Aranesp PFS

Section 4 Side Effects

CRF Patients:

Uncommon: may affect up to 1 in 100 people

• Blood clots (thrombosis)
• Convulsions (fits and seizures)
• Bruising and bleeding at the site of injection
• Blood clots in a dialysis access

Cancer patients

Very common: may affect more than 1 in 10 people

• Allergic reactions
• Fluid retention (oedema)

Common: may affect up to 1 in 10 people

• High blood pressure (hypertension)
• Blood clots (thrombosis)
• Pain around the area injected
• Rash and/or redness of the skin
• Fluid retention (oedema)

Uncommon: may affect up to 1 in 100 people

• Convulsions (fits and seizures)
• Bruising and bleeding at the site of injection

All Patients:

Not known:

• Serious skin rashes including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in association with epoetin treatment. These can appear as reddish target-like macules or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can be preceded by fever and flu-like symptoms. Stop using Aranesp if you develop these symptoms and contact your doctor or seek medical attention immediately. See also section 2.
• Bruising and bleeding at the site of injection

Date of revision of the text

November 2019

Section 4.4 Special Warnings and Precautions

The reported risk of thrombotic vascular events (TVEs) should be carefully weighed against the benefits to be derived from treatment with darbepoetin alfa particularly in patients with pre-existing risk factors for TVE, including obesity and prior history of TVEs (e.g., deep venous thrombosis, pulmonary embolism, and cerebral vascular accident).

And addition of the below to points to the “Cancer Patients” section:

• an observed 9% increase in risk for PD or death in the epoetin alfa plus SOC group from a primary analysis and a 15% increased risk that cannot be statistically ruled out in patients with metastatic breast cancer receiving chemotherapy when administered to achieve a haemoglobin concentration range of 10 to 12 g/dL (6.2 to 7.5 mmol/L).
• non-inferiority of darbepoetin alfa to placebo for overall survival and progression free survival in patients with advanced stage non-small cell lung cancer receiving chemotherapy when administered to a target haemoglobin of 12 g/dL (7.5 mmol/L) (see section 5.1).

Section 4.6 Pregnancy and Lactation

Breast-feeding

Women who become pregnant during Aranesp treatment are encouraged to enrol in Amgen’s Pregnancy Surveillance programme. Contact details are provided in section 6 of the Patient Information Leaflet.

It is unknown whether Aranesp is excreted in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Aranesp therapy taking into account the benefit of breast-feeding for the child and the benefit of

therapy for the woman.

Section 4.8 Undesirable Effects

To the CRF AE Table:

• Addition of Dialysis Vascular Access Thrombosis as a Uncommon AE
• Reclassification of Injection site bruising and Injection site haemorrhage as Uncommon AEs

Text added on the footnote of the table regarding specific AEs

To the Oncology AE Table:

• Reclassification of Oedema as a Common AE
• Reclassification of Injection site bruising and Injection site haemorrhage as Uncommon AEs

Text added on the footnote of the table regarding specific AEs

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.

In CRF patients on haemodialysis, 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.

Section 5.1 Pharmacodynamic Properties

Cancer patients receiving chemotherapy

EPO-ANE-3010, a randomised, open-label, multicentre study was conducted in 2,098 anaemic women with metastatic breast cancer, who received first line or second line chemotherapy. This was a non inferiority study designed to rule out a 15% risk increase in tumour progression or death of epoetin alfa plus standard of care (SOC) as compared with SOC alone. At the time of clinical data cutoff, the

median progression free survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. Significantly fewer patients received RBC transfusions in the epoetin alfa plus SOC arm (5.8% versus

11.4%); however, significantly more patients had thrombotic vascular events in the epoetin alfa plus SOC arm (2.8% versus 1.4%). At the final analysis, 1,653 deaths were reported. Median overall survival in the epoetin alfa plus SOC group was 17.8 months compared with 18.0 months in the SOC

alone group (HR 1.07, 95% CI: 0.97, 1.18). The median time to progression (TTP) based on investigator-determined progressive disease (PD) was 7.5 months in the epoetin alfa plus SOC group and 7.5 months in the SOC group (HR 1.099, 95% CI: 0.998, 1.210). The median TTP based on IRCdetermined PD was 8.0 months in the epoetin alfa plus SOC group and 8.3 months in the SOC group (HR 1.033, 95% CI: 0.924, 1.156).

In a randomised, double-blind, placebo-controlled phase 3 study 2,549 adult patients with anaemia receiving chemotherapy for the treatment of advanced stage non-small cell lung cancer (NSCLC), were randomised 2:1 to darbepoetin alfa or placebo and treated to a maximum Hb of 12 g/dL. The

results showed non-inferiority for the primary endpoint of overall survival with a median survival for darbepoetin alfa versus placebo of 9.5 and 9.3 months, respectively (stratified HR 0.92; 95% CI: 0.83– 1.01). The secondary endpoint of progression free survival was 4.8 and 4.3 months, respectively

(stratified HR 0.95; 95% CI: 0.87–1.04), ruling out the pre-defined 15% risk increase.

Date of revision of the text

November 2019