Adverse reactions : תופעות לוואי

4.8 Undesirable Effects

Summary of the safety profile

Identified adverse reactions associated with ARANESP® are hypertension, stroke, thromboembolic events, convulsions, allergic reactions, rash/erythema and pure red cell aplasia (PRCA); see section 4.4.

Injection site pain was reported as attributable to treatment in studies where ARANESP® was administered via subcutaneous injection. The injection site discomfort was generally mild and transient in nature and occurred predominantly after the first injection.

Tabulated list of adverse reactions

Incidence of adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Data are presented separately for CRF and cancer patients reflecting the different adverse reaction profile in these populations.

Chronic Renal Failure Patients

Data presented from controlled studies included 1,357 patients, 766 who received ARANESP® and 591 patients who received r-HuEPO. In the ARANESP® group, 83% were receiving dialysis and 17% were not receiving dialysis. Stroke was identified as an adverse reaction in an additional clinical study (TREAT, see section 5.1).

Incidence of adverse reactions from controlled clinical studies and post-marketing experience are: 
MedDRA system organ class             Subject incidence            Adverse reaction 
Blood and lymphatic system            Not known2                   Pure red cell aplasia disorders
Immune system disorders               Very common                  Hypersensitivitya 
Nervous system disorders              Common                       Strokeb Uncommon1                    Convulsions
Cardiac disorders                     Very common                  Hypertension Vascular disorders                    Uncommon                     Thromboembolic eventsc Uncommon1                    Dialysis       vascular      access thrombosisd
Skin and subcutaneous tissue          Common                       Rash/erythemae disorders                             Not known2                   SJS/TEN, erythema multiforme, blistering, skin exfoliation

General      disorders      and       Common                       Injection site pain administration site conditions        Uncommon1                    Injection site bruising Injection site hemorrhage

Source: Includes 5 randomized, double-blind, active-controlled studies (970200, 970235, 980117, 980202, and 980211) except for the adverse reaction of stroke which was identified as an adverse reaction in the TREAT study (study 20010184).
1 Adverse reactions identified in the post-marketing environment. Per the Guideline on Summary of Product 
Characteristics (Revision 2, September 2009), frequency of adverse reactions identified in the post-marketing setting was determined using the “Rule of three”.
2 Frequency cannot be estimated from the available data.
a Hypersensitivity events includes all events under the hypersensitivity SMQ.
b Stroke events includes PT hemorrhagic stroke, ischemic stroke, cerebrovascular accident, and stroke in evolution.
c Thromboembolic events adverse reaction includes PT embolism arterial, thrombophlebitis, thrombosis, venous  thrombosis limb.
d Dialysis vascular access thrombosis includes all adverse reactions under the dialysis vascular access thrombosis 
AMQ.
e Rash/erythema adverse reaction includes PT rash, rash pruritic, rash macular, rash generalized, erythema.


Cancer Patients

Adverse reactions were determined based on pooled data from eight randomized, double-blind, placebo-controlled studies of ARANESP® with a total of 4,630 patients (ARANESP® 2,888, placebo 1,742). Patients with solid tumors (e.g., lung, breast, colon, ovarian cancers) and lymphoid malignancies (e.g., lymphoma, multiple myeloma) were enrolled in the clinical studies.

Incidences of adverse reactions from controlled clinical studies and post-marketing experience are: 
MedDRA system organ class             Subject incidence                 Adverse reaction Immune system disorders                    Very common                       Hypersensitivitya Nervous system disorders                   Uncommon1                         Convulsions Cardiac disorders                          Common                            Hypertension Vascular disorders                         Common                            Thromboembolic             eventsb, including pulmonary embolism
Skin and       subcutaneous       tissue   Common                            Rash/erythemac disorders                                  Not known2                        SJS/TEN, erythema multiforme, blistering, skin exfoliation
General        disorders            and    Common                            Edemad administration site conditions             Common                            Injection site paine Uncommon1                         Injection site bruising
Injection site hemorrhage
1 ADRs identified in the post-marketing environment. Per the Guideline on Summary of Product Characteristics (Revision 2, September 2009), frequency of ADRs identified in the post-marketing setting was determined using the “Rule of three”.
2 Frequency cannot be estimated from the available data.

Source: includes 8 randomized, double-blind, placebo-controlled studies (980291-schedule 1 and 2, 980297, 990114, 20000161, 20010145, 20030232, and 20070782).
a Hypersensitivity events includes all events under the hypersensitivity SMQ.
b Thromboembolic events adverse reactions includes PT embolism, thrombosis, deep vein thrombosis, jugular vein  thrombosis, venous thrombosis, arterial thrombosis, pelvic venous thrombosis, peripheral embolism, pulmonary embolism, as well as thrombosis in device from SOC product issues.
c Rash adverse reactions includes PT rash, rash pruritic, rash generalized, rash papular, erythema, exfoliative rash,  rash maculo-papular, rash vesicular as well as rash pustular from SOC Infections and Infestations.
d Edema: includes PT Edema Peripheral, Edema, Generalized Edema, Edema due to Cardiac Disease, Face Edema.
e Injection site pain adverse reaction includes PT injection site pain, administration site pain, catheter site pain,  infusion site pain and vessel puncture site pain.

Description of selected adverse reactions
Chronic renal failure patients

Stroke was reported as common in CRF patients in TREAT (see section 5.1).

In isolated cases, neutralizing anti-erythropoietin antibody mediated pure red cell aplasia (PRCA) associated with ARANESP® therapy have been reported predominantly in patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with ARANESP® must be discontinued and patients should not be switched to another recombinant erythropoietic protein (see section 4.4).
The frequency of all hypersensitivity reactions was estimated from clinical trial data as very common in CRF patients. Hypersensitivity reactions were also very common in the placebo groups. There have been reports, from post-marketing experience, of serious hypersensitivity reactions including anaphylactic reaction, angioedema, allergic bronchospasm, skin rash and urticaria associated with darbepoetin alfa.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported (see section 4.4).

Convulsions have been reported in patients receiving darbepoetin alfa (see section 4.4). The frequency is estimated from clinical trial data as uncommon in CRF patients.

In CRF patients on hemodialysis, events of vascular access thrombosis (such as vascular access complication, arteriovenous fistula thrombosis, graft thrombosis, shunt thrombosis, arteriovenous fistula site complication, etc.) have been reported in post-marketing data. The frequency is estimated from clinical trial data as uncommon.

Cancer patients

Hypertension has been observed in cancer patients in post-marketing experience (see section 4.4). The frequency is estimated from clinical trial data as common in cancer patients and was also common in the placebo groups.

Hypersensitivity reactions have been observed in cancer patients in post-marketing experience. The frequency of all hypersensitivity reactions was estimated from clinical trial data as very common in cancer patients. Hypersensitivity reactions were also very common in the placebo groups. There have been reports of serious hypersensitivity reactions including anaphylactic reaction, angioedema, allergic bronchospasm, skin rash and urticaria associated with darbepoetin alfa.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported (see section 4.4).

Convulsions have been reported in patients receiving darbepoetin alfa in post-marketing experience (see section 4.4). The frequency is estimated from clinical trial data as uncommon in cancer patients.
Convulsions were common in the placebo groups.

Pediatric chronic renal failure population

In all pediatric CRF studies, there were no additional adverse reactions identified for pediatric patients compared to those previously reported for adult patients (see section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/