GlaxoSmithKline (Ireland) Ltd

Arzerra 1,000 mg concentrate for solution for infusion.

One ml of concentrate contains 20 mg of ofatumumab.

Each vial contains 1,000 mg of ofatumumab in 50 ml.

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

Excipients:

This medicinal product contains 34.8 mg sodium per 300 mg dose and 232 mg sodium per 2,000 mg dose.

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless liquid. Visible particles may be present.

Arzerra is indicated for the treatment of chronic lymphocytic leukaemia (CLL) in patients who are refractory to fludarabine and alemtuzumab.

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.

Pre-medication

Patients should be pre-medicated 30 minutes to 2 hours prior to Arzerra infusion according to the following dosing schedule:

Posology

The recommended dose is 300 mg ofatumumab for the first infusion and 2,000 mg ofatumumab for all subsequent infusions. The infusion schedule is 8 consecutive weekly infusions, followed 4-5 weeks later by 4 consecutive monthly (i.e. every 4 weeks) infusions.

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 doubled every 30 minutes to a maximum of 200 ml/hour (see section 6.6).

Subsequent infusions

If the second infusion has been completed without severe infusion related adverse drug reactions (ADRs), the remaining infusions can start at a rate of 25 ml/hour and should be doubled every 30 minutes up to a maximum of 400 ml/hour (see section 6.6).

Dose modification and reinitiation of therapy

Infusion related ADRs may lead to slower infusion rates.

• In case of a mild or moderate ADR, the infusion should be interrupted and restarted at half of the infusion rate at the time of interruption, when 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, according to physician discretion and patient tolerance (not to exceed doubling the rate every 30 minutes).

• In case 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, according to physician discretion and patient tolerance (not to exceed doubling the rate every 30 minutes).

Paediatric population

Arzerra is not recommended for use in children below 18 years due to insufficient data on safety and/or efficacy.

Elderly

No substantial differences were seen in safety and efficacy related to age. 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(see section 6.6).

Hypersensitivity to ofatumumab or to any of the excipients (see section 6.1).

Infusion reactions

Ofatumumab has been associated with infusion reactions leading to temporary interruption of treatment or withdrawal of treatment. Pre-medications attenuate infusion reactions but these may still occur, predominantly during the first infusion. Infusion reactions may include anaphylactoid events, cardiac events, chills/rigors, cough, cytokine release syndrome, diarrhoea, dyspnoea, fatigue, flushing, hypertension, hypotension, nausea, pain, pyrexia, rash, and urticaria. Even with pre-medication, severe reactions, including cytokine release syndrome, have been reported following use of ofatumumab. In cases of severe infusion reaction, the infusion of Arzerra must be interrupted immediately and symptomatic treatment instituted (see section 4.2).

Infusion reactions occur more frequently on the first day of 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 ofatumumab.

Tumour lysis syndrome

In patients with CLL, tumour lysis syndrome (TLS) may occur with use of ofatumumab. 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

Progressive multifocal leukoencephalopathy (PML) and death has 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 neurologic 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 therapy with ofatumumab should be considered.

Hepatitis B

Hepatitis B infection (HBV), including fatal infection, can occur in patients taking ofatumumab. Hepatitis B reactivation including fulminant hepatitis and death occurs with other monoclonal antibodies directed against CD20. Patients at high risk of HBV infection should be screened before initiation of Arzerra. Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection during treatment with ofatumumab and for 6-12 months following the last infusion of Arzerra. Arzerra should be discontinued in patients who develop viral hepatitis, and appropriate treatment should be instituted. Insufficient data exist regarding the safety of administration of ofatumumab in patients with active hepatitis.

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.

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

Since ofatumumab binds to all CD-20-positive lymphocytes (malignant and non-malignant), complete blood counts and platelet counts should be obtained at regular intervals during ofatumumab therapy and more frequently in patients who develop cytopenias.

Sodium content

This medicinal product contains 34.8 mg sodium per 300 mg dose and 232 mg sodium per 2,000 mg dose. This should be taken into consideration by patients on a controlled sodium diet.

Although no formal interaction studies have been performed with ofatumumab, there are no known clinically significant interactions with other medicinal products.

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).

Pregnancy

There are no data from the use of ofatumumab in pregnant women. The effect on human pregnancy is unknown. Besides an expected pharmacological effect, i.e., depletion of B-cells, animal studies do not indicate direct or indirect harmful effects with respect to maternal toxicity, pregnancy or embryonal/foetal development (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.

Women of childbearing potential should use effective contraception during and for 12 months after the last ofatumumab treatment.

Lactation

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. It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Breastfeeding should be discontinued for the duration of treatment with ofatumumab 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.

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 subject 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).

The safety of ofatumumab in patients with relapsed or refractory CLL has been evaluated in two open-label studies. In study Hx-CD20-406, 154 patients were enrolled to receive an initial dose of 300 mg followed by 7 consecutive weekly infusions of 2,000 mg, followed five weeks later with 4 consecutive monthly infusions of 2,000 mg. The second study (Hx-CD20-402) was a dose-finding study and patients in three cohorts (3 patients, 3 patients, 27 patients) received a starting dose of 100 mg, 300 mg or 500 mg, followed a week later with 3 consecutive weekly infusions of 500 mg, 1,000 mg or 2,000 mg of ofatumumab, respectively. The adverse reactions reported are from final data from the initial dose-range finding and a planned interim analysis of study Hx-CD20-406.

Adverse reactions are listed below by MedDRA body system organ class and by frequency. 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, undesirable effects are presented in order of decreasing seriousness.

Infusion reactions: In the pivotal study (Hx-CD20-406), infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions (see section 4.4).

Infections: In the pivotal study, a total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the indicated fludarabine- and alemtuzumab-refractory group was 17%.

Neutropenia: Of 108 patients with normal neutrophil counts at baseline who were part of the pivotal study, 45 (42%) developed Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia > 2 weeks in duration.

No case of overdose has been reported.

Pharmacotherapeutic group: monoclonal antibodies, ATC code: L01XC10

This medicinal product has been authorised under a so-called 'conditional approval' scheme.

This means that further evidence on this medicinal product is awaited. The European Medicines Agency (EMA) will review new information on the product every year and this SmPC will be updated as necessary.

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% 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 cells counts decreased after the first ofatumumab infusion in patients with haematologic malignancies. In patients with refractory CLL, the median decrease in B cell counts was 23% after the first infusion and 92% after the eighth infusion. Peripheral B cell counts remained low throughout the remainder of therapy in most patients, then gradually recovered (median decrease in B cell counts was 68% below baseline 3 months after the end of ofatumumab therapy).

Immunogenicity

There is a potential for immunogenicity with therapeutic proteins such as ofatumumab; however the formation of anti-ofatumumab antibodies may be decreased because ofatumumab is a human antibody that depletes B cells in patients already immunocompromised by CLL.

In the pivotal clinical study (Hx-CD20-406), serum samples from 154 CLL patients treated with ofatumumab were tested for anti-ofatumumab antibodies. In the 46 patients who received at least 8 infusions and had serum ofatumumab concentrations that had decreased sufficiently to allow detection of anti-ofatumumab antibodies (33 of whom received all 12 infusions), all samples tested negative for anti-ofatumumab antibodies.

Clinical studies

The clinical efficacy of ofatumumab has been demonstrated in a planned interim analysis of an ongoing study Hx-CD20-406 (single-arm, open-label, multicentre), and one completed supportive study, Hx-CD20-402 (open-label, dose ranging, multicentre).

Hx-CD20-406

Arzerra was administered as a monotherapy to 154 patients with CLL. Patient median age was 63 years (range: 41 to 86 years), and the majority were male (72%) and white (97%). Patients received a median of 5 prior therapies, including rituximab (57%). Of these 154 patients, 59 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 151 patients. Chromosomal aberrations were detected in 118 patients; there were 33 patients with 17p deletion, 50 patients with 11q deletion, 16 patients with trisomy 12q, 30 patients with a normal karyotype and 19 patients with 13q deletion as the sole aberration.

The overall response rate was 58% in patients refractory to fludarabine and alemtuzumab (see Table 1 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 ofatumumab at a similar rate as those who had not had prior rituximab therapy.

Table 1. Summary of response to Arzerra in patients with CLL

Improvements also were demonstrated in components of the NCIWG response criteria. These included improvements associated with constitutional symptoms, lymphadenopathy, organomegaly, or cytopenias (see Table 2).

Table 2. Summary of clinical improvement with a minimum duration of 2 months in subjects with abnormalities at baseline

Arzerra was also given to a group of patients (n=79) with bulky lymphadenopathy (defined as at least one lymph node > 5cm) who were also refractory to fludarabine. The overall response rate in this group was 47% (99% CI: 32%, 62%). The median progression-free survival was 5.9 months (95% CI: 4.9, 6.4) and the median overall survival was 15.4 months (95% CI: 10.2, 20.2). The response rate in patients with prior rituximab therapy was 44% (95% CI: 29, 60). 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 56% (99% CI: 24%, 85%).

Hx-CD20-402

A dose-ranging study 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 ofatumumab (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 weeks) in the full analysis population, and 23 weeks (CI: 20-31.4 weeks) in responders. The duration of response was 16 weeks (CI: 13.3 – 19.0 weeks) 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).

Absorption

Ofatumumab is administered by intravenous infusion; therefore, absorption is not applicable. Maximum ofatumumab serum concentrations were generally observed at or shortly after the end of the infusion. Pharmacokinetic data were available from 146 patients with refractory CLL. The geometric mean C_max value was 63 μg/ml after the first infusion (300 mg); after the eighth weekly infusion (seventh infusion of 2,000 mg), the geometric mean C_max value was 1,482 μg/ml and geometric mean AUC_(0-) value was 674,463 μg.h/ml; after the twelfth infusion (fourth monthly infusion; 2,000 mg), the geometric mean C_max value was 881 μg/ml and geometric mean AUC_(0-) was 265,707 μg.h/ml.

Distribution

Ofatumumab has a small volume of distribution, with mean Vss values ranging from 1.7 to 5.1 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 t_½ values were significantly larger after later infusions than after the initial infusion; during repeated weekly infusions, ofatumumab AUC and C_max values increased more than the expected accumulation based on first infusion data.

Across the studies in patients with CLL, the mean values for CL and t_½ were 64 ml/h (range 4.3-1,122 ml/h) and 1.3 days (range 0.2-6.0 days) after the first infusion, 8.5 ml/h (range 1.3-41.5 ml/h) and 11.5 days (range 2.3-30.6 days) after the fourth infusion, 9.5 ml/h (range 2.2-23.7 ml/h) and 15.8 days (range 8.8-61.5 days) after the eighth infusion, and 10.1 ml/h (range 3.3-23.6 ml/h) and 13.9 days (range 9.0-29.2 days) after the twelfth infusion.

Elderly (greater than or equal to 65 years of age)

Age was not found to be a significant factor on ofatumumab pharmacokinetics in a cross-study population pharmacokinetic analysis of patients ranging in age from 21 to 86 years of age.

Children and adolescents

No pharmacokinetic data are available in paediatric patients.

Gender

Gender had a modest effect (14-25%) on ofatumumab pharmacokinetics in a cross-study analysis, with higher C_max and AUC values observed in female patients (41% of the patients in this analysis were male and 59% 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 clinically significant factor on ofatumumab pharmacokinetics in a cross-study population analysis in patients with calculated creatinine clearance values ranging from 33 to 287 ml/min. No dose adjustment is recommended for mild to moderate renal impairment (creatinine clearance >30 ml/min). There are no pharmacokinetic data in patients with severe renal impairment (creatinine clearance <30 ml/min).

Hepatic impairment

No pharmacokinetic data are available in patients with 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.

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 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. 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.

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 in section 6.6.

Vial

2 years.

Diluted infusion

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 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.

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 of the diluted medicinal product, see section 6.3.

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

Arzerra is available in 1 vial packs and it is supplied with two extension sets.

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 discoloration prior to dilution. Ofatumumab should be a colourless solution. Do not use the Arzerra concentrate if there is discolouration.

Do not shake the ofatumumab vial for this inspection.

The concentrate may contain a small amount of visible translucent-to-white, amorphous, ofatumumab particles. The filters provided as part of the extension set will remove these particles.

• 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.

2,000 mg dose - Use 2 vials (100 ml total, 50 ml per vial):

- withdraw and discard 100 ml from a 1,000 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 1,000 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, using the 0.2 micron in-line filter extension sets provided. The in-line filter must be used during the entire infusion.

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.

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:

Infusions 1 and 2: schedule

If the second infusion has been 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:

Infusions 3 to 12: schedule

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

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

Glaxo Group Ltd

Glaxo Wellcome House

Berkeley Avenue

Greenford

Middlesex

UB6 0NN

United Kingdom

EU/1/10/625/003

Date of first authorisation: 19/04/2010

Date of last renewal: 21 April 2011

April 2011.

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/.