ARANESP Solution for injection in pre-filled syringe / pre-filled pen / vial Ref.[2701] Active ingredients: Darbepoetin alfa

Generalx

In order to improve the traceability of erythropoiesis-stimulating agents (ESAs), the trade name of the administered ESA should be clearly recorded (or stated) in the patient file.

Blood pressure should be monitored in all patients, particularly during initiation of Aranesp therapy. If blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be reduced by decreasing or withholding the dose of Aranesp (see section 4.2). Cases of severe hypertension, including hypertensive crisis, hypertensive encephalopathy, and seizures, have been observed in CRF patients treated with Aranesp.

In order to ensure effective erythropoiesis, iron status should be evaluated for all patients prior to and during treatment and supplementary iron therapy may be necessary.

Non-response to therapy with Aranesp should prompt a search for causative factors. Deficiencies of iron, folic acid or vitamin B12 reduce the effectiveness of ESAs and should therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis may also compromise the erythropoietic response. A reticulocyte count should be considered as part of the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, an examination of the bone marrow should be considered. If the bone marrow is consistent with PRCA, testing for anti-erythropoietin antibodies should be performed.

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 in association with epoetin treatment. More severe cases have been observed with long-acting epoetins. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, Aranesp should be withdrawn immediately and an alternative treatment considered. If the patient has developed a severe cutaneous skin reaction such as SJS or TEN due to the use of Aranesp, treatment with Aranesp must not be restarted in this patient at any time.

Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in association with ESAs, including Aranesp. This has been predominantly reported in patients with CRF treated subcutaneously. These antibodies have been shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have neutralising antibodies to erythropoietin should not be switched to Aranesp (see section 4.8).

A paradoxical decrease in haemoglobin and development of severe anaemia associated with low reticulocyte counts should prompt to discontinue treatment with epoetin and perform anti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis C treated with interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved in the management of anaemia associated with hepatitis C.

Active liver disease was an exclusion criteria in all studies of Aranesp, therefore no data are available from patients with impaired liver function. Since the liver is thought to be the principal route of elimination of darbepoetin alfa and r-HuEPO, Aranesp should be used with caution in patients with liver disease.

Aranesp should also be used with caution in those patients with sickle cell anaemia.

Misuse of Aranesp by healthy persons may lead to an excessive increase in packed cell volume. This may be associated with life-threatening complications of the cardiovascular system.

The needle cap of the pre-filled syringe or pre-filled pen contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

Aranesp should be used with caution in patients with epilepsy. Convulsions have been reported in patients receiving Aranesp.

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

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- free’.

Chronic renal failure patients

In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical studies, an increased risk of death, serious cardiovascular or cerebrovascular events including stroke, and vascular access thrombosis was observed when ESAs were administered to target a haemoglobin of greater than 12 g/dl (7.5 mmol/l).

Caution should be exercised with escalation of Aranesp doses in patients with chronic renal failure, since high cumulative epoetin doses may be associated with an increased risk of mortality, serious cardiovascular and cerebrovascular events. In patients with a poor haemoglobin response to epoetins, alternative explanations for the poor response should be considered (see sections 4.2 and 5.1).

Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins when haemoglobin concentration is increased beyond the level necessary to control symptoms of anaemia and to avoid blood transfusion.

Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 mcg/L or whose transferrin saturation is below 20%.

Serum potassium levels should be monitored regularly during Aranesp therapy. Potassium elevation has been reported in a few patients receiving Aranesp, though causality has not been established. If an elevated or rising potassium level is observed then consideration should be given to ceasing Aranesp administration until the level has been corrected.

Cancer patients

Effect on tumour growth

Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of tumours. In several controlled studies, epoetins have not been shown to improve overall survival or decrease the risk of tumour progression in patients with anaemia associated with cancer.

In controlled clinical studies, use of Aranesp and other ESAs have shown:

• shortened time to tumour progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a haemoglobin of greater than 14 g/dl (8.7 mmol/l), ESAs are not indicated for use in this patient population.
• shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l).
• increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for use in this patient population.
• 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).

In view of the above, in some clinical situations blood transfusion should be the preferred treatment for the management of anaemia in patients with cancer. The decision to administer recombinant erythropoietins should be based on a benefit-risk assessment with the participation of the individual patient, which should take into account the specific clinical context. Factors that should be considered in this assessment should include the type of tumour and its stage; the degree of anaemia; life-expectancy; the environment in which the patient is being treated; and patient preference (see section 5.1).

In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 12 g/dl (7.5 mmol/l), the dosage adaptation described in section 4.2 should be closely respected, in order to minimise the potential risk of thromboembolic events. Platelet counts and haemoglobin level should also be monitored at regular intervals.

The clinical results obtained so far do not indicate any interaction of darbepoetin alfa with other substances. However, there is potential for an interaction with substances that are highly bound to red blood cells e.g. cyclosporin, tacrolimus. If Aranesp is given concomitantly with any of these treatments, blood levels of these substances should be monitored and the dosage adjusted as the haemoglobin rises.

Pregnancy

There are no adequate and well-controlled studies with Aranesp in pregnant women.

Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. No alteration of fertility was detected.

Caution should be exercised when prescribing Aranesp to pregnant women.

Breast-feeding

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.

Aranesp has no or negligible influence on the ability to drive and use machines.

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:

Blood and lymphatic system disorders

Not known²: Pure red cell aplasia

Immune system disorders

__Very common Hypersensitivity^a

Nervous system disorders

Common: Stroke^b

Uncommon¹: Convulsions

Cardiac disorders

Very common: Hypertension

Vascular disorders

Uncommon: Thromboembolic events^c

Uncommon¹: Dialysis vascular access thrombosis^d

Skin and subcutaneous tissue disorders

Common: Rash/erythemae

Not known²: SJS/TEN, erythema multiforme, blistering, skin exfoliation

General disorders and administration site conditions

Common: Injection site pain

Uncommon¹: Injection site bruising, Injection site haemorrhage

Source: Includes 5 randomised, 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 haemorrhagic stroke, ischaemic 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 generalised, erythema.

Cancer patients

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

Incidence of adverse reactions from controlled clinical studies and post-marketing experience are:

Immune system disorders

Very common: Hypersensitivity^a

Nervous system disorders

Uncommon¹: Convulsions

Cardiac disorders

Common: Hypertension

Vascular disorders

Common: Thromboembolic events^b, including pulmonary embolism

Skin and subcutaneous tissue disorders

Common: Rash/erythema^c

Not known²: SJS/TEN, erythema multiforme, blistering, skin exfoliation

General disorders and administration site conditions

Common: Oedema^d

Common: Injection site pain^e

Uncommon¹: Injection site bruising, Injection site haemorrhage

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 randomised, 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 generalised, rash papular, erythema, exfoliative rash, rash maculo-papular, rash vesicular as well as rash pustular from SOC Infections and Infestations.
^d Oedema: includes PT Oedema Peripheral, Oedema, Generalised Oedema, Oedema due to Cardiac Disease, Face oedema
^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, neutralising 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 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.

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.

Paediatric chronic renal failure population

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

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 incompatibility studies, this medicinal product must not be mixed or administered as an infusion with other medicinal products.