Arzerra - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

4. CLINICAL PARTIC

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.

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 i related reactions, including cytokine release syndrome, particularly during the first infu

Pre-medication

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.

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: 1 followed 1 week later by

y for 7 doses (infusions 2 to 8) followed 4–5 weeks later by 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”.

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 reactio medicinal product.

Special populations

Paediatric population

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

Elderly

No substantial differences related to age were seen in safety an available safety and efficacy data in the elderly, no dose adjust

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 w patients with hepatic impairment are

Method of administration

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

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

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

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 premedication, 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).

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 la dehydrogenase levels. Management of TLS includes correction of electrolyte abnormaliti monitoring of renal function, maintenance of fluid balance and supportive care.

Progressive multifocal leukoencephalo­pathy

Hepatitis B

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.

Cardiovascular

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

open-label studies in patients with CLL (N=85). Increases above 5 msec wer median/mean QT/QTc intervals in the pooled analysis. No large changes in

>20 milliseconds) were detected. None of the patients had an increase o

concentration-dependent increase in QTc was not detected. It is recom      d 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 own.

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).

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 st ith

administration of ofatumumab to pregnant monkeys (see section 5.3). Ofatumumab sh 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, h       human IgG is secreted in human

milk. The safe use of ofatumumab in humans during lactati      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.

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).

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.

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                                                     ­4 ûv

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 s with CLL (N=85). Increases above 5 msec were observed in the vals in the pooled analysis. No large changes in the mean QTc interval (i.e. cted. None of the patients had an increase of QTc to >500 msec. A professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

5.2 Pharmacokinetic properties

Overall, the pharmacokinetics of ofatumumab were consistent across the indicati a single agent or in combination with fludarabine and cyclophosphamide or Ofatumumab had non-linear pharmacokinetics related to its decreasing clea

Absorption

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

Distribution

Ofatumumab has a small volume of distribution, wit 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 ubi have not been performed.

n two ways: a target-independent route like other IgG molecules and a ich is related to binding to B-cells. There was a rapid and sustained depletion the first ofatumumab infusion, leaving a reduced number of CD20+ cells available for t tibody to bind at subsequent infusions. As a result, ofatumumab clearance values were lower and t>/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.

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

Table 5 Ofatumumab pharmacokinetic parameters (geometric mean)

(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, T>/2 = 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.

r

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.

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, were no effects on delayed-type hypersensitivity responses. In a few animals, increased red c destruction occurred, presumably as a result of monkey anti-drug antibodies coating the re corresponding increase in reticulocyte counts seen in these monkeys was indicative of response in the bone marrow.

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

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.

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 °C, 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 sectio

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 DilutionArzerra concentrate be carried out under of preparation. Any

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.

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.

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

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