40mL Ipilimumab Injection 200mg Ipilimumab Colorectal Cancer Drugs

【Drug Name】

Generic name: Ipilimumab injection

Trade name: YERVOY®/YERVOY®

English name: Ipilimumab Injection

Chinese Pinyin: Yipimu Dankang Zhusheye

【Indications】

Malignant pleural mesothelioma (MPM)

This product combined with nivolumab is indicated for adult patients with unresectable, treatment-naïve, non-epitheloid malignant pleural mesothelioma.

This indication was granted conditional approval based on analysis of subjects with non-epitheloid malignant pleural mesothelioma in the CheckMate 743 clinical study. Full approval of this indication will depend on subsequent clinical trials to confirm the clinical benefit of this product in the Chinese population (see [Clinical Trials]).

【Dosage】

This product is combined with nivolumab in the treatment of malignant pleural mesothelioma

The recommended dose of this product is 1 mg/kg, once every 6 weeks, as a 30-minute intravenous infusion, combined with 360 mg nivolumab , once every 3 weeks, or combined with 3 mg/kg nivolumab , Intravenous infusion for 30 minutes once every 2 weeks until disease progression or unacceptable toxicity occurs, or until 24 months in patients with no disease progression.

▼Table 1: Recommended doses and infusion times of ipilimumab and nivolumab combination therapy

Indications Recommended dosage and infusion time
malignant pleural mesothelioma Ipilimumab 1 mg/kg, once every 6 weeks, intravenously infused over 30 minutes
Nivolumab

360mg, once every 3 weeks, intravenously infused over 30 minutes or

3 mg/kg, once every 2 weeks, intravenously infused over 30 minutes

Atypical reactions (such as temporary tumor enlargement or the appearance of new small lesions during the first few months, followed by tumor shrinkage) have been observed. For patients who are clinically stable and have preliminary evidence of disease progression, it is recommended to continue treatment with this product in combination with nivolumab until disease progression is confirmed.

Liver function tests (LFTs) and thyroid function tests should be assessed at baseline and before each dose of this product. In addition, any signs or symptoms of immune-related adverse reactions (including diarrhea and colitis) must be evaluated during treatment with this product.

Permanently discontinue ipilimumab therapy or suspend dosing

Management of immune-related adverse reactions may require withholding dosing or permanent discontinuation of ipilimumab therapy and administration of systemic high-dose corticosteroids. In some cases, the addition of additional immunosuppressive therapy may be considered. Dosage increases or decreases are not recommended. Dosing suspension or discontinuation may be necessary based on individual patient safety and tolerability.

Guidelines for permanently discontinuing or suspending treatment with ipilimumab in combination with nivolumab or during the second phase after combination therapy ( nivolumab monotherapy) are described in Table 2 .

Table 2: Recommended treatment modifications for combination therapy with nivolumab or in the second phase after combination therapy ( nivolumab monotherapy)

Immune related adverse reactions severity treatment modification plan
immune related pneumonia grade 2 pneumonia Withhold medication until symptoms resolve, imaging abnormalities improve, and corticosteroid therapy is completed
Grade 3 or 4 pneumonia permanently disabled
immune related colitis Grade 2 diarrhea or colitis Withhold medication until symptoms resolve and corticosteroid therapy (if needed) has ended
Grade 3 or 4 diarrhea or colitis permanently disabled
immune related hepatitis Grade 2 elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin Withhold medication until laboratory values ​​return to baseline and corticosteroid therapy (if needed) has ended
Grade 3 or 4 elevation of AST, ALT, or total bilirubin permanently disabled
Immune-related nephritis and renal dysfunction Grade 2 or 3 creatinine elevation Withhold medication until creatinine returns to baseline and corticosteroid therapy is discontinued
Grade 4 creatinine elevation permanently disabled
immune-related endocrine diseases

Symptomatic grade 2 or 3 hypothyroidism, hyperthyroidism, hypophysitis

Grade 2 adrenal insufficiency

Withhold medication until symptoms resolve and corticosteroid therapy (if needed to address acute inflammatory symptoms) is completed.
stage 3 diabetes When undergoing hormone replacement therapya, treatment should be continued as long as there are no symptoms.

Grade 4 hypothyroidism

Grade 4 hyperthyroidism

Grade 4 hypophysitis

Grade 3 or 4 adrenal insufficiency

stage 4 diabetes

permanently disabled
Immune-related adverse skin reactions Grade 3 rash Withhold medication until symptoms resolve and corticosteroid therapy is completed
Grade 4 rash Permanently discontinue treatment
Stevens Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) permanently disabled
immune-related myocarditis Grade 2 myocarditis Withhold medication until symptoms resolve and corticosteroid therapy is completed
Grade 3 or 4 myocarditis permanently disabled
Other immune-related adverse reactions Level 3 (first occurrence) Suspension of medication

Grade 4 or recurrent grade 3; persistent grade 2 or 3 response despite treatment modification;

Corticosteroid dose cannot be reduced to 10 mg prednisone per day or equivalent

permanently disabled

Note: Toxicity grading was determined in accordance with the National Cancer Institute's Common Terminology Criteria for Assessment of Adverse Events version 4.0 (NCI-CTCAE v4).

a For recommendations on the use of hormone replacement therapy, see [Precautions].

b For patients who have previously experienced immune-related myocarditis, the safety of re-administering this product combined with nivolumab has not been determined.

Combination therapy with this product and nivolumab should be permanently discontinued in the following situations:

Grade 4 or recurrent grade 3 adverse reactions;

Grade 2 or 3 adverse reactions that persist despite treatment modifications.

When this product is co-administered with nivolumab , if either drug is suspended, the other drug should be suspended at the same time. If dosing is restarted after a pause, combination therapy or nivolumab monotherapy should be restarted based on individual patient assessment.

Special groups

Pediatric Population: The safety and efficacy of this product in the pediatric population have not been established.

Geriatric Population: No overall differences in safety or efficacy were reported between elderly patients (≥ 65 years) and younger patients (< 65 years).

Renal Impairment: The safety and efficacy of this product have not been studied in patients with renal impairment. Based on population pharmacokinetic results, no dose adjustment is required in patients with mild to moderate renal impairment.

Hepatic Impairment: The safety and efficacy of ipilimumab have not been studied in patients with hepatic impairment . Based on population pharmacokinetic results, no dose adjustment is required in patients with mild hepatic impairment. This product must be used with caution in patients with baseline transaminase levels ≥5 times ULN or bilirubin levels >3 times ULN.

Dosing method

This product is for intravenous injection only. The recommended infusion time is 30 minutes.

This product can be used for intravenous infusion without dilution, or can be diluted with sodium chloride solution for injection (9 mg/mL, 0.9%) or glucose solution for injection (50 mg/mL, 5%) to a concentration of 1-4 mg/ mL for infusion.

This product should not be administered as an intravenous push or a single rapid intravenous injection.

When used in combination with nivolumab , the nivolumab should be infused first , followed by the infusion of nivolumab on the same day. Use a separate infusion bag and filter for each infusion.

【Adverse reactions】

Malignant pleural mesothelioma (MPM)

In the data set of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg in MPM (n = 300, minimum follow-up 17.4 months), the most common adverse reactions (≥10%) were Rash (25%), fatigue (22%), diarrhea (21%), pruritus (16%), hypothyroidism (11%), and nausea (10%). Most adverse reactions were mild to moderate (1 level or level 2).

▼ This product 1 mg/kg combined with nivolumab 3 mg/kg for the treatment of MPM*

Blood and lymphatic system diseases unknown Hemophagocytic lymphohistiocytosisd
immune system diseases common Infusion-related reactions, hypersensitivity reactions
unknown solid organ transplant rejectiond
endocrine system diseases Very common Hypothyroidism
common Hyperthyroidism, adrenal insufficiency, hypophysitis, hypopituitarism
meet occasionally Thyroiditis
Metabolic and nutritional diseases common decreased appetite
Hepatobiliary system diseases common hepatitis
Various neurological diseases meet occasionally encephalitis
heart disease meet occasionally myocarditis
Respiratory, thoracic and mediastinal diseases common pneumonia
Gastrointestinal system diseases Very common diarrhea, nausea
common Constipation, colitis, pancreatitis
Skin and subcutaneous tissue diseases Very common Rashb , itching
Various musculoskeletal and connective tissue diseases common Musculoskeletal painc , arthritis
meet occasionally Myositis
Kidney and urinary system diseases common acute kidney injury
meet occasionally Renal Failure
Systemic diseases and various reactions at the administration site Very common tired
Various inspectionsa Very common Elevated AST, elevated ALT, elevated alkaline phosphatase, elevated lipase, elevated amylase, elevated creatinine, hyperglycemiac, lymphopenia, anemia, hypercalcemia, hypocalcemia, hyper Potassemia, hypokalemia, hyponatremia, hypomagnesemia
common Elevated total bilirubin, hypoglycemia, leukopenia, neutropeniac, thrombocytopenia, hypernatremia, hypermagnesemia

Laboratory term frequency reflects the proportion of patients whose laboratory test results worsened from baseline. See "Description of Selected Adverse Reactions: Laboratory Abnormalities" below.

Rash is a general term that includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, morbilliform rash, papule, pustular rash, papulosquamous rash, vesicular rash, generalized rash, exfoliative rash, dermatitis , acneiform dermatitis, atopic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriatic dermatitis, drug eruption and pemphigoid.

Musculoskeletal pain is an umbrella term that includes back pain, bone pain, chest musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, extremity pain, and spinal pain.

Immune related gastrointestinal system reactions

This product is associated with severe immune-related gastrointestinal system reactions. Death due to gastrointestinal perforation was reported in <1% of patients treated with ipilimumab 3 mg/kg in combination with gp100.

Diarrhea and colitis (any severity) were reported in 27% and 8% of patients, respectively, in the ipilimumab 3 mg/kg monotherapy group. The incidence of severe (grade 3 or 4) diarrhea and severe (grade 3 or 4) colitis was both 5%. The median time from the start of treatment to the development of severe or fatal (grade 3-5) immune-related gastrointestinal reactions was 8 weeks (range 5-13 weeks). According to protocol management guidelines, the majority of cases (90%) experienced response (defined as reduction to mild [Grade 1] or better or to baseline), with a median time from onset to response of 4 weeks (range 0.6 -22 weeks). In clinical trials, immune-related colitis has been associated with evidence of mucosal inflammation (with or without ulceration) and lymphocyte and neutrophil infiltration.

immune related colitis

The incidence of diarrhea or colitis was 22.0% (66/300) of MPM patients treated with nivolumab 1 mg/kg in combination with nivolumab 3 mg/kg. The incidence of grade 2 and grade 3 events was 7.3% (22/300) and 5.3% (16/300), respectively. Median time to onset was 3.9 months (range: 0.0-21.7). Remission occurred in 62 patients (93.9%) , and the median time to remission was 3.1 weeks (range: 0.1-100.0+).

immune related pneumonia

The incidence of pneumonia, including interstitial lung disease, was 6.7% (20/300) in patients with MPM who received nivolumab 1 mg/kg in combination with nivolumab 3 mg/kg. The incidence of grade 2 and 3 events was 5.3% (16/300) and 0.7% (2/300), respectively. Median time to onset was 1.8 months (range: 0.3-20.8). Sixteen patients (80%) experienced remission, with a median time to remission of 6.1 weeks (range: 1.1-113.1+).

immune-related liver toxicity

This product is associated with severe immune-related liver toxicity. Fatal hepatic failure has been reported in <1% of patients receiving ipilimumab 3 mg/kg monotherapy.

Elevated AST and ALT (any severity) were reported in 1% and 2% of patients, respectively. No severe (grade 3 or 4) AST or ALT elevations were reported. The time from the start of treatment to the onset of moderate to severe or fatal (grade 2-5) immune-related liver toxicity ranged from 3 to 9 weeks. According to protocol-specified management guidelines, the time from onset to resolution ranged from 0.7 to 2 weeks. In clinical trials, liver biopsies from patients with immune-related hepatotoxicity showed evidence of acute inflammation (neutrophils, lymphocytes, and macrophages).

Immune-related hepatotoxicity occurred more frequently in patients who received higher than recommended doses of dacarbazine in combination with dacarbazine than in patients who received dacarbazine at 3 mg/kg as monotherapy.

The incidence of abnormal liver function tests was 12.0% (36/300) of MPM patients treated with nivolumab 1 mg/kg in combination with nivolumab 3 mg/kg. The incidence rates of grade 2, 3, and 4 events were 1.7% (5/300), 4.3% (13/300), and 1.0% (3/300), respectively. Median time to onset was 1.8 months (range: 0.5-20.3). Remission occurred in 31 patients (86.1%), and the median time to remission was 4.1 weeks (range: 1.0-78.3+).

Immune-related adverse skin reactions

This product has been associated with severe cutaneous adverse reactions that may be immune-related. Fatal toxic epidermal necrolysis (including SJS) has been reported in <1% of patients treated with this product in combination with gp100 (see Pharmacology and Toxicology). Drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported very rarely during clinical trials and postmarketing use of ipilimumab . Occasional cases of pemphigoid have been reported during postmarketing use.

Rash and pruritus (of any severity) were reported in 26% of patients in the 3 mg/kg monotherapy group, respectively. Ipilimumab- induced rash and pruritus are mostly mild (Grade 1) or moderate (Grade 2), and symptomatic treatment is effective. The median time from the start of treatment to the development of moderate to severe or fatal (grade 2-5) cutaneous adverse reactions was 3 weeks (range 0.9-16). The majority of cases (87%) achieved response according to protocol management guidelines, with a median time from onset to response of 5 weeks (range 0.6-29 weeks).

The incidence of rash was 36.0% (108/300) of MPM patients treated with nivolumab 1 mg/kg in combination with nivolumab 3 mg/kg. The incidence of grade 2 and 3 events was 10.3% (31/300) and 3.0% (9/300), respectively. Median time to onset was 1.6 months (range: 0.0-22.3). Seventy-one patients (66.4%) experienced remission, and the median time to remission was 12.1 weeks (range: 0.4-146.4+).

immune-related nervous system responses

This product is associated with severe immune-related neurological reactions. Fatal Guillain-Barré syndrome has been reported in <1% of patients receiving 3 mg/kg of this product in combination with gp100. Myasthenia gravis-like symptoms were also reported in <1% of patients receiving high-dose ipilimumab in clinical trials .

Immune-related nephritis and renal dysfunction

Renal insufficiency occurred in 5.0% (15/300) of MPM patients treated with nivolumab 1 mg/kg in combination with nivolumab 3 mg/kg. The incidence of grade 2 and 3 events was 2.0% (6/300) and 1.3% (4/300), respectively. Median time to onset was 3.6 months (range: 0.5-14.4). Twelve patients (80.0%) experienced remission, and the median time to remission was 6.1 weeks (range: 0.9-126.4+).

immune-related endocrine diseases

Hypopituitarism (of any severity) occurred in 4% of patients in the 3 mg/kg monotherapy group. Adrenal insufficiency, hyperthyroidism, and hypothyroidism (of any severity) occurred in 2% of patients. The frequency of severe (grade 3 or 4) hypopituitarism is 3%. Severe or very severe (grade 3 or 4) adrenal insufficiency, hyperthyroidism, or hypothyroidism have not been reported. The time to onset of moderate to very severe (grade 2-4) immune-related endocrine disorders ranged from 7 to nearly 20 weeks from the start of treatment. Immune-related endocrine disorders observed in clinical trials are often managed with hormone replacement therapy.

Thyroid disease occurred in 14% (43/300) of MPM patients treated with nivolumab 1 mg/kg in combination with nivolumab 3 mg/kg. The incidence of grade 2 and grade 3 thyroid disease was 9.3% (28/300) and 1.3% (4/300), respectively. Hypophysitis occurred in 2% (6/300) of patients. The incidence of grade 2 events was 1.3% (4/300). The incidence of grade 2 and 3 hypopituitarism was 1.0% (3/300) and 1.0% (3/300), respectively. The incidence of grade 2 and grade 3 adrenal insufficiency was 1.7% (5/300) and 0.3% (1/300), respectively. No cases of immune-related diabetes have been reported. The median time to the onset of endocrinopathy was 2.8 months (range: 0.5-20.8). Remission occurred in 17 patients (32.7%). The time to onset of remission ranged from 0.3 to 144.1+ weeks.

infusion reaction

In MPM patients receiving nivolumab 1 mg/kg in combination with nivolumab 3 mg/kg, the incidence of hypersensitivity reactions/infusion reactions was 12% (36/300); 5.0% (15/300) ) and 1.3% (4/300) of patients reported grade 2 and 3 cases, respectively.

Laboratory abnormalities in combination therapy with nivolumab

Among patients with MPM who received nivolumab 1 mg/kg in combination with nivolumab 3 mg/kg, the proportion of patients with worsening from baseline to grade 3 or 4 laboratory abnormalities was as follows: anemia 2.4%, thrombocytopenia, and Leukopenia was 1.0%, lymphocytes decreased by 8.4%, neutrophils decreased by 1.3%, alkaline phosphatase increased by 3.1%, AST and ALT increased by 7.1%, and total bilirubin increased by 1.7%. , creatinine increased 0.3%, hyperglycemia 2.8%, amylase increased 5.4%, lipase increased 12.8%, hypernatremia 0.7%, hyponatremia 8.1%, hyperkalemia 4.1%, hypokalemia disease 2.0% and hypocalcemia 0.3%.

Immunogenicity - Global Patient Data

Anti-drug antibodies to ipilimumab developed in less than 2% of patients with advanced melanoma treated with ipilimumab in Phase 2 and 3 clinical trials . These patients did not have any infusion-related or peri-infusion hypersensitivity or anaphylaxis. No neutralizing antibodies against ipilimumab were detected . Overall, no clear correlation was observed between antibody production and adverse effects.

The incidence of ipilimumab anti- drug antibodies was 13.7% in patients receiving ipilimumab in combination with nivolumab who could be evaluated for ipilimumab anti-drug antibodies. The incidence of neutralizing antibodies against ipilimumab was 0.4%. In patients evaluable for the presence of anti-nivolumab antibodies, nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks The incidence rate of monoclonal anti- drug antibodies was 25.7%. The incidence of neutralizing antibodies against nivolumab was 0.7% when nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks were administered .

When ipilimumab was used in combination with nivolumab , ipilimumab clearance remained unchanged in the presence of anti-ipilimumab antibodies and there was no evidence of a change in its toxicity profile.

Immunogenicity-Chinese patient data

In the Chinese studies CA184247 and CA184248, among patients who could be evaluated for anti-drug antibodies (23 patients in the CA184247 study and 121 patients in the CA184248 study), 1 and 10 patients (10% and 8.3%) received ipilimumab , respectively3 mg/kg every 3 weeks and 2 (15.4%) subjects receiving 10 mg/kg every 3 weeks tested positive. No patients were found to be positive for anti- ipilimumab neutralizing antibodies.

In the Chinese study CA209672, among Chinese patients treated with nivolumab plus ipilimumab , 25 patients were evaluable for the presence of nivolumab and ipilimumab anti- drug antibodies. Three patients (12%) developed positive anti -nivolumab antibodies during treatment, and 1 patient developed positive anti-nivolumab neutralizing antibodies. When receiving nivolumab in combination with ipilimumab , no patient developed positive anti-ipilimumab antibodies or anti -ipilimumab neutralizing antibodies during treatment .

No anti-drug antibody-positive patients experienced allergic or infusion-related reactions.

【Storage】

Store in refrigerator (2°C-8°C).

Do not freeze.

Store in original packaging away from light.

Unopened

36 months

After opening

According to the microbiological point of view, once the drug is opened, it should be infused or diluted for infusion immediately. Undiluted or diluted solutions (1-4 mg/mL) have been shown to remain chemically and physically stable at the time of use for 24 hours at 25°C and 2°C-8°C. If not for immediate use, infusion solutions (undiluted or diluted) can be stored in the refrigerator (2°C-8°C) or at room temperature (20°C-25°C) for up to 24 hours.