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治療オプション:
Fedorchenko Olga Valeryevna 、薬局による医学的評価、 最終更新日:21.03.2022
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同じ成分を持つトップ20の薬:
イクセルは線維筋痛症の管理に使用されます。. Ixelは小児患者での使用は承認されていません。.
Ixelは、食事の有無にかかわらず経口投与されます。. イクセルを食物と一緒に服用すると、薬物の忍容性が向上する可能性があります。.
推奨投与量。
Ixelの推奨用量は100 mg /日です(50 mgを1日2回)。.
有効性と忍容性に基づいて、投与は次のスケジュールに従って滴定されます。
1日目:。 12.5 mg 1回。
2〜3日目:。 25 mg /日(12.5 mg 1日2回)。
4〜7日目:。 50 mg /日(25 mg 1日2回)。
7日目後:。 100 mg /日(50 mg 1日2回)。
個々の患者の反応に基づいて、用量を200 mg /日(1日2回100 mg)に増やすことができます。.
200 mg /日を超える用量は研究されていません。.
Ixelはテーパー処理し、長期使用後に突然中止しないでください。.
腎不全患者。
軽度の腎機能障害のある患者では、用量調整は必要ありません。.
イクセルは、中等度の腎機能障害のある患者には注意して使用する必要があります。.
重度の腎機能障害のある患者(推定クレアチニンクリアランスが5〜29 mL / minで示される)の場合、維持量を50%から50 mg /日(25 mgを1日2回)に減らす必要があります。.
個々の患者の反応に基づいて、用量を100 mg /日(50 mg 1日2回)に増やすことができます。.
Ixelは末期腎疾患の患者には推奨されません。.
肝不全の患者。
肝障害のある患者には投与量の調整は必要ありません。. 他の薬物と同様に、重度の肝機能障害のある患者には注意が必要です。.
Ixelを中止します。
他のセロトニンおよびノルエピネフリン再取り込み阻害剤(SNRI)および選択的セロトニン再取り込み阻害剤(SSRI)と同様に、ミルナシプランの中止後の臨床試験で離脱症状が観察されています。. 治療を中止するときは、これらの症状について患者を監視する必要があります。. Ixelはテーパー処理し、長期使用後に突然中止しないでください。.
精神障害を治療することを目的としたモノアミンオキシダーゼ阻害剤(MAOI)への患者の切り替え。
精神障害の治療を目的としたMAOIの中止からIxelによる治療の開始までに少なくとも14日が経過するはずです。. 逆に、精神障害の治療を目的としたMAOIを開始する前に、Ixelを停止してから少なくとも5日間は許可する必要があります。.
LinezolidやMetiene Blueなどの他のMAOIとのIxelの使用。
セロトニン症候群のリスクが高いため、リネゾリドまたは静脈内メチレンブルーで治療されている患者でイクセルを開始しないでください。. 精神状態のより緊急の治療を必要とする患者では、入院を含む他の介入が考慮されるべきです。.
場合によっては、すでにイクセル療法を受けている患者は、リネゾリドまたは静脈内メチレンブルーによる緊急治療を必要とする場合があります。. ラインゾリドまたは静脈内メチレンブルー治療の許容できる代替手段が利用できず、ラインゾリドまたは静脈内メチレンブルー治療の潜在的な利点が特定の患者のセロトニン症候群のリスクを上回ると判断された場合。, Ixelは迅速に停止する必要があります。, リネゾリドまたは静脈内メチレンブルーを投与できます。. 患者は、セロトニン症候群の症状がないか、5日間、またはリネゾリドまたは静脈内メチレンブルーの最後の投与から24時間後のいずれか早い方まで監視する必要があります。. イクセルによる治療は、リネゾリドまたは静脈内メチレンブルーの最後の投与から24時間後に再開することができます。.
非静脈内経路(経口錠剤や局所注射など)またはイクセルで1 mg / kgをはるかに下回る静脈内投与でメチレンブルーを投与するリスクは不明です。. それにもかかわらず、臨床医は、そのような使用によるセロトニン症候群の発現症状の可能性を認識している必要があります。.
モノアミンオキシダーゼ阻害剤(MAOI)。
セロトニン症候群のリスクが高いため、イクセルによる精神障害の治療またはイクセルによる治療の中止から5日以内のMAOIの使用は禁 ⁇ です。. 精神障害の治療を目的としたMAOIを停止してから14日以内にIxelを使用することも禁 ⁇ です。.
セロトニン症候群のリスクが高いため、リネゾリドや静脈内メチレンブルーなどのMAOIで治療されている患者でイクセルを開始することも禁 ⁇ です。.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Suicide Risk
Ixel is a selective serotonin and norepinephrine re-uptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders.
Patients, both adult and pediatric, with depression or other psychiatric disorders may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking these medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants, including drugs that inhibit the reuptake of norepinephrine and/or serotonin, may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
In the placebo-controlled clinical trials of adults with fibromyalgia, among the patients who had a history of depression at treatment initiation, the incidence of suicidal ideation was 0.5% in patients treated with placebo, 0% in patients treated with Ixel 100 mg/day, and 1.3% in patients treated with Ixel 200 mg/day. No suicides occurred in the short-term or longer-term (up to 1 year) fibromyalgia trials.
Pooled analyses of short-term placebo-controlled trials of drugs used to treat depression (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with these drugs compared to placebo in adults beyond age 24; there was a reduction in suicidality risk with antidepressants compared to placebo in adults age 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 drugs used to treat depression in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1: Risk Differences (Drug – Placebo) in the number of Cases of Suicidality, per 1000 patients treated
Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
< 18 | 14 additional cases |
18-24 | 5 additional cases |
Decreases Compared to Placebo | |
25-64 | 1 fewer case |
≥ 65 | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, have been reported in adult and pediatric patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who may experience worsening depressive symptoms, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment due to worsening depressive symptoms or emergent suicidality, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can produce withdrawal symptoms.
Families and caregivers of patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Ixel should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Ixel, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of Ixel with MAOIs intended to treat psychiatric disorders is contraindicated. Ixel should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Ixel. Ixel should be discontinued before initiating treatment with the MAOI.
If concomitant use of Ixel with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with Ixel and any concomitant serotonergic agents should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated.
Elevated Blood Pressure
A double-blind, placebo-controlled ambulatory blood pressure monitoring (ABPM) study was conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients. Among fibromyalgia patients who were normotensive at baseline, an analysis of the blood pressure findings demonstrated a substantially higher proportion of Ixeltreated patients had a hypertensive blood pressure measurement at the Week 4, 50 mg BID steady state visit (17.7% [n=21/119]) and the Week 7, 100 mg BID steady state visit (14.3% [n=15/105]) as compared to placebo-treated patients (3.7% [n=2/54] and 0% [0/49] at the Week 4 and Week 7 visits, respectively). Hypertension was defined as mean systolic blood pressure (SBP) ≥ 140 mmHg and change from baseline in mean SBP ≥ 10 mmHg or mean diastolic blood pressure (DBP) ≥ 90 mmHg and change from baseline in mean DBP ≥ 5 mmHg for the 12-hour period post AM study drug measurement at that visit. Furthermore, 1.9% (4/210) of Ixeltreated and 0.9% (1/111) of placebo patients discontinued treatment for increases in blood pressure.
The increased risk of blood pressure measurements in the hypertensive range in Ixel-treated patients is supported by substantial increases in mean SBP and DBP measurements observed in the ABPM study. Table 2 shows that, following treatment with Ixel 50 mg BID for three weeks in patients who were normotensive at baseline, the mean increase from baseline was 5 mmHg in systolic blood pressure (SBP) and diastolic blood pressure (DBP). After further treatment with Ixel 100 mg BID for two weeks, the mean increase from baseline in SBP and DBP was 6 mmHg. Similar elevations occurred in Ixel-treated patients who were hypertensive at baseline.
Table 2: Mean (Standard Error) Change from Baseline in Mean 24-hour Systolic and Diastolic Blood Pressure (mmHg) of Milnacipran or Placebo following 4 Weeks of Treatment (50mg BID) and a Subsequent 2 Weeks of Treatment (100mg BID)
Normotensive | Hypertensive | |||||
n | Systolic | Diastolic | n | Systolic | Diastolic | |
Placebo | 39 | 0 (2) | -1 (1) | 50 | 0 (2) | 0 (2) |
50 mg BID* | 92 | 5 (1) | 5 (1) | 84 | 5 (2) | 4 (1) |
Placebo | 37 | 0 (2) | -1 (1) | 47 | -1 (2) | 0 (1) |
100 mg BID^ | 82 | 6 (1) | 6 (1) | 80 | 5 (2) | 4 (1) |
*Blood pressure measurements made after 3 weeks of milnacipran 50mg BID ^Blood pressure measurements made after 2 weeks of milnacipran 100mg BID |
Similar patterns of treatment-emergent blood pressure elevations were observed in Phase 3 and clinical pharmacology studies as manifested by an increased risk of new onset hypertension or substantial increases in end of study blood pressure measurements in patients with hypertension at baseline (Table 3).
Table 3: Blood pressure changes in Phase 3 randomized controlled trials
Milnacipran 50 mg BID | Milnacipran 100 mg BID | Placebo | |
FM patients normotensive at baseline who became hypertensive (defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg on three consecutive post-baseline visits) | 20% | 17% | 7% |
FM patients with sustained increases in SBP (increase of ≥ 15 mmHg on three consecutive post-baseline visits) | 9% | 6% | 2% |
FM patients with sustained increases in DBP (increase of ≥ 10 mmHg on three consecutive post-baseline visits) | 13% | 10 % | 4% |
FM patients hypertensive at baseline who had increases in SBP ≥ 15 mmHg at end of study | 10% | 7% | 4% |
FM patients hypertensive at baseline who had increases in DBP ≥ 10 mmHg at end of study | 8% | 6% | 3% |
Sustained increases in blood pressure may have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported.
Concomitant use of Ixel with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution.
Effects of Ixel on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. Ixel should be used with caution in these patients.
Measure blood pressure prior to initiating treatment and periodically monitor blood pressure throughout Ixel treatment. Treat pre-existing hypertension and other cardiovascular disease before starting therapy with Ixel. For patients who experience a sustained increase in blood pressure while receiving Ixel, either reduce the dose or discontinue treatment with Ixel if clinically warranted.
Elevated Heart Rate
A double-blind, placebo-controlled ABPM study was conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients. Information on heart rate was also collected. Following treatment with Ixel 50mg BID for three weeks in patients who were normotensive at baseline, the mean increase in mean 24-hour heart rate from baseline was 13 beats per minute. After further treatment with Ixel 100 mg BID for two weeks, the mean increase from baseline in heart rate was 13 beats per minute.
Similar trends were observed in the clinical trials where Ixel treatment was associated with mean increases in heart rate of approximately 7 to 8 beats per minute.
Increases in heart rate ≥ 20 beats per minute occurred more frequently in Ixel-treated patients when compared to placebo (8% in the Ixel 50 mg BID and 100 mg BID treatment arms versus 0.3% in the placebo arm).
Ixel has not been systematically evaluated in patients with a cardiac rhythm disorder.
Measure heart rate prior to initiating treatment and periodically monitor the heart rate throughout Ixel treatment. Treat pre-existing tachyarrhythmias and other cardiac disease before starting therapy with Ixel. For patients who experience a sustained increase in heart rate while receiving Ixel, either reduce the dose or discontinue treatment with Ixel if clinically warranted.
Seizures
Ixel has not been systematically evaluated in patients with a seizure disorder. In clinical trials evaluating Ixel in patients with fibromyalgia, seizures/convulsions have not been reported. However, seizures have been reported infrequently in patients treated with Ixel for disorders other than fibromyalgia. Ixel should be prescribed with care in patients with a history of a seizure disorder.
Hepatotoxicity
In the placebo-controlled fibromyalgia trials, increases in the number of patients treated with Ixel with mild elevations of ALT or AST (1-3 times the upper limit of normal, ULN) were observed. Increases in ALT were more frequently observed in the patients treated with Ixel 100 mg/day (6%) and Ixel 200 mg/day (7%), compared to the patients treated with placebo (3%). One patient receiving Ixel 100 mg/day (0.2%) had an increase in ALT greater than 5 times the upper limit of normal but did not exceed 10 times the upper limit of normal. Increases in AST were more frequently observed in the patients treated with Ixel 100 mg/day (3%) and Ixel 200 mg/day (5%) compared to the patients treated with placebo (2%).
The increases of bilirubin observed in the fibromyalgia clinical trials were not clinically significant.
No case met the criteria of elevated ALT > 3x ULN and associated with an increase in bilirubin ≥ 2x ULN.
There have been cases of increased liver enzymes and reports of severe liver injury, including fulminant hepatitis with milnacipran from foreign postmarketing experience. In the cases of severe liver injury, there were significant underlying clinical conditions and/or the use of multiple concomitant medications. Because of underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions.
Ixel should be discontinued in patients who develop jaundice or other evidence of liver dysfunction. Treatment with Ixel should not be resumed unless another cause can be established.
Ixel should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
Discontinuation Of Treatment With Ixel
Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other SNRIs and SSRIs.
During marketing of milnacipran, and other SNRIs and SSRIs, there have been spontaneous reports of adverse events indicative of withdrawal and physical dependence occurring upon discontinuation of these drugs, particularly when discontinuation is abrupt. The adverse events include the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.
Patients should be monitored for these symptoms when discontinuing treatment with Ixel. Ixel should be tapered and not abruptly discontinued after extended use. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
Hyponatremia
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Ixel. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs, SSRIs, or Ixel. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk. Discontinuation of Ixel should be considered in patients with symptomatic hyponatremia.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Abnormal Bleeding
SSRIs and SNRIs, including Ixel, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of Ixel and NSAIDs, aspirin, or other drugs that affect coagulation.
Activation Of Mania
No activation of mania or hypomania was reported in the clinical trials evaluating effects of Ixel in patients with fibromyalgia. However those clinical trials excluded patients with current major depressive episode. Activation of mania and hypomania have been reported in patients with mood disorders who were treated with other similar drugs for major depressive disorder. As with these other agents, Ixel should be used cautiously in patients with a history of mania.
Patients With A History Of Dysuria
Angle Closure Glaucoma
The pupillary dilation that occurs following use of SNRI drugs including Ixel may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Concomitant Use With Alcohol
In clinical trials, more patients treated with Ixel developed elevated transaminases than did placebo treated patients. Because it is possible that milnacipran may aggravate pre-existing liver disease, Ixel should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
Patient Counseling Information
See Medication Guide
Information For Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Ixel and should counsel them in its appropriate use. A patient Medication Guide is available for Ixel. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Ixel:
Clinical Worsening And Suicide Risk
Patients and their families and caregivers should be advised that Ixel is a selective norepinephrine and serotonin reuptake inhibitor and therefore belongs to the same class of drugs as antidepressants. Patients, their families, and their caregivers should be advised that patients with depression may be at increased risk for clinical worsening and/or suicidal ideation if they stop taking anti-depressant medication, change the dose, or start a new medication.
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, or other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during treatment with Ixel or other drugs that inhibit the reuptake of norepinephrine and/or serotonin, and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Serotonin Syndrome
Patients should be cautioned about the risk of serotonin syndrome with concomitant use of Ixel with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John's Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid).
Patients should be advised of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms.
Elevated Blood Pressure And Heart Rate
Patients should be advised that Ixel may increase their blood pressure and heart rate and that they should have their blood pressure and heart rate monitored at regular intervals when receiving treatment with Ixel.
Abnormal Bleeding
Patients should be cautioned about the concomitant use of Ixel and NSAIDs, aspirin, or other drugs that affect coagulation, since the combined use of agents that interfere with serotonin reuptake and these agents has been associated with an increased risk of abnormal bleeding.
Angle Closure Glaucoma
Patients should be advised that taking Ixel can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
Ability To Drive And Use Machinery
Ixel might diminish mental and physical capacities necessary to perform certain tasks such as operating machinery, including motor vehicles. Patients should be cautioned about operating machinery or driving motor vehicles until they are reasonably certain that Ixel treatment does not affect their ability to engage in such activities.
Alcohol
Patients should talk to their healthcare provider about their alcohol intake prior to initiating treatment with Ixel.
Discontinuation
Patients should be advised that withdrawal symptoms can occur when discontinuing treatment with Ixel, particularly when discontinuation is abrupt.
Missing a Dose
Patients should be advised that if they miss a dose, they should skip the missed dose and take the next dose at their regular time.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during Ixel therapy.
Patients should be encouraged to enroll in the Ixel Pregnancy Registry if they become pregnant, preferably before any prenatal testing is done. This registry is collecting information about the safety of milnacipran during pregnancy. To enroll, patients or their healthcare providers may call the toll-free number 1-877-643-3010 , download data forms from our website, www.Ixelpregnancyregistry.com, or email the registry for further information at [email protected]
Nursing
Advise patients to notify their physician if they are breast feeding.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
Dietary administration of milnacipran to rats at doses of 50 mg/kg/day (2 times the MRHD on a mg/m² basis) for 2 years caused a statistically significant increase in the incidence of thyroid C-cell adenomas and combined adenomas and carcinomas in males. A carcinogenicity study was conducted in Tg.rasH2 mice for 6 months at oral gavage doses of up to 125 mg/kg/day.
Milnacipran did not induce tumors in Tg.rasH2 mice at any dose tested.
Mutagenesis
Milnacipran was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) or in the L5178Y TK +/-mouse lymphoma forward mutation assay. Milnacipran was also not clastogenic in an in vitro chromosomal aberration test in human lymphocytes or in the in vivo mouse micronucleus assay.
Impairment of Fertility
Although administration of milnacipran to male and female rats had no statistically significant effect on mating or fertility at doses up to 80 mg/kg/day (4 times the MRHD on an mg/m² basis), there was an apparent dose-related decrease in the fertility index at clinically relevant doses based on body surface area.
Use In Specific Populations
Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate or well-controlled studies in pregnant women. Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine (such as Ixel), or selective serotonin reuptake inhibitors late in the third trimester have developed complications that can arise immediately upon delivery. Reproduction studies have been performed in rats, rabbits and mice. Milnacipran was shown to increase embryo fetal and perinatal lethality in rats and the incidence of a minor skeletal variation in rabbits at doses below (rat) or approximately equal to (rabbit) the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m² basis. No effects were seen in mice when treated with milnacipran during the period of organogenesis at doses up to 3 times the MHRD on a mg/m² basis. Because animal reproduction studies are not always predictive of human response, Ixel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Registry
Physicians are advised to recommend that pregnant patients taking Ixel enroll in the Ixel Pregnancy Registry. Enrollment is voluntary and may be initiated by pregnant patients or their healthcare providers by contacting the registry at 1-877-643-3010 or by email at [email protected] Data forms may also be downloaded from the registry website at www.Ixelpregnancyregistry.com.
Clinical Consideration
Neonates exp
臨床試験の経験。
臨床試験はさまざまな条件下で行われるため、薬物の臨床試験で観察された副作用率は、他の薬物の臨床試験の率と直接比較することはできず、実際に観察された率を反映しない場合があります。.
患者暴露。
Ixelは、29週間までの治療期間、2209人の線維筋痛症患者(Ixelで治療された1557人の患者とプラセボで治療された652人の患者)を含む3つの二重盲検プラセボ対照試験で評価されました。.
記載されている副作用の頻度は、リストされたタイプの治療に伴う副作用を少なくとも1回経験した個人の割合を表しています。. 反応は、それが初めて発生した場合、またはベースライン評価後に治療を受けている間に悪化した場合、治療が緊急であると見なされました。.
廃止につながる有害反応。
線維筋痛症の患者を対象としたプラセボ対照試験では、患者の23%がイクセルで治療されました。
プラセボで治療された患者の12%と比較して、100 mg /日、Ixel 200 mg /日で治療された患者の26%が副作用のために早期に中止されました。. Ixel治療グループの患者の1%以上で離脱につながり、プラセボ治療グループよりも発生率が高い副作用は吐き気でした。 (ミルナシプラン6%。, プラセボ1%。) 動 ⁇ 。 (ミルナシプラン3%。, プラセボ1%。) 頭痛。 (ミルナシプラン2%。, プラセボ0%。) 便秘。 (ミルナシプラン1%。, プラセボ0%。) 心拍数が増加しました。 (ミルナシプラン1%。, プラセボ0%。) 多汗症。 (ミルナシプラン1%。, プラセボ0%。) ⁇ 吐。 (ミルナシプラン1%。, プラセボ0%。) そしてめまい。 (ミルナシプラン1%およびプラセボ0.5%。). 副作用による中止は、一般的に、Ixel 100 mg /日と比較して、Ixel 200 mg /日で治療された患者の間でより一般的でした。.
プラセボ対照試験における最も一般的な副作用。
プラセボ対照線維筋痛症患者試験では、臨床試験で最も頻繁に発生した副作用は吐き気でした。. Ixelで治療された患者で最も一般的な副作用(発生率≥5%および2倍のプラセボ)は、便秘、ほてり、多汗症、 ⁇ 吐、動 ⁇ 、心拍数の増加、口渇、高血圧でした。.
表4。 100または200 mg /日でイクセルで治療された患者の少なくとも2%で発生し、プラセボよりも発生率が高いすべての副作用をリストします。.
表4:線維筋痛症患者のプラセボ対照試験における治療-緊急有害反応の発生率(すべてのイクセル治療患者の少なくとも2%で発生し、プラセボ治療グループよりもいずれかのイクセル治療グループでより頻繁に発生するイベント)。
システムオルガンクラス優先用語。 | Ixel 100 mg /日。 (n = 623)%。 | Ixel 200 mg /日。 (n = 934)%。 | すべてのイクセル。 (n = 1557)%。 | プラセボ。 (n = 652)%。 |
心臓障害。 | ||||
動 ⁇ 。 | 8 | 7 | 7 | 2 |
頻脈。 | 3 | 2 | 2 | 1 |
眼疾患。 | ||||
視力がぼやけている。 | 1 | 2 | 2 | 1 |
胃腸障害。 | ||||
吐き気。 | 35 | 39 | 37 | 20 |
便秘。 | 16 | 15 | 16 | 4 |
⁇ 吐。 | 6 | 7 | 7 | 2 |
口渇。 | 5 | 5 | 5 | 2 |
腹痛。 | 3 | 3 | 3 | 2 |
一般的な障害。 | ||||
胸の痛み。 | 3 | 2 | 2 | 2 |
悪寒。 | 1 | 2 | 2 | 0 |
胸の不快感。 | 2 | 1 | 1 | 1 |
感染症。 | ||||
上気道感染症。 | 7 | 6 | 6 | 6 |
調査。 | ||||
心拍数が増加しました。 | 5 | 6 | 6 | 1 |
血圧が上がった。 | 3 | 3 | 3 | 1 |
代謝と栄養障害。 | ||||
食欲減退。 | 1 | 2 | 2 | 0 |
神経系障害。 | ||||
頭痛。 | 19 | 17 | 18 | 14 |
めまい。 | 11 | 10 | 10 | 6 |
片頭痛。 | 6 | 4 | 5 | 3 |
感覚異常。 | 2 | 3 | 2 | 2 |
振戦。 | 2 | 2 | 2 | 1 |
知覚鈍麻。 | 1 | 2 | 1 | 1 |
緊張頭痛。 | 2 | 1 | 1 | 1 |
精神障害。 | ||||
不眠症。 | 12 | 12 | 12 | 10 |
不安。 | 5 | 3 | 4 | 4 |
呼吸器疾患。 | ||||
呼吸困難。 | 2 | 2 | 2 | 1 |
皮膚疾患。 | ||||
多汗症。 | 8 | 9 | 9 | 2 |
発疹。 | 3 | 4 | 3 | 2 |
⁇ 。 | 3 | 2 | 2 | 2 |
血管障害。 | ||||
ほてり。 | 11 | 12 | 12 | 2 |
高血圧。 | 7 | 4 | 5 | 2 |
フラッシング。 | 2 | 3 | 3 | 1 |
体重の変化。
プラセボ対照線維筋痛症の臨床試験では、平均体重減少と比較して、Ixel 100 mg /日とIxel 200 mg /日の治療グループの両方で、Ixelで最大3か月間治療された患者の平均体重減少は約0.8 kgでしたプラセボ治療患者では約0.2 kg。.
男性の生殖器有害反応。
プラセボ対照線維筋痛症の研究で。, ⁇ 尿生殖器系に関連する以下の治療に伴う副作用は、イクセルで治療された男性患者の少なくとも2%で観察されました。, プラセボで治療された男性患者よりも大きな割合で発生しました:排尿障害。, 射精障害。, 勃起不全。, 射精の失敗。, 性欲は減少した。, 前立腺炎。, 陰 ⁇ の痛み。, 精巣の痛み。, 精巣の腫れ。, ⁇ 。, 尿閉。, 尿道痛。, 尿の流れが減少しました。.
線維筋痛症におけるイクセルの臨床試験中に観察された他の副作用。
以下は、68週間までイクセルで治療された1824人の線維筋痛症患者から報告された、頻繁に発生する(少なくとも1/100人の患者で1回以上発生する)治療に伴う副作用のリストです。. リストには、すでに表4にリストされているイベントは含まれていません。, 薬物の原因が遠いそれらのイベント。, 有益ではないほど一般的だったイベント。, そして、それらの出来事は一度だけ報告され、それは深刻な生命を脅かす実質的な確率を持っていませんでした。.
副作用は身体系によって分類され、頻度の低下順にリストされています。. 主要な臨床的重要性の副作用は、 警告と注意。 セクション。.
胃腸障害-。 下 ⁇ 、消化不良、胃食道逆流症、 ⁇ 腸、腹部膨満。
一般的な障害-。 疲労、末 ⁇ 浮腫、過敏症、発熱。
感染症 -。 尿路感染症、 ⁇ 炎。
けが、中毒、および手続き上の合併症-。 ⁇ 傷、秋。
調査 -。 体重が減少または増加した。
代謝と栄養障害-。 高コレステロール血症。
神経系障害-。 傾眠、味覚異常。
精神障害-。 うつ病、ストレス。
皮膚疾患-。 寝汗。
市販後の経験。
以下の追加の副作用は、世界中で受けたイクセルの自発的な報告から確認されています。. これらの副作用は、深刻さ、報告の頻度、またはイクセルへの潜在的な因果関係の組み合わせのために、含めるために選択されました。. ただし、これらの副作用は不確実なサイズの集団から自発的に報告されたため、その頻度を確実に推定したり、薬物曝露との因果関係を確立したりすることは常に可能ではありません。. これらのイベントは次のとおりです。
血液およびリンパ系障害-。 白血球減少症、好中球減少症、血小板減少症。
心臓障害-。 脳室上頻脈。
眼疾患 -。 宿泊障害。
内分 ⁇ 障害-。 過プロラクチン血症。
肝胆道疾患-。 肝炎。
代謝と栄養障害-。 拒食症、低ナトリウム血症。
筋骨格系および結合組織障害-。 横紋筋融解症。
神経系障害-。 けいれん(グランドマルを含む)、意識喪失、パーキンソン病。
精神障害-。 攻撃性、怒り、せん妄、幻覚、殺人思想。
腎および尿路障害-。 急性腎不全。
生殖器系と乳房障害-。 ガラクターレア。
皮膚疾患-。 多形紅斑、スティーブンスジョンソン症候群。
血管障害-。 高血圧の危機。
ヒトでのイクセルの過剰摂取の臨床経験は限られています。. 臨床試験では、1000 mgまでの急性摂取の症例が単独で、または他の薬物と組み合わせて報告され、致命的なものはありませんでした。.
市販後の経験では、主に複数の薬物を含むが、イクセルのみを含む急性の過剰摂取について致命的な結果が報告されています。. 最も一般的な兆候と症状には、血圧の上昇、心肺停止、意識レベルの変化(傾眠から ⁇ 睡まで)、 ⁇ 乱状態、めまい、および肝酵素の増加が含まれていました。.
過剰摂取の管理。
イクセルに対する特定の解毒剤はありませんが、セロトニン症候群が続く場合は、特定の治療(シプロヘプタジンや温度調節など)を検討できます。. 急性の過剰摂取の場合、治療は、薬物の過剰摂取の管理に使用される一般的な対策で構成する必要があります。.
適切な気道、酸素化、換気を保証し、心臓のリズムとバイタルサインを監視する必要があります。. ⁇ 吐の誘発は推奨されません。. 必要に応じて、適切な気道保護を備えた大口径の卵巣管を備えた胃洗浄は、摂取直後または症候性患者で実施した場合に示されることがあります。. Ixelには特定の解毒剤がないため、Ixelの過剰摂取を経験した患者では、症状のケアと胃洗浄と活性炭による治療をできるだけ早く検討する必要があります。.
この薬物の大量の分布のため、強制利尿、透析、 ⁇ 流、および交換輸血は有益である可能性は低いです。.
過剰摂取の管理では、複数の薬物関与の可能性を考慮する必要があります。. 医師は、過剰摂取の治療に関する追加情報について、毒物管理センターに連絡することを検討する必要があります。. 認定毒物管理センターの電話番号は、医師のデスクリファレンス(PDR)に記載されています。.
心血管電気生理学。
QTcF間隔に対するイクセルの効果は、600 mg /日のイクセル(線維筋痛症の推奨治療用量の3〜6倍)を使用した88人の健康な被験者を対象とした二重盲検プラセボ対照並行試験で測定されました。. ベースラインとプラセボの調整後、最大平均QTcF変化は8ミリ秒(2面90%CI、3〜12ミリ秒)でした。. この増加は臨床的に重要であるとは考えられていません。.
ミルナシプランは経口投与後によく吸収され、約85%から90%の絶対バイオアベイラビリティがあります。. ミルナシプランへの曝露は、治療用量範囲内で比例的に増加しました。. それは主に変化せずに尿中に排 ⁇ され(55%)、約6〜8時間の最終排出半減期があります。. 定常状態レベルは36〜48時間以内に到達し、単回投与データから予測できます。. 活性エナンチオマーであるd-ミルナシプランは、l-エナンチオマー(4-6時間)よりも排 ⁇ 半減期(8-10時間)が長い。. エナンチオマー間の相互変換はありません。.
吸収と分布。
イクセルは経口投与後に吸収され、最大濃度(Cmax)は投与後2〜4時間以内に達します。. イクセルの吸収は食物に影響されません。. 絶対バイオアベイラビリティは約85%から90%です。. 健康な被験者への単回静脈内投与後のミルナシプランの平均分布量は約400 Lです。
血漿タンパク質結合は13%です。.
代謝と排除。
ミルナシプランとその代謝産物は、主に腎排 ⁇ によって排除されます。. の経口投与後。 14C-ミルナシプラン塩酸塩、用量の約55%が未変化のミルナシプランとして尿中に排 ⁇ されました(l-ミルナシプランとして24%、d-ミルナシプランとして31%)。. ルミルナシプランカルバモイル-O-グルクロニドは、尿中に排 ⁇ される主要な代謝物であり、用量の約17%を占めました。用量の約2%が、ジミルナシプランカルバモイルO-グルクロニドとして尿中に排 ⁇ されました。. 用量の約8%がN-デスエチルミルナシプラン代謝物として尿中に排 ⁇ されました。.
特殊集団における薬物動態。
腎障害。: ミルナシプランの薬物動態は、軽度(クレアチニンクリアランス[CLcr] 50-80 mL / min)、中等度(CLcr 30-49 mL / min)、および重度(CLcr 5-29 mL / min)の被験者に50 mgのイクセルを単回経口投与した後に評価されました)腎障害および健康な被験者(CLcr> 80 mL. 平均AUC0-∞は16%、52%、199%増加し、末期排 ⁇ 半減期は、軽度、中等度、および重度の腎機能障害のある被験者でそれぞれ38%、41%、および122%増加しました。健康な被験者。.
軽度の腎機能障害のある患者では、用量調整は必要ありません。. 中等度の腎機能障害のある患者には注意が必要です。. 重度の腎機能障害患者では、用量調整が必要です。.
肝障害。: ミルナシプランの薬物動態は、軽度(Child-Pugh A)、中等度(Child-Pugh B)、および重度(Child-Pugh C)の肝機能障害のある被験者と健康な被験者に50 mgのイクセルを単回経口投与した後に評価されました。. AUC0-∞とT½は、健康な被験者と軽度および中等度の肝機能障害のある被験者で類似していた。. ただし、重度の肝機能障害のある被験者は、健康な被験者よりもAUC0-∞が31%高く、T½が55%高くなりました。. 重度の肝機能障害のある患者には注意が必要です。.
高齢者。: ミルナシプランのCmaxおよびAUCパラメータは、年齢に関連した腎機能の低下により、若い被験者と比較して高齢者(> 65歳)の被験者で約30%高くなりました。.
腎機能が著しく損なわれない限り、年齢に基づく投与量の調整は必要ありません。.
性別。:ミルナシプランのCmaxおよびAUCパラメータは、男性の被験者と比較して女性の被験者で約20%高くなりました。. 性別による投与量調整は必要ありません。.
授乳研究。: 薬物動態研究では、産後12週間以上乳児の離乳後8人の授乳中の女性に、50 mgミルナシプランHCl錠剤の単回経口投与が投与されました。. 母乳からのミルナシプランの最大推定1日乳児用量(平均乳消費量150 mL / kg /日を想定)は、ピーク血漿濃度に基づいて母体用量の5%でした。. ほとんどの患者では、母乳中のミルナシプランのピーク濃度は、母体投与後4時間以内に見られました。. イクセルへの乳児の曝露に関するデータは限られているため、イクセルを授乳中の女性に投与する場合は注意が必要です。.
However, we will provide data for each active ingredient