Duloxetine Hydrochloride Enteric Capsules Instruction

Date of approval.
Date of revision.
 Duloxetine Hydrochloride Enteric Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
Results of short-term clinical trials of depression (MDD) and other psychiatric disorders have shown that antidepressants increase the risk of suicidal ideation (suicidal thoughts and committing suicidal acts) in children, adolescents, and young adults (≤ 24 years of age) compared to placebo. Anyone considering the use of this or other antidepressants in children, adolescents, or young adults (≤24 years of age) must weigh the clinical need against the risks. Short-term clinical trials have not shown an increased risk of suicidal ideation in adult patients aged >24 years using antidepressants compared with the placebo group; in adult patients aged 65 years and older using antidepressants, the risk of suicidal ideation was reduced compared with the placebo group. Depression and certain psychiatric disorders are inherently associated with an increased risk of suicide, and the worsening of clinical symptoms, suicidal ideation, and abnormal changes in behavior after initiation of antidepressant treatment in patients of all ages must be closely observed and reasonably monitored. Families and caregivers should be advised that patients must be closely observed and communicated with their physicians. This product has not been approved for use in pediatric patients in China (see [Warnings], [Precautions] and [Pediatric Use]).
 Drug Name]
Generic Name: Duloxetine Hydrochloride Enteric Capsules
English name: Duloxetine Hydrochloride Enteric Capsules
Hanyu Pinyin: Yansuan Duluoxiting Changrongjiaonang
Ingredients
Main Component: Duloxetine Hydrochloride
Chemical name: (+)-(S)-N-methyl-γ-(1-naphthoxy)-2-thiophenepropanolamine hydrochloride
Chemical structure formula.
Molecular formula: C18H19NOS-HCl
Molecular weight: 333.88
Properties
The content of this product is non-adhesive uniform small pills.
20mg*capsule: yellow capsule with “OE 660” printed on the capsule.
30mg*capsule: white capsule with blue cap with “OE 860”.
60mg*capsule: yellow capsule with blue cap with “OE 794”.
Indications
Depression.
Generalized anxiety disorder.
Chronic musculoskeletal pain.
Specification
According to C18H19NOS (1) 20mg (2) 30mg (3) 60mg
Dosage]
This product should be swallowed whole. It should not be chewed or crushed; nor should it be taken by opening the capsule shell and spreading the contents on food or mixing with liquid. Because these operations may have an effect on the enteric coating. This product should be used without regard to diet. If you forget to take the medication, take it as soon as you remember. If it is close to the time of the next dose, ignore the last missed dose and take the normal dose directly according to the previous dose. Do not take twice the dose at the same time.
Depression.
The recommended dose is 40mg/day (20mg twice a day each time) to 60mg/day (60mg once a day or 30mg twice a day). Some patients may require a starting dose of 30 mg once a day for 1 week, increasing to 60 mg once a day as the patient adjusts to the medication. The available clinical study data do not confirm that dosing above 60 mg/day will increase efficacy. The need for maintenance therapy and the required dose need to be re-evaluated periodically.
Generalized Anxiety Disorder.
Adults – For most patients, the recommended starting dose is 60 mg once a day. Some patients may require a starting dose of 30 mg once a day for 1 week, increasing to 60 mg once a day as the patient adjusts to the medication. Although the effectiveness of the 120 mg once-daily dose has been demonstrated, there is no evidence that dosing beyond 60 mg once-daily provides additional benefit. However, if the decision is made to increase the dose beyond 60 mg once a day, the dose increase should be 30 mg once a day. The safety of doses above 120 mg once a day has not been adequately evaluated. The need for maintenance therapy and the dose required need to be re-evaluated periodically.
Elderly – The recommended starting dose is 30 mg once a day and after two weeks, an increase in the target dose to 60 mg may be considered, after which the patient may benefit from a dose higher than 60 mg once a day. If the decision is made to increase the dose beyond 60 mg once a day, the dose increase should be 30 mg once a day. The maximum dose is 120 mg/day. The safety of doses above 120 mg once a day has not been adequately evaluated.
Chronic musculoskeletal pain
The recommended dose of duloxetine is 60 mg once a day. The starting dose is 30 mg administered continuously for 1 week, increasing to 60 mg once daily as the patient adjusts to the drug therapy. No evidence of additional benefit at higher doses has been observed, even in patients who did not respond to the 60 mg dose, and higher doses are associated with a higher incidence of adverse events.
Dosing for Special Populations
Hepatic insufficiency – Avoid this product in patients with chronic liver disease or cirrhosis.
Severe renal impairment – Avoid this product in patients with severe renal impairment (glomerular filtration rate <30mL/min).
Discontinuation of Duloxetine
Adverse reactions associated with discontinuation of this drug (abrupt discontinuation or taper) include: dizziness, headache, nausea, diarrhea, abnormal sensation, irritability, vomiting, insomnia, anxiety, excessive sweating, and fatigue. It is recommended to taper the drug as much as possible rather than stopping it abruptly.
Switching between medications with monoamine oxidase inhibitors (MAOIs)
Do not start treatment with MAOIs until at least 14 days after discontinuation of MAOIs. Treatment with MAOIs should not be started until at least 5 days after discontinuation of this product.
Combination with other MAOIs (e.g., linezolid and methylene blue)
This product should not be started in patients who are using MAOIs such as linezolid or intravenous methylene blue because of the increased risk of developing pentraxin syndrome. Other interventions (including hospitalization) should be considered for patients with psychiatric disorders requiring urgent treatment.
In some cases, patients already receiving this product may require emergency treatment with linezolid or intravenous methylene blue. Exceptionally, if treatment other than linezolid or IV methylene blue is not an option and the potential benefit of linezolid or IV methylene blue treatment can be judged to outweigh the risk of pentraxin syndrome, this product should be discontinued immediately and linezolid administration or IV methylene blue should be initiated. Patients should be monitored for pentraxin syndrome for 5 days or until 24 hours after the final administration of linezolid or intravenous methylene blue (choose the shorter period). Re-administer this product 24 hours after the last dose of linezolid or intravenous methylene blue.
The risks of combining this product with methylene blue administered non-intravenously (e.g., oral tablet or topical injection) or at intravenously administered doses less than 1 mg/kg are unknown. However, clinicians should be aware that such administration may result in the development of emergency symptoms of pentothal syndrome.
Adverse Reactions
Duloxetine hydrochloride enteric capsules have not been approved in China for indications other than depression, generalized anxiety disorder and chronic musculoskeletal pain. The following adverse reactions are derived from the [Adverse Reactions] information in this product’s foreign instructions.
1 Clinical trial data sources
Clinical trials are conducted under very different circumstances compared to clinical practice, so the incidence of adverse reactions observed in clinical trials of one drug cannot be directly compared to the incidence of adverse reactions observed in clinical trials of another drug, and do not reflect the incidence in clinical practice.
The reported incidence of adverse reactions represents the proportion of patients who experienced at least one case of an adverse reaction of the type listed that occurred during treatment. An adverse reaction was considered to have occurred during treatment if it first occurred or was exacerbated while receiving treatment after the baseline evaluation. Reactions reported during the clinical study were not necessarily caused by the treatment and the frequency does not reflect the investigator’s impression (assessment) of causality.
Adults – The following data reflect patient exposure to duloxetine in placebo-controlled trials for the treatment of depression (N=3779), generalized anxiety disorder (N=1018), osteoarthritis (N=503), chronic low back pain (N=600), diabetic peripheral neuralgia (N=906), and fibromyalgia (N=1294). The study population was 17 to 89 years of age; 65.7%, 60.8%, 60.6%, 42.9%, and 94.4% of patients with depression, generalized anxiety disorder, osteoarthritis and chronic low back pain, diabetic peripheral neuralgia, and fibromyalgia, respectively, were female; and 81.8%, 72.6%, 85.3%, 74.0%, and 85.7%, respectively, were white . Most patients received a total daily dose of 60 mg to 120 mg of duloxetine The following data do not include the results of trials conducted to assess the efficacy of duloxetine in generalized anxiety disorder in patients ≥65 years of age; however, the adverse reactions observed in this older patient population were generally similar to those observed in the overall adult population.
2 Adverse reactions leading to treatment discontinuation reported in placebo-controlled trials in adults
Depression – In placebo-controlled trials for the treatment of depression, approximately 8.4% (319/3779) of patients in the duloxetine treatment group had treatment discontinuation due to adverse reactions compared to 4.6% (117/2536) of patients in the placebo treatment group. Nausea (1.1% in the duloxetine group versus 0.4% in the placebo group) was the only common adverse reaction reported that led to treatment discontinuation and was considered to be related to drug treatment (e.g., at least 1% of patients in the duloxetine group discontinued treatment as a result, and the incidence was at least twice as high as in the placebo group).
Generalized anxiety disorder – In placebo-controlled trials for the treatment of generalized anxiety disorder, approximately 13.7% (139/1018) of patients in the duloxetine treatment group discontinued treatment due to adverse reactions, compared to 5.0% (38/767) of patients in the placebo treatment group. Common adverse reactions reported as causes of treatment discontinuation and considered drug-related (as defined above) included nausea (3.3% in the duloxetine group versus 0.4% in the placebo group) and dizziness (1.3% in the duloxetine group versus 0.4% in the placebo group).
Chronic pain due to osteoarthritis – In the 13-week placebo-controlled clinical trial for the treatment of chronic pain due to osteoarthritis, 15.7% (79/503) of patients treated with duloxetine discontinued due to adverse reactions and 7.3% (37/508) of patients in the placebo group discontinued due to adverse reactions. Common adverse reactions reported as causes of treatment discontinuation and considered drug-related (as defined above) included nausea (2.2% for duloxetine and 1.0% for placebo).
Chronic Low Back Pain – In the 13-week placebo-controlled clinical trial of chronic low back pain, 16.5% (99/600) of patients treated with duloxetine discontinued due to adverse reactions and 6.3% (28/441) of patients in the placebo group discontinued due to adverse reactions. Common adverse reactions reported as causes of treatment discontinuation and considered drug-related (defined above) included nausea (3.0% for duloxetine and 0.7% for placebo) and drowsiness (1.0% for duloxetine and 0.0% for placebo).
3 Most common adverse reactions in adults
All trials with approved indications combined – The most common adverse reactions in patients in the duloxetine treatment group (occurring at least 5% and at least twice as often as in patients in the placebo group) were nausea, dry mouth, drowsiness, constipation, decreased appetite, and excessive sweating.
Chronic pain due to osteoarthritis – The most common adverse reactions (as defined above) in patients in the duloxetine treatment group were nausea, fatigue, constipation, dry mouth, insomnia, drowsiness, and dizziness.
The most common adverse reactions (defined above) in patients in the chronic low back pain – duloxetine treatment group were nausea, dry mouth, insomnia, drowsiness, constipation, dizziness, and fatigue.
4 Adverse reactions with an incidence of 5% or more in patients in the duloxetine treatment arm of the adult placebo-controlled trial
Table 1 lists the adverse reactions that occurred in 5% or more of patients in the duloxetine treatment group in placebo-controlled trials for the treatment-approved indication and that occurred at a higher incidence than in the placebo group.
Table 1: Adverse reactions occurring on treatment: 5% or more in placebo-controlled trials for treatment-approved indications in the United States and at a higher incidence than in the placebo groupa
Adverse reactions Percentage of patients reporting adverse reactions Duloxetine
(N=8100) Placebo
(N=5655) Nauseac
238 headache 1412 dry mouth 135 drowsinesse 103 fatigueb,c 95 insomniad 95 constipationc94 dizzinessc95 diarrhea 96 decreased appetitec72 excessive sweatingc61 abdominal painf54a Events included in the table are based on percentages before revision; however, percentages in the table have been rounded to the nearest whole number.
b Also includes malaise.
c Events with significant dose-dependent relationships in fixed-dose studies, excluding 3 studies of depression without placebo introduction periods or dose-escalation.
d Also includes difficulty falling asleep, mid-term insomnia, and early awakening.
e
Also includes hypersomnia and sedation.
f
Also includes abdominal discomfort, lower abdominal pain, upper abdominal pain, abdominal tenderness, and gastrointestinal pain.
5 Adverse reactions with an incidence of 2% or more in patients in the duloxetine treatment arm of the placebo-controlled trial in adults
Combined Depression and Generalized Anxiety Disorder Trial – Table 2 lists the adverse reactions that occurred in the placebo-controlled trial for the treatment of the approved indications of depression and generalized anxiety disorder that occurred in 2% or more of patients in the duloxetine treatment group and had a higher incidence than those in the placebo group.
Table 2: Adverse reactions occurring on treatment: by 2% or more in placebo-controlled trials of depression and generalized anxiety disordera,b and at a higher incidence than in the placebo group
Systemic organ classification/adverse reactions Percentage of patients reporting adverse reactions Duloxetine
(N=4797) Placebo
(N=3303) Heart organ disorders Palpitations21 Eye organ disorders Blurred vision31 Gastrointestinal system disorders
Nauseac
Dry mouth
Constipationc
Diarrhea
Abdominal paind
Vomiting
 
 23
14
9
9
5
4
 
 8
6
4
6
4
2 Systemic diseases and various reactions at the drug administration site
Fatiguee
 9
 5 Metabolic and nutritional disorders Decreased appetitec62 Various neurological disorders Headache1414 Dizzinessc
95 Drowsinessf93 Tremor31 Psychiatric disorders Insomniag95 Agitationh42 Anxiety32 Reproductive and breast disorders Erectile dysfunction 41 Delayed ejaculationc
Decreased libidoi
Abnormal orgasmj2
3
21
1
< 1 Respiratory, thoracic, and mediastinal disorders Yawning2< 1 Skin and subcutaneous tissue-like disorders Hyperhidrosis62a Events included in the table are based on pre-revision percentages; however, the percentages in the table have been rounded to the nearest whole number.
b For generalized anxiety disorder, these adverse events were not significantly different between adults aged 65 years and older and adults under 65 years.
c Events with significant dose-dependent relationships in fixed-dose studies, excluding 3 studies of depression without placebo introduction periods or dose-escalation.
d Also includes epigastric pain, lower abdominal pain, abdominal pressure, abdominal discomfort, and gastrointestinal pain.
e Also includes malaise.
f Also includes hypersomnia and sedation.
g Also includes difficulty falling asleep, mid-term insomnia, and early awakening.
h Also includes restlessness, nervousness, agitation, nervousness and psychomotor hyperactivity.
i Also includes loss of sexual desire
j Also includes absence of sexual pleasure.
Diabetic peripheral neuralgia, fibromyalgia, osteoarthritis, and chronic low back pain – Table 3 lists the placebo-controlled trials of the treatment of diabetic peripheral neuralgia, fibromyalgia, osteoarthritis, and chronic low back pain in the premarketing acute phase that occurred in 2% or more of patients in the duloxetine treatment group (determined before rounding) and had a higher incidence than the placebo group of adverse reactions that occurred during treatment.
Table 3: Adverse reactions in placebo-controlled trials for the treatment of diabetic peripheral neuralgia, fibromyalgia, osteoarthritis, and chronic low back pain in the U.S. approved indications with an incidence of 2% or more and a higher incidence than in the placebo group
Systemic Organ Classification/Adverse Reaction Percentage of patients reporting adverse reactions Duloxetine
(N=3303) Placebo
(N=2352) Gastrointestinal system disorders Nausea237 Dry mouthb113 Constipationb103 Diarrhea95 Abdominal painc54 Vomiting32 Dyspepsia21 Systemic diseases and various reactions at the site of administration Fatigued115 Infectious and invasive diseases Nasopharyngitis44 Upper respiratory tract infections33 Influenza22 Metabolic and nutritional diseases Decreased appetiteb81 Various musculoskeletal and connective tissue disorders Musculoskeletal Paine33 Myospasm22 Various neurological disorders Headache138 Drowsinessb,f113 Dizziness95 Abnormal sensationsg22 Tremorb2<1 Psychiatric disorders Insomniab,h105 Agitationi31 Reproductive and breast disorders Erectile dysfunctionb4<1 Ejaculatory disordersj2<1 Respiratory, thoracic and mediastinal disorders Cough22 Skin and subcutaneous tissue disorders Hyperhidrosis 61 Vascular and lymphovascular disorders Flushing k31 Elevated blood pressure l21a Events included in the table were determined based on percentages before revision; however, percentages in the table have been rounded to the nearest whole number.
b Significantly higher incidence in the 120 mg/day dose group than in the 60 mg/day dose group.
c Also includes upper abdominal discomfort, lower abdominal pain, epigastric pain, abdominal pressure, and gastrointestinal pain.
d Also includes malaise.
e Also includes myalgia and neck pain.
f Also includes hypersomnia and sedation.
g Also includes hyperalgesia, facial hyperalgesia, genital hyperalgesia, and oral hyperalgesia.
h Also includes difficulty falling asleep, mid-term insomnia, and early awakening.
i Also includes catatonia, neurotic restlessness, agitation, nervousness and psychomotor hyperactivity.
j Also includes failure to ejaculate.
k Also includes hot flashes.
l Also includes elevated diastolic blood pressure, elevated systolic blood pressure, diastolic hypertension, primary hypertension, hypertension, hypertensive crisis, unstable hypertension, upright hypertension, secondary hypertension, and systolic hypertension.
6 Effects on adult male and female sexual function
Changes in libido, sexual behavior, and sexual satisfaction are often manifestations of mental illness or diabetes, but they may also be the result of drug therapy. Because adverse sexual function reactions are considered spontaneously underreported, four placebo-controlled trials for depression prospectively used the Arizona Sexual Experience Scale (ASEX), a validated measurement tool designed to identify sexual function side effects. In these trials, as shown in Table 4 below, significantly more sexual dysfunction occurred in patients treated with duloxetine than in patients in the placebo-treated group, as assessed by the ASEX total score. Gender analysis showed that the difference was only seen in male patients. Male patients treated with duloxetine had more difficulty achieving orgasm than male patients treated with placebo (ASEX item 4). Based on the total ASEX score, sexual dysfunction occurred no more in female patients treated with duloxetine than in female patients in the placebo group. Negative numbers indicate improvement compared to baseline levels of sexual dysfunction and are usually seen in patients who experience depression. Physicians should routinely ask patients about possible sexual function side effects.
Table 4: Mean change in ASEX scores in patients by gender in placebo-controlled trials for depression
 Male patientsa Female patientsa Duloxetine
(N=175) Placebo
(N=83) Duloxetine
(N=241) Placebo
(N=126) ASEX (items 1-5) 0.56b-1.07-1.15-1.07 item 1 -sexual urge -0.07-0.12-0.32-0.24 item 2 -sexual arousal 0.01-0.26-0.21-0.18 item 3 -Erection ability (male); secretion of love juices (female) 0.03-0.25-0.17-0.18 item 4 -Ease of reaching orgasm 0.40c-0.24-0.09-0.13 item 5 -Orgasmic satisfaction 0.09-0.13-0.11- 0.17a n = number of patients with no deficits in ASEX total change scores.
b Compared with the placebo group, p = 0.013.
c Compared with the placebo group, p < 0.001.
7 Change in vital signs in adults
In clinical trials treating various indications, duloxetine treatment caused an increase in blood pressure from baseline to endpoint with a mean increase in systolic blood pressure of 0.23 mmHg and a mean increase in diastolic blood pressure of 0.73 mmHg compared with placebo; the placebo group had a mean decrease in systolic blood pressure of 1.09 mmHg and a mean decrease in diastolic blood pressure of 0.55 mmHg. The frequency of sustained blood pressure elevation (3 consecutive visits) did not significantly difference.
In placebo-controlled trials treating various indications, duloxetine treatment for up to 26 weeks caused a slight increase in heart rate compared with placebo treatment, with an increase of 1.37 beats per minute at endpoint compared with baseline (1.20 beats per minute for patients in the duloxetine group and 0.17 beats per minute for patients in the placebo group).
8 Changes in adult laboratory parameters
In placebo-controlled clinical trials for each indication treated, duloxetine treatment resulted in a slight increase in ALT, AST, CPK, and alkaline phosphatase levels from baseline to endpoint on average; rare, moderate, transient, and abnormal values for these test parameters were found in patients treated with duloxetine when compared to placebo-treated patients. Hyperbicarbonate and cholesterol and potassium abnormalities (high or low) were observed more frequently in patients in the duloxetine group than in the placebo group.
9 ECG changes in adults
In a randomized, double-blind, double-crossover study in 117 healthy female subjects, the effects of 160 mg and 200 mg duloxetine administered twice daily were evaluated. No prolongation of the QT interval was detected. Duloxetine had a concentration-dependent correlation, but no clinically meaningful QT shortening occurred.
10 Other Adverse Reactions Identified in Pre- and Post-Marketing Clinical Trial Evaluations of Duloxetine (Adults)
The following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical trials treating all indications, 34,756 patients were treated with duloxetine. Of these patients, 26.9% (9337) took duloxetine for at least 6 months and 12.4% (4317) took duloxetine for at least 1 year. The following list does not include reactions that (1) were listed in previous tablet instructions or elsewhere in the instructions, (2) had minimal drug cause, (3) were too general to be informative, (4) were not considered clinically significant, or (5) occurred at a rate equal to or less than the placebo group.
Reactions were classified according to body systems according to the following definitions: common adverse reactions were those occurring in at least 1/100 patients; occasional adverse reactions were those occurring in 1/100 to 1/1000 patients; and rare adverse reactions were those occurring in less than 1/1000 patients.
Heart Organ Disease
– Common: palpitations; Occasional: myocardial infarction, tachycardia, and Takotsubo cardiomyopathy (stress cardiomyopathy).
Ear and vagus disorders – common: vertigo; occasional: ear pain and tinnitus
Endocrine system disorders – Occasionally: hypothyroidism.
Diseases of the eye organs – common: blurred vision; occasionally: diplopia, dry eyes and visual disturbances.
Gastrointestinal system disorders – common: intestinal gas and bloating; occasional: dysphagia, hiccups, gastritis, gastrointestinal bleeding, halitosis and stomatitis; rare: gastric ulcer.
Systemic diseases and reactions at the site of administration – common: chills; occasional: falls, abnormal sensations, sensations of heat and/or cold, discomfort and thirst; rare: gait disturbances.
Infections and Infectious Diseases – Occasionally: gastroenteritis and laryngitis.
Various tests – Common: weight gain, weight loss; Occasionally: elevated blood cholesterol.
Metabolic and nutritional disorders – Occasional: dehydration and hyperlipidemia; Rare: abnormal lipid disorders.
Various musculoskeletal and connective tissue disorders – Common: musculoskeletal pain; Occasionally: muscle tension and muscle tremors.
All types of neurological disorders
– Common: taste disorders, sleepiness, sensory abnormalities/ hyperalgesia; Occasionally: attention disorders, movement disorders, myoclonus and poor sleep quality; Rare: dysarthria.
Psychiatric disorders – common: abnormal dreaming and sleep disorders; occasional: affective apathy, nocturnal molar disorder, disorientation/disorientation, irritability, mood swings, and suicide attempts; rare: suicide attempts.
Renal and urological disorders –
Common: urinary frequency; Occasionally: dysuria, urgency, nocturia, polyuria, and abnormal urine odor.
Reproductive and breast disorders – common: lack of sexual pleasure/abnormal orgasm; occasional: menopausal symptoms, sexual dysfunction and testicular pain; rare: menstrual disorders.
Respiratory, thoracic and mediastinal disorders – Common: yawning, oropharyngeal pain; Occasionally: throat tightness
Skin and subcutaneous tissue disorders – common: pruritus; occasionally: cold sweats, contact dermatitis, erythema, increased tendency to bruising, night sweats and photosensitivity reactions; rare: petechiae.
Vascular and lymphatic vessel disorders – common: hot flashes; occasional: flushing, upright hypotension, and chills to extremities
 11 Post-marketing spontaneous reports
The following adverse reactions have been identified during post-marketing use of this product. Because these adverse reactions were spontaneously reported by a population of unknown size, it is not always possible to estimate a reliable frequency of adverse reactions or to establish a causal relationship with drug exposure.
Adverse reactions reported since marketing that are potentially but indefinitely associated with duloxetine and not mentioned elsewhere in the insert include: acute pancreatitis, tachyphylaxis, aggression and anger (especially early in treatment or after treatment discontinuation), angioneurotic edema, closed-angle glaucoma, colitis (microscopic or not specifically defined), cutaneous vasculitis (sometimes with systemic involvement), extrapyramidal disease, breast overflow , gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity reactions, hypertensive crisis, myoclonus, rash, restless legs syndrome, seizures on treatment cessation, supraventricular arrhythmias, tinnitus (on treatment cessation), clenching of teeth, and urticaria.
[Contraindication].
Allergy
Duloxetine enteric-coated capsules are contraindicated in patients with known hypersensitivity to duloxetine or any of the inactive ingredients in the product.
Monoamine oxidase inhibitors
MAOIs are contraindicated within 5 days of taking or discontinuing this product for the treatment of psychiatric disorders due to the increased risk of pentraxin syndrome. MAOIs should also be contraindicated within 14 days of discontinuation.
It should also be contraindicated in patients taking MAOIs such as linezolid or intravenous methylene blue because of the increased risk of pentraxin syndrome.
Untreated narrow-angle glaucoma
Clinical trials have shown that duloxetine has an increased risk of pupillary dilation; therefore, duloxetine should be avoided in patients with untreated narrow-angle glaucoma.
[Caution].
Suicidal thoughts and suicidal behavior in children, adolescents and young adults
Adults and children with depression, with or without antidepressant treatment, may experience worsening of depressive symptoms and/or
or develop suicidal ideation with suicidal behavior (suicide) or abnormal behavioral changes, and this risk will persist until the condition is in significant remission. Suicide is a known risk associated with depression and other psychiatric disorders, which themselves are the most obvious precursors to suicide. It has long been thought that early in the treatment of certain specific populations, antidepressants may induce worsening of depressive symptoms or lead to suicide.
Comprehensive analyses of short-term placebo-controlled trials of antidepressants (SSRIs and other antidepressants) have shown that antidepressants increase the risk of suicidal ideation and suicidal behavior (suicide) in children, adolescents, and young adults (aged 18-24 years) with depression (MDD) and other psychiatric disorders. The short-term study also showed that antidepressants did not increase the risk of suicide in adults aged >24 years compared with placebo, and that antidepressant treatment reduced the risk of suicide in adults aged 65 years and older compared with placebo.
A pooled analysis of placebo-controlled trials of 9 antidepressants (SSRIs and other antidepressants) for the treatment of depression, obsessive-compulsive disorder, or other psychiatric disorders in children and adolescents (a total of 24 trials including 4400 patients), and a pooled placebo-controlled trial of 11 antidepressants (a total of 295 short-term trials with a median treatment period of 2 months, including more than 77,000 patients) The results of this analysis showed considerable variation in the risk of suicide due to various drug treatments, although there was a trend toward an increased risk of suicide in younger patients for almost all drugs studied. The absolute suicide risk varied between indications, with the highest being depression. The differences in suicide risk (difference in the number of suicides per 1000 patients for treatment drugs versus placebo) are shown in the following table.
Age range Difference in the number of cases of suicide per 1000 patients with treatment drugs versus placebo Number of cases increased compared with placebo treatment <18 years 14 cases increased 18-24 years 5 cases decreased compared with placebo treatment 25-64 years 1 case decreased ≥65 years 6 cases decreased Although no suicidal events occurred in trials conducted in children and suicidal events occurred in trials conducted in adults, the number of cases is not sufficient to conclude any drug effect on suicide. It is unclear whether the risk of suicide in pediatric patients persists into the long-term treatment period, i.e., beyond several months. Placebo-controlled maintenance treatment trials conducted in adults with depression provide sufficient evidence that the administration of antidepressants delays the recurrence of depression.
All patients receiving antidepressants for any indication should be appropriately monitored and closely observed for worsening clinical symptoms, suicidality, or changes in abnormal behavior, particularly during the first few months of medication, or when doses are changed, such as by increasing or decreasing the dose.
The following symptoms have been reported in adult and pediatric patients treated with antidepressants for depression and other indications, either psychotic or nonpsychotic disorders: anxiety, euphoria, panic attacks, insomnia, irritability, hostility, aggression, impulsivity, inability to sit still (psychomotor agitation), hypomania, and mania. Although a causal relationship between the presence of the above symptoms and worsening depression and/or leading to suicide has not been demonstrated, these symptoms may be precursors to the occurrence of suicide.
When experiencing persistent worsening of depressive symptoms or the development of suicide, or when precursor symptoms of worsening depression or suicide occur, especially when these symptoms are very severe, occur suddenly, or when new symptoms appear, a change in treatment regimen, including possible discontinuation of treatment, needs to be considered. If a decision is made to discontinue treatment, the medication should be tapered as soon as possible, but some symptoms should be noted with discontinuation (see [Dosage] and [Precautions] for a description of the risks of discontinuing duloxetine treatment).
For patients using antidepressants for depression or other indications, including psychotic and nonpsychotic disorders, the patient’s family and caregivers should be reminded to monitor the patient for the development of agitation, irritability, abnormal behavioral changes, other symptoms described above, and the development of suicidal behavior, and to report these symptoms to health care personnel as soon as they occur; such monitoring should also include daily observation by family and caregivers. Duloxetine enteric-coated capsules should be prescribed in the smallest capsule size that achieves a good therapeutic effect to reduce the risk of overdose.
Screening for patients with bipolar disorder: Depressive episodes may be an early manifestation of bipolar disorder. It is commonly believed (although not confirmed in controlled studies) that treatment of depressive episodes with antidepressants alone may increase mixed/manic episodes in patients with bipolar disorder. Although it is not possible to predict which of the symptoms mentioned above will occur, depressed patients should be appropriately screened for risk of bipolar disorder prior to antidepressant treatment. Screening methods include a detailed psychiatric history, with a family history of suicidal behavior, bipolar disorder, and depression. It should be noted that duloxetine is not approved for the treatment of depressive episodes in bipolar disorder.
Hepatotoxicity
Hepatic failure, sometimes fatal, has been reported in duloxetine treated patients. These cases manifest as hepatitis with abdominal pain, hepatomegaly, and elevation of aminotransferases with or without jaundice exceeding the upper limit of normal by a factor of 20. Patients who develop jaundice or other clinically significant liver dysfunction should discontinue duloxetine and should not continue treatment unless there is some other reason.
Cases of biliary depression jaundice with mild elevation of aminotransferase have also been reported. Post-marketing reports indicate that elevations in aminotransferases, bilirubin and alkaline phosphatase also occur in patients with chronic liver disease or cirrhosis.
In development studies, duloxetine was associated with an increased risk of serum aminotransferase levels. Elevation of this enzyme resulted in treatment discontinuation in 0.3% (92/34,756) of duloxetine treated patients. The median time to aminotransferase elevation in these patients was 2 months. In placebo-controlled studies for all indications, 1.25% (144/11496) of patients in the duloxetine group had ALT elevations greater than 3 times the upper limit of normal compared with 0.45% (39/8716) in the placebo group. In fixed-dose placebo-controlled studies, there was evidence of a dose-effect relationship between ALT elevations above the upper limit of normal 3-fold and AST elevations above the upper limit of normal 5-fold.
Because the interaction of duloxetine and alcohol may cause liver damage or because duloxetine has the potential to exacerbate the worsening of existing liver disease, duloxetine is not usually used in the treatment of patients with heavy alcohol consumption and chronic liver disease.
Orthostatic hypotension, falls and syncope
Upright hypotension, falls, and syncope have been reported with therapeutic doses of duloxetine. They usually occur within the first week of treatment, but can also occur at any time during treatment, especially after dose increases. The occurrence of falls is associated with the degree of reduction in upright blood pressure, as well as with other factors that may increase the potential risk of falls.
In an analysis of all patients enrolled in the placebo-controlled study, the rate of falls was higher in the duloxetine group than in the placebo group. The risk of falls was associated with the occurrence of lowered upright blood pressure. Patients were at increased risk of developing a fall when taking other drugs that cause upright hypotension (e.g., blood pressure lowering drugs) or strong CYP1A2 enzyme inhibitors, and when taking duloxetine at doses greater than 60 mg/day. Patients receiving duloxetine should consider dose reduction or discontinuation if upright hypotension, falls, and syncope occur while on duloxetine therapy.
The risk of falls is proportional to the potential risk of falls associated with the patient and increases with age. Because risk factors such as comorbid medications, coexisting conditions and gait disturbances are more prevalent in older adults, resulting in a higher potential risk of falls, the effect of advancing age per se on falls is unknown. Serious consequences of falls that have been reported include fractures and hospitalization.
Pentazocine syndrome
Monotherapy with SNRIs (including duloxetine) and SSRIs, especially in combination with other pentraxinergic drugs (including tritans, tricyclic antidepressants, fentanyl, lithium salts, tramadol, tryptophan, buspirone, bupropion, and St. John’s wort) and drugs that impair pentraxin metabolism (especially MAOIs, proposed for the treatment of psychiatric disorders and other conditions, such as linezolid or intravenous methylene blue) when pentraxin syndrome has been reported to occur, which can be life-threatening.
Pentazocine syndrome includes altered mental status (e.g., agitation, hallucinations, confusion, and coma), autonomic instability (e.g., tachycardia, blood pressure instability, dizziness, sweating, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, tonicity, myoclonus, tendon reflex hyperactivity, ataxia), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Monitoring of patients for pentazocine syndrome is required.
Combination of duloxetine with MAOIs for the treatment of psychiatric disorders is prohibited. Patients on MAOIs (e.g., linezolid or intravenous methylene blue) should not be started on this product. All reports of the route of administration of methylene blue are for intravenous administration at doses ranging from 1 mg/kg-8 mg/kg. no other routes of administration (e.g., oral tablets or local tissue injections) or lower doses of methylene blue have been reported. Treatment with MAOIs (e.g., linezolid or intravenous methylene blue) may be required for patients taking this product, if necessary. This product should be discontinued prior to initiating treatment with MAOIs.
If a combination of duloxetine and other pentazocine medications (including tretinoin, tricyclic antidepressants, fentanyl, lithium salts, tramadol, tryptophan, buspirone, bupropion, and St. John’s wort) is clinically indicated, patients should be made aware of the potential increased risk of developing pentazocine syndrome, especially when initiating treatment and increasing doses.
If any of these events occur, immediate discontinuation of duloxetine and any combination of pentraxetine medications is required and supportive symptomatic therapy is initiated.
Abnormal bleeding
SSRIs and SNRIs, including duloxetine, increase the risk of bleeding events. Combined use of aspirin, NSAIDs, warfarin, and other anticoagulants increases this risk. Case reports and epidemiological studies (case-control and cohort studies) demonstrate an association between the use of drugs that interfere with pentraxin reuptake and gastrointestinal bleeding. Bleeding events associated with the use of SSRIs and SNRIs have ranged from petechiae, hematomas, epistaxis, and petechiae to life-threatening bleeding.
Patients need to be concerned about the risk of bleeding when combining duloxetine with NSAIDs, aspirin, or other medications that affect coagulation.
Serious skin reactions
Serious skin reactions that may occur with duloxetine include erythema multiforme and Stevens-Johnson syndrome (SJS). The reported rate of SJS associated with duloxetine exceeds the total population background incidence of severe skin reactions (1 to 2 cases per 1 million people). Due to underreporting, it is generally believed that this reporting rate is underestimated.
Duloxetine should be discontinued in the presence of blisters, desquamative rash, mucosal ulcers, or allergic symptoms without any other etiology established.
Duloxetine Discontinuation
Discontinuation symptoms of duloxetine have been systematically studied. In placebo-controlled trials in adults, the incidence of symptoms observed in duloxetine treated patients was greater than or equal to 1% when the drug was discontinued abruptly or slowly, and was significantly higher in duloxetine treated patients than in discontinued placebo patients including: dizziness, headache, nausea, diarrhea, abnormal sensation, irritability, vomiting, insomnia, anxiety, hyperhidrosis and fatigue.
Since the introduction of other SSRIs and SNRIs (pentraxin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse drug reactions due to discontinuation of these drugs, especially after abrupt discontinuation, including: dysphoria, irritability, agitation, dizziness, sensory disturbances (sensory abnormalities and electric shocks), anxiety, confusion, headache, emotional vulnerability, fatigue, insomnia, mild mania, tinnitus, epilepsy, etc. Although these adverse reactions are self-limiting, some are serious.
After discontinuation of duloxetine, patients should be observed for the appearance of these symptoms. It is recommended to taper the drug as gradually as possible rather than stopping it abruptly. When intolerable symptoms are caused by reducing the drug dose or discontinuing the drug, consider re-prescribing at the previous dose. The clinician will then reduce the medication at a slower rate.
Promoting mania/hypomania
In placebo-controlled trials for the treatment of depression, 0.1% (4/3779) of patients in the duloxetine group converted to mania/hypomania, compared to 0.04% (1/2536) in the placebo group. No manic/light manic behavior was reported in placebo-controlled trials for the treatment of generalized anxiety disorder or chronic musculoskeletal pain. Conversion to mania/hypomania has been reported in a small proportion of patients treated with other marketed antidepressants for depression. As with other antidepressants, duloxetine should be used with caution in patients with a prior history of mania.
Closed-angle glaucoma
In patients with anatomically narrow angles who have not undergone iridotomy, pupil dilation caused by the use of antidepressants, including duloxetine, may lead to the development of closed-angle glaucoma.
Epilepsy
The efficacy of duloxetine in patients with epilepsy has not been systematically evaluated, and these patients were excluded from clinical trials. In placebo-controlled clinical trials, seizures occurred in 0.02% (3/12722) of patients in the duloxetine group compared with 0.01% (1/9513) in the placebo group. Use duloxetine with caution in patients with a prior history of seizures.
Effect on blood pressure
In placebo-controlled clinical studies in adults for various indications, duloxetine treatment caused an increase in blood pressure, with a mean increase of 0.5 mm Hg systolic and 0.8 mm Hg diastolic, compared with a mean increase of 0.6 mm Hg systolic and 0.3 mm Hg diastolic in the placebo group. The frequency of sustained elevations (3 consecutive follow-up visits) was not significantly different. A clinical pharmacology study evaluating multiple effects of duloxetine, including the effect of exceeding therapeutic doses (accelerated dose titration) on blood pressure, showed an increase in ambulatory blood pressure during dose increases to 200 mg twice daily. At the highest dose (200 mg twice daily) taken for 12 hours, the mean pulse rate increased by 5.0 to 6.8 beats, the mean systolic blood pressure increased by 4.7 to 6.8 mmHg, and the mean diastolic blood pressure increased by 4.5 to 7.0 mmHg.
Blood pressure should be measured prior to the start of treatment and monitored periodically throughout the treatment period.
Clinically Important Drug Interactions
Duloxetine is metabolized primarily by CYP1A2 and CYP2D6.
Potential effects of other drugs on duloxetine.
CYP1A2 inhibitors – Duloxetine should be avoided in combination with strong CYP1A2 inhibitors.
CYP2D6 Inhibitors – Increased blood levels (mean 60%) occur with duloxetine in combination with strong CYP2D6 inhibitors.
Potential effects of duloxetine on other drugs.
Caution should be exercised when combining CYP2D6 metabolized drugs-duloxetine with drugs that are primarily metabolized by CYP2D6 and have a narrow therapeutic index, including tricyclic antidepressants (TCAs) (including nortriptyline, amitriptyline, and promethazine), phenothiazines, and class 1C antiarrhythmics (e.g., propafenone, flecainide). If TCA and duloxetine are used together, the blood levels of TCA need to be monitored and the dosage of TCA needs to be reduced. Because of the risk of severe ventricular arrhythmias and sudden death associated with increased blood levels of methiodarazine, duloxetine should not be used with methiodarazine.
Other important drug interactions.
Alcohol – Heavy alcohol consumption while taking duloxetine can lead to serious liver damage, so duloxetine should not usually be prescribed to patients who have consumed large amounts of alcohol.
Central nervous system (CNS) active drugs – Duloxetine acts primarily on the CNS and should be used with caution with other centrally active drugs, including those with similar mechanisms of action.
Hyponatremia
Hyponatremia can occur with treatment with SSRIs and SNRIs, including duloxetine. In many cases, this hyponatremia appears to be the result of the syndrome of dysregulated secretion of antidiuretic hormone (SIADH). Cases with blood sodium concentrations below 110 mmol/L have been reported and reversed with discontinuation of duloxetine. Older patients taking SSRIs and SNRIs are at increased risk of hyponatremia. In addition, patients taking diuretics or with other fluid depletion factors may also be at higher risk of hyponatremia. Patients who develop hyponatremia need to be considered for discontinuation and appropriate treatment.
Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness and unsteadiness, which can lead to falls. More severe and/or emergency conditions include hallucinations, fainting, seizures, coma, respiratory arrest, and death.
Medication in patients with comorbid somatic disorders
There is limited experience with the use of duloxetine in patients with comorbid systemic disease. There is no information on the effect of altered gastric dynamics on the stability of enteric coating of duloxetine. Under extreme gastric acid conditions, duloxetine may hydrolyze to form naphthol if not protected by the enteric coating. Caution is required when using duloxetine in patients with slowed gastric emptying (e.g., some diabetic patients).
The use of duloxetine in patients with a recent history of myocardial infarction or unstable coronary artery disease has not been systematically studied, as such patients are generally excluded from premarketing studies.
Hepatic insufficiency-Duloxetine should not normally be used in patients with chronic liver disease or cirrhosis.
Severe renal impairment-Duloxetine should not normally be used in patients with end-stage renal disease or severe renal impairment (glomerular filtration rate <30 mL/min). In patients with end-stage renal disease (requiring dialysis), blood levels of duloxetine, especially its metabolites, are increased.
Urinary hesitancy and retention
Duloxetine is a class of drugs that can affect urinary tract resistance. If urinary hesitancy occurs during duloxetine treatment, it needs to be considered as possibly drug related.
In post-marketing experience, cases of urinary retention have been observed. If urinary retention occurs during duloxetine treatment, hospitalization and/or catheterization may be required in some cases.
Laboratory Tests
No specific laboratory tests are required.
Patient Information
Physicians and other health professionals should inform patients, families, and caregivers of the benefits and risks of duloxetine therapy and advise them on the appropriate use of the drug. Medication guidelines for patients who may use duloxetine. Patients, their families, and health care professionals should be instructed to read the patient medication guide before starting duloxetine and before each prescription update and should be helped to understand the contents of the guide. Patients should be given the opportunity to discuss the contents of the medication guide and be able to provide answers to questions that they may have.
Patients should be cautioned about the following problems and asked to report them to their physician if they occur while taking duloxetine
Suicidal ideation and suicidal behavior-Patients, their families, and their caregivers should be alert to the following problems: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, impulsivity, inability to sit still (psychomotor agitation), hypomania, mania, abnormal changes in behavior, exacerbation of depression, and light thoughts, especially early in antidepressant therapy and during upward or downward dose adjustments When the dose is adjusted upward or downward. Because these changes often occur suddenly, the patient’s family and caregivers should be cautioned to observe daily for the onset of these symptoms. They should be reported to the patient’s physician or health professional, especially if they are extremely severe, occur suddenly, or are not the patient’s usual symptom profile. These symptoms that may lead to an increased risk of suicidal thoughts and behaviors require close monitoring and may even require a change in medication.
Duloxetine enteric-coated capsules should be swallowed whole and neither chewed or crushed, nor should the capsule shell be opened and the contents spilled on food or mixed in liquid, which may affect the enteric coating.
Continued Treatment Prescription-Patients may notice improvement in symptoms with duloxetine treatment for 1 to 4 weeks, but should be advised to continue treatment as prescribed.
Hepatotoxicity-Patients should be informed that serious liver problems, sometimes fatal, have been reported in patients treated with duloxetine. Patients should inform their health care practitioner if they develop signs of possible liver problems while taking this product: itching, right upper abdominal pain, darkened urine, or yellowing of the skin/eyes Patients should inform their health care practitioner of their alcohol consumption. Heavy alcohol consumption while taking this product may cause serious liver damage.
Alcohol – Although duloxetine does not aggravate the mental and driving skills impairment caused by alcohol, heavy alcohol consumption with duloxetine has been associated with severe liver damage. Therefore, patients who consume large amounts of alcohol should not usually take duloxetine.
Upright hypotension, falls, and syncope – Patients need to be informed of the risk of upright hypotension, falls, and syncope, especially when starting treatment and at increased doses, and when taking other drugs that promote upright hypotension.
Pentazocine syndrome – The risk of pentazocine syndrome needs to be noted with the combination of duloxetine and other pentazocine medications (including tretinoin, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamine, and St. John’s wort).
Patients should be informed of the signs and symptoms associated with pentraxin syndrome, including altered mental status (e.g., agitation, hallucinations, confusion, and coma), autonomic instability (e.g., tachycardia, unstable blood pressure, dizziness, sweating, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, tonicity, myoclonus, hyperreflexia, ataxia), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting , diarrhea). If patients develop these symptoms, they should be treated immediately with medication.
Abnormal bleeding – The combination of duloxetine with aspirin, NSAIDs, warfarin, and other anticoagulants increases the risk of bleeding.
Severe skin reactions-Patients need to be aware that duloxetine may cause severe skin reactions. Severe skin reactions may require hospital admission and may be life-threatening. Patients who develop skin blisters, peeling rashes, mouth sores, hives, or other allergic reactions should contact their doctor or get emergency medical help immediately.
Discontinuation – Patients may experience dizziness, headache, nausea, diarrhea, abnormal sensations, irritability, vomiting, insomnia, anxiety, excessive sweating and fatigue when they discontinue the drug and should be advised not to change their dosing regimen or discontinue the drug without consulting their physician.
Manic or hypomanic behavior – Patients with depressive symptoms should be adequately screened for risk of bipolar disorder (e.g., family history of suicide, bipolar disorder and depression) prior to initiating treatment with this product. Patients are advised to report any signs or symptoms of a manic response such as extreme energy, severe sleep problems, racing thoughts, reckless behavior, increased or faster speech, unusual thoughts, and excessive pleasure or excitement.
Closed-angle glaucoma – Patients should be informed that duloxetine can cause mild pupil dilation, which can lead to closed-angle glaucoma attacks in susceptible individuals. People with a history of glaucoma almost always have open-angle glaucoma, as closed-angle glaucoma is treated with iridectomy when diagnosed. Open-angle glaucoma is not a risk factor for closed-angle glaucoma. Patients may request testing to determine if they are susceptible to closed-angle glaucoma; if so, whether prophylactic surgery (e.g., iridotomy) is required
Epilepsy – Patients should inform their physician if they have a history of epilepsy.
Effects on blood pressure – Warn patients that this product may cause an increase in blood pressure.
Concomitant medications-due to drug interactions, patients need to be informed to notify their physician if they are taking or plan to take other prescription or over-the-counter medications
Hyponatremia – Inform patients that hyponatremia has been reported from SNRI and SSRI therapy (including duloxetine). Inform patients of the signs and symptoms of hyponatremia.
Patients with co-morbidities should inform the physician of all their medical conditions.
Urinary hesitancy and urinary retention-The product may affect urination. Patients should consult their physician if they experience problems with urinary flow rate.
Pregnancy and breastfeeding-Patients need to consult a physician if
Pregnancy during treatment
Pregnancy is planned during the course of treatment
Breastfeeding
Interference with mental performance – Any medication that affects the mind can impair judgment, thinking, or motor skills. Although duloxetine has not been found to impair mental behavior, cognitive function, or memory in controlled studies, caution should be taken when operating dangerous machinery, including motor vehicles, due to the potential sedative effects and dizziness associated with duloxetine. Unless the patient can be sure that duloxetine has no effect on his or her ability in this area.
For Pregnant and Lactating Women
Pregnancy
Teratogenic effects, FDA pregnancy safety class C.
Risk Summary – There are no adequate, well-controlled studies of duloxetine use in pregnant women. Duloxetine should be considered for use during pregnancy only if the potential benefit to the fetus is demonstrated to outweigh the potential risk.
Clinical considerations
Fetal/Neonatal Adverse Reactions – Complications resulting in prolonged hospitalization, need for respiratory support and tube feeding have occurred in neonates exposed to pentazocine-norepinephrine reuptake inhibitors (SNRIs) or selective pentazocine reuptake inhibitors (SSRIs) during pregnancy and can occur immediately after birth. Reported clinical findings include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, decreased muscle tone, increased muscle tone, hyperreflexia, tremors, hypersensitivity, irritability, and crying. These conditions may be the result of direct toxic effects of SNRIs or SSRIs or may be a discontinuation syndrome. It should be noted that in some cases, the clinical presentation is consistent with pentraxin syndrome.
Lactating women
Risk Summary
This product can be secreted into breast milk. In one published study, it was given to lactating women whose infants were being weaned. At steady state, the concentration of duloxetine in breast milk was approximately 25% of the maternal plasma concentration. The estimated daily dose indirectly received by the infant is approximately 0.14% of the maternal dose. The developmental and health benefits of breastfeeding, the clinical need for this product in the mother, and any potential adverse effects of this product or the mother’s underlying condition on the breastfed child should be considered in conjunction. This product should be used with caution in breastfeeding women.
Data
The distribution of duloxetine was studied in 6 lactating women who were at least 12 weeks postpartum and chose to wean their infants. Duloxetine was administered at a dose of 40 mg twice a day for 3.5 days, with a median time to peak concentration measured in breast milk of 3 hours after administration. At this dose, the amount of duloxetine in breast milk was approximately 7 mcg/day; the estimated daily dose for the infant was approximately 2 mcg/kg/day. The secretion of duloxetine metabolites in breast milk was not detected.
Pediatric Use]
The efficacy and safety of this product in pediatric and adolescent patients under 18 years of age in China have not been established.
Geriatric Use]
In the pre-marketing clinical study of duloxetine for depression (MDD), 5.9% (143) of 2418 patients were 65 years of age or older. In the premarketing study for chronic low back pain (CLBP), 21.2% (221) of the 1041 patients were 65 years of age or older. Of the 487 patients in the premarketing study for the treatment of osteoarthritis (OA), 40.5% (197) were 65 years of age or older. Of the 1,074 patients in the premarketing study for diabetic peripheral neuralgia (DPNP), 33% (357) were 65 years of age or older. Of the 1,761 patients in the premarketing study for fibromyalgia (FM), 7.9% (140) were 65 years of age or older. Overall, no significant differences in safety and efficacy were observed between these patients and younger patients in studies treating MDD, GAD, DPNP, FM, OA, and CLBP, and other clinical aspects have not been reported to find significant differences between older and younger populations, although increased sensitivity in some older patients cannot be excluded. SSRIs and SNRIs, including duloxetine, were associated with clinically significant hyponatremia in elderly patients. In an analysis of all patients enrolled in the placebo-controlled study, patients in the duloxetine group had a higher rate of falls than the placebo group. The increased risk of falls was proportional to the potential risk of falls that the patients had and increased with age. Because fall-related risk factors such as comorbid medications, coexisting conditions and gait disturbances are more prevalent in older adults, the effect of increasing age per se on falls during treatment with duloxetine is unknown. Serious consequences of falls that have been reported include fractures and hospitalization.
Comparing the pharmacokinetics after a single oral dose of 40 mg of duloxetine in healthy older women (65 to 77 years) with those in healthy middle-aged women (32 to 50 years), there was no difference in maximum plasma concentration (Cmax), but the area under the concentration-time curve (AUC) was slightly higher in older women (approximately 25%) and the half-life was prolonged by 4 hours. Population pharmacokinetic analysis suggested that drug clearance decreased by approximately 1% for each 1-year increase in age from 25 to 75 years. However, age, as a predictor, explains only a small portion of the individual variation among patients. Dose adjustment based on age is not necessary.
Drug Interactions]
Duloxetine is mainly metabolized by CYP1A2 and CYP2D6.
CYP1A2 inhibitor
The combination of duloxetine 60 mg and fluvoxamine 100 mg (strong CYP1A2 inhibitor) in male subjects (n=14) resulted in an approximately 6-fold increase in AUC, a 2.5-fold increase in Cmax, and a 3-fold increase in T1/2 of duloxetine. Other drugs with inhibitory effects on CYP1A2 metabolism include cimetidine, quinolone antibiotics such as ciprofloxacin and enoxacin.
CYP2D6 inhibitors
Combined use of duloxetine (40 mg once daily) and paroxetine (20 mg once daily) increases the AUC of duloxetine by approximately 60%, with higher doses of paroxetine increasing the inhibitory effect. Other strong CYP2D6 inhibitors (e.g., fluoxetine, quinidine) will have similar effects.
Dual CYP1A2 and CYP2D6 inhibition
Duloxetine AUC and Cmax were increased 6-fold in subjects with poor CYP2D6 metabolism (n=14) on concomitant duloxetine 40 mg twice daily and fluvoxamine 100 mg.
Drugs that interfere with coagulation (e.g., NSAID, aspirin, and warfarin)
Platelet-released pentoxifylline plays an important role in the coagulation process. Epidemiological studies (case-control and cohort designs) have demonstrated an association between the use of psychotropic drugs that interfere with pentoxifylline reuptake and upper gastrointestinal bleeding, and have also shown that concomitant use of NSAIDs or aspirin increases the risk of bleeding. alterations in coagulation including bleeding have been reported with SSRI and SNRI combined with warfarin use. At steady state, changes in the international normalized ratio (INR) were not significantly different from baseline in healthy subjects (n=15) on warfarin (2 to 9 mg once daily) combined with duloxetine 60 mg or 120 mg once daily for up to 14 days (mean INR change ranged from 0.05 to +0.07). Duloxetine did not alter total R-warfarin and total S-warfarin (protein-bound and free drug) pharmacokinetics (AUCτ,ss,Cmax,ss or Tmax,ss), and patients receiving warfarin therapy need to be carefully monitored when starting or discontinuing duloxetine therapy.
Lorazepam
When steady-state duloxetine (60 mg every 12 h) is combined with lorazepam (2 mg every 12 h), the pharmacokinetics of duloxetine are not affected by the combination therapy.
Temazepam
When steady-state duloxetine (20 mg once daily at bedtime) is combined with temazepam (30 mg once daily at bedtime), the pharmacokinetics of duloxetine are not affected by the combination therapy.
Drugs affecting gastric acid
Duloxetine has an enteric coating and is released in the gastrointestinal tract only at pH levels above 5.5. In extreme gastric acid environments, it may hydrolyze to form naphthol if not protected by the enteric coating. Caution is needed when using duloxetine in patients with slowed gastric emptying (e.g., some diabetics). Drugs that elevate the pH of the gastrointestinal tract can cause premature release of duloxetine. However, the rate and extent of duloxetine absorption was not significantly altered when duloxetine 40 mg was administered orally with concomitant use of an aluminum- and magnesium-containing acid regulator (51 mEq) or famotidine. It is not known whether concomitant administration of proton pump inhibitors affects the absorption of duloxetine.
Drugs metabolized by CYP1A2
In vitro drug interaction studies have demonstrated that duloxetine does not induce CYP1A2 activity. Therefore, although no clinical studies of induction have been performed, no increase in metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) is expected. In vitro studies have shown that duloxetine is an inhibitor of CYP1A2 isoenzymes and that theophylline AUC increased by 7% (90% confidence interval, 1 to 15%) and 20% (90% confidence interval, 13 to 27%) when duloxetine 60 mg twice daily was administered concomitantly in two studies.
Drugs metabolized by CYP2D6
Duloxetine is a moderate CYP2D6 inhibitor. When duloxetine 60 mg twice daily was administered with a single dose of desipramine (a CYP2D6 substrate) 50 mg, the AUC of desipramine was increased 3-fold.
Drugs metabolized by CYP2C9
In vitro, duloxetine does not inhibit CYP2C9 activity. Although no clinical trials have been conducted, inhibition of CYP2C9 substrate metabolism is not foreseen.
Drugs metabolized by CYP3A
In vitro studies have shown that duloxetine does not inhibit the activity of CYP3A. Although no clinical trials have been conducted, no increase or decrease in CYP3A substrate metabolism can be expected.
Drugs metabolized by CYP2C19
In vitro studies have demonstrated that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Although no clinical trials have been conducted, inhibition of CYP2C19 substrate metabolism is not foreseen.
Monoamine oxidase inhibitors
See [Dosage] and [Contraindications].
Pentoxifylline drugs
Based on the mechanism of action of SNRIs and SSRIs, including duloxetine, caution is required when combining drugs that affect the pentraxin neurotransmitter system, including trimetazidine, linezolid (an antibacterial agent that is a reversible, nonselective MAOIs), lithium salts, tramadol, amphetamines, or St. John’s wort. Concomitant use of duloxetine and other SSRIs, SNRIs, or tryptophan is not recommended.
Alcohol
Duloxetine does not exacerbate the psychiatric or motor skill impairment caused by alcohol when duloxetine and alcohol are ingested separately resulting in overlapping peak concentrations of both.
Central Nervous System Drugs
See [Precautions].
Drugs that are highly bound to plasma proteins
Because duloxetine is highly bound to plasma proteins, patients being treated with other highly plasma protein-bound drugs may experience increased free concentrations of other drugs when taking duloxetine, which may result in adverse drug reactions. However, duloxetine (60 or 120 mg) does not significantly alter the INR and pharmacokinetics of total S-warfarin or total R-warfarin (protein-bound drug and free drug) when administered concomitantly with warfarin (2 to 9 mg), a drug highly bound to plasma proteins.
[Drug overdose].
Signs and Symptoms
Post-marketing acute drug overdose deaths have been reported, mainly mixed drug overdoses, but also duloxetine 1000 mg alone. Signs and symptoms of overdose (duloxetine alone or in combination with other drugs) include drowsiness, coma, pentraxin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.
Management of overdose
There is no specific antidote for duloxetine; if pentraxin syndrome occurs, consider specific therapy (e.g., cycloheximide and/or temperature control). In the event of an acute overdose, treatment should include methods commonly used to manage acute overdoses of any of the drugs.
Maintain a patent airway, oxygen and ventilation, monitor heart rate and vital signs, and do not recommend inducing vomiting. Gastric lavage with a large-bore gastric tube under appropriate airway protection may be indicated if needed for those who have taken the drug recently or are still symptomatic.
Activated charcoal can be used to reduce the absorption of duloxetine in the gastrointestinal tract. Studies have shown that activated charcoal can reduce the AUC and Cmax by approximately 1/3, but the effect of activated charcoal is limited in some patients. Due to the large volume of distribution of this product, forced diuresis, dialysis, blood transfusions, and exchange transfusions are not effective.
Management of drug overdose should consider the possibility of including multiple drugs, with particular attention to the ingestion of excessive TCA in patients who are taking or have recently taken duloxetine; the accumulation of tricyclics and their active metabolites in such patients may exacerbate clinical symptoms and require extended close observation. Physicians should consider contacting a poison control center for additional information when treating any drug overdose.
[Clinical Trials].
Depression
Four randomized, double-blind, placebo-controlled, fixed-dose trials in adult outpatients (18 to 83 years of age) who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria for depression were conducted to determine the effectiveness of duloxetine in the treatment of depression. In two trials, patients were randomized to receive 9 weeks of duloxetine 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) administration; in a third trial, patients were randomized to 8 weeks of duloxetine 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) administration; in In the fourth trial, patients were randomized to receive 8 weeks of duloxetine 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93). There was no evidence of a greater benefit with doses greater than 60 mg/day.
In all four trials, duloxetine was superior to placebo as measured by improvement in the 17-item Hamilton Depression Inventory (HAMD-17) total score.
In all of these clinical trials, analysis of the relationship between treatment effects and patient age, gender and race showed no differences in effectiveness.
In another trial, 533 patients with depression meeting DSM-IV diagnostic criteria received duloxetine 60 mg administered once daily during an initial 12-week open treatment phase. 278 were effective in open treatment (defined as meeting the following criteria at weeks 10 and 12: HAMD-17 total score ≤9; Clinical Global Impression-Severity Score (CGI-S) ≤2 and did not meet DSM-IV diagnostic criteria for depression) were randomized to receive the same dose of duloxetine (N=136) or placebo (N=142) for 6 months of continued treatment. The time to depression relapse was longer in duloxetine treated patients compared to placebo treated patients, with a statistically significant difference. Relapse was defined as a ≥2-point increase in CGI-S score compared with week 12 and meeting the DSM-IV diagnostic criteria for depression at 2 consecutive visits at least 2 weeks apart, but only the 2-week criterion for duration of depression in the DSM-IV diagnostic criteria needed to be met at the 2nd visit. The effect of duloxetine has not been studied in inpatients with depression.
Generalized anxiety disorder
The effectiveness of duloxetine in the treatment of generalized anxiety disorder was determined in a fixed-dose, randomized, double-blind, placebo-controlled trial and two non-fixed-dose, randomized, double-blind, placebo-controlled trials in adult generalized anxiety disorder outpatients aged 18 to 83 years who met DSM-IV diagnostic criteria.
In the fixed-dose trial and one non-fixed-dose trial, the starting dose was 60 mg/day, with downward adjustment of the starting dose to 30 mg/day allowed for tolerability reasons. 15% of patients had a downward dose adjustment. In another non-fixed-dose trial, the starting dose was 30 mg/day, which was then adjusted upward to 60 mg/day after one week of treatment.
In both 10-week non-fixed dose trials, the dose range of duloxetine was 60 to 120 mg/day (N=168 and N=162) and was compared to placebo (N=159 and N=161). In the non-fixed dose trial, the mean dose for completers at endpoint was 104.75 mg/day. In the 9-week fixed-dose trial, duloxetine 60 mg/day (N=168) and 120 mg/day (N=170) were evaluated and compared to placebo (N=175). Although the 120 mg/day dose was effective, there was no evidence of greater benefit beyond 60 mg/day.
In all 3 trials, duloxetine was superior to placebo based on greater improvement in total scores on the Hamilton Anxiety Scale (HAM-A) and as measured by the overall functional impairment score on the Sheehan Disability Scale (SDS), a widely used and well-validated scale that measures the extent to which emotional symptoms affect patients’ functional impairment in 3 aspects of life: work /study, social life/leisure activities, and family life/family responsibilities.
In another trial, 887 patients with generalized anxiety disorder meeting DSM-IV-TR criteria received duloxetine 60-120 mg once daily during a 26-week open treatment phase. 429 patients were effective in open treatment (defined as meeting the following criteria at weeks 24 and 26: at least 50% reduction in total HAMA score compared to baseline, score no greater than 11 score, and a 1- or 2-point improvement in clinical global impression-improvement [CGI-improvement]) were randomized to continue treatment with the same dose of duloxetine (N=216) or placebo (N=213) and observed for relapse. Among randomized patients, 73% could remain effective for at least 10 weeks. Relapse was defined as an elevated CGI severity score of ≥4 and a diagnosis of generalized anxiety disorder according to the Brief International Neuropsychiatric Interview (MINI) (excluding duration criteria), or discontinuation of the trial due to lack of effectiveness. The time to relapse of generalized anxiety disorder was longer in patients taking duloxetine than in those taking placebo, with a statistically significant difference.
Subgroup analysis showed no differences in treatment outcomes when categorized according to age or gender.
Chronic musculoskeletal pain
Duloxetine is indicated for the treatment of chronic musculoskeletal pain. This has been confirmed in studies conducted in patients suffering from chronic pain due to chronic low back pain and osteoarthritis.
Studies conducted in chronic low back pain
The effectiveness of duloxetine in chronic low back pain (CLBP) was evaluated in two double-blind, placebo-controlled, randomized clinical trials of 13 weeks duration (Study CLBP-1 and Study CLBP-2) and one study of 12 weeks duration (CLBP-3).CLBP-1 and CLBP-3 demonstrated the effectiveness of duloxetine in the treatment of chronic low back pain. All patients in the study were free of signs of radiculopathy and spinal stenosis.
Study CLBP-1: 236 adult patients were enrolled (duloxetine group, N=115, placebo group, N=121), of whom 182 (77%) completed the 13-week treatment period. After 7 weeks of treatment, patients in the duloxetine group (i.e., those with an average daily pain reduction of less than 30% and those who could tolerate duloxetine 60 mg once daily) took the duloxetine dose assigned to them, increasing the dose to 120 mg once daily in a double-blind fashion for the remainder of the study. On a numeric scale ranging from 0 (no pain) to 10 (most severe possible pain), patients had a mean baseline pain rating of 6. After 13 weeks of treatment, patients taking duloxetine 60-120 mg once daily had significantly greater pain relief compared to the placebo group. Patients were randomly stratified according to their baseline NSAID use. As a function of NSAID use, subgroup analysis did not show differences between treatment regressions.
Study CLBP-2: 404 patients were randomly assigned to receive a fixed dose of duloxetine once daily or matching placebo (duloxetine 20 mg group, N=59; duloxetine 60 mg group, N=116; duloxetine 120 mg group, N=112; placebo group, N=117), of whom 267 (66%) completed all 13 weeks of the study. After 13 weeks of treatment, none of the 3 duloxetine dose groups showed statistically significant differences in pain reduction compared to the placebo group.
Study CLBP-3: 401 patients were randomly assigned to receive a fixed dose of duloxetine 60 mg once daily or placebo (duloxetine group, N=198; placebo group, N=203), of which 303 (76%) completed the study. On a numeric scale ranging from 0 (no pain) to 10 (most severe possible pain), patients had a mean baseline pain rating of 6. After 12 weeks of treatment, patients taking duloxetine 60 mg once daily had significantly greater pain relief compared to the placebo group.
For varying degrees of improvement in pain from baseline to the study endpoint, Figures 1 and 2 show the fraction of patients who achieved improvement in CLBP-1 and CLBP-3. The data are cumulative, so that patients with a change from baseline (for example) of 50% are also included in each level of improvement below 50%. Improvement data for patients who did not complete the study were designated as 0%.
 Figure 1: Percentage of patients achieving different levels of pain relief as measured by 24-hour average pain severity – CLBP-1
 Figure 2: Percentage of patients achieving different levels of pain relief as measured by 24-hour average pain severity – CLBP-3
 Studies conducted in chronic pain due to osteoarthritis
The effectiveness of duloxetine in chronic pain due to osteoarthritis was evaluated in two double-blind, placebo-controlled, randomized clinical trials of 13 weeks duration (Study OA-1 and Study OA-2). All patients in both studies met the ACR clinical and imaging criteria for classification of primary osteoarthritis of the knee. Patients were randomly stratified according to their baseline NSAID use. In both studies, patients assigned to the duloxetine group started treatment at a dose of 30 mg once daily for 1 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, patients who had a suboptimal response to treatment (<30% pain reduction) in OA-1 and who 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, will again be randomized for the remainder of the study to Continue to receive duloxetine 60 mg once daily or have their dose increased to 120 mg once daily. Patients in the placebo treatment arm of both studies receive matching placebo for the entire duration of the study. For both studies, efficacy analyses were conducted using 13 weeks of data obtained from the combined duloxetine 60 mg and 120 mg once daily treatment groups compared to the placebo group.
Study OA-1: 256 patients were enrolled (duloxetine group, N=128; placebo group, N=128), of whom 204 (80%) completed the study. On a numeric scale ranging from 0 (no pain) to 10 (most severe possible pain), patients had a mean baseline pain rating of 6. After 13 weeks of treatment, patients taking duloxetine had significantly greater pain relief. As a function of NSAID use, subgroup analyses did not show differences between treatment regressions.
Study OA-2: 231 patients were enrolled (duloxetine group, N=111; placebo group, N=120), of whom 173 (75%) completed the study. On a numeric scale ranging from 0 (no pain) to 10 (most severe possible pain), patients had a mean baseline pain rating of 6. After 13 weeks of treatment, patients taking duloxetine did not show a greater degree of significant pain relief.
In study OA-1, for varying degrees of improvement in pain from baseline to the study endpoint, Figure 3 shows the fraction of patients who achieved a degree of improvement. The data are cumulative, so that patients with a change from baseline (for example) of 50% are also included in each level of improvement below 50%. Improvement data for patients who did not complete the study were designated as 0%.
 
 
 
 
 
Figure 3: Percentage of patients achieving different levels of pain relief as measured by 24-hour average pain severity – OA-1
[Pharmacology and Toxicology].
Pharmacological effects
The exact mechanism of the antidepressant, central analgesic and anxiolytic effects of duloxetine is not known, but it is thought to be related to its enhancement of central nervous system 5-hydroxytryptamine and noradrenergic functions.
Preclinical studies have shown that duloxetine is a strong inhibitor of neuronal 5-hydroxytryptamine and norepinephrine reuptake and a relatively weak inhibitor of dopamine reuptake. In in vitro tests, duloxetine showed no significant affinity for dopamine receptors, adrenergic receptors, cholinergic receptors, histamine receptors, opioid receptors, glutamate receptors, and g-aminobutyric acid (GABA) receptors. Duloxetine does not inhibit monoamine oxidase (MAO).
Toxicological studies
Genotoxicity
The results of Ames test, mouse lymphoma cell forward mutation test, rat hepatocyte out-of-programme DNA synthesis (UDS) test, Chinese hamster bone marrow cell sister chromatid exchange test, and mouse bone marrow micronucleus test were all negative for duloxetine.
Reproductive toxicity
No effects on mating or fertility were observed in female or male rats given duloxetine at doses up to 45 mg/kg/day orally before and during mating [extrapolated from mg/m2, equivalent to 4 times the maximum recommended human dose (MRHD) of 120 mg/day].
Oral administration of duloxetine up to 45 mg/kg/day (4 and 7 times the MRHD, respectively, extrapolated from mg/m2) in rats and rabbits during organogenesis did not show teratogenic effects, but a reduction in fetal weight was observed; the no-effect dose was 10 mg/kg/day (1 and 2 times the MRHD, respectively, extrapolated from mg/m2).
In pregnant rats given duloxetine orally during gestation and lactation, pup survival at 1 day after birth and body weight during lactation were reduced at a dose of 30 mg/kg/day; at this dose, pups showed behavioral manifestations consistent with increased reactivity, such as increased startle response to noise and reduced voluntary activity; no adverse effects on post-delactation growth and reproductive behavior of offspring were observed; the no-effect dose was The no-effect dose was 10 mg/kg.
Carcinogenicity
A carcinogenicity test was conducted in rats and mice given duloxetine by adulteration for 2 years.
An increased incidence of hepatocellular adenoma and hepatocellular carcinoma was seen in female mice at a dose of 140 mg/kg/day (6 times the MRHD at mg/m2) and a no-effect dose of 50 mg/kg/day (2 times the MRHD at mg/m2). No increase in tumor incidence was seen in male mice at duloxetine doses up to 100 mg/kg/day (extrapolated from mg/m2, equivalent to 4 times the MRHD).
No increase in tumor incidence was observed in female and male rats at doses up to 27 mg/kg/day and 36 mg/kg/day (2-fold and 3-fold of MRHD, respectively, extrapolated from mg/m2).
Pharmacokinetics]
The elimination half-life of duloxetine enteric-coated capsules is approximately 12 hours (with a variation range of 8-17 hours), and its pharmacokinetic parameters are proportional to the dose within the therapeutic range. Steady-state blood levels are generally achieved after 3 days of administration. Duloxetine is primarily metabolized by the liver, involving two P450 enzymes: CYP2D6 and CYP1A2.
Absorption and Distribution – Oral duloxetine hydrochloride enteric coated capsules are completely absorbed. The average lag time is 2 hours before the drug begins to be absorbed (Tlag), and duloxetine reaches Cmax after 6 hours of oral administration. eating does not affect Cmax, but will delay the time to peak by 6 to 10 hours, slightly reducing the degree of absorption by about 10%. Compared to a single morning dose, a single evening dose of duloxetine had a 3-hour absorption lag and a 1/3 increase in apparent clearance.
The mean apparent volume of distribution was 1640 liters. Duloxetine has a high affinity (>90%) for human plasma proteins and binds primarily to albumin and alpha1-acidic glycoproteins. No drug interactions have been evaluated between duloxetine and other highly protein-bound drugs, and hepatic or renal insufficiency does not affect plasma protein binding of duloxetine.
Metabolism and Excretion – Oral administration of 14C-labeled duloxetine to determine its biotransformation and degradation in humans. Plasma duloxetine accounts for only 3% of the total radiolabel, suggesting extensive metabolism of duloxetine and numerous metabolites. The major biotransformation pathways of duloxetine include post-binding naphthyl cyclo-oxidation and further oxidation. Both CYP2D6 and CYP1A2 catalyzed naphthyl cyclo-oxidation in in vitro assays, and the metabolites in plasma included glucuronide-conjugated 4-hydroxy-duloxetine and sulfate-conjugated 5-hydroxy-6-methoxy-duloxetine. A variety of other metabolites have been isolated in urine, some of which occur only in small elimination metabolic bypasses. Only a small amount of unmetabolized duloxetine hydrochloride in its original form (approximately 1% of the oral dose) is excreted in the urine, with the majority (approximately 70% of the oral dose) being excreted as duloxetine hydrochloride metabolites in the urine and approximately 20% in the feces. Duloxetine is widely metabolized, but the major circulatory metabolites are not associated with the potency of duloxetine.
Special Populations
Gender – Duloxetine has a similar half-life in males and females and no dose adjustment is required for different genders.
Smoking – The bioavailability (AUC) of duloxetine hydrochloride is reduced by approximately 1/3 in smokers, and dose adjustment is not recommended for smokers.
Race – No pharmacokinetic studies have been conducted specifically to investigate the pharmacokinetic profile of different races.
Hepatic Insufficiency – Metabolism and clearance of duloxetine are decreased in patients with clinically significant hepatic insufficiency. After a single oral dose of 20 mg duloxetine, six patients with moderately hepatic insufficiency with cirrhosis (Child-Pugh class B) had a mean plasma clearance of 15% of the latter and a 5-fold increase in mean exposure (AUC) compared to a healthy population of comparable age and sex. Although the Cmax in patients with cirrhosis approximated that of those with normal liver function, the former had a 3-fold longer half-life.
Severe renal impairment – Data on the effects of duloxetine in patients with end-stage renal disease (ESRD) are very limited. After a single oral dose of 60 mg duloxetine, patients with end-stage renal disease receiving long-term intermittent hemodialysis had an approximately 100% increase in Cmax and AUC values compared to those with normal renal function, yet both had similar elimination half-lives. Most of the major circulating metabolites excreted via urine are glucuronide-conjugated 4-hydroxyduloxetine, and sulfate-conjugated 5-hydroxy-6-methoxyduloxetine, which have approximately 7- to 9-fold higher AUCs, with more pronounced increases expected after multiple oral doses of the drug. Pharmacokinetic analysis of the population showed no significant effect on the apparent clearance of duloxetine in those with mild to moderate renal dysfunction (creatinine clearance [CrCL] of 30-80 ml/min).
Storage]
Store sealed at 15-30℃.
Package】
Packed in high-density polyethylene bottle for oral solid medicine, 30 capsules/bottle.
Expiration date
36 months
Execution Standard
Approval number】
【Drug marketing license holder
Name: Shiyapharm Group Ouyi Pharmaceutical Co.
Registered address: No. 88 Yangzi Road, Shijiazhuang Economic and Technological Development Zone
Postal Code: 052165
Telephone number: 0311-87886158, 0311-67163660
Fax number: 0311-87171665
Manufacturer
Company name: Shiyapharm Group Ouyi Pharmaceutical Co.
Address: No. 88 Yangzi Road, Shijiazhuang Economic and Technological Development Zone
Postal Code: 052165
Telephone number: 0311-87886158, 0311-67163660
Fax number: 0311-87171665