Novartis is fully committed to keeping health care professionals updated on the safety of crizanlizumab.
Crizanlizumab is currently being investigated in clinical trials globally. Marketing authorization has been obtained in the following countries: United States, Bahrain, Brazil, Albania, India, United Arab Emirates, Oman and Qatar.
As of July 5, 2020, approximately 1,800 patients with sickle cell disease (SCD) have been treated with crizanlizumab 5.0 mg/kg in clinical trials and the postmarketing setting.
Novartis proactively monitors and assesses crizanlizumab safety data from all available sources on a continuous basis. Since its marketing authorization in different countries, Novartis has received three postmarketing reports* of patients with SCD who have experienced severe pain during infusion (Infusion-related reaction [IRR]) and subsequently developed complications. All three cases have resolved or are resolving and a brief summary of them is provided in the safety event information section.
*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 cases.
Infusion-related reactions are a known side effect of monoclonal antibodies including crizanlizumab, and are included in the Warnings and Precautions and Adverse Reactions section of 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 a pain event within 24 hours of infusion along with other events that occurred. Due to the nature of postmarketing reports, the available information on these cases is incomplete, including a confirmed diagnosis of the adverse event. Novartis is actively gathering additional information to better understand these reports, as part of our ongoing comprehensive analysis. As of July 5, 2020, none of the patients who experienced these adverse events have died.
Ongoing actions and reviews
The following initiatives are ongoing:
- Novartis is conducting a comprehensive analysis of all available safety information including postmarketing reports and clinical trial data.
- A dedicated Novartis team is working with external sickle cell disease specialists to better understand and characterize these events and determine appropriate actions.
- 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 is 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.
Novartis will provide updates on this website as new information and considerations for health care professionals become available.
Safety event information
Postmarketing adverse event reports
As of July 5, 2020, there were three known postmarketing reports of patients with SCD who experienced severe pain during infusion associated with complications and were hospitalized:
- In one of these cases, a patient was reported to have experienced pain during the second infusion (first infusion was tolerated well) and subsequently developed acute chest syndrome (ACS); the event has resolved.
- In the second case, a patient was reported to have experienced pain during the first infusion and subsequently experienced fat embolism, ACS and multiorgan failure reported as life-threatening; the event was reported as resolving.
- In the third case, a patient was reported to have experienced pain during the first infusion and subsequently experienced exacerbation of hemolysis, requiring transfusion. It was reported that the reaction seemed to fit the pattern of what has been described as complement activation-related pseudoallergy (CARPA). The event has resolved.
All reports require further confirmation as acute and chronic pain are a clinical hallmark of SCD and ACS, fat emboli and multiorgan failure are known complications of the disease. As noted above, Novartis has also received other reports of patients who have experienced a pain event that occurred during or within 24 hours of infusion. Novartis is actively following up to better understand the reports to allow appropriate assessment of a potential causal relationship with treatment, as part of our ongoing comprehensive analysis.
SUSTAIN clinical trial data
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
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 signs and symptoms of infusion-related reactions, which may include pain events and hypersensitivity reactions.
- 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 can 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.
- Patients should be monitored until resolution of all observed symptoms, after which the infusion may be resumed at a slower rate, under continuous observation.
- Prior to reinitiating the infusion, health care professionals should consider premedication (eg, with antihistamine and/or analgesics).
- In the event of a previous mild/moderate infusion-related reaction, health care professionals should consider premedication (eg, with antihistamine and/or analgesics) prior to initiating any future infusions.
- In the event of recurring infusion-related reactions, despite premedication and prolonged infusion, discontinue crizanlizumab.
- Corticosteroids should be used with caution in patients with SCD. 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
- Patients should be informed about the possibility of infusion-related reactions, including pain events, and should be instructed to contact their health care professional if these symptoms occur.
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.