Drug Safety-related Labeling Changes (SrLC)

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SARCLISA (BLA-761113)

(ISATUXIMAB-IRFC)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/25/2024 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Second Primary Malignancies

Additions and/or revisions underlined:

The incidence of second primary malignancies, during treatment and post-treatment, is increased in patients treated with SARCLISA-containing regimens. In clinical trials (ICARIA-MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), second primary malignancies occurred in 71 patients (12%).

In ICARIA-MM, at a median follow-up time of 52 months, second primary malignancies occurred in 7% of patients in the Isa-Pd arm and in 2% of patients in the Pd arm.

In IKEMA study, at a median follow-up time of 57 months, second primary malignancies occurred in 10% of patients in the Isa-Kd arm and in 8% of patients in the Kd arm.

…

5.5 Laboratory Test Interference

Additions and/or revisions underlined:

Interference with Serological Testing (Indirect Antiglobulin Test)

SARCLISA binds to CD38 on red blood cells (RBCs) and may result in a false positive indirect antiglobulin test (indirect Coombs test). This interference with the indirect Coombs test may persist for approximately 6 months after the last infusion of SARCLISA. The indirect antiglobulin test was positive during Isa-Pd treatment in 68% of the tested patients, and during Isa-Kd treatment in 63% of patients. In patients with a positive indirect antiglobulin test, blood transfusions were administered without evidence of hemolysis. ABO/RhD typing was not affected by SARCLISA treatment.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Interference with Laboratory Tests

Advise patients to inform healthcare providers and transfusion center personnel that they are treated with SARCLISA in case a red blood cell transfusion is planned. Advise patients that SARCLISA may affect the results of blood tests to match their blood type for approximately 6 months after their last infusion of SARCLISA [see Warnings and Precautions (5.5) and Drug Interactions (7.1)].

…

PATIENT INFORMATION

Additions and/or revisions underlined:

What are the possible side effects of SARCLISA?

SARCLISA may cause serious side effects including:

…

• Changes in blood tests. SARCLISA may affect the results of blood tests to match your blood type for about 6 months after your last infusion of SARCLISA. Your healthcare provider will do blood tests to match your blood type before you start treatment with SARCLISA. Tell all of your healthcare providers that you are being treated with SARCLISA before receiving blood transfusions.

…

10/25/2024 (SUPPL-12)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of SARCLISA in pediatric patients have not been established.

The safety and efficacy of SARCLISA in combination with chemotherapy were assessed, but not established, in an open-label study (ACT15378, ISAKIDS, NCT03860844) in 62 pediatric patients aged 1.4 years to < 17 years with relapsed or refractory T-acute lymphoblastic leukemia (T-ALL), B-acute lymphoblastic leukemia (B-ALL), or acute myeloid leukemia (AML). No new safety signals were observed in pediatric patients in this trial.

Body weight adjusted clearance at steady state and volume of distribution of isatuximab in pediatric patients were within the range of values that were observed in adults.

09/20/2024 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Infusion-Related Reactions

Additions and revisions underlined:

Serious infusion-related reactions including life-threatening anaphylactic reactions have occurred with SARCLISA treatment. Severe signs and symptoms included cardiac arrest, hypertension, hypotension, bronchospasm, dyspnea, angioedema, and swelling. In clinical trials (ICARIA- MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), infusion-related reactions occurred in 206 patients (35%). Among these 206 patients, 92% experienced infusion- related reactions during the first infusion and 12% after the first cycle. The most common symptoms (?5%) of an infusion-related reaction included dyspnea and cough. Grade 1 infusion- related reactions were reported in 6% of patients, grade 2 in 28%, and grade 3 or 4 in 1.2%.

Anaphylactic reactions occurred in less than 1% of patients. The total incidence of SARCLISA infusion interruptions was less than 1% and the incidence of patients with at least one SARCLISA infusion interruption due to infusion-related reactions was 26%. The median time to first SARCLISA infusion interruption was 61 minutes (range 4 to 240 minutes). SARCLISA was discontinued in 1% of patients due to infusion-related reactions.

5.2 Infections

Newly added subsection:

SARCLISA can cause severe, life-threatening, or fatal infections. In patients who received SARCLISA at the recommended dose in ICARIA-MM, IKEMA, and IMROZ (N=592), serious infections, including opportunistic infections, occurred in 46% of patients, grade 3 or 4 infections occurred in 43%, and fatal infections occurred in 4.7%. The most common type of serious infection reported was pneumonia (32%).

Monitor patients for signs and symptoms of infection prior to and during treatment with SARCLISA and treat appropriately. Administer prophylactic antimicrobials according to guidelines [see Dosage and Administration (2.2)].

5.3 Neutropenia

Additions and revisions underlined:

SARCLISA can cause neutropenia.

In clinical trials (ICARIA-MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), neutropenia based on laboratory values occurred in 81%, with grade 3 or 4 occurring in 52%. Neutropenic infections occurred in 12% of patients, with grade 3 or 4 in 4.9%, and febrile neutropenia in 4% [see Adverse Reactions (6.1)].

Monitor complete blood cell counts periodically during treatment. If needed, use antibacterial and antiviral prophylaxis during treatment [see Dosage and Administration (2.2)].

. . .

5.4 Second Primary Malignancies

Additions and revisions underlined:

The incidence of second primary malignancies, during treatment and post-treatment, is increased in patients treated with SARCLISA-containing regimens. In clinical trials (ICARIA-MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), second primary malignancies occurred in 71 patients (12%).

In ICARIA-MM, at a median follow-up time of 52 months, second primary malignancies occurred in 7% of patients in the Isa-Pd arm and in 2% of patients in the Pd arm.

In ongoing IKEMA study, at a median follow-up time of 21 months, second primary malignancies occurred in 7% of patients in the Isa-Kd arm and in 4.9% of patients in the Kd arm.

In IMROZ study, at a median follow-up time of 60 months, second primary malignancies occurred in 16% of patients in the Isa-VRd arm and in 9% of patients in the VRd arm.

The most common (?1%) second primary malignancies in ICARIA-MM, IKEMA, and IMROZ (N=592) included skin cancers (7% with SARCLISA-containing regimens and 3.1% with comparative regimens) and solid tumors other than skin cancer (4.6% with SARCLISA-containing regimens and 2.9% with comparative regimens). Patients with non-melanoma skin cancer continued treatment after resection of the skin cancer, except 2 patients on the Isa-VRd arm and 1 patient on the VRd arm of the IMROZ study.

6 Adverse Reactions

Additions and revisions underlined:

The following clinically significant adverse reactions from SARCLISA are also described in other sections of the labeling:

• Infusion-Related Reactions [see Warnings and Precautions (5.1)]

• Infections [see Warnings and Precautions (5.2)]

. . .

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.1 Pregnancy

Additions and revisions underlined:

The combination of SARCLISA and pomalidomide or lenalidomide is contraindicated in pregnant women because pomalidomide and lenalidomide may cause birth defects and death of the unborn child. Refer to the pomalidomide or lenalidomide prescribing information on use during pregnancy. Pomalidomide and lenalidomide are only available through a REMS program.

8.2 Lactation

Additions and revisions underlined:

Because of the potential for serious adverse reactions in the breastfed child from isatuximab-irfc administered in combination with pomalidomide or lenalidomide and dexamethasone, advise lactating women not to breastfeed during treatment with SARCLISA. Refer to pomalidomide or lenalidomide prescribing information for additional information.

8.3 Females and Males of Reproductive Potential

Additions and revisions underlined:

SARCLISA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

With the combination of SARCLISA with pomalidomide or lenalidomide, refer to the pomalidomide or lenalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential.

8.5 Geriatric Use

Additions and revisions underlined:

Of the total number of patients with relapsed or refractory multiple myeloma in clinical studies of SARCLISA, 56% (n=586) were 65 years of age and older, while 16% (n=163) were 75 years of age and older [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between patients 65 years of age and older compared to younger patients and other reported clinical experience has not identified differences in responses between the adults 65 years of age and older and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Of the total number of SARCLISA-treated patients with newly diagnosed multiple myeloma in IMROZ, 72% (n=319) were less than 75 years of age and 28% (n=125) were 75 years of age and older. The clinical trial did not enroll patients over age 80 [see Clinical Studies (14)]. Adverse reactions occurring at a higher frequency in the SARCLISA arm (?5%) in patients 75 years of age and older included neutropenia. Adverse reactions leading to dose modifications in patients 75 years of age and older occurred at a higher frequency (?5%) in the SARCLISA arm. The hazard ratio for overall survival (OS) in patients 75 years of age and older was 1.25 [95% CI: 0.68 to 2.3].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and revisions underlined:

Infections

Inform patients about the risk of developing infections during SARCLISA treatment, and to report immediately any fever or symptoms of infection to their healthcare provider [see Warnings and Precautions (5.2)].

Inform patients of the risk of developing second primary malignancies during treatment with SARCLISA when given with pomalidomide and dexamethasone, or with carfilzomib and dexamethasone, or with bortezomib, lenalidomide, and dexamethasone [see Warnings and Precautions (5.4)].

Advise patients that pomalidomide or lenalidomide have the potential to cause fetal harm and have specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm.

Patient Information

Extensive changes; please refer to label

11/01/2023 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Neutropenia

Additions and/or revisions underlined:

…

Monitor complete blood cell counts periodically during treatment. Consider the use of antibacterial and antiviral prophylaxis during treatment [see Dosage and Administration (2.2)].

5.3 Second Primary Malignancies

Additions and/or revisions underlined:

The incidence of second primary malignancies is increased in patients treated with SARCLISA- containing regimens. The overall incidence of second primary malignancies in all the SARCLISA-exposed patients was 4.1%.

In ICARIA-MM, at a median follow-up time of 52 months, second primary malignancies occurred in 7% of patients in the Isa-Pd arm and in 2% of patients in the Pd arm.

In ongoing IKEMA study, at a median follow-up time of 21 months, second primary malignancies occurred in 7% of patients in the Isa-Kd arm and in 4.9% of patients in the Kd arm.

The most common (greater than or equal to 1%) second primary malignancies in ICARIA-MM and IKEMA (N=329) included skin cancers (5% with SARCLISA-containing regimens and 2.6% with comparative regimens) and solid tumors other than skin cancer (3% with SARCLISA-containing regimens and 1.8% with comparative regimens). All patients with non-melanoma skin cancer continued treatment after resection of the skin cancer.

Monitor patients for the development of second primary malignancies.

7 Drug Interactions

7.1 Laboratory Test Interference

Additions and/or revisions underlined:

…

Interference with Serum Protein Electrophoresis and Immunofixation Tests

SARCLISA may be incidentally detected by serum protein electrophoresis and immunofixation assays used for the monitoring of M-protein and may interfere with accurate response classification based on International Myeloma Working Group (IMWG) criteria [see Warnings and Precautions (5.4)]. In patients with persistent very good partial response, where interference is suspected, consider using an FDA-cleared isatuximab-irfc-specific IFE assay to distinguish isatuximab from any remaining endogenous M protein in the patient’s serum to facilitate determination of a complete response.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 5 months after the last dose of SARCLISA [see Use in Specific Populations (8.1, 8.3)].

…

PATIENT INFORMATION

Additions and/or revisions underlined:

Before receiving SARCLISA, tell your healthcare provider about all of your medical conditions, including if you:

…

• Before receiving SARCLISA in combination with pomalidomide, females and males must agree to the instructions in the pomalidomide REMS program. The pomalidomide REMS program has specific requirements about birth control, pregnancy testing, blood donation, and sperm donation that you need to know. Talk to your healthcare provider to learn more about pomalidomide.

07/15/2022 (SUPPL-6)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added information:

In relapsed and refractory multiple myeloma clinical trials, herpes zoster was reported in 2% of patients. In ICARIA-MM, the incidence of herpes zoster was 4.6% in the Isa-Pd group compared to 0.7% in the Pd group, and in IKEMA, incidence was 2.3% in the Isa-Kd group compared to 1.6% in the Kd group.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

Additions and revisions underlined:

Before receiving SARCLISA, tell your healthcare provider about all of your medical conditions, including if you:

• have heart problems, if your healthcare provider prescribes SARCLISA in combination with carfilzomib and dexamethasone for you.

• have had shingles (herpes zoster).

• are pregnant or plan to become pregnant. SARCLISA may harm your unborn baby. You should not receive SARCLISA during pregnancy.

  • Females who are able to become pregnant should use an effective method of birth control during treatment and for 5 months after your last dose of SARCLISA. Talk to your healthcare provider about birth control methods that you can use during this time.

    Tell your healthcare provider right away if you think you are pregnant or become pregnant during treatment with SARCLISA.

• are breastfeeding or plan to breastfeed. It is not known if SARCLISA passes into your breast milk. You should not breastfeed during treatment with SARCLISA.

Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements.

03/31/2021 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Infusion-Related Reactions

(Additions and/or revisions underlined)

Serious infusion-related reactions including life-threatening anaphylactic reactions have occurred with SARCLISA treatment. Severe signs and symptoms included cardiac arrest, hypertension, hypotension, bronchospasm, dyspnea, angioedema, and swelling.

Based on ICARIA-MM, infusion-related reactions occurred in 38% of patients treated with SARCLISA, pomalidomide, and dexamethasone (Isa-Pd) [see Adverse Reactions (6.1)]. All infusion-related reactions started during the first SARCLISA infusion and resolved on the same day in 98% of the cases.

In IKEMA, infusion-related reactions occurred in 46% of patients treated with SARCLISA, carfilzomib, and dexamethasone (Isa-Kd). In the Isa-Kd arm, the infusion-related reactions occurred on the infusion day in 99% of episodes. In patients treated with Isa-Kd, 95% of those experiencing an infusion-related reaction experienced it during the first cycle of treatment. All infusion-related reactions resolved: within the same day in 74% of episodes, and the day after in 24% of episodes [see Adverse Reactions (6.1)].

The most common symptoms (greater than or equal to 5%) of an infusion-related reaction in ICARIA-MM and IKEMA (N=329) included dyspnea, cough, nasal congestion, and nausea. Anaphylactic reactions occurred in less than 1% of patients.

To decrease the risk and severity of infusion-related reactions, premedicate patients prior to SARCLISA infusion with acetaminophen, H2 antagonists, diphenhydramine, or equivalent, and dexamethasone [see Dosage and Administration (2.2)].

Monitor vital signs frequently during the entire SARCLISA infusion. For patients with grade greater than or equal to 2 reactions, interrupt SARCLISA infusion and provide appropriate medical management. For patients with grade 2 or grade 3 reactions, if symptoms improve to grade less than or equal to 1, restart SARCLISA infusion at half of the initial infusion rate, with supportive care as needed, and closely monitor patients. If symptoms do not recur after 30 minutes, the infusion rate may be increased to the initial rate, and then increased incrementally, as shown in Table 2 [see Dosage and Administration (2.5)]. In case symptoms do not improve to grade less than or equal to 1 after interruption of SARCLISA infusion, persist or worsen despite appropriate medications, or require hospitalization, permanently discontinue SARCLISA and institute appropriate management.

Permanently discontinue SARCLISA if an anaphylactic reaction or life-threatening (grade 4) infusion-related reaction occurs and institute appropriate management.

5.2 Neutropenia

(Additions and/or revisions underlined)

SARCLISA may cause neutropenia.

In patients treated with Isa-Pd, neutropenia occurred in 96% of patients and grade 3-4 neutropenia occurred in 85% of patients. Neutropenic complications occurred in 30% of patients, including febrile neutropenia (12%) and neutropenic infections (25%), defined as infection with concurrent grade greater than or equal to 3 neutropenia. The most frequent neutropenic infections included infections of the upper respiratory tract (10%), lower respiratory tract (9%), and urinary tract (3%) [see Adverse Reactions (6.1)].

In patients treated with Isa-Kd, neutropenia occurred in 55% of patients, with grade 3-4 neutropenia in 19% of patients (grade 3 in 18% and grade 4 in 1.7%). Neutropenic complications occurred in 2.8% of patients, including febrile neutropenia (1.1%) and neutropenic infections (1.7%) [see Adverse Reactions (6.1)]. Monitor complete blood cell counts periodically during treatment. Consider the use of antibiotics and antiviral prophylaxis during treatment. Monitor patients with neutropenia for signs of infection. In case of grade 4 neutropenia delay SARCLISA dose until neutrophil count recovery to at least 1.0 × 109/L, and provide supportive care with growth factors, according to institutional guidelines. No dose reductions of SARCLISA are recommended.

5.3 Second Primary Malignancies

(Additions and/or revisions underlined)

The incidence of second primary malignancies is increased in patients treated with SARCLISA- containing regimens. The overall incidence of secondary primary malignancies in all the SARCLISA-exposed patients was 3.6%.

In ICARIA-MM, second primary malignancies occurred in 3.9% of patients in the Isa-Pd arm and in 0.7% of patients in the Pd arm.

In IKEMA, secondary primary malignancies occurred in 7% of patients in the Isa-Kd arm and in 4.9% of patients in the Kd arm.

The most common (greater than or equal to 1%) second primary malignancies in ICARIA-MM and IKEMA (N=329) included skin cancers (4% with SARCLISA-containing regimens and 1.5% with comparative regimens) and solid tumors other than skin cancer (1.8% with SARCLISA-containing regimens and 1.5% with comparative regimens). All patients with skin cancer continued treatment after resection of the skin cancer.

5.4 Laboratory Test Interference

(Additions and/or revisions underlined)

Interference with Serological Testing (Indirect Antiglobulin Test)

SARCLISA binds to CD38 on red blood cells (RBCs) and may result in a false positive indirect antiglobulin test (indirect Coombs test). The indirect antiglobulin test was positive during Isa-Pd treatment in 68% of the tested patients, and during Isa-Kd treatment in 63% of patients. In patients with a positive indirect antiglobulin test, blood transfusions were administered without evidence of hemolysis. ABO/RhD typing was not affected by SARCLISA treatment.

Before the first SARCLISA infusion, conduct blood type and screen tests on SARCLISA-treated patients. Consider phenotyping prior to starting SARCLISA treatment. If treatment with SARCLISA has already started, inform the blood bank that the patient is receiving SARCLISA and SARCLISA interference with blood compatibility testing can be resolved using dithiothreitol-treated RBCs. If an emergency transfusion is required, non–cross-matched ABO/RhD-compatible RBCs can be given as per local blood bank practices [see Drug Interactions (7.1)].

Interference with Serum Protein Electrophoresis and Immunofixation Tests

SARCLISA is an IgG kappa monoclonal antibody that can be incidentally detected on both serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the accuracy of the determination of complete response in some patients with IgG kappa myeloma protein [see Drug Interactions (7.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

6.2 Immunogenicity

(Additions and/or revisions underlined)

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other isatuximab-irfc products may be misleading.

In ICARIA-MM and IKEMA, no patients tested positive for antidrug antibodies (ADA). Therefore, the neutralizing ADA status was not determined. Overall, across 9 clinical studies in multiple myeloma (MM) with SARCLISA single-agent and combination therapies including ICARIA-MM and IKEMA (N=1018), the incidence of treatment emergent ADAs was 1.9%. No clinically significant differences in the pharmacokinetics, safety, or efficacy of isatuximab-irfc were observed in patients with ADAs.

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the total number of subjects in clinical studies of SARCLISA, 56% (586 patients) were 65 and over, while 16% (163 patients) were 75 and over. No overall differences in safety or effectiveness were observed between subjects 65 and over and younger subjects, and other reported clinical experience has not identified differences in responses between the adults 65 years and over and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Infusion-Related Reaction

Advise patients to seek immediate medical attention for any of the following signs and symptoms of infusion-related reactions: shortness of breath, wheezing or trouble breathing; swelling of the face, mouth, throat, or tongue; throat tightness; palpitations; dizziness, lightheadedness, or fainting; headache; cough; rash or itching; nausea; runny or stuffy nose; or chills [see Warnings and Precautions (5.1)].

Neutropenia

Inform patients about the risk of neutropenia and infection during SARCLISA treatment and the importance of reporting immediately any fever or symptoms of infection to their healthcare provider [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Second Primary Malignancies

Inform patients of the risk of developing second primary malignancies during treatment with SARCLISA when given with pomalidomide and dexamethasone or with carfilzomib and dexamethasone [see Warnings and Precautions (5.3)].

Cardiac Toxicities

Inform patients about the risk of cardiac failure during treatment with SARCLISA when given with carfilzomib and dexamethasone, and the importance of reporting immediately any difficulty breathing, cough, or leg swelling to their healthcare provider [see Adverse Reactions (6.1)].

Interference with Laboratory Tests

Advise patients to inform healthcare providers and transfusion center personnel that they are treated with SARCLISA in case a red blood cell transfusion is planned [see Warnings and Precautions (5.4) and Drug Interactions (7.1)].

Embryo-Fetal Toxicity

Advise women of the potential hazard to a fetus and to avoid becoming pregnant during treatment and for at least 5 months after the last dose of SARCLISA [see Use in Specific Populations (8.1, 8.3)].

Advise patients that pomalidomide has the potential to cause fetal harm and has specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Advise patients to report suspected or known pregnancies. Pomalidomide is only available through a REMS program [see Use in Specific Populations (8.1, 8.3)].

PATIENT INFORMATION

(Extensive changes; please refer to label)

03/18/2021 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Infusion-Related Reactions

(Additions and/or revisions underlined)

Serious infusion-related reactions including life-threatening anaphylactic reactions have occurred with SARCLISA treatment. Severe signs and symptoms included cardiac arrest, hypertension, hypotension, bronchospasm, dyspnea, angioedema, and swelling.

Infusion-related reactions have been observed in 39% of patients treated with SARCLISA [see Adverse Reactions (6.1)]. All infusion-related reactions started during the first SARCLISA infusion and resolved on the same day in 98% of the cases. The most common symptoms of an infusion-related reaction included dyspnea, cough, chills, and nausea. Anaphylactic reactions occurred in less than 1% of patients.

To decrease the risk and severity of infusion-related reactions, premedicate patients prior to SARCLISA infusion with acetaminophen, H2 antagonists, diphenhydramine, or equivalent; dexamethasone [see Dosage and Administration (2.2)]. Monitor vital signs frequently during the entire SARCLISA infusion. For patients with grade greater than or equal to 2 reactions, interrupt SARCLISA infusion and provide appropriate medical management. For patients with grade 2 or grade 3 reactions, if symptoms improve to grade less than or equal to 1, restart SARCLISA infusion at half of the initial infusion rate, with supportive care as needed, and closely monitor patients. If symptoms do not recur after 30 minutes, the infusion rate may be increased to the initial rate, and then increased incrementally, as shown in Table 2 [see Dosage and Administration (2.5)]. In case symptoms do not improve to grade less than or equal to 1, after interruption of SARCLISA infusion, persist or worsen despite appropriate medications, or require hospitalization, permanently discontinue SARCLISA and institute appropriate management. Permanently discontinue SARCLISA if an anaphylactic reaction or life threatening (grade 4) infusion-related reaction occurs and institute appropriate management.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Infusion-Related Reaction

Advise patients to seek immediate medical attention for any of the following signs and symptoms of infusion-related reactions: shortness of breath, wheezing or trouble breathing; swelling of the face, mouth, throat, or tongue; throat tightness; palpitations; dizziness, lightheadedness, or fainting; headache; cough; rash or itching; nausea; runny or stuffy nose; or chills [see Warnings and Precautions (5.1)].

Patient Information

(Additions and/or revisions underlined)

Infusion reactions. Infusion reactions are common with SARCLISA and can sometimes be severe or life

threatening.

Get medical help right away if you develop any of the following symptoms of infusion reaction during or after

an infusion of SARCLISA:

o shortness of breath, wheezing or

trouble breathing

o swelling of the face, mouth, throat, or

tongue

o throat tightness

o palpitations

o dizziness, lightheadedness,

or fainting

o headache

o cough

o rash or itching

o nausea

o runny or stuffy nose

o chills