Daratumumab

Registered South African indications:

• Multiple myeloma

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Coadministration of live attenuated vaccines
  (See additional prescribing points)

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

South African manufacturer recommendations

• Women of childbearing potential and for 3 months after cessation of treatment
• History of chronic obstructive pulmonary disease
• Positive hepatitis B virus serology
• Mannitol intolerance
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Women of childbearing potential and for 3 months after cessation of treatment
• Breastfeeding
• History of chronic obstructive pulmonary disease
• Positive hepatitis B virus serology
• May impair ability to drive and operate machinery

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

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Daratumumab should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions (IRRs) if they occur

Used for the treatment of

• Newly diagnosed multiple myeloma (Additional agents are required)
  - In combination with bortezomib, melphalan and prednisone OR lenalidomide and dexamethasone in those who are ineligible for autologous stem cell transplant (ASCT)
  - In combination with bortezomib, thalidomide and dexamethasone in those who are eligible for autologous stem cell transplant (ASCT)
• Multiple myeloma (Additional agents are required)
  - In combination with lenalidomide and dexamethasone OR bortezomib and dexamethasone in those who have received at least one prior therapy
  - In combination with pomalidomide and dexamethasone in those who have received at least two prior therapies
• Relapsed and refractory multiple myeloma
  - In those whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy

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If a planned dose of daratumumab is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval

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No dose reductions of daratumumab are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of haematological toxicity

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See additional prescribing points for administration directions; management of infusion related reactions; and pre- and post-infusion medication

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Consult specialist for dosages and regimens

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International manufacturer recommendations

Daratumumab should be administered by a healthcare professional, in an environment where resuscitation facilities are available

Used for the treatment of

• Newly diagnosed multiple myeloma (Additional agents are required)
  - In combination with lenalidomide and dexamethasone, OR with bortezomib, melphalan and prednisone in those who are ineligible for autologous stem cell transplant
• Newly diagnosed multiple myeloma (Additional agents are required)
  - In combination with bortezomib, thalidomide and dexamethasone in those who are eligible for autologous stem cell transplant
• Multiple myeloma (Additional agents are required)
  - In combination with lenalidomide and dexamethasone, OR bortezomib and dexamethasone in those who have received at least one prior therapy
• Relapsed and refractory multiple myeloma
  - In those whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy 

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If a planned dose of daratumumab is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval

---

No dose reductions of daratumumab are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of haematological toxicity

---

See additional prescribing points for administration directions; management of infusion related reactions; and pre- and post-infusion medication

---

Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

South African manufacturer recommendations

• Contraindicated
• Daratumumab should not be used during pregnancy
• IgG1 monoclonal antibodies are known to cross the placenta after the first trimester of pregnancy
• If the patient becomes pregnant while taking daratumumab, the patient should be informed of the potential risk to the foetus
• To avoid exposure to the foetus, women of childbearing potential should use effective contraception during, and for 3 months after cessation of daratumumab treatment

International manufacturer recommendations

• Caution; not recommended
• There are no or limited amount of data from the use of daratumumab in pregnant women
• Animal studies are insufficient with respect to reproductive toxicity
• Daratumumab is not recommended during pregnancy and in women of childbearing potential not using contraception
• Women of childbearing potential should use effective contraception during, and for 3 months after cessation of daratumumab treatment

Breastfeeding

South African manufacturer recommendations

• Contraindicated 
• Maternal IgG is excreted in human milk but does not enter the neonatal and infant circulations in substantial amounts as they are degraded in the gastrointestinal tract and not absorbed
• Because the risks of daratumumab to the infant from oral ingestion are unknown, a woman receiving daratumumab should not breastfeed her infant

International manufacturer recommendations

• Caution; not recommended 
• It is unknown whether daratumumab is excreted in human milk
• A risk to newborns/infants cannot be excluded
• A decision must be made whether to discontinue/abstain from breastfeeding or to discontinue daratumumab therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

South African manufacturer recommendations

• No information available

International manufacturer recommendations

• No data are available to determine potential effects of daratumumab on fertility in males or females

Renal Impairment

• No dose adjustment recommended 

Hepatic Impairment

• No dose adjustment recommended 

Elderly

• No dose adjustment recommended 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Peripheral sensory neuropathy
• Headache
• Paraesthesia
• Fatigue
• Syncope

Cardiovascular Disorders

• Hypertension
• Atrial fibrillation

Respiratory Disorders

• Upper respiratory tract infection
• Bronchitis
• Pneumonia
• Cough
• Dyspnoea
• Influenza
• Pulmonary oedema

Gastrointestinal Disorders

• Constipation
• Diarrhoea
• Nausea and vomiting
• Pancreatitis

Genitourinary Disorders

• Urinary tract infection

Endocrine and Metabolic Disorders

• Decreased appetite
• Hyperglycaemia
• Hypocalcaemia
• Dehydration

Musculoskeletal Disorders

• Back pain
• Muscle spasms

Immune, Blood and Lymphatic System Disorders

• Neutropenia
• Thrombocytopenia
• Anaemia
• Lymphopenia
• Leukopenia
• Peripheral oedema
• Pyrexia
• Chills
• Sepsis
• Cytomegalovirus infection
• Hypogammaglobulinemia
• Hepatitis B virus reactivation (including fatal outcomes)
  (See additional prescribing points)
• Anaphylactic reaction
• Infusion-related reaction
  - Bronchospasm
  - Dyspnoea
  - Laryngeal oedema
  - Pulmonary oedema
  - Hypoxia
  - Hypertension
  - Nasal congestion
  - Cough
  - Chills
  - Throat irritation
  - Nausea and vomiting

Other interactions

• Indirect Coombs test
  (See additional prescribing points)
• Serum protein electrophoresis and immunofixation tests
  (See additional prescribing points)

• Full blood count
• Blood type and screening
• Hepatitis B virus screening
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Specific cases may require

• Ophthalmologic examination

Additional observations

• Signs and symptoms of
  - Hepatitis B virus (HBV) reactivation
  - Infection
  - Ocular adverse reactions
  - Bleeding
• 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

Interference with indirect antiglobulin test (indirect Coombs test)

• Daratumumab binds to CD38 found at low levels on red blood cells (RBCs) and may result in a positive indirect Coombs test
• Daratumumab-mediated positive indirect Coombs test may persist for up to 6 months after the last daratumumab infusion
• It should be recognised that daratumumab bound to RBCs may mask detection of antibodies to minor antigens in the patient's serum
• The determination of a patient's ABO and Rh blood type are not impacted
• Patients should be typed and screened prior to starting daratumumab treatment
• Phenotyping may be considered prior to starting daratumumab treatment as per local practice. Red blood cell genotyping is not impacted by daratumumab and may be performed at any time
• In the event of a planned transfusion blood transfusion centres should be notified of this interference with indirect antiglobulin tests
• If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices

Interference with serum protein electrophoresis and immunofixation tests

• Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein)
• This can lead to false positive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria
• In patients with persistent very good partial response, where daratumumab interference is suspected, consider using a validated daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient's serum, to facilitate determination of a complete response

Method of preparation and storage

• This medicinal product is for single-use only
• Prepare the solution for infusion using aseptic technique
• Calculate the dose (mg), total volume (ml) of daratumumab solution required and the number of daratumumab vials needed based on patient weight
• Check that the daratumumab solution is colourless to yellow. Do not use if opaque particles, discolouration or other foreign particles are present
• Using aseptic technique, remove a volume of 0.9% sodium chloride from the infusion bag/container that is equal to the required volume of daratumumab solution
• Withdraw the necessary amount of daratumumab solution and dilute to the appropriate volume by adding to an infusion bag/container containing 0.9% sodium chloride
• Infusion bags/containers must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE)
• Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial
• Gently invert the bag/container to mix the solution. Do not shake
• Parenteral medicines should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit
• The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discolouration or foreign particles are observed
• Since daratumumab does not contain a preservative, diluted solutions should be administered within 15 hours (including infusion time) at room temperature (15-25°C) and in room light
• If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours at refrigerated conditions (2-8°C) and protected from light. Do not freeze
• This medicinal product must not be mixed with other medicinal products except those mentioned as per manufacturer's prescribing information

Method of administration

• Daratumumab is administered as an intravenous infusion following dilution with 0.9% sodium chloride
• Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in line, sterile, non-pyrogenic, low protein binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometre)
• Polyurethane (PU), polybutadiene (PBD), PVC, PP or PE administration sets must be used
• Do not infuse daratumumab concomitantly in the same intravenous line with other medicines
• Following dilution, the daratumumab infusion should be intravenously administered at the appropriate initial infusion rate
• Incremental escalation of the infusion rate should be considered only in the absence of infusion reactions
• Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements

Pre-infusion medication

• Pre-infusion medications should be administered to reduce the risk of IRRs to all patients 1-3 hours prior to every infusion of daratumumab
• Corticosteroid (long-acting or intermediate-acting)
  - Monotherapy: Methylprednisolone 100mg, or equivalent, administered intravenously. Following the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60mg)
  - Combination therapy: Administer 20mg dexamethasone (or equivalent) prior to every daratumumab infusion. When dexamethasone is the background regimen specific corticosteroid, the dexamethasone treatment dose will instead serve as pre-medication on daratumumab infusion days. Dexamethasone is given intravenously prior to the first daratumumab infusion and oral administration may be considered prior to subsequent infusions. Additional background regimen specific corticosteroids (e.g. prednisone) should not be taken on daratumumab infusion days when patients have received dexamethasone as a pre-medication
• Antipyretics (oral paracetamol 650-1000mg)
• Antihistamine (oral or intravenous diphenhydramine 25-50mg or equivalent)

Post-infusion medication

• Post-infusion medications should be administered to reduce the risk of delayed infusion-related reactions
• Monotherapy: Oral corticosteroid (20mg methylprednisolone or equivalent dose of an intermediate-acting or long-acting corticosteroid in accordance with local standards) should be administered on each of the two days following all infusions (beginning the day after the infusion)
• Combination therapy: Consider administering low-dose oral methylprednisolone (≤20mg) or equivalent the day after the daratumumab infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the daratumumab infusion, additional post-infusion medications may not be needed
• Additionally, for patients with a history of chronic obstructive pulmonary disease, consider the use of post-infusion medications including short and long acting bronchodilators, and inhaled corticosteroids. Following the first four infusions, if the patient experiences no major IRRs, these inhaled post-infusion medications may be discontinued at the discretion of the medical practitioner

Management of infusion-related reactions (IRRs)

• Administer pre-infusion medications to reduce the risk of IRRs prior to treatment with daratumumab
• For IRRs of any grade/severity, immediately interrupt the daratumumab infusion and manage symptoms
• Management of IRRs may further require reduction in the rate of infusion, or treatment discontinuation of daratumumab
• Grade 1-2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the IRR occurred. If the patient does not experience any further IRR symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to a maximum rate of 200ml/hour
• Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as appropriate. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue daratumumab upon the third occurrence of a Grade 3 or greater infusion reaction
• Grade 4 (life-threatening): Permanently discontinue daratumumab treatment

Prophylaxis for herpes zoster virus reactivation

• Anti-viral prophylaxis should be considered for the prevention of herpes zoster virus reactivation

Hepatitis B virus (HBV) reactivation

• Hepatitis B virus reactivation, in some cases fatal, has been reported in patients treated with daratumumab
• HBV screening should be performed in all patients before initiation of treatment with daratumumab
• For patients with evidence of positive HBV serology, monitor for clinical and laboratory signs of HBV reactivation during, and for at least six months following the end of daratumumab treatment. Manage patients according to current clinical guidelines. Consider consulting a hepatitis disease expert as clinically indicated
• In patients who develop reactivation of HBV while on daratumumab, suspend treatment with daratumumab and institute appropriate treatment
• Resumption of daratumumab treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV

Coadministration with vaccines

• Currently, there are no data regarding a potential interaction between daratumumab and vaccines
• It is recommended that live viral or live bacterial vaccines should not be given concurrently with monoclonal antibodies

Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed at a high level on the surface of multiple myeloma tumour cells, as well as other cell types and tissues at various levels. CD38 protein has multiple functions such as receptor mediated adhesion, signalling and enzymatic activity. Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumour cells. Based on in vitro studies, daratumumab may utilise multiple effector functions, resulting in immune mediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysis through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+T_regs) and B cells (CD38+B_regs) are decreased by daratumumab mediated cell lysis. T cells (CD3+, CD4+, and CD8+) are also known to express CD38 depending on the stage of development and the level of activation. Significant increases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observed with daratumumab treatment in peripheral whole blood and bone marrow. In addition, T-cell receptor DNA sequencing verified that T-cell clonality was increased with daratumumab treatment, indicating immune modulatory effects that may contribute to clinical response. Daratumumab induced apoptosis in vitro after Fc mediated cross-linking. In addition, daratumumab modulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating the hydrolase activity. The significance of these in vitro effects in a clinical setting, and the implications on tumour growth, are not well-understood.

Infusion (per ml) 20mg

• Darzalex (Janssen Pharmaceutica) originator