Lfast

Perennial Allergic Rhinitis

Lfast is indicated for the relief of symptoms associated with perennial allergic rhinitis in children 6 months to 2 years of age.

Chronic Idiopathic Urticaria

Lfast is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months of age and older.

Lfastは2.5 mg / 5 mL(0.5 mg / mL)経口溶液および5 mgの分解性(スコア付き)錠剤として入手可能で、必要に応じて2.5 mgの投与が可能です。. Lfastは、食品消費量に関係なく摂取できます。.

多年生のアレルギー性鼻炎。

6ヶ月から2歳の子供。

Lfastの推奨初期用量は、1日1回、夕方に1.25 mg(小さじ1/2経口溶液)[2.5mL]です。. 5 mgを投与された成人への同等の曝露に基づいて、1日1回の1.25 mgを超えてはなりません。.

慢性特発性じんま疹。

12歳以上の大人と子供。

Lfastの推奨用量は、5 mg(1錠または小さじ2杯[10 mL]経口溶液)で、夕方に1日1回です。. 一部の患者は、夕方に1日1回2.5 mg(1/2錠または小さじ1杯[5 mL]経口溶液)で適切に制御される場合があります。.

6〜11歳の子供。

Lfastの推奨用量は、2.5 mg(1/2錠または小さじ1杯[5 mL]経口溶液)で、夕方に1日1回です。. 5 mgの全身曝露は成人の約2倍であるため、2.5 mgの用量を超えてはなりません。.

6ヶ月から5歳までの子供。

Lfastの推奨初期用量は、1日1回、夕方に1.25 mg(小さじ1/2経口溶液)[2.5mL]です。. 5 mgを投与された成人への同等の曝露に基づいて、1日1回の1.25 mgを超えてはなりません。.

腎障害および肝障害の用量調整。

12歳以上の大人と子供:

• 軽度の腎障害(クレアチニンクリアランス[CL。_CR] = 50-80 mL / min):1日1回2.5 mgの用量が推奨されます。
• 中程度の腎障害(CL。_CR = 30-50 mL / min):1日1回2.5 mgの用量が推奨されます。
• 重度の腎障害(CL。_CR = 10-30 mL / min):週2回2.5 mgの用量(3〜4日に1回投与)が推奨されます。
• 末期腎疾患患者(CL。_CR <10 mL / min)および血液透析を受けている患者はLfastを投与されるべきではありません。.

肝機能障害のみの患者では、用量調整は必要ありません。. 肝障害と腎障害の両方の患者では、用量の調整が推奨されます。.

Lfastの使用は以下では禁 ⁇ です。

既知の過敏症の患者。

レボセチリジンまたはLfastの成分のいずれか、またはセチリジンに対する過敏症が知られている患者。. 観察された反応は、じんま疹からアナフィラキシーまでさまざまです。.

末期腎疾患患者。

末期腎疾患(CL。_CR <10 mL / min)および血液透析を受けている患者。

腎機能障害のある小児患者。

腎機能障害のある6か月から11歳の子供。

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Somnolence

In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with Lfast. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving a motor vehicle after ingestion of Lfast. Concurrent use of Lfast with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.

Urinary Retention

Urinary retention has been reported post-marketing with Lfast. Lfast should be used with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as Lfast may increase the risk of urinary retention. Discontinue Lfast if urinary retention occurs.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No carcinogenicity studies have been performed with levocetirizine. However, evaluation of cetirizine carcinogenicity studies are relevant for determination of the carcinogenic potential of levocetirizine. In a 2-year carcinogenicity study, in rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 15 times the maximum recommended daily oral dose in adults, approximately 10 times the maximum recommended daily oral dose in children 6 to 11 years of age and approximately 15 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m² basis). In a 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign hepatic tumors in males at a dietary dose of 16 mg/kg (approximately 6 times the maximum recommended daily oral dose in adults, approximately 4 times the maximum recommended daily oral dose in children 6 to 11 years of age, and approximately 6 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m² basis). No increased incidence of benign tumors was observed at a dietary dose of 4 mg/kg (approximately 2 times the maximum recommended daily oral dose in adults, equivalent to the maximum recommended daily oral dose in children 6 to 11 years of age and approximately 2 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m² basis). The clinical significance of these findings during long-term use of Lfast is not known.

Levocetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte assay, the mouse lymphoma assay, and in vivo micronucleus test in mice.

In a fertility and general reproductive performance study in mice, cetirizine did not impair fertility at an oral dose of 64 mg/kg (approximately 25 times the recommended daily oral dose in adults on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Lfast should be used during pregnancy only if clearly needed.

Teratogenic Effects

In rats and rabbits, levocetirizine was not teratogenic at oral doses approximately 320 and 390, respectively, times the maximum recommended daily oral dose in adults on a mg/m² basis.

Nursing Mothers

No peri-and post-natal animal studies have been conducted with levocetirizine. In mice, cetirizine caused retarded pup weight gain during lactation at an oral dose in dams that was approximately 40 times the maximum recommended daily oral dose in adults on a mg/m² basis. Studies in beagle dogs indicated that approximately 3% of the dose of cetirizine was excreted in milk. Cetirizine has been reported to be excreted in human breast milk. Because levocetirizine is also expected to be excreted in human milk, use of Lfast in nursing mothers is not recommended.

Pediatric Use

The recommended dose of Lfast for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in patients 6 months to 17 years of age is based on extrapolation of efficacy from adults 18 years of age and older.

The recommended dose of Lfast in patients 6 months to 2 years of age for the treatment of the symptoms of perennial allergic rhinitis and 6 months to 11 years of age with chronic idiopathic urticaria is based on cross-study comparisons of the systemic exposure of Lfast in adults and pediatric patients and on the safety profile of Lfast in both adult and pediatric patients at doses equal to or higher than the recommended dose for patients 6 months to 11 years of age.

The safety of Lfast 5 mg once daily was evaluated in 243 pediatric patients 6 to 12 years of age in two placebo-controlled clinical trials lasting 4 and 6 weeks. The safety of Lfast 1.25 mg twice daily was evaluated in one 2-week clinical trial in 114 pediatric patients 1 to 5 years of age and the safety of Lfast 1.25 mg once daily was evaluated in one 2-week clinical trial in 45 pediatric patients 6 to 11 months of age.

The effectiveness of Lfast 1.25 mg once daily (6 months to 5 years of age) and 2.5 mg once daily (6 to 11 years of age) for the treatment of the symptoms of perennial allergic rhinitis and chronic idiopathic urticaria is supported by the extrapolation of demonstrated efficacy of Lfast 5 mg once daily in patients 12 years of age and older based on the pharmacokinetic comparison between adults and children.

Cross-study comparisons indicate that administration of a 5 mg dose of Lfast to 6 to 12 year old pediatric patients resulted in about 2-fold the systemic exposure (AUC) observed when 5 mg of Lfast was administered to healthy adults. Therefore, in children 6 to 11 years of age the recommended dose of 2.5 mg once daily should not be exceeded. In a population pharmacokinetics study the administration of 1.25 mg once daily in children 6 months to 5 years of age resulted in systemic exposure comparable to 5 mg once daily in adults..

Geriatric Use

Clinical studies of Lfast for each approved indication did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Renal Impairment

Lfast is known to be substantially excreted by the kidneys and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.

Hepatic Impairment

As levocetirizine is mainly excreted unchanged by the kidneys, it is unlikely that the clearance of levocetirizine is significantly decreased in patients with solely hepatic impairment.

Use of Lfast has been associated with somnolence, fatigue, asthenia, and urinary retention.

Clinical Trials Experience

The safety data described below reflect exposure to Lfast in 2708 patients with allergic rhinitis or chronic idiopathic urticaria in 14 controlled clinical trials of 1 week to 6 months duration.

The short-term (exposure up to 6 weeks) safety data for adults and adolescents are based upon eight clinical trials in which 1896 patients (825 males and 1071 females aged 12 years and older) were treated with Lfast 2.5, 5, or 10 mg once daily in the evening.

The short-term safety data from pediatric patients are based upon two clinical trials in which 243 children with allergic rhinitis (162 males and 81 females 6 to 12 years of age) were treated with Lfast 5 mg once daily for 4 to 6 weeks, one clinical trial in which 114 children (65 males and 49 females 1 to 5 years of age) with allergic rhinitis or chronic idiopathic urticaria were treated with Lfast 1.25 mg twice daily for 2 weeks, and one clinical trial in which 45 children (28 males and 17 females 6 to 11 months of age) with symptoms of allergic rhinitis or chronic urticaria were treated with Lfast 1.25 mg once daily for 2 weeks.

The long-term (exposure of 4 or 6 months) safety data in adults and adolescents are based upon two clinical trials in which 428 patients (190 males and 238 females) with allergic rhinitis were exposed to treatment with Lfast 5 mg once daily. Long term safety data are also available from an 18-month trial in 255 Lfast-treated subjects 12-24 months of age.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

Adults And Adolescents 12 Years Of Age And Older

In studies up to 6 weeks in duration, the mean age of the adult and adolescent patients was 32 years, 44% of the patients were men and 56% were women, and the large majority (more than 90%) was Caucasian.

In these trials 43% and 42% of the subjects in the Lfast 2.5 mg and 5 mg groups, respectively, had at least one adverse event compared to 43% in the placebo group.

In placebo-controlled trials of 1-6 weeks in duration, the most common adverse reactions were somnolence, nasopharyngitis, fatigue, dry mouth, and pharyngitis, and most were mild to moderate in intensity. Somnolence with Lfast showed dose ordering between tested doses of 2.5, 5 and 10 mg and was the most common adverse reaction leading to discontinuation (0.5%).

Table 1 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 12 years and older exposed to Lfast 2.5 mg or 5 mg in eight placebo-controlled clinical trials and that were more common with Lfast than placebo.

Table 1 Adverse Reactions Reported in ≥ 2%* of Subjects Aged 12 Years and Older Exposed to Lfast 2.5 mg or 5 mg Once Daily in Placebo-Controlled Clinical Trials 1-6 Weeks in Duration

Additional adverse reactions of medical significance observed at a higher incidence than in placebo in adults and adolescents aged 12 years and older exposed to Lfast are syncope (0.2%) and weight increased (0.5%).

Pediatric Patients 6 To 12 Years Of Age

A total of 243 pediatric patients 6 to 12 years of age received Lfast 5 mg once daily in two short-term placebo controlled double-blind trials. The mean age of the patients was 9.8 years, 79 (32%) were 6 to 8 years of age, and 50% were Caucasian. Table 2 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 6 to 12 years exposed to Lfast 5 mg in placebo-controlled clinical trials and that were more common with Lfast than placebo.

Table 2 Adverse Reactions Reported in ≥2%* of Subjects Aged 6-12 Years Exposed to Lfast 5 mg Once Daily in Placebo-Controlled Clinical Trials 4 and 6 Weeks in Duration

Pediatric Patients 1 To 5 Years Of Age

A total of 114 pediatric patients 1 to 5 years of age received Lfast 1.25 mg twice daily in a two week placebo-controlled double-blind safety trial. The mean age of the patients was 3.8 years, 32% were 1 to 2 years of age, 71% were Caucasian and 18% were Black. Table 3 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 1 to 5 years exposed to Lfast 1.25 mg twice daily in the placebo-controlled safety trial and that were more common with Lfast than placebo.

Table 3 Adverse Reactions Reported in ≥2%* of Subjects Aged 1-5 Years Exposed to Lfast 1.25 mg Twice Daily in a 2-Week Placebo-Controlled Clinical Trial

Pediatric Patients 6 To 11 Months Of Age

A total of 45 pediatric patients 6 to 11 months of age received Lfast 1.25 mg once daily in a two week placebo-controlled double-blind safety trial. The mean age of the patients was 9 months, 51% were Caucasian and 31% were Black. Adverse reactions that were reported in more than 1 subject (i.e. greater than or equal to 3% of subjects) aged 6 to 11 months exposed to Lfast 1.25 mg once daily in the placebo-controlled safety trial and that were more common with Lfast than placebo included diarrhea and constipation which were reported in 6 (13%) and 1 (4%) and 3 (7%) and 1 (4%) children in the Lfast and placebo-treated groups, respectively.

Long-Term Clinical Trials Experience

In two controlled clinical trials, 428 patients (190 males and 238 females) aged 12 years and older were treated with Lfast 5 mg once daily for 4 or 6 months. The patient characteristics and the safety profile were similar to that seen in the short-term studies. Ten (2.3%) patients treated with Lfast discontinued because of somnolence, fatigue or asthenia compared to 2 (<1%) in the placebo group.

There are no long term clinical trials in children below 12 years of age with allergic rhinitis or chronic idiopathic urticaria.

Laboratory Test Abnormalities

Elevations of blood bilirubin and transaminases were reported in <1% of patients in the clinical trials. The elevations were transient and did not lead to discontinuation in any patient.

Post-Marketing Experience

In addition to the adverse reactions reported during clinical trials and listed above, the following adverse reactions have also been identified during post-approval use of Lfast. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Cardiac disorders: palpitations, tachycardia
• Ear and labyrinth disorders: vertigo
• Eye disorders: blurred vision, visual disturbances
• Gastrointestinal disorders: nausea, vomiting
• General disorders and administration site conditions: edema
• Hepatobiliary disorders: hepatitis
• Immune system disorders: anaphylaxis and hypersensitivity
• Metabolism and nutrition disorders: increased appetite
• Musculoskeletal, connective tissues, and bone disorders: arthralgia, myalgia
• Nervous system disorders: dizziness, dysgeusia, febrile seizure, movement disorders (including dystonia and oculogyric crisis), paraesthesia, seizure (reported in subjects with and without a known seizure disorder), tremor
• Psychiatric disorders: aggression and agitation, depression, hallucinations, insomnia, nightmare, suicidal ideation
• Renal and urinary disorders: dysuria, urinary retention
• Respiratory, thoracic, and mediastinal disorders: dyspnea
• Skin and subcutaneous tissue disorders: angioedema, fixed drug eruption, pruritus, rash and urticaria

Besides these reactions reported under treatment with Lfast, other potentially severe adverse events have been reported from the post-marketing experience with cetirizine. Since levocetirizine is the principal pharmacologically active component of cetirizine, one should take into account the fact that the following adverse events could also potentially occur under treatment with Lfast.

• Cardiac disorders: severe hypotension
• Gastrointestinal disorders: cholestasis
• Nervous system disorders: extrapyramidal symptoms, myoclonus, orofacial dyskinesia, tic
• Pregnancy, puerperium and perinatal conditions: stillbirth
• Renal and urinary disorders: glomerulonephritis
• Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis (AGEP)

Lfastで過剰摂取が報告されています。.

過剰摂取の症状には、成人の眠気が含まれる場合があります。. 子供では、興奮と落ち着きのなさが最初に起こり、その後眠気が続くことがあります。. Lfastに対する既知の特定の解毒剤はありません。. 過剰摂取が発生した場合は、対症療法または支持療法が推奨されます。. Lfastは透析によって効果的に除去されず、透析可能な薬剤が同時に摂取されない限り、透析は効果がありません。.

レボセチリジンの急性最大非致死経口投与量は、マウスで240 mg / kgでした。 (成人の最大推奨経口投与量の約190倍。, 6〜11歳の子供における最大推奨経口投与量の約230倍。, mg / mで6か月から5歳の子供における最大推奨経口投与量の約180倍。² 基礎)。. ラットでは、最大の非致死的経口投与量は240 mg / kgでした。 (成人の最大推奨経口投与量の約390倍。, 6〜11歳の子供における最大推奨経口投与量の約460倍。, mg / mで6か月から5歳の子供における最大推奨経口投与量の約370倍。² 基礎)。.

成人の健康な被験者を対象とした研究では、2.5 mgおよび5 mgの用量のレボセチリジンが、ヒスタミンの皮内注射によって引き起こされる皮膚の膨疹とフレアを阻害することが示されました。. 対照的に、デキストロセチリジンは、膨疹およびフレア反応の阻害に明確な変化を示さなかった。. 5 mgの用量のレボセチリジンは、14人の小児被験者(6〜11歳)でのヒスタミンの皮内注射によって引き起こされる膨疹とフレアを阻害し、その活動は少なくとも24時間持続しました。. ヒスタミン ⁇ 頭皮膚検査の臨床的関連性は不明です。.

30 mgのレボセチリジンの単回投与を使用したQT / QTc研究では、QTc間隔への影響は示されませんでした。. レボセチリジンの単回投与は効果がなかったが、レボセチリジンの効果は単回投与後の定常状態ではない可能性がある。. 複数回投与後のQTc間隔に対するレボセチリジンの効果は不明です。. レボセチリジンは、セチリジンを用いたQTc研究の結果と、QT延長の報告のないセチリジンの市販後の長い歴史のため、QT / QTc効果があるとは予想されていません。.

レボセチリジンは、成人の健康な被験者の治療用量範囲にわたって線形の薬物動態を示しました。.

吸収。

レボセチリジンは経口投与後に急速かつ広範囲に吸収されます。. 成人では、経口錠剤の投与後0.9時間でピーク血漿濃度が達成されます。. 毎日の経口投与後の蓄積率は1.12で、2日後に定常状態が達成されます。. ピーク濃度は通常、1日1回投与で1回5 mgを繰り返し投与した後、それぞれ270 ng / mLおよび308 ng / mLです。. 食品はレボセチリジン錠剤の曝露範囲(AUC)に影響を与えませんでしたが、Tmaxは約1.25時間遅れ、Cmaxは高脂肪食による投与後に約36%減少しました。したがって、レボセチリジンは食事の有無にかかわらず投与できます。.

5 mg(10 mL)のLfast経口溶液の用量は、5 mgのLfast錠剤の用量と生物学的に同等です。. 健康な成人被験者に5 mg用量のLfast経口溶液を経口投与した後、平均ピーク血漿濃度は投与後約0.5時間で達成されました。.

分布。

レボセチリジンの平均血漿タンパク質結合。 in vitro。 観察された治療血漿レベルを含む90-5000 ng / mLの範囲の濃度に関係なく、91〜92%の範囲でした。. 経口投与後の分布の平均見かけの体積は約0.4 L / kgであり、全身水での分布を表しています。.

代謝。

ヒトにおけるレボセチリジンの代謝の程度は用量の14%未満であり、したがって、遺伝的多型または肝薬物代謝酵素阻害剤の併用摂取に起因する違いは無視できると予想されます。. 代謝経路には、 ⁇ 香族酸化、N-およびO-脱アルキル化、およびタウリン抱合が含まれます。. 脱アルキル化経路は主にCYP 3A4によって媒介されますが、 ⁇ 香族酸化には複数の、および/または未確認のCYPアイソフォームが含まれます。.

除去。

成人の健康な被験者の血漿半減期は、経口錠剤と経口溶液の投与後約8〜9時間であり、レボセチリジンの平均経口全身クリアランスは約0.63 mL / kg / minでした。. レボセチリジンとその代謝産物の主要な排 ⁇ 経路は尿を経由し、平均用量の85.4%を占めます。. ⁇ 便による排 ⁇ は、用量の12.9%にすぎません。. レボセチリジンは、糸球体 ⁇ 過と活発な尿細管分 ⁇ の両方によって排 ⁇ されます。. レボセチリジンの腎クリアランスは、クレアチニンクリアランスの腎クリアランスと相関しています。. 腎障害のある患者では、レボセチリジンのクリアランスが低下します。.