Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use


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.


Infusion-related reactions
DARZALEX 20MG/ML I.V can cause serious IRRs, including anaphylactic reactions (see section 4.8). These reactions can be life-threatening and fatal outcomes have been reported.

All patients should be monitored throughout the infusion for IRRs. For patients that experience any grade IRRs, continue monitoring post-infusion until symptoms resolve.
In clinical studies, IRRs were reported in approximately half of all patients treated with DARZALEX 20MG/ML I.V.

The majority of IRRs occurred at the first infusion and were grade 1-2 (see section 4.8). Four percent of all patients had an IRR at more than one infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension, laryngeal oedema, pulmonary oedema and ocular adverse reactions (including choroidal effusion, acute myopia and acute angle closure glaucoma).
Symptoms predominantly included nasal congestion, cough, throat irritation, chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision (see section 4.8).

Patients should be pre-medicated with antihistamines, antipyretics and corticosteroids to reduce the risk of IRRs prior to treatment with DARZALEX 20MG/ML I.V. DARZALEX 20MG/ML I.V.
infusion should be interrupted for IRRs of any severity and medical management/supportive treatment for IRRs should be instituted as needed. For patients with grade 1, 2, or 3 IRRs, the infusion rate should be reduced when re-starting the infusion. If an anaphylactic reaction or life-threatening (grade 4) infusion reaction occurs, appropriate emergency resuscitation should be initiated immediately. DARZALEX 20MG/ML I.V. therapy should be discontinued immediately and permanently (see sections 4.2 and 4.3).

To reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patients following DARZALEX 20MG/ML I.V infusions. Additionally the use of post-infusion medicinal products (e.g. inhaled corticosteroids, short and long acting bronchodilators) should be considered for patients with a history of chronic obstructive pulmonary disease to manage respiratory complications should they occur If ocular symptoms occur, interrupt DARZALEX 20MG/ML I.V. infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX 20MG/ML I.V. (see section 4.2).

Neutropenia/thrombocytopenia
DARZALEX 20MG/ML I.V may increase neutropenia and thrombocytopenia induced by background therapy (see section 4.8).
Complete blood cell counts should be monitored periodically during treatment according to prescribing information for background therapies. Patients with neutropenia should be monitored for signs of infection. DARZALEX 20MG/ML I.V delay may be required to allow recovery of blood cell counts. No dose reduction of DARZALEX 20MG/ML I.V is recommended. Consider supportive care with transfusions or growth factors.

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 (see section 4.5). If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices.

Interference with determination of complete response
Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of 
endogenous M-protein (see section 4.5). This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Hepatitis B virus (HBV) reactivation
Hepatitis B virus reactivation, in some cases fatal, has been reported in patients treated with DARZALEX 20MG/ML I.V. HBV screening should be performed in all patients before initiation of treatment with DARZALEX 20MG/ML I.V.
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 DARZALEX 20MG/ML I.V 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 DARZALEX 20MG/ML I.V, suspend treatment with DARZALEX 20MG/ML I.V and institute appropriate treatment. Resumption of DARZALEX 20MG/ML I.V treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.

Excipients
Each 5 mL and 20 mL vial of DARZALEX 20MG/ML I.V contains 0.4 mmol and 1.6 mmol (9.3 mg and 37.3 mg) sodium, respectively. This corresponds to 0.46% and 1.86% of the WHO recommended maximum daily intake of 2 g sodium for an adult, respectively.

Effects on Driving

4.7   Effects on ability to drive and use machines

DARZALEX 20MG/ML I.V has no or negligible influence on the ability to drive and use machines.
However, fatigue has been reported in patients taking daratumumab and this should be taken into account when driving or using machines.