Novartis is fully committed to keeping health care professionals updated on the safety of crizanlizumab.
This site was initially launched on July 29, 2020 and previously updated on December 7, 2020. The reports presented previously are included as part of this update.
Crizanlizumab is currently being investigated in clinical trials globally. Marketing authorization has been obtained in more than 40 countries including the United States, all 27 EU member states plus the United Kingdom, Iceland, Norway, and Liechtenstein, as well as Albania, Australia, Bahrain, Brazil, Dominican Republic, India, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, South Africa and United Arab Emirates (UAE).
As of May 14, 2021, approximately 5,000 patients with sickle cell disease (SCD) have been treated with crizanlizumab 5.0 mg/kg in clinical trials including healthy volunteers and in postmarketing setting. As of the same cut-off date but using a different methodology to calculate patient treatment years*, the estimated number of SCD patients exposed with crizanlizumab 5.0 mg/kg in the postmarketing setting is 1,545 patient treatment years.
*Estimation of exposure calculated based on annual dose schedule of crizanlizumab and average number of vials consumed annually to treat one patient. This cumulative data is obtained from International Birth Date (15 Nov 2019) till end of April 2021.
Novartis proactively monitors and assesses crizanlizumab safety data from all available sources on a continuous basis. As of June 15, 2021, Novartis has received 28 postmarketing reports** of patients with SCD who have experienced severe pain during or within 24 hours of the infusion (classified as Infusion-related reaction [IRR]). Amongst the reports received, nine were reported with complications, of which seven recovered, one is recovering, and one had a fatal outcome due to underlying SCD and refusal of blood transfusions due to personal reasons. In seven out of the nine reports with complications, steroids were used to treat the initial IRR.
Within the ongoing clinical program for crizanlizumab, two reports of IRRs similar to those received in the postmarketing setting have been reported; no complications have been reported and while one patient remains on therapy, one patient has discontinued therapy.
IRRs are a known side effect of monoclonal antibodies including crizanlizumab, and are included in the crizanlizumab label in countries where crizanlizumab has obtained marketing authorization for treatment of SCD as well as in investigational study documents and treatment plans for the ongoing trials in patients with SCD. Pain events, such as back pain, oropharyngeal pain, arthralgia, myalgia, abdominal pain, musculoskeletal chest pain, and infusion site pain are also included in the label (where applicable), investigational study documents and treatment plans, as adverse reactions. Arthralgia and back pain are listed as very common adverse (>10%) drug reactions in the label.
Novartis has also received other reports of patients who have experienced pain events within 24 hours of infusion along with other events that have occurred at or around the same time. Due to the nature of postmarketing reports, the information available in these reports is incomplete, and a confirmed diagnosis of the adverse event is often not included. Novartis is actively gathering additional information to better understand these reports.
**Postmarketing adverse event reports include spontaneous reports, managed access program (MAP) reports and patient orientation program (POP) reports. Spontaneous postmarketing reporting systems have several limitations, which can include underreporting and incompletely documented reports. Each report can include more than one event.
Ongoing actions and reviews
The following initiatives are ongoing:
- Novartis continues to analyze such reports to allow appropriate assessment of a potential causal relationship with treatment, as part of our routine safety monitoring for crizanlizumab.
- Novartis has informed health authorities and will continue to provide updates to those agencies.
Novartis is committed to patient safety and diligently monitors adverse events as part of our routine and ongoing safety monitoring processes across all Novartis products.
Considerations for health care professionals are provided here.
Novartis would like to sincerely thank health care professionals who have shared reports. Please report any observed or suspected adverse events according to local country requirements. You can also make a report to Novartis at https://www.report.novartis.com.
Safety event information
Postmarketing adverse event reports
As of June 15, 2021, 28 reports of severe pain events occurring during or within 24 hours of infusion have been reported, which differed in location, severity and/or nature from the patient’s baseline (with/without other associated signs/symptoms) and which are likely to represent symptomology of IRR.
All events were considered to have a potential causal relationship to crizanlizumab treatment based on the close temporal association of the event with crizanlizumab infusion and/or recurrence upon subsequent infusion.
- Of the 28 reports, 20 patients required hospitalization.
- In a majority of the reports, the pain events (IRR) occurred during infusion (5 to 30 minutes after initiation of infusion) and on the day of first or second dose of infusion. In four reports, the pain events (IRR) occurred after the second infusion (2 on 4th infusion, 1 on 8th infusion and 1 on 9th infusion).
- Nine (9) reports of complications such as acute chest syndrome (ACS), fat embolism syndrome, hemolytic crisis, pneumonia, and multi-organ failure were reported, of which in seven (7) reports patients had received steroid treatment for the initial presentation of IRR.
- Crizanlizumab treatment was discontinued in nearly all reports.
- Outcome in majority of reports was reported as recovered with one patient still recovering and one with a fatal outcome due to underlying SCD and refusal of blood transfusions due to personal reasons.
- Nine (9) reports received pretreatment prior to crizanlizumab infusion; the pretreatments included acetaminophen/paracetamol, hydration, ketorolac, diphenhydramine, methylprednisolone, and hydromorphone; however, no pattern/commonality of certain pretreatments was noted.
Acute and chronic pain are the clinical hallmark of SCD and complications as reported above are known to occur in SCD patients. Novartis continues to analyze such reports to allow appropriate assessment of a potential causal relationship with treatment, as part of the ongoing routine safety monitoring for crizanlizumab. The benefit-risk of crizanlizumab remains unchanged.
Clinical trial data (completed and ongoing trials)
The efficacy and safety of crizanlizumab was studied in a 52-week, randomized, multicenter, placebo-controlled, double-blind, Phase II, clinical trial SUSTAIN (NCT01895361). The study enrolled 198 patients with SCD across 60 centers in the United States, Brazil, and Jamaica. The study was designed to compare crizanlizumab 5.0 mg/kg and crizanlizumab 2.5 mg/kg vs placebo with the primary endpoint being the annual rate of vaso-occlusive crises (VOCs) in the crizanlizumab 5.0 mg/kg group vs placebo.
In the SUSTAIN trial, mild to moderate pain events commonly occurred during or within 24 hours of crizanlizumab infusions (approximately 5% of the infusions); however, only a few of these events differed in frequency between placebo and investigational arms. In SUSTAIN, infusion-related reactions were observed in patients treated with crizanlizumab; however, no severe hypersensitivity/anaphylactic reactions have been reported. Click here to access the primary manuscript published in New England Journal of Medicine.1
In the ongoing STAND trial (NCT03814746), a Phase III, multicenter, randomized, double-blind study to assess efficacy and safety of crizanlizumab versus placebo in adolescent and adult SCD patients with vaso-occlusive crises, a 21-year-old experienced IRR presenting as severe back, arm and leg pain within minutes of the first infusion requiring hospitalization and treatment of pain. The patient recovered without sequelae and continued on blinded study therapy; the patient also experienced a similar IRR of less severity within minutes of the second infusion (no hospitalization required) and recovered with pain treatment. The patient continues to receive blinded study therapy.
In the ongoing SOLACE-Kids trial (NCT03474965), a Phase 2, multicenter, open label study to assess appropriate dosing and to evaluate safety of crizanlizumab in pediatric (>6 month) SCD patients with vaso-occlusive crisis, a 10-year-old with history of back pain experienced few mild to moderate IRRs within 24 hours of infusions presenting as back pain (not requiring hospitalization) with the most recent IRR presenting as back pain following the 13th infusion which required hospitalization; patient was treated with pain medications and recovered without sequelae; however, discontinued upon parents’ request.
Note: Health care professionals and clinical trial investigators report what they diagnose or observe. In a clinical trial report submitted to health authorities, the terms reported by investigators are mapped to the closest terms found within a medical coding dictionary.
Considerations for health care professionals
Crizanlizumab diluted solution should be administered as per investigational study documents/treatment plans and label (in countries where it has been approved).
Consistent with standard clinical practice and sickle cell disease guidelines2,3:
- Patients should be monitored for and advised of signs and symptoms of infusion-related reactions after each infusion, which may include pain events along with other signs and symptoms of a hypersensitivity reaction and should be instructed to contact their health care professional if these symptoms occur.
- In the event of a severe reaction, discontinue crizanlizumab and initiate appropriate therapy.
- If a patient experiences a mild/moderate infusion-related reaction, the infusion should be slowed or interrupted and appropriate treatment initiated (eg, with analgesics, such as paracetamol/acetaminophen or NSAID, and antihistamines), as per institutional standard of care and at the discretion of the health care professional.
- In the event of a previous mild/moderate infusion-related reaction, health care professionals should consider premedication (eg, with antihistamine and/or analgesics) and/or slower infusion rate prior to initiating any future infusions.
- Corticosteroids should be used with caution in patients with SCD, unless clinically indicated (eg, treatment of anaphylaxis). For patients presenting with acute pain related to SCD, the 2020 guidelines from American Society of Hematology (available here) suggest against corticosteroids for acute pain management.3
Physicians, other health care professionals and patients are encouraged to report any observed or suspected adverse events according to local country requirements. You can make a report to Novartis at https://www.report.novartis.com.
- Ataga K, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017; 376:429-439.
- Picard M, Galvão VR. Current knowledge and management of hypersensitivity reactions to monoclonal antibodies. J Allergy Clin Immunol Pract. 2017; 5:600.
- 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.
In the European Union / European Economic Area, this medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See the local Product Information for how to report adverse reactions.