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Novartis provides update on safety information about crizanlizumab.

This global site will be updated as new information and considerations for health care professionals become available.

Patient safety is our utmost priority at Novartis.

The benefit-risk of crizanlizumab remains unchanged.

Background

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 has been updated with additional information. The cases presented previously are included as part of the 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, Bahrain, Brazil, India, Kuwait, Lebanon, Oman, Qatar, South Africa and UAE.

As of October 20, 2020, approximately 3,500 patients with sickle cell disease (SCD) have been treated with crizanlizumab 5.0 mg/kg in clinical trials and in 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 22 postmarketing reports* of patients with SCD who have experienced severe pain during or within 24 hours of the infusion (infusion-related reaction [IRR]). Seven cases reported complications, which all resolved.

*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. Each report can include more than one event.

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 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, 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 October 20, 2020, none of the patients who experienced these adverse events have died.

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.

Further information

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.

Novartis will provide updates on this website as new information and considerations for health care professionals become available.

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Safety event information

Postmarketing adverse event reports

As of October 20, 2020, 22 cases 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 22 reports, 16 reports 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
  • Seven (7) reports complications such as acute chest syndrome (ACS), fat embolism syndrome, hemolytic crisis, pneumonia, and multi-organ failure were reported, of which in six (6) reports patients had received steroid treatment for the initial presentation of IRR
  • Crizanlizumab treatment was discontinued in nearly all cases.
  • All events resolved
  • Seven (7) cases received pretreatment prior to crizanlizumab infusion; the pretreatments included acetaminophen/paracetamol, hydration, ketorolac, diphenhydramine, methylprednisolone, and hydromorphone; however, no pattern/commonality of certain pre-treatments 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 our ongoing routine safety monitoring for crizanlizumab. The benefit risk of crizanlizumab remains unchanged.

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.

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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, 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 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.
  • 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.

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References

  1. 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.
  2. Picard M, Galvão VR. Current knowledge and management of hypersensitivity reactions to monoclonal antibodies. J Allergy Clin Immunol Pract. 2017; 5:600.
  3. 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.
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