Stability of nivolumab in its original vials after opening and handing in normal saline bag for intravenous infusion

Guyader, Guillaume Le; Vieillard, Victoire; Mouraud, S.; Do, Bernard; Marabelle, Aurélien; Paul, Muriel

doi:10.1016/j.ejca.2020.04.042

Cited by 18 publications

(13 citation statements)

References 27 publications

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“…Considering the stability of nivolumab, our desensitization dilutions were never under 2 mg/mL. 11 Among the previous case reports published about HSR to nivolumab, only two of them reported a successful management through desensitization 4,12 including IgE mediated reactions and CRR, respectively. However, the concentration of the dilutions was lower than ours.…”

Section: Discussionmentioning

confidence: 95%

Refractory cytokine release reaction to Nivolumab: Following desensitization algorithms to optimize the management of drug hypersensitivity

Togneri

Durán

Fernández

et al. 2021

J Oncol Pharm Pract

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Introduction Nivolumab is a fully human IgG4 monoclonal antibody (moAb) against programmed cell death protein 1, approved for the treatment of over ten types of cancer. The use of this and other moAbs has augmented considerably in recent years and this in turn has caused an increase of hypersensitivity reactions (HSR). Case report We present the case of a patient with metastatic renal cell cancer (RCC) who developed a grade 3 cytokine release reaction (CRR) to nivolumab. The maintenance of the symptoms despite of the administration of symptomatic treatment and slowing down the infusion rate of nivolumab during the 1st and 2nd reaction required an allergy evaluation of our patient. Management and outcome Skin testing to Nivolumab with negative results and baseline tryptase within the normal range were observed during the allergy workout. A desensitization protocol with specific premedication was applied to reintroduce the moAb, with no further issues. Moreover, a follow up of the patient in the oncology setting was done showing disease stabilization. Discussion The CRR should be treated by desensitization, in contrast to infusion reactions. The diagnosis of CRR phenotype is based on the clinical presentation and recently, and elevation of IL-6 levels has been shown to be a useful biomarker along with negative skin testing. We can conclude that after a HSR and an appropriate allergy diagnosis of CRR, nivolumab can be safely reintroduced by desensitization without reducing the target dose or the appropriate dilution concentration.

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Section: Discussionmentioning

confidence: 95%

Refractory cytokine release reaction to Nivolumab: Following desensitization algorithms to optimize the management of drug hypersensitivity

Togneri

Durán

Fernández

et al. 2021

J Oncol Pharm Pract

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“…Now, with data suggesting the stability of the compound even after opening the vial for 1 month, drug vial optimization is possible in routine use. 30,31 The dose of 20 mg once every 3 weeks was selected as laboratory data, which suggested that 0.3 mg/kg once every 3 weeks might be effective, [15][16][17] the average weight of a patient with HNSCC in palliative settings in our country is usually below 60 kg, and even with 60 kg, the calculated dose was 18 mg once every 3 weeks. Hence, for logistic issues of division of vial, the dose of 20 mg once every 3 weeks was selected.…”

Section: Discussionmentioning

confidence: 99%

Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study

Patil

Noronha

Menon

et al. 2023

JCO

108

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PURPOSE The regimens approved for the treatment of advanced head and neck squamous cell carcinoma are accessible to only 1%-3% of patients in low- and middle-income countries because of their cost. In our previous study, metronomic chemotherapy improved survival in this setting. Retrospective data suggest that a low dose of nivolumab may be efficacious. Hence, we aimed to assess whether the addition of low-dose nivolumab to triple metronomic chemotherapy (TMC) improved overall survival (OS). METHODS This was a randomized phase III superiority study. Adult patients with recurrent or newly diagnosed advanced head and neck squamous cell carcinoma being treated with palliative intent with an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Patients were randomly assigned 1:1 to TMC consisting of oral methotrexate 9 mg/m2 once a week, celecoxib 200 mg twice daily, and erlotinib 150 mg once daily, or TMC with intravenous nivolumab (TMC-I) 20 mg flat dose once every 3 weeks. The primary end point was 1-year OS. RESULTS One hundred fifty-one patients were randomly assigned, 75 in TMC and 76 in the TMC-I arm. The addition of low-dose nivolumab led to an improvement in the 1-year OS from 16.3% (95% CI, 8.0 to 27.4) to 43.4% (95% CI, 30.8 to 55.3; hazard ratio, 0.545; 95% CI, 0.362 to 0.820; P = .0036). The median OS in TMC and TMC-I arms was 6.7 months (95% CI, 5.8 to 8.1) and 10.1 months (95% CI, 7.4 to 12.6), respectively ( P = .0052). The rate of grade 3 and above adverse events was 50% and 46.1% in TMC and TMC-I arms, respectively ( P = .744). CONCLUSION To our knowledge, this is the first-ever randomized study to demonstrate that the addition of low-dose nivolumab to metronomic chemotherapy improved OS and is an alternative standard of care for those who cannot access full-dose checkpoint inhibitors.

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“…The physicochemical stability of cetuximab was estimated using previously published methods that have been validated as stability indicators for antibodies [4][5][6][7][8][9][10][11][12][13] and include: estimation of deamidation of asparagine residues and changes of charge by gradient IC; estimation of cleavage of disulfide bridges (fragmentation) by SEC; estimation of thermal stability curve (measurement of aggregation and determination of melting point) by DLS; turbidity assessments at 350 nm and aggregation index calculation (abs. ratio: λ 350 /[ λ 279 − λ 350 ]); measurement of the optical density (OD) at 279 nm for calculation of the protein concentration; determination of tertiary structure integrity and tryptophan-type aromatic residues modification; derivative UV spectrophotometry and fluorescence spectroscopy; estimation of high molecular weight aggregates (dimers and low-order polymers) by SEC; estimation of submicron aggregates by DLS; sterility tests (bacteria, fungi, and yeasts) performed on samples at D90 in conformity with monograph 2.6.1 of the European Pharmacopoeia (10th edition) 3 ; and study of colligative parameters of density (U-tube method), pH, and osmolality.…”

Section: Assessmentsmentioning

confidence: 99%

Extended physicochemical stability of cetuximab in opened vials and infusion bags when stored at 4°C and 25°C

Vieillard

Guyader

Jallades

et al. 2023

J Oncol Pharm Pract

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Introduction This study aimed to determine the stability of cetuximab: (1) under “in-use” conditions after dilution to 1 mg/mL in 0.9% sodium chloride in polyolefin bags and (2) as an undiluted solution (5 mg/mL) repackaged in polypropylene bags or kept in the vial after opening. Methods Ready-to-use 500 mg/100 mL vials of cetuximab solution were diluted to 1 mg/mL in 100 mL bags of 0.9% sodium chloride or repackaged as a 5 mg/mL solution into empty 100 mL bags. Bags and vials were stored at 4°C for 90 days and 25°C for 3 days. A syringe sample of 7 mL was taken from each bag for the initial determinations. The sampled bags were weighed to determine their initial weight and placed under the planned storage conditions. The physicochemical stability of cetuximab was estimated using validated methods. Results No changes in turbidity, no protein loss, and no changes in cetuximab tertiary structure were observed after 30 days of storage or when subjected to a temperature excursion of 3 days at 25°C and when stored at 4°C for up to 90 days, regardless of the concentrations and batches. The colligative parameters did not change under any of the tested conditions. No evidence of microbial growth was found in bags after 90 days of storage at 4°C. Conclusion These results support the extended in-use shelf-life of cetuximab vials and bags, which can be cost-effective for healthcare providers.

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Stability of nivolumab in its original vials after opening and handing in normal saline bag for intravenous infusion

Cited by 18 publications

References 27 publications

Refractory cytokine release reaction to Nivolumab: Following desensitization algorithms to optimize the management of drug hypersensitivity

Refractory cytokine release reaction to Nivolumab: Following desensitization algorithms to optimize the management of drug hypersensitivity

Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study

Extended physicochemical stability of cetuximab in opened vials and infusion bags when stored at 4°C and 25°C

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