ARZERRA 100mg 20mg / ml perfusive solution concentrate medication leaflet

Arzerra 100 mg concentrate for solution for infusion

Arzerra 1000 mg concentrate for solution for infusion

One ml of concentrate contains 20 mg of ofatumumab.

Arzerra 100 mg concentrate for solution for infusion

Each vial contains 100 mg of ofatumumab in 5 ml.

Arzerra 1000 mg concentrate for solution for infusion

Each vial contains 1000 mg of ofatumumab in 50 ml.

Ofatumumab is a human monoclonal antibody produced in a recombinant murine cell line (NS0).

This medicinal product contains 34.8 mg sodium per 300 mg dose, 116 mg sodium per 1000 mg doseand 232 mg sodium per 2000 mg dose.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to opalescent, colourless to pale yellow liquid.

Previously untreated chronic lymphocytic leukaemia (CLL)

Arzerra in combination with chlorambucil or bendamustine is indicated for the treatment of adultpatients with CLL who have not received prior therapy and who are not eligible for fludarabine-basedtherapy.

See section 5.1 for further information.

Relapsed CLL

Arzerra is indicated in combination with fludarabine and cyclophosphamide for the treatment of adultpatients with relapsed CLL.

See section 5.1 for further information.

Refractory CLL

Arzerra is indicated for the treatment of CLL in adult patients who are refractory to fludarabine andalemtuzumab.

See section 5.1 for further information.

Arzerra should be administered under the supervision of a physician experienced in the use of cancertherapy and in an environment where full resuscitation facilities are immediately available.

Patients should be closely monitored during administration of ofatumumab for the onset of infusion-related reactions, including cytokine release syndrome, particularly during the first infusion.

Pre-medication

Patients should receive the following pre-medication medicinal products 30 minutes to 2 hours prior toeach Arzerra infusion according to the following dosing schedules:

Premedication schedule for Arzerra

Previously untreated

CLL or relapsed Refractory CLL

CLL

Infusion number 1 and 2 3 to n* 1 and 2 3 to 8 9 10 to 12

Intravenouscorticosteroid 0 to 0 to 50 to50 mg 100 mg 100 mg(prednisolone or 50 mg** 100 mg** 100 mg***equivalent)

Oral paracetamol1000 mg(acetaminophen)

Oral or intravenous

Diphenhydramine 50 mg or cetirizine 10 mg (or equivalent)antihistamine

*Up to 13 infusions in previously untreated CLL; up to 7 infusions in relapsed CLL

**Corticosteroid may be either reduced or omitted for subsequent infusions at the discretion of thephysician, if a severe infusion-related adverse drug reaction (ADR) did not occur with the precedinginfusion(s).

***Corticosteroid may be reduced for subsequent infusions at the discretion of the physician, if asevere infusion-related ADR did not occur with the preceding infusion(s).

Previously untreated CLL

For previously untreated CLL, the recommended dosage and schedule is:

- Cycle 1: 300 mg on day 1 followed 1 week later by 1000 mg on day 8

- Subsequent cycles (until best response or a maximum of 12 cycles): 1000 mg on day 1 every28 days.

Each cycle lasts 28 days and is counted from day 1 of the cycle.

Best response is a clinical response that did not improve with 3 additional cycles of treatment.

Relapsed CLL

For relapsed CLL, the recommended dosage and schedule is:

- Cycle 1: 300 mg on day 1 followed 1 week later by 1000 mg on day 8

- Subsequent cycles (up to a maximum of 6 cycles in total): 1000 mg on day 1 every 28 days.

Each cycle lasts 28 days and is counted from day 1 of the cycle.

Previously untreated CLL and relapsed CLL

The initial rate of the first infusion of Arzerra should be 12 ml/h. During infusion, the rate should beincreased every 30 minutes to a maximum of 400 ml/h (see section 6.6). If an infusion-related ADR isobserved during infusion, see below section “Dose modification and reinitiation of therapy afterinfusion-related ADRs”.

If the preceding infusion(s) has (have) been completed without severe infusion related ADRs, thesubsequent infusions can start at a rate of 25 ml/h and should be increased every 30 minutes up to amaximum of 400 ml/h (see section 6.6). If an infusion-related ADR is observed during infusion, seebelow section “Dose modification and reinitiation of therapy after infusion-related ADRs”.

Dose modification and reinitiation of therapy after infusion-related ADRs

In the event of a mild or moderate ADR, the infusion should be interrupted and restarted at half of theinfusion rate at the time of interruption once the patient’s condition is stable. If the infusion rate hadnot been increased from the starting rate of 12 ml/hour prior to interrupting due to an ADR, theinfusion should be restarted at 12 ml/hour, the standard starting infusion rate. The infusion rate cancontinue to be increased according to standard procedures, to physician discretion and to patienttolerance (not to exceed doubling the rate every 30 minutes).

In the event of a severe ADR, the infusion should be interrupted and restarted at 12 ml/hour when thepatient’s condition is stable. The infusion rate can continue to be increased according to standardprocedures, to physician discretion and to patient tolerance (not to exceed increasing the rate every30 minutes).

Arzerra should be permanently discontinued in patients who develop an anaphylactic reaction to themedicinal product.

Refractory CLL

The recommended dose and schedule is 12 doses administered as follows:

- 300 mg on day 1 followed 1 week later by

- 2000 mg weekly for 7 doses (infusions 2 to 8) followed 4-5 weeks later by

- 2000 mg every 28 days for 4 doses (infusions 9 to 12)

First and second infusions

The initial rate of the first and second infusion of Arzerra should be 12 ml/hour. During infusion, therate should be increased every 30 minutes to a maximum of 200 ml/hour (see section 6.6). If aninfusion-related ADR is observed during an infusion, see below section “Dose modification andreinitiation of therapy after infusion-related ADRs”.

If the preceding infusion(s) has (have) been completed without severe infusion-related ADRs, thesubsequent infusions can start at a rate of 25 ml/hour and should be increased every 30 minutes up to amaximum of 400 ml/hour (see section 6.6). If an infusion-related ADR is observed during an infusion,see below section “Dose modification and reinitiation of therapy after infusion-related ADRs”.

Dose modification and reinitiation of therapy after infusion-related ADRs

In the event of a mild or moderate ADR, the infusion should be interrupted and restarted at half of theinfusion rate at the time of interruption, once the patient’s condition is stable. If the infusion rate hadnot been increased from the starting rate of 12 ml/hour prior to interrupting due to an ADR, theinfusion should be restarted at 12 ml/hour, the standard starting infusion rate. The infusion rate cancontinue to be increased according to standard procedures, to physician discretion and to patienttolerance (not to exceed doubling the rate every 30 minutes).

In the event of a severe ADR, the infusion should be interrupted and restarted at 12 ml/hour, once thepatient’s condition is stable. The infusion rate can continue to be increased according to standardprocedures, to physician discretion and to patient tolerance (not to exceed increasing the rate every30 minutes).

Arzerra should be permanently discontinued in patients who develop an anaphylactic reaction to themedicinal product.

The safety and efficacy of Arzerra in children aged below 18 years have not been established. Arzerrais therefore not recommended for use in this patient population.

No substantial differences related to age were seen in safety and efficacy (see section 5.1). Based onavailable safety and efficacy data in the elderly, no dose adjustment is required (see section 5.2).

No formal studies of Arzerra in patients with renal impairment have been performed. No doseadjustment is recommended for mild to moderate renal impairment (creatinine clearance >30 ml/min)(see section 5.2).

No formal studies of Arzerra in patients with hepatic impairment have been performed. However,patients with hepatic impairment are unlikely to require dose modification (see section 5.2).

Arzerra is for intravenous infusion and must be diluted prior to administration. For instructions ondilution of the medicinal product before administration, see section 6.6.

Hypersensitivity to ofatumumab or to any of the excipients listed in section 6.1.

Intravenous ofatumumab has been associated with infusion-related reactions. These reactions mayresult in temporary interruption or withdrawal of treatment. Pre-medication attenuates infusion-relatedreactions but these may still occur, predominantly during the first infusion. Infusion-related reactionsmay include, but are not limited to, anaphylactoid events, bronchospasm, cardiac events (e.g.

myocardial ischaemia/infarction, bradycardia), chills/rigors, cough, cytokine release syndrome,diarrhoea, dyspnoea, fatigue, flushing, hypertension, hypotension, nausea, pain, pulmonary oedema,pruritus, pyrexia, rash, and urticaria. In rare cases, these reactions may lead to death. Even with pre-medication, severe reactions, including cytokine release syndrome, have been reported following useof ofatumumab. In the event of a severe infusion-related reaction, the infusion of Arzerra must beinterrupted immediately and symptomatic treatment instituted (see section 4.2).

If an anaphylactic reaction occurs, Arzerra should be immediately and permanently discontinued andappropriate medical treatment should be initiated.

Infusion-related reactions occur predominantly during the first infusion and tend to decrease withsubsequent infusions. Patients with a history of decreased pulmonary function may be at a greater riskfor pulmonary complications from severe reactions and should be monitored closely during infusion of

Arzerra.

In patients with CLL, tumour lysis syndrome (TLS) may occur with use of Arzerra. Risk factors for

TLS include a high tumour burden, high concentrations of circulating cells (≥25,000/mm3),hypovolaemia, renal insufficiency, elevated pre-treatment uric acid levels and elevated lactatedehydrogenase levels. Management of TLS includes correction of electrolyte abnormalities,monitoring of renal function, maintenance of fluid balance and supportive care.

Cases of progressive multifocal leukoencephalopathy (PML) resulting in death have been reported in

CLL patients receiving cytotoxic pharmacotherapy, including ofatumumab. A diagnosis of PMLshould be considered in any Arzerra patient who reports the new onset of or changes in pre-existingneurological signs and symptoms. If a diagnosis of PML is suspected Arzerra should be discontinuedand referral to a neurologist should be considered.

The safety of, and ability to generate a primary or anamnestic response to, immunisation with liveattenuated or inactivated vaccines during treatment with ofatumumab has not been studied. Theresponse to vaccination could be impaired when B-cells are depleted. Due to the risk of infection,administration of live attenuated vaccines should be avoided during and after treatment withofatumumab, until B-cell counts are normalised. The risks and benefits of vaccinating patients during

Arzerra therapy should be considered.

Hepatitis B

Hepatitis B virus (HBV) infection and reactivation, in some cases resulting in fulminant hepatitis,hepatic failure and death, has occurred in patients treated with medicinal products classified as CD20-directed cytolytic antibodies, including Arzerra. Cases have been reported in patients who are hepatitis

B surface antigen (HBsAg) positive and also in those who are hepatitis B core antibody (anti-HBc)positive but HBsAg negative. Reactivation has also occurred in patients who appear to have resolvedhepatitis B infection (i.e. HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-

HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increasein serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negativeand anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e. increase intransaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

All patients should be screened for HBV infection by measuring HBsAg and anti-HBc beforeinitiation of Arzerra treatment. For patients who show evidence of prior (HBsAg negative, anti-HBcpositive) hepatitis B infection, physicians with expertise in managing hepatitis B should be consultedregarding monitoring and initiation of HBV antiviral therapy. Arzerra treatment should not be initiatedin patients with evidence of current hepatitis B infection (HBsAg positive) until the infection has beenadequately treated.

Patients with evidence of prior HBV infection should be monitored for clinical and laboratory signs ofhepatitis or HBV reactivation during treatment with and for 6-12 months following the last infusion of

Arzerra. HBV reactivation has been reported up to 12 months following completion of therapy.

Discontinuation of HBV antiviral therapy should be discussed with physicians with expertise inmanaging hepatitis B.

In patients who develop reactivation of HBV while receiving Arzerra, Arzerra and any concomitantchemotherapy should be interrupted immediately, and appropriate treatment instituted. Insufficientdata exist regarding the safety of resuming Arzerra in patients who develop HBV reactivation.

Resumption of Arzerra in patients whose HBV reactivation resolves should be discussed withphysicians with expertise in managing hepatitis B.

Patients with a history of cardiac disease should be monitored closely. Arzerra should be discontinuedin patients who experience serious or life-threatening cardiac arrhythmias.

The effect of multiple doses of Arzerra on the QTc interval was evaluated in a pooled analysis of threeopen-label studies in patients with CLL (N=85). Increases above 5 msec were observed in themedian/mean QT/QTc intervals in the pooled analysis. No large changes in the mean QTc interval (i.e.

>20 milliseconds) were detected. None of the patients had an increase of QTc to >500 msec. Aconcentration-dependent increase in QTc was not detected. It is recommended that patients haveelectrolytes such as potassium and magnesium measured prior to and during the administration ofofatumumab. Electrolyte abnormalities should be corrected. The effect of ofatumumab on patientswith prolonged QT intervals (e.g. acquired or congenital) is unknown.

Bowel obstruction

Bowel obstruction has been reported in patients receiving anti-CD20 monoclonal antibody therapy,including ofatumumab. Patients who present with abdominal pain, especially early in the course ofofatumumab therapy, should be evaluated and appropriate treatment instituted.

Laboratory monitoring

Cytopenias, including prolonged and late-onset neutropenia, have been reported during ofatumumabtherapy. Complete blood counts, including neutrophil and platelet counts, should be obtained atregular intervals during Arzerra therapy and more frequently in patients who develop cytopenias.

This medicinal product contains 34.8 mg sodium per 300 mg dose, 116 mg sodium per 1000 mg doseand 232 mg sodium per 2000 mg dose. This should be taken into consideration by patients on acontrolled sodium diet.

Although limited formal drug-drug interaction data exist for ofatumumab, there are no knownclinically significant interactions with other medicinal products. No clinically relevantpharmacokinetic interactions were observed between ofatumumab and fludarabine,cyclophosphamide,bendamustine, chlorambucil, or its active metabolite, phenylacetic acid mustard.

Live attenuated or inactivated vaccine efficacy may be impaired with ofatumumab. Therefore, theconcomitant use of these agents with ofatumumab should be avoided. If the coadministration is judgedunavoidable, the risks and benefits of vaccinating patients during therapy with ofatumumab should beconsidered (see section 4.4).

Since ofatumumab may cause foetal B-cell depletion, effective contraception (methods that result inless than 1% pregnancy rates) has to be used during Arzerra therapy and for 12 months after the last

Arzerra dose. After this period, planning of a pregnancy in relation to the underlying disease, shouldbe evaluated by the treating physician.

Ofatumumab may cause foetal B-cell depletion based on findings from animal studies and on itsmechanism of action (see section 5.1).

There are no adequate and well-controlled studies in pregnant women to inform a product-associatedrisk. No teratogenicity or maternal toxicity were observed in an animal reproduction study withadministration of ofatumumab to pregnant monkeys (see section 5.3). Ofatumumab should not beadministered to pregnant women unless the possible benefit to the mother outweighs the possible riskto the foetus.

Administration of live vaccines to neonates and infants exposed to ofatumumab in utero should beavoided until B-cell recovery occurs (see sections 4.4 and 4.5).

It is unknown whether Arzerra is excreted in human milk, however human IgG is secreted in humanmilk. The safe use of ofatumumab in humans during lactation has not been established. The excretionof ofatumumab in milk has not been studied in animals. Published data suggest that neonatal andinfant consumption of breast milk does not result in substantial absorption of these maternal antibodiesinto circulation. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinuedduring treatment with Arzerra and for 12 months following treatment.

There are no data on the effects of ofatumumab on human fertility. Effects on male and female fertilityhave not been evaluated in animal studies.

No studies on the effects of Arzerra on the ability to drive and use machines have been performed.

No detrimental effects on such activities are predicted from the pharmacology of ofatumumab. Theclinical status of the patient and the ADR profile of ofatumumab should be borne in mind whenconsidering the patient's ability to perform tasks that require judgement, motor or cognitive skills (seesection 4.8).

The overall safety profile of ofatumumab is based on data from 1,168 patients in clinical trials in CLL(see section 5.1). This includes 643 patients treated with ofatumumab as monotherapy (in patients withrelapsed or refractory CLL) and 525 patients treated with ofatumumab in combination withchemotherapy (chlorambucil or bendamustine or fludarabine and cyclophosphamide).

Adverse reactions reported in patients treated with ofatumumab as monotherapy and with ofatumumabin combination with chemotherapy, are listed below by MedDRA body system organ class and byfrequency, using the following convention: 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); not known(cannot be estimated from available data). Within each frequency grouping, adverse reactions areranked in order of decreasing seriousness.

MedDRA System Very common Common Uncommon

Organ Class

Infections and Lower respiratory Sepsis (including Hepatitis B infection and

Infestations tract infection neutropenic sepsis and reactivation, progressive(including septic shock) herpes viral multifocalpneumonia), upper infection, urinary tract leukoencephalopathyrespiratory tract infectioninfection

Blood and Neutropenia, Febrile neutropenia, Agranulocytosis,lymphatic system anaemia thrombocytopenia, coagulopathy, red celldisorders leukopenia aplasia, lymphopenia

Immune system Hypersensitivity* Anaphylactic reactionsdisorders (including anaphylacticshock)*

Nervous system Headache*disorders

Metabolism and Tumour lysis syndromenutrition disorders

Cardiac disorders Tachycardia* Bradycardia*

Vascular disorders Hypotension*,hypertension*

Respiratory, Dyspnoea*, cough* Bronchospasm*, chest Pulmonary oedema*,thoracic and discomfort*, hypoxia*mediastinal oropharyngeal pain*,disorders nasal congestion*

Gastrointestinal Nausea*, Small intestinaldisorders diarrhoea* obstruction

Skin and Rash* Urticaria*, pruritus*,subcutaneous flushing*tissue disorders

Musculoskeletal Back pain*and connectivetissue disorders

General disorders Pyrexia*, fatigue* Cytokine releaseand administration syndrome*, chillssite conditions (including rigors)*,hyperhidrosis*

Injury, poisoning Infusion-related reaction*and proceduralcomplications

*These events are likely attributable to ofatumumab in the setting of an infusion-related reaction andtypically occur after the start of infusion and within 24 hours after the completion of the infusion (seesection 4.4).

Of the 1,168 patients receiving ofatumumab in clinical trials for CLL, the most frequently observed

ADRs were infusion-related reactions which occurred in 711 patients (61%) at any time duringtreatment. The majority of infusion-related reactions were Grade 1 or Grade 2 in severity. Sevenpercent of patients had ≥Grade 3 infusion-related reactions at any time during treatment. Two percentof the infusion-related reactions led to discontinuation of treatment. There were no fatal infusion-related reactions (see section 4.4).

Of the 1,168 patients receiving ofatumumab in clinical trials for CLL, 682 patients (58%) experiencedan infection. These included bacterial, viral and fungal infections. 268 (23%) of the 1,168 patientsexperienced ≥Grade 3 infections. 65 (6%) of the 1,168 patients experienced a fatal infection.

Of the 1,168 patients receiving ofatumumab in clinical trials, 420 patients (36%) experienced anadverse event associated with a decreased neutrophil count; 129 (11%) experienced a serious adverseevent associated with a decreased neutrophil count.

In the pivotal study for untreated CLL (OMB110911; ofatumumab plus chlorambucil 217 patients,chlorambucil alone 227 patients), prolonged neutropenia (defined as Grade 3 or 4 neutropenia notresolved between 24 and 42 days after last dose of study treatment) was reported in 41 patients (9%)(23 patients [11%] treated with ofatumumab and chlorambucil, 18 patients [8%] treated withchlorambucil alone). Nine patients (4%) treated with ofatumumab and chlorambucil, and three patientstreated with chlorambucil alone had late-onset neutropenia (defined as Grade 3 or 4 neutropeniastarting at least 42 days after the last treatment). In the pivotal study (OMB110913, ofatumumab plusfludarabine and cyclophosphamide 181 patients; fludarabine and cyclophosphamide 178 patients) inrelapsed CLL patients, prolonged neutropenia was reported in 38 (11%) patients (18 patients [10%]treated with ofatumumab in combination with fludarabine and cyclophosphamide compared to20 patients [11%] in the fludarabine and cyclophosphamide arm). Thirteen (7%) patients treated withofatumumab in combination with fludarabine and cyclophosphamide, and 5 (3%) patients treated withfludarabine and cyclophosphamide had late-onset neutropenia.

The effect of multiple doses of Arzerra on the QTc interval was evaluated in a pooled analysis of threeopen-label studies in patients with CLL (N=85). Increases above 5 msec were observed in themedian/mean QT/QTc intervals in the pooled analysis. No large changes in the mean QTc interval (i.e.

>20 milliseconds) were detected. None of the patients had an increase of QTc to >500 msec. Aconcentration dependent increase in QTc was not detected.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported.

Pharmacotherapeutic group: antineoplasic agents, monoclonal antibodies, ATC code: L01XC10

Ofatumumab is a human monoclonal antibody (IgG1) that binds specifically to a distinct epitopeencompassing both the small and large extracellular loops of the CD20 molecule. The CD20 moleculeis a transmembrane phosphoprotein expressed on B lymphocytes from the pre-B to mature Blymphocyte stage and on B-cell tumours. The B-cell tumours include CLL (generally associated withlower levels of CD20 expression) and non-Hodgkin's lymphomas (where >90% of tumours have highlevels of CD20 expression). The CD20 molecule is not shed from the cell surface and is notinternalised following antibody binding.

The binding of ofatumumab to the membrane-proximal epitope of the CD20 molecule inducesrecruitment and activation of the complement pathway at the cell surface, leading to complement-dependent cytotoxicity and resultant lysis of tumour cells. Ofatumumab has been shown to induceappreciable lysis of cells with high expression levels of complement defence molecules. Ofatumumabhas also been shown to induce cell lysis in both high and low CD20 expressing cells and in rituximab-resistant cells. In addition, the binding of ofatumumab allows the recruitment of natural killer cellsallowing the induction of cell death through antibody-dependent cell-mediated cytotoxicity.

Peripheral B-cell counts decreased after the first ofatumumab infusion in patients with haematologicalmalignancies. In all patients with CLL, ofatumumab induces rapid and profound B-cell depletion,whether given as a single agent or in combination.

When ofatumumab was administered as single agent in patients with refractory CLL, the mediandecrease in B-cell counts was 22% after the first infusion and 92% at the eighth weekly infusion.

Peripheral B-cell counts remained low throughout the remainder of therapy in most patients andremained below baseline up to 15 months after the last dose in patients who responded.

When ofatumumab was administered in combination with chlorambucil in patients with previouslyuntreated CLL, the median decreases in B-cell counts after the first cycle and prior to the sixthmonthly cycle were 94% and >99%. At 6 months after the last dose, the median reductions in B-cellcounts were >99%.

When ofatumumab was administered in combination with fludarabine and cyclophosphamide inpatients with relapsed CLL, the median decrease from baseline was 60% after the first infusion andcomplete depletion (100%) was reached after 4 cycles.

There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samplesfrom more than 1,000 patients across the CLL clinical programme were tested for anti-ofatumumabantibodies during and after treatment periods ranging from 8 weeks to 2 years. Formation ofanti-ofatumumab antibodies was observed for less than 0.5% of patients with CLL after treatment withofatumumab.

Previously untreated CLL

Study OMB110911 (randomised, open-label, parallel-arm, multicentre) evaluated the efficacy of

Arzerra in combination with chlorambucil compared with chlorambucil alone in 447 patients withpreviously untreated CLL considered inappropriate for fludarabine-based treatment (e.g. due toadvanced age or presence of co-morbidities), with active disease and indicated for treatment. Patientsreceived either Arzerra as monthly intravenous infusions (cycle 1: 300 mg on day 1 and 1000 mg onday 8; subsequent cycles: 1000 mg on day 1 every 28 days) in combination with chlorambucil(10 mg/m2orally on days 1-7 every 28 days) or chlorambucil alone (10 mg/m2orally on days 1-7 every28 days). Patients received treatment for a minimum of 3 months until best response or up to amaximum of 12 cycles. The median age was 69 years (range: 35 to 92 years), 27% patients were≥75 years of age, 63% were male and 89% were white. Median Cumulative Illness Rating Score for

Geriatrics (CIRS-G) was 9 and 31% of patients had a CIRS-G >10. Median creatinine clearance(CrCl), assessed with the use of the Cockroft-Gault formula, was 70 ml/min and 48% of patients had a

CrCl of <70 ml/min. Patients with an Eastern Cooperative Oncology Group (ECOG) performancestatus of 0 to 2 were enrolled into the study and 91% had an ECOG performance status of 0 or 1.

Approximately 60% of patients received 3-6 cycles of Arzerra and 32% received 7-12 cycles. Themedian number of cycles completed in patients was 6 (total Arzerra dose of 6300 mg).

The primary endpoint was median progression-free survival (PFS) as assessed by a blinded

Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic

Leukaemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG)guidelines (2008). The overall response rate (ORR) including complete response (CR) was alsoassessed by an IRC using the 2008 IWCLL guidelines.

Arzerra in combination with chlorambucil showed a statistically significant (71%) improvement inmedian PFS compared with chlorambucil alone (HR: 0.57; 95% CI: 0.45, 0.72) (see Table 1 and

Figure 1). PFS benefit with the addition of Arzerra was observed in all patients, including those withpoor-risk biological features (such as 17p or 11q deletion, unmutated IGHV, β2M >3500 μg/l, and

ZAP-70 expression).

Table 1 Summary of PFS with Arzerra in combination with chlorambucil compared withchlorambucil in previously untreated CLL

IRC-assessed primary and Chlorambucil Arzerra andsubgroup analyses of PFS, months chlorambucil(N=226) (N=221)

Median, all patients 13.1 22.495% CI (10.6, 13.8) (19.0, 25.2)

Hazard ratio 0.57 (0.45, 0.72)

P value p<0.001

Age ≥75 years (n=119) 12.2 23.8

Co-morbidity 0 or 1 (n=126) 10.9 23.0

Co-morbidity 2 or more (n=321) 13.3 21.9

ECOG 0, 1 (n=411) 13.3 23.0

ECOG 2 (n=35) 7.9 20.9

CIRS-G ≤10 (n=310) 13.1 21.7

CIRS-G >10 (n=137) 12.2 23.2

CrCl <70 ml/min (n=214) 10.9 23.1

CrCl ≥70 ml/min (n=227) 14.5 22.117p or 11q deletion (n=90) 7.9 13.6

IGHV mutated (≤98%) (n=177) 12.2 30.5

IGHV unmutated (>98%) (n=227) 11.7 17.3β2M ≤3500 μg/l (n=109) 13.8 25.5β2M >3500 μg/l (n=322) 11.6 19.6

ZAP-70 positive (n=161) 9.7 17.7

ZAP-70 intermediate (n=160) 13.6 25.3

ZAP-70 negative (n=100) 13.8 25.6

IGHV mutated & ZAP-70 negative10.5 NR(n=60)

IGHV mutated & ZAP-70 positive7.9 27.2(n=35)

IGHV unmutated & ZAP-70 negative16.7 16.2(n=27)

IGHV unmutated & ZAP-70 positive11.2 16.2(n=122)

Abbreviations: β2M = beta-2-microglobulin, CI = confidence interval; CIRS-G = Cumulative

Illness Rating Scale for Geriatrics, CLL = chronic lymphocytic leukaemia, CrCl = creatinineclearance, ECOG = Eastern Cooperative Oncology Group, IGHV = Immunoglobulin Heavy

Chain Variable Region, IRC = Independent Review Committee, N = number, NR = not reached,

PFS = progression-free survival, ZAP-70 = zeta-chain-associated protein kinase 70.

Limited data are available in the heterogeneous non-white population and in patients with an ECOGperformance status of PS = 2.

Figure 1 Kaplan-Meier estimates of IRC-assessed PFS in previously untreated CLL

- -----Chlorambucil (N=226)

Median 13.11.0 months____Ofatumumab +

Chlorambucil (N=221)0.9

Median 22.4 months0.8

Hazard Ratio=0.570.7 95% CI (0.45, 0.72)p-value<0.0010.60.50.40.30.20.10.0

Number at risks at

Chlorambucil 226 R1i7s3k : 130 92 67 52 33 17 6 1 1

Ofatumumab 221 192 169 148 125 104 70 46 28 15 9 3 1plus

Chlorambuci +

C hl0 4 8 12 16 20 24 28 32 36 40 44 48 52

Time of Progression-free Survival (Months)

Table 2 Summary of secondary outcomes of Arzerra in combination with chlorambucilcompared with chlorambucil in previously untreated CLL

IRC-assessed secondary outcome Chlorambucil Arzerra andchlorambucil(N=226) (N=221)

ORR (%) 69 8295% CI (62.1, 74.6) (76.7, 87.1)

P value p<0.001

CR (%) 1 12

CR with MRD negativity (% of CR) 0 37

Median duration of response, all patients,13.2 22.1months95% CI (10.8, 16.4) (19.1, 24.6)

P value p<0.001

Abbreviations: CI = confidence interval, CLL = chronic lymphocytic leukaemia, CR = completeresponse, IRC = Independent Review Committee, MRD = minimal residue disease, N = number,

ORR = overall response rate

Study OMB115991 evaluated the efficacy of Arzerra in combination with bendamustine in 44 patientswith previously untreated CLL considered inappropriate for fludarabine-based treatment. Patientsreceived Arzerra as monthly intravenous infusions (cycle 1 300 mg on day 1 and 1000 mg on day 8;subsequent cycles: 1000 mg on day 1 every 28 days) in combination with intravenous bendamustine90 mg/m2 on days 1 and 2 every 28 days. Patients received treatment for a maximum of 6 cycles. Themedian number of cycles completed in patients was 6 (total Arzerra dose of 6300 mg).

Probability of Progression-free Survival

The primary endpoint was ORR assessed by the investigator according to the 2008 IWCLL guidelines.

The results of this study demonstrated that Arzerra in combination with bendamustine is an effectivetherapy providing an ORR of 95% (95% CI: 85, 99) and a CR of 43%. More than half of the patients(56%) with CR were MRD negative following the completion of study treatment.

No data comparing Arzerra in combination with bendamustine or with chlorambucil versus arituximab based regimen such as rituximab with chlorambucil is available. Thus, the benefit of such anew combination over a rituximab based regimen is unknown.

Relapsed CLL

Study OMB110913 (randomised, open-label, parallel-arm, multicentre trial) evaluated the efficacy ofofatumumab in combination with fludarabine and cyclophosphamide compared with fludarabine andcyclophosphamide in 365 patients with relapsed CLL (defined as a patient who has received at leastone prior CLL therapy and previously achieved a complete or partial remission/response, but after aperiod of six or more months demonstrated evidence of disease progression). Baseline diseasecharacteristics and prognostic markers were balanced between treatment arms and representative of arelapsed CLL population. Patient median age was 61 years (range: 32 to 90 years, 7% were 75 years ofage or older), 60% were male and 16%, 55% and 28% of patients were Binet stage A, B and C,respectively. The majority of patients (81%) received 1-2 prior lines of treatments (of whomapproximately 50% received 1 prior treatment) and 21% of patients had received prior rituximab. Themedian CIRS score was 7 (range: 4 to 17), 36% of patients had CrCL <70 ml/min, 93% of patients had

ECOG 0 or 1. Limited data are available in the heterogeneous non-white population and in patientswith an ECOG performance status of 2.

Patients received ofatumumab as intravenous infusions (cycle 1: 300 mg on day 1 and 1000 mg onday 8; subsequent cycles: 1000 mg on day 1 every 28 days). Approximately 90% of patients received3-6 cycles of ofatumumab and 66% completed 6 cycles.

The primary endpoint of progression-free survival (PFS), as assessed by a blinded independent reviewcommittee (IRC) using the updated National Cancer Institute-sponsored Working Group (NCI-WG)guidelines (2008), was prolonged in the ofatumumab plus fludarabine-cyclophosphamide (OFA+FC)arm compared to the fludarabine-cyclophosphamide (FC) arm (28.9 months versus 18.8 months; HR:

0.67; 95% CI: 0.51-0.88, p=0.0032) resulting in a 10-month improvement in median PFS (see

Figure 2). PFS based on local (investigator) assessment was consistent with the primary endpoint andresulted in a ~11-month improvement in median PFS (OFA+FC 27.2 months versus 16.8 months for

FC; HR=0.66 (95% CI: 0.51, 0.85, p=0.0009).

Figure 2 Kaplan-Meier estimates of PFS in relapsed CLL

- ---OFA + FC (N=183)

Median 28.94 months1.0 95% CI (22.80, 35.88)0.9 ____FC (N=182)0.8 Median 18.83 months0.7 95% CI (14.42,25.82)0.6 Hazard Ratio=0.670.5 95% CI (0.51,0.88)0.4 p-value=0.00320.30.20.10.0

Number at risks at

OFA + 183 164 141 124 108 93 86 78 67 51 37 25 14 12 7 4 1 0

FC

FC 182 145 112 88 73 61 56 45 37 24 13 10 6 3 1 1 0 0

Number at risk at

Risk:0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68

Time of Progression-free Survival (Months)

The overall response rate (ORR) was also assessed by an IRC using the 2008 NCI-WG guidelines.

The ORR was higher for OFA+FC versus FC (84% versus 68%, p=0.0003). Median time to nexttherapy was longer for the OFA+FC arm versus FC (48.1 months versus 40.1 months; HR: 0.73; 95%

CI: 0.51-1.05). Median time to progression was longer for the OFA+FC arm versus FC (42.1 monthsversus 26.8 months; HR: 0.63; 95% CI: 0.45-0.87).

With a median follow-up of approximately 34 months, 67 deaths (37%) in the OFA+FC arm and69 deaths (38%) in the FC arm were reported. The overall survival results showed a HR=0.78(56.4 months versus 45.8 months for the OFA+FC arm versus FC arm; 95% CI: 0.56-1.09; p=0.1410).

Refractory CLL

Arzerra was administered as monotherapy to 223 patients with refractory CLL (study Hx-CD20-406).

Patient median age was 64 years (range: 41 to 87 years), and the majority were male (73%) and white(96%). Patients received a median of 5 prior therapies, including rituximab (57%). Of these223 patients, 95 patients were refractory to fludarabine and alemtuzumab therapy (defined as failure toachieve at least a partial response with fludarabine or alemtuzumab treatment or disease progressionwithin 6 months of the last dose of fludarabine or alemtuzumab). Baseline cytogenetic (FISH) datawere available for 209 patients. 36 patients had a normal karyotype and chromosomal aberrations weredetected in 174 patients; there were 47 patients with 17p deletion, 73 patients with 11q deletion,23 patients with trisomy 12q, and 31 patients with 13q deletion as the sole aberration.

The ORR was 49% in patients refractory to fludarabine and alemtuzumab (see Table 3 for a summaryof the efficacy data from the study). Patients who had prior rituximab therapy, either as monotherapyor in combination with other medicinal products, responded to treatment with Arzerra at a similar rateto those who had not had prior rituximab therapy.

Probability of Progression-free Survival

Table 3 Summary of response to Arzerra in patients with refractory CLL

Patients refractory to fludarabine and(Primary) endpoint1 alemtuzumabn=95

Overall response rate

Responders, n (%) 47 (49)95.3% CI (%) 39, 60

Response rate in patients with prior rituximab therapy

Responders, n (%) 25/56 (45)95% CI (%) 31, 59

Response rate in patients with chromosomal abnormality17p deletion

Responders, n (%) 10/27 (37)95% CI (%) 19, 5811q deletion

Responders, n (%) 15/32 (47)95% CI (%) 29, 65

Median overall survival

Months 13.995% CI 9.9, 18.6

Progression-free survival

Months 4.695% CI 3.9, 6.3

Median duration of response

Months 5.595% CI 3.7, 7.2

Median time to next CLL therapy

Months 8.595% CI 7.2, 9.91 The overall response was assessed by an Independent Response Committee using the 1996 NCI-WGguidelines for CLL.

Improvements also were demonstrated in components of the NCI-WG response criteria. Theseincluded improvements associated with constitutional symptoms, lymphadenopathy, organomegaly, orcytopenias (see Table 4).

Table 4 Summary of clinical improvement with a minimum duration of 2 months inrefractory patients with abnormalities at baseline

Patients with benefit/patients with abnormality atbaseline (%)

Efficacy endpoint or haematological parametera Patients refractory to fludarabine and alemtuzumab

Lymphocyte count≥50% decrease 49/71 (69)

Normalisation (≤4x109/l) 36/71 (51)

Complete resolution of constitutional 21/47 (45)symptomsb

Lymphadenopathyc50% improvement 51/88 (58)

Complete resolution 17/88 (19)

Splenomegaly50% improvement 27/47 (57)

Complete resolution 23/47 (49)

Hepatomegaly50% improvement 14/24 (58)

Complete resolution 11/24 (46)

Haemoglobin <11 g/dl at baseline to >11 g/dl 12/49 (24)post baseline

Platelet counts ≤100x109/l at baseline to >50% 19/50 (38)increase or >100x109/l post baseline

Neutrophils <1x109/l at baseline to >1.5x109/l 1/17 (6)a Excludes patients’ visits from date of first transfusion, treatment with erythropoietin, ortreatment with growth factors. For patients with missing baseline data, latestscreening/unscheduled data was carried forward to baseline.b Complete resolution of constitutional symptoms (fever, night sweats, fatigue, weight loss)defined as the presence of any symptoms at baseline, followed by no symptoms present.c Lymphadenopathy measured by sum of the products of greatest diameters (SPD) as assessed byphysical examination.

Arzerra was also given to a group of patients (n=112) with bulky lymphadenopathy (defined as at leastone lymph node >5 cm) who were also refractory to fludarabine. The ORR in this group was 43%(95.3% CI: 33, 53). The median progression-free survival was 5.5 months (95% CI: 4.6, 6.4) and themedian overall survival was 17.4 months (95% CI: 15.0, 24.0). The response rate in patients with priorrituximab therapy was 38% (95% CI: 23, 61). These patients also experienced comparable clinicalimprovement, in terms of the efficacy endpoints and haematological parameters detailed above, topatients refractory to both fludarabine and alemtuzumab.

Additionally a group of patients (n=16) who were intolerant/ineligible for fludarabine treatment and/orintolerant to alemtuzumab treatment were treated with Arzerra. The overall response rate in this groupwas 63% (95.3% CI: 35, 85).

An open-label, two arm, randomised study (OMB114242) was conducted in patients with bulkyfludarabine refractory CLL who had failed at least 2 prior therapies (n=122) comparing Arzerramonotherapy (n=79) to physicians’ choice (PC) of therapy (n=43). There was no statisticallysignificant difference in the primary endpoint of IRC assessed PFS (5.4 vs. 3.6 months, HR=0.79,p=0.27). The PFS in the monotherapy Arzerra arm was comparable to the results seen with Arzerramonotherapy in study Hx-CD20-406.

A dose-ranging study (Hx-CD20-402) was conducted in 33 patients with relapsed or refractory CLL.

Patient median age was 61 years (range: 27 to 82 years), the majority were male (58%), and all werewhite. Treatment with Arzerra (when given as 4 once-weekly infusions), led to a 50% objectiveresponse rate in the highest dose group (1st dose: 500 mg; 2nd, 3rd and 4th dose: 2,000 mg) andincluded 12 partial remissions and one nodular partial remission. For the highest dose group, themedian time to progression was 15.6 weeks (95% CI: 15,22.6) in the full analysis population, and23 weeks (CI: 20,31) in responders. The duration of response was 16 weeks (CI: 13, 19) and the timeto next CLL therapy was 52.4 weeks (CI: 36.9 - non-estimable).

The European Medicines Agency has waived the obligation to submit the results of studies with

Arzerra in all subsets of the paediatric population in chronic lymphocytic leukaemia (see section 4.2for information on paediatric use).

Overall, the pharmacokinetics of ofatumumab were consistent across the indications, whether given asa single agent or in combination with fludarabine and cyclophosphamide or chlorambucil.

Ofatumumab had non-linear pharmacokinetics related to its decreasing clearance over time.

Arzerra is administered by intravenous infusion; therefore, absorption is not applicable.

Ofatumumab has a small volume of distribution, with mean Vss values ranging from 1.7 to 8.1 l acrossstudies, dose levels, and infusion number.

Ofatumumab is a protein for which the expected metabolic pathway is degradation to small peptidesand individual amino acids by ubiquitous proteolytic enzymes. Classical biotransformation studieshave not been performed.

Ofatumumab is eliminated in two ways: a target-independent route like other IgG molecules and atarget-mediated route which is related to binding to B-cells. There was a rapid and sustained depletionof CD20+ B-cells after the first ofatumumab infusion, leaving a reduced number of CD20+ cellsavailable for the antibody to bind at subsequent infusions. As a result, ofatumumab clearance valueswere lower and t½ values were significantly larger after later infusions than after the initial infusion;during repeated weekly infusions, ofatumumab AUC and Cmax values increased more than theexpected accumulation based on first infusion data.

The main pharmacokinetic parameters of ofatumumab as a single agent or in combination aresummarised in Table 5.

Table 5 Ofatumumab pharmacokinetic parameters (geometric mean)

Population (treatment) Dosing Cycle(1) Cmax AUC CL t½regimen (µg/ml) (µg.h/ml) (ml/h) (days)1st infusion Cycle 1 61.4(300 mg)2000 mg: 12th dose 827 166000 12.1 11.5

Refractory CLL 8 weekly(ofatumumab) infusionsfollowed by4 monthlyinfusions1st infusion Cycle 1 51.8 2620

Previously untreated(300 mg)patients1000 mg Cycle 4 285 65100 15.4 18.5(ofatumumab +monthlychlorambucil)infusions1st infusion Cycle 1 61.4 3560(300 mg)1000 mg on Cycle 4 313 89100 11.2 19.9the 8th day of

Relapsed CLLcycle 1(ofatumumab + FC)followed by1000 mgmonthlyinfusions(1) Cycle for which the pharmacokinetic parameters are presented in this table.

Cmax = maximum ofatumumab concentration at the end of infusion, AUC = exposure to ofatumumabover a dosing period, CL = ofatumumab clearance after multiple doses, T½ = terminal half-life

Numbers rounded to three significant digits

Age was not found to be a significant factor for ofatumumab pharmacokinetics in a cross-studypopulation pharmacokinetic analysis of patients ranging in age from 21 to 87 years of age.

No pharmacokinetic data are available in paediatric patients.

Gender had a modest effect (12%) on ofatumumab central volume of distribution in a cross-studypopulation analysis, with higher Cmax and AUC values observed in female patients (48% of thepatients in this analysis were male and 52% were female); these effects are not considered clinicallyrelevant, and no dose adjustment is recommended.

Baseline calculated creatinine clearance was not found to be a significant factor on ofatumumabpharmacokinetics in a cross-study population analysis in patients with calculated creatinine clearancevalues ranging from 26 to 287 ml/min. No dose adjustment is recommended for mild to moderaterenal impairment (creatinine clearance >30 ml/min). There are limited pharmacokinetic data inpatients with severe renal impairment (creatinine clearance <30 ml/min).

No formal studies were conducted to examine the effect of hepatic impairment. IgG1 molecules suchas ofatumumab are catabolised by ubiquitous proteolytic enzymes, which are not restricted to hepatictissue; therefore, changes in hepatic function are unlikely to have any effect on the elimination ofofatumumab.

Preclinical data reveal no special hazards for humans.

Intravenous and subcutaneous administration to monkeys resulted in the expected depletion ofperipheral and lymphoid tissue B-cell counts with no associated toxicological findings. As anticipated,a reduction in the IgG humoral immune response to keyhole limpet haemocyanin was noted, but therewere no effects on delayed-type hypersensitivity responses. In a few animals, increased red celldestruction occurred, presumably as a result of monkey anti-drug antibodies coating the red cells. Acorresponding increase in reticulocyte counts seen in these monkeys was indicative of a regenerativeresponse in the bone marrow.

Intravenous administration of ofatumumab to pregnant cynomolgus monkeys at 100 mg/kg onceweekly from days 20 to 50 of gestation did not elicit maternal or foetal toxicity or teratogenicity. Atthe end of organogenesis (day 48 of gestation), the ofatumumab exposure (AUCinf) corresponded to0.46 to 3.6 times the human exposure after the eighth infusion of the maximum recommended humandose (MRHD) of 2000 mg. At day 100 of gestation, depletion of B-cells relating to thepharmacological activity of ofatumumab were observed in foetal cord blood and foetal splenic tissues.

Spleen weights decreased by approximately 15% in the low-dose group and by approximately 30% inthe high-dose group, compared with control values. Pre- and post-natal development studies have notbeen performed. Post-natal recovery has therefore not been demonstrated.

As ofatumumab is a monoclonal antibody, genotoxicity and carcinogenicity studies have not beenconducted with ofatumumab.

Arginine

Sodium acetate (E262)

Sodium chloride

Polysorbate 80 (E433)

Edetate disodium (E386)

Hydrochloric acid (E507) (for pH-adjustment)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Vial3 years.

Diluted infusion solution

Chemical and physical in-use stability has been demonstrated for 48 hours at ambient conditions (lessthan 25°C).

From a microbiological point of view, the medicinal product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2-8 ºC, unless reconstitution/dilution has taken place incontrolled and validated aseptic conditions.

Store and transport refrigerated (2°C - 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Arzerra 100 mg concentrate for solution for infusion

Clear Type I glass vial with a bromobutyl rubber stopper and aluminium over-seal, containing 5 ml ofconcentrate for solution for infusion.

Arzerra is available in packs of 3 vials.

Arzerra 1000 mg concentrate for solution for infusion

Clear Type I glass vial with a bromobutyl rubber stopper and aluminium over-seal, containing 50 mlof concentrate for solution for infusion.

Arzerra is available in packs of 1 vial.

Arzerra concentrate for solution for infusion does not contain a preservative; therefore dilution shouldbe carried out under aseptic conditions. The diluted solution for infusion must be used within 24 hoursof preparation. Any unused solution remaining after this time should be discarded.

Before diluting Arzerra

Check the Arzerra concentrate for particulate matter and discolouration prior to dilution. Ofatumumabshould be a colourless to pale yellow solution. Do not use the Arzerra concentrate if there isdiscolouration.

Do not shake the ofatumumab vial for this inspection.

How to dilute the solution for infusion

The Arzerra concentrate must be diluted in sodium chloride 9 mg/ml (0.9%) solution for injectionprior to administration, using aseptic technique.

Arzerra 100 mg concentrate for solution for infusion300 mg dose: Use 3 vials (15 ml total, 5 ml per vial)

- Withdraw and discard 15 ml from a 1000 ml bag of sodium chloride 9 mg/ml (0.9%) solutionfor injection;

- Withdraw 5 ml of ofatumumab from each of 3 vials and inject into the 1000 ml bag;

- Do not shake; mix diluted solution by gentle inversion.

Arzerra 1000 mg concentrate for solution for infusion1000 mg dose: Use 1 vial (50 ml total, 50 ml per vial)

- Withdraw and discard 50 ml from a 1000 ml bag of sodium chloride 9 mg/ml (0.9%) solutionfor injection;

- Withdraw 50 ml of ofatumumab from the vial and inject into the 1000 ml bag;

- Do not shake; mix diluted solution by gentle inversion.

2000 mg dose: Use 2 vials (100 ml total, 50 ml per vial)

- Withdraw and discard 100 ml from a 1000 ml bag of sodium chloride 9 mg/ml (0.9%) solutionfor injection;

- Withdraw 50 ml of ofatumumab from each of 2 vials and inject into the 1000 ml bag;

- Do not shake; mix diluted solution by gentle inversion.

How to administer the diluted solution

Arzerra must not be administered as an intravenous push or bolus. Administer using an intravenousinfusion pump.

The infusion must be completed within 24 hours after preparation. Discard any unused solution afterthis time.

Arzerra must not be mixed with, or administered as an infusion with other medicinal products orintravenous solutions. Flush line before and after ofatumumab administration with sodium chloride9 mg/ml (0.9%) solution for injection to avoid this.

Previously untreated CLL and relapsed CLL

For the first infusion, administer over 4.5 hours (see section 4.2), through a peripheral line orindwelling catheter, according to the schedule below:

If the first infusion was completed without a severe adverse reaction, the remaining infusions of1000 mg should be administered over 4 hours (see section 4.2), through a peripheral line or indwellingcatheter, according to the schedule below. If any infusion-related adverse reactions are observed,infusion should be interrupted and restarted when the patient’s condition is stable (see section 4.2 forfurther information).

Infusion schedule

Infusion 1 Subsequent infusions*

Time after start of infusion (minutes)

Infusion rate (ml/hour) Infusion rate (ml/hour)0-30 12 2531-60 25 5061-90 50 10091-120 100 200121-150 200 400151-180 300 400180+ 400 400

*If the previous infusion was completed without severe infusion-related ADRs. If any infusion-related

ADRs are observed, infusion should be interrupted and restarted when the patient’s condition is stable(see section 4.2 of the SmPC).

Refractory CLL

For the first and second infusion, administer over 6.5 hours (see section 4.2), through a peripheral lineor indwelling catheter, according to the schedule below:

If the second infusion was completed without a severe adverse reaction, the remaining infusions (3-12)should be administered over 4 hours (see section 4.2), through a peripheral line or indwelling catheter,according to the schedule below. If any infusion-related adverse reactions are observed, infusionshould be interrupted and restarted when the patient’s condition is stable (see section 4.2 for furtherinformation).

Infusion schedule

Time after start of infusion Infusions 1 and 2 Infusions 3* to 12(minutes) Infusion rate (ml/hour) Infusion rate (ml/hour)0-30 12 2531- 60 25 5061-90 50 10091-120 100 200121+ 200 400

*If the second infusion is completed without severe infusion-related ADRs. If anyinfusion-related ADRs are observed, infusion should be interrupted and restarted when thepatient’s condition is stable (see section 4.2).

If any adverse reactions are observed, infusion rates should be reduced (see section 4.2).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novartis Europharm Limited

Frimley Business Park

Camberley GU16 7SR

United Kingdom

Arzerra 100 mg concentrate for solution for infusion

EU/1/10/625/001

Arzerra 1000 mg concentrate for solution for infusion

EU/1/10/625/003

Date of first authorisation: 19 April 2010

Date of latest renewal: 17 February 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMA) http://www.ema.europa.eu/.