EMPLICITI Powder for concentrate for solution for infusion Ref.[8967] Active ingredients: Elotuzumab

Infusion reaction

Infusion reactions have been reported in patients receiving elotuzumab (see section 4.8).

Premedication consisting of dexamethasone, H1 blocker, H2 blocker, and paracetamol must be administered prior to Empliciti infusion (see section 4.2 Premedication). The rate of infusion reactions was much higher in patients who were not premedicated.

If any of the symptoms of infusion reaction reach Grade ≥2, Empliciti infusion must be interrupted and appropriate medical and supportive measures instituted. Vital signs should be monitored every 30 minutes for 2 hours after the end of the Empliciti infusion. Once the reaction has resolved (symptoms ≤ Grade 1), Empliciti can be restarted at the initial infusion rate of 0.5 mL/min. If symptoms do not recur, the infusion rate may be gradually escalated every 30 minutes to a maximum of 5 mL/min (see section 4.2 Method of administration).

Very severe infusion reactions may require permanent discontinuation of Empliciti therapy and emergency treatment. Patients with mild or moderate infusion reactions may receive Empliciti with a reduced infusion rate and close monitoring (see section 4.2 Method of administration).

Conditions for use of medicinal products used with Empliciti

Empliciti is used in combination with other medicinal products; therefore, the conditions for use applicable to those medicinal products also apply to the combination therapy. The Summary of Product Characteristics for all medicinal products used in combination with Empliciti must be consulted before starting therapy.

Infections

In clinical trials of patients with multiple myeloma, the incidence of all infections, including pneumonia, were higher in patients treated with Empliciti (see section 4.8). Patients should be monitored and infections should be managed with standard treatment.

Second primary malignancies (SPMs)

In a clinical trial of patients with multiple myeloma that compared Empliciti combined with lenalidomide and dexamethasone treatment to lenalidomide and dexamethasone treatment (CA204004), the incidence of SPMs, and specifically of solid tumours and non-melanoma skin cancer, was higher in patient treated with Empliciti (see section 4.8). SPMs are known to be associated with lenalidomide exposure, which was extended in patients treated with Empliciti combined with lenalidomide and dexamethasone vs. lenalidomide and dexamethasone. The rate of haematologic malignancies was the same between the two treatment arms. Patients should be monitored for the development of SPMs.

Pharmacokinetic interaction studies have not been conducted. Empliciti, as a humanised monoclonal antibody, is not expected to be metabolised by cytochrome P450 (CYP) enzymes or other drug metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal products is not anticipated to affect the pharmacokinetics of Empliciti.

Empliciti may be detected in the serum protein electrophoresis (SPEP) and serum immunofixation assays of myeloma patients and could interfere with correct response classification. The presence of elotuzumab in patient’s serum may cause a small peak in the early gamma region on SPEP that is IgGƙ on serum immunofixation. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein. In case of detection of additional peaks on serum immunofixation, the possibility of a biclonal gammopathy should be excluded.

The Summary of Product Characteristics for all medicinal products used in combination with Empliciti must be consulted before starting therapy.

Woman of childbearing potential/Contraception in the males and females

Empliciti should not be used in women of childbearing potential, unless the clinical condition of the woman requires treatment with elotuzumab. Women of childbearing potential should use effective contraception. Male patients must use effective contraception measures during and for 180 days following treatment if their partner is pregnant or of childbearing potential and not using effective contraception.

Pregnancy

There is no human experience with elotuzumab during pregnancy. Elotuzumab will be given in combination with lenalidomide, which is contraindicated during pregnancy. No animal data are present regarding the effect on reproductive toxicity because of the lack of an adequate animal model. Empliciti should not be used during pregnancy unless the clinical condition of the woman requires treatment with elotuzumab.

The Summary of Product Characteristics for all medicinal products used in combination with Empliciti must be consulted before starting therapy. When Empliciti is used with lenalidomide or pomalidomide there is a risk of foetal harm, including severe life-threatening human birth defects associated with these agents and the need to follow requirements regarding pregnancy avoidance, including testing and contraception. Lenalidomide and pomalidomide are present in the blood and sperm of patients receiving the medicine. Refer to the Summary of Product Characteristics for requirements regarding contraception due to presence and transmission in sperm and for additional detail. Patients receiving Empliciti in combination with lenalidomide or pomalidomide should adhere to the pregnancy prevention programme of lenalidomide or pomalidomide respectively.

Breast-feeding

Elotuzumab is not expected to be excreted into human milk. Elotuzumab will be given in combination with lenalidomide or pomalidomide and breast-feeding should be stopped because of the use of lenalidomide or pomalidomide.

Fertility

Studies to evaluate the effect of elotuzumab on fertility have not been performed. Thus, the effect of elotuzumab on male and female fertility is unknown.

On the basis of reported adverse reactions, Empliciti is not expected to influence the ability to drive or use machines. Patients experiencing infusion reactions should be advised not to drive and use machines until symptoms abate.

Summary of safety profile

The safety data of elotuzumab have been assessed from a total of 682 patients with multiple myeloma treated with elotuzumab in combination with lenalidomide and dexamethasone (451 patients), bortezomib and dexamethasone (103 patients) or pomalidomide and dexamethasone (128 patients) pooled across 8 clinical trials. The majority of adverse reactions were mild to moderate (Grade 1 or 2).

The most serious adverse reaction that may occur during elotuzumab treatment is pneumonia.

The most common adverse reactions (occurring in >10% of patients) with elotuzumab treatment were infusion related reactions, diarrhoea, herpes zoster, nasopharyngitis, cough, pneumonia, upper respiratory tract infection, lymphopenia and weight decreased.

Tabulated list of adverse reactions

Adverse reactions reported in 682 patients with multiple myeloma who were treated with elotuzumab in 8 clinical trials are presented in Table 5.

These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from available data).

Table 5. Adverse reactions in patients with multiple myeloma treated with Empliciti:

^a The term herpes zoster is a grouping of the following terms: herpes zoster, oral herpes, and herpes virus infection.
^b The term pneumonia is a grouping of the following terms: pneumonia, atypical pneumonia, bronchopneumonia, lobar pneumonia, bacterial pneumonia, fungal pneumonia, pneumonia influenza, and pneumococcal pneumonia.
^c The term lymphopenia includes the following terms: lymphopenia and lymphocyte count decreased.
^d The term cough includes the following terms: cough, productive cough, and upper airway cough syndrome.

Exposure-adjusted rates for adverse reactions (all Grades and Grade ¾) in CA204004, a clinical trial in patients with multiple myeloma comparing Empliciti combined with lenalidomide and dexamethasone treatment (N=318) to lenalidomide and dexamethasone treatment (N=317), is shown in Table 6.

Table 6. CA204004 Exposure-adjusted rates for adverse reactions for Empliciti-treated patients versus lenalidomide and dexamethasone-treated patients [includes multiple occurrences in all treated patients]:

^a The term cough includes the following terms: cough, productive cough, and upper airway cough syndrome.
^b The term lymphopenia includes the following terms: lymphopenia and lymphocyte count decreased.
^c The term pneumonia is a grouping of the following terms: pneumonia, atypical pneumonia, bronchopneumonia, lobar pneumonia, bacterial pneumonia, fungal pneumonia, pneumonia influenza, and pneumococcal pneumonia.
^d The term herpes zoster is a grouping of the following terms: herpes zoster, oral herpes, and herpes virus infection.

Exposure-adjusted rates for adverse reactions (all Grades and Grade ¾) in CA204125, a clinical trial in patients with multiple myeloma comparing Empliciti combined with pomalidomide and dexamethasone treatment (N=60) to pomalidomide and dexamethasone treatment (N=55), is shown in Table 7.

Table 7. CA204125 Exposure-adjusted rates for adverse reactions for Empliciti-treated patients versus pomalidomide and dexamethasone-treated patients [includes multiple occurrences in all treated patients]:

^a The term cough includes the following terms: cough, productive cough, and upper airway cough syndrome.
^b The term lymphopenia includes the following terms: lymphopenia and lymphocyte count decreased.
^c The term pneumonia is a grouping of the following terms: pneumonia, atypical pneumonia, bronchopneumonia, lobar pneumonia, bacterial pneumonia, fungal pneumonia, pneumonia influenza, and pneumococcal pneumonia.
^d The term herpes zoster is a grouping of the following terms: herpes zoster, oral herpes, herpes virus infection and ophthalmic herpes zoster.

Description of selected adverse reactions

Infusion reactions

In the clinical trials of patients with multiple myeloma infusion reactions were reported in approximately 10% of premedicated patients treated with Empliciti combined with lenalidomide and dexamethasone (N=318) and 3% of premedicated patients treated with Empliciti combined with pomalidomide and dexamethasone (N=60) (see section 4.4). The rate of mild to moderate infusion reactions was >50% in patients who were not premedicated. All reports of infusion reaction were ≤ Grade 3. Grade 3 infusion reactions occurred in 1% of patients. In study CA204004, the most common symptoms of an infusion reaction included fever, chills, and hypertension. Five percent (5%) of patients required interruption of the administration of Empliciti for a median of 25 minutes due to infusion reaction, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had the reaction during the first dose. In study CA204125, all of the reported infusion reactions occurred during the first treatment cycle and were ≤ Grade 2.

Infections

The incidence of infections, including pneumonia, was higher with Empliciti treatment than with control (see section 4.4). In a clinical trial of patients with multiple myeloma (CA204004), infections were reported in 81.4% of patients in the Empliciti combined with lenalidomide and dexamethasone arm (N=318) and 74.4% in lenalidomide and dexamethasone arm (N=317). Grade 3-4 infections were noted in 28% and 24.3% of Empliciti combined with lenalidomide and dexamethasone and lenalidomide and dexamethasone treated patients, respectively. Fatal infections were infrequent and were reported in 2.5% of Empliciti combined with lenalidomide and dexamethasone and 2.2% of lenalidomide and dexamethasone treated patients. The incidence of pneumonia was higher in the Empliciti combined with lenalidomide and dexamethasone arm compared to lenalidomide and dexamethasone arm reported at 15.1% vs. 11.7% with a fatal outcome at 0.6% vs. 0%, respectively.

In a clinical trial of patients with multiple myeloma (CA204125), infections were reported in 65% of patients in the Empliciti combined with pomalidomide and dexamethasone arm (N=60) and 65.5% in the pomalidomide and dexamethasone arm (N=55). Grade 3-4 infections were noted in 13.3% and 21.8% of Empliciti combined with pomalidomide and dexamethasone and pomalidomide and dexamethasone treated patients, respectively. Fatal infections (i.e. Grade 5 infections) were reported in 5% of Empliciti combined with pomalidomide and dexamethasone and 3.6% of pomalidomide and dexamethasone treated patients.

Second Primary Malignancies

The incidence of SPMs was higher with Empliciti treatment than with control (see section 4.4). In the clinical trial of patients with multiple myeloma (CA204004), invasive SPMs have been observed in 6.9% of patients treated with Empliciti combined with lenalidomide and dexamethasone (N=318) and 4.1% of patients treated with lenalidomide and dexamethasone (N=317). Second Primary Malignancies are known to be associated with lenalidomide exposure which was extended in patients treated with Empliciti combined with lenalidomide and dexamethasone vs. lenalidomide and dexamethasone. The rate of haematologic malignancies were the same between the two treatment arms (1.6%). Solid tumours were reported in 2.5% and 1.9% of Empliciti combined with lenalidomide and dexamethasone and lenalidomide and dexamethasone treated patients, respectively. Non-melanoma skin cancer was reported in 3.1% and 1.6% of patients treated with Empliciti combined with lenalidomide and dexamethasone and lenalidomide and dexamethasone, respectively.

There were no SPM events reported in patients treated in the Empliciti combined with pomalidomide and dexamethasone study arm (N=60) and 1 (1.8%) in patients treated in the pomalidomide and dexamethasone arm (N=55) in study CA204125.

Deep vein thrombosis

In a clinical trial of patients with multiple myeloma (CA204004), deep vein thromboses were reported in 7.2% of patients treated with Empliciti combined with lenalidomide and dexamethasone (N=318) and 3.8% of patients treated with lenalidomide and dexamethasone (N=317). Among, patients treated with aspirin, deep vein thromboses were reported in 4.1% of patients treated with Empliciti combined with lenalidomide and dexamethasone (E-Ld) and 1.4% of patients treated with lenalidomide and dexamethasone (Ld). The rates of deep vein thromboses observed between treatment arms were similar for patients given prophylaxis with low molecular weight heparin (2.2% in both treatment arms), and for patients given vitamin K antagonists the rates were 0% for patients treated with E-Ld and 6.7% for patients treated with Ld.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity to Empliciti. Of 390 patients across four clinical studies who were treated with Empliciti and evaluable for the presence of anti-product antibodies, 72 patients (18.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies were detected in 19 of 299 patients in CA204004. In the majority of patients, immunogenicity occurred early in treatment and was transient resolving by 2 to 4 months. There was no clear causal evidence of altered pharmacokinetic, efficacy, or toxicity profiles with anti-product antibody development based on the population pharmacokinetic and exposure-response analyses.

Of the 53 patients in CA204125 treated with Empliciti and evaluable for the presence of anti-product antibodies, 19 patients (36%) tested positive, of whom 1 patient tested persistent positive, for treatment-emergent anti-product antibodies by an ECL assay. In these 19 patients, anti-product antibodies occurred within the first 2 months of the initiation of Empliciti treatment. Anti-product antibodies resolved by 2 to 3 months in 18 (95%) of these 19 patients. Neutralizing antibodies were detected in 2 of 53 patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.