What Factors Affect a Sufficient Duloxetine Dose?

Duloxetine hydrochloride enteric-coated capsules are used for the treatment of depression.

Duloxetine hydrochloride enteric-coated capsules are used for the treatment of depression.

Drug Name

Duloxetine Hydrochloride Enteric-Coated Capsules

Drug type

Prescription drugs, medicines for medical workers' injuries

Use classification

Other antidepressants

Warnings for Duloxetine Hydrochloride Enteric Capsules

Warn suicide in children and adolescents-Short-term studies in children and adolescents with depression and other mental illness suggest that antidepressants increase the risk of suicidal ideation and suicidal behavior (suicide) if you consider using duloxetine or any Antidepressants must weigh this risk with clinical needs. Patients who have already started treatment should be closely monitored for clinical deterioration, suicide or abnormal behavioral changes. Family members and caregivers should be advised to monitor patients closely and communicate with prescribers. Duloxetine is not approved for use in children (see Warnings and Precautions, Pediatric Use).
Deterioration and suicidal riskAdults, children with depression, whether or not receiving antidepressant medication, may experience worsening depressive symptoms and / or suicidal concepts and suicidal behaviors (suicide) or abnormal changes in behavior, before the condition is significantly alleviated This risk will persist. It has long been thought that in certain populations, antidepressants may induce worsening depression symptoms or lead to suicide. In short-term clinical studies on depression in children and adolescents and other mental illnesses, antidepressants increase the risk of suicidal ideation and suicidal behavior (suicide).
A comprehensive analysis of acute placebo-controlled trials (a total of 24 trials including 4,400 patients) and 9 antidepressants (SSRIs and other antidepressants) for the treatment of depression, obsessive-compulsive disorder, or other mental disorders in children and adolescents. Children and adolescents treated with depression medications have a significantly increased risk of adverse events such as suicidal perceptions and suicidal behaviors (suicide) during the first few months of treatment. The average risk of these adverse events in patients receiving antidepressants was 4%, which was twice the risk of placebo (2%). No suicides occurred in these trials. Although the risks vary from drug to drug, almost all drugs can increase this risk. The risk of suicide observed in trials of depression is very similar, and some clinical trials in other mental illnesses (obsessive-compulsive disorder and social anxiety disorder) have also found signs of increased risk. No suicides occurred in these clinical trials. It is unclear whether the risk of suicide in pediatric patients persists into long-term treatment, such as more than several months. It is also unclear whether the risk of suicide affects adults.
Pediatric patients receiving antidepressant treatment for any indication should closely observe whether there are clinical symptoms worsening, suicide, or abnormal behavior changes, especially during the first few months of drug treatment, or when the dosage changes, such as adding or reducing drugs . Close observation includes: in-person contact with the patient or his or her family or caregiver at least once a week during the first 4 weeks of treatment; contact every two weeks for the next 4 weeks; at 12 weeks of treatment, and after 12 weeks if For clinical needs, make face-to-face contact with the patient. During face-to-face contact, additional telephone interviews may be required.
Adult depression patients receiving antidepressant treatment, or comorbid depression and other mental illnesses also need to be closely monitored for clinical signs of worsening and suicide, especially in the first few months of initiating medication or changing doses Time, such as increase or decrease.
Antidepressants have been reported in the treatment of adult, childhood depression, and other indications, whether psychotic or nonpsychotic, with the following symptoms: anxiety, excitement, panic attacks, insomnia, irritability, hostility (aggressiveness), Impulsiveness, agitation (psychomotor excitement), hypomania and mania. Although a causal link between the appearance of the above symptoms and worsening depression and / or suicide has not been confirmed, these symptoms may be a precursor to suicide.
When depressive symptoms continue to worsen or appear suicidal, or symptoms of worsening or suicidal symptoms occur, especially when these symptoms are very severe, sudden, or new symptoms appear, consider changing treatment options, including the possibility of discontinuing treatment. If you decide to discontinue treatment, the drug should be gradually tapered down as quickly as possible, but some symptoms may occur if you stop the drug suddenly. (See Notes, Dosage, and Description of Risk of Terminating Duloxetine Treatment).
Children with depression and other indications treated with antidepressants, including psychotic and non-psychiatric disorders, patients' families and caregivers should be vigilant and need to monitor the patient's agitation, irritability, abnormal behavior changes, appearance Suicide and other symptoms mentioned above should be monitored and information provided to health care facilities as soon as they occur. These monitoring should also include daily observations by family members or caregivers. Duloxetine enteric-coated capsules should be prescribed in a minimum amount to reduce the risk of overdose. Adults receiving antidepressants should give the same advice to their families or caregivers.
Screening for Bipolar Disorders-Depression episodes may be an early manifestation of bipolar disorder. It is generally believed (though not confirmed by controlled studies) that antidepressant medication alone for depressive episodes may increase mixed / manic episodes in patients with bipolar disorder. Although it is impossible to predict which of the above symptoms will occur, patients with depression should be screened appropriately to determine the risk of bipolar disorder before antidepressant treatment. Screening methods include a detailed history of a psychiatric illness and a family history of suicide, bipolar disorder, and depression. It should be noted that duloxetine has not been approved for the treatment of bipolar depression.
Monoamine Oxidase Inhibitors (MAOI)-Serotonin reuptake inhibitors have been reported to cause severe adverse reactions when used in combination with monoamine oxidase inhibitors, such as fever, tonicity, myoclonus, restlessness, rapid fluctuations in vital signs, and changes in mental status, including Extremely excited to delirium, coma, can be fatal in severe cases. The recent withdrawal of serotonin reuptake inhibitors may also occur when switching to monoamine oxidase inhibitors. Sometimes the clinical manifestations are similar to those of malignant syndrome caused by psychotropic substances. The consequences of duloxetine in combination with monoamine oxidase inhibitors have not been evaluated in humans and animals. Therefore, duloxetine is not recommended as a serotonin and norepinephrine reuptake inhibitor in combination with a monoamine oxidase inhibitor, or duloxetine cannot be used within 14 days of discontinuation of a monoamine oxidase inhibitor. Based on the half-life of duloxetine, duloxetine is discontinued for at least 5 days before commencing treatment with a monoamine oxidase inhibitor.

Duloxetine hydrochloride enteric-coated capsule ingredients

The main composition is duloxetine hydrochloride.
Chemical name: (+)-(S) -N-methyl-- (1-naphthyloxy) -2-thiophenepropanolamine hydrochloride Chemical structural formula:

Molecular formula: C ₁₈ H ₁₉ NOS · HCl
Molecular weight: 333.88

Properties of Duloxetine Hydrochloride Enteric Capsules

The content of this product is white or almost white spherical enteric particles.
30mg * capsule: opaque white capsule and blue capsule with "30mg" printed on the capsule shell.
60mg * capsule: opaque green capsule and blue capsule cap, "60mg" is printed on the capsule shell.

Indications of Duloxetine Hydrochloride Enteric Capsules

Used to treat depression.

Duloxetine hydrochloride enteric-coated capsules specifications

(1) 30 mg; (2) 60 mg (based on duloxetine).

Duloxetine hydrochloride enteric-coated capsules dosage

Initial treatment < br Recommended starting dose of this product is 40mg / day (20mg twice a day) to 60mg / day (once a day or 30mg twice a day), regardless of eating conditions.
Existing clinical research data have not confirmed that doses exceeding 60 mg / day will increase efficacy.
Maintenance / continued / long-term treatment < br It is generally believed that acute episodes of depression require medication for several months or more, but there is no sufficient experimental data to determine how long patients should take duloxetine continuously . For such patients, the need for maintenance treatment and the corresponding required dose should be regularly evaluated.
Special population < br Dosage for patients with impaired renal function-For patients with advanced renal disease (requiring dialysis), or patients with severe renal impairment (estimated creatinine clearance <30 mL / min), this product is not recommended ( (See Pharmacology and Toxicology).
Dosage for patients with liver dysfunction-It is recommended to avoid taking this product in patients with any liver dysfunction (see Pharmacology and Toxicology and Precautions)
Dosage for elderly patients-For elderly patients, it is recommended that doses not be adjusted based on age. As with any medicine, care should be taken in treating elderly patients. When adjusting the dose individually in elderly patients, extra care should be taken when increasing the dose.
Treatment of female patients in the third trimester of pregnancy-Newborns who have been exposed to SSRIs or SNRIs (serotonin and norepinephrine reuptake inhibitors) within the third trimester of pregnancy have complications that lead to longer hospital stays and require Respiratory support and tube feeding (see notes). When pregnant women are treated with duloxetine, in the third trimester of pregnancy, doctors should carefully evaluate the potential risks and benefits of treatment. Doctors should consider gradually reducing the amount of Losoxetine in the third trimester.
Duloxetine discontinuation <br The discontinuation of this product and other SSRIs and SNRIs have been reported (see Precautions). These symptoms should be monitored when the drug is discontinued. It is recommended to reduce the drug gradually as much as possible instead of stopping the drug suddenly. In case of intolerable symptoms due to reduction in drug dose or discontinuation, consideration may be given to resuming the use of previous prescribed doses. The drug is then reduced at a slower rate.
Dressing change with monoamine oxidase inhibitor (MAOI) The treatment of this product should be started at least 14 days after MAOI is discontinued. MAOI treatment should be initiated at least 5 days after discontinuation of this product (see Contraindications and Warnings).

Adverse reactions of duloxetine hydrochloride enteric-coated capsules

Adverse reactions in all indications

Notes: 1. This data is from a placebo-controlled database before March 12, 2008, including approved indications and completed clinical studies under other conditions. 2. Including stress, urgency, and mixed urinary incontinence. 3. Including chronic back pain and osteoarthritis. 4. Upset stomach. 5. Weakness. 6. Upper abdominal pain, lower abdominal pain, abdominal tenderness, abdominal discomfort, gastrointestinal pain. 7. Elevated systolic and diastolic blood pressure. 8. Alanine aminotransferase, liver enzymes increased AST / GOT test, liver function test abnormalities, g-aminobutyric acid transaminase, serum alkaline phosphatase, and bilirubin increased. 9. Anorexia. 10. Musculoskeletal stiffness. 11. Myalgia and neck pain. 12. The incidence was greater in the placebo group than in the duloxetine group (depression only). 13. Sleep transition and sedation. 14. Includes reduced sensation, decreased facial sensation, and abnormal paresthesia. 15. Insomnia in the middle, early awakening, and insomnia in the early stages. 16. Pleasure is missing. 17. Lack of libido. 18. Nervousness, restlessness, nervousness, agitation. 19. Consciousness. 20. Nightmare. 21. Ejaculation failure and abnormal ejaculation. 22. Including hot flashes.
General adverse reactions dizziness, nausea, and headache are also seen after discontinuation of duloxetine, with an incidence of 5%. In placebo-controlled clinical trials, duloxetine treatment was accompanied by a small mean increase from baseline to endpoints of ALT, AST, and CPK; compared with the control group, duloxetine-treated patients may have rare, temporary Outliers.
Glycemic Adjustment-In three clinical trials for diabetic neuralgia, the average duration of diabetes was 12 years, the average baseline fasting blood glucose was 176 mg / dL, and the average baseline hemoglobin (HbA1c) was 7.81%. During the first 12 weeks of acute treatment in these three trials, a slight increase in fasting blood glucose was seen in patients in the duloxetine-treated group. HbA1c was stable in both the duloxetine-treated and placebo control groups. At 52 weeks of treatment, HbA1c increased in both the duloxetine-treated and placebo groups. The mean increase in the duloxetine-treated group was 0.3% higher than that of the placebo group. Although patients in the conventional treatment group showed a slight decrease, fasting blood glucose and total cholesterol showed small increases.
After discontinuation, symptoms after discontinuation have been reported. The most commonly reported symptoms include sudden or gradual discontinuation of duloxetine in the following clinical trials, dizziness, nausea, headache, paresthesia, fatigue, vomiting, excitement, nightmares , Insomnia, diarrhea, anxiety, sweating and dizziness.
Report of spontaneous adverse reactions after treatment with duloxetine after marketing <br The incidence of the following adverse reactions (<0.01%):
Heart disease: supraventricular arrhythmia.
Ear and labyrinth disorder: Tinnitus endocrine disorders after treatment termination: Adverse reactions include excessive antidiuretic hormone secretion syndrome.
Eye disease: glaucoma.
Hepatobiliary disorders: hepatitis, yellow bile.
Immune system disorders: allergic reactions, hypersensitivity reactions.
Laboratory tests: elevated alanine aminotransferase, alkaline phosphatase, AST / GOT, and bilirubin.
Metabolic, nutritional disorders: hyponatremia, hyperglycemia (especially in patients with diabetes).
Bone and connective tissue diseases: closed teeth.
Nervous system disorders: extrapyramidal syndrome, restless legs syndrome, 5-HT syndrome, seizures, seizures after withdrawal.
Psychotic disorders: mania, aggression, and anger (especially early in treatment or after treatment has stopped).
Symptoms of skin and subcutaneous tissue: angioedema, dark wounds, ecchymosis, Stevens-Johnson syndrome, urticaria.
Vascular disorders: orthostatic hypotension (especially at the beginning of treatment), syncope (especially at the beginning of treatment), hypertension crisis.
Reproductive and breast disorders: bleeding in obstetrics and gynecology.
The incidence of the following adverse reactions (0.01%-[0.1%):
Psychotic disorders: hallucinations.
Renal and urinary disorders: urinary retention.
Skin and subcutaneous tissue symptoms: rash.

Duloxetine hydrochloride enteric-coated capsules contraindications

Allergies < br Duloxetine enteric-coated capsules are contraindicated in patients who are allergic to duloxetine enteric-coated capsules or any inactive ingredient in the product.
Monoamine oxidase inhibitors < br Do not use in combination with monoamine oxidase inhibitors (MAOIs). (See warning)
Untreated narrow-angle glaucoma. Clinical trials have shown that duloxetine increases the risk of dilated pupils. Therefore, duloxetine should be avoided in patients with untreated narrow-angle glaucoma.

Precautions for Duloxetine Hydrochloride Enteric Capsules

General Precautions Hepatotoxicity-Duloxetine has the risk of increasing serum aminotransferase levels. Elevated liver transaminase results in discontinuation of treatment in 0.4% (31/8454) of patients treated with duloxetine. The median time to elevation of transaminase in these patients was 2 months. In controlled trials performed in patients with depression, 0.9% (8/930) of patients treated with duloxetine increased their ALT by more than three times the upper limit of normal, compared with 0.3% (2/652) in the placebo group. In all placebo-controlled studies, 1% (39/3732) of patients in the duloxetine group had ALT elevations more than three times the upper limit of normal, compared to 0.2% (6/2568) in the placebo group. In a fixed-dose placebo-controlled study, there is evidence that ALT rises more than three times the upper limit of normal and AST rises more than five times the upper limit of normal, with a dose-response relationship to drug dose. Post-marketing surveillance also reported cases of hepatitis with abdominal pain, hepatomegaly, transaminase with or without jaundice that was 20 times higher than the upper limit of normal, reflecting mixed or hepatocellular injury, and bile with no significant increase in transaminase Report of cases of stagnation jaundice.
In the case of obstruction, it is generally considered that elevated transaminase accompanied by elevated bilirubin is an important indicator of severe liver damage. In clinical trials abroad, three patients taking duloxetine showed elevated transaminase, bilirubin, and alkaline phosphatase, suggesting obstruction. The above-mentioned patients have severe excessive drinking, which may be the reason for the above abnormal indicators. Two patients treated with placebo also had elevated transaminase and bilirubin. Post-market reports show that elevated transaminase, bilirubin, and alkaline phosphatase can also occur in patients with chronic liver disease or cirrhosis. Because the interaction of duloxetine and alcohol may cause liver damage or exacerbate existing liver disease, duloxetine is generally not used for the treatment of patients with habitual drinking and chronic liver disease.
Elevated liver enzymes have been observed in some patients during clinical trials, and these phenomena are usually transient and self-limiting, or resumed after discontinuation. Severe liver enzyme elevation (> 10 times the upper limit of normal) or liver injury with cholestasis, or mixed liver disease are rarely reported, and some cases are related to alcohol abuse or previous liver disease. Duloxetine should be used with caution in patients with alcohol use or patients with a previous history of liver disease.
Effect on blood pressure-Compared with placebo, duloxetine treatment caused an increase in blood pressure, with an average increase: systolic blood pressure of 2 mm Hg, diastolic blood pressure of 0.5 mm Hg, and occasionally at least one measurement of systolic blood pressure greater than 140 mm Hg. Blood pressure should be measured before the start of treatment and should be measured regularly after treatment. (See Adverse Reactions, Changes in Vital Signs)
Transition to mania / hypomania-In the MDD placebo-controlled trial, it was reported that 0.1% (1/1139) of patients in the duloxetine group converted to mania / hypomania compared to 0.1 in the placebo group % (1/777). A small percentage of patients treated with other drugs that have been marketed as effective for MDD have reportedly turned into mania / hypomania. Therefore, like other antidepressants, duloxetine should be used with caution in patients with a previous history of mania.
Epilepsy-Duloxetine has not been systematically evaluated in patients with epilepsy disorders who have been excluded from clinical trials. In placebo-controlled clinical trials in patients with depression, seizures occurred in 0.1% (1/1139) of patients in the duloxetine group compared to 0% (0/777) in the placebo group. Use duloxetine with caution in patients with a previous history of seizures.
Treatment of controlled narrow-angle glaucoma-clinical trials have shown that duloxetine increases the risk of dilated pupils, so duloxetine is used with caution in patients with stabilized narrow-angle glaucoma (see contraindications, banned without Angle-closure glaucoma).
Withdrawal-A systematic study of the withdrawal symptoms of duloxetine has been performed. In a 9-week placebo-controlled trial in patients with depression, the incidence of duloxetine treatment in patients treated with duloxetine was observed to be 2% or significantly higher than those in placebo, including: dizziness, nausea, Headache, paresthesia, fatigue, vomiting, excitement, nightmares, insomnia, diarrhea, anxiety, sweating and dizziness.
Since the launch of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), adverse drug reactions caused by the discontinuation of these drugs have been frequently reported, especially after sudden drug discontinuation, including: bad mood, irritability, Excitement, dizziness, sensory disturbances (paresthesia and electric shock), anxiety, confusion, headaches, fragile emotions, fatigue, insomnia, hypomania, tinnitus, epilepsy, etc. Although these adverse reactions are self-limiting, some are serious.
After discontinuing duloxetine, patients should be observed for the above symptoms. It is recommended to reduce the drug gradually as much as possible instead of stopping the drug suddenly. In case of intolerable symptoms caused by reducing the dose of the drug or discontinuing the drug, the previous prescribed dose may be considered. The clinician then takes the medicine at a slower rate (see Dosage and Administration).
Patients with physical illness-Duloxetine has limited clinical experience in treating patients with physical illness. There is no data on the effect of changes in gastric motility on the stability of duloxetine enteric coatings. Because duloxetine is rapidly hydrolyzed to naphthol in an acidic medium, patients with slowed gastric emptying should avoid duloxetine (such as some diabetic patients).
Duloxetine has not been systematically evaluated in patients with recent myocardial infarction or unstable coronary artery disease. In pre-marketing clinical studies, these patients were often excluded as they were excluded. However, in the MDD placebo-controlled trial, 321 patients taking duloxetine did not increase clinically significant ECG abnormalities compared to normal ECG at baseline (see Adverse Reactions, ECG Changes).
Patients with end-stage renal disease (requiring dialysis) and severe renal insufficiency (Cr clearance <30ml / min) will increase the blood concentration of duloxetine, especially its metabolites. Therefore, duloxetine is not recommended for patients with end-stage renal disease (see Pharmacology, Toxicology, and Dosage).
Duloxetine in patients with liver dysfunction will have a significant increase in blood concentration, so it is not recommended for such patients to take duloxetine (see Pharmacology and Toxicology and Dosage and Administration).
Patient Information < br Doctors and other health professionals should inform patients, family members, and caregivers of the benefits and risks of duloxetine treatment, and advise them to use the drug appropriately. There are "Guidelines for the use of antidepressants in children and adolescents" provided to patients. Doctors and health professionals should introduce patients, family members or caregivers to read the medication guide to help them understand its content. Patients should be given the opportunity to discuss medication guidelines and be able to respond to questions raised by patients. The full text of the medication guide is attached at the end of this article.
Patients should be reminded to pay attention to the following problems, and ask patients to report duloxetine to these doctors if they occur.
Symptoms worsening and risk of suicide-Patients, families and their caregivers should be alert to the following issues: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsiveness, inability to sit still (psychomotor restlessness), hypomania , Mania, abnormal behavioral changes, exacerbation of depression, and resignation, especially in the early stages of antidepressant treatment, and when the dose is increased or decreased. Because these changes often occur suddenly, family members and caregivers should be warned to observe these symptoms daily. These symptoms should be reported to the patient's doctor or health professional, especially if they are extremely severe, sudden, or not the patient's usual symptoms. These symptoms, which may lead to increased suicidal perceptions and behavioral risks, require close monitoring and may even change treatment.
Duloxetine enteric-coated capsules should be swallowed as a whole, neither chewed or crushed, nor sprinkled on food or mixed with beverages, as this may affect enteric coating.
Any psychoactive drug can impair judgment, thinking or exercise. Although duloxetine has not been found to impair psychomotor performance, cognitive function, or memory in controlled studies, due to the possible sedative effects and dizziness of duloxetine, attention should be paid to the operation of dangerous machinery, including motor vehicles. Unless patients are certain that duloxetine has no effect on their ability to do so.
Due to drug interactions, patients are advised to inform their doctor if they are or plan to take other prescription or over-the-counter medications.
Although duloxetine does not increase the mental and motor skills impairment caused by alcohol, duloxetine can cause severe liver damage when accompanied by high alcohol intake. Therefore, for patients who drink a lot of alcohol, duloxetine is generally not recommended.
Patients should be reminded that if they become pregnant or are planning to become pregnant during treatment, their doctor should be informed, as they are during breastfeeding.
The condition of patients with depression treated with duloxetine will improve within 1-4 weeks of treatment, but patients should be advised to maintain treatment.

Duloxetine hydrochloride enteric-coated capsules for pregnant and lactating women

Pregnancy:
Pregnancy Category C-In animal reproduction studies, duloxetine was found to have adverse effects on embryo / fetal and postnatal development.
Rats and rabbits take duloxetine during the organogenesis of embryos at a dose of 45 mg / kg / day (7 times the rat dose [MRHD, 60 mg / kg / day] and 4 times the body weight / body Human body dose calculated from surface area index was 120 mg / day; rabbit dose was 15 times [MRHD] and 7 times human dose calculated from body weight / body surface area index (120 mg / day). No teratogenic effect was found. At this dose, the fetus loses weight. The no-effect dose is 10 mg / kg / day (2 times [MRHD] in rats, about 1 times the human dose 120 mg / day calculated according to body weight / body surface area index; the dose in rabbits is 3 times [MRHD] , About 2 times the human dose of 120 mg / day calculated according to the weight / body surface area index).
Pregnant rats were given oral duloxetine throughout pregnancy and lactation at a dose of 30 mg / kg / day (5 times [MRHD], 2 times the human dose calculated as 120 mg / m2 based on body weight / body surface area index). / Day), infants survive one day after birth, lose weight at birth and lactation; the ineffective dose is 10 mg / kg / day. Moreover, when the mother's dose of duloxetine reached 30 mg / kg / day, young children's behavior was consistent with increased responsiveness, such as increased startle response to noise and decreased habituation of voluntary activities. However, maternal use of duloxetine did not negatively affect the growth and reproductive behavior of offspring after weaning.
Due to the lack of adequate, well-designed, controlled female studies in pregnancy, the use of duloxetine in maternal pregnancy should only be considered if the potential benefits to the fetus outweigh the risks. Mothers who have recently taken duloxetine may experience withdrawal symptoms in their newborns, including decreased muscle tone, tremors, nervousness, difficulty feeding, respiratory distress, and seizures.
Non-teratogenic effects-Complications in neonates exposed to SSRIs or SNRIs (serotonin and norepinephrine reuptake inhibitors) during the third trimester of pregnancy can lead to prolonged hospital stays, respiratory support and tube feeding. These complications occur immediately after birth. Existing clinical findings include respiratory distress, cyanosis, apnea, seizures and body temperature instability, difficulty feeding, vomiting, hypoglycemia, dystonia, increased muscle tone, hyperreflexia, tremor, overreaction, irritability, crying Noisy. These conditions are either due to the direct toxic effects of SSRIs and SNRIs or may be a withdrawal response to the drug. It should be noted that in some cases the clinical manifestations are consistent with serotonin syndrome (see Warnings, Monoamine Oxidase Inhibitors). When pregnant women are receiving duloxetine in the third trimester of pregnancy, doctors should carefully evaluate the potential risks and benefits of treatment (see Dosage and Administration).
childbirth:
The effect of duloxetine on human delivery is unknown. Therefore, the use of duloxetine in childbirth should only be considered if it proves that the potential benefits to the fetus outweigh the risks.
breast-feeding:
Duloxetine is secreted from breast milk of lactating women. The estimated daily dose for infants is about 0.14% (mg / kg) of the mother's medication dose. Due to the unknown effects of duloxetine on infants, breastfeeding is not recommended for patients taking duloxetine.

Duloxetine hydrochloride enteric capsules for children

The efficacy and safety of pediatric patients is unknown (see warning). If considering duloxetine in children and adolescents, the potential risks and clinical needs must be weighed.

Duloxetine hydrochloride enteric-coated capsules for the elderly

Of the 2,418 patients in the clinical study of duloxetine in the treatment of depression (MDD), 5.9% (143) were patients over 65 years of age. No significant differences in safety and efficacy were observed between these patients and young patients, and other clinical reports did not find significant differences between the elderly and younger populations, but the increased sensitivity of some elderly patients cannot be ruled out.

Duloxetine hydrochloride enteric-coated capsules drug interactions

Other drugs that may affect duloxetine <br /> Dualoxetine metabolism is related to CYP1A2 and CYP2D6 CYP1A2 inhibitors-Duloxetine and fluvoxamine (strong CYP1A2 inhibitors) are used in male subjects (N = 14), duloxetine AUC increased more than 5 times, Cmax increased approximately 2.5 times, and T _1/2 increased approximately 3 times. Other drugs that inhibit CYP1A2 metabolism include: cimetidine, quinolone antibiotics such as ciprofloxacin, enoxacin.
CYP2D6 inhibitor-Because CYP2D6 is involved in the metabolism of duloxetine, the drug concentration of duloxetine hydrochloride will increase when duloxetine and strong CYP2D6 inhibitors are used in combination (see [Notes] effect).
Other drugs that duloxetine may affect < br br Drug-in vitro drug interaction studies through CYP1A2 metabolism show that duloxetine does not induce CYP1A2 activity. Therefore, although no clinical studies on enzyme induction have been conducted, it is not expected that metabolism of CYP1A2 substrates (eg, theophylline, caffeine) will be increased due to enzyme induction. Although in vitro studies have shown that duloxetine is a CYP1A2 inhibitor, there is no significant change in the pharmacokinetics of theophylline when duloxetine (60 mg twice daily) is used in combination with theophylline as a substrate for CYP1A2. . Therefore, duloxetine is unlikely to have a clinically significant effect on the metabolism of CYP1A2 substrates.
Duloxetine, a drug metabolized by CYP2D6, is a moderate inhibitor of CYP2D6 and can increase the AUC and Cmax of drugs metabolized by CYP2D6. (See [Notes]). Therefore, the combined use of duloxetine and other drugs that are mainly metabolized by this enzyme and have a narrow therapeutic dose range should be used with caution (see Drug Interactions under [Precautions]).
Drugs metabolized by CYP2C9-in vitro studies have shown that duloxetine has no inhibitory effect on CYP2C9 enzyme activity. Therefore, although no relevant clinical studies have been performed, duloxetine is not expected to inhibit the metabolism of the CYP2C9 enzyme substrate.
Drugs metabolized by CYP3A-in vitro studies have shown that duloxetine does not inhibit or induce CYP3A enzyme activity. Therefore, although no relevant clinical studies have been conducted, it is expected that CYP3A enzyme substrates (such as oral contraceptives and other steroid drugs) will not result in metabolic enhancement or inhibition due to enzyme induction or inhibition.
Drugs metabolized by CYP2C19-in vitro studies have shown that duloxetine at therapeutic concentrations has no inhibitory effect on CYP2C19 enzyme activity. Therefore, although no relevant clinical studies have been conducted, duloxetine is not expected to inhibit the metabolism of the CYP2C19 enzyme substrate.
Study on the combined application of benzodiazepines <br /> Laurazepam-steady state concentration of duloxetine (60mg Q 12 hrs) and laurazepam (2mg Q 12hrs) in combination, laurazepam The pharmacokinetics were not affected by the combination therapy.
Timothel-The steady-state concentration of duloxetine (20mg qhs) in combination with telmazepam (30mg qhs) does not affect the pharmacokinetics of telmazepam.
Drugs with high plasma protein binding-Because duloxetine is highly bound to plasma proteins, patients receiving other high plasma protein binding drugs may increase the free concentration of other drugs when taking duloxetine, which may lead to Adverse drug reactions occurred.
Central Nervous System DrugsWhen duloxetine is used in combination with other centrally acting drugs, especially those with similar mechanisms of action (including alcohol), it should be used with caution. Combination with serotonergic drugs (egSNRIs, selective serotonin reuptake inhibitors, amitriptyline, tramadol) can cause 5-HT syndrome.

Duloxetine hydrochloride enteric-coated capsules overdose

3000 mg were swallowed quickly in clinical trials, alone or with other drugs, and no fatal event was reported. However, there have been reports of acute drug overdose deaths after marketing, mainly mixed drug overdose, and about 1000 mg of duloxetine alone. Signs and symptoms of overdose (duloxetine alone or in combination with other drugs) include drowsiness, coma, serotonin syndrome, seizures, vomiting, and tachycardia.
Treatment of overdose <br /> Duloxetine has no specific antagonists. If serotonin syndrome occurs, specific therapies (such as antihistamines and / or temperature control) should be considered.
Keep the airway open, inhale oxygen and ventilation, monitor heart rate and vital signs, do not recommend vomiting. For those who have taken the medicine shortly or still have symptoms, if necessary, insert a large-hole gastric tube under proper airway protection.
Activated carbon can be used to reduce the absorption of duloxetine in the gastrointestinal tract. Studies have shown that activated carbon can reduce AUC and Cmax by about 1/3. Due to the large distribution volume of this product, the effects of forced diuresis, dialysis, blood transfusion, and infusion exchange are not obvious.
When dealing with drug overdose, you should consider the possibility of taking multiple drugs. Pay special attention to patients who are taking or have recently taken duloxetine. TCA overdose in these patients. The accumulation of tricyclics and their active metabolites in these patients may aggravate clinical symptoms and need to be prolonged. Observation time (see Precautions, Drug Interactions). Doctors should consider contacting a poison control center for symptoms beyond the treatment of drug overdose. The phone number for registering a poison control center is listed in the doctor's manual.

Clinical trial of duloxetine hydrochloride enteric-coated capsules

Four randomized, double-blind, placebo-controlled, fixed-dose clinical studies evaluated the efficacy of this product in the treatment of depressive disorders. The enrolled subjects were adult outpatients, aged 18-83 years, who met the DSM-IV diagnostic criteria for major depressive disorder. In two of these studies, patients were randomly assigned to duloxetine hydrochloride capsules 60 mg once daily (123 and 128 patients, respectively) or placebo (122 and 139 patients, respectively) for 9 weeks; In 3 studies, patients were randomized into duloxetine hydrochloride capsules 20 mg or 40 mg twice daily (86 and 91 patients) or placebo (89 patients) for 8 weeks; in the fourth study Patients were randomly assigned to duloxetine hydrochloride capsules 40 mg or 60 mg twice daily (95 and 93 patients) or placebo (93 patients) for 8 weeks. There is no evidence that duloxetine hydrochloride capsules have more benefits at daily doses exceeding 60 mg.
In the above 4 studies, this product is better than the placebo group in improving the total score of 17 factors of HAMD.
Analysis of the correlation between demographic characteristics such as age, gender, ethnicity, and treatment results, did not find different effects due to the aforementioned demographic characteristics.

Pharmacology and Toxicology of Duloxetine Hydrochloride Enteric Capsules

Pharmacological effects < br Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). The exact mechanism of duloxetine's antidepressant and central analgesic effects has not been clarified, but it is believed that it is related to its enhancement of the serotoninergic and noradrenergic functions of the central nervous system. The results of preclinical studies show that duloxetine is a strong inhibitor of neuronal serotonin and norepinephrine reuptake, and its inhibitory effect on dopamine reuptake is relatively weak. In vitro studies have shown that duloxetine has no apparent affinity for dopaminergic receptors, adrenergic receptors, cholinergic receptors, histaminergic receptors, opioid receptors, glutamate receptors, and GABA receptors. Duloxetine does not inhibit monoamine oxidase.
Toxicology research <br Genetic toxicity:
The results of the duloxetine Ames test, mouse lymphoma cell forward gene mutation test, rat liver cell extraprogrammed DNA synthesis (UDS) test, Chinese hamster bone marrow cell sister chromatid exchange test, and mouse micronucleus test were all negative.
Reproductive toxicity:
Female or male rats orally administer duloxetine at a dose of 45 mg / kg / day before and during mating (based on mg / m ² , 7 times the maximum recommended human dose of 60 mg / day [MRHD]) No effects on mating or fertility were seen.
Duloxetine was orally administered to rats and rabbits at a teratogenic period of 45 mg / kg / day (calculated based on mg / m ^2. Rats and rabbits were equivalent to 7 and 15 times the MRHD, respectively.) Reduced, no teratogenic effect. The unaffected dose was 10 mg / kg / day (calculated based on mg / m ² , rats and rabbits were equivalent to 2 and 3 times the MRHD, respectively).
When duloxetine was orally administered to rats at 30 mg / kg / day during perinatal period (based on mg / m ² , the rat is equivalent to 5 times the MRHD), the survival rate at 1 day after birth, birth and lactation The weight loss during the period was 10 mg / kg / day. At a dose of 30 mg / kg / day, the pups exhibited behavioral changes, which were manifested as increased responsiveness, such as increased response to noise shock and reduced voluntary activity. The offspring had no adverse effects on growth and reproductive behavior after weaning.
Carcinogenicity:
Duloxetine was administered to rats and mice for 2 years. When female mice received a dose of duloxetine of 140 mg / kg / day (calculated based on mg / m ² , which is equivalent to 11 times the MRHD), the incidence of hepatocellular adenoma and hepatocellular carcinoma increased. 50mg / kg / day (calculated based on mg / m ² , equivalent to 4 times the MRHD). Male mice did not see an increase in tumor incidence when the duloxetine dose was 100 mg / kg / day (calculated based on mg / m ² , which is equivalent to 8 times the MRHD). Female and male rats did not see an increase in tumor incidence at doses of 27 and 36 mg / kg / day (based on mg / m ² , which is equivalent to 4 and 6 times the MRHD, respectively).

Pharmacokinetics of Duloxetine Hydrochloride Enteric Capsules

Duloxetine enteric-coated capsules have an elimination half-life of approximately 12 hours (ranging from 8-17 hours). Within the therapeutic range, its pharmacokinetic parameters are directly proportional to the dose. Steady-state blood drug concentration is generally reached 3 days after taking the drug. Duloxetine is mainly metabolized by the liver and involves two P450 enzymes: CYP2D6 and CYP1A2.
Absorption and Distribution-Complete absorption of oral duloxetine hydrochloride enteric-coated capsules. The average lag was 2 hours, and the drug began to be absorbed (Tlag). Duloxetine reached the maximum plasma concentration (Cmax) 6 hours after oral administration. Eating does not affect Cmax, but it will delay the peak time by 6 to 10 hours, slightly reducing the degree of absorption, about 10%. Compared with a single dose in the morning, the absorption of duloxetine was delayed by 3 hours, and apparent clearance was increased by 1/3.
The apparent distribution volume is on average 1640 liters. Duloxetine has a high affinity (> 90%) with human plasma proteins, and mainly binds albumin and 1-acid glycoprotein. It has not yet been evaluated whether there is a drug interaction between duloxetine and other high-protein binding drugs, and liver or renal insufficiency does not affect the plasma protein binding of duloxetine.
Metabolism and excretion-C14 labeled duloxetine is orally administered to determine its biotransformation and degradation in the human body. Duloxetine in plasma only accounts for 3% of the total radiolabels, suggesting that duloxetine is extensively metabolized and has many metabolites. The main biotransformation pathways of duloxetine include naphthyl epoxidation after binding and further oxidation. Both CYP2D6 and CYPIA2 can catalyze naphthyl epoxidation in vitro. Metabolites in plasma include glucuronic acid-bound 4-hydroxyduloxetine and sulfuric acid-bound 5-hydroxy6-methoxyduloxetine. A variety of other metabolites are isolated in the urine, some of which appear only in small elimination metabolic pathways. There is only a small amount of unmetabolized duloxetine hydrochloride in the urine (about 1% of the oral dose), and most (about 70% of the oral dose) is excreted in the form of metabolites of duloxetine hydrochloride. About 20% are excreted through feces.
Special populations < br Gender-Duloxetine has similar half-life in men and women, and no dose adjustment is required for different genders.
Age-Comparing the pharmacokinetics of healthy elderly women (65-77 years old) and healthy middle-aged women (32-50 years old) after a single oral dose of 40 mg duloxetine, there was no difference in Cmax, but the plasma concentration of elderly women -The area under the time curve (AUC) is slightly higher (about 25%) and the half-life is extended by 4 hours. Population pharmacokinetic analysis suggests that from 25 to 75 years of age, drug clearance decreases by approximately 1% for each additional year of age. But age as a predictor can only explain a small part of individual variation among patients. There is no need to adjust the dose according to age (see Dosage and Administration).
Smoking-The bioavailability (AUC) of duloxetine hydrochloride has been reduced by about 1/3 in smokers. Smokers are not recommended to adjust the dose.
Race-No specific pharmacokinetic studies have been conducted to explore the pharmacokinetic characteristics of different races.
Renal insufficiency-There is very limited data on the effects of duloxetine on patients with end-stage renal disease (ESRD). After a single oral dose of 60 mg duloxetine, patients with end-stage renal disease undergoing long-term intermittent hemodialysis have increased their Cmax and AUC values by approximately 100% compared with those with normal renal function, but their elimination half-life is similar. Most of the main circulating metabolites excreted through the urine are glucuronic acid-bound 4-hydroxyduloxetine, and sulfuric acid-bound 5-hydroxy 6-methoxyduloxetine, whose AUC is increased approximately 7-9 times The increase is expected to be more pronounced after repeated oral medications. Therefore, patients with end-stage renal disease (those requiring dialysis) or those with severe renal impairment (estimated creatinine clearance [CrCL] <30mL / min) are not recommended to use duloxetine enteric-coated capsules (see [Dosage and Administration]) . Population pharmacokinetic analysis showed that mild to moderate renal dysfunction (creatinine clearance [CrCL] 30-80 ml / min) had no significant effect on the apparent clearance of duloxetine.
Hepatic insufficiency-Duloxetine metabolism and clearance are reduced in patients with clinically significant liver insufficiency. After a single oral dose of 20 mg duloxetine, 6 patients with moderate liver cirrhosis (Child-Pugh B) had an average plasma clearance rate of 15% of the latter compared with healthy people of the same age and sex. AUC increased 5 times over the latter. Although the Cmax in patients with liver cirrhosis is similar to that of normal liver function, the half-life of the former is increased by 3 times (see [Precautions]). Duloxetine is not recommended for patients with any liver dysfunction (see [Dosage and Administration]).

Storage of Duloxetine Hydrochloride Enteric Capsules

15 30 stored at room temperature

Duloxetine Hydrochloride Enteric Capsule Packaging

Aluminum plastic blister pack, 7 capsules / box, 14 capsules / box, 28 capsules / box

Validity of Duloxetine Hydrochloride Enteric Capsules

36 months

Duloxetine hydrochloride enteric-coated capsules

Import drug registration standard JX20050132 ^[1]