Date of approval: 21 November 2017
Date of revision: 26 February 2018
Instructions for vortioxetine hydrobromide tablets
Please read the instructions carefully and use under the guidance of a physician
Drug name].
Generic Name: Vortioxetine Hydrobromide TabletsTrade Name: 心达悦®; Brintellix®English Name: Vortioxetine Hydrobromide Tablets汉语拼音：Qingxiusuan Fuliuxiting Pian
Ingredients
The active ingredient of this product is vortioxetine hydrobromide
Chemical name: 1-[2-(2,4-dimethyl-phenylthio)-phenyl]-piperazine, hydrobromide
Chemical structure formula.
Molecular formula: C18 H22 N2S, HBr
Molecular weight: 379.36
This product contains the following excipients: (tablet core) mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch (type A), magnesium stearate; (film coating) hydroxypropyl methyl cellulose, polyethylene glycol 400, titanium dioxide, iron oxide red (5mg), iron oxide yellow (10mg).
Characteristic】
This product is a shaped film-coated tablet, which appears white or off-white after removing the coating.
Indications
This product is used for the treatment of depression in adults.
Specification
(1) 5mg (2) 10mg (based on C18H22N2S)
Dosage and Administration
This product should be administered orally and can be taken with food or on an empty stomach.
The initial and recommended dose of this product is 10 mg once daily. Adjustments may be made based on individual patient response, down to a minimum of 5 mg once daily.
After remission of depressive symptoms, continued treatment with this product for at least 6 months is recommended to consolidate the antidepressant effect.
Discontinuation of treatment
Patients receiving this product do not need to taper when discontinuing treatment (see [Pharmacology and Toxicology]).
Adverse reactions
The most common adverse effect of this product is nausea.
Adverse reactions are usually mild or moderate and occur within the first 2 weeks of treatment initiation. These adverse reactions are usually transient and do not usually lead to discontinuation of the drug. Gastrointestinal adverse reactions, such as nausea, are more common in women.
List of adverse reactions
The incidence of adverse reactions is expressed as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); occasional (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); unknown (available data cannot be predicted).
Systemic Organ Classification Incidence Adverse Reactions Metabolic and Nutritional Disorders Unknown Hyponatremia Psychiatric Symptoms Common Dream Abnormalities Neurological Common Dizziness Unknown 5-Hydroxytryptamine Syndrome Vascular System Occasional Flushing Gastrointestinal System Very Common Nausea Common Diarrhea,.
Constipation.
Vomiting pruritus common in skin and subcutaneous tissue, including generalized pruritus occasional night sweats
Description of specific adverse reactions
Geriatric patients
Withdrawal rates are higher in elderly patients 65 years of age and older taking 10 mg of this product once daily or above.
The incidence of nausea and constipation was higher in elderly patients aged 65 years and older (42% and 15%, respectively) than in patients younger than 65 years (27% and 4%, respectively) when taking 20 mg of this product once daily (see [Precautions]).
Sexual Dysfunction
Sexual dysfunction was assessed in clinical studies using the Arizona Sexual Experience Scale (ASEX). There was no difference between this product at doses of 5-15 mg and placebo. However, there was an increase in treatment-emergent sexual dysfunction (TESD) at a dose of 20 mg (see [Pharmacology and Toxicology]).
Category effects
Epidemiologic studies conducted primarily in patients aged 50 years and older have shown an increased risk of fracture in patients treated with the relevant antidepressant class (SSRIs or TCAs). The mechanism by which this risk occurs is unknown, and it is not known whether there is a correlation between this risk and this product.
Contraindications]
Contraindicated in patients with hypersensitivity to the active ingredient or any of the excipients.
Combination with non-selective monoamine oxidase inhibitors (MAOIs) or selective monoamine oxidase A (MAO-A) inhibitors is prohibited (see [Drug Interactions]).
Precautions]
Children
Safety and efficacy have not been established and therefore this product is not recommended for the treatment of depression in patients under 18 years of age (see [Pediatric Use]). In clinical studies in children and adolescents treated with other antidepressants, suicide-related behaviors (suicide attempts and suicidal thoughts) and hostile behaviors (primarily aggression, oppositional behavior, anger) were observed more frequently in the treatment group compared to the placebo group.
Suicidal/suicidal thoughts or clinical worsening
Depression is associated with an elevated risk of suicidal thoughts, self-harm, and suicide (suicide-related events). This risk can persist until the patient reaches clinical cure. Improvement may not be achieved within the first few weeks or more of treatment, so patients should be monitored closely until the clinical symptoms described above improve. In routine clinical experience, the risk of suicide may be elevated early in treatment.
Patients with known suicide-related events or those who exhibit significant suicidal thoughts prior to initiating treatment are at higher risk for suicidal thoughts or attempts and should be monitored closely during treatment. A meta-analysis of clinical studies of antidepressants versus placebo controls for the treatment of patients with psychiatric disorders showed an elevated risk of suicidal behavior after medication compared with placebo in adult patients younger than 25 years of age.
Patients should be closely monitored during treatment, especially in high-risk patients and early in treatment and after dose adjustment. Patients (and patient caregivers) should be reminded of the need to monitor for clinical deterioration, suicidal behavior or thoughts, and abnormal changes in behavior, and to seek immediate medical attention if these symptoms occur.
Seizures
Seizures are a potential risk of taking antidepressants. Therefore, this product should be given with caution to patients with a history of seizures or in patients with unstable epilepsy (see [Drug Interactions]). Treatment should be discontinued in patients who develop seizures or in patients with increased seizure frequency.
5-hydroxytryptamine syndrome (SS) or neuroblocker malignant syndrome (NMS)
Potentially life-threatening 5-hydroxytryptamine syndrome (SS) or neuroblocker malignant syndrome (NMS) may occur after administration of this drug. There is an increased risk of 5-hydroxytryptamine syndrome or nerve blocker malignant syndrome following the combination of: 5-hydroxytryptaminergic active substances (including tretinoin), drugs that interfere with 5-hydroxytryptamine metabolism (including MAOIs), antipsychotics, and other dopamine antagonists. Patients should be monitored for signs and symptoms of 5-hydroxytryptamine syndrome or neuroblocker malignant syndrome (see [Contraindications] and [Drug Interactions]).
Symptoms of 5-hydroxytryptamine syndrome include altered mental status (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, unstable blood pressure, overheating), neuromuscular abnormalities (e.g., hyperreflexia, dyskinesia), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). If any of these occur, the medication should be discontinued immediately and symptomatic treatment should be initiated.
Mania/Mild Mania
This product should be used with caution in patients with a history of mania/hypomania and should be discontinued if the patient enters a manic phase.
Bleeding
Antidepressants with 5-hydroxytryptaminergic effects (SSRIs, SNRIs) have rare reports of bleeding abnormalities such as petechiae, purpura, and other bleeding events (including gastrointestinal or gynecologic bleeding). Caution is recommended in patients taking anticoagulants and/or drugs known to affect platelet function [e.g., atypical antipsychotics and phenothiazines, most tricyclic antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (ASA)], and in patients with known bleeding tendencies/disorders (see [Drug Interactions]).
Hyponatremia
Antidepressants with 5-hydroxytryptaminergic effects (SSRIs, SNRIs) have been reported rarely for hyponatremia, most likely due to dysregulation of antidiuretic hormone secretion (SIADH). Caution is advised in patients at risk, such as the elderly, patients with cirrhosis, or those who are co-administering drugs known to cause hyponatremia.
In patients who develop symptomatic hyponatremia, discontinuation of the drug should be considered and appropriate medical interventions should be taken.
Renal Impairment
Data for use in patients with severe renal impairment are limited. Therefore, it should be used with caution (see [Pharmacokinetics]).
Hepatic Impairment
This product has not been studied in patients with severe hepatic impairment and should be used with caution in such patients (see [Pharmacokinetics]).
Pregnant women and nursing mothers
Pregnancy
Data on the use of this product in pregnant women are limited.
Animal studies have shown reproductive toxicity (see [Pharmacology and Toxicology]).
The following symptoms may occur in newborns with maternal use of 5-hydroxytryptamines in late pregnancy: respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, tremor, hypersensitivity, irritability, lethargy, incessant crying, drowsiness, and sleep difficulties. These symptoms may be due to the effects of withdrawal or excessive 5-hydroxytryptamine activity. In most cases, such complications occur immediately after delivery or within a short period of time (<24 hours).
Epidemiological data suggest that the use of SSRIs during pregnancy (especially late pregnancy) may increase the risk of persistent pulmonary hypertension of the newborn (PPHN). Although no studies have examined the association between PPHN and this product, this potential risk cannot be excluded given the mechanism of action involved (increased 5-hydroxytryptamine concentration).
This product should not be used in women during pregnancy unless clinically necessary.
Lactation
Available animal data indicate that this product and its metabolites can be secreted into breast milk. Therefore, it is expected that this product can be secreted into human milk (see [Pharmacology and Toxicology]). Risks to the infant from breast-feeding cannot be excluded. Therefore, the benefits of breastfeeding for the child must be weighed against the benefits of drug therapy for the mother to decide whether to discontinue breastfeeding or discontinue/abandon treatment with this product.
Fertility
Fertility studies in male and female rats have shown no effect on fertility, sperm quality or mating function (see [Pharmacology and Toxicology]).
There are case reports of reversible effects on sperm quality from administration of antidepressants of related classes (SSRIs). No effects on human fertility have been observed to date.
[Pediatric Use].
There are no data to determine the safety and efficacy of this product for use in children and adolescents under 18 years of age (see [Precautions]).
Geriatric Use]
For patients 65 years of age and older, the initial dose of this product is the lowest effective dose of 5 mg daily once daily.
Effect on driving and mechanical ability]
This product has no or negligible effect on the ability to drive and operate machinery. However, patients should exercise caution when driving or operating dangerous machinery, especially when starting treatment with this product or changing the dose.
Drug Interaction]
This product is extensively metabolized in the liver, primarily mediated by cytochrome CYP2D6. CYP3A4/5 and CYP2C9 are also involved in its metabolism, but the effects are minor (see [Pharmacokinetics]).
Potential for other drugs to affect this product
Irreversible non-selective MAOIs
The combination of this product with irreversible non-selective MAOIs is prohibited due to the risk of developing 5-hydroxytryptamine syndrome. Irreversible non-selective MAOIs should not be started until 14 days after discontinuation of this product. Treatment with irreversible, non-selective MAOIs should not be started until 14 days after discontinuation of this product (see [Contraindications]).
Reversible, Selective MAO-A Inhibitors (Moclobemide)
Combination of this product with a reversible, selective MAO-A inhibitor (e.g., moclobemide) is prohibited (see [Contraindications]). If combination is proven necessary, the added drug should be used at the lowest dose and the 5-hydroxytryptamine syndrome should be closely monitored clinically (see [Precautions]).
Reversible, non-selective MAOI (linezolid)
Combination of this product with a weakly reversible, non-selective MAOI (e.g., the antibiotic linezolid) is prohibited (see [Contraindications]). If a combination is necessary, the lowest dose of the added drug should be used and the 5-hydroxytryptamine syndrome should be closely monitored clinically (see [Precautions]).
Irreversible, selective MAO-B inhibitors (Slegiline, Resagiline)
The risk of developing 5-hydroxytryptamine syndrome is lower when combined with selective MAO-B inhibitors (e.g., slegiline or resagiline) than when combined with MAO-A inhibitors, but caution should still be exercised and close monitoring for 5-hydroxytryptamine syndrome is necessary (see [Precautions]).
5-hydroxytryptamine analogues
Combination with drugs that have 5-hydroxytryptaminergic effects (e.g., tramadol, sumatriptan, and other trimethoxans) may lead to 5-hydroxytryptamine syndrome (see [Precautions]).
St. John’s Wort
Combination with antidepressants with 5-hydroxytryptaminergic effects and herbs containing St. John’s wort (Onchocarpus) may result in an increased incidence of adverse reactions, including 5-hydroxytryptamine syndrome (see [Precautions]).
Drugs that lower the seizure threshold
Antidepressants with 5-hydroxytryptaminergic effects can lower seizure thresholds. Caution should be exercised when combining with other medications that can lower seizure threshold [e.g., antidepressants (tricyclic antidepressants, SSRIs, SNRIs), psychostimulants (phenothiazines, thiazides, and phenylbutazones), mefloquine, bupropion, tramadol] (see [Precautions]).
ECT (electroconvulsive therapy)
There is no clinical experience with simultaneous administration of this product and ECT, and caution is required.
CYP2D6 inhibitors
In healthy subjects, exposure levels (area under the blood concentration-time curve (AUC)) were increased 2.3-fold after 14 days of concomitant administration of this product (10 mg/day) with bupropion (potent CYP2D6 inhibitor, 150 mg/dose, twice daily). Adverse reactions associated with administration of this product followed by bupropion were higher than those associated with administration of bupropion followed by this product. Depending on the individual patient’s response, a lower dose of this product may be considered if a potent CYP2D6 inhibitor (e.g., bupropion, quinidine, fluoxetine, paroxetine) is added to treatment with this product (see [Dosage]).
CYP3A4 inhibitors and CYP2C9 inhibitors
In healthy subjects, 1.3- and 1.5-fold increases in AUC were observed if ketoconazole 400 mg/day (CYP3A4/5 and P-glycoprotein inhibitors) was added after 6 days or fluconazole 200 mg/day (CYP2C9, CYP2C19, and CYP3A4/5 inhibitors) was added after 6 days. No dose adjustment was required.
Interactions in CYP2D6 Weak Metabolizers
The combination of potent CYP3A4 inhibitors (e.g., itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, conivaptan, and many HIV protease inhibitors) and CYP2C9 inhibitors (e.g., fluconazole and amiodarone) in CYP2D6 weak metabolizers has not been specifically studied, but compared with the moderate effects described above, combination therapy is predicted to result in a a more pronounced increase in the level of exposure to this product to occur (see [Pharmacokinetics]).
In healthy subjects, no inhibitory effect of omeprazole (CYP2C19 inhibitor) 40 mg single dose on the pharmacokinetics of multiple doses of this product was observed.
Cytochrome P450 Inducer
In healthy subjects, a 72% reduction in the AUC of this product was observed if rifampicin 600 mg/day (a broad-spectrum inducer of CYP isoenzymes) was administered for 10 days followed by a single dose of 20 mg of this product. Dose adjustment may be considered if cytochrome P450 broad-spectrum inducers (e.g., rifampin, carbamazepine, phenytoin) are added to this treatment depending on individual patient response (see [Dosage and Administration]).
Alcohol
No significant effects on the pharmacokinetics of alcohol (0.6 g/kg) or alcohol were observed in healthy subjects following a single combination of alcohol (0.6 g/kg) and 20 mg or 40 mg of this product, and no significant cognitive impairment was observed relative to the placebo group. However, alcohol consumption is not recommended during antidepressant treatment.
Acetylsalicylic acid
No effect of multiple doses of acetylsalicylic acid 150 mg/day on the pharmacokinetics of multiple doses of this product was observed in healthy subjects.
The potential for this product to affect other drugs
Anticoagulants and antiplatelet agents
No significant effects on the international normalized (prothrombin time) ratio (INR), prothrombin or plasma R-S-warfarin values were observed in healthy subjects following multiple administration of this product in combination with fixed doses of warfarin relative to the placebo group. In addition, in healthy subjects, no significant inhibitory effect on platelet agglutination, or on the pharmacokinetics of acetylsalicylic acid/salicylic acid was observed if multiple doses of this product were followed by the addition of acetylsalicylic acid 150 mg/day, relative to the placebo group. However, pharmacodynamic interactions exist with the combination of 5-hydroxytryptamines with oral anticoagulants or antiplatelet agents, which may result in an increased risk of bleeding and therefore caution should be exercised when combining (see [Precautions]).
Cytochrome P450 substrates
Under in vitro conditions, this product did not show any potential inhibition or induction of CYP450 isozymes (see [Pharmacokinetics]).
In healthy subjects, no inhibition of the following cytochrome P450 isozymes was observed after multiple dosing: CYP2C19 (omeprazole, diazepam), CYP3A4/5 (ethinyl estradiol, midazolam), CYP2B6 (bupropion), CYP2C9 (methanesulfonylurea, S-warfarin), CYP1A2 (caffeine), or CYP2D6 ( dextromethorphan).
No pharmacodynamic interactions have been observed in combination with diazepam or combination oral contraceptives. No significant impairment of cognitive function was observed in the placebo group when diazepam 10 mg (single dose) was administered in combination with diazepam. No significant effects on sex hormone levels were observed following the combination of this product with a combination oral contraceptive (ethinyl estradiol 30 µg/levonorgestrel 150 µg) relative to the placebo group.
Lithium salts, tryptophan
No clinically meaningful effects on this product were observed after multiple administrations in healthy subjects who reached steady-state blood levels with lithium salts. However, it has been reported that the combination with lithium or tryptophan has enhanced 5-hydroxytryptaminergic effects on antidepressants, so caution should be exercised when combining this product with these drugs.
Overdose]
There is limited experience with overdose of this product.
The following adverse effects may be exacerbated after administration of 40-75 mg of this product: nausea, postural dizziness, diarrhea, abdominal discomfort, generalized pruritus, drowsiness, and flushing.
The management of overdose includes symptomatic treatment and related monitoring, and medical follow-up is recommended.
[Clinical Trials].
Clinical Efficacy and Safety
The efficacy and safety of this product for the treatment of depression has been demonstrated in clinical studies (over 6700 patients), including short-term studies (≤12 weeks) including over 3700 patients. Twelve double-blind, placebo-controlled, 6/8-week, fixed-dose studies have been conducted in adults (including the elderly) to evaluate the short-term effectiveness of this product in MDD. 9 of the 12 studies showed effectiveness in at least 1 dose group, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) or the 24-item Hamilton Depression Rating Scale (HAMRS). Hamilton Depression Rating Scale (HAM-D24) with a difference of at least 2 points between the total score and the placebo group. The proportion of patients achieving effectiveness and clinical remission, as well as the degree of Clinical Global Impression-Improvement (CGI-I), was significantly higher in the treatment group than in the placebo group, demonstrating the clinical significance of the treatment and supporting the effectiveness of the product. The effectiveness of this product increased with increasing dose.
A meta-analysis (MMRM) of the mean change from baseline in total MADRS scores at week 6/8 in short-term placebo-controlled studies in adults provided support for the effects in individual studies. In the meta-analysis, the overall mean differences between studies and placebo were statistically significant: -2.3 (p=0.007), -3.6 (p<0.001) and -4.6 (p<0.001) for the 5, 10 and 20 mg/day doses, respectively; the difference between the 15 mg/day dose and placebo in the meta-analysis did not reach statistical significance, and but the mean difference with placebo reached a score of -2.6. A pooled analysis of those who were treatment effective provided support for the effectiveness of this product, with the proportion of patients who achieved treatment effectiveness on this product ranging from 46% to 49% compared with 34% on placebo (p<0.01; NRI analysis).
In addition, the 5-20 mg/day dose range of this product had broad-spectrum antidepressant effectiveness in patients with depression (as assessed by improvement in all MADRS individual scores).
A 12-week double-blind, variable-dose comparative study in patients with MDD examining this product and agomelatine 25 or 50 mg/day further demonstrated the effectiveness of this product at 10 or 20 mg/day. Assessment by improvement in MADRS total score showed statistically significant superiority over agomelatine, supported by clinical relevance as demonstrated by the proportion of treatment effective and clinically remitted patients and by improvement in CGI-I.
Maintenance therapy
The persistence of antidepressant efficacy was verified in a relapse prevention study in which patients who achieved clinical cure after 12 weeks of open treatment were randomly assigned to the treatment (5 or 10 mg/day) or placebo group and then observed for relapse during a double-blind period of at least 24 weeks (24-64 weeks). For the primary endpoint assessed (time to relapse of depression), this product was superior to placebo (p=0.004) with a risk ratio of 2.0, meaning that the risk of relapse was twice as high in the placebo group as in the this product group.
Geriatric patients
In an 8-week double-blind, placebo-controlled, fixed-dose study in elderly patients with depression (age ≥65 years, n=452, of whom 156 were taking this product), the superiority of this product (5 mg/day) over placebo was confirmed by assessing improvements in MADRS and HAM-D24 total scores. The observed effect was a 4.7-point difference between the MADRS total score and placebo at week 8 (MMRM analysis).
Patients with major depression or depression combined with high anxiety symptoms
It was also shown to be effective in short-term studies in patients with major depression (baseline MADRS total score ≥ 30) and depression combined with high anxiety symptoms (baseline HAM-A total score ≥ 20) (overall mean difference between MADRS total score and placebo at week 6/8 ranged from 2.8-7.3 and 3.6-7.3 points, respectively (MMRM analysis)). It was also effective in these patients in studies specifically targeting the elderly.
Long-term relapse prevention studies in this patient population have also shown maintenance of the antidepressant effect of this product.
Effects on scores on the Digit Symbol Switching Test (DSST), the University of San Diego Task-Based Ability to Live (UPSA) (objective assessment) and the Self-Inspection of Cognitive Impairment Questionnaire (PDQ) and the Cognitive and Physical Functioning Questionnaire (CPFQ) (subjective assessment)
The effectiveness of this product (5-20 mg/day) in patients with MDD has been studied in 2 adult and 1 short-term placebo-controlled study in the elderly.
There was a significant effect on the Digit Symbol Switching Test (DSST) compared to placebo, with a difference ranging from Δ = 1.75 (p = 0.019) to 4.26 (p <0.0001) in the 2 adult studies and an amount of difference of Δ = 2.79 (p = 0.023) in the elderly study. In a meta-analysis of mean change in DSST correct sign number from baseline in all 3 studies (ANCOVA, LOCF), this product was significantly different from placebo (p <0.05) with a standard effect size of 0.35. In the meta-analysis of the same 3 studies, after controlling for changes in total MADRS score, the results showed that this product was significantly different from placebo in DSST correct sign number compared to baseline remained significantly different (p<0.05) with a standard effect size of 0.24.
One study evaluated the effect of this product on function using the University of San Diego Task-based Ability to Live (UPSA) test. There was a statistically significant difference between this product and placebo. The score for this product was 8.0 compared to 5.1 for placebo (p=0.0003).
In a study evaluating subjective cognitive function using the Self-Assessment of Cognitive Impairment Questionnaire (PDQ), this product outperformed placebo with a reduced score of 14.6 compared to 10.5 for placebo at baseline (p=0.002). When evaluated using the Cognitive and Physiological Functioning Questionnaire, there was no significant difference between this product and placebo in the evaluation of subjective cognitive function, with an attenuated score of 8.1 compared to 6.9 for placebo compared to baseline (p=0.086).
Tolerability and safety
The safety and tolerability of this product in the dose range of 5-20 mg/day has been established in short- and long-term studies. For information on adverse reactions, see [Adverse Reactions].
This product did not cause an increased incidence of insomnia and drowsiness relative to the placebo group.
Possible withdrawal symptoms following abrupt discontinuation of this product were systematically evaluated in short-term and long-term placebo-controlled clinical studies. There were no clinical differences in the incidence or presentation of discontinuation symptoms between placebo and placebo following short-term (6-12 weeks) or long-term (24-64 weeks) treatment with this product.
The incidence of self-reported adverse sexual function reactions in short- and long-term clinical studies with this product was low and similar to placebo. In studies using the Arizona Sexual Experience Scale (ASEX), the incidence of treatment-emergent sexual dysfunction (TESD) and the total ASEX score did not show clinically meaningful differences from placebo at doses of 5-15 mg/day. At a dose of 20 mg/day, an increase in TESD was observed compared to placebo (incidence difference 14.2%, 95% CI [1.4, 27.0]).
There was no effect on body weight, heart rate, or blood pressure in the short- and long-term clinical studies relative to the placebo group.
No clinically meaningful changes in liver and kidney assessment results were observed in clinical studies.
In patients with MDD, this product did not produce any clinically meaningful effects on ECG parameters, including QT, QTc, PR and QRS interval. In a comprehensive QTc study in healthy subjects, no potential for prolongation of the QTc interval was observed at doses up to 40 mg daily.
Pediatric Patients
No clinical trials have been conducted in children and adolescents to determine the safety and efficacy of this product in pediatric and adolescent populations (see [Pediatric Dosage]).
Clinical Trials in China
An 8-week, double-blind, randomized, fixed-dose, multicenter, comparative trial including Chinese patients with depression examined the efficacy and safety of this product in patients treated with either this product at 10 mg/day (126 Chinese patients) or venlafaxine at 150 mg/day (130 Chinese patients). changes in MADRS total scores relative to baseline confirmed that the improvement in MADRS scores in the product group was comparable to the improvement in MADRS scores in the venlafaxine group. The improvement in the venlafaxine group was comparable (-19.99 ± 0.95 and -20.09 ± 0.97 for the change in total MARDS score in the product and venlafaxine groups, respectively).
The secondary efficacy endpoints of HAM-A total score, CGI-S score, CGI-I score, and efficiency and remission rates during treatment also showed improvements similar to those in the venlafaxine group.
The safety profile of this product in Chinese patients was similar to the overall safety profile of this product, see [Adverse Reactions].
The overall incidence of adverse reactions in Chinese patients and the rate of patient withdrawal due to adverse reactions were lower than in the venlafaxine group.
There are no data from a phase 3 study of 20 mg in China.
Pharmacology and Toxicology
Pharmacological effects
The mechanism of the antidepressant effect of vortioxetine hydrobromide is not fully understood, but it is thought to be related to the enhancement of serotonin activity due to the inhibition of 5-hydroxytryptamine (5-HT) reuptake. Vortioxetine hydrobromide also has several other activities, including 5HT3 receptor antagonism and 5-HT1A
receptor agonism, and the role of these activities in the antidepressant effects of vortioxetine hydrobromide has not been determined.
Toxicological studies
Genotoxicity
The Ames test, human peripheral blood lymphocyte chromosome aberration test, and rat micronucleus test were all negative.
Reproductive toxicity
In the rat fertility and early embryonic development toxicity test, the highest dose of 120 mg/kg/day (approximately 58 times the maximum recommended human dose of MRHD based on body surface area) did not show any significant effects on fertility and early embryonic development in male and female rats.
In the rat and rabbit embryo-fetal development toxicity tests, no significant teratogenic effects on fetuses were observed at the maximum doses of 160 mg/kg/day and 60 mg/kg/day (approximately 77 and 58 times the MRHD based on body surface area), respectively. However, at doses of 30 mg/kg/day (rats) and 10 mg/kg/day (rabbits) (15 and 10 times the MRHD in terms of body surface area), some developmental toxicity was observed, mainly in the form of reduced fetal body weight and delayed ossification.
In the rat perinatal toxicity test, a dose of ≥40 mg/kg/day (approximately 20 times the MRHD in terms of body surface area) resulted in lower live fetal numbers, higher early pup mortality and delayed development (especially eye opening time). The highest dose of 120 mg/kg/day (approximately 58 times the MRHD in terms of body surface area) resulted in lower offspring body weight from birth to lactation. The NOAEL for pup development was 10 mg/kg/day (approximately 5 times the MRHD based on body surface area) and the NOAEL for post-delactation development, sexual development, mating ability and fertility of the F1 generation was 120 mg/kg/day (approximately 58 times the MRHD based on body surface area).
Carcinogenicity
The highest doses of 50 mg/kg/day (males) and 100 mg/kg/day (females) were administered to mice and 40 mg/kg/day (males) and 80 mg/kg/day (females) were administered to rats, which were approximately 12, 24 and 20, 39 times higher than MRHD, respectively, based on body surface area. , 24 and 20, 39 times of MRHD, respectively.
In rats, a statistically significant increase in the incidence of rectal polypoid adenomas was seen in female rats at 80 mg/kg/day (approximately 39 times the MRHD) but not in female rats at 30 mg/kg/day (approximately 15 times the MRHD) or male rats at 40 mg/kg/day (approximately 20 times the MRHD). This may be related to inflammation and hyperplasia caused by the solubilizer used (10% hydroxypropyl β-cyclodextrin).
In mouse carcinogenicity tests, the highest doses administered were 50 mg/kg/day (males, 12 times the MRHD) and 100 mg/kg/day (females, 24 times the MRHD), respectively, and no significant carcinogenicity was observed.
Pharmacokinetics]
Absorption
The product is slowly and adequately but well absorbed after oral administration, with peak plasma concentrations within 7-11 h. Mean Cmax values of 9-33 ng/mL were observed after multiple doses of 5, 10, or 20 mg/day. absolute bioavailability was 75%. No effect of food on pharmacokinetics was observed (see [DOSAGE]). Steady-state plasma concentrations were achieved in approximately 2 weeks.
Distribution
The mean volume of distribution (Vss) was 2,600 L, suggesting a broad extravascular distribution. A high degree of binding (98-99%) occurs between this product and plasma proteins, and this binding is shown to be independent of the plasma concentration of this product.
Biotransformation
The product is extensively metabolized in the liver, primarily by CYP2D6 and to a lesser extent by CYP3A4/5 and CYP2C9 catalyzed oxidation and subsequent glucuronide binding.
No inhibition or induction of CYP isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5 was observed in drug interaction tests. This product is a weak P-gp substrate and inhibitor.
The major metabolite of this product is not pharmacologically active.
Elimination
The mean elimination half-life and oral clearance are 66 h and 33 L/h, respectively. Approximately 2/3 of the inactive metabolite is excreted in the urine and approximately 1/3 is excreted in the feces. The amount of this product excreted in the feces is negligible.
Linearity/nonlinearity
The pharmacokinetics are linear and not time-dependent over the dose range studied (2.5-60 mg/day).
The accumulation index is 5-6 based on an AUC of 0-24h after multiple doses of 5-20 mg/day, which is consistent with a half-life.
Special Populations
Geriatric patients
In healthy elderly subjects (age ≥ 65 years; n = 20), exposure levels (Cmax and AUC) of this product after multiple dosing at 10 mg/day were 27% higher than in healthy young control subjects (age ≤ 45 years). For patients 65 years of age and older, the lowest effective dose of 5 mg once daily should be used as the initial dose of this product (see [Geriatric Dosing]).
Patients with renal impairment
Renal impairment (mild, moderate, or severe; n= 8 per group) estimated using the Cockcroft-Gault formula after a single dose of 10 mg of this product resulted in moderately elevated exposure levels (up to 30%) compared to corresponding healthy controls. In patients with end-stage renal disease, a single administration of a 10 mg dose of this product resulted in only a small reduction in this product during dialysis (13% and 27% reduction in AUC and Cmax; n=8). No dose adjustment was required (see [Precautions]).
Patients with hepatic impairment
No effect of mild or moderate hepatic impairment (Child-Pugh criteria A or B; n=8 per group) on the pharmacokinetics of this product was observed after a single dose of 10 mg (change in AUC less than 10%). No dose adjustment was required. This product has not been studied in patients with severe liver injury and should be used with caution (see [Precautions]).
CYP2D6 Genotype
Plasma concentrations of this product in CYP2D6 weak metabolizers are approximately two times higher than in strong metabolizers. The combination of a potent CYP3A4/2C9 inhibitor in CYP2D6 weak metabolizers may result in higher exposure levels (see [Drug Interactions]).
In CYP2D6 ultrafast metabolizers, plasma concentrations of this product at 10 mg/day ranged between those achieved after 5 mg/day and 10 mg/day doses in strong metabolizers. Similar to all patients, dose adjustments may be considered based on individual patient response (see [DOSAGE AND ADMINISTRATION]).
Storage
Store in a sealed container at a temperature not exceeding 30°C.
Packaging
Transparent aluminum plastic blister
7 Tablets/box; 14 Tablets/box; 28 Tablets/box; 56 Tablets/box
Expiration date
48 months.
Executive Standard
JX20140377
Imported drug registration number
5mg: H20170381; H20170382
10mg: H20170383; H20170384
Manufacturer
Manufacturer: H. Lundbeck A/S
Address: Ottiliavej 9, 2500 Valby, Denmark
Telephone number: +45 36301311
Fax
Fax: +45 36303456
Web
Address: www.lundbeck.com
Domestic Contact.
Company Name: Lingbei (Beijing) Pharmaceutical Information Consulting Co.
Address: Unit 03-06, 12/F, Tower A, Qiaofu Fangcaodi Building, No. 9 Dongdaqiao Road, Chaoyang District, Beijing, China
Hotline：4008 102 919
Fax
Fax: +86 10 5875 0188