Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 27 February 2017

Indication(s)

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: •CINQAIR is not indicated for treatment of other eosinophilic conditions.

•CINQAIR is not indicated for the relief of acute bronchospasm or status asthmaticus [see Warnings and Precautions (5.2)].

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: •treatment of other eosinophilic conditions (1) •relief of acute bronchospasm or status asthmaticus (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS CINQAIR is contraindicated in patients who have known hypersensitivity to reslizumab or any of its excipients [see Warnings and Precautions (5.1)]. Known hypersensitivity to reslizumab or any of its excipients (4)
Adverse reactions

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: •Anaphylaxis [see Warnings and Precautions (5.1)] •Malignancy [see Warnings and Precautions (5.3)] 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.

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 can not 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 evaluated.

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.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION •CINQAIR is for intravenous infusion only.

Do not administer as an intravenous push or bolus (2.1) •CINQAIR should be administered in a healthcare setting by a healthcare professional prepared to manage anaphylaxis (2.2) •Recommended dosage regimen is 3 mg/kg once every 4 weeks by intravenous infusion over 20-50 minutes (2.1) 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

1. Remove CINQAIR from the refrigerator. To minimize foaming, do not shake CINQAIR. 2. 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. 3. Withdraw the proper volume of CINQAIR from the vial(s), based on the recommended weight-based dosage. Discard any unused portion.

4. 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.

5. 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 25?C (77?F), protected from light, for up to 16 hours. The time between preparation of CINQAIR and administration should not exceed 16 hours. Administration instructions 1. CINQAIR should be administered in a healthcare setting by a healthcare professional prepared to manage anaphylaxis [see Warnings and Precautions (5.1)]. 2. If refrigerated prior to administration, allow the diluted CINQAIR solution to reach room temperature.

3. 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.

4. 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.

5. Do not infuse CINQAIR concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of CINQAIR with other agents. 6. Observe the patient over the infusion and for an appropriate period of time following infusion.

7. 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.

Use in special populations

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The data on pregnancy exposure from the clinical trials are insufficient to inform on drug-associated risk.

Monoclonal antibodies, such as reslizumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential effects on a fetus are likely to be greater during the second and third trimester of pregnancy.

Reslizumab has a long half-life [see Clinical Pharmacology (12.3)].

This should be taken into consideration.

In animal reproduction studies, there was no evidence of embryo-fetal adverse developmental effects with intravenous administration of reslizumab during organogenesis to pregnant mice and rabbits at doses that produced exposures up to approximately 6 times the exposure at the maximum recommended human dose (MRHD) in mice and approximately 17 times the exposure at the MRHD in rabbits [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20 %, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate.

The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.

Data Animal Data In 2 separate embryo-fetal development studies, pregnant mice and rabbits received a single reslizumab dose during the period of organogenesis at 2, 10, and 50 mg/kg (0.4, 1.5, and 6 times the exposures achieved at the MRHD in mice on an AUC basis and 0.67, 3.3, and 17 times the exposures achieved at the MRHD in rabbits on a mg/ kg basis).

Reslizumab was not teratogenic in mice or rabbits.

Embryo-fetal development of interleukin-5 (IL-5) deficient mice has been reported to be generally unaffected relative to wild-type mice.

In a prenatal and postnatal development study, pregnant CD-1 mice received reslizumab during organogenesis on gestation days 6 and 18 and on postnatal day 14 at 10 or 50 mg/kg (1.5 and 6 times the exposures achieved at the MRHD on an AUC basis).

Reslizumab did not have any effects on fetal development up to approximately 4 months after birth.

Reslizumab crossed the placenta of pregnant mice.

Serum concentrations in pups were approximately 6-8 % of those in the dams (parental female mice) on postnatal day 14.

8.2 Lactation Risk Summary It is not known whether reslizumab is present in human milk, and the effects of reslizumab on the breast fed infant and on milk production are not known.

However, human IgG is known to be present in human milk.

Reslizumab was present in the milk of lactating mice following dosing during pregnancy [see Data].

The developmental and health benefits of breastfeeding should be considered along with the mother 's clinical need for CINQAIR and any potential adverse effects on the breast-fed child from CINQAIR or the underlying maternal condition.

Data Reslizumab was excreted in milk of lactating CD-1 mice that received reslizumab at 10 or 50 mg/kg (1.5 and 6 times the exposures achieved at the MRHD on an AUC basis) during pregnancy on gestation days 6 and 18 and on postnatal day 14.

Levels of reslizumab in milk were approximately 5-7 % of maternal serum concentrations.

8.4 Pediatric Use CINQAIR is not indicated for use in pediatric patients less than 18 years of age.

The safety and effectiveness in pediatric patients (aged 17 years and younger) have not been established.

CINQAIR was evaluated in 39 patients aged 12 to less than 18 years with asthma in two 52-week exacerbation studies and one 16-week lung function study.

In the exacerbation studies, patients were required to have at least 1 asthma exacerbation requiring systemic corticosteroid use in the year prior to study entry.

In these studies, the asthma exacerbation rate was higher in adolescent patients treated with CINQAIR than placebo (CINQAIR n= 14, rate 2.86, 95 % CI [1.02 to 8.09] and placebo n= 11, rate 1.37, 95 % CI [0.57 to 3.28]: rate ratio 2.09, 95 % CI [0.82 to 5.36]).

8.5 Geriatric Use CINQAIR was evaluated in 122 patients aged 65 years and older with asthma in two 52-week exacerbation studies and two 16-week lung function studies.

No overall differences in safety or effectiveness were observed between these patients and younger patients.

Based on available data, no adjustment of the dosage of CINQAIR in geriatric patients is necessary.

Interactions

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed with CINQAIR.

More information

Category Value
Authorisation number BLA761033
Agency product number 35A26E427H
Orphan designation No
Product NDC 59310-610
Date Last Revised 09-06-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 1746893
Marketing authorisation holder Teva Respiratory, LLC
Warnings

WARNING:

ANAPHYLAXIS Anaphylaxis has been observed with CINQAIR infusion in 0.3 % of patients in placebo-controlled clinical studies.

Anaphylaxis was reported as early as the second dose of CINQAIR [see Warnings and Precautions (5.1), Adverse Reactions (6)].

Anaphylaxis can be life-threatening.

Patients should be observed for an appropriate period of time after CINQAIR administration by a healthcare professional prepared to manage anaphylaxis.

Discontinue CINQAIR immediately if the patient experiences signs or symptoms of anaphylaxis [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

WARNING:

ANAPHYLAXIS See full prescribing information for complete boxed warning.

• Anaphylaxis occurred with CINQAIR infusion in 0.3 % of patients in placebo-controlled studies (5.1) • 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) Discontinue CINQAIR immediately if the patient experiences anaphylaxis (5.1)