Consumer medicine information

Arzerra

Ofatumumab

BRAND INFORMATION

Brand name

Arzerra

Active ingredient

Ofatumumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Arzerra.

What is in this leaflet

Please read all 5 pages in this leaflet carefully before you start using Arzerra.

This leaflet answers some common questions about Arzerra (ofatumumab). It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Arzerra against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Arzerra 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 a 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 binds to them, decreasing the amount of lymphocytes in the body.

Your doctor may have prescribed Arzerra for another reason.

This medicine is available only with a doctor's prescription.

ARZERRA is not recommended for use in children and adolescents, under the age of 18 years.

Arzerra is not addictive.

Before you are given Arzerra

When you must not receive Arzerra

You must not receive Arzerra if you have ever had a:

  • Severe allergic (hypersensitive) reaction to Arzerra (ofatumumab).
  • An allergic reaction to any of the ingredients listed toward the end of this leaflet.
    See "Ingredients" on Page 4.

Some of the symptoms of an allergic reaction may include:

  • Shortness of breath
  • Wheezing or difficulty breathing
  • Swelling of the face, lips, tongue or other parts of the body
  • Rash, itching or hives on the skin

Check with your doctor if you think that any of these reactions may apply to you.

Arzerra must not be used after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to the hospital pharmacist or pharmacist for disposal.

If you are not sure whether you should start to be given this medicine, talk to your doctor.

Tell your doctor if

Before you are given Arzerra your doctor needs to know if you have:

  • Lung disease
  • Had heart problems
  • Ever had hepatitis B (a liver disease).
    Arzerra could cause your hepatitis B to become active again. Your doctor may treat you with a suitable anti-viral medicine to help prevent this.
  • Ever had an Infusion reaction.
    See "Infusion reactions" on Page 2 for more information about this.
  • Progressive multifocal leukoencephalopathy (PML), a rare is a disease that attacks part of your brain.
    See "Progressive multifocal leukoencephalopathy (PML)" in the following text.

Tell 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.

Infusion reactions

Medicines of this type (monoclonal antibodies) are given into a vein (intravenously) as an infusion (a drip) over several hours. These medicines can cause infusion reactions (side effects) when they are injected into your body. You will be given medicines such as anti-histamines, steroids or pain relievers to help reduce any reaction (see also 'Side effects').

Progressive multifocal leukoencephalopathy (PML)

Medicines like Arzerra may cause a serious and life threatening brain condition called progressive multifocal leukoencephalopathy (PML). This condition damages myelin, the fatty substance which protects nerves in the brain.

Tell your doctor immediately if you have any of these symptoms: memory loss, trouble with 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.

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.

Taking other medicines

Tell your doctor, health care professional, or pharmacist if you are taking any other medicines, have taken any recently, or if you start new ones. This includes herbal medicines and other medicines you've bought without a prescription. These might interact with Arzerra.

Pregnancy

Tell your doctor if you are pregnant or think you could be, before you are given Arzerra. There is limited information about the safety of Arzerra in pregnant women. Your doctor will consider the benefit to you and the risk to your baby of taking Arzerra while you are pregnant.

Use a reliable method of contraception to prevent pregnancy while you're being treated with Arzerra, and for at least six months after your last infusion.

Breast-feeding

It is not known whether the ingredients in Arzerra pass into human breast milk.

If you are breast-feeding, you must check with your doctor before you take Arzerra.

Patients on controlled sodium diets

Arzerra contains 34.8 mg sodium in each 300 mg dose and 232 mg sodium in each 2000 mg dose.

If you are on a controlled sodium diet, you and your doctor or nurse need to take this into account.

Driving and using machines

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

How Arzerra is used

Arzerra is to be administered by a physician or healthcare professional only.

Arzerra must not be mixed with, or administered with other medicinal products or intravenous solutions.

If you have any questions on the use of this product, ask the doctor, nurse, or healthcare professional who is giving Arzerra to you.

How much Arzerra will be given to you

The usual dose for the first infusion is 300 mg. This dose will usually be increased 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 usually have a maximum of 13 infusions. You will be given an 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, 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 be given once a month for four months.

Pre-medications

Before each infusion of Arzerra, you will be given 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.

Possible side effects

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Check with your doctor as soon as possible if you think you are experiencing any side effects or allergic reactions due to receiving Arzerra, even if the problem is not listed below.

Like all medicines, Arzerra can cause side effects, although not everybody gets them. If they occur, they are most likely to be minor and temporary. However, some may be serious and need medical attention.

Infusion reactions

Medicines of this type (monoclonal antibodies) can cause infusion reactions, which are occasionally severe, and can cause death. They are more likely during the first treatment. You may also experience some of these side effects outside of the infusion time.

Very common symptoms of an infusion reaction

These symptoms may affect more than 1 in 10 people:

  • Nausea (feeling sick)
  • High temperature
  • Skin rash
  • Breathlessness
  • Cough
  • Diarrhoea
  • Lack of energy.

Common symptoms of an infusion reaction

These symptoms may affect up to 1 in 10 people:

  • Allergic reaction, sometimes severe, including:
    - Raised and itchy rash (hives)
    - Swelling, sometimes of the face or mouth (angioedema), causing difficulty in breathing and collapse
  • Difficulty breathing, shortness of breath, tight chest and cough (possible symptoms of bronchospasm)
  • Headache
  • Flushing
  • Excessive sweating
  • Shaking or shivering (possible symptoms of chills)
  • Back pain
  • Drop in blood pressure which may make you feel dizzy or lightheaded
  • Throat pain or irritation
  • High blood pressure
  • Rapid heart beat
  • Feeling tired
  • Shaking or excessive shivering
  • Blocked nose
  • Excessive sweating

Uncommon symptoms of an infusion reaction

These symptoms may affect up to 1 in 100 people:

  • Breathlessness (possible sign of fluid in the lungs (pulmonary oedema))
  • Anaphylactic reaction including anaphylactic shock, where symptoms include breathlessness or difficult breathing, wheezing or coughing, light-headedness, dizziness, changes in levels of consciousness, hypotension, with or without mild generalized itching, skin reddening, facial/throat swelling, blue discolouration of the lips, tongue or skin)
  • Blue discolouration of the lips and extremities (possible symptom of hypoxia) and slow heart beat.

Bowel obstruction

Contact your doctor immediately if you experience:

  • constipation, a swollen abdomen, or abdominal pain.
    These may be possible symptoms of blockage in the bowel, especially during the early stages of your therapy.

Tell your doctor or a nurse giving you the infusion immediately if you get any of these symptoms. The infusion may need to be slowed down. Your doctor may decide to stop your Arzerra treatment if these reactions are serious.

Other possible serious side effects

If you notice these symptoms, contact your doctor straight away.

Very common serious symptoms

These symptoms may affect more than 1 in 10 people:

  • Frequent infections, fever, chills, sore throat or mouth ulcers due to infections, possible symptoms of low white blood cell count (neutropenia)
  • Fever, coughing, difficulty breathing, wheezing, possible symptoms of infections of the lungs or airways including pneumonia)

Common serious symptoms

These symptoms 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 (sepsis including neutropenic sepsis and septic shock).

Uncommon serious symptoms

These symptoms may affect up to 1 in 100 people:

  • 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)
  • Stomach pain, possible symptom of blockage in the bowel
  • Producing less urine than normal and/or muscle spasms, possible symptoms of an increase in potassium, phosphate and uric acid in the blood that may cause kidney problems (tumour lysis syndrome).

Other possible side effects

Additional side effects have been observed with Arzerra. Most of these side effects are mild to moderate and will generally disappear after a few days to a week of treatment.

If you notice these symptoms, contact your doctor if this affects you severely.

Very common side effects

These may affect more than 1 in 10 people:

  • Sore throat, feeling of pressure or pain in the cheeks and forehead, possible symptoms of infections of the ear, nose or throat.

Common side effects

These may affect up to 1 in 10 people:

  • Shingles, cold sores, possible symptoms of viral infection that can be potentially severe (herpes viral infection)
  • Difficulty and pain when passing urine, exaggerated sense of needing to urinate, possible symptoms of urinary tract infection.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor or pharmacist if any of the side effects listed become severe or troublesome, or if you notice any side effects not listed in this leaflet.

How to store Arzerra

Arzerra Concentrate

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

Do not freeze.

Store the vial in the in the original packaging to protect from light.

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

Do not use Arzerra after the expiry date which is stated on the carton and vial label. The expiry date refers to the last day of that month.

Diluted solution for infusion

Store the diluted infusion solution between 2°C and 8°C and use within 24 hours.

Do not freeze.

Discard any unused infusion solution 24 hours after it was prepared.

Product description

What Arzerra looks like

Arzerra is a colourless to pale yellow solution containing 20 mg/mL of ofatumumab.

Arzerra 100 mg
This is available in a pack containing 3 clear glass vials with a latex-free stopper and aluminium over-seal. The vial contains 5 mL of concentrate (100 mg of ofatumumab).

Arzerra 1,000 mg
This is available in a pack containing 1 clear glass vial with a latex-free stopper and aluminium over-seal. The vial contains 50 mL of concentrate (1,000 mg of ofatumumab).

Ingredients

Each mL of Arzerra contains ofatumumab 20 mg as the active ingredient. The other ingredients are:

  • arginine
  • disodium edetate
  • hydrochloric acid (E507)
  • polysorbate 80 (E433)
  • sodium acetate (E262)
  • sodium chloride
  • water for injections.

Sponsor

Arzerra is supplied in Australia by:

Novartis Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road, Macquarie Park NSW 2113 Australia
Telephone 1 800 671 203
www.novartis.com.au
® Registered Trademark

Arzerra Australian Registration Numbers:

AUST R 196945 Arzerra ofatumumab (rmc) 100 mg/5 mL injection concentrate vial

AUST R 218896 Arzerra ofatumumab (rmc) 1000 mg/50 mL injection concentrate vial

This leaflet was prepared in March 2018

Internal document code:
arz160318c based on PI arz160318i

Published by MIMS May 2018

BRAND INFORMATION

Brand name

Arzerra

Active ingredient

Ofatumumab

Schedule

S4

 

Name of the medicine

Ofatumumab (rmc).

Excipients.

Arginine, sodium acetate, sodium chloride (see Precautions - Sodium content), polysorbate 80, edetate disodium, hydrochloric acid, and water for injections.

Description

Molecular weight: approximately 149 kDa. CAS number: 679818-59-8. Ofatumumab is a human monoclonal antibody (IgG1 kappa) that is generated via transgenic mouse and hybridoma technology and produced in a recombinant murine cell line (NS0).
Arzerra is a sterile, clear to slightly opalescent, colourless, preservative-free, concentrated solution (20 mg/mL) for intravenous infusion. Each single-use vial of Arzerra contains either 100 mg of ofatumumab in 5 mL of solution or 1000 mg of ofatumumab in 50 mL of solution. The excipients: arginine, sodium acetate, sodium chloride (see Precautions - Sodium content), polysorbate 80, edetate disodium, hydrochloric acid, and water for injections.

Pharmacology

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies.
ATC Code: L01XC10.

Mechanism of action.

Ofatumumab is a recombinant human monoclonal antibody (IgG1) that binds specifically to 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 on B cell tumours. The B cell tumours include chronic lymphocytic leukaemia (CLL), that is generally associated with lower levels of CD20 expression, and non-Hodgkin's lymphomas (where > 90% of tumours have high levels of CD20 expression).
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. In addition, the binding of ofatumumab induces cell death through antibody dependent cell mediated cytotoxicity. Ofatumumab has been shown to induce lysis in cells both with high and low CD20 expression, including cells with high expression levels of complement defense molecules.

Pharmacodynamic effects.

B-cell depletion.

Peripheral B cell 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 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.
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% for ofatumumab in combination with chlorambucil and 73% and 97% for chlorambucil alone. At 6 months after the last dose, the median reductions in B cell counts were > 99% for ofatumumab in combination with chlorambucil and 94% for chlorambucil alone.

Immunogenicity.

There is a potential for immunogenicity with therapeutic proteins such as Arzerra. Serum samples from more than 440 patients across the CLL clinical program were tested for anti-ofatumumab antibodies during and after treatment periods ranging from 4 to 45 weeks (either by enzyme linked immunosorbent assay or electrochemiluminescence). There was no formation of anti-ofatumumab antibodies in patients with CLL after treatment with ofatumumab.

Pharmacokinetics.

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 215 patients with refractory CLL. The geometric mean Cmax value was 61 microgram/mL after the first infusion (300 mg); after the eighth weekly infusion (seventh infusion of 2000 mg), the geometric mean Cmax value was 1391 microgram/mL and geometric mean AUC(0-∞) value was 463,418 microgram.h/mL; after the twelfth infusion (fourth monthly infusion; 2000 mg), the geometric mean Cmax value was 827 microgram/mL and geometric mean AUC(0-∞) was 203,536 microgram.h/mL. In patients with previously untreated CLL receiving ofatumumab and chlorambucil, the geometric mean Cmax values after the first infusion (300 mg), the 1000 mg infusion on day 8, and the 1000 mg infusion at the fourth monthly cycle were 52 microgram/mL, 241 microgram/mL, and 285 microgram/mL, respectively; the geometric mean AUC(0-τ) value at the fourth cycle was 65,100 microgram.h/mL.

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 t1/2 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.
Across the studies in patients with refractory CLL, the geometric mean values for CL and t1/2 were 64 mL/h (range 4.3-1122 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, 11.7 mL/h (range 3.9-54.2 mL/h) and 13.6 days (range 2.4-36.0 days) after the eighth infusion, and 12.1 mL/h (range 3.0-233 mL/h) and 11.5 days (range 1.8-36.4 days) after the twelfth infusion.
In patients with previously untreated CLL receiving ofatumumab and chlorambucil, geometric mean CL and t1/2 values for ofatumumab were 15.4 mL/h (range 4.1-146 mL/h) and 18.5 days (range 2.7-82.6 days) after the fourth infusion.
Special patient populations.

Elderly (greater than 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 87 years of age.

Children and adolescents (up to 18 years of age).

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).

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.

Clinical Trials

The efficacy of ofatumumab have been evaluated in two clinical studies (OMB110911 and OMB115991) in patients with previously untreated CLL considered inappropriate for a fludarabine based treatment, and two clinical studies (Hx-CD20-406 and Hx-CD20-402) in patients with refractory CLL.

Previously untreated CLL.

Open label studies.

Study OMB110911.

This randomised, open label, parallel arm, multicentre study 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 comorbidities). Patients received either Arzerra as monthly intravenous infusions (cycle 1: 300 mg day 1 and 1000 mg 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), 63% were male, and 89% were white. 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 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). The overall response rate (ORR) including complete response (CR) was also assessed by an IRC using the 2008 NCI-WG guidelines.
Arzerra in combination with chlorambucil (O+Chl) showed a statistically significant longer median PFS compared with chlorambucil (Chl) alone (O+Chl: 22.4 months; Chl: 13.1 months; HR: 0.57; 95% CI: 0.45-0.72), and the risk of experiencing a PFS event was reduced by 43% (see Table 1, 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, IGVH unmutated status, β2M > 3500 microgram/L, and ZAP-70 expression). See Table 2.

Study OMB115991.

This study evaluated the efficacy of ofatumumab in combination with bendamustine in 44 patients with previously untreated CLL considered inappropriate for fludarabine based treatment. Patients received ofatumumab as monthly intravenous infusions (cycle 1 300 mg day 1 and 1000 mg day 8, subsequent cycles: 1000 mg at day 1 every 28 days) in combination with bendamustine 90 mg/m2 intravenous at days 1-2 every 28 days. Patients received treatment for a minimum of 3 cycles until best response or a maximum of 6 cycles. The median number of cycles completed in patients was 6 (total ofatumumab dose of 6300 mg).
The primary endpoint was ORR assessed by the investigator according to the 2008 NCI-WG 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.

Refractory CLL.

Open label studies.

Study Hx-CD20-406.

Arzerra was administered as a monotherapy to 223 patients with refractory CLL in this study. 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 overall response rate 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 as those who had not had prior rituximab therapy.
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).

Study Hx-CD20-402.

This 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 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: 2000 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, 31.4) in responders. The duration of response was 16 weeks (CI: 13.3, 19.0) and the time to next CLL therapy was 52.4 weeks (CI: 36.9, nonestimable).

Indications

Previously untreated CLL.

Arzerra is indicated in combination with chlorambucil or bendamustine for the treatment of patients with chronic lymphocytic leukaemia (CLL) who have not received prior therapy and are inappropriate for fludarabine based therapy.

Refractory CLL.

Arzerra, as a single agent, is indicated for the treatment of patients with chronic lymphocytic leukaemia (CLL) refractory to fludarabine and alemtuzumab.

Contraindications

Arzerra is contraindicated in patients with hypersensitivity to the active substance ofatumumab or to any of the excipients (see Excipients).

Precautions

Infusion-related reactions.

Intravenous Arzerra has been associated with infusion-related reactions. These reactions may result in temporary interruption or withdrawal of treatment or death. Premedications attenuate infusion-related reactions but these may still occur, predominantly during the first infusion (see Dosage and Administration).
Infusion-related reactions may include, but are not limited to anaphylactic reactions, 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. Even with premedication, severe reactions, including cytokine release syndrome, have been reported following Arzerra use. In the event of severe infusion-related reaction, the infusion of Arzerra must be interrupted immediately and symptomatic treatment instituted (see Dosage and Administration for changes to infusion rates following infusion-related reactions). If an anaphylactic reaction occurs, Arzerra should be immediately and permanently discontinued and appropriate medical treatment should be initiated.
Infusion-related reactions occur more frequently 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.

Haematologic.

Cytopenias.

Prolonged (≥ 1 week) severe neutropenia and thrombocytopenia can occur with Arzerra. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop grade 3 or 4 cytopenias. Also see Precautions - Laboratory monitoring.

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 pretreatment 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.

Infections.

Arzerra causes a marked reduction in B lymphocytes and therefore may increase the risk of infection. In the pivotal study in CLL patients, 14 of 154 patients (9%) had serious infections that were considered drug related. Fatal infections occurred in 16 of 154 patients (10%). Of these, 4 (3%) were considered drug related.

Progressive multifocal leukoencephalopathy (PML).

Progressive multifocal leukoencephalopathy (PML) and death has been reported in CLL patients receiving cytotoxic pharmacotherapy, including Arzerra. A diagnosis of PML should be considered in any patient treated with Arzerra 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.

Hepatitis B infection and/or reactivation.

Hepatitis B virus (HBV) infection and reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has occurred in patients treated with drugs 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 patients 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.
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.

Immunisations.

The safety of, and ability to generate a primary or anamnestic response to, immunisation with live attenuated or inactivated vaccines during Arzerra treatment 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 Arzerra, until B cell counts are normalised. The risks and benefits of vaccinating patients during Arzerra therapy should be considered.

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 milliseconds (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 msec) 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 Arzerra. Patients who present with abdominal pain, especially early in the course of Arzerra therapy, should be evaluated and appropriate treatment instituted.

Skin reactions.

Severe mucocutaneous reactions can occur in this disease setting and have been reported in patients receiving anti-CD20 monoclonal antibody therapy, including Arzerra. In case of such an event, treatment should be discontinued.

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. Appropriate management should be considered should cytopenias occur.

Sodium content.

Arzerra contains 34.8 mg sodium per 300 mg dose and 232 mg sodium per 2000 mg dose. This should be taken into consideration by patients on a controlled sodium diet.

Effects on fertility.

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

Use in pregnancy.

(Category C)
There are no adequate and well controlled data for the use of Arzerra in pregnant women. Ofatumumab may cause fetal B-cell depletion based on findings from the drug’s mechanism of action (see Pharmacology).
An embryofetal study in which cynomolgus monkeys were treated during the period of organogenesis revealed no evidence of external, visceral or skeletal defects of the fetus at exposures similar to the anticipated clinical AUC. However, ofatumumab could be detected in the fetal circulation 50 days after the final dose and exposed fetuses had lower spleen weights and depleted B cells. Since Arzerra may cause fetal B-cell depletion, precautions should be taken to avoid pregnancy, and effective contraception (methods that result in less than 1% pregnancy rates) should be used while using Arzerra and for at least 12 months after the last Arzerra treatment.
Arzerra should not be administered to pregnant women unless the possible benefit to the mother outweighs the possible risk to the fetus.

Use in lactation.

The safe use of Arzerra in humans during lactation has not been established. It is not known whether ofatumumab is excreted in human breast milk. The excretion of ofatumumab in milk has not been studied in animals. However, maternal IgG is secreted in breast milk, it is recommended that breastfeeding should be discontinued for the entire duration of treatment with Arzerra.

Use in children and adolescents (up to 18 years of age).

The safety and effectiveness of Arzerra have not been established in the paediatric age group.

Use in the elderly (greater than 65 years of age).

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

Ability to perform tasks that require judgement, motor or cognitive skills.

No studies on the effects of Arzerra on the ability to drive and use machines have been performed. No detrimental effect on such activities are predicted from the pharmacology of Arzerra. The clinical status of the subject and the adverse event profile of Arzerra should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills.

Carcinogenicity.

The carcinogenic potential of ofatumumab has not been investigated.

Genotoxicity.

As ofatumumab is a monoclonal antibody, the genotoxic potential of ofatumumab has not been investigated.

Interactions

No clinically significant interactions were observed between ofatumumab does not have a clinically relevant effect on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard.
Live attenuated or inactivated vaccine efficacy may be impaired with Arzerra. Therefore, the concomitant use of these agents with Arzerra should be avoided. (See Precautions - Immunisations.) If the coadministration is judged unavoidable, the risks and benefits of vaccinating patients during therapy with Arzerra should be considered.

Adverse Effects

Summary of the safety profile.

Clinical trial data.

Previously untreated CLL.

The safety of Arzerra was evaluated in 2 studies conducted in patients previously untreated for CLL and considered inappropriate for fludarabine based therapy. Study 1 was an open label, parallel arm, randomized study of 447 patients who 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 oral on days 1 to 7 every 28 days) or chlorambucil alone (10 mg/m2 oral on days 1 to 7 every 28 days). The median number of cycles completed was 6 (total dose of Arzerra was 6300 mg). The median age was 69 years (range: 35 to 92 years); 63% of patients were male and 89% were white.
Study 2 was an open label, single arm study including 44 patients with previously untreated CLL who 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 bendamustine (90 mg/m2 on days 1 and 2 every 28 days). The majority of patients (89%) received all 6 cycles of Arzerra. The median age was 63 years (range: 34 to 86 years); 66% of patients were male and 98% were white.
The data described in Table 5 include adverse reactions occurring in ≥ 5% of 261 patients with previously untreated CLL who received Arzerra with either chlorambucil or bendamustine.

Refractory CLL.

The safety of Arzerra in patients with refractory CLL has been evaluated in two open label studies. In study Hx-CD20-406, 223 patients were enrolled to receive 12 infusions of Arzerra administered as 300 mg initial dose (dose 1), followed 1 week later by 2000 mg weekly for 7 doses (doses 2 through 8), followed 4 weeks later by 2000 mg every 4 weeks for 4 doses (doses 9 through 12). 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, 1000 mg or 2000 mg of Arzerra, respectively.
The data in Table 6 are derived from 223 patients in study Hx-CD20-406. All patients received 2000 mg weekly from the second dose onward. 90% of patients received at least 8 infusions of Arzerra and 51% received all 12 infusions. The median age was 64 years (range: 41 to 87 years), 73% were male, and 96% were white.

Description of selected adverse reactions.

Infusion-related reactions.

In the pivotal study (Hx-CD20-406), infusion reactions occurred in 43% of patients on the day of the first infusion (300 mg), 31% on the day of the second infusion (2000 mg), and less frequently during subsequent infusions (see Precautions).

Infections.

Of the 223 patients enrolled in the pivotal study, a total of 162 patients (73%) experienced bacterial, viral, or fungal infections. 64 patients (29%) experienced ≥ grade 3 infections, of which 21 (9%) were fatal. The proportion of fatal infections in the indicated fludarabine and alemtuzumab refractory group was 14%.

Neutropenia.

Of 154 patients with normal neutrophil counts at baseline who were part of the pivotal study, 44 (29%) developed ≥ grade 3 neutropenia. Twenty two (14%) developed grade 4 neutropenia. Some patients experienced new onset grade 4 neutropenia > 2 weeks in duration.

Postmarketing data.

Adverse reactions are listed below by MedDRA body system organ class and by frequency. The frequency categories used are the following.
Very common: ≥ 1 in 10.
Common: ≥ 1 in 100 and < 1 in 10.
Uncommon: ≥ 1 in 1,000 and < 1 in 100.
Rare: ≥ 1/10,000 and < 1/1,000.

Infections and infestations.

Rare: hepatitis B (infection and reactivation) (see Precautions).

Cardiac.

Rare: bradycardia (in setting of an infusion reaction, see Precautions).

Respiratory, thoracic and mediastinal disorders.

Rare: pulmonary oedema (in setting of an infusion reaction, see Precautions).

Dosage and Administration

Method of administration.

Arzerra is for intravenous infusion and must be diluted prior to administration (see Use and handling).
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. Patients should be closely monitored during administration of Arzerra for the onset of infusion-related reactions, including cytokine release syndrome, particularly during the first infusion. (See Precautions - Infusion-related reactions.)

Premedication.

Patients should receive oral paracetamol (or equivalent) plus oral or intravenous antihistamine plus intravenous corticosteroid premedication agents half an hour to 2 hours (30-120 minutes) prior to each infusion (see Table 7).

Dosage.

Previously untreated CLL. The recommended dosage and schedule is 300 mg on day 1 followed 1 week later by 1000 mg on day 8 (cycle 1), followed by 1000 mg on day 1 of subsequent cycles until best response or a maximum of 12 cycles (every 28 days).

First infusion.

The initial rate of the first infusion of Arzerra should be 12 mL/hour. During infusion, the rate should be doubled every 30 minutes to a maximum of 400 mL/hour (see Dosage and Administration - Use and handling).

Subsequent infusions.

If the first infusion has been completed without severe infusion related ADRs, the subsequent 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 Dosage and Administration - Use and handling).
Refractory CLL. The recommended dose is 300 mg for the first infusion and 2000 mg 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 (see Figure 2).

First and second infusions.

The initial rate of the first and second infusion of Arzerra diluted solution should be 12 mL/hour. During infusion, the rate should be doubled every 30 minutes to a maximum of 200 mL/hour (see Dosage and Administration - Use and handling).

Subsequent infusions.

If the second infusion has been completed without severe infusion related 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 Use and handling).
Dose modification and reinitiation of therapy in patients with previously untreated CLL and refractory CLL. Infusion related ADRs may lead to slower infusion rates.

Mild or moderate ADR.

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).

Severe ADR.

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).

Life-threatening ADR.

In case of a life threatening ADR, do not resume the infusion.
Therapy should be permanently discontinued in patients who develop an anaphylactic reaction to Arzerra (see Precautions - Infused-related reactions).
Special populations.

Use in children and adolescents (up to 18 years of age).

The safety and effectiveness of Arzerra have not been established in the paediatric age group.

Use in the elderly (greater than 65 years of age).

No substantial differences were seen in safety and efficacy related to age (see Clinical Trials). Based on available safety and efficacy data in the elderly, no dosage adjustment is required (see Pharmacology - Pharmacokinetics, Special patient populations).

Renal impairment.

No formal studies of Arzerra in patients with renal impairment have been performed. However, patients with renal impairment are unlikely to require dose modification (see Pharmacology - Pharmacokinetics, Special patient populations).

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 Pharmacology - Pharmacokinetics, Special patient populations).

Use and handling.

Arzerra concentrate should be diluted using aseptic practices. Arzerra does not contain a preservative and is for single use in one patient only. Therefore it is recommended that the diluted solution be used as soon as possible after preparation. The diluted solution for infusion must be stored at 2°C to 8°C and used within 24 hours of preparation. Any unused solution remaining after this time should be discarded.
1. Before diluting Arzerra. Check the Arzerra concentrate for particulate matter and discoloration prior to dilution. Arzerra should be a colourless to pale yellow solution. Do not use the Arzerra concentrate if there is discolouration.
Do not shake the Arzerra vial for this inspection.
2. How to dilute the solution for infusion. The Arzerra concentrate must be diluted in saline prior to administration, using aseptic technique.

300 mg dose.

Use 3 x 5 mL vials (15 mL total, 5 mL per vial):
Withdraw and discard 15 mL from a 1000 mL bag of 0.9% sodium chloride for infusion;
Withdraw 5 mL of Arzerra from each of 3 vials (15 mL total) and inject into the 1000 mL bag;
Do not shake, mix diluted solution by gentle inversion.

1000 mg dose.

Use 1 x 50 mL vial (50 mL total, 50 mL per vial):
Withdraw and discard 50 mL from a 1000 mL bag of 0.9% sodium chloride for infusion;
Withdraw 50 mL of Arzerra from the vial (50 mL total) and inject into the 1000 mL bag;
Do not shake, mix diluted solution by gentle inversion.

2000 mg dose with 5 mL vials.

Use 20 x 5 mL vials (100 mL total, 5 mL per vial):
Withdraw and discard 100 mL from a 1000 mL bag of 0.9% sodium chloride for infusion;
Withdraw 5 mL of Arzerra from each of 20 vials (100 mL total) and inject into the 1000 mL bag;
Do not shake, mix diluted solution by gentle inversion.

2000 mg dose with 50 mL vials.

Use 2 x 50 mL vials (100 mL total, 50 mL per vial):
Withdraw and discard 100 mL from a 1000 mL bag of 0.9% sodium chloride for infusion;
Withdraw 50 mL of Arzerra from each of 2 vials (100 mL total) 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 i.v. push or bolus. Administer using an i.v. infusion pump and an i.v. administration set.
Compatibility of Arzerra has been established with the following dosing components.
1. Polyolefin saline bags.
2. PVC and PVC lined with polyethylene administration sets.
Arzerra must not be mixed with, or administered as an infusion with other medicinal products or intravenous solutions. Flush line before and after Arzerra administration with 0.9% sodium chloride to avoid this.

a. Previously untreated CLL.

For the first infusion, administer over 4.5 hours (see Dosage and Administration), through a peripheral line or indwelling catheter, according to Table 8.
If the first infusion has been completed without a severe adverse reaction, the remaining infusions (2-13) of 1000 mg should be administered over 4 hours (see Dosage and Administration), through a peripheral line or indwelling catheter, according to the schedule above.

Refractory CLL.

For the first and second infusion, administer over 6.5 hours (see Dosage and Administration), through a peripheral line or indwelling catheter, according to Table 9.
If the second infusion has been completed without a severe adverse reaction, the remaining infusions (3-12) should be administered over 4 hours (see Dosage and Administration), through a peripheral line or indwelling catheter, according to the schedule above.
If any adverse reactions are observed, infusion rates should be reduced (see Dose modification and reinitiation of therapy).
Any unused product or waste material should be disposed of in accordance with local requirements.

Overdosage

Symptoms and signs.

No case of overdose has been reported.

Treatment.

Further management should be as clinically indicated or as recommended by the Poisons Information Centre on telephone number 131 126 (local call in all areas).

Presentation

Concentrate for infusion (sterile, clear to slightly opalescent, colourless, preservative free), 100 mg/5 mL: 3's (10 mL single use, clear type 1 glass vial with a latex free rubber stopper and aluminium over seal); 1000 mg/50 mL: 1's (60 mL single use, clear type 1 glass vial with a latex free rubber stopper and aluminium over seal).

Storage

Concentrated injection.

Store at 2°C-8°C. (Refrigerate. Do not freeze.)
Protect from light.

Diluted infusion storage.

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°C to 8°C.

Incompatibilities.

The concentrate for solution for infusion must only be mixed with 0.9% sodium chloride solution for infusion (see Dosage and Administration, Use and handling).
Do not mix Arzerra with any other drug in an infusion bag.

Poison Schedule

S4.