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CINQAIR(reslizumab)injection, for intravenous
CINQAIR(reslizumab)injection获FDA批准治疗严重哮喘
美国FDA日前批准Cinqair（reslizumab）与其它哮喘药物联合用于18岁及以上年龄严重哮喘患者维持治疗。Cinqair获批用于使用现有哮喘药物后仍有严重哮喘发作史的患者。
哮喘是一种慢性疾病，它可引起肺部呼吸道炎症。哮喘发作期间，呼吸道变窄使得呼吸困难。严重哮喘发作可导致哮喘相关住院，因为这些发作可以是严重的，甚至是危及生命的。据美国疾病控制与预防中心提供的信息，自2013年起，美国逾2200人有哮喘，每年的哮喘相关住院病例超过40万。
当这种疾病通过目前哮喘治疗药物不能很好地控制时，医疗保健供应商及他们的严重哮喘患者现在有了另一种治疗选择可以考虑，FDA药物评价与研究中心肺病、过敏及风湿病产品部门主任、医学博士、哲学博士 Chowdhury称。
Cinqair 由医疗保健专业人员经静脉输注使用，每四周用药一次，临床使用时要做好过敏症管理准备。Cinqair是一种人源化白介素-5拮抗剂单克隆抗体，在小鼠骨髓瘤非分泌0（NS0）细胞中通过重组DNA技术产生。Cinqair通过降低血液嗜酸性粒细胞水平而减少严重哮喘发作，嗜酸性粒细胞是一种白细胞，它有助于哮喘的发生。
Cinqair的安全性及有效性基于四项双盲、随机、安慰剂对照试验，受试者为使用现有可供使用治疗药物的严重哮喘患者。患者每四周一次接受Cinqair或安慰剂作为哮喘一种辅助治疗。与安慰剂相比，接受Cinqair治疗的严重哮喘患者有更少的哮喘发作，并且发生首次发作需要的时间更长。此外，Cinqair治疗导致肺功能显著改善，这一指标以1秒钟内患者呼出气体的体积来衡量。
Cinqair可导致严重副作用，包括过敏（过敏症）反应。这些反应可以是致命的。临床试验中，Cinqair-的最常见副作用包括过敏、癌症及肌肉疼痛。Cinqair 由宾夕法尼亚州弗雷泽的梯瓦制药制造。
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CINQAIR safely and effectively. See full prescribing information for CINQAIR.
CINQAIR ® (reslizumab) injection, for intravenous use
Initial U.S. Approval: 2016
WARNING: ANAPHYLAXIS
See full prescribing information for complete boxed warning.
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Anaphylaxis occurred with CINQAIR infusion in 0.3% of patients in placebo-controlled studies (5.1)
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Patients should be observed for an appropriate period of time after CINQAIR infusion; healthcare professionals should be prepared to manage anaphylaxis that can be life-threatening (5.1)
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Discontinue CINQAIR immediately if the patient experiences anaphylaxis (5.1)
INDICATIONS AND USAGE
CINQAIR is an interleukin-5 antagonist monoclonal antibody (IgG4 kappa) indicated for add-on maintenance treatment of patients with severe asthma aged 18 years and older, and with an eosinophilic phenotype (1).
Limitations of Use: CINQAIR is not indicated for:
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treatment of other eosinophilic conditions ( 1)
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relief of acute bronchospasm or status asthmaticus ( 1)
DOSAGE AND ADMINISTRATION
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CINQAIR is for intravenous infusion only. Do not administer as an intravenous push or bolus ( 2.1)
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CINQAIR should be administered in a healthcare setting by a healthcare professional prepared to manage anaphylaxis ( 2.2)
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Recommended dosage regimen is 3 mg/kg once every 4 weeks by intravenous infusion over 20-50 minutes ( 2.1)
DOSAGE FORMS AND STRENGTHS
Injection: 100 mg/10 mL (10 mg/mL) solution in single-use vials (3)
CONTRAINDICATIONS
Known hypersensitivity to reslizumab or any of its excipients (4)
WARNINGS AND PRECAUTIONS
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Malignancy: Malignancies were observed in clinical studies. ( 5.3)
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Reduction in Corticosteroid Dosage: Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with CINQAIR. Decrease corticosteroids gradually, if appropriate. ( 5.4)
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Parasitic (Helminth) Infection: Treat patients with pre-existing helminth infections before therapy with CINQAIR. If patients become infected while receiving CINQAIR and do not respond to anti-helminth treatment, discontinue CINQAIR until the parasitic infection resolves. ( 5.5)
ADVERSE REACTIONS
The most common adverse reaction (incidence greater than or equal to 2%) includes oropharyngeal pain. (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 4/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
CINQAIR® is indicated for the add-on maintenance treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype [see Clinical Studies (14)].
Limitation of Use:
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CINQAIR is not indicated for treatment of other eosinophilic conditions.
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CINQAIR is not indicated for the relief of acute bronchospasm or status asthmaticus [see Warnings and Precautions (5.2)].
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
CINQAIR is for intravenous infusion only. Do not administer as an intravenous push or bolus.
The recommended dosage regimen is 3 mg/kg once every 4 weeks administered by intravenous infusion over 20-50 minutes [see Dosage and Administration (2.2)].
Discontinue the infusion immediately if the patient experiences a severe systemic reaction, including anaphylaxis [see Contraindications (4), Warnings and Precautions (5.1)].
2.2 Preparation and Administration Instructions
CINQAIR is provided as a solution in a single-use vial for intravenous infusion only and should be prepared by a healthcare professional using aseptic technique as follows:
Preparation of intravenous infusion
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Remove CINQAIR from the refrigerator. To minimize foaming, do not shake CINQAIR.
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Inspect visually for particulate matter and discoloration prior to administration. CINQAIR solution is clear to slightly hazy/opalescent, colorless to slightly yellow liquid. Since CINQAIR is a protein, proteinaceous particles may be present in the solution that appear as translucent to white, amorphous particulates. Do not administer if discolored or if other foreign particulate matter is present.
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Withdraw the proper volume of CINQAIR from the vial(s), based on the recommended weight-based dosage. Discard any unused portion.
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Dispense syringe contents slowly into an infusion bag containing 50 mL of 0.9% Sodium Chloride Injection, USP to minimize foaming of CINQAIR (CINQAIR is compatible with polyvinylchloride (PVC) or polyolefin infusion bags). Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other drugs.
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Administer immediately after preparation. If not used immediately, store diluted solutions of CINQAIR in the refrigerator at 2°C to 8°C (36°F to 46°F) or at room temperature up to 25ºC (77ºF), protected from light, for up to 16 hours. The time between preparation of CINQAIR and administration should not exceed 16 hours.
Administration instructions
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CINQAIR should be administered in a healthcare setting by a healthcare professional prepared to manage anaphylaxis [see Warnings and Precautions (5.1)].
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If refrigerated prior to administration, allow the diluted CINQAIR solution to reach room temperature.
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Use an infusion set with an in-line, low protein-binding filter (pore size of 0.2 micron). CINQAIR is compatible with polyethersulfone (PES), polyvinylidene fluoride (PVDF), nylon, and cellulose acetate in-line infusion filters.
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Infuse the diluted solution of CINQAIR intravenously, over a 20–50 minute period. Infusion time may vary depending on the total volume to be infused as based upon patient weight.
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Do not infuse CINQAIR concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to eva luate the co-administration of CINQAIR with other agents.
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Observe the patient over the infusion and for an appropriate period of time following infusion.
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Upon completion of the infusion, flush the intravenous administration set with 0.9% Sodium Chloride Injection, USP to ensure that all CINQAIR has been administered.
3 DOSAGE FORMS AND STRENGTHS
Injection: 100 mg/10 mL (10 mg/mL), clear to slightly hazy/opalescent, colorless to slightly yellow solution in single-use vials.
4 CONTRAINDICATIONS
CINQAIR is contraindicated in patients who have known hypersensitivity to reslizumab or any of its excipients [see Warnings and Precautions (5.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylaxis
Anaphylaxis to CINQAIR was reported in 0.3% of asthma patients in placebo-controlled clinical studies [see Adverse Reactions (6.1)]. These events were observed during or within 20 minutes after completion of the CINQAIR infusion and reported as early as the second dose of CINQAIR. Manifestations included dyspnea, decreased oxygen saturation, wheezing, vomiting, and skin and mucosal involvement, including urticaria. In all 3 cases, CINQAIR was discontinued.
Anaphylaxis can be life-threatening. CINQAIR should be administered in a healthcare setting by a healthcare professional prepared to manage anaphylaxis. Patients should be observed for an appropriate period of time after CINQAIR administration. If severe systemic reactions, including anaphylaxis, occur, stop administration of CINQAIR immediately and provide appropriate medical treatment. Prior to discharge, inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care if symptoms occur. Discontinue CINQAIR use permanently if the patient experiences signs or symptoms of anaphylaxis [see Contraindications (4)].
5.2 Acute Asthma Symptoms or Deteriorating Disease
CINQAIR should not be used to treat acute asthma symptoms or acute exacerbations. Do not use CINQAIR to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with CINQAIR.
5.3 Malignancy
In placebo-controlled clinical studies, 6/1028 (0.6%) patients receiving 3 mg/kg CINQAIR had at least 1 malignant neoplasm reported compared to 2/730 (0.3%) patients in the placebo group. The observed malignancies in CINQAIR-treated patients were diverse in nature and without clustering of any particular tissue type. The majority of malignancies were diagnosed within less than six months of exposure to CINQAIR.
5.4 Reduction of Corticosteroid Dosage
No clinical studies have been conducted to assess reduction of maintenance corticosteroid dosages following administration of CINQAIR. Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with CINQAIR. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.
5.5 Parasitic (Helminth) Infection
Eosinophils may be involved in the immunological response to some helminth infections. Patients with known parasitic infections were excluded from participation in clinical studies. It is unknown if CINQAIR will influence the immune response against parasitic infections. Treat patients with pre-existing helminth infections before initiating CINQAIR. If patients become infected while receiving treatment with CINQAIR and do not respond to anti-helminth treatment, discontinue treatment with CINQAIR until infection resolves.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in other sections of the labeling:
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Anaphylaxis [see Warnings and Precautions (5.1)]
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Malignancy [see Warnings and Precautions (5.3)]
6.1 Clinical Trials Experience
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 trials of another drug and may not reflect the rates observed in clinical practice.
Overall, 2195 subjects received at least 1 dose of CINQAIR. The data described below reflect exposure to CINQAIR in 1611 patients with asthma, including 1120 exposed for up to 16 weeks, 1006 exposed for 6 months, 759 exposed for 1 year, and 249 exposed for longer than 2 years. The above referenced safety exposure for CINQAIR is derived from placebo-controlled studies ranging from 15 to 52 weeks in duration (CINQAIR 0.3 mg/kg and 3 mg/kg [n=1131] and placebo [n=730]) and 480 new CINQAIR 3 mg/kg exposures (previously on placebo) from a single open-label extension study (n=1051). While a lower dose of CINQAIR 0.3 mg/kg (n=103) was included in a clinical trial, 3 mg/kg is the only recommended dose [see Dosage and Administration (2.1)]. Of the 1611 patients, 1596 received the 3 mg/kg dose, 1028 of which were in the placebo-controlled studies. In the placebo-controlled asthma studies, the population studied was 12 to 76 years of age, 62% female, and 73% white. While subjects aged 12 to 17 years were included in these trials, CINQAIR is not approved for use in this age group [see Use in Specific Populations (8.4)].
Serious adverse reactions that occurred in placebo-controlled studies in more than 1 subject and in a greater percentage of subjects treated with CINQAIR (n=1131) than placebo (n=730) included anaphylaxis (3 subjects vs. 0 subjects, respectively). The 3 subjects who experienced anaphylaxis were discontinued from the clinical studies [see Warnings and Precautions (5.1)]. Malignancy also occurred more commonly in patients treated with CINQAIR than placebo (0.6% and 0.3%, respectively) [see Warnings and Precautions (5.3)].
Adverse reactions that occurred at greater than or equal to 2% incidence and more commonly than in the placebo group included 1 event: oropharyngeal pain (2.6% vs. 2.2%).
CPK elevations and muscle-related adverse reactions
Elevated baseline creatine phosphokinase (CPK) was more frequent in patients randomized to CINQAIR (14%) versus placebo (9%). Transient CPK elevations in patients with normal baseline CPK values were observed more frequently with CINQAIR (20%) versus placebo (18%) during routine laboratory assessments. CPK elevations >10 x ULN, regardless of baseline CPK value, were 0.8% in the CINQAIR group compared to 0.4% in the placebo group. CPK elevations >10 x ULN were asymptomatic and did not lead to treatment discontinuation.
Myalgia was reported in 1% (10/1028) of patients in the CINQAIR 3 mg/kg group compared to 0.5% (4/730) of patients in the placebo group. On the day of infusion, musculoskeletal adverse reactions were reported in 2.2% and 1.5% of patients treated with CINQAIR 3 mg/kg and placebo, respectively. These reactions included (but were not limited to) musculoskeletal chest pain, neck pain, muscle spasms, extremity pain, muscle fatigue, and musculoskeletal pain.
6.2 Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. In placebo-controlled studies, a treatment-emergent anti-reslizumab antibody response developed in 53/983 (5.4%) of CINQAIR-treated patients (3 mg/kg). In the long-term, open-label study, treatment-emergent anti-reslizumab antibodies were detected in 49/1014 (4.8%) of CINQAIR-treated (3 mg/kg) asthma patients over 36 months. The antibody responses were of low titer and often transient. Neutralizing antibodies and product-specific IgE antibodies were not eva luated. There was no detectable impact of the antibodies on the clinical pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of CINQAIR [see Clinical Pharmacology (12.2)].
The data reflect the percentage of patients whose test results were positive for antibodies to reslizumab in specific assays. The observed incidence of antibody response is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to reslizumab with the incidence of antibodies to other products may be misleading.
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