Darzalex

/ J-C Health Care Ltd

The recommended dose is 16 mg/kg body weight administered as an intravenous infusion.
Dosing schedule in combination with lenalidomide and dexamethasone (4-week cycle regimen) and for monotherapy
Weeks 1 to 8 – weekly (total of 8 doses)
Weeks 9 to 24 – every two weeks (total of 8 doses) (First dose of the every-2-week dosing schedule is given at week 9)
Week 25 onwards until disease progression – every four weeks (First dose of the every 4 week dosing schedule is given at week 25).
Dexamethasone should be administered at 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years).
Dosing schedule in combination with bortezomib, melphalan and prednisone (6-week cycle regimens)
Weeks 1 to 6 – weekly (total of 6 doses)
Weeks 7 to 54 – every three weeks (total of 16 doses) (First dose of the every-3-week dosing schedule is given at week 7)
Week 55 onwards until disease progression – every four weeks  (First dose of the every-4-week dosing schedule is given at week 55)
Bortezomib is given twice weekly at weeks 1, 2, 4 and 5 for the first 6-week cycle, followed by once weekly at weeks 1, 2, 4 and 5 for eight more 6-week cycles.
Dosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycle regimens) for treatment of newly diagnosed patients eligible for autologous stem cell transplant (ASCT)
Induction
Weeks 1 to 8 – weekly (total of 8 doses)
Weeks 9 to 16 – every two weeks (total of 4 doses) (First dose of the every-2-week dosing schedule is given at week 9).
Stop for high dose chemotherapy and ASCT
Consolidation
Weeks 1 to 8 – every two weeks (total of 4 doses) (First dose of the every-2-week dosing schedule is given at week 1 upon re-initiation of treatment following ASCT).
Dexamethasone should be administered at 40 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 of cycles 1 and 2, and at 40 mg on days 1-2 and 20 mg on subsequent dosing days (days 8, 9, 15, 16) of cycles 3-4. Dexamethasone 20 mg should be administered on days 1, 2, 8, 9, 15, 16 in cycles 5 and 6.
Dosing schedule in combination with bortezomib and dexamethasone (3-week cycle regimen)
Weeks 1 to 9 – weekly (total of 9 doses)
Weeks 10 to 24 – every three weeks (total of 5 doses) (First dose of the every-3-week dosing schedule is given at week 10)
Week 25 onwards until disease progression – every four weeks (First dose of the every-4-week dosing schedule is given at week 25)
Dexamethasone should be administered at 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 bortezomib treatment cycles or a reduced dose of 20 mg/week for patients > 75 years, underweight (BMI <18.5), poorly controlled diabetes mellitus or prior intolerance to steroid therapy.
Infusion rates
Week 1 Infusion
Option 1 (Single dose infusion)
Week 1 day 1 (16 mg/kg) – 1000 mL – First hour 50 mL/hour – Rate increment 50 mL/hour every hour – Maximum rate 200 mL/hour
Option 2 (Split dose infusion)
Week 1 day 1 (8 mg/kg) – 500 mL – First hour 50 mL/hour – Rate increment 50 mL/hour every hour – Maximum rate 200 mL/hour
Week 1 day 2 (8 mg/kg) – 500 mL – First hour 50 mL/hour – Rate increment 50 mL/hour every hour – Maximum rate 200 mL/hour
Week 2 (16 mg/kg) infusion
500 mL – First hour 50 mL/hour – Rate increment 50 mL/hour every hour – Maximum rate 200 mL/hour
Subsequent (week 3 onwards, 16 mg/kg) infusions
500 mL – First hour 100 mL/hour – Rate increment 50 mL/hour every hour – Maximum rate 200 mL/hour
Incremental escalation of the infusion rate should be considered only in the absence of infusion reactions.
To facilitate administration, the first prescribed 16 mg/kg dose at week 1 may be split over two consecutive days i.e. 8 mg/kg on day 1 and day 2 respectively
* A dilution volume of 500 mL for the 16 mg/kg dose should be used only if there were no IRRs the previous week. Otherwise, use a dilution volume of 1000 mL.
* A modified initial rate (100 mL/hour) for subsequent infusions (i.e. week 3 onwards) should only be used only if there were no IRRs during the previous infusion. Otherwise, continue to use instructions indicated in the table for the week 2 infusion rate.
Management of infusion-related reactions
Pre-infusion medicinal products should be administered to reduce the risk of infusion-related reactions (IRRs) prior to treatment.
For IRRs of any grade/severity, immediately interrupt the infusion and manage symptoms.
• Grade 1-2 (mild to moderate): Once reaction symptoms resolve, the infusion should be resumed 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 be resumed at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour.
• Grade 3 (severe): Once reaction symptoms resolve, restarting of the infusion may be considered at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, infusion rate escalation may be resumed at increments and intervals as appropriate. The procedure above should be repeated in the event of recurrence of grade 3 symptoms. Permanently discontinue upon the third occurrence of a grade 3 or greater infusion reaction.
• Grade 4 (life-threatening): Permanently discontinue treatment.
Dose modifications
No dose reductions are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of haematological toxicity.
Pre-infusion
Pre-infusion medicinal products should be administered to reduce the risk of IRRs to all patients 1-3 hours prior to every infusion
Corticosteroid (long-acting or intermediate-acting):
Monotherapy:
Methylprednisolone 100 mg, or equivalent, administered intravenously. Following the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg).
Combination therapy:
Dexamethasone 20 mg (or equivalent), administered prior to every infusion. When dexamethasone is the background-regimen specific corticosteroid, the dexamethasone treatment dose will instead serve as pre-infusion medicinal product on infusion days.
Dexamethasone is given intravenously prior to the first infusion and oral administration may be considered prior to subsequent infusions. Additional background regimen specific corticosteroids (e.g. prednisone) should not be taken on infusion days when patients have received dexamethasone as a pre-infusion medicinal product.
Antipyretics: oral paracetamol 650 to 1000 mg
Antihistamine: oral or intravenous diphenhydramine 25 to 50 mg or equivalent
Post-infusion
Monotherapy:
Oral corticosteroid (20 mg 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 (≤ 20 mg) or equivalent the day after infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the infusion, additional post-infusion medicinal products may not be needed.
Additionally, for patients with a history of chronic obstructive pulmonary disease, the use of post-infusion medicinal products including short and long acting bronchodilators, and inhaled corticosteroids should be considered. Following the first four infusions, if the patient experiences no major IRRs, these inhaled post-infusion medicinal products may be discontinued.
Prophylaxis for herpes zoster virus reactivation
Anti-viral prophylaxis should be considered.
Method of administration
Intravenous use. It is administered as an intravenous infusion following dilution with sodium chloride 9 mg/mL (0.9%) solution for injection.
See prescribing information for full details.

* In combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

* In combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.

* In combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

* Monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

Hypersensitivity to the active substance or to any of the excipients.

Infusion-related reactions
Serious IRRs, including anaphylactic reactions. 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.
The majority of IRRs occurred at the first infusion and were grade 1-2. 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.
Patients should be pre-medicated with antihistamines, antipyretics and corticosteroids to reduce the risk of IRRs prior to treatment.
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 and permanently.
To reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patients following 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 infusion and seek immediate ophthalmologic evaluation prior to restarting.
Neutropenia/thrombocytopenia
Daratumumab may increase neutropenia and thrombocytopenia induced by background therapy.
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. Daratumumab delay may be required to allow recovery of blood cell counts. No dose reduction of daratumumab is recommended. Consider supportive care with transfusions or growth factors.
Infections
Daratumumab can cause serious, life-threatening, or fatal infections.
Patients should be closely monitored for signs and symptoms of infection prior to and during treatment and treated appropriately. Prophylactic antimicrobials according to treatment guidelines should be considered prior to, during or post-treatment
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.
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. 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 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 treatment.
In patients who develop reactivation of HBV while on daratumumab, suspend treatment and institute appropriate treatment.
Excipients: This medicinal product contains sorbitol. Patients with hereditary fructose intolerance (HFI) must not be given this medicinal product unless strictly necessary.
See prescribing information for full details.

Very common: Upper respiratory tract infection, COVID-19, Pneumonia, Bronchitis, Neutropenia, Thrombocytopenia, Anaemia, Lymphopenia, Leukopenia, Decreased appetite, Hypokalaemia, Hyperglycaemia, Hypocalcaemia, Dehydration, Insomnia, Peripheral neuropathy, Headache, Paraesthesia, Dizziness, Hypertension, Cough, Dyspnoea, Constipation, Diarrhoea, Nausea, Vomiting, Abdominal pain, Rash, Musculoskeletal pain, Arthralgia, Muscle spasms, Oedema peripheral, Fatigue, Pyrexia, Asthenia, Infusion-related reaction.
Common: Urinary tract infection, Sepsis, Cytomegalovirus infection, Hypogammaglobulinemia, Hyperglycaemia, Hypocalcaemia, Dehydration, Syncope, Atrial fibrillation, Pulmonary oedema, Pancreatitis, Pruritus, Chills.
See prescribing information for full details.

No interaction studies have been performed.
See prescribing information for full details.

Pregnancy: Women of child-bearing potential should use effective contraception during, and for 3 months. There are no human or animal data to assess the risk of daratumumab use during pregnancy.
See prescribing information for full details.
Lactation: It is not known whether daratumumab is excreted into human or animal milk.  

Symptoms and signs: There has been no experience of overdosage in clinical studies. Doses up to 24 mg/kg have been administered intravenously in a clinical study.
Treatment: There is no known specific antidote for daratumumab overdose. In the event of an overdose, the patient should be monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment should be instituted immediately.

Storage: Store in a refrigerator (2 °C-8 °C). Do not freeze or shake. Store in the original package in order to protect from light.