chronic musculoskeletal pain…
Verbatim from this product's FDA label. Tap a section to expand.
2 DOSAGE AND ADMINISTRATION Take duloxetine delayed-release capsules once daily, with or without food. 1 Important Administration Instructions Administer duloxetine delayed-release capsule orally (with or without meals) and swallow whole.
Do not chew or crush, and do not open the delayed-release capsule and sprinkle its contents on food or mix with liquids because these actions might affect the enteric coating. If a dose of duloxetine delayed-release capsule is missed, take the missed dose as soon as it is remembered.
If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time. Do not take two doses of duloxetine delayed-release capsule at the same time. 2 Dosage for Treatment of Major Depressive Disorder in Adults The recommended starting dosage in adults with MDD is 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 duloxetine delayed-release capsules 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.
Periodically reassess to determine the need for maintenance treatment and the appropriate dosage for such treatment. 3 Dosage for Treatment of Generalized Anxiety Disorder Recommended Dosage in Adults Less than 65 Years of Age For most adults less than 65 years of age with GAD, initiate duloxetine delayed-release capsules 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 duloxetine delayed-release capsules before increasing to 60 mg once daily. While a 120 mg once daily dosage 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 dosage beyond 60 mg once daily, increase dosage in increments of 30 mg once daily. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dosage for such treatment.
Recommended Dosage in Geriatric Patients In geriatric patients with GAD, initiate duloxetine delayed-release capsules at a dosage 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg/day. Thereafter, patients may benefit from doses above 60 mg once daily.
1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The stated frequencies of adverse reactions represent the proportion of patients who experienced, at least once, one 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.
Adverse Reactions in Adults Adult Clinical Trial Database The data described below reflect exposure to duloxetine delayed-release capsules in placebo-controlled adult trials for MDD (N=3,779), GAD (N=1,018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1,294).
The age range in this pooled population was 17 to 89 years of age. In this pooled population, 66%, 61%, 61%, 43%, and 94% of adult patients were female; and 82%, 73%, 85%, 74%, and 86% of adult patients were Caucasian in the MDD, GAD, OA and CLBP, DPNP, and FM populations, respectively.
Most patients received duloxetine delayed-release capsules dosages of a total of 60 to 120 mg per day [see Clinical Studies (14)] . 3)] ; however, the adverse reactions observed in this geriatric population were generally similar to adverse reactions in the overall adult population.
6% (117/2,536) of placebo-treated patients. , discontinuation occurring in at least 1% of the duloxetine delayed-release capsules-treated patients and at a rate of at least twice that of placebo-treated patients). 7% (139/1,018)of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5% (38/767) for placebo-treated patients.
5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Hepatic failure, sometimes fatal, has been reported. Discontinue duloxetine delayed-release capsule in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.
, SSRIs, SNRIs, triptans), but also when taken alone. 4) Increased Risk of Bleeding : May increase the risk of bleeding events. 1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 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 4,400 patients.
4 CONTRAINDICATIONS The use of MAOIs intended to treat psychiatric disorders with duloxetine delayed-release capsule or within 5 days of stopping treatment with duloxetine delayed-release capsule is contraindicated because of an increased risk of serotonin syndrome.
4)]. 4)]. Concomitant use of an MAOI antidepressant with duloxetine delayed-release capsule is contraindicated Use of duloxetine delayed-release capsule within 14 days of stopping an MAOI antidepressant is contraindicated In linezolid-or intravenous methylene blue-treated patients, initiation of duloxetine delayed-release capsule is contraindicated (4)
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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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. Recommended Dosage in Pediatric Patients 7 to 17 Years of Age Initiate duloxetine delayed-release capsules in pediatric patients 7 to 17 years of age with GAD at a dosage of30 mg once daily for 2 weeks before considering an increase to 60 mg once daily.
The recommended dosage range is 30 to 60 mg once daily. Some patients may benefit from dosages above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dosage in increments of 30 mg once daily.
The maximum dose studied was 120 mg per day. 4 Dosage for Treatment of Diabetic Peripheral Neuropathic Pain in Adults Administer 60 mg once daily in adults with diabetic peripheral neuropathic pain. There is no evidence that doses higher than 60 mg once daily confer additional significant benefit and the higher dosage is clearly less well tolerated.
For patients for whom tolerability is a concern, a lower starting dose may be considered. 10)] . 5 Dosage for Treatment of Fibromyalgia Recommended Dosage in Adults The recommended duloxetine delayed-release capsules dosage is 60 mg once daily in adults with fibromyalgia.
Begin treatment at 30 mg once daily for 1 week, to allow patients to adjust to duloxetine delayed-release capsulesbefore increasing to 60 mg once daily. Some patients may respond to the starting dosage. There is no evidence that dosages greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg/day dosage, and higher dosages were associated with a higher rate of adverse reactions.
6 Dosage for Treatment of Chronic Musculoskeletal Pain in Adults The recommended duloxetine delayed-release capsules dosage is 60 mg once daily in adults with chronic musculoskeletal pain. Begin treatment at 30 mg once daily for one week, to allow patients to adjust to duloxetine delayed-release capsules before increasing to 60 mg once daily.
6)] . 9)] . 10)] . 8 Discontinuing Duloxetine Delayed-Release Capsules Adverse reactions after discontinuation of duloxetine delayed-release capsules, after abrupt or tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.
7)] . 9 Switching Patients 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)] . 10 Use of Duloxetine Delayed-Release Capsules with Other MAOIs such as Linezolid or Methylene Blue Do not start duloxetine delayed-release capsule 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)]. In some cases, a patient already receiving duloxetine delayed-release capsule 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 capsule 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. 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 capsule is unclear.
4)] .
4%). 1% (23/448) for placebo-treated patients. 1%, placebo 0%). 1% (96/955) for placebo-treated patients. 1%). 3% (37/508) for placebo-treated patients. 2%, placebo 1%). 3% (28/441) for placebo-treated patients. 7%), and somnolence (duloxetine delayed-release capsules 1%, placebo 0%).
Most Common Adverse Reactions in Adult Trials The most commonly observed adverse reactions in duloxetine delayed-release capsules-treated patients (as defined above) were: Diabetic Peripheral Neuropathic Pain: nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.
Fibromyalgia: nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation. Chronic Pain due to Osteoarthritis: nausea, fatigue, constipation,dry mouth, insomnia, somnolence, and dizziness. Chronic Low Back Pain: nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.
, MDD, GAD, DPNP, FM, OA, and CLBP) (incidence of at least 5% and at least twice the incidence in placebo-treated patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis. , MDD, GAD, DPNP, FM, OA, and CLBP) that occurred in 5% or more of duloxetine delayed-release capsules-treated patients and with an incidence greater than placebo-treated patients.
The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. b Also includes asthenia. c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration.
d Also includes initial insomnia,middle insomnia, and early morning awakening. e Also includes hypersomnia and sedation. f Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain.
Adverse Reactions in Pooled MDD and GAD Trials in Adults Table 3 displays the incidence of adverse reactions in MDD and GAD placebo-controlled adult trials that occurred in 2% or more of duloxetine delayed-release capsules-treated patients and with an incidence greater than placebo-treated patients.
Table 3:
Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials in Adults a,b System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine delayed-release capsules (N= 4,797 ) Placebo (N= 3,303 ) Cardiac Disorders Palpitations 2 1 Eye Disorders Vision blurred 3 1 Gastrointestinal Disorders Nausea c Dry mouth Constipation c Diarrhea Abdominal pain d Vomiting 23 14 9 9 5 4 8 6 4 6 4 2 General Disorders and Administration Site Conditions Fatigue e 9 5 Metabolism and Nutrition Disorders Decreased appetite c 6 2 Nervous System Disorders Headache Dizziness c Somnolence f Tremor 14 9 9 3 14 5 3 1 Psychiatric Disorders Insomnia g Agitation h Anxiety 9 4 3 5 2 2 Reproductive System and Breast Disorders Erectile dysfunction Ejaculation delayed c Libido decreased i Orgasmabnormal j 4 2 3 2 1 1 1 <1 Respiratory, Thoracic, and Mediastinal Disorders Yawning 2 <1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 2 a The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer.
b For GAD, there were no adverse reactions that were significantlydifferentbetweentreatments in adults ≥65 years that were also not significant in the adults<65 years. c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration.
d Includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. e Includes asthenia. f Includes hypersomnia and sedation. g Includes initial insomnia,middle insomnia,and early morning awakening.
h Includes feeling jittery, nervousness, restlessness, tension and psychomotorhyperactivity. i Includes loss of libido. j Includes anorgasmia. Adverse Reactions in the DPNP, FM, OA, and CLBP Adult Trials Table 4 displays the incidence of adverse reactions that occurred in 2% or more of duloxetine delayed-release capsules treated patients (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled adult trials and with an incidence greater than placebo-treated patients.
Table 4:
Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trials a System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine delayed-release capsules (N= 3,303) Placebo (N= 2,352) Gastrointestinal Disorders Nausea Dry Mouth b Constipation b Diarrhea Abdominal Pain c Vomiting Dyspepsia 23 11 10 9 5 3 2 7 3 3 5 4 2 1 General Disorders and Administration Site Conditions Fatigue d 11 5 Infections and Infestations Nasopharyngitis Upper Respiratory Tract Infection Influenza 4 3 2 4 3 2 Metabolism and Nutrition Disorders Decreased Appetite b 8 1 Musculoskeletal and Connective Tissue Musculoskeletal Pain e Muscle Spasms 3 2 3 2 Nervous System Disorders Headache Somnolence b, f Dizziness Paraesthesia g Tremor b 13 11 9 2 2 8 3 5 2 <1 Psychiatric Disorders Insomnia b, h Agitation i 10 3 5 1 Reproductive System and Breast Disorders Erectile Dysfunction b Ejaculation Disorder j 4 2 <1 <1 Respiratory, Thoracic and Mediastinal Disorders Cough 2 2 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 1 Vascular Disorders Flushing k Blood pressure increased l 3 2 1 1 a The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer.
b Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day. c Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, abdominal tenderness and gastrointestinal pain. d Includes asthenia. e Includes myalgia and neck pain.
f Includes hypersomnia and sedation. g Includes hypoaesthesia, facial hypoaesthesia, genital hypoaesthesiaand oral paraesthesia. h Includes initial insomnia, middle insomnia, and early morning awakening. i Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity.
j Includes ejaculation failure. k Includes hot flush. l Includes increased diastolic blood pressure, increased systolic blood pressure, diastolic hypertension, essential hypertension, hypertension, hypertensive crisis, labile hypertension, orthostatic hypertension, secondary hypertension, and systolic hypertension.
Effects on Male and Female Sexual Function in Adults with MDD Changes 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.
2)] . The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction.
Positive numbers signify a worsening of sexual function from baseline. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. In these trials, duloxetine delayed-release capsules-treated male patients experienced significantly more sexual dysfunction, as measured by the total score on the ASEX and the ability to reach orgasm, than placebo-treated male patients (see Table 5).
Duloxetine delayed-release capsules-treated female patients did not experience more sexual dysfunction than placebo-treated female patients as measured by ASEX total score. Healthcare providers should routinely inquire about possible sexual adverse reactions in duloxetine delayed-release capsules-treated patients.
17 a n=Number of patients with non-missing change score for ASEX total. 013 versus placebo. 001 versus placebo. 55 mm Hg in DBP in placebo-treated patients. 11)] . 17 beats per minute in placebo-treated patients). 2)] . High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in duloxetine delayed-release capsules-treated patients compared to placebo-treated patients.
Other Adverse Reactions Observed During the Clinical Trial Evaluation of Duloxetine Delayed-Release Capsules in Adults Following is a list of adverse reactions reported by patients treated with duloxetine delayed-release capsules in clinical adult trials.
In clinical trials of all approved adult populations, 34,756 patients were treated with duloxetine delayed-release capsules. Of these, 27% (9,337) took duloxetine delayed-release capsules for at least 6 months, and 12% (4,317) took duloxetine delayed-release capsules 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 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients.
• Cardiac Disorders - Frequent: palpitations; Infrequent: myocardial infarction, tachycardia, and Takotsubo cardiomyopathy. • Ear and Labyrinth Disorders - Frequent: vertigo; Infrequent: ear pain and tinnitus. • Endocrine Disorders - Infrequent: hypothyroidism.
• Eye Disorders - Frequent: vision blurred; Infrequent: diplopia, dry eye,and visual impairment. • Gastrointestinal Disorders - 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.
• Investigations - 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. • Psychiatric Disorders - 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.
• Vascular Disorders - Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness. Adverse Reactions Observed in Placebo-Controlled Clinical Trials in Pediatric Patients Pediatric Clinical Trial Database The data described below reflect exposure to duloxetine delayed-release capsules (N=567) in pediatric patients aged 7 to 18 years of age from two 10-week, placebo-controlled trials in patients with MDD (N=341) (Studies MDD-6 and MDD-7), one 10-week placebo-controlled trial in GAD (N=135) (Study GAD-6), and a 13-week trial in fibromyalgia (N=91).
4)] . Of the duloxetine delayed-release capsules-treated patients in these studies, 36% were 7 to 11 years of age (64% were between 12 to 18 years old), 55% were female, and 69% were Caucasian. Patients received 30 to 120 mg of duloxetine delayed-release capsules per day during placebo-controlled acute treatment studies.
In the pediatric MDD, GAD, and fibromyalgia trials up to 40 weeks long, there were 988 duloxetine delayed-release capsules-treated pediatric patients aged 7 to 17 years of age (most patients received 30 to 120 mg per day) – 35% were 7 to 11 years of age (65% were 12 to 17 years old) and 56% were female.
Most Common Adverse Reactions in Pediatric Trials The most common adverse reactions (≥5% in duloxetine delayed-release capsules-treated patients and at least twice the incidence of placebo-treated patients) in all pooled pediatric populations (MDD, GAD, and fibromyalgia) were decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea.
Adverse Reactions in Pediatric Patients Aged 7 to 17 Years Old with MDD and GAD The adverse reaction profile observed in clinical trials in pediatric patients aged 7 to 18 years old with MDD and GAD was consistent with the adverse reaction profile observed in adult clinical trials.
The most common (≥5% and twice placebo) adverse reactions observed in these pediatric clinical trials included: nausea, diarrhea, decreased weight, and dizziness. Table 6 provides the incidence of adverse reactions in MDD and GAD pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with duloxetine delayed-release capsules and with an incidence greater than patients treated with placebo.
4)]. 4)] . The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. b Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain.
c Also includes asthenia. 5% weight loss (N=467 duloxetine delayed-release capsules; N=354 Placebo). e Also includes hypersomnia and sedation. f Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia. Other adverse reactions that occurred at an incidence of less than 2% and were reported by more duloxetine delayed-release capsules-treated patients than placebo-treated patients in pediatric MDD and GAD clinical trials included: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor (duloxetine delayed-release capsules is not approved to treat pediatric patients with MDD).
7)] . Growth (Height and Weight) in Pediatric Patients 7 to 17 Years Old with GAD and MDD Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. 9 kg in placebo-treated pediatric patients.
5%) was greater in the duloxetine delayed-release capsules group than in the placebo group (16% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension periods, duloxetine delayed-release capsules-treated patients on average trended toward recovery to their expected baseline weight percentile based on population data from age- and sex-matched peers.
3 cm increase in patients 12 to 17 years of age). 3% in patients 12 to 17 years of age). 4)]. 2 Postmarketing Experience The following adverse reactions have been identified during post approval use of duloxetine delayed-release capsules.
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: acute pancreatitis, anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, angle-closure glaucoma, colitis (microscopic or unspecified), cutaneous vasculitis (sometimes associated with systemic involvement), 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.
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 1,000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric duloxetine delayed-release capsules trials.
There were suicides in the adult duloxetine delayed-release capsules trials, but the number was not sufficient to reach any conclusion about duloxetine delayed-release capsules effect on suicide. , 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.
7)] for descriptions of the risks of discontinuation of duloxetine delayed-release capsules. 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 delayed-release capsules 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. 2 Hepatotoxicity There have been reports of hepatic failure, sometimes fatal, in patients treated with duloxetine delayed-release capsules. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal (ULN) with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury.
Duloxetine delayed-release capsules 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 hydrochloride increased the risk of elevation of serum transaminase levels in development program clinical trials.
3% (92/34,756) of duloxetine delayed-release capsules-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. 45% (39/8,716) of placebo-treated patients. In adult placebo-controlled studies using a fixed dose design, there was evidence of a duloxetine delayed-release capsules dose response relationship for ALT and AST elevation of >3 times the ULN and >5 times the ULN, respectively.
Because it is possible that duloxetine delayed-release capsules and alcohol may interact to cause liver injury or that duloxetine delayed-release capsules may aggravate pre-existing liver disease, duloxetine delayed-release capsules should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
3 Orthostatic Hypotension, Falls and Syncope Orthostatic hypotension, falls, and syncope have been reported in patients treated with the recommended duloxetine delayed-release capsules dosages. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during duloxetine delayed-release capsules treatment, particularly after dose increases.
The risk of falling appears to be related to the degree of orthostatic decrease in blood pressure (BP) as well as other factors that may increase the underlying risk of falls. In an analysis of patients from all placebo-controlled trials, patients treated with 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 BP. 1)] and in patients taking duloxetine delayed-release capsules at doses above 60 mg daily. Consideration should be given to dose reduction or discontinuation of duloxetine delayed-release capsules in patients who experience symptomatic orthostatic hypotension, falls and/or syncope during duloxetine delayed-release capsules therapy.
Risk of falling also appeared to be proportional to a patient’s underlying risk for falls and appeared to increase steadily with age. As geriatric patients tend to have a higher underlying risk for falls due to a higher prevalence of risk factors such as use of multiple medications, medical comorbidities and gait disturbances, the impact of increasing age by itself is unclear.
1)]. 4 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including duloxetine delayed-release capsules, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.
John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). , nausea, vomiting, diarrhea).
Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of duloxetine delayed-release capsules with MAOI antidepressants is contraindicated. Duloxetine delayed-release capsules 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 delayed-release capsules. 10), and Contraindications (4)]. If concomitant use of duloxetine delayed-release capsules with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St.
John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with duloxetine delayed-release capsules and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
5 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including duloxetine delayed-release capsules, may increase the risk of bleeding events. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.
A post-marketing study showed a higher incidence of postpartum hemorrhage in mothers taking duloxetine delayed-release capsules. Other bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. 4)] . 6 Severe Skin Reactions Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), 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 delayed-release capsules 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. 7 Discontinuation Syndrome Discontinuation symptoms have been systematically evaluated in patients taking duloxetine delayed-release capsules.
Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in duloxetine delayed-release capsules-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis and fatigue.
, 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 delayed-release capsules. 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.
8] . 04% (1/2,536) of placebo-treated patients. No activation of mania or hypomania was reported in DPNP, GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder.
As with these other agents, duloxetine delayed-release capsules should be used cautiously in patients with a history of mania. 9 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including duloxetine delayed-release capsules may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
10 Seizures Duloxetine delayed-release capsules have not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. 01% (1/9,513) of patients treated with placebo. Duloxetine delayed-release capsules should be prescribed with care in patients with a history of a seizure disorder.
3 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. 3 times the maximum recommended dosage). 5 to 7 mm Hg (diastolic) up to 12 hours after dosing.
1)] . 12 Clinically Important Drug Interactions Both CYP1A2 and CYP2D6 are responsible for duloxetine delayed-release capsules metabolism. 1)] . 2)] . , 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 delayed-release capsules.
9)] . Other Clinically Important Drug Interactions Alcohol - Use of duloxetine delayed-release capsules concomitantly with heavy alcohol intake may be associated with severe liver injury. 15)] . 16)] . 13 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including duloxetine delayed-release capsules.
In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported with duloxetine delayed-release capsules use and appeared to be reversible when duloxetine delayed-release capsules were discontinued.
Geriatric patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. 5)] . Discontinuation of duloxetine delayed-release capsules 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.
14 Use in Patients with Concomitant Illness Clinical experience with duloxetine delayed-release capsules 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 delayed-release capsules’s enteric coating.
In extremely acidic conditions, duloxetine delayed-release capsules, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. , some diabetics). Duloxetine delayed-release capsules have 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. 9)] . 10)] . Glycemic Control in Patients with Diabetes As observed in DPNP trials, duloxetine delayed-release capsules treatment worsened glycemic control in some patients with diabetes.
8%. In the 12-week acute treatment phase of these studies, duloxetine delayed-release capsules were associated with a small increase in mean fasting blood glucose as compared to placebo. 5 mg/dL in the routine care group. 2% in the routine care group.
If symptoms of urinary hesitation develop during treatment with duloxetine delayed-release capsules, 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 delayed-release capsules use, hospitalization and/or catheterization has been needed. 1)]. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction.
In female patients, SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of duloxetine delayed-release capsules and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported.
When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.