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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:29.03.2022
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同じ成分を持つトップ20の薬:
一般的な投薬勧告。
Rasaxがレボドパを服用していない患者の単剤療法または補助療法として処方されている場合、患者は1日1回経口投与される推奨用量1 mgでRasaxを開始できます。.
他のPD薬の有無にかかわらず、レボドパを服用している患者(例:.、ドーパミンアゴニスト、アマンタジン、抗コリン薬)、Rasaxの推奨初期用量は1日1回0.5 mgです。. 患者が毎日の0.5 mgの用量に耐えるが、十分な臨床反応が得られない場合、用量は1日1回1 mgに増やすことができます。. Rasaxをレボドパと組み合わせて使用 する場合、個々の反応に基づいて、レボドパ用量の削減を検討することができます。.
高血圧のリスクがあるため、Rasaxの推奨用量を超えてはなりません。.
シプロフロキサシンまたは他のCYP1A2阻害剤を服用している患者。
シプロフロキサシンまたは他のCYP1A2阻害剤を併用している患者は、1日1回Rasax 0.5 mgの用量を超えてはなりません。.
肝障害のある患者。
軽度の肝機能障害のある患者は、1日1回Rasax 0.5 mgの用量を超えてはなりません。. Rasaxは、中等度または重度の肝機能障害のある患者には使用しないでください。.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Hypertension
Exacerbation of hypertension may occur during treatment with Rasax. Medication adjustment may be necessary if elevation of blood pressure is sustained. Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting Rasax.
In Study 3, Rasax (1 mg/day) given in conjunction with levodopa, produced an increased incidence of significant blood pressure elevation (systolic > 180 or diastolic > 100 mm Hg) of 4% compared to 3% for placebo.
When used as an adjunct to levodopa (Studies 3 and 4), the risk for developing post-treatment high blood pressure (e.g., systolic > 180 or diastolic >100 mm Hg) combined with a significant increase from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for Rasax (2%) compared to placebo (1%).
Dietary tyramine restriction is not required during treatment with recommended doses of Rasax. However, certain foods that may contain very high amounts (i.e., more than 150 mg) of tyramine that could potentially cause severe hypertension because of tyramine interaction (including various clinical syndromes referred to as hypertensive urgency, crisis, or emergency) in patients taking Rasax, even at the recommended doses, due to increased sensitivity to tyramine. Patients should be advised to avoid foods containing a very large amount of tyramine while taking recommended doses of Rasax because of the potential for large increases in blood pressure including clinical syndromes referred to as hypertensive urgency, crisis, or emergency. Rasax is a selective inhibitor of MAO-B at the recommended doses of 0.5 or 1 mg daily. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses.
Serotonin Syndrome
Serotonin syndrome has been reported with concomitant use of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a nonselective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (Eldepryl) and rasagiline (Rasax). Serotonin syndrome has also been reported with concomitant use of Rasax with meperidine, tramadol, methadone, or propoxyphene. Rasax is contraindicated for use with meperidine, tramadol, methadone, propoxyphene and MAO inhibitors (MAOIs), including other selective MAO-B inhibitors.
In the postmarketing period, potentially life-threatening serotonin syndrome has been reported in patients treated with antidepressants concomitantly with Rasax. Concomitant use of Rasax with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommended.
The symptoms of serotonin syndrome have included behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor). Serotonin syndrome can result in death.
Rasax clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with Rasax, and the potential drug interaction between Rasax and antidepressants has not been studied systematically. Although a small number of Rasax-treated patients were concomitantly exposed to antidepressants (tricyclics n=115; SSRIs n=141), the exposure, both in dose and number of subjects, was not adequate to rule out the possibility of an untoward reaction from combining these agents. At least 14 days should elapse between discontinuation of Rasax and initiation of treatment with a SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant. Because of the long half-lives of certain antidepressants (e.g., fluoxetine and its active metabolite), at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of Rasax.
Falling Asleep During Activities Of Daily Living And Somnolence
It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should monitor patients for drowsiness or sleepiness, because some of the events occur well after initiation of treatment with dopaminergic medication. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
Cases of patients treated with Rasax and other dopaminergic medications have reported falling asleep while engaged in activities of daily living including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on Rasax with other dopaminergic medications, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported more than 1-year after initiation of treatment.
In Study 3, somnolence was a common occurrence in patients receiving Rasax and was more frequent in patients with Parkinson's disease receiving Rasax than in respective patients receiving placebo (6% Rasax compared to 4% Placebo).
Before initiating treatment with Rasax, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with Rasax such as concomitant sedating medications, the presence of sleep disorders, and concomitant medications that increase rasagiline plasma levels (e.g., ciprofloxacin). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), Rasax should ordinarily be discontinued. If a decision is made to continue these patients on Rasax, advise them to avoid driving and other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
Ciprofloxacin Or Other CYP1A2 Inhibitors
Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of Rasax 0.5 mg once daily.
Hepatic Impairment
Rasagiline plasma concentration may increase in patients with hepatic impairment. Patients with mild hepatic impairment should be given the dose of Rasax 0.5 mg once daily. Rasax should not be used in patients with moderate or severe hepatic impairment.
Hypotension / Orthostatic Hypotension
In Study 3, the incidence of orthostatic hypotension consisting of a systolic blood pressure decrease (≥ 30 mm Hg) or a diastolic blood pressure decrease (≥ 20 mm Hg) after standing was 13% with Rasax (1 mg/day) compared to 9% with placebo.
At the 1 mg dose, the frequency of orthostatic hypotension (at any time during the study) was approximately 44% for Rasax vs 33% for placebo for mild to moderate systolic blood pressure decrements (≥ 20 mm Hg), 40% for Rasax vs 33% for placebo for mild to moderate diastolic blood pressure decrements (≥10 mm Hg), 7% for Rasax vs 3% for placebo for severe systolic blood pressure decrements (≥ 40 mm Hg), and 9% for Rasax vs 6% for placebo for severe diastolic blood pressure decrements (≥ 20 mm Hg). There was also an increased risk for some of these abnormalities at the lower 0.5 mg daily dose and for an individual patient having mild to moderate or severe orthostatic hypotension for both systolic and diastolic blood pressure.
In Study 2 where Rasax was given as an adjunct therapy in patients not taking concomitant levodopa, there were 5 reports of orthostatic hypotension in patients taking Rasax 1 mg (3.1%) and 1 report in patients taking placebo (0.6%).
Clinical trial data further suggest that orthostatic hypotension occurs most frequently in the first two months of Rasax treatment and tends to decrease over time.
Some patients treated with Rasax experienced a mildly increased risk for significant decreases in blood pressure unrelated to standing but while supine.
The risk for post-treatment hypotension (e.g., systolic < 90 or diastolic < 50 mm Hg) combined with a significant decrease from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for Rasax 1 mg (3.2%) compared to placebo (1.3%).
There was no clear increased risk for lowering of blood pressure or postural hypotension associated with Rasax 1 mg/day as monotherapy.
When used as an adjunct to levodopa, postural hypotension was also reported as an adverse reaction in approximately 6% of patients treated with Rasax 0.5 mg, 9% of patients treated with Rasax 1 mg and 3% of patients treated with placebo. Postural hypotension led to drug discontinuation and premature withdrawal from clinical trials in one (0.7%) patient treated with Rasax 1 mg/day, no patients treated with Rasax 0.5 mg/day and no placebo-treated patients.
Dyskinesia
When used as an adjunct to levodopa, Rasax may cause dyskinesia or potentiate dopaminergic side effects and exacerbate pre-existing dyskinesia. In Study 3, the incidence of dyskinesia was 18% for patients treated with 0.5 mg or 1 mg Rasax as an adjunct to levodopa and 10% for patients treated with placebo as an adjunct to levodopa. Decreasing the dose of levodopa may mitigate this side effect.
Hallucinations / Psychotic-Like Behavior
In the monotherapy study (Study 1), the incidence of hallucinations reported as an adverse event was 1.3% in patients treated with Rasax 1 mg and 0.7% in patients treated with placebo. In Study 1, the incidence of hallucinations reported as an adverse reaction and leading to drug discontinuation and premature withdrawal was 1.3% in patients treated with Rasax 1 mg and 0% in placebo-treated patients.
When studied as an adjunct therapy without levodopa (Study 2), hallucinations were reported as an adverse reaction in 1.2% of patients treated with 1 mg/day Rasax and 1.8% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from the clinical trial in 0.6% of patients treated with Rasax 1 mg/day and in none of the placebo-treated patients.
When studied as an adjunct to levodopa (Study 3), the incidence of hallucinations was approximately 5% in patients treated with Rasax 0.5 mg/day, 4% in patients treated with Rasax 1 mg/day, and 3% in patients treated with placebo. The incidence of hallucinations leading to drug discontinuation and premature withdrawal was about 1% in patients treated with 0.5 mg Rasax and 1 mg Rasax/day, and 0% in placebo-treated patients.
Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with Rasax or after starting or increasing the dose of Rasax. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Patients should be informed of the possibility of developing hallucinations and instructed to report them to their health care provider promptly should they develop.
Patients with a major psychotic disorder should ordinarily not be treated with Rasax because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, many treatments for psychosis that decrease central dopaminergic tone may decrease the effectiveness of Rasax.
Consider dose reduction or stopping the medication if a patient develops hallucinations or psychotic like behaviors while taking Rasax.
Impulse Control / Compulsive Behaviors
Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including Rasax, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Rasax. Consider dose reduction or stopping the medication if a patient develops such urges while taking Rasax.
Withdrawal-Emergent Hyperpyrexia And Confusion
A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.
Melanoma
Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
Two-year carcinogenicity studies were conducted in mice at oral doses of 1, 15, and 45 mg/kg/day and in rats at oral doses of 0.3, 1, and 3 mg/kg/day (males) or 0.5, 2, 5, and 17 mg/kg/day (females). In rats, there was no increase in tumors at any dose tested. Plasma exposures (AUC) at the highest dose tested were approximately 33 and 260 times, in male and female rats, respectively, that in humans at the maximum recommended human dose (MRHD) of 1 mg/day.
In mice, there was an increase in lung tumors (combined adenomas/carcinomas) at 15 and 45 mg/kg in males and females. At the lowest dose tested, plasma AUCs were approximately 5 times those expected in humans at the MRHD.
The carcinogenic potential of rasagiline administered in combination with levodopa/carbidopa has not been examined.
Mutagenesis
Rasagiline was reproducibly clastogenic in in vitro chromosomal aberration assays in human lymphocytes in the presence of metabolic activation and was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the absence and presence of metabolic activation. Rasagiline was negative in the in vitro bacterial reverse mutation (Ames) assay and in the in vivo micronucleus assay in mice. Rasagiline was also negative in the in vivo micronucleus assay in mice when administered in combination with levodopa/carbidopa.
Impairment of Fertility
Rasagiline had no effect on mating performance or fertility in rats treated prior to and throughout the mating period and continuing in females through gestation day 17 at oral doses of up to 3 mg/kg/day (approximately 30 times the plasma AUC in humans at the MRHD). The effect of rasagiline administered in combination with levodopa/carbidopa on mating and fertility has not been examined.
Use In Specific Populations
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of rasagiline in pregnant women. Rasax should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In a combined mating/fertility and embryo-fetal development study in pregnant rats, no effect on embryo-fetal development was observed at oral doses up to 3 mg/kg/day (approximately 30 times the plasma exposure (AUC) in humans at the maximum recommended human dose [MRHD, 1 mg/day]).
In pregnant rabbits administered rasagiline throughout the period of organogenesis at oral doses of up to 36 mg/kg/day, no developmental toxicity was observed. At the highest dose tested, the plasma AUC was approximately 800 times that in humans at the MRHD.
In pregnant rats administered rasagiline (0.1, 0.3, 1 mg/kg/day) orally during gestation and lactation, offspring survival was decreased and offspring body weight was reduced at 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the plasma AUC in humans at the MRHD). No plasma data were available at the no-effect dose (0.1 mg/kg); however, that dose is similar to the MRHD on a mg/m² basis. The effect of rasagiline on physical and behavioral development was not adequately assessed in this study.
Rasagiline may be given as an adjunct therapy to levodopa/carbidopa treatment. In pregnant rats administered rasagiline (0.1, 0.3, 1 mg/kg/day) and levodopa/carbidopa (80/20 mg/kg/day) (alone and in combination) orally throughout the period of organogenesis, there was an increased incidence of wavy ribs in fetuses from rats treated with rasagiline in combination with levodopa/carbidopa at 1/80/20 mg/kg/day (approximately 8 times the rasagiline plasma AUC in humans at the MRHD and similar to the MRHD of levodopa/carbidopa [800/200 mg/day] on a mg/m² basis). In pregnant rabbits dosed orally throughout the period of organogenesis with rasagiline alone (3 mg/kg) or in combination with levodopa/carbidopa (rasagiline: 0.1, 0.6, 1.2 mg/kg, levodopa/carbidopa: 80/20 mg/kg/day), an increase in embryo-fetal death was noted at rasagiline doses of 0.6 and 1.2 mg/kg/day when administered in combination with levodopa/carbidopa (approximately 7 and 13 times, respectively, the rasagiline plasma AUC in humans at the MRHD). There was an increase in cardiovascular abnormalities with levodopa/carbidopa alone (similar to the MRHD on a mg/m² basis) and to a greater extent when rasagiline (at all doses; 1-13 times the rasagiline plasma AUC in humans at the MRHD) was administered in combination with levodopa/carbidopa.
Nursing Mothers
In rats rasagiline was shown to inhibit prolactin secretion and it may inhibit milk secretion in humans.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Rasax is administered to a nursing woman.
Pediatric Use
The safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Approximately half of patients in clinical trials were 65 years and over. There were no significant differences in the safety profile of the geriatric and nongeriatric patients.
Hepatic Impairment
Rasagiline plasma concentration may be increased in patients with mild (up to 2 fold, Child-Pugh score 5-6), moderate (up to 7 fold, Child-Pugh score 7-9), and severe (Child-Pugh score 10-15) hepatic impairment. Patients with mild hepatic impairment should not exceed a dose of 0.5 mg/day. Rasax should not be used in patients with moderate or severe hepatic impairment.
Renal Impairment
Dose adjustment of Rasax is not required for patients with mild or moderate renal impairment because Rasax plasma concentrations are not increased in patients with moderate renal impairment. Rasagiline has not been studied in patients with severe renal impairment.
10 mgのラサックスで治療された慢性レボドパ療法を受けている患者を対象とした用量 ⁇ 増研究では、治療中止後に解消した心血管副作用(高血圧や姿勢性低血圧を含む)の3つの報告がありました。.
臨床開発プログラム中にRasaxで過剰摂取の症例は観察されていませんが、症状と臨床経過を示す以下の説明は、非選択的MAO阻害剤の過剰摂取の説明に基づいています。.
非選択的MAOI過剰摂取の兆候と症状はすぐには現れない場合があります。. 薬物の摂取および兆候の出現後、最大12時間の遅延が発生する可能性があります。. 症候群のピーク強度は、過剰摂取の翌日まで到達しない場合があります。. 過剰摂取後に死亡が報告されている。したがって、過剰摂取によるそのような薬物の摂取後少なくとも2日間は患者の継続的な観察とモニタリングを行う即時入院を強くお勧めします。.
MAOIの過剰摂取の臨床徴候および症状の重症度はさまざまで、消費される薬物の量に関連している可能性があります。. 中枢神経系と心血管系が顕著に関与しています。.
MAOIの過剰摂取の兆候と症状には、眠気、めまい、失神、過敏症、多動、興奮、激しい頭痛、幻覚、トリスムス、オピストノス、けいれん、 ⁇ 睡などがあります。急速で不規則な脈拍、高血圧、低血圧、血管虚脱;経皮痛、呼吸抑制と失敗、高熱症、発汗、涼しい、ぬるぬるした皮膚。.
Rasaxの過剰摂取に対する特定の解毒剤はありません。. 以下の提案は、Rasaxの過剰摂取が非選択的MAO阻害剤中毒の後にモデル化される可能性があるという仮定に基づいて提供されています。. 非選択的MAO阻害剤による過剰摂取の治療は、症状があり、支持的です。. 呼吸は、必要に応じて、気道の管理、酸素補給の使用、および人工換気の支援を含む適切な手段によってサポートされるべきです。. 体温は注意深く監視する必要があります。. 過熱の集中的な管理が必要になる場合があります。. 流体と電解質のバランスの維持が不可欠です。. このため、Rasaxを過剰摂取した場合、高血圧チラミン反応のリスクを減らすために、食事療法チラミン制限を数週間観察する必要があります。.
毒物管理センターは、最新の治療ガイドラインのために呼び出されるべきです。.
市販後の報告では、自殺未遂で100 mgのラサックスを摂取した後に非致死的セロトニン症候群を発症した1人の患者が説明されていました。. 毎日4 mgのラサックスとトラマドールで誤って治療された別の患者もセロトニン症候群を発症しました。. 毎日3 mgのRasaxで誤って治療された1人の患者は、高血圧と起立性低血圧からなる血管変動の交互のエピソードを経験しました。.
タイラミンチャレンジテスト。
チラミンチャレンジ研究の結果は、推奨用量のラサギリンはMAO-Bを阻害するために比較的選択的であり、食事性チラミン制限なしで使用できることを示しています。. ただし、特定の食品(例:.、スティルトンチーズなどの熟成チーズ)には、非常に大量のチラミン(つまり、.、150 mg以上)、推奨用量でのチラミンに対する軽度の感受性の増加により、Rasaxを服用している患者にチラミン相互作用によって引き起こされる重度の高血圧を引き起こす可能性があります。. MAO-Bを阻害するためのRasaxの相対的選択性は、用量が推奨される最高用量(1 mg)を徐々に上回ったため、用量に関連して減少しました。.
臨床研究における血小板MAO活動。
健康な被験者とパーキンソン病の患者を対象とした研究では、ラサギリンが血小板MAO-Bを不可逆的に阻害することが示されています。. 阻害は最後の投与後少なくとも1週間続きます。. ほぼ25〜35%のMAO-B阻害は、1 mg /日のラサギリン単回投与後に達成され、2 mg /日のラサギリン単回投与後にMAO-B阻害の55%以上が達成されました。. ラサギリンを毎日2 mg /日で投与してから3日後に90%以上の阻害が達成され、この阻害レベルは投与後3日で維持されました。. 1日あたり0.5、1、2 mgのラサギリンを複数回投与すると、完全なMAO-B阻害が生じました。.