Important Safety Information

 

Infusion-Related Reactions (IRRs)

In the SUSTAIN clinical trial, IRRs (occurring during/within 24 hours of infusion) were observed in 2 (3%) patients treated with ADAKVEO

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Indication


ADAKVEO® (crizanlizumab-tmca) is indicated to reduce the frequency of vaso-occlusive crises (VOCs) in adults and pediatric patients, aged 16 years and older, with sickle cell disease.

Safety

Infusion-Related Reactions (IRRs)

IRRs may happen during/within 24 hours of infusion1

With monoclonal antibodies such as ADAKVEO, there is the potential for IRRs.

  • In the SUSTAIN study, IRRs were observed in 2 (3%) patients treated with ADAKVEO® (crizanlizumab-tmca) 5 mg/kg (N=66) during/within 24 hours of infusion1
  • Postmarketing cases of IRRs, including severe pain events requiring hospitalizations, have been reported. The majority of these IRRs occurred during the first and second infusions. Some patients have also experienced subsequent complications, such as acute chest syndrome and fat embolism, particularly those treated with steroids1
  • Monitor for and advise patients of signs and symptoms such as1:
  • Pain in various locations
  • Headache
  • Fever
  • Chills
  • Nausea
  • Vomiting
  • Diarrhea
  • Fatigue
  • Dizziness
  • Pruritus
  • Urticaria
  • Sweating
  • Shortness of breath or wheezing
  • These are not all the potential signs and symptoms of IRRs
  • Advise your patients to contact their health care provider immediately if they experience any possible signs and symptoms of IRRs during and within 24 hours of the infusion1

 

 

Recommended management for IRRs1

  • Counsel patients about the possibility of an IRR
  • Prophylaxis is not required
  • Administer ADAKVEO via IV infusion over a period of 30 minutes
  • If an IRR occurs, no dose reductions are recommended
No IRR   Complete infusion
Mild to Moderate
IRR
 
  • Temporarily interrupt the infusion or slow the rate of infusion*
  • Initiate symptomatic treatment (eg, acetaminophen, NSAIDs, opioids, antihistamines, IV fluids, and/or oxygen therapy)
  • For subsequent infusions, consider premedication and/or reduce the infusion rate
Severe IRR  
  • Discontinue infusion
  • Institute appropriate medical care
  • Consider permanent discontinuation of ADAKVEO

Exercise caution with the use of corticosteroids in patients with sickle cell disease unless clinically indicated (eg, treatment of anaphylaxis).1

*Slow rate of infusion at the clinical discretion of the treating physician or according to your institutional protocols.

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For patients with SCD, use of corticosteroids may cause complications1,2

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Adverse Reactions (ARs)

Majority of ARs with ADAKVEO were mild to moderate (grade 1 or 2)1

Adverse Drug Reactions Reported ≥10% of ADAKVEO® (crizanlizumab-tmca) Patients With a Difference Between Arms of >3% Compared With Placebo in SUSTAIN

 

 

 

ADAKVEO (5 mg/kg)
N=66; n (%)

Placebo
N=62; n (%)

Adverse
Drug Reactions

All Grades

Grades ≥3

All Grades

Grades ≥3

Gastrointestinal disorders

       

Nausea
Abdominal pain*

12 (18)
8 (12)

0
0

7 (11)
3 (5)

1 (2)
0

Musculoskeletal disorders and connective tissue disorders

 

 

 

 

Arthralgia
Back pain

12 (18)
10 (15)

1 (2)
0

5 (8)
7 (11)

1 (2)
0

General disorders and administration site conditions

 

 

 

 

Pyrexia

7 (11)

1 (2)

4 (7)

0

*Abdominal pain: abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness.

  • Clinically relevant ARs (all grades) that were reported in <10% of patients treated with ADAKVEO included: oropharyngeal pain, diarrhea, vomiting, pruritus (pruritus and vulvovaginal pruritus), musculoskeletal chest pain, myalgia, infusion-site reaction (infusion-site extravasation, infusion-site pain, and infusion-site swelling), and IRRs
  • Two deaths (3%) occurred in the ADAKVEO 5 mg/kg treatment group. None of the deaths were considered to be related to ADAKVEO
  • Serious ARs were reported in 2 patients (3%) treated with ADAKVEO 5 mg/kg; both reactions were pyrexia

 

Management considerations for the most common ARs1,3-8

 

Safety Profile and Management Considerations

Watch Nirmish R. Shah, MD, outline the safety profile of ADAKVEO and share considerations for managing infusion-related reactions and the most common adverse reactions.

Important Safety Information

Infusion-Related Reactions (IRRs)

In the SUSTAIN clinical trial, IRRs (occurring during/within 24 hours of infusion) were observed in 2 (3%) patients treated with ADAKVEO 5 mg/kg. Postmarketing cases of IRRs, including severe pain events requiring hospitalizations, have been reported. The majority of these IRRs occurred during the first and second infusions. The management of pain events included acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antihistamines, intravenous fluids, and/or oxygen therapy. Some patients have also experienced subsequent complications such as acute chest syndrome and fat embolism, particularly those treated with steroids.

Monitor patients for signs and symptoms of IRRs, which may include pain in various locations, headache, fever, chills, nausea, vomiting, diarrhea, fatigue, dizziness, pruritus, urticaria, sweating, or shortness of breath or wheezing.

For severe IRRs, discontinue infusion, institute appropriate medical care, and consider permanent discontinuation of ADAKVEO. For mild or moderate IRRs, temporarily interrupt or slow the rate of infusion and initiate symptomatic treatment. For subsequent infusions, consider premedication and/or reduce the infusion rate.

Exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (eg, treatment of anaphylaxis).

Laboratory Test Interference (Platelet Counts)

Interference with automated platelet counts (platelet clumping) has been observed following administration of ADAKVEO, in particular, when blood samples were collected in tubes containing EDTA.

Run blood samples within 4 hours of blood collection or collect blood samples in tubes containing citrate. When needed, estimate platelet count via peripheral blood smear.

Pregnancy

Based on animal data, ADAKVEO has the potential to cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. ADAKVEO should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.

Most Common Adverse Reactions

The most frequently reported adverse reactions (≥10%) in patients treated with ADAKVEO were nausea (18%), arthralgia (18%), back pain (15%), abdominal pain (12%), and pyrexia (11%).

Other Clinically Important Adverse Reactions

Clinically relevant adverse reactions (all grades) that were reported in <10% of patients treated with ADAKVEO included: oropharyngeal pain, diarrhea, vomiting, pruritus (pruritus and vulvovaginal pruritus), musculoskeletal chest pain, myalgia, infusion-site reaction (infusion-site extravasation, infusion-site pain, and infusion-site swelling), and infusion-related reaction.

Please see accompanying full Prescribing Information.

 

Other Safety Measures

Rates of infection, blood count results, and blood chemistry findings were similar to those with placebo9

Infection rates
  • Similar infection rates were observed with ADAKVEO and placebo (overall, 51.5% vs 53.2%; serious, 12.1% vs 16.1%)
    • Infections were observed with ADAKVEO and placebo, and included urinary tract infection (13.6% vs 11.3%), upper respiratory tract infection (10.6% vs 9.7%), pneumonia (6.1% vs 4.8%), and influenza (1.5% vs 0%)
Blood count results
  • The incidence of neutropenia was 3.0% for ADAKVEO vs 6.5% for placebo
  • No significant clinical differences between ADAKVEO vs placebo in hemoglobin (LSM: 1.5; 0.8 vs -0.7); reticulocyte count (LSM: -9.79; -7.12 vs 2.68); or haptoglobin (LSM: 0.03; 0.04 vs 0.01)
Blood chemistry findings
  • No significant clinical differences between ADAKVEO vs placebo in LDH (LSM: 8.2; -25.4 vs -33.5) or indirect bilirubin (LSM: -3.0; -2.3 vs 0.7)

 

Laboratory Test Interference (Platelet Counts)

Lab interference with automated platelet counts (platelet clumping) has been observed following administration of ADAKVEO when blood samples were collected in tubes containing ethylenediaminetetraacetic acid (EDTA).

Run test as soon as possible or use citrate tubes.

AR, adverse reaction; IRR, infusion-related reaction; LSM, least squares mean; LDH, lactate dehydrogenase; NSAID, nonsteroidal anti-inflammatory drug; SCD, sickle cell disease.

References: 1. Adakveo [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021. 2. Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4(12):2656-2701. 3. Nausea & vomiting. Cleveland Clinic. https://my.clevelandclinic.org/health/symptoms/8106-nausea-vomiting. Accessed September 1, 2020. 4. Flake ZA, Linn BS, Hornecker JR. Practical selection of antiemetics in the ambulatory setting. Am Fam Physician. 2015;91(5):293-296. 5. Joint pain. Mayo Clinic. https://www.mayoclinic.org/symptoms/joint-pain/basics/definition/sym-20050668. Accessed September 1, 2020. 6. Back pain. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/back-pain/symptomscauses/syc-20369906. Accessed September 1, 2020. 7. Yawn BP, John-Sowah J. Management of sickle cell disease: recommendations from the 2014 expert panel report. Am Fam Physician. 2015;92(12):1069-1076A. 8. Ahmed S, Shahid RK, Russo LA. Unusual causes of abdominal pain: sickle cell anemia. Best Pract Res Clin Gastroenterol. 2005;19(2):297-310. 9. Data on file. Study NCT01895361. Novartis Pharmaceuticals Corp; 2016.

Next: Dosing and Administration

Indication

ADAKVEO® (crizanlizumab-tmca) is indicated to reduce the frequency of vaso-occlusive crises (VOCs) in adults and pediatric patients, aged 16 years and older, with sickle cell disease.

Important Safety Information

Infusion-Related Reactions (IRRs)

In the SUSTAIN clinical trial, IRRs (occurring during/within 24 hours of infusion) were observed in 2 (3%) patients treated with ADAKVEO 5 mg/kg. Postmarketing cases of IRRs, including severe pain events requiring hospitalizations, have been reported. The majority of these IRRs occurred during the first and second infusions. The management of pain events included acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antihistamines, intravenous fluids, and/or oxygen therapy. Some patients have also experienced subsequent complications such as acute chest syndrome and fat embolism, particularly those treated with steroids.

Monitor patients for signs and symptoms of IRRs, which may include pain in various locations, headache, fever, chills, nausea, vomiting, diarrhea, fatigue, dizziness, pruritus, urticaria, sweating, or shortness of breath or wheezing.

For severe IRRs, discontinue infusion, institute appropriate medical care, and consider permanent discontinuation of ADAKVEO. For mild or moderate IRRs, temporarily interrupt or slow the rate of infusion and initiate symptomatic treatment. For subsequent infusions, consider premedication and/or reduce the infusion rate.

Exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (eg, treatment of anaphylaxis).

Laboratory Test Interference (Platelet Counts)

Interference with automated platelet counts (platelet clumping) has been observed following administration of ADAKVEO, in particular, when blood samples were collected in tubes containing EDTA.

Run blood samples within 4 hours of blood collection or collect blood samples in tubes containing citrate. When needed, estimate platelet count via peripheral blood smear.

Pregnancy

Based on animal data, ADAKVEO has the potential to cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. ADAKVEO should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.

Most Common Adverse Reactions

The most frequently reported adverse reactions (≥10%) in patients treated with ADAKVEO were nausea (18%), arthralgia (18%), back pain (15%), abdominal pain (12%), and pyrexia (11%).

Other Clinically Important Adverse Reactions

Clinically relevant adverse reactions (all grades) that were reported in <10% of patients treated with ADAKVEO included: oropharyngeal pain, diarrhea, vomiting, pruritus (pruritus and vulvovaginal pruritus), musculoskeletal chest pain, myalgia, infusion-site reaction (infusion-site extravasation, infusion-site pain, and infusion-site swelling), and infusion-related reaction.

Please see accompanying full Prescribing Information.