DARZALEX 20 mg/mL concentrate for solution for infusion.

  • Name:

    DARZALEX 20 mg/mL concentrate for solution for infusion.

  • Company:
    info
  • Active Ingredients:

    Daratumumab

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 02/07/19

files-icon(Click to Download)
Summary of Product Characteristics last updated on medicines.ie: 2/7/2019
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Click on this link to Download PDF directly

Janssen Sciences Ireland

Company Products

Medicine NameActive Ingredients
Medicine Name Caelyx pegylated liposomal 2mg/ml concentrate for solution for infusion Active Ingredients Doxorubicin hydrochloride
Medicine Name CONCERTA XL 18 mg prolonged-release tablets Active Ingredients Methylphenidate Hydrochloride
Medicine Name Concerta XL 27mg Active Ingredients Methylphenidate Hydrochloride
Medicine Name Concerta XL 36 mg prolonged-release tablets Active Ingredients Methylphenidate Hydrochloride
Medicine Name Dacogen 50 mg powder for concentrate for solution for infusion. Active Ingredients Decitabine
Medicine Name Daktacort 2% 1% Cream Active Ingredients Hydrocortisone, Miconazole nitrate
Medicine Name DARZALEX 20 mg/mL concentrate for solution for infusion. Active Ingredients Daratumumab
Medicine Name Durogesic DTrans 100 micrograms/hour Transdermal Patch Active Ingredients Fentanyl
Medicine Name Durogesic DTrans 12 micrograms/hour Transdermal Patch Active Ingredients Fentanyl
Medicine Name Durogesic DTrans 25 micrograms/hour Transdermal Patch Active Ingredients Fentanyl
Medicine Name Durogesic DTrans 50 micrograms/hour Transdermal Patch Active Ingredients Fentanyl
Medicine Name Durogesic DTrans 75 micrograms/hour Transdermal Patch Active Ingredients Fentanyl
Medicine Name Durogesic DTrans Transdermal Patch Active Ingredients Fentanyl
Medicine Name Edurant 25mg film-coated tablets Active Ingredients Rilpivirine Hydrochloride
Medicine Name Erleada 60 mg film coated tablets Active Ingredients Apalutamide
Medicine Name Evorel 50 micrograms per 24 hours Transdermal Patch Active Ingredients Estradiol Hemihydrate
Medicine Name Evorel Conti Active Ingredients Estradiol Hemihydrate, Norethisterone acetate
Medicine Name Evra transdermal patch Active Ingredients Ethinylestradiol, Norelgestromin
Medicine Name Gyno-Daktarin 20 mg/g vaginal cream Active Ingredients Miconazole nitrate
Medicine Name Gyno-Pevaryl Once 150mg vaginal pessary Active Ingredients Econazole Nitrate
Medicine Name Haldol Decanoate Active Ingredients Haloperidol decanoate
Medicine Name IMBRUVICA 140 mg, 280 mg, 420 mg and 560 mg film-coated tablets Active Ingredients Ibrutinib
Medicine Name Intelence 200 mg tablets Active Ingredients Etravirine
Medicine Name Invega 3 mg, 6mg, 9mg, 12mg prolonged-release tablets Active Ingredients Paliperidone
Medicine Name Lyrinel XL 5mg & 10mg prolonged release tablets Active Ingredients Oxybutynin Hydrochloride
1 - 0 of 55 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 2 July 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 2 July 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.4     Special warnings and precautions for use

 

 

Hepatitis B virus (HBV) Reactivation

Hepatitis B virus reactivation, in some cases fatal, has been reported in patients treated with DARZALEX. HBV screening should be performed in all patients before initiation of treatment with DARZALEX.

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 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, suspend treatment with DARZALEX and institute appropriate treatment. Resumption of DARZALEX treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.

 

 

4.8     Undesirable effects

 

 

Infections and infestations

Pneumoniaa

Very Common

16

11

Upper respiratory tract infectiona

50

5

Influenza

Common

4

1*

Hepatitis B Virus reactivationb

Uncommon

-

-

Updated on 21 December 2018 PIL

Reasons for updating

  • Change to section 3 - dose and frequency
  • Change to section 6 - date of revision

Updated on 21 December 2018 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

 

 

 

 

 

 

 

 

 

 

Updated on 10 December 2018 PIL

Reasons for updating

  • Change to section 6 - what the product looks like and pack contents
  • Change to section 6 - date of revision

Updated on 10 December 2018 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container
  • Change to section 8 - Marketing authorisation number(s)
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

6.5     Nature and contents of container

 

5 mL concentrate in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip‑off button containing 100 mg of daratumumab. Pack size of 1 vial.

20 mL concentrate in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip‑off button containing 400 mg of daratumumab. Pack size of 1 vial.

DARZALEX is also supplied as an initiation pack containing 11  vials : (6 x 5 mL vials + 5 x 20 mL vials).

 

8.       MARKETING AUTHORISATION NUMBER(S)

 

EU/1/16/1101/001

EU/1/16/1101/002

EU/1/16/1101/003

 

 

 

Updated on 30 October 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Change of distributor details

Updated on 4 September 2018 PIL

Reasons for updating

  • Change to section 1 - what the product is used for
  • Change to section 3 - duration of treatment
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 4 September 2018 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Addition 4.2       Posology and method of administrationof a new indication.

DARZALEX is indicated:

  • in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

4.2       Posology and method of administration

This section has been extensively revised

 

 

Section 4.8

 

 

Added. very common , hu ypertension  Common: pulmonary oedema

 

Section 5.1 and 5.2 updated

Updated on 28 June 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Unforunately the is section will not allow all the changes to be published. Please conatc Janssen-Cilag Ltd medical informatiomn if you would like the details of the changes

Updated on 28 June 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision
  • Change to information for healthcare professionals

Updated on 16 May 2018 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

 

Updated on 16 August 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 16 August 2017 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

6.3     Shelf life

 

Unopened vials

18  24 months

Updated on 16 August 2017 PIL

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

 

6.3     Shelf life

 

Unopened vials

18  24 months

Updated on 3 May 2017 PIL

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

4.1       Therapeutic indications

DARZALEX is indicated:

·                as monotherapy is indicated 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.

·                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

 

 

4.2          Posology and method of administration

 

Dose

Standard dosing for monotherapy and in combination with lenalidomide (4week cycle regimen):

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 1.:

 

 

Table 1:         Standard DARZALEX dosing schedule for monotherapy and in combination with lenalidomide (4-week cycle dosing regimen)

Weeks

Schedule

Weeks 1 to 8

weekly (total of 8 doses)

Weeks 9 to 24a

every two weeks (total of 8 doses)

Week 25 onwards until disease progressionb

every four weeks

a     First dose of the every-2-week dosing schedule is given at week 9

b     First dose of the every-4-week dosing schedule is given at week 25

 

 

For dose and schedule of medicinal products administered with DARZALEX, see section 5.1 and the corresponding Summary of Product Characteristics.

 

Modified dosing schedule in combination with bortezomib (3week cycle regimen):

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 2.

 

Table 2:         Modified DARZALEX dosing schedule in combination with bortezomib (3-week cycle dosing regimen)

Weeks

Schedule

Weeks 1 to 9

weekly (total of 9 doses)

Weeks 10 to 24a

every three weeks (total of 5 doses)

Week 25 onwards until disease progressionb

every four weeks

a     First dose of the every-3-week dosing schedule is given at week 10

b       First dose of the every-4-week dosing schedule is given at week 25

 

 

For dose and schedule of medicinal products administered with DARZALEX, see section 5.1 and the corresponding Summary of Product Characteristics.

 

Infusion rates

Following dilution the DARZALEX infusion should be intravenously administered at the appropriate initial infusion rate, as presented in Table 2 3 below. Incremental escalation of the infusion rate should be considered only if the previous infusion of daratumumab was well‑toleratedin the absence of infusion reactions. as defined in Table 2.

 

Table 32:              Infusion rates for DARZALEX administration

 

Dilution volume

Initial infusion rate (first hour)

Increments of infusion ratea

Maximum infusion rate

First infusion

1,000 mL

50 mL/hour

50 mL/hour every hour

200 mL/hour

Second infusionainfusionb

500 mL

50 mL/hour

50 mL/hour every hour

200 mL/hour

Subsequent infusionsbinfusionsc

500 mL

100 mL/hour

50 mL/hour every hour

200 mL/hour

a     Incremental escalation of the infusion rate should be considered only in the absence of infusion reactions.

ab   A dilution volume of 500 mL should be used only if there were no ≥ Grade 1 IRRs during the first 3 hours of the first infusion. Otherwise, continue to use a dilution volume of 1000 mL and instructions for the first infusion.Modified rates should only be used if the first infusion of DARZALEX was well‑tolerated as defined by an absence of ≥ Grade 1 IRRs during the first 3 hours.

bc   A modified initial rate for subsequent infusions (i.e. third infusion onwards) should only be used only if there were no ≥ Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr in the first two infusions. Otherwise, use instructions for the second infusionModified rates should only be used if the first 2 infusions of DARZALEX were well‑tolerated as defined by an absence of ≥ Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr.

 

 

Management of infusion‑related reactions

Management of IRRs may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined below (see section 4.4).

·                Grade 1‑2 (mild to moderate): Once the patient’s condition is stablereaction 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 (Table 23).

·                Grade 3 (severe): If the intensity of the IRR decreases to Grade 2 or lowerOnce 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 (Table 32). The procedure above should be repeated in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion reaction if the patient experiences a ≥ Grade 3 infusion‑related symptom at the subsequent infusion.

·                Grade 4 (life‑threatening): Permanently discontinue DARZALEX treatment.

 

Missed dose (s)

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

 

Dose modifications

No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of haematological toxicity (see section 4.4). For information concerning medicinal products given in combination with DARZALEX, see corresponding Summary of Product Characteristics.

 

Recommended concomitant medications

Pre‑infusion medication

Pre‑infusion medications should be administered to reduce the risk of IRRs to all patients approximately 1-3  hours prior to every infusion of DARZALEX as follows:

 

·                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, administered prior to every DARZALEX infusion (see section 5.1).

Dexamethasone is given intravenously prior to the first DARZALEX infusion and oral administration may be considered prior to subsequent infusions.

·                Antipyretics (oral paracetamol 650 to 1,000 mg)

Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

·                   intravenous corticosteroid (methylprednisolone 100 mg, or equivalent dose of an intermediate‑acting or long‑acting corticosteroid) plus

·                oral antipyretics (paracetamol 650 to 1,000 mg), plus

·                   oral or intravenous antihistamine (diphenhydramine 25 to 50 mg or equivalent).

 

Following the second infusion, the dose of intravenous corticosteroid may be reduced (methylprednisolone 60 mg) at the discretion of the physician.

 

Post‑infusion medication

 

Post-infusion medications should be administered to reduce the risk of delayed infusion‑related reactions as follows:

 

Monotherapy:

For the prevention of delayed IRRs, oOral 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 the DARZALEX infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone) is administered the day after the DARZALEX infusion, additional post-infusion medications may not be needed (see section 5.1).

 

Additionally, for patients with a history of chronic obstructive pulmonary disorderdisease, the use of post‑infusion medications 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 medications may be discontinued at the discretion of the physician.

 

Prophylaxis for herpes zoster virus reactivation

Anti‑viral prophylaxis should be considered for the prevention of herpes zoster virus reactivation.

 

Special populations

Renal impairment

No formal studies of daratumumab in patients with renal impairment have been conducted. Based on a population pharmacokinetic (PK) analysis analyses no dosage adjustment is necessary for patients with renal impairment (see section 5.2).

 

Hepatic impairment

No formal studies of daratumumab in patients with hepatic impairment have been conducted.

Based on a population PK analyseis, no dosage adjustments are necessary for patients with mild hepatic impairment (Total Bilirubin [TB] 1.0 x to 1.5 x upper limit of normal [ULN] or aspartate aminotransferase [AST] > ULN). Daratumumab has not been studied in patients with moderate to severe hepatic impairment (TB > 1.5 x ULN and any AST), therefore no dose recommendations can be made in these patient populations (see section 5.2).

 

 

4.4       Special warnings and precautions for use

Infusion‑related reactions

Infusion‑related reactions (IRRs) were reported in approximately half of all patients treated with DARZALEX. Monitor such patients throughout the infusion and the post‑infusion period.

 

The majority (95%) of IRRs occurred at the first infusion. Five Four percent of all patients had an IRR at more than one infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension, laryngeal oedema and pulmonary oedema. Symptoms predominantly included (≥ 5%) nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnoea,  chills, vomiting and nausea, and were mild to moderate in severity. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus and hypotension Severe IRRs (3%) including bronchospasm (1.3%), hypertension (0.6%), and hypoxia (0.6%) were also reported (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. DARZALEX infusion should be interrupted for IRRs of any severity. Medical management/supportive treatment for IRRs should be instituted as needed. The infusion rate should be reduced when re‑starting the infusion (see section 4.2).

 

For the preventionTo reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patients following DARZALEX infusions.the first and second day after all infusions. Additionally the use of post‑infusion medications (e.g. inhaled corticosteroids, short and long acting bronchodilators) should be considered for patients with a history of chronic obstructive pulmonary disorder disease to manage respiratory complications should they occur (see section 4.2).

 

 

DARZALEX therapy should be permanently discontinued in the event of life‑threatening IRRs.

 

Neutropenia/Thrombocytopenia

DARZALEX may increase neutropenia and thrombocytopenia induced by background therapy (see section 4.8).

Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX delay may be required to allow recovery of blood cell counts. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions or growth factors.

 

4.5       Interaction with other medicinal products and other forms of interaction

Clinical pharmacokinetic assessments of pomalidomide, thalidomide, and bortezomib indicated no clinically-relevant drug-drug interaction between DARZALEX and these combination therapies.

 

4.8       Undesirable effects

Summary of the safety profile

The safety data described below reflects exposure to DARZALEX (16 mg/kg) in 820 patients with multiple myeloma including 526 patients from two Phase III active-controlled trials who received DARZALEX in combination with either lenalidomide (DRd; n = 283; Study MMY3003) or bortezomib (DVd; n = 243; Study MMY3004) and five open-label, clinical trials in which patients received DARZALEX either in combination with pomalidomide (DPd; n = 103), in combination with lenalidomide (n = 35) or as monotherapy (n = 156).

The most frequent adverse reactions (> 20%) in individual randomised controlled studies were infusion reactions, fatigue, nausea, diarrhoea, muscle spasms, pyrexia, cough, dyspnoea, neutropenia, thrombocytopenia and upper respiratory tract infection. In addition, in combination with bortezomib, peripheral oedema and peripheral sensory neuropathy were frequently reported. Serious adverse reactions were pneumonia, upper respiratory tract infection, influenza, pyrexia, diarrhoea, atrial fibrillation.

The most frequently reported adverse reactions were IRRs (48%); see section 4.4. Other frequently reported adverse reactions (≥ 20%) were fatigue (39%), pyrexia (21%), cough (21%), nausea (27%), back pain (23%), upper respiratory tract infection (20%), anaemia (27%), neutropenia (22%) and thrombocytopenia (20%).

 

Tabulated list of adverse reactions

Table 3 4 summariszes the adverse drug reactions that occurred in patients receiving DARZALEX. The data reflect exposure to DARZALEX in three pooled open‑label, clinical studies that included 156 patients with relapsed and refractory multiple myeloma treated with DARZALEX at 16 mg/kg. The median duration of DARZALEX treatment was 3.3 months, with the longest duration of treatment being 20 months.

 

Adverse event table revised

 

Infusion‑related reactions

In clinical trials (monotherapy and combination treatments; N = 820) the incidence of any grade infusion‑related reactions was 46% with the first infusion of DARZALEX, 2% with the second infusion, and 3% with subsequent infusions. Less than 1% of patients had a Grade 3 infusion‑related reaction with second or subsequent infusions.

The median time to onset of a reaction was 1.4 hours (range: 0.02 to 72.8 hours). The incidence of infusion interruptions due to reactions was 42%. Median durations of infusion for the 1st, 2nd and subsequent infusions were 7, 4.3 and 3.5 hours respectively.

Severe (Grade 3) infusion‑related reactions included bronchospasm, dyspnoea, laryngeal oedema, pulmonary oedema, hypoxia, and hypertension. Other adverse infusion‑related reactions (any Grade,  5%) were nasal congestion, cough, chills, throat irritation, vomiting and nausea.

Infusion‑related reactions include but are not limited to the following multiple adverse reaction terms: nasal congestion, cough, chills, allergic rhinitis, throat irritation, dyspnoea, nausea (all ≥ 5%), bronchospasm (2.6%), hypertension (1.3%) and hypoxia (1.3%).

The median time to onset of a reaction was 1.5 hours (range: 0.02 to 9.3 hours). Median durations of infusion for the first, second and subsequent infusions were 7.0, 4.6 and 3.4 hours respectively.

 

Infections

In patients receiving DARZALEX combination therapy, Grade 3 or 4 infections were reported with DARZALEX combinations and background therapies (DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; DPd: 28%). Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. Discontinuations from treatment were reported in 2% to 5% of patients. Fatal infections were reported in 0.8% to 2% of patients across studies, primarily due to pneumonia and sepsis.

 

 

5.1       Pharmacodynamic properties ~significant updates

5.2       Pharmacokinetic properties ~significant updates

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Updated on 3 May 2017 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.1       Therapeutic indications

DARZALEX is indicated:

·                as monotherapy is indicated 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.

·                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

 

 

4.2          Posology and method of administration

 

Dose

Standard dosing for monotherapy and in combination with lenalidomide (4week cycle regimen):

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 1.:

 

 

Table 1:         Standard DARZALEX dosing schedule for monotherapy and in combination with lenalidomide (4-week cycle dosing regimen)

Weeks

Schedule

Weeks 1 to 8

weekly (total of 8 doses)

Weeks 9 to 24a

every two weeks (total of 8 doses)

Week 25 onwards until disease progressionb

every four weeks

a     First dose of the every-2-week dosing schedule is given at week 9

b     First dose of the every-4-week dosing schedule is given at week 25

 

 

For dose and schedule of medicinal products administered with DARZALEX, see section 5.1 and the corresponding Summary of Product Characteristics.

 

Modified dosing schedule in combination with bortezomib (3week cycle regimen):

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 2.

 

Table 2:         Modified DARZALEX dosing schedule in combination with bortezomib (3-week cycle dosing regimen)

Weeks

Schedule

Weeks 1 to 9

weekly (total of 9 doses)

Weeks 10 to 24a

every three weeks (total of 5 doses)

Week 25 onwards until disease progressionb

every four weeks

a     First dose of the every-3-week dosing schedule is given at week 10

b       First dose of the every-4-week dosing schedule is given at week 25

 

 

For dose and schedule of medicinal products administered with DARZALEX, see section 5.1 and the corresponding Summary of Product Characteristics.

 

Infusion rates

Following dilution the DARZALEX infusion should be intravenously administered at the appropriate initial infusion rate, as presented in Table 2 3 below. Incremental escalation of the infusion rate should be considered only if the previous infusion of daratumumab was well‑toleratedin the absence of infusion reactions. as defined in Table 2.

 

Table 32:              Infusion rates for DARZALEX administration

 

Dilution volume

Initial infusion rate (first hour)

Increments of infusion ratea

Maximum infusion rate

First infusion

1,000 mL

50 mL/hour

50 mL/hour every hour

200 mL/hour

Second infusionainfusionb

500 mL

50 mL/hour

50 mL/hour every hour

200 mL/hour

Subsequent infusionsbinfusionsc

500 mL

100 mL/hour

50 mL/hour every hour

200 mL/hour

a     Incremental escalation of the infusion rate should be considered only in the absence of infusion reactions.

ab   A dilution volume of 500 mL should be used only if there were no ≥ Grade 1 IRRs during the first 3 hours of the first infusion. Otherwise, continue to use a dilution volume of 1000 mL and instructions for the first infusion.Modified rates should only be used if the first infusion of DARZALEX was well‑tolerated as defined by an absence of ≥ Grade 1 IRRs during the first 3 hours.

bc   A modified initial rate for subsequent infusions (i.e. third infusion onwards) should only be used only if there were no ≥ Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr in the first two infusions. Otherwise, use instructions for the second infusionModified rates should only be used if the first 2 infusions of DARZALEX were well‑tolerated as defined by an absence of ≥ Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr.

 

 

Management of infusion‑related reactions

Management of IRRs may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined below (see section 4.4).

·                Grade 1‑2 (mild to moderate): Once the patient’s condition is stablereaction 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 (Table 23).

·                Grade 3 (severe): If the intensity of the IRR decreases to Grade 2 or lowerOnce 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 (Table 32). The procedure above should be repeated in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion reaction if the patient experiences a ≥ Grade 3 infusion‑related symptom at the subsequent infusion.

·                Grade 4 (life‑threatening): Permanently discontinue DARZALEX treatment.

 

Missed dose (s)

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

 

Dose modifications

No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of haematological toxicity (see section 4.4). For information concerning medicinal products given in combination with DARZALEX, see corresponding Summary of Product Characteristics.

 

Recommended concomitant medications

Pre‑infusion medication

Pre‑infusion medications should be administered to reduce the risk of IRRs to all patients approximately 1-3  hours prior to every infusion of DARZALEX as follows:

 

·                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, administered prior to every DARZALEX infusion (see section 5.1).

Dexamethasone is given intravenously prior to the first DARZALEX infusion and oral administration may be considered prior to subsequent infusions.

·                Antipyretics (oral paracetamol 650 to 1,000 mg)

Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

·                   intravenous corticosteroid (methylprednisolone 100 mg, or equivalent dose of an intermediate‑acting or long‑acting corticosteroid) plus

·                oral antipyretics (paracetamol 650 to 1,000 mg), plus

·                   oral or intravenous antihistamine (diphenhydramine 25 to 50 mg or equivalent).

 

Following the second infusion, the dose of intravenous corticosteroid may be reduced (methylprednisolone 60 mg) at the discretion of the physician.

 

Post‑infusion medication

 

Post-infusion medications should be administered to reduce the risk of delayed infusion‑related reactions as follows:

 

Monotherapy:

For the prevention of delayed IRRs, oOral 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 the DARZALEX infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone) is administered the day after the DARZALEX infusion, additional post-infusion medications may not be needed (see section 5.1).

 

Additionally, for patients with a history of chronic obstructive pulmonary disorderdisease, the use of post‑infusion medications 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 medications may be discontinued at the discretion of the physician.

 

Prophylaxis for herpes zoster virus reactivation

Anti‑viral prophylaxis should be considered for the prevention of herpes zoster virus reactivation.

 

Special populations

Renal impairment

No formal studies of daratumumab in patients with renal impairment have been conducted. Based on a population pharmacokinetic (PK) analysis analyses no dosage adjustment is necessary for patients with renal impairment (see section 5.2).

 

Hepatic impairment

No formal studies of daratumumab in patients with hepatic impairment have been conducted.

Based on a population PK analyseis, no dosage adjustments are necessary for patients with mild hepatic impairment (Total Bilirubin [TB] 1.0 x to 1.5 x upper limit of normal [ULN] or aspartate aminotransferase [AST] > ULN). Daratumumab has not been studied in patients with moderate to severe hepatic impairment (TB > 1.5 x ULN and any AST), therefore no dose recommendations can be made in these patient populations (see section 5.2).

 

 

4.4       Special warnings and precautions for use

Infusion‑related reactions

Infusion‑related reactions (IRRs) were reported in approximately half of all patients treated with DARZALEX. Monitor such patients throughout the infusion and the post‑infusion period.

 

The majority (95%) of IRRs occurred at the first infusion. Five Four percent of all patients had an IRR at more than one infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension, laryngeal oedema and pulmonary oedema. Symptoms predominantly included (≥ 5%) nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnoea,  chills, vomiting and nausea, and were mild to moderate in severity. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus and hypotension Severe IRRs (3%) including bronchospasm (1.3%), hypertension (0.6%), and hypoxia (0.6%) were also reported (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. DARZALEX infusion should be interrupted for IRRs of any severity. Medical management/supportive treatment for IRRs should be instituted as needed. The infusion rate should be reduced when re‑starting the infusion (see section 4.2).

 

For the preventionTo reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patients following DARZALEX infusions.the first and second day after all infusions. Additionally the use of post‑infusion medications (e.g. inhaled corticosteroids, short and long acting bronchodilators) should be considered for patients with a history of chronic obstructive pulmonary disorder disease to manage respiratory complications should they occur (see section 4.2).

 

 

DARZALEX therapy should be permanently discontinued in the event of life‑threatening IRRs.

 

Neutropenia/Thrombocytopenia

DARZALEX may increase neutropenia and thrombocytopenia induced by background therapy (see section 4.8).

Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX delay may be required to allow recovery of blood cell counts. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions or growth factors.

 

4.5       Interaction with other medicinal products and other forms of interaction

Clinical pharmacokinetic assessments of pomalidomide, thalidomide, and bortezomib indicated no clinically-relevant drug-drug interaction between DARZALEX and these combination therapies.

 

4.8       Undesirable effects

Summary of the safety profile

The safety data described below reflects exposure to DARZALEX (16 mg/kg) in 820 patients with multiple myeloma including 526 patients from two Phase III active-controlled trials who received DARZALEX in combination with either lenalidomide (DRd; n = 283; Study MMY3003) or bortezomib (DVd; n = 243; Study MMY3004) and five open-label, clinical trials in which patients received DARZALEX either in combination with pomalidomide (DPd; n = 103), in combination with lenalidomide (n = 35) or as monotherapy (n = 156).

The most frequent adverse reactions (> 20%) in individual randomised controlled studies were infusion reactions, fatigue, nausea, diarrhoea, muscle spasms, pyrexia, cough, dyspnoea, neutropenia, thrombocytopenia and upper respiratory tract infection. In addition, in combination with bortezomib, peripheral oedema and peripheral sensory neuropathy were frequently reported. Serious adverse reactions were pneumonia, upper respiratory tract infection, influenza, pyrexia, diarrhoea, atrial fibrillation.

The most frequently reported adverse reactions were IRRs (48%); see section 4.4. Other frequently reported adverse reactions (≥ 20%) were fatigue (39%), pyrexia (21%), cough (21%), nausea (27%), back pain (23%), upper respiratory tract infection (20%), anaemia (27%), neutropenia (22%) and thrombocytopenia (20%).

 

Tabulated list of adverse reactions

Table 3 4 summariszes the adverse drug reactions that occurred in patients receiving DARZALEX. The data reflect exposure to DARZALEX in three pooled open‑label, clinical studies that included 156 patients with relapsed and refractory multiple myeloma treated with DARZALEX at 16 mg/kg. The median duration of DARZALEX treatment was 3.3 months, with the longest duration of treatment being 20 months.

 

Adverse event table revised

 

Infusion‑related reactions

In clinical trials (monotherapy and combination treatments; N = 820) the incidence of any grade infusion‑related reactions was 46% with the first infusion of DARZALEX, 2% with the second infusion, and 3% with subsequent infusions. Less than 1% of patients had a Grade 3 infusion‑related reaction with second or subsequent infusions.

The median time to onset of a reaction was 1.4 hours (range: 0.02 to 72.8 hours). The incidence of infusion interruptions due to reactions was 42%. Median durations of infusion for the 1st, 2nd and subsequent infusions were 7, 4.3 and 3.5 hours respectively.

Severe (Grade 3) infusion‑related reactions included bronchospasm, dyspnoea, laryngeal oedema, pulmonary oedema, hypoxia, and hypertension. Other adverse infusion‑related reactions (any Grade,  5%) were nasal congestion, cough, chills, throat irritation, vomiting and nausea.

Infusion‑related reactions include but are not limited to the following multiple adverse reaction terms: nasal congestion, cough, chills, allergic rhinitis, throat irritation, dyspnoea, nausea (all ≥ 5%), bronchospasm (2.6%), hypertension (1.3%) and hypoxia (1.3%).

The median time to onset of a reaction was 1.5 hours (range: 0.02 to 9.3 hours). Median durations of infusion for the first, second and subsequent infusions were 7.0, 4.6 and 3.4 hours respectively.

 

Infections

In patients receiving DARZALEX combination therapy, Grade 3 or 4 infections were reported with DARZALEX combinations and background therapies (DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; DPd: 28%). Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. Discontinuations from treatment were reported in 2% to 5% of patients. Fatal infections were reported in 0.8% to 2% of patients across studies, primarily due to pneumonia and sepsis.

 

 

5.1       Pharmacodynamic properties ~significant updates

5.2       Pharmacokinetic properties ~significant updates

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Updated on 28 April 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 22 November 2016 SmPC

Reasons for updating

  • New SPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

None provided

Updated on 22 November 2016 PIL

Reasons for updating

  • New SPC for new product

Free text change information supplied by the pharmaceutical company

None provided