Crizanlizumab

Registered South African indications:

• Prevention of vaso-occlusive crises in sickle cell disease

Contraindications
South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to Chinese Hamster Ovary (CHO) cell agents

Cautions
South African manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Diabetes mellitus
• Fructose intolerance
• Glucose galactose malabsorption 
• Sucrase-isomaltase insufficiency
• Coadministration with corticosteroids in patients with sickle cell disease unless clinically indicated (e.g. treatment of anaphylaxis)
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Women of childbearing potential 
• Breastfeeding
• Severe renal impairment (eGFR<35ml/min/1.73m²)
• Hepatic impairment
• Elderly
• Coadministration with corticosteroids in patients with sickle cell disease unless clinically indicated (e.g. treatment of anaphylaxis)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Prevention of vaso-occlusive crises in sickle cell disease (Additional agent may be required)

• IV: 5mg/kg, as an infusion over 30min at week 0, week 2, and every 4 weeks thereafter

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Crizanlizumab can be given alone or with hydroxyurea (hydroxycarbamide)

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Method of administration: See additional prescribing points

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Instructions for use and handling: Crizanlizumab vials are for single use only

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Preparation of crizanlizumab solution for infusion: See additional prescribing points

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Delayed or missed dose: See additional prescribing points

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Management recommendations for infusion-related reactions: See additional prescribing points

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Special precautions for disposal: Any unused product or waste material should be disposed of in accordance with local requirements

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International manufacturer recommendations

Treatment should be initiated by physicians experienced in the management of sickle cell disease

Prevention of recurrent vaso-occlusive crises (VOCs) in sickle cell disease (Additional agent may be required)
- Given as add-on therapy to hydroxyurea/hydroxycarbamide (HU/HC) or as monotherapy in patients for whom HU/HC is inappropriate or inadequate

• IV: 5mg/kg, as an infusion over 30min at week 0, week 2, and every 4 weeks thereafter

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Delayed or missed doses: See additional prescribing points

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Management recommendations for infusion-related reactions: See additional prescribing points

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Method of administration: See additional prescribing points

Not established for use in children below 16 years

Pregnancy
South African manufacturer recommendations 

• Caution
• The safety of crizanlizumab in pregnancy has not been established
• Crizanlizumab is an immunoglobulin G (IgG) antibody that crosses the placental barrier. As there is no adequate experience in pregnant women, crizanlizumab should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus
• Animal reproduction studies in cynomolgus monkeys have not shown embryo-foetal toxicity or risk of increased foetal abnormalities after intravenous administration of crizanlizumab during organogenesis at doses up to 50mg/kg (approximately 16 times the human clinical exposure based on area under the curve (AUC) in patients with sickle cell disease at 5mg/kg once every 4 weeks)

International manufacturer recommendations

• Caution; positive evidence of risk in animal studies
• There is a limited amount of data from the use of crizanlizumab in pregnant women. Based on data from animal studies, crizanlizumab has the potential to cause foetal losses when administered to a pregnant woman. As a precautionary measure, it is preferable to avoid the use of crizanlizumab during pregnancy and in women of childbearing potential not using contraception
• To help determine the effects in pregnant women, healthcare professionals are encouraged to report all pregnancy cases and complications during pregnancy (from 105 days prior to the last menstrual period onward) to the local representative of the marketing authorisation holder, in order to allow monitoring of these patients through the pregnancy outcomes intensive monitoring programme (PRIM)

Breastfeeding
South African manufacturer recommendations

• Caution 
• A decision must be made whether to discontinue breastfeeding or to discontinue crizanlizumab therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. Because many medicinal agents, including antibodies, can be transferred into human milk, a risk to the newborns/infants cannot be excluded

International manufacturer recommendations

• Caution 
• It is unknown whether crizanlizumab is excreted in human milk after administration of crizanlizumab. There are no data on the effects of crizanlizumab on the breastfed newborn/infant or on milk production
• Because many medicinal agents, including antibodies, can be transferred into human milk, a risk to the newborns/infants cannot be excluded
• A decision must be made whether to discontinue breastfeeding or to discontinue crizanlizumab therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility 
South African manufacturer recommendations

• There are no data on the effect of crizanlizumab on human fertility. In a 26-week repeat-dose toxicity study, cynomolgus monkeys were administered crizanlizumab once every 4 weeks at doses up to 50mg/kg (at least 13.5 times the human clinical exposure based on AUC in patients with sickle cell disease at 5mg/kg once every four weeks). There were no adverse effects of crizanlizumab on male and female reproductive organs (organ weights, macroscopic and microscopic evaluations), sperm evaluations (motility, counts, morphology) and female menstrual cycles (number and mean duration) suggesting no effect on fertility under crizanlizumab treatment

International manufacturer recommendations

• There are no data on the effect of crizanlizumab on human fertility. Available non-clinical data do not suggest an effect on fertility under crizanlizumab treatment

Renal Impairment 
South African manufacturer recommendations

• Caution; no information available 

International manufacturer recommendations

• Mild to moderate (eGFR 35-202ml/min/1.73m²): No dose adjustment recommended 
  In a population pharmacokinetic (PK) analysis no clinically important differences in the pharmacokinetics of crizanlizumab were found between patients with mild or moderate renal impairment and patients with normal renal function
• Severe (eGFR<35ml/min/1.73m²): Caution; no information available 
  Data is too limited to draw conclusions 

Hepatic Impairment
South African manufacturer recommendations

• Caution; no information available

International manufacturer recommendations

• Caution; no information available 
  The safety and efficacy of crizanlizumab in patients with hepatic impairment have not been established. Crizanlizumab is a monoclonal antibody and is cleared via catabolism (i.e. breakdown into peptides and amino acids), and a change in dose is not expected to be required for patients with hepatic impairment

Elderly 
South African manufacturer recommendations

• Caution; no information available 

International manufacturer recommendations

• Caution; no dose adjustment recommended 
  Crizanlizumab has not been studied in elderly patients. No dose adjustment is required as the pharmacokinetics of crizanlizumab in adults are not affected by age

Central Nervous System Disorders

• Headache

 Respiratory Disorders 

• Chest pain

Gastrointestinal Disorders 

• Oropharyngeal pain
• Nausea and vomiting
• Abdominal pain
  - Upper abdominal pain 
  - Lower abdominal pain 
  - Abdominal discomfort
  - Abdominal tenderness
• Diarrhoea

Musculoskeletal Disorders 

• Arthralgia
• Back pain
• Myalgia
• Musculoskeletal chest pain
• Musculoskeletal pain
• Bone pain
• Muscle spasms
• Pain in extremity

Skin and Subcutaneous Tissue Disorders 

• Pruritus
  - Vulvovaginal pruritus
• Infusion site reaction
  - Infusion site extravasation
  - Infusion site pain
  - Infusion site swelling

Immune, Blood and Lymphatic System Disorders 

• Pyrexia

Others

• Pain
  - General body pain

No information available

Laboratory test interference

• Tubes containing ethylenediaminetetraacetic acid (EDTA) (See additional prescribing points)

Observations

• Signs and/or symptoms of infusion-related reactions

Traceability

• In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded

Method of administration 
South African manufacturer recommendations

• Crizanlizumab should be administered by a healthcare professional. Crizanlizumab should be diluted before administration with either sodium chloride 0.9% or dextrose 5%, and must be dosed on the basis of body weight
• Crizanlizumab diluted solution must be administered through a sterile, non-pyrogenic 0.2micron in-line filter by intravenous (IV) infusion over a period of 30 minutes. It must not be administered as IV push or bolus

International manufacturer recommendations

• Crizanlizumab should be diluted with sodium chloride 9mg/ml (0.9%) solution for injection or dextrose 5% before administration
• The diluted solution must be administered through a sterile, non-pyrogenic 0.2micron in-line filter by intravenous infusion over a period of 30 minutes. It must not be administered by intravenous push or bolus

Preparing the infusion

• The diluted solution for infusion should be prepared by a healthcare professional using aseptic techniques
• The total dose and required volume of crizanlizumab depend on the patient's body weight; 5mg of crizanlizumab is administered per kg body weight
• The volume to be used for the preparation of the infusion is calculated according to the following equation
  Volume (ml) = Patient body weight (kg) x prescribed dose [5mg/kg]/ Concentration of crizanlizumab [10mg/ml]
• Obtain the number of vials required to deliver the prescribed dose and bring them to room temperature (for a maximum of 4 hours). One vial is needed for every 10ml of crizanlizumab

Body weight (kg)	Dose (mg)	Volume (ml)	Vials (n)
40	200	20	2
60	300	30	3
80	400	40	4
100	500	50	5
120	600	60	6

• Visually inspect the vials
  - The solution in the vials should be clear to opalescent. Do not use if particles are present in the solution
  - The solution should be colourless or may have a slight brownish-yellow tint
• Withdraw a volume equal to the required volume of crizanlizumab from a 100ml infusion bag containing either sodium chloride 9mg/ml (0.9%) solution for injection or dextrose 5% and discard
  - No incompatibilities between the diluted crizanlizumab solution and infusion bags composed of polyvinylchloride (PVC), polyethylene (PE) and polypropylene (PP) have been observed
• Withdraw the necessary volume of crizanlizumab from the vials and inject slowly into the previously prepared infusion bag
  - The solution must not be mixed or co-administered with other medicinal products through the same intravenous line
  - Keep the volume of crizanlizumab added to the infusion bag in the range of 10-96ml to obtain a final concentration in the infusion bag within 1mg/ml to 9.6mg/ml
• Mix the diluted solution by gently inverting the infusion bag. DO NOT SHAKE
• Discard any unused crizanlizumab

After administration

• After administration of crizanlizumab, flush the line with at least 25ml sodium chloride 9mg/ml (0.9%) solution for injection or dextrose 5%

Storage of the diluted solution (South African manufacturer recommendations)

• The diluted solution for infusion should be administered as soon as possible. If not administered immediately, store the prepared solution either
  - At room temperature up to 25°C for no more than 4.5 hours from the start of the preparation to completion of the infusion
  - Under refrigeration at 2-8°C for no more than 24 hours from the start of the preparation to completion of the infusion. This includes the storage of the diluted solution at 2-8°C and the time to warm up at room temperature

Delayed or missed dose

• If a dose is missed, crizanlizumab should be administered as soon as possible
• If crizanlizumab is administered within 2 weeks after the missed dose, dosing should be continued according to the patient's original schedule
• If crizanlizumab is administered more than 2 weeks after the missed dose, dosing should be continued every 4 weeks thereafter

Management of infusion-related reactions

Severity of adverse reaction	Management recommendation
Mild (Grade 1) to moderate (Grade 2) infusion-related reactions	Temporarily interrupt or reduce the infusion rate Initiate symptomatic treatment* For subsequent infusions, consider premedication and/or slower infusion rate
Severe (≥ Grade 3) infusion-related reactions	Discontinue treatment with crizanlizumab Initiate symptomatic treatment*
*E.g. antipyretic, analgesic and/or antihistamine. Caution should be exercised with corticosteroids in patients with sickle cell disease unless clinically indicated (e.g. treatment of anaphylaxis)

Disposal (International manufacturer recommendations)

• Any unused medicinal product or waste material should be disposed of in accordance with local requirements

Laboratory test interference

• Interference with automated platelet counts (platelet clumping) has been observed in patients treated with crizanlizumab in clinical studies, in particular when tubes containing EDTA (ethylenediaminetetraacetic acid) were used. This may lead to unevaluable or falsely decreased platelet counts. There is no evidence that crizanlizumab causes a reduction in circulating platelets or has a pro-aggregant effect in vivo
• To mitigate the potential for laboratory test interference, it is recommended to run the test as soon as possible (within 4 hours of blood collection) or use citrate tubes. When needed, platelet counts can be estimated via a peripheral blood smear

Crizanlizumab is a selective immunoglobulin G (IgG2) kappa humanised monoclonal antibody (mAb) that binds to P-selectin with high affinity and blocks the interaction with its ligands, including P-selectin glycoprotein ligand 1. Crizanlizumab can also dissociate preformed P-selectin/PSGL-1 complex. P-selectin is an adhesion molecule expressed on activated endothelial cells and platelets. It plays an essential role in the initial recruitment of leukocytes and the aggregation of platelets to the site of vascular injury during inflammation. In the chronic pro-inflammatory state associated with sickle cell disease, P-selectin is over-expressed and circulating blood cells and the endothelium are activated and become hyperadhesive. P-selectin-mediated multi-cellular adhesion is a key factor in the pathogenesis of vaso-occlusion and vaso-occlusive crises (VOC). Elevated levels of P-selectin are found in patients with sickle cell disease. Binding P-selectin on the surface of the activated endothelium and platelets has been shown to effectively block interactions between endothelial cells, platelets, red blood cells and leukocytes, thereby preventing vaso-occlusion.

Injection (per 10ml) 100mg

• Ryverna 10mg/ml (Novartis) originator