Arzerra

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 

 

Arzerra 100 mg concentrate for solution for infusion 

Arzerra 1000 mg concentrate for solution for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

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). 

 

Excipient with known effect 

 

This medicinal product contains 34.8 mg sodium per 300 mg dose, 116 mg sodium per 1000 mg dose 

and 232 mg sodium per 2000 mg dose. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Concentrate for solution for infusion (sterile concentrate). 

 

Clear to opalescent, colourless to pale yellow liquid. 

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 

 

Previously untreated chronic lymphocytic leukaemia (CLL) 

 

Arzerra in combination with chlorambucil or bendamustine is indicated for the treatment of adult 

patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based 

therapy. 

 

See section 5.1 for further information. 

 

Relapsed CLL 

 

Arzerra is indicated in combination with fludarabine and cyclophosphamide for the treatment of adult 

patients with relapsed CLL. 

 

See section 5.1 for further information. 

 

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Refractory CLL 

 

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

alemtuzumab. 

 

See section 5.1 for further information. 

 

4.2 Posology and method of administration 

 

Arzerra should be administered under the supervision of a physician experienced in the use of cancer 

therapy and in an environment where full resuscitation facilities are immediately available. 

 

Monitoring 

 

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 to 

each Arzerra infusion according to the following dosing schedules: 

 

Premedication schedule for Arzerra 

 

 
Previously untreated 

CLL or relapsed 

CLL  

Refractory CLL 

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

Intravenous 

corticosteroid 

(prednisolone or 

equivalent) 

50 mg 
0 to 

50 mg** 
100 mg 

0 to 

100 mg** 
100 mg 

50 to 

100 mg*** 

Oral paracetamol 

(acetaminophen) 
1000 mg 

Oral or intravenous 

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

*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 the 

physician, if a severe infusion-related adverse drug reaction (ADR) did not occur with the preceding 

infusion(s). 

***Corticosteroid may be reduced for subsequent infusions at the discretion of the physician, if a 

severe infusion-related ADR did not occur with the preceding infusion(s). 

 

Posology 

 

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 every 
28 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. 

 

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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 

First infusion 

The initial rate of the first infusion of Arzerra should be 12 ml/h. During infusion, the rate should be 

increased every 30 minutes to a maximum of 400 ml/h (see section 6.6). If an infusion-related ADR is 

observed during infusion, see below section “Dose modification and reinitiation of therapy after 

infusion-related ADRs”. 

 

Subsequent infusions 

If the preceding infusion(s) has (have) been completed without severe infusion related ADRs, the 

subsequent infusions can start at a rate of 25 ml/h and should be increased every 30 minutes up to a 

maximum of 400 ml/h (see section 6.6). If an infusion-related ADR is observed during 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 the 

infusion rate at the time of interruption once the patient’s condition is stable. If the infusion rate had 

not been increased from the starting rate of 12 ml/hour prior to interrupting due to an ADR, the 

infusion should be restarted at 12 ml/hour, the standard starting infusion rate. The infusion rate can 

continue to be increased according to standard procedures, to physician discretion and to patient 

tolerance (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 the 

patient’s condition is stable. The infusion rate can continue to be increased according to standard 

procedures, to physician discretion and to patient tolerance (not to exceed increasing the rate every 

30 minutes). 

 

Arzerra should be permanently discontinued in patients who develop an anaphylactic reaction to the 

medicinal 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, the 

rate should be increased every 30 minutes to a maximum of 200 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”. 

 

Subsequent infusions 

If the preceding infusion(s) has (have) been completed without severe infusion-related ADRs, the 

subsequent infusions can start at a rate of 25 ml/hour and should be increased every 30 minutes up to a 

maximum 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”. 

 

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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 the 

infusion rate at the time of interruption, once the patient’s condition is stable. If the infusion rate had 

not been increased from the starting rate of 12 ml/hour prior to interrupting due to an ADR, the 

infusion should be restarted at 12 ml/hour, the standard starting infusion rate. The infusion rate can 

continue to be increased according to standard procedures, to physician discretion and to patient 

tolerance (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 the 

patient’s condition is stable. The infusion rate can continue to be increased according to standard 

procedures, to physician discretion and to patient tolerance (not to exceed increasing the rate every 

30 minutes). 

 

Arzerra should be permanently discontinued in patients who develop an anaphylactic reaction to the 

medicinal product. 

 

Special populations 

Paediatric population 

The safety and efficacy of Arzerra in children aged below 18 years have not been established. Arzerra 

is therefore not recommended for use in this patient population. 

 

Elderly 

No substantial differences related to age were seen in safety and efficacy (see section 5.1). Based on 

available safety and efficacy data in the elderly, no dose adjustment is required (see section 5.2). 

 

Renal impairment 

No formal studies of Arzerra in patients with renal impairment have been performed. No dose 

adjustment is recommended for mild to moderate renal impairment (creatinine clearance >30 ml/min) 

(see section 5.2). 

 

Hepatic impairment 

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). 

 

Method of administration 

 

Arzerra is for intravenous infusion and must be diluted prior to administration. For instructions on 

dilution of the medicinal product before administration, see section 6.6. 

 

4.3 Contraindications 

 

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

 

4.4 Special warnings and precautions for use 

 

Infusion-related reactions 

 

Intravenous ofatumumab has been associated with infusion-related reactions. These reactions may 

result in temporary interruption or withdrawal of treatment. Pre-medication attenuates infusion-related 

reactions but these may still occur, predominantly during the first infusion. Infusion-related reactions 

may 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 use 

of ofatumumab. In the event of a severe infusion-related reaction, the infusion of Arzerra must be 

interrupted immediately and symptomatic treatment instituted (see section 4.2). 

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If an anaphylactic reaction occurs, Arzerra should be immediately and permanently discontinued and 

appropriate medical treatment should be initiated. 

 

Infusion-related reactions occur predominantly during the first infusion and tend to decrease with 

subsequent infusions. Patients with a history of decreased pulmonary function may be at a greater risk 

for pulmonary complications from severe reactions and should be monitored closely during infusion of 

Arzerra. 

 

Tumour lysis syndrome 

 

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 lactate 

dehydrogenase levels. Management of TLS includes correction of electrolyte abnormalities, 

monitoring of renal function, maintenance of fluid balance and supportive care. 

 

Progressive multifocal leukoencephalopathy 

 

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

CLL patients receiving cytotoxic pharmacotherapy, including ofatumumab. A diagnosis of PML 

should be considered in any Arzerra patient who reports the new onset of or changes in pre-existing 

neurological signs and symptoms. If a diagnosis of PML is suspected Arzerra should be discontinued 

and referral to a neurologist should be considered. 

 

Immunisations 

 

The safety of, and ability to generate a primary or anamnestic response to, immunisation with live 

attenuated or inactivated vaccines during treatment with ofatumumab has not been studied. The 

response 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 with 

ofatumumab, 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 resolved 

hepatitis 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 increase 

in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative 

and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e. increase in 

transaminase 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 before 

initiation of Arzerra treatment. For patients who show evidence of prior (HBsAg negative, anti-HBc 

positive) hepatitis B infection, physicians with expertise in managing hepatitis B should be consulted 

regarding monitoring and initiation of HBV antiviral therapy. Arzerra treatment should not be initiated 

in patients with evidence of current hepatitis B infection (HBsAg positive) until the infection has been 

adequately treated. 

 

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Patients with evidence of prior HBV infection should be monitored for clinical and laboratory signs of 

hepatitis 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 in 

managing hepatitis B. 

 

In patients who develop reactivation of HBV while receiving Arzerra, Arzerra and any concomitant 

chemotherapy should be interrupted immediately, and appropriate treatment instituted. Insufficient 

data 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 with 

physicians with expertise in managing hepatitis B. 

 

Cardiovascular 

 

Patients with a history of cardiac disease should be monitored closely. Arzerra should be discontinued 

in 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 three 

open-label studies in patients with CLL (N=85). Increases above 5 msec were observed in the 

median/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. A 

concentration-dependent increase in QTc was not detected. It is recommended that patients have 

electrolytes such as potassium and magnesium measured prior to and during the administration of 

ofatumumab. Electrolyte abnormalities should be corrected. The effect of ofatumumab on patients 

with 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 of 

ofatumumab therapy, should be evaluated and appropriate treatment instituted. 

 

Laboratory monitoring 

 

Cytopenias, including prolonged and late-onset neutropenia, have been reported during ofatumumab 

therapy. Complete blood counts, including neutrophil and platelet counts, should be obtained at 

regular intervals during Arzerra therapy and more frequently in patients who develop cytopenias. 

 

Sodium content 

 

This medicinal product contains 34.8 mg sodium per 300 mg dose, 116 mg sodium per 1000 mg dose 

and 232 mg sodium per 2000 mg dose. This should be taken into consideration by patients on a 

controlled sodium diet. 

 

4.5 Interaction with other medicinal products and other forms of interaction 
 

Although limited formal drug-drug interaction data exist for ofatumumab, there are no known 

clinically significant interactions with other medicinal products. No clinically relevant 

pharmacokinetic 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, the 

concomitant use of these agents with ofatumumab should be avoided. If the coadministration is judged 

unavoidable, the risks and benefits of vaccinating patients during therapy with ofatumumab should be 

considered (see section 4.4). 

 

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4.6 Fertility, pregnancy and lactation 
 

Women of child-bearing potential 

 

Since ofatumumab may cause foetal B-cell depletion, effective contraception (methods that result in 

less 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, should 

be evaluated by the treating physician. 

 

Pregnancy 

 

Ofatumumab may cause foetal B-cell depletion based on findings from animal studies and on its 

mechanism of action (see section 5.1). 

 

There are no adequate and well-controlled studies in pregnant women to inform a product-associated 

risk. No teratogenicity or maternal toxicity were observed in an animal reproduction study with 

administration of ofatumumab to pregnant monkeys (see section 5.3). Ofatumumab should not be 

administered to pregnant women unless the possible benefit to the mother outweighs the possible risk 

to the foetus. 

 

Administration of live vaccines to neonates and infants exposed to ofatumumab in utero should be 

avoided until B-cell recovery occurs (see sections 4.4 and 4.5). 

 

Breast-feeding 

 

It is unknown whether Arzerra is excreted in human milk, however human IgG is secreted in human 

milk. The safe use of ofatumumab in humans during lactation has not been established. The excretion 

of ofatumumab in milk has not been studied in animals. Published data suggest that neonatal and 

infant consumption of breast milk does not result in substantial absorption of these maternal antibodies 

into circulation. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued 

during treatment with Arzerra and for 12 months following treatment. 

 

Fertility 

 

There are no data on the effects of ofatumumab on human fertility. Effects on male and female fertility 

have not been evaluated in animal studies. 

 

4.7 Effects on ability to drive and use machines 
 

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. The 

clinical status of the patient and the ADR profile of ofatumumab should be borne in mind when 

considering the patient's ability to perform tasks that require judgement, motor or cognitive skills (see 

section 4.8). 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

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 with 

relapsed or refractory CLL) and 525 patients treated with ofatumumab in combination with 

chemotherapy (chlorambucil or bendamustine or fludarabine and cyclophosphamide). 

 

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Tabulated list of adverse reactions 

 

Adverse reactions reported in patients treated with ofatumumab as monotherapy and with ofatumumab 

in combination with chemotherapy, are listed below by MedDRA body system organ class and by 

frequency, 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 are 

ranked in order of decreasing seriousness. 

 

MedDRA System 

Organ Class 

Very common Common Uncommon  

Infections and 

Infestations 

Lower respiratory 

tract infection 

(including 

pneumonia), upper 

respiratory tract 

infection  

Sepsis (including 

neutropenic sepsis and 

septic shock) herpes viral 

infection, urinary tract 

infection 

Hepatitis B infection and 

reactivation, progressive 

multifocal 

leukoencephalopathy 

 

Blood and 

lymphatic system 

disorders 

Neutropenia, 

anaemia 

Febrile neutropenia, 

thrombocytopenia, 

leukopenia 

Agranulocytosis, 

coagulopathy, red cell 

aplasia, lymphopenia 

 

Immune system 

disorders 

 Hypersensitivity* Anaphylactic reactions 

(including anaphylactic 

shock)* 

 

Nervous system 

disorders 

 Headache*   

Metabolism and 

nutrition disorders 

  Tumour lysis syndrome  

Cardiac disorders  Tachycardia* Bradycardia*  

Vascular disorders  Hypotension*, 

hypertension* 

  

Respiratory, 

thoracic and 

mediastinal 

disorders 

Dyspnoea*, cough* Bronchospasm*, chest 

discomfort*, 

oropharyngeal pain*, 

nasal congestion* 

Pulmonary oedema*, 

hypoxia* 

 

Gastrointestinal 

disorders 

Nausea*, 

diarrhoea* 

 Small intestinal 

obstruction 

 

Skin and 

subcutaneous 

tissue disorders 

Rash* Urticaria*, pruritus*, 

flushing* 

  

Musculoskeletal 

and connective 

tissue disorders 

 Back pain*   

General disorders 

and administration 

site conditions 

Pyrexia*, fatigue* Cytokine release 

syndrome*, chills 

(including rigors)*, 

hyperhidrosis* 

  

Injury, poisoning 

and procedural 

complications 

 Infusion-related reaction*   

*These events are likely attributable to ofatumumab in the setting of an infusion-related reaction and 

typically occur after the start of infusion and within 24 hours after the completion of the infusion (see 

section 4.4). 

 

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Description of selected adverse reactions 

 

Infusion-related reactions 

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 during 

treatment. The majority of infusion-related reactions were Grade 1 or Grade 2 in severity. Seven 

percent of patients had ≥Grade 3 infusion-related reactions at any time during treatment. Two percent 

of the infusion-related reactions led to discontinuation of treatment. There were no fatal infusion-

related reactions (see section 4.4). 

 

Infections 

Of the 1,168 patients receiving ofatumumab in clinical trials for CLL, 682 patients (58%) experienced 

an infection. These included bacterial, viral and fungal infections. 268 (23%) of the 1,168 patients 

experienced ≥Grade 3 infections. 65 (6%) of the 1,168 patients experienced a fatal infection. 

 

Neutropenia 

Of the 1,168 patients receiving ofatumumab in clinical trials, 420 patients (36%) experienced an 

adverse event associated with a decreased neutrophil count; 129 (11%) experienced a serious adverse 

event 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 not 

resolved 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 with 

chlorambucil alone). Nine patients (4%) treated with ofatumumab and chlorambucil, and three patients 

treated with chlorambucil alone had late-onset neutropenia (defined as Grade 3 or 4 neutropenia 

starting at least 42 days after the last treatment). In the pivotal study (OMB110913, ofatumumab plus 

fludarabine and cyclophosphamide 181 patients; fludarabine and cyclophosphamide 178 patients) in 

relapsed CLL patients, prolonged neutropenia was reported in 38 (11%) patients (18 patients [10%] 

treated with ofatumumab in combination with fludarabine and cyclophosphamide compared to 

20 patients [11%] in the fludarabine and cyclophosphamide arm). Thirteen (7%) patients treated with 

ofatumumab in combination with fludarabine and cyclophosphamide, and 5 (3%) patients treated with 

fludarabine and cyclophosphamide had late-onset neutropenia. 

 

Cardiovascular 

The effect of multiple doses of Arzerra on the QTc interval was evaluated in a pooled analysis of three 

open-label studies in patients with CLL (N=85). Increases above 5 msec were observed in the 

median/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. A 

concentration dependent increase in QTc was not detected. 

 

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. 

 

4.9 Overdose 
 

No case of overdose has been reported. 

 

 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


11 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

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

 

Mechanism of action 

 

Ofatumumab is a human monoclonal antibody (IgG1) that binds specifically to a distinct epitope 

encompassing both the small and large extracellular loops of the CD20 molecule. The CD20 molecule 

is a transmembrane phosphoprotein expressed on B lymphocytes from the pre-B to mature B 

lymphocyte stage and on B-cell tumours. The B-cell tumours include CLL (generally associated with 

lower levels of CD20 expression) and non-Hodgkin's lymphomas (where >90% of tumours have high 

levels of CD20 expression). The CD20 molecule is not shed from the cell surface and is not 

internalised following antibody binding. 

 

The binding of ofatumumab to the membrane-proximal epitope of the CD20 molecule induces 

recruitment 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 induce 

appreciable lysis of cells with high expression levels of complement defence molecules. Ofatumumab 

has 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 cells 

allowing the induction of cell death through antibody-dependent cell-mediated cytotoxicity. 

 

Pharmacodynamic effects 

 

Peripheral B-cell counts decreased after the first ofatumumab infusion in patients with haematological 

malignancies. 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 median 

decrease 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 and 

remained 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 previously 

untreated CLL, the median decreases in B-cell counts after the first cycle and prior to the sixth 

monthly cycle were 94% and >99%. At 6 months after the last dose, the median reductions in B-cell 

counts were >99%. 

 

When ofatumumab was administered in combination with fludarabine and cyclophosphamide in 

patients with relapsed CLL, the median decrease from baseline was 60% after the first infusion and 

complete depletion (100%) was reached after 4 cycles. 

 

Immunogenicity 

There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples 

from more than 1,000 patients across the CLL clinical programme were tested for anti-ofatumumab 

antibodies during and after treatment periods ranging from 8 weeks to 2 years. Formation of 

anti-ofatumumab antibodies was observed for less than 0.5% of patients with CLL after treatment with 

ofatumumab. 

 

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Clinical efficacy and safety 

 

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 with 

previously untreated CLL considered inappropriate for fludarabine-based treatment (e.g. due to 

advanced age or presence of co-morbidities), with active disease and indicated for treatment. Patients 

received either 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 chlorambucil 

(10 mg/m2 orally on days 1-7 every 28 days) or chlorambucil alone (10 mg/m2 orally on days 1-7 every 

28 days). Patients received treatment for a minimum of 3 months until best response or up to a 

maximum 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) performance 

status 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. The 

median 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 also 

assessed by an IRC using the 2008 IWCLL guidelines. 

 

Arzerra in combination with chlorambucil showed a statistically significant (71%) improvement in 

median 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 with 

poor-risk biological features (such as 17p or 11q deletion, unmutated IGHV, β2M >3500 μg/l, and 

ZAP-70 expression). 

 

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Table 1 Summary of PFS with Arzerra in combination with chlorambucil compared with 

chlorambucil in previously untreated CLL 

 

IRC-assessed primary and 

subgroup analyses of PFS, months 

Chlorambucil 

 

(N=226) 

Arzerra and 

chlorambucil 

(N=221) 

Median, all patients 13.1 22.4 

95% CI (10.6, 13.8) (19.0, 25.2) 

Hazard ratio 

P value 

0.57 (0.45, 0.72) 

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 22.1 

17p 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  17.3 

β2M ≤3500 μg/l (n=109) 13.8 25.5 

β2M >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 negative 

(n=60) 
10.5 NR 

IGHV mutated & ZAP-70 positive 

(n=35) 
7.9 27.2 

IGHV unmutated & ZAP-70 negative 

(n=27) 
16.7 16.2 

IGHV unmutated & ZAP-70 positive 

(n=122) 
11.2 16.2 

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

Illness Rating Scale for Geriatrics, CLL = chronic lymphocytic leukaemia, CrCl = creatinine 

clearance, 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 ECOG 

performance status of PS = 2. 

 

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

Median 13.1 

months____Ofatumumab + 

Chlorambucil  (N=221) 

Median 22.4 months 

 

Hazard Ratio=0.57 

95% CI (0.45, 0.72) 

p-value<0.001 

 

Number at risks at 
Risk: 

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

 

 

1.0 
 

0.9 
 

0.8 
 

0.7 
 

0.6 
 

0.5 
 

0.4 
 

0.3 
 

0.2 
 

0.1 
 

0.0 
 

 

 

 

 

                   

 

Time of Progression-free Survival (Months) 

 

Table 2 Summary of secondary outcomes of Arzerra in combination with chlorambucil 

compared with chlorambucil in previously untreated CLL 

 

IRC-assessed secondary outcome Chlorambucil 

 

(N=226) 

Arzerra and 

chlorambucil 

(N=221) 

ORR (%) 69 82 

95% 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, 

months 
13.2 22.1 

95% CI (10.8, 16.4) (19.1, 24.6) 

P value p<0.001 

Abbreviations: CI = confidence interval, CLL = chronic lymphocytic leukaemia, CR = complete 

response, 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 patients 

with previously untreated CLL considered inappropriate for fludarabine-based treatment. Patients 

received 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 bendamustine 

90 mg/m2 on days 1 and 2 every 28 days. Patients received treatment for a maximum of 6 cycles. The 

median number of cycles completed in patients was 6 (total Arzerra dose of 6300 mg). 

 

Chlorambucil 226 173 130 92 67 52 33 17 6 1 1    

Ofatumumab 
plus 
Chlorambuci + 
Chl 

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

 

0 4 8 12 16 20 24 28 32 36 40 44 48 52 

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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 effective 

therapy 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 a 

rituximab based regimen such as rituximab with chlorambucil is available. Thus, the benefit of such a 

new combination over a rituximab based regimen is unknown. 

 

Relapsed CLL 

 

Study OMB110913 (randomised, open-label, parallel-arm, multicentre trial) evaluated the efficacy of 

ofatumumab in combination with fludarabine and cyclophosphamide compared with fludarabine and 

cyclophosphamide in 365 patients with relapsed CLL (defined as a patient who has received at least 

one prior CLL therapy and previously achieved a complete or partial remission/response, but after a 

period of six or more months demonstrated evidence of disease progression). Baseline disease 

characteristics and prognostic markers were balanced between treatment arms and representative of a 

relapsed CLL population. Patient median age was 61 years (range: 32 to 90 years, 7% were 75 years of 

age 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 whom 

approximately 50% received 1 prior treatment) and 21% of patients had received prior rituximab. The 

median 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 patients 

with an ECOG performance status of 2. 

 

Patients received ofatumumab as 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). Approximately 90% of patients received 

3-6 cycles of ofatumumab and 66% completed 6 cycles. 

 

The primary endpoint of progression-free survival (PFS), as assessed by a blinded independent review 

committee (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 and 

resulted 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). 

 

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

Median 28.94 months 

95% CI (22.80, 35.88) 

____FC (N=182) 

Median 18.83 months 

95% CI (14.42,25.82) 
 

Hazard Ratio=0.67 

95% CI (0.51,0.88) 

p-value=0.0032 

 

Number at risk at 
Risk: 

Figure 2 Kaplan-Meier estimates of PFS in relapsed CLL 

 

 

 
1.0 

0.9 

0.8 

0.7 

0.6 

0.5 

0.4 

0.3 

0.2 

0.1 
 

0.0 
 

 

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 next 

therapy 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 months 

versus 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 and 

69 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 these 

223 patients, 95 patients were refractory to fludarabine and alemtuzumab therapy (defined as failure to 

achieve at least a partial response with fludarabine or alemtuzumab treatment or disease progression 

within 6 months of the last dose of fludarabine or alemtuzumab). Baseline cytogenetic (FISH) data 

were available for 209 patients. 36 patients had a normal karyotype and chromosomal aberrations were 

detected 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 summary 

of the efficacy data from the study). Patients who had prior rituximab therapy, either as monotherapy 

or in combination with other medicinal products, responded to treatment with Arzerra at a similar rate 

to those who had not had prior rituximab therapy. 

 

OFA + 
FC 

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

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

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

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

 

(Primary) endpoint1 
Patients refractory to fludarabine and 

alemtuzumab 

n=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 abnormality  

17p deletion  

Responders, n (%) 10/27 (37) 

95% CI (%) 19, 58 

11q deletion  

Responders, n (%) 15/32 (47) 

95% CI (%) 29, 65 

Median overall survival  

Months 13.9 

95% CI 9.9, 18.6 

Progression-free survival  

Months 4.6 

95% CI 3.9, 6.3 

Median duration of response  

Months 5.5 

95% CI 3.7, 7.2 

Median time to next CLL therapy  

Months 8.5 

95% CI 7.2, 9.9 
1 The overall response was assessed by an Independent Response Committee using the 1996 NCI-WG 

guidelines for CLL. 

 

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Improvements also were demonstrated in components of the NCI-WG response criteria. These 

included improvements associated with constitutional symptoms, lymphadenopathy, organomegaly, or 

cytopenias (see Table 4). 

 

Table 4 Summary of clinical improvement with a minimum duration of 2 months in 

refractory patients with abnormalities at baseline 

 

Efficacy endpoint or haematological parametera 

Patients with benefit/patients with abnormality at 

baseline (%) 

Patients refractory to fludarabine and alemtuzumab 

Lymphocyte count  

≥50% decrease 49/71 (69) 

Normalisation (≤4x109/l) 36/71 (51) 

Complete resolution of constitutional 

symptomsb 

21/47 (45)  

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 

post baseline 

12/49 (24) 

Platelet counts ≤100x109/l at baseline to >50% 

increase or >100x109/l post baseline 

19/50 (38) 

Neutrophils <1x109/l at baseline to >1.5x109/l 1/17 (6) 
a Excludes patients’ visits from date of first transfusion, treatment with erythropoietin, or 

treatment with growth factors. For patients with missing baseline data, latest 

screening/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 by 

physical examination. 

 

Arzerra was also given to a group of patients (n=112) with bulky lymphadenopathy (defined as at least 

one 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 the 

median overall survival was 17.4 months (95% CI: 15.0, 24.0). The response rate in patients with prior 

rituximab therapy was 38% (95% CI: 23, 61). These patients also experienced comparable clinical 

improvement, in terms of the efficacy endpoints and haematological parameters detailed above, to 

patients refractory to both fludarabine and alemtuzumab. 

 

Additionally a group of patients (n=16) who were intolerant/ineligible for fludarabine treatment and/or 

intolerant to alemtuzumab treatment were treated with Arzerra. The overall response rate in this group 

was 63% (95.3% CI: 35, 85). 

 

An open-label, two arm, randomised study (OMB114242) was conducted in patients with bulky 

fludarabine refractory CLL who had failed at least 2 prior therapies (n=122) comparing Arzerra 

monotherapy (n=79) to physicians’ choice (PC) of therapy (n=43). There was no statistically 

significant 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 Arzerra 

monotherapy in study Hx-CD20-406. 

 

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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 were 

white. Treatment with Arzerra (when given as 4 once-weekly infusions), led to a 50% objective 

response rate in the highest dose group (1st dose: 500 mg; 2nd, 3rd and 4th dose: 2,000 mg) and 

included 12 partial remissions and one nodular partial remission. For the highest dose group, the 

median time to progression was 15.6 weeks (95% CI: 15,22.6) in the full analysis population, and 

23 weeks (CI: 20,31) in responders. The duration of response was 16 weeks (CI: 13, 19) and the time 

to next CLL therapy was 52.4 weeks (CI: 36.9 – non-estimable). 

 

Paediatric population 

 

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 4.2 

for information on paediatric use). 

 

5.2 Pharmacokinetic properties 
 

Overall, the pharmacokinetics of ofatumumab were consistent across the indications, whether given as 

a single agent or in combination with fludarabine and cyclophosphamide or chlorambucil. 

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

 

Absorption 

 

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

 

Distribution 

 

Ofatumumab has a small volume of distribution, with mean Vss values ranging from 1.7 to 8.1 l across 

studies, dose levels, and infusion number. 

 

Biotransformation 

 

Ofatumumab is a protein for which the expected metabolic pathway is degradation to small peptides 

and individual amino acids by ubiquitous proteolytic enzymes. Classical biotransformation studies 

have not been performed. 

 

Elimination 

 

Ofatumumab is eliminated in two ways: a target-independent route like other IgG molecules and a 

target-mediated route which is related to binding to B-cells. There was a rapid and sustained depletion 

of CD20+ B-cells after the first ofatumumab infusion, leaving a reduced number of CD20+ cells 

available for the antibody to bind at subsequent infusions. As a result, ofatumumab clearance values 

were 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 the 

expected accumulation based on first infusion data. 

 

The main pharmacokinetic parameters of ofatumumab as a single agent or in combination are 

summarised in Table 5. 

 

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Table 5 Ofatumumab pharmacokinetic parameters (geometric mean) 

 

Population (treatment) Dosing 

regimen  

Cycle(1) Cmax 

(µg/ml) 

AUC 

(µg.h/ml) 

CL 

(ml/h) 

t½ 

(days) 

Refractory CLL 

(ofatumumab) 

1st infusion 

(300 mg)  

Cycle 1 61.4    

2000 mg: 

8 weekly 

infusions 

followed by 

4 monthly 

infusions 

12th dose 827 166000 12.1 11.5 

Previously untreated 

patients 

(ofatumumab + 

chlorambucil) 

1st infusion 

(300 mg) 

Cycle 1 51.8 2620   

1000 mg 

monthly 

infusions 

Cycle 4 285 65100 15.4  18.5 

Relapsed CLL 

(ofatumumab + FC) 

1st infusion 

(300 mg) 

Cycle 1 61.4 3560   

1000 mg on 

the 8th day of 

cycle 1 

followed by 

1000 mg 

monthly 

infusions 

Cycle 4 313 89100 11.2 19.9 

(1) Cycle for which the pharmacokinetic parameters are presented in this table. 

Cmax = maximum ofatumumab concentration at the end of infusion, AUC = exposure to ofatumumab 

over a dosing period, CL = ofatumumab clearance after multiple doses, T½ = terminal half-life 

Numbers rounded to three significant digits 

 

Special populations 

 

Elderly (≥65 years of age) 

Age was not found to be a significant factor for ofatumumab pharmacokinetics in a cross-study 

population pharmacokinetic analysis of patients ranging in age from 21 to 87 years of age. 

 

Paediatric population 

No pharmacokinetic data are available in paediatric patients. 

 

Gender 

Gender had a modest effect (12%) on ofatumumab central volume of distribution in a cross-study 

population analysis, with higher Cmax and AUC values observed in female patients (48% of the 

patients in this analysis were male and 52% were female); these effects are not considered clinically 

relevant, and no dose adjustment is recommended. 

 

Renal impairment 

Baseline calculated creatinine clearance was not found to be a significant factor on ofatumumab 

pharmacokinetics in a cross-study population analysis in patients with calculated creatinine clearance 

values ranging from 26 to 287 ml/min. No dose adjustment is recommended for mild to moderate 

renal impairment (creatinine clearance >30 ml/min). There are limited pharmacokinetic data in 

patients with severe renal impairment (creatinine clearance <30 ml/min). 

 

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Hepatic impairment 

No formal studies were conducted to examine the effect of hepatic impairment. IgG1 molecules such 

as ofatumumab are catabolised by ubiquitous proteolytic enzymes, which are not restricted to hepatic 

tissue; therefore, changes in hepatic function are unlikely to have any effect on the elimination of 

ofatumumab. 

 

5.3 Preclinical safety data 
 

Preclinical data reveal no special hazards for humans. 

 

Intravenous and subcutaneous administration to monkeys resulted in the expected depletion of 

peripheral 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 there 

were no effects on delayed-type hypersensitivity responses. In a few animals, increased red cell 

destruction occurred, presumably as a result of monkey anti-drug antibodies coating the red cells. A 

corresponding increase in reticulocyte counts seen in these monkeys was indicative of a regenerative 

response in the bone marrow. 

 

Intravenous administration of ofatumumab to pregnant cynomolgus monkeys at 100 mg/kg once 

weekly from days 20 to 50 of gestation did not elicit maternal or foetal toxicity or teratogenicity. At 

the end of organogenesis (day 48 of gestation), the ofatumumab exposure (AUCinf) corresponded to 

0.46 to 3.6 times the human exposure after the eighth infusion of the maximum recommended human 

dose (MRHD) of 2000 mg. At day 100 of gestation, depletion of B-cells relating to the 

pharmacological 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% in 

the high-dose group, compared with control values. Pre- and post-natal development studies have not 

been performed. Post-natal recovery has therefore not been demonstrated. 

 

As ofatumumab is a monoclonal antibody, genotoxicity and carcinogenicity studies have not been 

conducted with ofatumumab. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Arginine 

Sodium acetate (E262) 

Sodium chloride 

Polysorbate 80 (E433) 

Edetate disodium (E386) 

Hydrochloric acid (E507) (for pH-adjustment) 

Water for injections 

 

6.2 Incompatibilities 
 

This medicinal product must not be mixed with other medicinal products except those mentioned in 

section 6.6. 

 

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6.3 Shelf life 

 

Vial 

3 years. 

 

Diluted infusion solution 

Chemical and physical in-use stability has been demonstrated for 48 hours at ambient conditions (less 

than 25°C). 

 

From a microbiological point of view, the medicinal product should be used immediately. If not used 

immediately, in-use storage times and conditions prior to use are the responsibility of the user and 

would normally not be longer than 24 hours at 2-8 ºC, unless reconstitution/dilution has taken place in 

controlled and validated aseptic conditions. 

 

6.4 Special precautions for storage 
 

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. 

 

6.5 Nature and contents of container 

 

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 of 

concentrate 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 ml 

of concentrate for solution for infusion. 

 

Arzerra is available in packs of 1 vial. 

 

6.6 Special precautions for disposal and other handling 
 

Dilution 

 

Arzerra concentrate for solution for infusion does not contain a preservative; therefore dilution should 

be carried out under aseptic conditions. The diluted solution for infusion must be used within 24 hours 

of 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. Ofatumumab 

should be a colourless to pale yellow solution. Do not use the Arzerra concentrate if there is 

discolouration. 

 

Do not shake the ofatumumab vial for this inspection. 

 

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How to dilute the solution for infusion 

The Arzerra concentrate must be diluted in sodium chloride 9 mg/ml (0.9%) solution for injection 

prior to administration, using aseptic technique. 

 

Arzerra 100 mg concentrate for solution for infusion 

300 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%) solution 
for 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 infusion 

1000 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%) solution 
for 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%) solution 
for 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 intravenous 

infusion pump. 

 

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

this time. 

 

Arzerra must not be mixed with, or administered as an infusion with other medicinal products or 

intravenous solutions. Flush line before and after ofatumumab administration with sodium chloride 

9 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 or 

indwelling catheter, according to the schedule below: 

 

If the first infusion was completed without a severe adverse reaction, the remaining infusions of 

1000 mg 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, 

infusion should be interrupted and restarted when the patient’s condition is stable (see section 4.2 for 

further information). 

 
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Infusion schedule 

 

Time after start of infusion (minutes) 
Infusion 1 Subsequent infusions* 

Infusion rate (ml/hour) Infusion rate (ml/hour) 

0-30 12 25 

31-60 25 50 

61-90 50 100 

91-120 100 200 

121-150 200 400 

151-180 300 400 

180+ 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 line 

or 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, infusion 

should be interrupted and restarted when the patient’s condition is stable (see section 4.2 for further 

information). 

 

Infusion schedule 

 

Time after start of infusion 

(minutes) 

Infusions 1 and 2 Infusions 3* to 12 

Infusion rate (ml/hour) Infusion rate (ml/hour) 

0-30 12 25 

31- 60 25 50 

61-90 50 100 

91-120 100 200 

121+ 200 400 

*If the second infusion is 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). 

 

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

 

Disposal 

 

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

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

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8. MARKETING AUTHORISATION NUMBER(S) 

 

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 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 19 April 2010 

Date of latest renewal: 17 February 2015 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

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

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

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http://www.ema.europa.eu/


26 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 
 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE 

SUBSTANCE AND MANUFACTURERS RESPONSIBLE 

FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 

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27 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturers of the biological active substance 

 

Lonza Biologics plc 

228 Bath Road 

Slough, Berks SL1 4DX 

United Kingdom 

 

Lonza Biologics, Inc. 

101 International Drive 

Portsmouth, NH 03801-2815 

United States 

 

Name and address of the manufacturers responsible for batch release 

 

Glaxo Operations UK Ltd. 

Harmire Road 

Barnard Castle 

Durham, DL12 8DT 

United Kingdom 

 

Novartis Pharmaceuticals UK Limited 

Frimley Business Park 

Frimley 

Camberley, Surrey GU16 7SR 

United Kingdom 

 

Novartis Pharma GmbH 

Roonstrasse 25 

90429 Nuremberg 

Germany 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 

 Periodic Safety Update Reports 
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

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28 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

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29 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

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30 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

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31 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Arzerra 100 mg concentrate for solution for infusion 

ofatumumab 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One ml contains 20 mg ofatumumab. 

Each vial contains 100 mg ofatumumab in 5 ml. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains: arginine, sodium acetate (E262), sodium chloride, polysorbate 80 (E433), edetate 

disodium (E386), hydrochloric acid (E507), water for injections. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion. 

 

100 mg/5 ml 

 

3 vials 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Intravenous use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

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9. SPECIAL STORAGE CONDITIONS 

 

Store and transport refrigerated. 

Do not freeze. 

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

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/10/625/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Arzerra 100 mg sterile concentrate 

ofatumumab 

IV 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

100 mg/5 ml 

 

 

6. OTHER 

 

 

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34 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Arzerra 1000 mg concentrate for solution for infusion 

ofatumumab 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One ml contains 20 mg ofatumumab. 

Each vial contains 1000 mg ofatumumab in 50 ml. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains: arginine, sodium acetate (E262), sodium chloride, polysorbate 80 (E433), edetate 

disodium (E386), hydrochloric acid (E507), water for injections. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion. 

 

1000 mg/50 ml 

 

1 vial 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Intravenous use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

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35 

9. SPECIAL STORAGE CONDITIONS 

 

Store and transport refrigerated. 

Do not freeze. 

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

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/10/625/003 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Arzerra 1000 mg sterile concentrate 

ofatumumab 

IV 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

1000 mg/50 ml 

 

 

6. OTHER 

 

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37 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

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38 

Package leaflet: Information for the user 

 

Arzerra 100 mg concentrate for solution for infusion 

Arzerra 1000 mg concentrate for solution for infusion 

ofatumumab 

 

Read all of this leaflet carefully before you are given this medicine because it contains important 

information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or nurse. 
- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 

 

What is in this leaflet 
 

1. What Arzerra is and what it is used for 

2. What you need to know before you are given Arzerra 

3. How Arzerra is given 

4. Possible side effects 

5. How to store Arzerra 

6. Contents of the pack and other information 

 

 

1. What Arzerra is and what it is used for 

 

Arzerra contains ofatumumab, which belongs to a group of medicines called monoclonal antibodies. 

 

Arzerra is used to treat chronic lymphocytic leukaemia (CLL). CLL is a cancer of the blood which 

affects a type of white blood cell called lymphocytes. The lymphocytes multiply too quickly and live 

too long, so there are too many of them circulating in your blood. The disease can also affect other 

organs in your body. The antibody in Arzerra recognises a substance on the surface of lymphocytes 

and causes the lymphocyte to die. 

 

 

2. What you need to know before you are given Arzerra 

 

You must not be given Arzerra: 

 if you are allergic (hypersensitive) to ofatumumab or any of the other ingredients of this 
medicine (listed in section 6). 

Check with your doctor if you think this may apply to you. 

 

Warnings and precautions 

Talk to your doctor or nurse before you are given Arzerra: 

 if you have had heart problems, 

 if you have lung disease, 
Check with your doctor if you think any of these may apply to you. You may need extra check-ups 

while you are being treated with Arzerra. 

 

Your doctor may test the amount of electrolytes, such as magnesium and potassium, in your blood 

before and during your treatment with Arzerra. Your doctor may treat you if any electrolyte imbalance 

is detected. 

 

Vaccination and Arzerra 

If you are having any vaccinations tell your doctor, or the person giving you the vaccine, that you are 

being treated with Arzerra. Your response to the vaccine may be weakened and you may not be fully 

protected. 

 

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39 

Hepatitis B 

You should be tested for hepatitis B (a liver disease) before starting Arzerra treatment. If you have had 

hepatitis B, Arzerra could cause it to become active again. Your doctor may treat you with a suitable 

anti-viral medicine to help prevent this. 

 

If you have or have had hepatitis B, tell your doctor before you are given Arzerra. 

 

Infusion reactions 

Medicines of this type (monoclonal antibodies) can cause infusion reactions when they are injected 

into the body. You will be given medicines such as anti-histamines, steroids or pain relievers to help 

reduce any reaction. See also section 4, ‘Possible side effects’. 

 

If you think you have had such a reaction before, tell your doctor before you are given Arzerra. 

 

Progressive multifocal leukoencephalopathy (PML) 

Progressive multifocal leukoencephalopathy (PML), a serious and life-threatening brain condition, has 

been reported with medicines like Arzerra. Tell your doctor immediately if you have memory loss, 

trouble thinking, difficulty with walking or loss of vision. If you had these symptoms prior to 

treatment with Arzerra, tell your doctor immediately about any changes in these symptoms. 

 

Bowel obstruction 

Contact your doctor immediately if you experience constipation, a swollen abdomen or abdominal 

pain. These could be symptoms of a blockage in the bowel, especially during the early stages of your 

treatment. 

 

Children and adolescents 

It is not known whether Arzerra works in children and adolescents. Therefore Arzerra is not 

recommended for use in children and adolescents. 

 

Other medicines and Arzerra 

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 

This includes herbal medicines and other medicines you can obtain without a prescription. 

 

Pregnancy, breast-feeding and fertility 

Arzerra is not usually recommended for use during pregnancy. 

 Tell your doctor if you are pregnant or breast-feeding, think you may be pregnant, or are 
planning to have a baby. Your doctor will weigh up the benefit to you against the risk to your 

baby of taking Arzerra while you're pregnant. 

 Use a reliable method of contraception to avoid becoming pregnant while you are being treated 
with Arzerra, and for 12 months after your last dose of Arzerra. Ask your doctor for advice if 

you are planning to become pregnant after this period. 

 If you do become pregnant during treatment with Arzerra, tell your doctor. 
 

It is not known whether the ingredients in Arzerra pass into human milk. Breast-feeding is not 

recommended during treatment with Arzerra and for 12 months after the last dose. 

 

Driving and using machines 

Arzerra is unlikely to affect your ability to drive or use machines. 

 

Arzerra contains sodium 

Arzerra contains 34.8 mg sodium in each 300 mg dose, 116 mg sodium in each 1000 mg dose and 

232 mg sodium in each 2000 mg dose. You need to take this into account if you are on a controlled 

sodium diet. 

 

 

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40 

3. How Arzerra is given 

 

If you have any questions on the use of Arzerra, ask the doctor or nurse who is giving you the 

infusion. 

 

The usual dose 

The usual dose of Arzerra for the first infusion is 300 mg. This dose will be increased, usually to 

1000 mg or 2000 mg, for the remaining infusions. 

 

How it is given 

Arzerra is given into a vein (intravenously) as an infusion (a drip) over several hours. 

 

If you have not been previously treated for CLL you will have a maximum of 13 infusions. You 

will be given an initial infusion followed by a second infusion 7 days later. The remaining infusions 

will then be given once a month for up to 11 months. 

 

If you have been previously treated for CLL but the disease returns you will have a maximum of 

7 infusions. You will be given an initial infusion followed by a second infusion 7 days later. The 

remaining infusions will then be given once a month for up to 6 months. 

 

If you have been previously treated for CLL you will usually have a course of 12 infusions. You 

will be given an infusion once a week for eight weeks. This is followed by a four- to five-week gap. 

The remaining infusions will then be given once a month for four months. 

 

Medicines given before each infusion 

Before each infusion of Arzerra, you will be given pre-medication - medicines which help to reduce 

any infusion reactions. These may include anti-histamines, steroids and pain relievers. You will be 

checked closely and if you do have any reactions these will be treated. 

 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Infusion-related reactions 
Medicines of this type (monoclonal antibodies) can cause infusion-related reactions, which are 

occasionally severe, and can cause death. They are more likely during the first treatment. 

 

Very common symptoms of an infusion-related reaction (may affect more than 1 in 10 people): 

 feeling sick (nausea) 

 high temperature 

 skin rash 

 breathlessness, cough 

 diarrhoea 

 lack of energy 
 

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41 

Common symptoms of an infusion-related reaction (may affect up to 1 in 10 people): 

 allergic reactions, sometimes severe where symptoms include raised and itchy rash (hives), 
swelling of the face or the mouth (angioedema) causing difficulty breathing and collapse 

 difficulty in breathing, shortness of breath, chest tightness, cough 

 low blood pressure (can cause light-headedness when you stand up) 

 flushing 

 excessive sweating 

 shaking or shivering 

 rapid heart beat 

 headache 

 back pain 

 high blood pressure 

 throat pain or irritation 

 blocked nose. 
 

Uncommon symptoms of an infusion-related reaction (may affect up to 1 in 100 people): 

 anaphylactic reaction including anaphylactic shock, where symptoms include breathlessness or 
difficulty breathing, wheezing or coughing, light-headedness, dizziness, changes in levels of 

consciousness, hypotension, with or without mild generalised itching, skin reddening, swelling 

of the face and/or throat, blue discolouration of the lips, tongue or skin 

 fluid in the lungs (pulmonary oedema) causing breathlessness 

 slow heart beat 

 blue discolouration of the lips and extremities (possible symptoms of hypoxia) 
 

Tell your doctor or a nurse immediately if you get any of these symptoms. 

 

Other possible side effects 

 

Very common side effects 

These may affect more than 1 in 10 people: 

 frequent infections, fever, chills, sore throat or mouth ulcers due to infections 

 fever, coughing, difficulty breathing, wheezing, possible symptoms of infections of the lungs or 
airways (respiratory tract) including pneumonia 

 sore throat, feeling of pressure or pain in the cheeks and forehead, infections of the ear, nose or 
throat. 

 

Very common side effects that may show up in your blood tests: 

 low levels of white blood cells (neutropenia) 

 low levels of red blood cells (anaemia). 
 

Common side effects 

These may affect up to 1 in 10 people: 

 fever or, alternatively, a very low body temperature, chest pain, shortness of breath or rapid 
breathing, shaking, chills, confusion, dizziness, decreased urination and rapid pulse, (possible 

symptoms of blood infection) 

 difficulty and pain when passing urine, exaggerated sense of needing to urinate, urinary tract 
infections 

 shingles, cold sores (possible symptoms of herpes viral infection that can potentially be severe). 
 

Common side effects that may show up in your blood tests: 

 low levels of platelets in the blood (cells that help blood to clot). 
 

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42 

Uncommon side effects 

These may affect up to 1 in 100 people: 

 blockage in the gut (intestine), which may feel like stomach pain. 

 If you have persistent stomach pain, see your doctor as soon as possible. 

 yellow skin and eyes, nausea, loss of appetite, dark urine (possible symptoms of an infection or 
reactivation of hepatitis B virus) 

 memory loss, trouble with thinking, and difficulty with walking or loss of vision (possible 
symptoms of progressive multifocal leukoencephalopathy) 

 increase in potassium, phosphate and uric acid in the blood that can cause kidney problems 
(tumour lysis syndrome) 

The symptoms of this condition include: 

 producing less urine than normal 

 muscle spasms. 
If you notice these symptoms, contact your doctor as soon as possible. 

 

Uncommon side effects that may show up in your blood tests: 

 problems with blood clotting 

 the bone marrow failing to produce enough red or white blood cells 
 

Reporting of side effects 

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 

listed in this leaflet. You can also report side effects directly via the national reporting system listed in 

Appendix V. By reporting side effects you can help provide more information on the safety of this 

medicine. 

 

 

5. How to store Arzerra 
 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date shown on the carton and vial label. The expiry date 

refers to the last day of that month. 

 

Store and transport refrigerated (2 C – 8C). 

Do not freeze. 

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

 

Store the diluted infusion solution between 2C and 8 C and use within 24 hours. Any unused infusion 

solution should be discarded 24 hours after preparation. 

 

 

6. Contents of the pack and other information 

 

What Arzerra contains 

- The active substance is ofatumumab. One ml of concentrate contains 20 mg of ofatumumab. 
- The other ingredients are arginine, sodium acetate (E262), sodium chloride, polysorbate 80 

(E433), edetate disodium (E386), hydrochloric acid (E507) (for pH-adjustment), water for 

injections (see “Arzerra contains sodium” under section 2). 

 

What Arzerra looks like and contents of the pack 

Arzerra is a colourless to pale yellow concentrate for solution for infusion. 

 

Arzerra 100 mg is available in a pack containing 3 vials. Each glass vial is closed with a rubber 

stopper and aluminium over-seal, and contains 5 ml of concentrate (100 mg of ofatumumab). 

 

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43 

Arzerra 1000 mg is available in a pack containing 1 vial. Each glass vial is closed with a rubber 

stopper and aluminium over-seal, and contains 50 ml of concentrate (1000 mg of ofatumumab). 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Frimley Business Park 

Camberley GU16 7SR 

United Kingdom 

 

Manufacturer 

Glaxo Operations UK Limited (Trading as Glaxo Wellcome Operations), Harmire Road, Barnard 

Castle, County Durham, DL12 8DT, United Kingdom 

Novartis Pharmaceuticals UK Limited, Frimley Business Park, Frimley, Camberley, Surrey GU16 

7SR, United Kingdom 

Novartis Pharma GmbH, Roonstrasse 25, 90429 Nuremberg, Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

Novartis Pharma Services Inc. 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 555 

Eesti 

Novartis Pharma Services Inc. 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

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44 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA “Novartis Baltics” 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 
 

 

Detailed information on this medicine is available on the European Medicines Agency (EMA) web 

site: http://www.ema.europa.eu/. 

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45 

The following information is intended for healthcare professionals only: 

 

1) Before diluting Arzerra 

 

Check the Arzerra concentrate for particulate matter and discolouration prior to dilution. Ofatumumab 

should be a colourless to pale yellow solution. Do not use the Arzerra concentrate if there is 

discolouration. 

 

Do not shake the ofatumumab vial for this inspection. 

 

2) How to dilute the solution for infusion 
 

The Arzerra concentrate must be diluted in sodium chloride 9 mg/ml (0.9%) solution for injection 

prior to administration, using aseptic technique. 

 

300 mg dose - Use three 100 mg/5 ml 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%) solution 
for injection; 

 Withdraw 5 ml of ofatumumab from each of the three 100 mg vials and inject into the 1000 ml 
bag; 

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

1000 mg dose – Use one 1000 mg/50 ml 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%) solution 
for injection; 

 Withdraw 50 ml of ofatumumab from the 1000 mg vial and inject into the 1000 ml bag 

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

2000 mg dose – Use two 1000 mg/50 ml 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%) solution 
for injection; 

 Withdraw 50 ml of ofatumumab from each of the two 1000 mg vials and inject into the 1000 ml 
bag; 

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

3) How to administer the diluted solution 

 

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

infusion pump. 

 

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

this time. 

 

Arzerra must not be mixed with, or administered as an infusion with other medicinal products or 

intravenous solutions. Flush line before and after ofatumumab administration with sodium chloride 

9 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 of the SmPC), through a peripheral 

line or indwelling catheter, according to the schedule below: 

 

If the first infusion was completed without a severe adverse reaction, the remaining infusions of 

1000 mg should be administered over 4 hours (see section 4.2 of the SmPC), through a peripheral line 

or indwelling catheter, 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 of the SmPC). 

 

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46 

Infusion schedule 

 

Time after start of infusion (minutes) 
Infusion 1 Subsequent infusions* 

Infusion rate (ml/hour) Infusion rate (ml/hour) 

0-30 12 25 

31-60 25 50 

61-90 50 100 

91-120 100 200 

121-150 200 400 

151-180 300 400 

180+ 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). 

 

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

requirements. 

 

Refractory CLL: 

For the first and second infusion, administer over 6.5 hours (see section 4.2 of the SmPC), through a 

peripheral line or 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 of the SmPC), through a peripheral line or 

indwelling catheter, 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 of the SmPC). 

 

Infusion schedule 

 

Time after start of infusion 

(minutes) 

Infusions 1 and 2 Infusions 3* to 12 

Infusion rate (ml/hour) Infusion rate (ml/hour) 

0-30 12 25 

31- 60 25 50 

61-90 50 100 

91-120 100 200 

121+ 200 400 

*If the second 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). 

 

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

requirements. 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET